Zhang H

References (346)

Title : The Overexpression of Zea mays Strigolactone Receptor Gene D14 Enhances Drought Resistance in Arabidopsis thaliana L - Zhang_2024_Int.J.Mol.Sci_25_
Author(s) : Zhang C , Wang F , Jiao P , Liu J , Zhang H , Liu S , Guan S , Ma Y
Ref : Int J Mol Sci , 25 : , 2024
Abstract : Strigolactones (SLs) represent a recently identified class of plant hormones that are crucial for plant tillering and mycorrhizal symbiosis. The D14 gene, an essential receptor within the SLs signaling pathway, has been well-examined in crops, like rice (Oryza sativa L.) and Arabidopsis (Arabidopsis thaliana L.), yet the research on its influence in maize (Zea mays L.) remains scarce. This study successfully clones and establishes Arabidopsis D14 gene overexpression lines (OE lines). When compared with the wild type (WT), the OE lines exhibited significantly longer primary roots during germination. By seven weeks of age, these lines showed reductions in plant height and tillering, alongside slight decreases in rosette and leaf sizes, coupled with early aging symptoms. Fluorescence-based quantitative assays indicated notable hormonal fluctuations in OE lines versus the WT, implying that D14 overexpression disrupts plant hormonal homeostasis. The OE lines, exposed to cold, drought, and sodium chloride stressors during germination, displayed an especially pronounced resistance to drought. The drought resistance of OE lines, as evident from dehydration-rehydration assays, outmatched that of the WT lines. Additionally, under drought conditions, the OE lines accumulated less reactive oxygen species (ROS) as revealed by the assessment of the related physiological and biochemical parameters. Upon confronting the pathogens Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), post-infection, fluorescence quantitative investigations showed a significant boost in the salicylic acid (SA)-related gene expression in OE lines compared to their WT counterparts. Overall, our findings designate the SL receptor D14 as a key upregulator of drought tolerance and a regulator in the biotic stress response, thereby advancing our understanding of the maize SL signaling pathway by elucidating the function of the pivotal D14 gene.
ESTHER : Zhang_2024_Int.J.Mol.Sci_25_
PubMedSearch : Zhang_2024_Int.J.Mol.Sci_25_
PubMedID: 38279328

Title : Inhibition of soluble epoxide hydrolase as a therapeutic approach for blood-brain barrier dysfunction - Li_2024_Biochimie__
Author(s) : Li S , Song H , Sun Y , Zhang H , Gao Z
Ref : Biochimie , : , 2024
Abstract : The blood-brain barrier (BBB) is a protective semi-permeable structure that regulates the exchange of biomolecules between the peripheral blood and the central nervous system (CNS). Due to its specialized tight junctions and low vesicle trafficking, the BBB strictly limits the paracellular passage and transcellular transport of molecules to maintain the physiological condition of brain tissues. BBB breakdown is associated with many CNS disorders. Soluble epoxide hydrolase (sEH) is a hydrolase enzyme that converts epoxy-fatty acids (EpFAs) to their corresponding diols and is involved in the onset and progression of multiple diseases. EpFAs play a protective role in the central nervous system via preventing neuroinflammation, making sEH a potential therapeutic target for CNS diseases. Recent studies showed that sEH inhibition prevented BBB impairment caused by stroke, hemorrhage, traumatic brain injury, hyperglycemia and sepsis via regulating the expression of tight junctions. In this review, the protective actions of sEH inhibition on BBB and potential mechanisms are summarized, and some important questions that remain to be resolved are also addressed.
ESTHER : Li_2024_Biochimie__
PubMedSearch : Li_2024_Biochimie__
PubMedID: 38531484
Gene_locus related to this paper: human-EPHX2

Title : Influence of Different Ratios of DSPE-PEG2k on Ester Prodrug Self-Assembly Nanoparticles for Cell Migration and Proliferation Suppression - Zhang_2024_Int.J.Nanomedicine_19_2807
Author(s) : Zhang H , Wei S , Hu Y , Zhang Y , Yao H , Qi G , Adu-Frimpong M , Sun C
Ref : Int J Nanomedicine , 19 :2807 , 2024
Abstract : BACKGROUND: Bufalin (BFL, an active anti-tumor compound derived from toad venom) is limited in its application due to high toxicity and rapid metabolism of the cardiotonic steroid. Ester prodrug self-assembly nanoparticles have shown significant improved effects in addressing the above-mentioned issues. METHODS: An ester bond was formed between linoleic acid and bufalin to synthesize linoleic acid-bufalin prodrug (LeB). The self-assembly nanoparticles (LeB-PSNs) containing different mass ratios of DSPE-PEG2k and prodrug (6:4, 7:3, 8:2, 9:1 and 10:0) were prepared via co-precipitation method and defined as 6:4-PSNs, 7:3-PSNs, 8:2-PSNs, 9:1-PSNs and LeB-PSNs, respectively. Further, the characterization (particle size, zeta potential, surface morphology and stability) of the nanoparticles was carried out. Finally, we evaluated the impact of different ratios of DSPE-PEG2k on the hydrolysis rate, cytotoxicity, cellular uptake, cell migration and proliferation suppression potential of the prodrug nanoparticles. RESULTS: The linoleic acid-bufalin prodrug (LeB) was successfully synthesized. Upon the addition of DSPE-PEG2k at different weight ratios, both particle size and polydispersity index (PDI) significantly decreased, while the zeta potential increased remarkably. No significant differences in particle size, PDI and Zeta potential were observed among the 9:1, 8:2 and 7:3 PSNs. Notably, the 8:2 (w/w) DSPE-PEG2k nanoparticles exhibited superior stability, hydrolysis and cellular uptake rates, along with efficient cell cytotoxicity, cell migration and proliferation suppression. CONCLUSION: These findings indicate that DSPE-PEG2k could improve the performance of BFL prodrug nanoparticles, namely enhancing stability and achieving adaptive drug release by modulating the hydrolysis rate of esterase. This study therefore provides more opportunities for the development of BFL application.
ESTHER : Zhang_2024_Int.J.Nanomedicine_19_2807
PubMedSearch : Zhang_2024_Int.J.Nanomedicine_19_2807
PubMedID: 38525014

Title : Degradation and enhanced oil recovery potential of Alcanivorax borkumensis through production of bio-enzyme and bio-surfactant - Deng_2024_Bioresour.Technol_400_130690
Author(s) : Deng S , Wang B , Zhang H , Qu R , Sun S , You Q , She Y , Zhang F
Ref : Bioresour Technol , 400 :130690 , 2024
Abstract : Microbial enhanced oil recovery (EOR) has become the focus of oilfield research due to its low cost, environmental friendliness and sustainability. The degradation and EOR capacity of A. borkumensis through the production of bio-enzyme and bio-surfactant were first investigated in this study. The total protein concentration, acetylcholinesterase, esterase, lipase, alkane hydroxylase activity, surface tension, and emulsification index (EI) were determined at different culture times. The bio-surfactant was identified as glycolipid compound, and the yield was 2.6 +/- 0.2 g/L. The nC(12) and nC(13) of crude oil were completely degraded, and more than 40.0 % of nC(14)-nC(24) was degraded by by A. borkumensis. The results of the microscopic etching model displacement and core flooding experiments showed that emulsification was the main mechanism of EOR. A. borkumensis enhanced the recovery rate by 20.2 %. This study offers novel insights for the development of environmentally friendly and efficient oil fields.
ESTHER : Deng_2024_Bioresour.Technol_400_130690
PubMedSearch : Deng_2024_Bioresour.Technol_400_130690
PubMedID: 38614150

Title : A lipase-conjugated carbon nanotube fiber-optic SPR sensor for sensitive and specific detection of tributyrin - Zhang_2024_Nanoscale__
Author(s) : Zhang H , Li X , Zhou X , Zhang Y , Zhao Y
Ref : Nanoscale , : , 2024
Abstract : As a low-density lipoprotein, tributyrin plays an essential role in food safety and human health. In this study, a novel lipase-conjugated carbon nanotube (CNT) surface plasmon resonance (SPR) fiber-optic sensor is used to specifically detect tributyrin for the first time. In this work, CNTs can be used as an amplifying material to significantly increase the sensitivity of SPR sensors due to their high refractive index and large surface area. CNTs can also be used as an enzyme carrier to provide abundant carboxyl groups for the specific binding of lipases. Covering the surface of the sensor with CNTs can not only enhance the performance of the sensor, but also provide sufficient detection sites for subsequent biomass detection, reduce the functionalization steps, and simplify the sensor preparation process. The experimental results demonstrate that the refractive index sensitivity of the traditional multimode fiber (MMF)-single mode fiber (SMF)-MMF transmissive optical fiber sensor is 1705 nm RIU(-1). After covering the sensor with CNTs, the sensitivity is 2077 nm RIU(-1), and the sensitivity has been improved very well. In addition, there are abundant functional groups on CNTs, which can provide abundant binding sites. Conjugating lipase on carbon nanotubes helps to achieve linear detection in the range of 0.5 mM to 4 mM tributyrin, with a sensitivity of 4.45 nm mM(-1) and a detection limit of 0.34 mM, which is below the 2.26 mM detection standard and meets food safety monitoring requirements. Compared with other sensors, the optical fiber biosensor proposed in this study expands the concentration detection range of tributyrin. Furthermore, the sensor also has good stability, anti-interference performance and specificity. Therefore, the sensor proposed in this paper has good application prospects in the fields of food safety and biomedicine.
ESTHER : Zhang_2024_Nanoscale__
PubMedSearch : Zhang_2024_Nanoscale__
PubMedID: 38258424

Title : An Esterase-Responsive SLC7A11 shRNA Delivery System Induced Ferroptosis and Suppressed Hepatocellular Carcinoma Progression - Zhang_2024_Pharmaceutics_16_
Author(s) : Zhang H , Wang J , Xiang X , Xie C , Lu X , Guo H , Sun Y , Shi Z , Song H , Qiu N , Xu X
Ref : Pharmaceutics , 16 : , 2024
Abstract : Ferroptosis has garnered attention as a potential approach to fight against cancer, which is characterized by the iron-driven buildup of lipid peroxidation. However, the robust defense mechanisms against intracellular ferroptosis pose significant challenges to its effective induction. In this paper, an effective gene delivery vehicle was developed to transport solute carrier family 7 member 11 (SLC7A11) shRNA (shSLC7A11), which downregulates the expression of the channel protein SLC7A11 and glutathione peroxidase 4 (GPX4), evoking a surge in reactive oxygen species production, iron accumulation, and lipid peroxidation in hepatocellular carcinoma (HCC) cells, and subsequently leading to ferroptosis. This delivery system is composed of an HCC-targeting lipid layer and esterase-responsive cationic polymer, a poly{N-[2-(acryloyloxy)ethyl]-N-[p-acetyloxyphenyl]-N} (PQDEA) condensed shSLC7A11 core (G-LPQDEA/shSLC7A11). After intravenous (i.v.) injection, G-LPQDEA/shSLC7A11 quickly accumulated in the tumor, retarding its growth by 77% and improving survival by two times. This study is the first to construct a gene delivery system, G-LPQDEA/shSLC7A11, that effectively inhibits HCC progression by downregulating SLC7A11 expression. This underscores its therapeutic potential as a safe and valuable candidate for clinical treatment.
ESTHER : Zhang_2024_Pharmaceutics_16_
PubMedSearch : Zhang_2024_Pharmaceutics_16_
PubMedID: 38399303

Title : Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice - Boutagy_2024_J.Clin.Invest__
Author(s) : Boutagy NE , Gamez-Mendez A , Fowler JW , Zhang H , Chaube BK , Esplugues E , Lee S , Horikami D , Zhang J , Citrin KM , Singh AK , Coon BG , Suarez Y , Fernandez-Hernando C , Sessa WC
Ref : J Clinical Investigation , : , 2024
Abstract : Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. In this study, we showed that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, led to neutral lipid accumulation in vessels and impaired endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.
ESTHER : Boutagy_2024_J.Clin.Invest__
PubMedSearch : Boutagy_2024_J.Clin.Invest__
PubMedID: 38175710

Title : Neuroligin1 in excitatory synapses contributes to long-term cognitive impairments after repeated neonatal sevoflurane exposures - Zhang_2024_Exp.Neurol__114755
Author(s) : Zhang H , Niu Y , Yuan P , Liu W , Zhu W , Sun J
Ref : Experimental Neurology , :114755 , 2024
Abstract : BACKGROUND: Repeated sevoflurane exposures in neonatal rats may lead to neuronal apoptosis affecting long-term cognitive function, the mechanism is unknown. Neuroligin1 (NL1) is essential for normal excitatory transmission and long-term synaptic plasticity in the hippocampus of intact animals. Herein, we explore the role of NL1 in hippocampal excitatory synapses on long-term cognitive impairments induced by repeated sevoflurane exposures in neonatal rats. METHODS: From postnatal day six (P6) to P8, neonatal rats were exposed to 30% oxygen or 3% sevoflurane +30% oxygen for 2 h daily. Rats from each litter were randomly assigned to five groups: control group (Con), native control adeno-associated virus (NC-AAV) group (Con + NC-AAV), sevoflurane group (Sev), sevoflurane + recombinant RNAi adeno-associated virus targeting NL1 downregulation (NL1(-)-AAV) group (Sev + NL1(-)-AAV) and control + recombinant RNAi adeno-associated virus targeting NL1 upregulation (NL1(+)-AAV) group (Con + NL1(+)-AAV). Animals were injected with NC-AAV or NL1-AAV into the bilateral hippocampal CA1 area and caged on P21. From P35 to P40, behavioral tests including open field (OF), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function in adolescent rats. In another experiment, rat brains were harvested for immunofluorescence staining, western blotting, co-immunoprecipitation, and real-time polymerase chain reaction (PCR). RESULTS: We found that the mRNA and protein levels of NL1 were substantially higher in the Sev group than in the Con group. Immunofluorescence showed that NL1 and PSD95 were highly colocalized in hippocampal CA1 area and vesicular GABA transporter (vGAT) around neurons decreased after repeated sevoflurane exposures. Co-immunoprecipitation showed that the amount of PSD95 with NL1 antibody was significantly increased in the Sev group compared to the Con group. These rats had a poorer performance in the NOR and FC tests than control rats when they were adolescents. These results were reversed by NL1(-)-AAV injection into the CA1 area. NL1(+)-AAV group was similar to the Sev group. CONCLUSION: We have demonstrated that repeated neonatal sevoflurane exposures decreased inhibitory synaptic inputs (labelled by vGAT) around neurons, which may influence the upregulation of NL1 in hippocampal excitatory synapses and enhanced NL1/PSD95 interaction, ultimately leading to long-term cognitive impairments in adolescent rats. Injecting NL1(-)-AAV reversed this damage. These results suggested that NL1 in excitatory synapses contributes to long-term cognitive impairments after repeated neonatal sevoflurane exposures.
ESTHER : Zhang_2024_Exp.Neurol__114755
PubMedSearch : Zhang_2024_Exp.Neurol__114755
PubMedID: 38493982

Title : Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease - Wu_2024_Molecules_29_
Author(s) : Wu X , Ze X , Qin S , Zhang B , Li X , Gong Q , Zhang H , Zhu Z , Xu J
Ref : Molecules , 29 : , 2024
Abstract : Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC(50) = 0.223 microM) with pyrimidone compound 5 (GSK-3beta: IC(50) = 3 microM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3beta (GSK-3beta). The optimal compound 18a possessed potent dual AChE/GSK-3beta inhibition (AChE: IC(50) = 0.047 +/- 0.002 microM, GSK-3beta: IC(50) = 0.930 +/- 0.080 microM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 microM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.
ESTHER : Wu_2024_Molecules_29_
PubMedSearch : Wu_2024_Molecules_29_
PubMedID: 38675602

Title : Diosmetin derivatives as multifunctional anti-AD ligands: Design, synthesis, and biological evaluation - Yang_2024_Chem.Biol.Drug.Des_103_e14529
Author(s) : Yang A , Yi X , Zhang H , Shen R , Kou X
Ref : Chemical Biology Drug Des , 103 :e14529 , 2024
Abstract : With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1-4) were designed, synthesized, and characterized by (1)H NMR, (13)C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and beta-amyloid (Abeta) aggregation inhibition in vitro were evaluated. The results showed that 1-4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu(2+) ions), antioxidation, self-induced, Cu(2+)-induced, and AChE-induced Abeta aggregation inhibition activities, and suitable blood-brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10(-8)M magnitude) and BuChE (10(-7)M magnitude) and showed the best inhibition on AChE-induced Abeta aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.
ESTHER : Yang_2024_Chem.Biol.Drug.Des_103_e14529
PubMedSearch : Yang_2024_Chem.Biol.Drug.Des_103_e14529
PubMedID: 38670598

Title : Carboxylesterase-activated near-infrared fluorescence probe for highly sensitive imaging of liver tumors - Jiang_2024_J.Mater.Chem.B__
Author(s) : Jiang R , Xia Y , Liu Q , Zhang H , Yang X , He L , Cheng D
Ref : J Mater Chem B , : , 2024
Abstract : Carboxylesterases (CESs) are critical for metabolizing ester-containing biomolecules and are specifically important in liver metabolic disorders. The modulation of CESs is also an important issue in pharmacology and clinical applications. Herein, we present a near-infrared (NIR) CES fluorescent probe (NCES) based on the protection-deprotection of the hydroxyl group for monitoring CES levels in living systems. The NCES probe has good selectivity and sensitivity for CESs with a limit of detection (LOD) of 5.24 mU mL(-1), which allows for tracing the fluctuation of cellular CES after treatment with anticancer drugs and under inflammation and apoptosis states. Furthermore, NCES can be successfully applied for guiding liver cancer surgery with high-contrast in vivo imaging and detecting clinical serum samples from liver cancer patients. This work showed that the NCES probe has great potential in drug development, imaging applications for medical diagnosis, and early-stage detection for clinical liver diseases.
ESTHER : Jiang_2024_J.Mater.Chem.B__
PubMedSearch : Jiang_2024_J.Mater.Chem.B__
PubMedID: 38251432

Title : Leafhopper salivary carboxylesterase suppresses JA-Ile synthesis to facilitate initial arbovirus transmission in rice phloem - Chi_2024_Plant.Commun__100939
Author(s) : Chi Y , Zhang H , Chen S , Cheng Y , Zhang X , Jia D , Chen Q , Chen H , Wei T
Ref : Plant Commun , :100939 , 2024
Abstract : Plant jasmonoyl-L-isoleucine (JA-Ile) is a major defense signal against insect feeding, but whether or how insect salivary effectors suppress JA-Ile synthesis and thus facilitate viral transmission in plant phloem remains elusive. Insect carboxylesterases (CarEs) are the third major family of detoxification enzymes. Here, we identify a new leafhopper CarE10 that specifically expressed in salivary glands and is secreted into rice phloem as the saliva component. Leafhopper CarE10 directly binds and promotes rice Jasmonate resistant 1 (JAR1) degradation by the proteasome system. Moreover, the direct association of CarE10 with JAR1 obviously impairs JAR1 enzyme activity for JA conversion to JA-Ile in in-vitro JA-Ile synthesis system. A devastating rice reovirus activates and promotes co-secretion of virions and CarE10 by virus-induced vesicles into saliva-stored salivary cavities of leafhopper vectors and ultimately into rice phloem to establish initial infection. Furthermore, virus-mediated increase of CarE10 secretion or overexpression of CarE10 in transgenic rice plants causes the reduced levels of JAR1 and thus suppresses JA-Ile synthesis, thereby promoting host attractiveness to insect vectors and facilitating initial viral transmission. Our findings provide insights into how insect salivary protein CarE10 suppresses host JA-Ile synthesis to benefit initial virus transmission in rice phloem.
ESTHER : Chi_2024_Plant.Commun__100939
PubMedSearch : Chi_2024_Plant.Commun__100939
PubMedID: 38725245

Title : Kj-mhpC Enzyme in Klebsiella jilinsis 2N3 Is Involved in the Degradation of Chlorimuron-Ethyl via De-Esterification - Zhai_2024_J.Agric.Food.Chem__
Author(s) : Zhai Q , Zheng S , Zhang C , Lu Z , Liang S , Li R , Zhang X , Pan H , Zhang H
Ref : Journal of Agricultural and Food Chemistry , : , 2024
Abstract : Microbial degradation is a highly efficient and reliable approach for mitigating the contamination of sulfonylurea herbicides, such as chlorimuron-ethyl, in soil and water. In this study, we aimed to assess whether Kj-mhpC plays a pivotal role in the degradation of chlorimuron-ethyl. Kj-mhpC enzyme purified via prokaryotic expression exhibited the highest catalytic activity for chlorimuron-ethyl at 35 degreesC and pH 7. Bioinformatic analysis and three-dimensional homologous modeling of Kj-mhpC were conducted. Additionally, the presence of Mg(+) and Cu(2+) ions partially inhibited but Pb(2+) ions completely inhibited the enzymatic activity of Kj-mhpC. LC/MS revealed that Kj-mhpC hydrolyzes the ester bond of chlorimuron-ethyl, resulting in the formation of 2-(4-chloro-6-methoxypyrimidine-2-amidoformamidesulfonyl) benzoic acid. Furthermore, the point mutation of serine at position 67 (Ser67) confirmed that it is the key amino acid at the active site for degrading chlorimuron-ethyl. This study enhanced the understanding of how chlorimuron-ethyl is degraded by microorganisms and provided a reference for bioremediation of the environment polluted with chlorimuron-ethyl.
ESTHER : Zhai_2024_J.Agric.Food.Chem__
PubMedSearch : Zhai_2024_J.Agric.Food.Chem__
PubMedID: 38417018
Gene_locus related to this paper: klep7-a6tb98

Title : Metformin inhibits OCTN1- and OCTN2-mediated hepatic accumulation of doxorubicin and alleviates its hepatotoxicity in mice - Chen_2024_Toxicology__153757
Author(s) : Chen M , Yi Y , Chen B , Zhang H , Dong M , Yuan L , Zhou H , Jiang H , Ma Z
Ref : Toxicology , :153757 , 2024
Abstract : Doxorubicin (DOX) is a widely used antitumor agent; however, its clinical application is limited by dose-related organ damage. Because organic cation/carnitine transporters (OCTN1 and OCTN2), which are critical for DOX uptake, are highly expressed in hepatocytes, we aimed to elucidate the role of these transporters in hepatic DOX uptake. The results indicated that inhibitors and RNA interference both significantly reduced DOX accumulation in HepG2 and HepaRG cells, suggesting that OCTN1/2 contribute substantially to DOX uptake by hepatocytes. To determine whether metformin (MET, an inhibitor of OCTN1 and OCTN2) ameliorates DOX-induced hepatotoxicity, we conducted in vitro and in vivo studies. MET (1-100microM) inhibited DOX (500nM) accumulation and cytotoxicity in vitro in a concentration-dependent manner. Furthermore, intravenous MET administration at 250 or 500mg/kg or by gavage at 50, 100, or 200mg/kg reduced DOX (8mg/kg) accumulation in a dose-dependent manner in the mouse liver and attenuated the release of alanine aminotransferase, aspartate aminotransferase, and carboxylesterase 1. Additionally, MET reduced the distribution of DOX in the heart, liver, and kidney and enhanced the urinary elimination of DOX; however, it did not increase the nephric toxicity of DOX. In conclusion, our study demonstrated that MET alleviates DOX hepatotoxicity by inhibiting OCTN1- and OCTN2-mediated DOX uptake in vitro (mouse hepatocytes and HepaRG or HepG2 cells) and in mice.
ESTHER : Chen_2024_Toxicology__153757
PubMedSearch : Chen_2024_Toxicology__153757
PubMedID: 38364893

Title : Characterization of a Novel Esterase Belonging to Family V from Marinobacter flavimaris - He_2024_J.Ocean.Univ.China_23_221
Author(s) : He J , Zhang Y , Wu L , Wang Y , Zhang H , Liu Z , Shi X
Ref : J. Ocean Univ. China (Oceanic and Coastal Sea Research) , 23 :221 , 2024
Abstract : Lipolytic enzymes have attracted enormous attentions because of their ability in ester hydrolysis, ester synthesis, transesterification and other biochemical reactions. Bacteria are important sources of lipolytic enzymes applied in industry. Here, a novel lipolytic enzyme encoded by esterase gene est1347 was identified in Marinobacter flavimaris WLL162, and was purified and characterized. The lipolytic enzyme Est1347 consisted of 312 amino acid residues and a 21-amino-acids N-terminal signal peptide with a predicted molecular weight of 34.2 kDa. It belongs to family V of bacterial lipolytic enzymes based on the amino acid sequence homology analysis. Est1347 is a mesophilic and alkali-resistant enzyme with the highest activity at 45? and pH 8.5; it is stable at temperatures below 50C and pH 7.511.0. Est1347 showed a preference for middle-length chain substrate p-NPC10 and a wide range of other substrates. The Km, Vmax, Kcat and Kcat/Km values of Est1347 for p-NPC10 in pH 8.5 at 45C were 0.9411 mmol L-1, 1285 micromol min-1 mg-1, 698.91 s-1 and 743.65 s-1 (mmol L-1)-1, respectively. It is also tolerant to the metal ions, organic solvents and detergents. In conclusion, the esterase Est1347 laid a foundation for further study of bacterial lipolytic enzyme family V.
ESTHER : He_2024_J.Ocean.Univ.China_23_221
PubMedSearch : He_2024_J.Ocean.Univ.China_23_221
Gene_locus related to this paper: 9gamm-g6yq95

Title : Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes - Bian_2024_Diabetes.Obes.Metab__
Author(s) : Bian YC , Meng J , Hu T , Ma S , Huang CR , Zhang FY , Wu QH , Zhang H , Chen XY , Miao LY
Ref : Diabetes Obes Metab , : , 2024
Abstract : AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80microCi (25mg) [(14)C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t(1/2)) of 111h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t(1/2) of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.
ESTHER : Bian_2024_Diabetes.Obes.Metab__
PubMedSearch : Bian_2024_Diabetes.Obes.Metab__
PubMedID: 38646838

Title : Plasma Protein Binding Determination for Unstable Ester Prodrugs: Remdesivir and Tenofovir Alafenamide - Wen_2023_J.Pharm.Sci__
Author(s) : Wen A , Qin AR , Tarnowski T , Ling KHJ , Zhang H , Humeniuk R , Regan S , Saquing J , Liu W , Venkatarangan L , Xiao D
Ref : J Pharm Sci , : , 2023
Abstract : Remdesivir (RDV) and tenofovir alafenamide (TAF) are prodrugs designed to be converted to their respective active metabolites. Plasma protein binding (PPB) determination of these prodrugs is important for patients with possible alteration of free fraction of the drugs due to plasma protein changes in renal impairment, hepatic impairment, or pregnancy. However, the prodrugs' instability in human plasma presents a challenge for accurate PPB determination. In this research work, two approaches were used in the method development and qualification for PPB assessment of RDV and TAF. For RDV, dichlorvos was used to inhibit esterase activity to stabilize the prodrug in plasma during equilibrium dialysis (ED). The impact of dichlorvos on protein binding was evaluated and determined to be insignificant by comparing the unbound fraction (f(u)) determined by the ED method with dichlorvos present and the f(u) determined by an ultrafiltration method without dichlorvos. In contrast to RDV, TAF degradation in plasma is -3-fold slower, and TAF stability cannot be improved by dichlorvos. Fit-for-purpose acceptance criteria for the TAF PPB method were chosen, and an ED method was developed based on these criteria. These two methods were then qualified and applied for PPB determinations in clinical studies.
ESTHER : Wen_2023_J.Pharm.Sci__
PubMedSearch : Wen_2023_J.Pharm.Sci__
PubMedID: 37722451

Title : Complementary Homogeneous Electrochemical and Photothermal Dual-Modal Sensor for Highly Sensitive Detection of Organophosphorus Pesticides via Stimuli-Responsive COF\/Methylene Blue@MnO(2) Composite - Wen_2023_Anal.Chem__
Author(s) : Wen SH , Zhang H , Yu S , Ma J , Zhu JJ , Zhou Y
Ref : Analytical Chemistry , : , 2023
Abstract : Credible and on-site detection of organophosphorus pesticides (OPs) in complex matrixes is significant for food security and environmental monitoring. Herein, a novel COF/methylene blue@MnO(2) (COF/MB@MnO(2)) composite featured abundant signal loading, a specific recognition unit, and robust oxidase-like activity was successfully prepared through facile assembly processes. The multifunctional composite acted as a homogeneous electrochemical and photothermal dual-mode sensing platform for OPs detection through stimuli-responsive regulation. Without the presence of OPs, the surface MnO(2) coating could recognize thiocholine (TCh), originating from acetylcholinesterase (AChE)-catalyzed hydrolysis of acetylthiocholine (ATCh), and exhibited a distinctly amplified diffusion current due to the release of plentiful MB; while the residual MnO(2) nanosheets could only catalyze less TMB into oxidized TMB (oxTMB) with a typical near-infrared (NIR) absorption, enabling NIR-driven photothermal assay with a low temperature using a portable thermometer. Based on the inhibitory effect of OPs on AChE activity and OP-regulated generation of TCh, chlorpyrifos as a model target can be accurately detected with a low limit of detection of 0.0632 and 0.108 ng/mL by complementary electrochemical and photothermal measurements, respectively. The present dual-mode sensor was demonstrated to be excellent for application to the reliable detection of OPs in complex environmental and food samples. This work can not only provide a complementary dual-mode method for convenient and on-site detection of OPs in different scenarios but also expand the application scope of the COF-based multifunctional composite in multimodal sensors.
ESTHER : Wen_2023_Anal.Chem__
PubMedSearch : Wen_2023_Anal.Chem__
PubMedID: 37769195

Title : The PET-Degrading Potential of Global Metagenomes: From In Silico Mining to Active Enzymes - Chow_2023_Methods.Mol.Biol_2555_139
Author(s) : Chow J , Perez-Garcia P , Dierkes RF , Zhang H , Streit WR
Ref : Methods Mol Biol , 2555 :139 , 2023
Abstract : Against the background of the steadily increasing amount of plastic waste in the sea and on land, it is more important than ever to find ways out of this situation. In recent years, microorganisms have been discovered that are capable of degrading artificial polymers such as polyethylene terephthalate (PET). Even if the turnover rates of the enzymes responsible for this reaction may be too low to solve the global plastic pollution problem, it is still of great societal interest to find microorganisms that are able to degrade the polymer. The corresponding enzymes, PET esterases (PETases) can be used in biotechnological processes and could contribute to a resource-saving circular economy. In this chapter, we present a sequence-based in silico screening method to find new PETases in metagenomic datasets. This method can easily be adapted to find other enzyme classes. We also list a number of assays that can be used to test the enzymes for activity on PET as well as other substrates.
ESTHER : Chow_2023_Methods.Mol.Biol_2555_139
PubMedSearch : Chow_2023_Methods.Mol.Biol_2555_139
PubMedID: 36306084

Title : The transcription factor CREB3-2 regulated neutral lipase gene expression in ovary of Nilaparvata lugens - Lin_2023_Pestic.Biochem.Physiol_196_105632
Author(s) : Lin X , Zhang H , Gao H , Yuan X , Liu Z
Ref : Pestic Biochem Physiol , 196 :105632 , 2023
Abstract : The cyclic AMP-responsive element-binding protein 3 (CREB3) members have unique regulatory roles in cellular lipid metabolism as transcription factors. Two CREB3 proteins in Nilaparvata lugens were identified and analyzed. In ovary, when silencing NlCREB3-2, triacylglycerol (TAG) content dramatically increased but glycerol and free fatty acid (FFA) significantly decreased, which implicated that NlCREB3-2 was involved in the lipase-related TAG metabolism. In N. lugens, five neutral lipases with complete features for TAG hydrolytic activity and high expression in ovary were focused. Among them, the expression levels of three neutral lipase genes were significantly down-regulated by NlCREB3-2 RNAi. The direct regulation of NlCREB3-2 towards the three neutral lipase genes was evidenced by the dual-luciferase reporter assay. After jointly silencing three neutral lipase genes, TAG and glycerol contents displayed similar changes as NlCREB3-2 RNAi. The study proved that NlCREB3-2 participated in TAG metabolism in ovary via the direct activation towards the ovary-specific neutral lipase genes.
ESTHER : Lin_2023_Pestic.Biochem.Physiol_196_105632
PubMedSearch : Lin_2023_Pestic.Biochem.Physiol_196_105632
PubMedID: 37945264

Title : The NLR immune receptor ADR1 and lipase-like proteins EDS1 and PAD4 mediate stomatal immunity in Nicotiana benthamiana and Arabidopsis - Wang_2023_Plant.Cell__
Author(s) : Wang H , Song S , Gao S , Yu Q , Zhang H , Cui X , Fan J , Xin X , Liu Y , Staskawicz B , Qi T
Ref : Plant Cell , : , 2023
Abstract : In the presence of pathogenic bacteria, plants close their stomata to prevent pathogen entry. Intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogenic effectors and activate effector-triggered immune responses. However, the regulatory and molecular mechanisms of stomatal immunity involving NLR immune receptors are unknown. Here, we show that the Nicotiana benthamiana RPW8-NLR central immune receptor ACTIVATED DISEASE RESISTANCE 1 (NbADR1), together with the key immune proteins ENHANCED DISEASE SUSCEPTIBILITY 1 (NbEDS1) and PHYTOALEXIN DEFICIENT 4 (NbPAD4), plays an essential role in bacterial pathogen- and flg22-induced stomatal immunity by regulating the expression of salicylic acid (SA) and abscisic acid (ABA) biosynthesis or response-related genes. NbADR1 recruits NbEDS1 and NbPAD4 in stomata to form a stomatal immune response complex. The transcription factor NbWRKY40e, in association with NbEDS1 and NbPAD4, modulates the expression of SA and ABA biosynthesis or response-related genes to influence stomatal immunity. NbADR1, NbEDS1, and NbPAD4 are required for the pathogen infection-enhanced binding of NbWRKY40e to the ISOCHORISMATE SYNTHASE 1 promoter. Moreover, the ADR1-EDS1-PAD4 module regulates stomatal immunity in Arabidopsis (Arabidopsis thaliana). Collectively, our findings show the pivotal role of the core intracellular immune receptor module ADR1-EDS1-PAD4 in stomatal immunity, which enables plants to limit pathogen entry.
ESTHER : Wang_2023_Plant.Cell__
PubMedSearch : Wang_2023_Plant.Cell__
PubMedID: 37851863

Title : Identification of Novel Dipeptidyl Peptidase-IV Inhibitory Peptides in Chickpea Protein Hydrolysates - Zan_2023_J.Agric.Food.Chem__
Author(s) : Zan R , Wu Q , Chen Y , Wu G , Zhang H , Zhu L
Ref : Journal of Agricultural and Food Chemistry , : , 2023
Abstract : Dipeptidyl peptidase-IV (DPP-IV) is one of the main targets for blood sugar control. Some food protein-derived peptides are thought to have DPP-IV inhibitory (DPP-IVi) activity. In this study, chickpea protein hydrolysates (CPHs) obtained through Neutrase hydrolysis for 60 min (CPHs-Pro-60) exhibited the highest DPP-IVi activity. DPP-IVi activity after simulated in vitro gastrointestinal digestion was maintained at >60%. Peptide libraries are established after the identification of peptide sequences. Molecular docking verified that the four screened peptides (AAWPGHPEF, LAFP, IAIPPGIPYW, and PPGIPYW) could bind to the active center of DPP-IV. Notably, IAIPPGIPYW exhibited the most potent DPP-IVi activity (half maximal inhibitory concentration (IC(50)): 12.43 microM). Both IAIPPGIPYW and PPGIPYW exhibited excellent DPP-IVi activity in Caco-2 cells. These results indicated that chickpea could be used as a source of natural hypoglycemic peptides for food and nutritional applications.
ESTHER : Zan_2023_J.Agric.Food.Chem__
PubMedSearch : Zan_2023_J.Agric.Food.Chem__
PubMedID: 37191584

Title : Integration of clinical demographics and routine laboratory analysis parameters for early prediction of gestational diabetes mellitus in the Chinese population - Zhang_2023_Front.Endocrinol.(Lausanne)_14_1216832
Author(s) : Zhang H , Dai J , Zhang W , Sun X , Sun Y , Wang L , Li H , Zhang J
Ref : Front Endocrinol (Lausanne) , 14 :1216832 , 2023
Abstract : Gestational diabetes mellitus (GDM) is one of the most common complications in pregnancy, impairing both maternal and fetal health in short and long term. As early interventions are considered desirable to prevent GDM, this study aims to develop a simple-to-use nomogram based on multiple common risk factors from electronic medical health records (EMHRs). A total of 924 pregnant women whose EMHRs were available at Peking University International Hospital from January 2022 to October 2022 were included. Clinical demographics and routine laboratory analysis parameters at 8-12 weeks of gestation were collected. A novel nomogram was established based on the outcomes of multivariate logistic regression. The nomogram demonstrated powerful discrimination (the area under the receiver operating characteristic curve = 0.7542), acceptable agreement (Hosmer-Lemeshow test, P = 0.3214) and favorable clinical utility. The C-statistics of 10-Fold cross validation, Leave one out cross validation and Bootstrap were 0.7411, 0.7357 and 0.7318, respectively, indicating the stability of the nomogram. A novel nomogram based on easily-accessible parameters was developed to predict GDM in early pregnancy, which may provide a paradigm for repurposing clinical data and benefit the clinical management of GDM. There is a need for prospective multi-center studies to validate the nomogram before employing the nomogram in real-world clinical practice.
ESTHER : Zhang_2023_Front.Endocrinol.(Lausanne)_14_1216832
PubMedSearch : Zhang_2023_Front.Endocrinol.(Lausanne)_14_1216832
PubMedID: 37900122

Title : Targeting ANGPTL3 by GalNAc-conjugated siRNA ANGsiR10 lowers blood lipids with long-lasting and potent efficacy in mice and monkeys - Wang_2023_Mol.Ther.Nucleic.Acids_31_68
Author(s) : Wang J , Zheng W , Zheng S , Yuan Y , Wen W , Cui W , Xue L , Sun X , Shang H , Zhang H , Xiao RP , Gao S , Zhang X
Ref : Mol Ther Nucleic Acids , 31 :68 , 2023
Abstract : Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipoproteins by inhibiting both lipoprotein and endothelial lipases. It has been intensively investigated as a drug target for the treatment of dyslipidemia. In the present study, a modified small interfering RNA (siRNA) conjugated with GalNAc ANGsiR10 was characterized by insvivo and insvitro studies for its effect on ANGPTL3 silencing, the reduction of plasma triglycerides (TGs), and cholesterol levels in disease models. The results showed that ANGsiR10 displayed a significant and long-lasting efficacy in reducing blood TG and cholesterol levels in both mice and monkeys. Remarkably, the maximal reductions of plasma TG levels in the hApoC3-Tg mice, a model with high TG levels, and the spontaneous dyslipidemia model of rhesus monkey were 96.3% and 67.7%, respectively, after a single dose of ANGsiR10, with long-lasting effects up to 15sweeks. The cholesterol levels were also reduced in response to treatment, especially the non-HDL-c level, without altering the ApoA/ApoB ratio. This study showed that ANGsiR10 is effective in treating dyslipidemia and is worth further development.
ESTHER : Wang_2023_Mol.Ther.Nucleic.Acids_31_68
PubMedSearch : Wang_2023_Mol.Ther.Nucleic.Acids_31_68
PubMedID: 36618267

Title : The primary neurotoxic factor, Lansamide I, from Clausena lansium fruits and metabolic dysfunction invoked - Chen_2023_Food.Chem.Toxicol_181_114087
Author(s) : Chen J , Zhang X , Zhang Y , Zhang H , Zhang Q
Ref : Food & Chemical Toxicology , 181 :114087 , 2023
Abstract : Wampee (Clausena lansium) is a common fruit in South Asia. The pulp is a tasty food, and the seed is a typical traditional herb in China. However, we identified a primary toxic compound, Lansamide I, by NMR and X-ray diffraction of single-crystal. The compound occurred at 4.17 +/- 0.16 mg/kg of dried seed and 0.08 +/- 0.01 g/kg of fresh fruit. In our phenotype-based toxicity investigation, the compound caused decreased hatchability of zebrafish eggs, increased malformations such as enlarged yolk sacs and pericardial edema, and delayed body length development. Moreover, the compound also caused nerve cell damage and decreased locomotor activity. The compound caused an increase in peroxidation levels in vivo, with increases in both malondialdehyde and superoxide dismutase levels, but did not interfere with acetylcholinesterase levels. Metabolomic studies found that the compound caused significant up-regulation of 16 metabolites, mainly amino acids and peptides, which were involved in the nucleotide metabolism pathway and the betaine biosynthesis module. The qRT-PCR revealed that the substance interfered with the mRNA expression of tat and dctpp. These discoveries offer fresh perspectives on the toxicity mechanisms and metabolic response to the primary harmful molecules in wampee, which could inform the rational usage of wampee resources.
ESTHER : Chen_2023_Food.Chem.Toxicol_181_114087
PubMedSearch : Chen_2023_Food.Chem.Toxicol_181_114087
PubMedID: 37804914

Title : Degradation of poly(butylene adipate-co-terephthalate) films by Thermobifida fusca FXJ-1 isolated from compost - Jia_2023_J.Hazard.Mater_441_129958
Author(s) : Jia X , Zhao K , Zhao J , Lin C , Zhang H , Chen L , Chen J , Fang Y
Ref : J Hazard Mater , 441 :129958 , 2023
Abstract : In recent years, Poly(butylene adipate-co-terephthalate) (PBAT) films were wildly used due to its biodegradable properties. However, there are few reports of strains that can high efficiently degrade PBAT. Thermobifida fusca FXJ-1, a thermophilic actinomycete, was screened and identified from compost. FXJ-1 can efficiently degrade PBAT at 55C in MSM medium. The degradation rates of the pure PBAT film (PF), PBAT film used for mulching on agricultural fields (PAF), and PBAT-PLA-ST film (PPSF) were 82.871.01%, 87.832.00% and 52.530.54%, respectively, after nine days of incubation in MSM medium. Cracking areas were monitored uniformly distributed on the surfaces of three kinds of PBAT-based films after treatment with FXJ-1 using scanning electron microscopy. The LC-MS results showed that PBAT might be degraded into adipic acid, terephthalic acid, butylene adipate, butylene terephthalate and butylene adipate-co-terephthalate, and these products are involved in the cleavage of ester bonds. We also found that amylase produced by FXJ-1 played an important role in the degradation of PPSF. FXJ-1 also showed an efficient PBAT-based films degradation ability in simulating compost environment, which implied its potential application in PBAT and starch-based film degradation by industrial composting.
ESTHER : Jia_2023_J.Hazard.Mater_441_129958
PubMedSearch : Jia_2023_J.Hazard.Mater_441_129958
PubMedID: 36122523

Title : The stereoselective toxicity of dinotefuran to Daphnia magna: A systematic assessment from reproduction, behavior, oxidative stress and digestive function - Zhang_2023_Chemosphere_327_138489
Author(s) : Zhang H , Ren X , Liu T , Zhao Y , Gan Y , Zheng L
Ref : Chemosphere , 327 :138489 , 2023
Abstract : Dinotefuran is a promising neonicotinoid insecticide with chiral structure. In the present study, the stereoselective toxicity of dinotefuran to Daphnia magna (D. magna) was studied. The present result showed that S-dinotefuran inhibited the reproduction of D. magna at 5.0 mg/L. However, both R-dinotefuran and S-dinotefuran had no genotoxicity to D. magna. Additionally, neither R-dinotefuran nor S-dinotefuran had negative influences on the motor behavior of D. magna. However, S-dinotefuran inhibited the feeding behavior of D. magna at 5.0 mg/L. Both R-dinotefuran and S-dinotefuran induced oxidative stress effect in D. magna after exposure. R-dinotefuran significantly activated the activities of superoxide dismutase (SOD) and glutathione S-transferase (GST), while S-dinotefuran showed the opposite effect. S-dinotefuran had more obvious activation effect on the acetylcholinesterase (AchE) activity and trypsin activity compared to R-dinotefuran. The transcriptome sequencing results showed that S-dinotefuran induced more DEGs in D. magna, and affected the normal function of ribosome. The DEGs were mainly related to the synthesis and metabolism of biomacromolecules, indicating the binding mode between dinotefuran enantiomer and biomacromolecules were different. Additionally, the present result indicated that the digestive enzyme activity and digestive gene expression levels in D. magna were greatly enhanced to cope with the inhibition of S-dinotefuran on the feeding.
ESTHER : Zhang_2023_Chemosphere_327_138489
PubMedSearch : Zhang_2023_Chemosphere_327_138489
PubMedID: 36996914

Title : The metagenome-derived esterase PET40 is highly promiscuous and hydrolyses polyethylene terephthalate (PET) - Zhang_2023_Febs.j__
Author(s) : Zhang H , Dierkes RF , Perez-Garcia P , Costanzi E , Dittrich J , Cea PA , Gurschke M , Applegate V , Partus K , Schmeisser C , Pfleger C , Gohlke H , Smits SHJ , Chow J , Streit WR
Ref : Febs J , : , 2023
Abstract : Polyethylene terephthalate (PET) is a widely used synthetic polymer and known to contaminate marine and terrestrial ecosystems. Only few PET-active microorganisms and enzymes (PETases) are currently known and it is debated whether degradation activity for PET originates from promiscuous enzymes with broad substrate spectra that primarily act on natural polymers or other bulky substrates, or whether microorganisms evolved their genetic makeup to accepting PET as a carbon source. Here, we present a predicted diene lactone hydrolase designated PET40, which acts on a broad spectrum of substrates, including PET. It is the first esterase with activity on PET from a GC-rich Gram-positive Amycolatopsis species belonging to the Pseudonocardiaceae (Actinobacteria). It is highly conserved within the genera Amycolatopsis and Streptomyces. PET40 was identified by sequence-based metagenome search using a PETase-specific Hidden Markov Model (HMM). Besides acting on PET, PET40 has a versatile substrate spectrum, hydrolyzing delta-lactones, beta-lactam antibiotics, the polyester-polyurethane Impranil(a) DLN, and various para-nitrophenyl (pNP) ester substrates. Molecular docking suggests that the PET degradative activity is likely a result of the promiscuity of PET40, as potential binding modes were found for substrates encompassing mono(2-hydroxyethyl) terephthalate (MHET), bis(2-hydroxyethyl) terephthalate (BHET), and a PET trimer (PET(3) ). We also solved the crystal structure of the inactive PET40 variant S178A to 1.60 A resolution. PET40 is active throughout a wide pH (pH 4-10) and temperature range (4-65 degreesC) and remarkably stable in the presence of 5% sodium dodecyl sulfate (SDS), making it a promising enzyme as a starting point for further investigations and optimization approaches.
ESTHER : Zhang_2023_Febs.j__
PubMedSearch : Zhang_2023_Febs.j__
PubMedID: 37549040
Gene_locus related to this paper: 9pseu-PET40

Title : JLR-D-23-00401-R1 Dissecting cell type-specific impact in lysosomal acid lipase deficiency-associated disorders -
Author(s) : Westerterp M , Li F , Zhang H
Ref : J Lipid Res , :100474 , 2023
PubMedID: 37972729
Gene_locus related to this paper: human-LIPA , mouse-1llip

Title : Elamipretide alleviates pyroptosis in traumatically injured spinal cord by inhibiting cPLA2-induced lysosomal membrane permeabilization - Zhang_2023_J.Neuroinflammation_20_6
Author(s) : Zhang H , Chen Y , Li F , Wu C , Cai W , Ye H , Su H , He M , Yang L , Wang X , Zhou K , Ni W
Ref : J Neuroinflammation , 20 :6 , 2023
Abstract : Spinal cord injury (SCI) is a devastating injury that may result in permanent motor impairment. The active ingredients of medications are unable to reach the affected area due to the blood-brain barrier. Elamipretide (SS-31) is a new and innovative aromatic cationic peptide. Because of its alternating aromatic and cationic groups, it freely crosses the blood-brain barrier. It is also believed to decrease inflammation and protect against a variety of neurological illnesses. This study explored the therapeutic value of SS-31 in functional recovery after SCI and its possible underlying mechanism. A spinal cord contusion injury model as well as the Basso Mouse Scale, footprint assessment, and inclined plane test were employed to assess how well individuals could function following SCI. The area of glial scarring, the number of dendrites, and the number of synapses after SCI were confirmed by HE, Masson, MAP2, and Syn staining. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were employed to examine the expression levels of pyroptosis-, autophagy-, lysosomal membrane permeabilization (LMP)- and MAPK signalling-related proteins. The outcomes showed that SS-31 inhibited pyroptosis, enhanced autophagy and attenuated LMP in SCI. Mechanistically, we applied AAV vectors to upregulate Pla2g4A in vivo and found that SS-31 enhanced autophagy and attenuated pyroptosis and LMP by inhibiting phosphorylation of cPLA2. Ultimately, we applied asiatic acid (a p38-MAPK agonist) to test whether SS-31 regulated cPLA2 partially through the MAPK-P38 signalling pathway. Our group is the first to suggest that SS-31 promotes functional recovery partially by inhibiting cPLA2-mediated autophagy impairment and preventing LMP and pyroptosis after SCI, which may have potential clinical application value.
ESTHER : Zhang_2023_J.Neuroinflammation_20_6
PubMedSearch : Zhang_2023_J.Neuroinflammation_20_6
PubMedID: 36609266

Title : Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase - Yu_2023_J.Pharm.Anal_13_1024
Author(s) : Yu H , Xu H , Yang X , Zhang Z , Hu J , Lu J , Fu J , Bu M , Zhang H , Zhai Z , Wang J , Jiang J , Wang Y
Ref : J Pharm Anal , 13 :1024 , 2023
Abstract : Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.
ESTHER : Yu_2023_J.Pharm.Anal_13_1024
PubMedSearch : Yu_2023_J.Pharm.Anal_13_1024
PubMedID: 37842660

Title : Biotransformation to synthesize the methylated derivatives of baicalein using engineered Escherichia coli - Zhang_2023_Bioprocess.Biosyst.Eng_46_735
Author(s) : Zhang X , Zhang H , Shen T , Pei J , Zhao L
Ref : Bioprocess Biosyst Eng , 46 :735 , 2023
Abstract : Oroxylin A and negletein are flavonoid compounds existing in plants, with excellent pharmacological activities such as anti-inflammatory, anti-viropexis, and anti-cancer. Nevertheless, the natural abundance of these compounds in plants is extremely low. Here, a biotransformation pathway was developed in engineered strains to synthesize oroxylin A and negletein from baicalin by using the crude extract of Scutellaria baicalensis as the substrate. Briefly, the precursor baicalin in this crude extract was hydrolyzed by a beta-glucuronidase to form the intermediate baicalein, then O-methyltransferases utilize this intermediate to synthesize oroxylin A and negletein. Through screening strains and carbon sources, regulating intercellular S-adenosyl L-methionine synthesis, and optimizing culture conditions, the titers of the target products increased gradually, with 188.0 mg/L for oroxylin A and 222.7 mg/L for negletein finally. The study illustrates a convenient method to synthesize oroxylin A and negletein from a low-cost substrate, paving the way for the mass acquisition and further bioactivities development and utilization of these rare and high-value compounds.
ESTHER : Zhang_2023_Bioprocess.Biosyst.Eng_46_735
PubMedSearch : Zhang_2023_Bioprocess.Biosyst.Eng_46_735
PubMedID: 36932217

Title : A caprylate esterase-activated fluorescent probe for sensitive and selective detection of Salmonella enteritidis - Zhang_2023_Anal.Bioanal.Chem_415_2163
Author(s) : Zhang H , Wang X , Xu Z , Ma J , Li ZL , Cheng WM , Jiang H
Ref : Anal Bioanal Chem , 415 :2163 , 2023
Abstract : Salmonella enteritidis is one of the most common foodborne pathogens. Many methods have been developed to detect Salmonella, but most of them are expensive, time-consuming, and complex in experimental procedures. Developing a rapid, specific, cost-effective, and sensitive detection method is still demanded. In this work, a practical detection method is presented using salicylaldazine caprylate as the fluorescent probe, which could be hydrolyzed by caprylate esterase liberated from Salmonella lysed by phage, to form strong fluorescent salicylaldazine. The Salmonella could be detected accurately with a low limit of detection of 6 CFU/mL and a broad concentration range of 10-10(6) CFU/mL. Moreover, this method was successfully used for the rapid detection of Salmonella in milk within 2 h through pre-enrichment by ampicillin-conjugated magnetic beads. The novel combination of fluorescent turn-on probe salicylaldazine caprylate and phage ensures this method has excellent sensitivity and selectivity.
ESTHER : Zhang_2023_Anal.Bioanal.Chem_415_2163
PubMedSearch : Zhang_2023_Anal.Bioanal.Chem_415_2163
PubMedID: 36869898

Title : The role of s-palmitoylation in neurological diseases: implication for zDHHC family - Liao_2023_Front.Pharmacol_14_1342830
Author(s) : Liao D , Huang Y , Liu D , Zhang H , Shi X , Li X , Luo P
Ref : Front Pharmacol , 14 :1342830 , 2023
Abstract : S-palmitoylation is a reversible posttranslational modification, and the palmitoylation reaction in human-derived cells is mediated by the zDHHC family, which is composed of S-acyltransferase enzymes that possess the DHHC (Asp-His-His-Cys) structural domain. zDHHC proteins form an autoacylation intermediate, which then attaches the fatty acid to cysteine a residue in the target protein. zDHHC proteins sublocalize in different neuronal structures and exert dif-ferential effects on neurons. In humans, many zDHHC proteins are closely related to human neu-rological disor-ders. This review focuses on a variety of neurological disorders, such as AD (Alz-heimer's disease), HD (Huntington's disease), SCZ (schizophrenia), XLID (X-linked intellectual disability), attention deficit hyperactivity disorder and glioma. In this paper, we will discuss and summarize the research progress regarding the role of zDHHC proteins in these neu-rological disorders.
ESTHER : Liao_2023_Front.Pharmacol_14_1342830
PubMedSearch : Liao_2023_Front.Pharmacol_14_1342830
PubMedID: 38293675

Title : A FRET sensor for the real-time detection of long chain acyl-CoAs and synthetic ABHD5 ligands - Mottillo_2023_Cell.Rep.Methods_3_100394
Author(s) : Mottillo EP , Mladenovic-Lucas L , Zhang H , Zhou L , Kelly CV , Ortiz PA , Granneman JG
Ref : Cell Rep Methods , 3 :100394 , 2023
Abstract : Intracellular long-chain acyl-coenzyme As (LC-acyl-CoAs) are thought to be under tight spatial and temporal controls, yet the ability to image LC-acyl-CoAs in live cells is lacking. Here, we developed a fluorescence resonance energy transfer (FRET) sensor for LC-acyl-CoAs based on the allosterically regulated interaction between alpha/beta hydrolase domain-containing 5 (ABHD5) and Perilipin 5. The genetically encoded sensor rapidly detects intracellular LC-acyl-CoAs generated from exogenous and endogenous fatty acids (FAs), as well as synthetic ABHD5 ligands. Stimulation of lipolysis in brown adipocytes elevated intracellular LC-acyl-CoAs in a cyclic fashion, which was eliminated by inhibiting PNPLA2 (ATGL), the major triglyceride lipase. Interestingly, inhibition of LC-acyl-CoA transport into mitochondria elevated intracellular LC-acyl-CoAs and dampened their cycling. Together, these observations reveal an intimate feedback control between LC-acyl-CoA generation from lipolysis and utilization in mitochondria. We anticipate that this sensor will be an important tool to dissect intracellular LC-acyl-CoA dynamics as well to discover novel synthetic ABHD5 ligands.
ESTHER : Mottillo_2023_Cell.Rep.Methods_3_100394
PubMedSearch : Mottillo_2023_Cell.Rep.Methods_3_100394
PubMedID: 36936069
Gene_locus related to this paper: human-ABHD5

Title : Dissecting cell type-specific impact in lysosomal acid lipase deficiency-associated disorders -
Author(s) : Westerterp M , Li F , Zhang H
Ref : J Lipid Res , 64 :100474 , 2023
PubMedID: 37972729
Gene_locus related to this paper: human-LIPA

Title : Bioimprinted lipase-catalyzed synthesis of medium- and long-chain structured lipids rich in docosahexaenoic acid for infant formula - Zou_2023_Food.Chem_424_136450
Author(s) : Zou X , Su H , Zhang F , Zhang H , Yeerbolati Y , Xu X , Chao Z , Zheng L , Jiang B
Ref : Food Chem , 424 :136450 , 2023
Abstract : Medium- and long-chain structured lipids (MLSLs) rich in docosahexaenoic acid (DHA) were obtained in shorter reaction time by acidolysis of single-cell oil (DHASCO) from Schizochytrium sp. with caprylic acid (CA) using a lipase bioimprinted with fatty acids as a catalyst. The conditions for preparation of the bioimprinted lipase for the acidolysis reaction were firstly optimized and the activity of the obtained lipase was 2.17 times higher than that of the non-bioimprinted. The bioimprinted lipase was then used as a catalyst and the reaction conditions were optimized. Under the optimal conditions, the equilibrium could be achieved in 4 h, and the total and sn-1,3 CA contents in the product were 29.18% and 42.34%, respectively, and the total and sn-2 DHA contents were 46.26% and 70.12%, respectively. Such MLSLs rich in sn-1,3 CA and sn-2 DHA are beneficial for DHA absorption, and thus have potential for use in infant formula.
ESTHER : Zou_2023_Food.Chem_424_136450
PubMedSearch : Zou_2023_Food.Chem_424_136450
PubMedID: 37247604

Title : Ultrasensitive Detection of Organophosphorus Pesticides Using Single-Molecule Conductance Measurement - Dong_2023_Anal.Chem_95_9831
Author(s) : Dong X , Tang Z , Zhang H , Hu Y , Yao Z , Huang R , Bai J , Yang Y , Hong W
Ref : Analytical Chemistry , 95 :9831 , 2023
Abstract : Detection of organophosphorus pesticides (OPs) with high sensitivity in environmental samples is of vital importance for environmental safety and human health. However, it remains a challenge to achieve fM (10(-15) mol/L) sensitivity for detecting OPs. Herein, we developed an acetylcholinesterase sensor based on 3,3',5,5'-tetramethylbenzidine (TMB) combining an enzyme-mediated strategy and scanning tunneling microscopy break junction (STM-BJ). Benefiting from the enzyme inhibition kinetics of OPs and the customized spectral clustering analysis method, our new strategy achieved the detection of methamidophos (MTMP) with a limit of 10 aM (10(-17) mol/L) and 3 times higher selectivity in mixed OPs. As applied to natural lake waters, it also exhibited high reproducibility, high stability, and good recovery. This work paves a new avenue toward the application of single-molecule conductance characterizations for biochemical analysis and environmental monitoring.
ESTHER : Dong_2023_Anal.Chem_95_9831
PubMedSearch : Dong_2023_Anal.Chem_95_9831
PubMedID: 37347983

Title : U-fiber-based biosensor for temperature-compensated acetylcholine-specific measurement - Zhang_2023_Opt.Lett_48_2138
Author(s) : Zhang H , Li X , Zhou X , Gong P , Zhao Y
Ref : Opt Lett , 48 :2138 , 2023
Abstract : This paper presents a U-fiber-based biosensor to achieve temperature-compensated acetylcholine-specific measurement. The surface plasmon resonance (SPR) and multimode interference (MMI) effects are simultaneously realized in a U-shaped fiber structure for the first time, to the best of our knowledge. The experimental results show refractive index (RI) sensitivities of 3042 and 2958nm/RIU and temperature sensitivities of -0.47 and -0.40nm/ degreesC for the MMI and SPR, which are greatly improved compared with the traditional structure. Simultaneously, a sensitivity matrix for detecting two parameters is introduced to solve the problem of temperature interference of biosensors based on RI changes. Label-free detection of acetylcholine (ACh) was achieved by immobilizing acetylcholinesterase (AChE) on optical fibers. The experimental results show that the sensor can realize the specific detection of acetylcholine and has good stability and selectivity, and the detection limit of the sensor is 30nM. The sensor has the advantages of simple structure, high sensitivity, convenient operation, direct insertion into small spaces, temperature compensation, etc., which provide an important supplement to traditional fiber-optic SPR biosensors.
ESTHER : Zhang_2023_Opt.Lett_48_2138
PubMedSearch : Zhang_2023_Opt.Lett_48_2138
PubMedID: 37058661

Title : Glioma synapses recruit mechanisms of adaptive plasticity - Taylor_2023_Nature__
Author(s) : Taylor KR , Barron T , Hui A , Spitzer A , Yalcin B , Ivec AE , Geraghty AC , Hartmann GG , Arzt M , Gillespie SM , Kim YS , Maleki Jahan S , Zhang H , Shamardani K , Su M , Ni L , Du PP , Woo PJ , Silva-Torres A , Venkatesh HS , Mancusi R , Ponnuswami A , Mulinyawe S , Keough MB , Chau I , Aziz-Bose R , Tirosh I , Suva ML , Monje M
Ref : Nature , : , 2023
Abstract : The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor(1-3) (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors(4,5). The consequent glioma cell membrane depolarization drives tumour proliferation(4,6). In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity(7,8) and strength(9-15). Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B(16) (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity(17-22) that contributes to memory and learning in the healthy brain(23-26). BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.
ESTHER : Taylor_2023_Nature__
PubMedSearch : Taylor_2023_Nature__
PubMedID: 37914930

Title : Nanoplastics induce neuroexcitatory symptoms in zebrafish (Danio rerio) larvae through a manner contrary to Parkinsonian's way in proteomics - Wang_2023_Sci.Total.Environ__166898
Author(s) : Wang Y , Wang J , Cong J , Zhang H , Gong Z , Sun H , Wang L , Duan Z
Ref : Sci Total Environ , :166898 , 2023
Abstract : Although nanoplastics (NPs) can penetrate the blood-brain barrier and accumulate in the brain, the neurotoxicity of these particles and the mechanisms associated with their unique physio-chemical properties have yet to be sufficiently ascertained. In this study, we assessed the neuroexcitatory symptoms of zebrafish (Danio rerio) larvae treated with polystyrene (PS) NPs based on an examination of locomotory behaviour, dopamine levels, and acetylcholinesterase activity. We found that PS NPs caused oxidative stress and inhibited atoh1a expression in the cerebellum of Tg(atoh1a:dTomato) transgenic zebrafish larvae, thereby indicating damage to the central nervous system. In contrast to the Parkinson's disease (PD) like effects induced by most types of nanoparticles, such as graphene oxide, we established that PS NPs influenced the neuronal proteomic profiles of zebrafish larvae in a manner contrary to the molecular pathways characteristic of PD-like effects, which could be explained by the molecular dynamic simulation. Unlike graphene oxide nanoparticles that promote significant change in the internal structure of neuroproteins, the complex macromolecular polymers of PS NPs promoted the coalescence and increased expression of neuroproteins, thereby plausibly contributing to the neuroexcitatory symptoms observed in treated zebrafish larvae. Consequently, compared with traditional nanoparticles, we believe that the unique physio-chemical properties of NPs could be a potential factor contributing to their toxicity.
ESTHER : Wang_2023_Sci.Total.Environ__166898
PubMedSearch : Wang_2023_Sci.Total.Environ__166898
PubMedID: 37683849

Title : Hormetic effects of EGC and EGCG on CES1 activity and its rescue from oxidative stress in rat liver S9 - Luo_2023_Chem.Biol.Interact__110612
Author(s) : Luo X , Lu F , Yin Z , Zhou Z , Wang Z , Zhang H
Ref : Chemico-Biological Interactions , :110612 , 2023
Abstract : Carboxylesterase 1 (CES1) is a hydrolytic enzyme that plays an important role in the activation or deactivation of many therapeutic agents, thus affecting their pharmacokinetic and pharmacodynamic outcomes. Using rat liver S9 as an enzyme source and enalapril as a CES1 substrate, the present study examined effects of a number of flavonoids on the formation of enalaprilat (the active form of enalapril) produced by CES1-mediated hydrolysis. While a majority of flavonoids tested showed inhibition on CES1, an unexpected hormetic effect was observed for epigallocatechin (EGC) and epigallocatechin gallate (EGCG), i.e., stimulatory effect at low concentrations and enzyme inhibition at high concentrations. Further experiments revealed that oxidative stress caused by hydrogen peroxide, arachidonic acid plus iron, and oxidized low density lipoproteins (oxLOL) reduced CES1 activity in rat liver S9 and the loss of CES1 enzyme activity could be rescued largely by EGC or EGCG. In contrast, such effects were minimal in human liver S9, probably due to the presence of a higher ratio of reduced vs oxidized forms of glutathione. The above findings suggest that the polyphenolic nature of EGC or EGCG might be responsible for rescuing CES1 activity under oxidative stress. Because of the importance of CES1 in drug activation or deactivation and rat liver S9 as a versatile in vitro system used for drug metabolism studies and drug safety assessment, caution should be exercised to avoid potential biases for data interpretation and decision making when CES1 activity in rat liver S9 is evaluated with dependency on experimental conditions.
ESTHER : Luo_2023_Chem.Biol.Interact__110612
PubMedSearch : Luo_2023_Chem.Biol.Interact__110612
PubMedID: 37353134

Title : Application of Marine Natural Products against Alzheimer's Disease: Past, Present and Future - Hu_2023_Mar.Drugs_21_
Author(s) : Hu D , Jin Y , Hou X , Zhu Y , Chen D , Tai J , Chen Q , Shi C , Ye J , Wu M , Zhang H , Lu Y
Ref : Mar Drugs , 21 : , 2023
Abstract : Alzheimer's disease (AD), a neurodegenerative disease, is one of the most intractable illnesses which affects the elderly. Clinically manifested as various impairments in memory, language, cognition, visuospatial skills, executive function, etc., the symptoms gradually aggravated over time. The drugs currently used clinically can slow down the deterioration of AD and relieve symptoms but cannot completely cure them. The drugs are mainly acetylcholinesterase inhibitors (AChEI) and non-competitive N-methyl-D-aspartate receptor (NDMAR) antagonists. The pathogenesis of AD is inconclusive, but it is often associated with the expression of beta-amyloid. Abnormal deposition of amyloid and hyperphosphorylation of tau protein in the brain have been key targets for past, current, and future drug development for the disease. At present, researchers are paying more and more attention to excavate natural compounds which can be effective against Alzheimer's disease and other neurodegenerative pathologies. Marine natural products have been demonstrated to be the most prospective candidates of these compounds, and some have presented significant neuroprotection functions. Consequently, we intend to describe the potential effect of bioactive compounds derived from marine organisms, including polysaccharides, carotenoids, polyphenols, sterols and alkaloids as drug candidates, to further discover novel and efficacious drug compounds which are effective against AD.
ESTHER : Hu_2023_Mar.Drugs_21_
PubMedSearch : Hu_2023_Mar.Drugs_21_
PubMedID: 36662216

Title : Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease - Li_2023_EBioMedicine_90_104543
Author(s) : Li Z , Zhang B , Liu Q , Tao Z , Ding L , Guo B , Zhang E , Zhang H , Meng Z , Guo S , Chen Y , Peng J , Li J , Wang C , Huang Y , Xu H , Wu Y
Ref : EBioMedicine , 90 :104543 , 2023
Abstract : BACKGROUND: Some observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD. METHODS: Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators. FINDINGS: No significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR(1) = 0.60 [95% CI 0.50-0.72], p(1) = 2.07 x 10(-8); OR(2) = 0.57 [95% CI 0.39-0.82], p(2) = 3.00 x 10(-3)). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 x 10(-3)) and strong colocalisation association (PP.H(4) = 0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk. INTERPRETATION: Our findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects. FUNDING: Capital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010).
ESTHER : Li_2023_EBioMedicine_90_104543
PubMedSearch : Li_2023_EBioMedicine_90_104543
PubMedID: 37002989

Title : Molecular Modeling of ABHD5 Structure and Ligand Recognition - Shahoei_2022_Front.Mol.Biosci_9_935375
Author(s) : Shahoei R , Pangeni S , Sanders MA , Zhang H , Mladenovic-Lucas L , Roush WR , Halvorsen G , Kelly CV , Granneman JG , Huang YM
Ref : Front Mol Biosci , 9 :935375 , 2022
Abstract : Alpha/beta hydrolase domain-containing 5 (ABHD5), also termed CGI-58, is the key upstream activator of adipose triglyceride lipase (ATGL), which plays an essential role in lipid metabolism and energy storage. Mutations in ABHD5 disrupt lipolysis and are known to cause the Chanarin-Dorfman syndrome. Despite its importance, the structure of ABHD5 remains unknown. In this work, we combine computational and experimental methods to build a 3D structure of ABHD5. Multiple comparative and machine learning-based homology modeling methods are used to obtain possible models of ABHD5. The results from Gaussian accelerated molecular dynamics and experimental data of the apo models and their mutants are used to select the most likely model. Moreover, ensemble docking is performed on representative conformations of ABHD5 to reveal the binding mechanism of ABHD5 and a series of synthetic ligands. Our study suggests that the ABHD5 models created by deep learning-based methods are the best candidate structures for the ABHD5 protein. The mutations of E41, R116, and G328 disturb the hydrogen bonding network with nearby residues and suppress membrane targeting or ATGL activation. The simulations also reveal that the hydrophobic interactions are responsible for binding sulfonyl piperazine ligands to ABHD5. Our work provides fundamental insight into the structure of ABHD5 and its ligand-binding mode, which can be further applied to develop ABHD5 as a therapeutic target for metabolic disease and cancer.
ESTHER : Shahoei_2022_Front.Mol.Biosci_9_935375
PubMedSearch : Shahoei_2022_Front.Mol.Biosci_9_935375
PubMedID: 35836935
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Title : Development of novel 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as balanced multifunctional agents against Alzheimer's disease - Shi_2022_Eur.J.Med.Chem_230_114098
Author(s) : Shi Y , Zhang H , Song Q , Yu G , Liu Z , Zhong F , Tan Z , Liu X , Deng Y
Ref : Eur Journal of Medicinal Chemistry , 230 :114098 , 2022
Abstract : Based on multitarget-directed ligands approach, through two rounds of screening, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized and evaluated as innovative multifunctional agents against Alzheimer's disease. In vitro biological assays indicated that most of the hybrids were endowed with great AChE inhibitory activity, excellent antioxidant activity and moderate Abeta(1-42) aggregation inhibition. Taken both efficacy and balance into account, 12a was identified as the optimal multifunctional ligand with significant inhibition of AChE (EeAChE, IC(50) = 0.20 microM; HuAChE, IC(50) = 37.02 nM) and anti-Abeta activity (IC(50) = 1.92 microM for self-induced Abeta(1-42) aggregation; IC(50) = 1.80 microM for disaggregation of Abeta(1-42) fibrils; IC(50) = 2.18 microM for Cu(2+)-induced Abeta(1-42) aggregation; IC(50) = 1.17 microM for disaggregation of Cu(2+)-induced Abeta(1-42) fibrils; 81.7% for HuAChE-induced Abeta(1-40) aggregation). Moreover, it was equipped with the potential to serve as antioxidant (3.03 Trolox equivalents), metals chelator and anti-neuroinflammation agent for synergetic treatment. Finally, in vivo study demonstrated that 12a, with suitable BBB permeability (log BB = -0.61), could efficaciously ameliorate cognitive dysfunction on scopolamine-treated mice by regulating cholinergic system and oxidative stress simultaneously. Altogether, these results highlight the potential of 12a as an innovative balanced multifunctional candidate for Alzheimer's disease treatment.
ESTHER : Shi_2022_Eur.J.Med.Chem_230_114098
PubMedSearch : Shi_2022_Eur.J.Med.Chem_230_114098
PubMedID: 35026532

Title : Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites - Meier-Stephenson_2022_Alzheimers.Dement.(N.Y)_8_e12283
Author(s) : Meier-Stephenson FS , Meier-Stephenson VC , Carter MD , Meek AR , Wang Y , Pan L , Chen Q , Jacobo S , Wu F , Lu E , Simms GA , Fisher L , McGrath AJ , Fermo V , Barden CJ , Clair HDS , Galloway TN , Yadav A , Campagna-Slater V , Hadden M , Reed M , Taylor M , Kelly B , Diez-Cecilia E , Kolaj I , Santos C , Liyanage I , Sweeting B , Stafford P , Boudreau R , Reid GA , Noyce RS , Stevens L , Staniszewski A , Zhang H , Murty M , Lemaire P , Chardonnet S , Richardson CD , Gabelica V , DePauw E , Brown R , Darvesh S , Arancio O , Weaver DF
Ref : Alzheimers Dement (N Y) , 8 :e12283 , 2022
Abstract : INTRODUCTION: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Abeta) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. METHODS: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Abeta-mediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. RESULTS: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Abeta is released as an early responder immunopeptide triggering an innate immunity cascade in which Abeta exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Abeta. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Abeta, leading to a chronic self-perpetuating autoimmune cycle. AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. DISCUSSION: Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.
ESTHER : Meier-Stephenson_2022_Alzheimers.Dement.(N.Y)_8_e12283
PubMedSearch : Meier-Stephenson_2022_Alzheimers.Dement.(N.Y)_8_e12283
PubMedID: 35415204

Title : Diversified Chaetoglobosins from the Marine-Derived Fungus Emericellopsis sp. SCSIO41202 - Shao_2022_Molecules_27_
Author(s) : Shao S , Wang X , She J , Zhang H , Pang X , Lin X , Zhou X , Liu Y , Li Y , Yang B
Ref : Molecules , 27 : , 2022
Abstract : Two undescribed cytochalasins, emeriglobosins A (1) and B (2), together with nine previously reported analogues (3-11) and two known tetramic acid derivatives (12, 13) were isolated from the solid culture of Emericellopsis sp. SCSIO41202. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis and the calculated ECD. Some of the isolated compounds were evaluated for their cytotoxicity and enzyme inhibitory activity against acetylcholinesterase (AChE) in vitro. Among them, 8 showed potent AChE inhibitory activity, with an IC(50) value of 1.31 microM, and 5 showed significant cytotoxicity against PC-3 cells, with an IC(50) value of 2.32 microM.
ESTHER : Shao_2022_Molecules_27_
PubMedSearch : Shao_2022_Molecules_27_
PubMedID: 35335187

Title : Rebuilding the lid region from conformational and dynamic features to engineering applications of lipase in foods: Current status and future prospects - Chen_2022_Compr.Rev.Food.Sci.Food.Saf__
Author(s) : Chen G , Khan IM , He W , Li Y , Jin P , Campanella OH , Zhang H , Huo Y , Chen Y , Yang H , Miao M
Ref : Compr Rev Food Sci Food Saf , : , 2022
Abstract : The applications of lipases in esterification, amidation, and transesterification have broadened their potential in the production of fine compounds with high cumulative values. Mostly, the catalytic triad of lipases is covered by either one or two mobile peptides called the "lid" that control the substrate channel to the catalytic center. The lid holds unique conformational allostery via interfacial activation to regulate the dynamics and catalytic functions of lipases, thereby highlighting its importance in redesigning these enzymes for industrial applications. The structural characteristic of lipase, the dynamics of lids, and the roles of lid in lipase catalysis were summarized, providing opportunities for rebuilding lid region by biotechniques (e.g., metagenomic technology and protein engineering) and enzyme immobilization. The review focused on the advantages and disadvantages of strategies rebuilding the lid region. The main shortcomings of biotechnologies on lid rebuilding were discussed such as negative effects on lipase (e.g., a decrease of activity). Additionally, the main shortcomings (e.g., enzyme desorption at high temperatre) in immobilization on hydrophobic supports via interfacial action were presented. Solutions to the mentioned problems were proposed by combinations of computational design with biotechnologies, and improvements of lipase immobilization (e.g., immobilization protocols and support design). Finally, the review provides future perspectives about designing hyperfunctional lipases as biocatalysts in the food industry based on lid conformation and dynamics.
ESTHER : Chen_2022_Compr.Rev.Food.Sci.Food.Saf__
PubMedSearch : Chen_2022_Compr.Rev.Food.Sci.Food.Saf__
PubMedID: 35470946

Title : Biodegradation of highly crystallized poly(ethylene terephthalate) through cell surface codisplay of bacterial PETase and hydrophobin - Chen_2022_Nat.Commun_13_7138
Author(s) : Chen Z , Duan R , Xiao Y , Wei Y , Zhang H , Sun X , Wang S , Cheng Y , Wang X , Tong S , Yao Y , Zhu C , Yang H , Wang Y , Wang Z
Ref : Nat Commun , 13 :7138 , 2022
Abstract : The process of recycling poly(ethylene terephthalate) (PET) remains a major challenge due to the enzymatic degradation of high-crystallinity PET (hcPET). Recently, a bacterial PET-degrading enzyme, PETase, was found to have the ability to degrade the hcPET, but with low enzymatic activity. Here we present an engineered whole-cell biocatalyst to simulate both the adsorption and degradation steps in the enzymatic degradation process of PETase to achieve the efficient degradation of hcPET. Our data shows that the adhesive unit hydrophobin and degradation unit PETase are functionally displayed on the surface of yeast cells. The turnover rate of the whole-cell biocatalyst toward hcPET (crystallinity of 45%) dramatically increases approximately 328.8-fold compared with that of purified PETase at 30 degreesC. In addition, molecular dynamics simulations explain how the enhanced adhesion can promote the enzymatic degradation of PET. This study demonstrates engineering the whole-cell catalyst is an efficient strategy for biodegradation of PET.
ESTHER : Chen_2022_Nat.Commun_13_7138
PubMedSearch : Chen_2022_Nat.Commun_13_7138
PubMedID: 36414665
Gene_locus related to this paper: idesa-peth

Title : Plastics degradation by hydrolytic enzymes: The plastics-active enzymes database-PAZy - Buchholz_2022_Proteins_90_1443
Author(s) : Buchholz PCF , Feuerriegel G , Zhang H , Perez-Garcia P , Nover LL , Chow J , Streit WR , Pleiss J
Ref : Proteins , 90 :1443 , 2022
Abstract : Petroleum-based plastics are durable and accumulate in all ecological niches. Knowledge on enzymatic degradation is sparse. Today, less than 50 verified plastics-active enzymes are known. First examples of enzymes acting on the polymers polyethylene terephthalate (PET) and polyurethane (PUR) have been reported together with a detailed biochemical and structural description. Furthermore, very few polyamide (PA) oligomer active enzymes are known. In this article, the current known enzymes acting on the synthetic polymers PET and PUR are briefly summarized, their published activity data were collected and integrated into a comprehensive open access database. The Plastics-Active Enzymes Database (PAZy) represents an inventory of known and experimentally verified enzymes that act on synthetic fossil fuel-based polymers. Almost 3000 homologs of PET-active enzymes were identified by profile hidden Markov models. Over 2000 homologs of PUR-active enzymes were identified by BLAST. Based on multiple sequence alignments, conservation analysis identified the most conserved amino acids, and sequence motifs for PET- and PUR-active enzymes were derived.
ESTHER : Buchholz_2022_Proteins_90_1443
PubMedSearch : Buchholz_2022_Proteins_90_1443
PubMedID: 35175626

Title : Recent advance on carbamate-based cholinesterase inhibitors as potential multifunctional agents against Alzheimer's disease - Zhang_2022_Eur.J.Med.Chem_240_114606
Author(s) : Zhang H , Wang Y , Li X , Wang S , Wang Z
Ref : Eur Journal of Medicinal Chemistry , 240 :114606 , 2022
Abstract : Alzheimer's disease (AD), as the fourth leading cause of death among the elderly worldwide, has brought enormous challenge to the society. Due to its extremely complex pathogeneses, the development of multi-target directed ligands (MTDLs) becomes the major strategy for combating AD. Carbamate moiety, as an essential building block in the development of MTDLs, exhibits structural similarity to neurotransmitter acetylcholine (ACh) and has piqued extensive attention in discovering multifunctional cholinesterase inhibitors. To date, numerous preclinical studies demonstrate that carbamate-based cholinesterase inhibitors can prominently increase the level of ACh and improve cognition impairments and behavioral deficits, providing a privileged strategy for the treatment of AD. Based on the recent research focus on the novel cholinesterase inhibitors with multiple biofunctions, this review aims at summarizing and discussing the most recent studies excavating the potential carbamate-based MTDLs with cholinesterase inhibition efficacy, to accelerate the pace of pleiotropic cholinesterase inhibitors for coping AD.
ESTHER : Zhang_2022_Eur.J.Med.Chem_240_114606
PubMedSearch : Zhang_2022_Eur.J.Med.Chem_240_114606
PubMedID: 35858523

Title : Steroid glycosides from the roots of Marsdenia tenacissima - Song_2022_Phytochemistry__113506
Author(s) : Song XQ , Tian LL , Ye T , Liu H , Zhang H
Ref : Phytochemistry , :113506 , 2022
Abstract : Eleven undescribed glycosylated C(21) steroids and nine known homologous glycosides with diverse acyl substituents, as well as their common steroid aglycone, have been obtained from the roots of Marsdenia tenacissima. Their structures were elucidated mainly by comprehensive spectroscopic analyses and comparison with previously reported analogues, with the absolute configuration assignment being supported by chemical degradation, X-ray crystallography and ECD exciton chirality method. Among them, two pairs of regioisomers were found to exist as inseparable equilibrium mixtures due to an interesting intramolecular transesterification, and nicotinoyl substitution was first reported for metabolites from the title plant. Screening of these compounds in a panel of bioassays revealed that two glycosides displayed mild inhibition against butyrylcholinesterase.
ESTHER : Song_2022_Phytochemistry__113506
PubMedSearch : Song_2022_Phytochemistry__113506
PubMedID: 36347308

Title : Discovery of pyrrole derivatives as acetylcholinesterase-sparing butyrylcholinesterase inhibitor - Sun_2022_Front.Pharmacol_13_1043397
Author(s) : Sun S , Shi T , Peng Y , Zhang H , Zhuo L , Peng X , Li Q , Wang M , Wang S , Wang Z
Ref : Front Pharmacol , 13 :1043397 , 2022
Abstract : Inspired by the crucial roles of (hetero)aryl rings in cholinesterase inhibitors and the pyrrole ring in new drug discovery, we synthesized 19 pyrrole derivatives and investigated their cholinesterase inhibitory activity. As a result, compounds 3o, 3p, and 3s with a 1,3-diaryl-pyrrole skeleton showed high selectivity toward BChE over AChE with a best IC(50) value of 1.71 +/- 0.087smicroM, which were comparable to donepezil. The pharmaceutical potential of these structures was further predicted and compounds 3o and 3p were proved to meet well with the Lipinsky's five rules. In combination of the inhibition kinetic studies with the results of molecular docking, we concluded that compound 3p inhibited BChE in a mixed competitive mode. This research has proved the potential of the 1,3-diaryl-pyrrole skeleton as a kind of selective BChE inhibitor.
ESTHER : Sun_2022_Front.Pharmacol_13_1043397
PubMedSearch : Sun_2022_Front.Pharmacol_13_1043397
PubMedID: 36561337

Title : Novel inhibitors of AChE and Abeta aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease - Liu_2022_Eur.J.Med.Chem_235_114305
Author(s) : Liu Y , Uras G , Onuwaje I , Li W , Yao H , Xu S , Li X , Phillips J , Allen S , Gong Q , Zhang H , Zhu Z , Liu J , Xu J
Ref : Eur Journal of Medicinal Chemistry , 235 :114305 , 2022
Abstract : A series of sulfone analogs of donepezil were designed and synthesized as novel acetylcholinesterase (AChE) inhibitors with the potent inhibiting Abeta aggregation and providing neuroprotective effects as potential modalities for Alzheimer's disease (AD). Most of the target compounds displayed effective inhibition of AChE, especially compound 24r which displayed powerful inhibitory activity (IC(50) = 2.4 nM). Kinetic and docking studies indicated that compound 24r was a mixed-type inhibitor. Furthermore, in glyceraldehyde (GA)-exposed SH-SY5Y differentiated neuronal cells, compound 24r could potently inhibit AChE, reduce tau phosphorylation at S396 residue, provide neuroprotection by rescuing neuronal morphology and increasing cell viability. It was also found to reduce amyloid aggregation in the presence of AChE. In addition, compound 24r showed evident protections from mitochondrial membrane dysfunction and oxidative stress in okadaic acid-induced pharmacological models. Moreover, compound 24r exhibited more effective treatment prospects in vivo than donepezil, including a moderate blood-brain barrier permeability, a more potent AChE inhibitory activity and behavioral improvement in scopolamine-induced cognition-impaired mice model at a much lower dose. Collectively, compound 24r is a promising lead compound for further investigation to discovery and development of new anti-AD agents.
ESTHER : Liu_2022_Eur.J.Med.Chem_235_114305
PubMedSearch : Liu_2022_Eur.J.Med.Chem_235_114305
PubMedID: 35339839

Title : The Comparative Analysis of Genomic Diversity and Genes Involved in Carbohydrate Metabolism of Eighty-Eight Bifidobacterium pseudocatenulatum Isolates from Different Niches of China - Lin_2022_Nutrients_14_
Author(s) : Lin G , Liu Q , Wang L , Li H , Zhao J , Zhang H , Wang G , Chen W
Ref : Nutrients , 14 : , 2022
Abstract : Eighty-eight Bifidobacterium pseudocatenulatum strains, which were isolated from human, chicken and cow fecal samples from different niches of China, were compared genomically in this study to evaluate their diversity. It was found that B. pseudocatenulatum displayed a closed pan-genome, including abundant glycoside hydrolase families of the carbohydrate active enzyme (CAZy). A total of 30 kinds of glycoside hydrolases (GHs), 14 kinds of glycosyl transferases (GTs), 13 kinds of carbohydrate-binding modules (CBMs), 6 kinds of carbohydrate-esterases (CEs), and 2 kinds of auxiliary activities (AAs) gene families were identified across the genomes of the 88 B. pseudocatenulatum strains. Specifically, this showed that significant differences were also present in the number of 10 carbohydrate-active enzyme gene families (GT51, GH13_32, GH26, GH42, GH121, GH3, AA3, CBM46, CE2, and CE6) among the strains derived from the hosts of different age groups, particularly between strains from infants and those from other human age groups. Twelve different individuals of B. pseudocatenulatum from four main clusters were selected for further study to reveal the genetic diversity of carbohydrate metabolism-related genes within the same phylogenetics. The animal experiment showed that 3 weeks of oral administration and 1 week after cessation of administration of these strains did not markedly alter the serum routine inflammatory indicators in mice. Furthermore, the administration of these strains did not significantly cause adverse changes in the gut microbiota, as indicated by the alpha- and beta-diversity indexes, relative to the control group (normal diet). Beyond that, FAHBZ9L5 significantly increased the abundance of B. pseudocatenulatum after 3 weeks and significantly increased the abundance of acetic acid and butyric acid in the host's intestinal tract 3 and 4 weeks after the first administration, respectively, compared with the control group. Corresponding to this, comparative genomic analyses of 12 B. pseudocatenulatum suggest that FAHBZ9L5-specific genes were rich in ABC transporters and carbohydrate esterase. Combining the results of comparative genomics analyses and animal experiment, it is suggested that the strains containing certain gene clusters contribute to another competitive growth advantage of B. pseudocatenulatum, which facilitates its intestinal carbohydrate metabolism in a host.
ESTHER : Lin_2022_Nutrients_14_
PubMedSearch : Lin_2022_Nutrients_14_
PubMedID: 35684146

Title : Isoprocarb causes neurotoxicity of zebrafish embryos through oxidative stress-induced apoptosis - Wang_2022_Ecotoxicol.Environ.Saf_242_113870
Author(s) : Wang S , Han X , Yu T , Liu Y , Zhang H , Mao H , Hu C , Xu X
Ref : Ecotoxicology & Environmental Safety , 242 :113870 , 2022
Abstract : Isoprocarb is a widely used carbamate insecticide in agriculture and aquaculture. Overuse of isoprocarb always leaves toxic residues in soil and water, however, the potential ecotoxicity of isoprocarb to organisms is still confusing. In this study, zebrafish embryo was used as a model to evaluate the toxicity of isoprocarb. Zebrafish embryos (96 hpf) were separately exposed at different concentrations of isoprocarb. The mortality rate, hatchability rate, average heart beat of the zebrafish embryo were separately calculated. Our results suggested that exposure to isoprocarb induced developmental toxicity in zebrafish embryos. HE staining showed that exposure to isoprocarb caused developmental defect in the hindbrain of zebrafish embryos. As expected, the behavioral analysis also showed that the motor ability of zebrafish embryos were significantly inhibited following exposure to isoprocarb. In terms of mechanism, The expressions of genes involved in neurodevelopment signaling pathways, such as foxo3a, gfap, syn2a, elavl3 and sox19b, were inhibited in zebrafish embryos after exposure to isoprocarb. The acetylcholinesterase (AChE) activity was also reduced in isoprocarb-treated zebrafish embryos. Moreover, oxidative stress was induced by increasing the reactive oxygen species (ROS) level and decreasing the activity of antioxidant enzyme (SOD) after exposure to isoprocarb. Expectedly, acridine orange (AO) staining and the detection of some apoptosis-related genes revealed that oxidative stress resulted in apoptosis. In short, the expressions of genes associated with the neurodevelopmental signaling pathway are inhibited, and oxidative stress is also induced in zebrafish embryos after exposure to isoprocarb, which may be the molecular basics of isoprocarb-induced neurotoxicity in zebrafish embryos.
ESTHER : Wang_2022_Ecotoxicol.Environ.Saf_242_113870
PubMedSearch : Wang_2022_Ecotoxicol.Environ.Saf_242_113870
PubMedID: 35816841

Title : Safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel AChE inhibitor: a singlecenter, phase I study in healthy young and elderly Chinese subjects - Qian_2022_ResearchSquare__
Author(s) : Qian H , Yu C , Zhu H , Ding Q , Cai Y , Jing J , Xu X , Guo R , Zhang H , Liu H , Chen X , Liu Y
Ref : ResearchSquare , : , 2022
Abstract : https://www.researchsquare.com/article/rs-1744060/latest.pdf Background Acetylcholinesterase (AChE) inhibitors attempt to reduce the breakdown of acetylcholine levels in the brain of patients with Alzheimers disease (AD) by inhibiting the responsible enzyme AChE in the synaptic cleft. This study evaluated the safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel AChE inhibitor under development for the treatment of AD in healthy young and elderly Chinese subjects. Methods The study on young subjects were divided into two arms: the multiple ascending-dose (MAD) arm (double-blind, randomized, placebo-controlled, multiple ascending-dose, 2 and 6 mg, N = 24), and the food effect arm (three-period, self-crossover, open-labeled, fasting/standard diet/high-fat diet administration, 4 mg, N = 12). A two-period, self-crossover, open-labeled, single ascending-dose study was designed for elderly subjects (2 and 4 mg, N = 11). Results For young subjects study: In the MAD arm, the accumulation ratios of DC20 in vivo were 2.29 and 2.15, respectively. In the food effect arm, compared with fasting administration, area under the concentrationtime curve from zero to t (AUC0-t) orally after a standard diet and high-fat diet slightly increased by about 19% and 29% and the Tmax were delayed by around 1 hour. For elderly subjects study, Tmax were 1.5 and 1.25 hour, t1/2 were 77.1 and 74.2 hour, respectively. After oral administration of DC20 in healthy young and elderly subjects, no serious adverse events occurred, the most common adverse events associated with the study drug were gastrointestinal reactions. Conclusion We predicted the safety risks of DC20 in the clinical treatment of AD, which were well tolerated by the healthy young and elderly subjects. The elimination of DC20 from the body was slower in elderly subjects than in young subjects.
ESTHER : Qian_2022_ResearchSquare__
PubMedSearch : Qian_2022_ResearchSquare__

Title : Structure-guided rational design of the Geobacillus thermoglucosidasius feruloyl esterase GthFAE to improve its thermostability - Yang_2022_Biochem.Biophys.Res.Commun_600_117
Author(s) : Yang W , Sun L , Dong P , Chen Y , Zhang H , Huang X , Wu L , Chen L , Jing D , Wu Y
Ref : Biochemical & Biophysical Research Communications , 600 :117 , 2022
Abstract : Feruloyl esterases are indispensable biocatalysts catalyzing the cleavage of ester bonds between polysaccharides and their hydroxycinnamoyl cross-links. GthFAE from Geobacillus thermoglucosidasius was identified as a thermophilic alkaline feruloyl esterase with potential applications in paper manufacturing. To improve the enzymatic properties rationally and efficiently, the structure of GthFAE was solved at 1.9 A, revealing a core domain of classical alpha/beta hydrolase fold and an inserted alpha/beta cap domain. In silico analysis based on it helped us to investigate whether the residues at the active center have positive effects on the stability, and how. Several site-directed mutations were conducted, of which substitutions at residues T41 and T150 apparently improved the thermostability. The combination mutant T41N/T150R exhibited an optimal temperature of 65 degreesC, a 6.4 degreesC higher T(m) compared to wild type by 80 degreesC, and a 35-fold longer in half-life (201 min) at 70 degreesC. Molecular dynamics simulations further illustrated that the structure of T41N/T150R was more stable than the wild type and T150R stabilized the cap domain by introducing salt bridges to the region with E154 and D164. This study not only highlighted residues within the active center on their thermostability improving effects, but also contributed to the prospective industrial application of GthFAE.
ESTHER : Yang_2022_Biochem.Biophys.Res.Commun_600_117
PubMedSearch : Yang_2022_Biochem.Biophys.Res.Commun_600_117
PubMedID: 35219099
Gene_locus related to this paper: partm-GthFAE

Title : Huperzine-A Improved Animal Behavior in Cuprizone-Induced Mouse Model by Alleviating Demyelination and Neuroinflammation - Zhang_2022_Int.J.Mol.Sci_23_16182
Author(s) : Zhang H , Wang D , Sun J , Wang Y , Wu S , Wang J
Ref : Int J Mol Sci , 23 :16182 , 2022
Abstract : Huperzine A (HupA) is a natural acetylcholinesterase inhibitor (AChEI) with the advantages of high efficiency, selectivity as well as reversibility and can exhibit significant therapeutic effects against certain neurodegenerative diseases. It is also beneficial in reducing the neurological impairment and neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a classic model for multiple sclerosis (MS). However, whether HupA can directly regulate oligodendrocyte differentiation and maturation and promote remyelination has not been investigated previously. In this study, we have analyzed the potential protective effects of HupA on the demylination model of MS induced by cuprizone (CPZ). It was found that HupA significantly attenuated anxiety-like behavior, as well as augmented motor and cognitive functions in CPZ mice. It also decreased demyelination and axonal injury in CPZ mice. Moreover, in CPZ mice, HupA increased mRNA levels of the various anti-inflammatory cytokines (Arg1, CD206) while reducing the levels of different pro-inflammatory cytokines (iNOS, IL-1beta, IL-18, CD16, and TNF-alpha). Mecamylamine, a nicotinic acetylcholinergic receptor antagonist, could effectively reverse the effects of HupA. Therefore, we concluded that HupA primarily exerts its therapeutic effects on multiple sclerosis through alleviating demyelination and neuroinflammation.
ESTHER : Zhang_2022_Int.J.Mol.Sci_23_16182
PubMedSearch : Zhang_2022_Int.J.Mol.Sci_23_16182
PubMedID: 36555825

Title : Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders - Zhang_2022_Front.Endocrinol.(Lausanne)_13_1067529
Author(s) : Zhang Z , Hou M , Ou H , Wang D , Li Z , Zhang H , Lu J
Ref : Front Endocrinol (Lausanne) , 13 :1067529 , 2022
Abstract : The development of autism spectrum disorders (ASDs) involves both environmental factors such as maternal diabetes and genetic factors such as neuroligins (NLGNs). NLGN2 and NLGN3 are two members of NLGNs with distinct distributions and functions in synapse development and plasticity. The relationship between maternal diabetes and NLGNs, and the distinct working mechanisms of different NLGNs currently remain unclear. Here, we first analyzed the expression levels of NLGN2 and NLGN3 in a streptozotocin-induced ASD mouse model and different brain regions to reveal their differences and similarities. Then, cryogenic electron microscopy (cryo-EM) structures of human NLGN2 and NLGN3 were determined. The overall structures are similar to their homologs in previous reports. However, structural comparisons revealed the relative rotations of two protomers in the homodimers of NLGN2 and NLGN3. Taken together with the previously reported NLGN2-MDGA1 complex, we speculate that the distinct assembly adopted by NLGN2 and NLGN3 may affect their interactions with MDGAs. Our results provide structural insights into the potential distinct mechanisms of NLGN2 and NLGN3 implicated in the development of ASD.
ESTHER : Zhang_2022_Front.Endocrinol.(Lausanne)_13_1067529
PubMedSearch : Zhang_2022_Front.Endocrinol.(Lausanne)_13_1067529
PubMedID: 36479216
Gene_locus related to this paper: human-NLGN2 , human-NLGN3

Title : The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [(14)C] cetagliptin in healthy volunteers - Lu_2022_Xenobiotica_52_38
Author(s) : Lu J , Bian Y , Zhang H , Tang D , Tian X , Zhou X , Xu Z , Xiong Y , Gu Z , Yu Z , Wang T , Ding J , Yu Q
Ref : Xenobiotica , 52 :38 , 2022
Abstract : The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50microCi [(14)C] cetagliptin.The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [(14)C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulphate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and faeces at low levels, except that metabolite M640B was not detected in faeces. All metabolites were observed with <10% of parent compound systemic exposure after oral administration.
ESTHER : Lu_2022_Xenobiotica_52_38
PubMedSearch : Lu_2022_Xenobiotica_52_38
PubMedID: 34743655

Title : Effects of the hemolytic index on the test results of a dry chemistry analyzer and a verification of the hemolytic interference threshold - Yang_2022_Ann.Palliat.Med_11_1381
Author(s) : Yang Q , Huang S , Han R , Lin B , Liu Q , Duan X , Ma Z , Zhang H , Shou H , Zhang S
Ref : Ann Palliat Med , 11 :1381 , 2022
Abstract : BACKGROUND: This study verified and assessed 26 biochemical indicators tested by a dry chemistry analyzer using the hemolytic index test function to determine the degree of interference and the trends among the hemolysis samples on the test results. This study also sought to ensure that reasonable test reports could be issued taking into account practical clinical needs. METHODS: The samples were manually divided into the control group and the test group. The hemolytic index and biochemical indicators of the samples were tested using the Ortho Vitros 5600 to compare the deviation of the test results between the 2 groups. The judgment standard was set as 1/3 of the total error allowable as required by the quality assessment criterion of the National Center for Clinical Laboratories. The interference degree of hemolysis on the dry chemistry-based biochemical indicators was assessed, and the hemolytic thresholds of 26 biochemical indicators provided by the manufacturer were verified in terms of their validity and rationality. RESULTS: The hemolytic thresholds of 26 dry chemistry-based biochemical indicators were verified to analyze the degree of interference. The results revealed that hemolysis interfered with 17 indicators. Hemolysis positively interfered with the test results of phosphorus, creatine kinase, gamma glutamyl transpeptidase (gamma-GGT), magnesium, iron, total protein, potassium, total bilirubin, lactate dehydrogenase, albumin, and aspartate aminotransferase, but negatively interfered with cholinesterase, direct high-density lipoprotein cholesterol, glucose, elevated carbon dioxide alkaline phosphatase, and alanine aminotransferase. A negative deviation of gamma-GGT by hemoglobin was described in the manufacturer's statement, but our test data showed a positive deviation by hemolysis. The hemolytic threshold verification results of the other biochemical indicators were consistent with the manufacturer's statement. CONCLUSIONS: The hemolytic index test function was used to determine which samples were interfered with by hemolysis to make an analytical judgment according to the hemolytic interference thresholds of the different test items, verify the validity of the hemolytic thresholds of the test items, perform reasonable tests on the hemolytic samples, and issue valid reports to reduce the rejection rate of the hemolytic samples, shorten the turnaround time (TAT) of laboratories.
ESTHER : Yang_2022_Ann.Palliat.Med_11_1381
PubMedSearch : Yang_2022_Ann.Palliat.Med_11_1381
PubMedID: 35523746

Title : Maintaining the thyroid gland in mutant thyroglobulin-induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood - Zhang_2022_J.Biol.Chem_298_102066
Author(s) : Zhang X , Malik B , Young C , Zhang H , Larkin D , Liao XH , Refetoff S , Liu M , Arvan P
Ref : Journal of Biological Chemistry , 298 :102066 , 2022
Abstract : Congenital hypothyroidism with biallelic thyroglobulin (Tg protein, encoded by the TG gene) mutation is an endoplasmic reticulum (ER) storage disease. Many patients (and animal models) grow an enlarged thyroid (goiter), yet some do not. In adulthood, hypothyroid TG(cog/cog) mice (bearing a Tg-L2263P mutation) exhibit a large goiter, whereas adult WIC rats bearing the TG(rdw/rdw) mutation (Tg-G2298R) exhibit a hypoplastic thyroid. Homozygous TG mutation has been linked to thyroid cell death, and cytotoxicity of the Tg-G2298R protein was previously thought to explain the lack of goiter in WIC-TG(rdw/rdw) rats. However, recent studies revealed that TG(cog/cog) mice also exhibit widespread ER stress-mediated thyrocyte death, yet under continuous feedback stimulation, thyroid cells proliferate in excess of their demise. Here, to examine the relative proteotoxicity of the Tg-G2298R protein, we have used CRISPR-CRISPR-associated protein 9 technology to generate homozygous TG(rdw/rdw) knock-in mice in a strain background identical to that of TG(cog/cog) mice. TG(rdw/rdw) mice exhibit similar phenotypes of defective Tg protein folding, thyroid histological abnormalities, hypothyroidism, and growth retardation. TG(rdw/rdw) mice do not show evidence of greater ER stress response or stress-mediated cell death than TG(cog/cog) mice, and both mouse models exhibit sustained thyrocyte proliferation, with comparable goiter growth. In contrast, in WIC-TG(rdw/rdw) rats, as a function of aging, the thyrocyte proliferation rate declines precipitously. We conclude that the mutant Tg-G2298R protein is not intrinsically more proteotoxic than Tg-L2263P; rather, aging-dependent difference in maintenance of cell proliferation is the limiting factor, which accounts for the absence of goiter in adult WIC-TG(rdw/rdw) rats.
ESTHER : Zhang_2022_J.Biol.Chem_298_102066
PubMedSearch : Zhang_2022_J.Biol.Chem_298_102066
PubMedID: 35618019

Title : Advances in enzyme biocatalysis for the preparation of functional lipids - Zhang_2022_Biotechnol.Adv__108036
Author(s) : Zhang H , Secundo F , Sun J , Mao X
Ref : Biotechnol Adv , :108036 , 2022
Abstract : Functional lipids, mainly omega-3 polyunsaturated fatty acids (n-3 PUFAs) such as eicosapentaenoic (EPA; 20:5n-3) and docosahexaenoic (DHA; 22:6n-3), are known to have a variety of health benefits. Lipases and phospholipases are widely used to prepare different forms of structured lipids, since biocatalytic methods can be carried out under mild conditions, preserving the quality of the products. On the other hand, many processes still are conducted at high temperatures and with organic solvents, which are conditions unfavorable for the production of nutritional products. This article gives an updated overview of enzyme biocatalysis methods for the preparation of different derivatives containing n-3 PUFAs, including specific reactions, enzyme immobilization research for high-efficiency catalysis, and enzyme engineering technologies (higher selectivity, stability, and activity). Furthermore, advanced control strategies of biocatalytic processes and reactors are presented. The future prospect and opportunities for marine functional lipids are also discussed. Therefore, the obtainment of enzymes endowed with superior properties and the development of optimized processes, still have to be pursued to achieve greener bio-catalyzed processes.
ESTHER : Zhang_2022_Biotechnol.Adv__108036
PubMedSearch : Zhang_2022_Biotechnol.Adv__108036
PubMedID: 36130694

Title : Fenpropathrin exposure induces neurotoxicity in zebrafish embryos - Yu_2022_Fish.Physiol.Biochem__
Author(s) : Yu T , Xu X , Mao H , Han X , Liu Y , Zhang H , Lai J , Gu J , Xia M , Hu C , Li D
Ref : Fish Physiol Biochem , : , 2022
Abstract : Fenpropathrin has been a commonly used insecticide to control agricultural and household insects over a few decades. Up to now, fenpropathrin residue in soil and water has been often determined due to its widespread use, which poses serious threat to environment and aquatic organisms. The potential of fenpropathrin to affect aquatic lives is still poorly understood. In this study, we used zebrafish (Danio rerio) embryo as an experimental model system to evaluate the toxicity of fenpropathrin to the development of zebrafish nervous system. Zebrafish embryos were separately exposed to fenpropathrin at the dose of 0.016 mg/L, 0.032 mg/L, 0.064 mg/L, starting at 6 h post-fertilizationhpf (hpf) up to 96 hpf. The results showed that fenpropathrin exposure gives rise to physiological, behavioral, and neurodevelopmental impairments in zebrafish embryos, including enhanced acetylcholinesterase (AChE) activity, abnormal swimming behavior, karyopyknosis in brain cells, increased intercellular space, and uneven migration of neuron in brain area. In addition, the expressions of genes concerning neurodevelopment and neurotransmitter system were inhibited following fenpropathrin exposure. We also found that fenpropathrin exposure distinctly induced oxidative stress by increasing reactive oxygen species (ROS) generation and inhibiting the production of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Expectedly, some apoptosis-associated genes were induced and the apoptosis appeared in the brain and heart cells of zebrafish embryos. Moreover, fenpropathrin exposure also inhibited the expressions of genes in Nrf2 signaling pathway, such as heme oxygenase-1 (HO-1) and SOD. In summary, the results of this study indicate that oxidative stress-triggered apoptosis may be an underlying fundamental of fenpropathrin-induced neurotoxicity in zebrafish embryos.
ESTHER : Yu_2022_Fish.Physiol.Biochem__
PubMedSearch : Yu_2022_Fish.Physiol.Biochem__
PubMedID: 36266516

Title : From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders - Wu_2022_Front.Pharmacol_13_1036030
Author(s) : Wu J , Zhang H , Wang Y , Yin G , Li Q , Zhuo L , Chen H , Wang Z
Ref : Front Pharmacol , 13 :1036030 , 2022
Abstract : A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H(2)O(2)-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.
ESTHER : Wu_2022_Front.Pharmacol_13_1036030
PubMedSearch : Wu_2022_Front.Pharmacol_13_1036030
PubMedID: 36518670

Title : Structural and functional insights into ABHD5, a ligand-regulated lipase co-activator - Tseng_2022_Sci.Rep_12_2565
Author(s) : Tseng YY , Sanders MA , Zhang H , Zhou L , Chou CY , Granneman JG
Ref : Sci Rep , 12 :2565 , 2022
Abstract : Alpha/beta hydrolase domain-containing protein 5 (ABHD5) is a highly conserved protein that regulates various lipid metabolic pathways via interactions with members of the perilipin (PLIN) and Patatin-like phospholipase domain-containing protein (PNPLA) protein families. Loss of function mutations in ABHD5 result in Chanarin-Dorfman Syndrome (CDS), characterized by ectopic lipid accumulation in numerous cell types and severe ichthyosis. Recent data demonstrates that ABHD5 is the target of synthetic and endogenous ligands that might be therapeutic beneficial for treating metabolic diseases and cancers. However, the structural basis of ABHD5 functional activities, such as protein-protein interactions and ligand binding is presently unknown. To address this gap, we constructed theoretical structural models of ABHD5 by comparative modeling and topological shape analysis to assess the spatial patterns of ABHD5 conformations computed in protein dynamics. We identified functionally important residues on ABHD5 surface for lipolysis activation by PNPLA2, lipid droplet targeting and PLIN-binding. We validated the computational model by examining the effects of mutating key residues in ABHD5 on an array of functional assays. Our integrated computational and experimental findings provide new insights into the structural basis of the diverse functions of ABHD5 as well as pathological mutations that result in CDS.
ESTHER : Tseng_2022_Sci.Rep_12_2565
PubMedSearch : Tseng_2022_Sci.Rep_12_2565
PubMedID: 35173175
Gene_locus related to this paper: human-ABHD5

Title : Discovery of benzamide derivatives containing urea moiety as soluble epoxide hydrolase inhibitors - Tian_2022_Bioorg.Chem_127_105898
Author(s) : Tian Y , Li S , Dong K , Su X , Fu S , Lv X , Duan M , Yang T , Han Y , Hu G , Liu J , Sun Y , Yue H , Zhang H , Du Z , Miao Z , Tong M , Liu Y , Qin M , Gong P , Hou Y , Gao Z , Zhao Y
Ref : Bioorg Chem , 127 :105898 , 2022
Abstract : The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC(50) value of 0.04 +/- 0.01 nM and a K(i) value of 0.2 +/- 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors.
ESTHER : Tian_2022_Bioorg.Chem_127_105898
PubMedSearch : Tian_2022_Bioorg.Chem_127_105898
PubMedID: 35792317

Title : Genome-wide expression analysis of carboxylesterase (CXE) gene family implies GBCXE49 functional responding to alkaline stress in cotton - Rui_2022_BMC.Plant.Biol_22_194
Author(s) : Rui C , Peng F , Fan Y , Zhang Y , Zhang Z , Xu N , Zhang H , Wang J , Li S , Yang T , Malik WA , Lu X , Chen X , Wang D , Chen C , Gao W , Ye W
Ref : BMC Plant Biol , 22 :194 , 2022
Abstract : BACKGROUND: Carboxylesterase (CXE) is a type of hydrolase with alpha/beta sheet hydrolase activity widely found in animals, plants and microorganisms, which plays an important role in plant growth, development and resistance to stress. RESULTS: A total of 72, 74, 39, 38 CXE genes were identified in Gossypium barbadense, Gossypium hirsutum, Gossypium raimondii and Gossypium arboreum, respectively. The gene structure and expression pattern were analyzed. The GBCXE genes were divided into 6 subgroups, and the chromosome distribution of members of the family were mapped. Analysis of promoter cis-acting elements showed that most GBCXE genes contain cis-elements related to plant hormones (GA, IAA) or abiotic stress. These 6 genes we screened out were expressed in the root, stem and leaf tissues. Combined with the heat map, GBCXE49 gene was selected for subcellular locate and confirmed that the protein was expressed in the cytoplasm. CONCLUSIONS: The collinearity analysis of the CXE genes of the four cotton species in this family indicated that tandem replication played an indispensable role in the evolution of the CXE gene family. The expression patterns of GBCXE gene under different stress treatments indicated that GBCXE gene may significantly participate in the response to salt and alkaline stress through different mechanisms. Through the virus-induced gene silencing technology (VIGS), it was speculated that GBCXE49 gene was involved in the response to alkaline stress in G. barbadense.
ESTHER : Rui_2022_BMC.Plant.Biol_22_194
PubMedSearch : Rui_2022_BMC.Plant.Biol_22_194
PubMedID: 35413814

Title : Carbamate-based N-Substituted tryptamine derivatives as novel pleiotropic molecules for Alzheimer's disease - Zhang_2022_Bioorg.Chem_125_105844
Author(s) : Zhang H , Wang Y , Liu D , Li J , Feng Y , Lu Y , Yin G , Li Z , Shi T , Wang Z
Ref : Bioorg Chem , 125 :105844 , 2022
Abstract : A novel series of carbamate-based N-substituted tryptamine derivatives were designed and synthesized based on functional group combination strategy, and possessed both cholinesterase inhibition and neuroprotective effects. After systematically evaluating the cholinesterase inhibitory activity of 24 synthesized compounds, compound 6H6, bearing n-heptyl residue as carbamate moiety, was highlighted due to its great BChE-selective inhibition (eeAChE IC(50) > 100 microM; eqBChE IC(50) = 7 nM), neuronal protection, antioxidation and anti-neuroinflammation efficacy. Cytotoxicity and acute toxicity assays confirmed the safety-efficacy profiles of compound 6H6. Besides, pharmacokinetic properties and blood-brain barrier (BBB) permeability of compound 6H6 were favorable and suitable for further study in vivo. The behavioral tests revealed that compound 6H6 could remarkably improve the scop-induced ethological changes and memory impairment, suggesting compound 6H6, as an attractive pleiotropic molecule, had great promise in treating Alzheimer's disease.
ESTHER : Zhang_2022_Bioorg.Chem_125_105844
PubMedSearch : Zhang_2022_Bioorg.Chem_125_105844
PubMedID: 35594720

Title : Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease - Wang_2022_Bioorg.Chem_127_105993
Author(s) : Wang Y , Zhang H , Liu D , Li X , Long L , Peng Y , Qi F , Jiang W , Wang Z
Ref : Bioorg Chem , 127 :105993 , 2022
Abstract : In this work, based on the potential anti-AD molecule previously studied by our group, we continue to introduce different substituents at different positions to improve both drug-like properties and on target activities. 33 N-salicyloyl tryptamine-carbamate hybrids were designed, synthesized and evaluated as cholinesterase inhibitors. H327 was the most potent BChE inhibitor (eqBChE IC(50) = 0.057 +/- 0.005 microM), and showed threefold improved inhibitory potency than the positive drug rivastigmine (eqBChE IC(50) = 0.19 +/- 0.001 microM). In addition, H327 as a pseudo-irreversible BChE inhibitor was endowed with neuroprotective, antioxidative and anti-neuroinflammatory properties. Cytotoxicity and acute toxicity tests confirmed the safety of compound H327. The pharmacokinetics study showed that compound H327 had a longer T(1/2) time and higher bioavailability than the lead compound 1 g. Compound H327 was able to cross the blood-brain barrier (BBB) in vivo. Moreover, the behavioral tests showed that compound H327 could significantly improve scopolamine-induced cognitive impairment in vivo. Overall, these results demonstrated that compound H327 is a promising multi-target agent for the treatment of AD.
ESTHER : Wang_2022_Bioorg.Chem_127_105993
PubMedSearch : Wang_2022_Bioorg.Chem_127_105993
PubMedID: 35834980

Title : Fine mapping of powdery mildew resistance gene MlWE74 derived from wild emmer wheat (Triticum turgidum ssp. dicoccoides) in an NBS-LRR gene cluster - Zhu_2022_Theor.Appl.Genet__
Author(s) : Zhu K , Li M , Wu H , Zhang D , Dong L , Wu Q , Chen Y , Xie J , Lu P , Guo G , Zhang H , Zhang P , Li B , Li W , Wang Q , Zhu J , Hu W , Guo L , Wang R , Yuan C , Li H , Liu Z , Hua W
Ref : Theor Appl Genet , : , 2022
Abstract : Powdery mildew resistance gene MlWE74, originated from wild emmer wheat accession G-748-M, was mapped in an NBS-LRR gene cluster of chromosome 2BS. Wheat powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally devastating disease. Wild emmer wheat (Triticum turgidum var. dicoccoides) is a valuable genetic resource for improving disease resistance in common wheat. A powdery mildew resistance gene was transferred to hexaploid wheat line WE74 from wild emmer accession G-748-M. Genetic analysis revealed that the powdery mildew resistance in WE74 is controlled by a single dominant gene, herein temporarily designated MlWE74. Bulked segregant analysis (BSA) and molecular mapping delimited MlWE74 to the terminal region of chromosome 2BS flanking by markers WGGBD412 and WGGBH346 within a genetic interval of 0.25 cM and corresponding to 799.9 kb genomic region in the Zavitan reference sequence. Sequence annotation revealed two phosphoglycerate mutase-like genes, an alpha/beta-hydrolases gene, and five NBS-LRR disease resistance genes that could serve as candidates for map-based cloning of MlWE74. The geographical location analysis indicated that MlWE74 is mainly distributed in Rosh Pinna and Amirim regions, in the northern part of Israel, where environmental conditions are favorable to the occurrence of powdery mildew. Moreover, the co-segregated marker WGGBD425 is helpful in marker-assisted transfer of MlWE74 into elite cultivars.
ESTHER : Zhu_2022_Theor.Appl.Genet__
PubMedSearch : Zhu_2022_Theor.Appl.Genet__
PubMedID: 35006335

Title : Chlorophyll Inhibits the Digestion of Soybean Oil in Simulated Human Gastrointestinal System - Wang_2022_Nutrients_14_
Author(s) : Wang X , Li Y , Shen S , Yang Z , Zhang H , Zhang Y
Ref : Nutrients , 14 : , 2022
Abstract : Nowadays, much available processed and highly palatable food such as cream products and fried and convenient food, which usually showed a high energy density, had caused an increase in the intake of dietary lipids, further leading to significant growth in the prevalence of obesity. Chlorophyll, widespread in fruits and vegetables, was proven to have beneficial effects on alleviating obesity. This study investigated the effects of chlorophyll on the digestive characteristics of lipids under in vitro simulated adult and infant gastrointestinal systems. Chlorophyll decreased the release rate of free fatty acid (FFA) during in vitro adult and infant intestinal digestion by 69.2% and 60.0%, respectively. Meanwhile, after gastrointestinal digestion, chlorophyll changed the FFA composition of soybean oil emulsion and increased the particle size of oil droplets. Interestingly, with the addition of chlorophyll, the activity of pancreatic lipase was inhibited during digestion, which may be related to pheophytin (a derivative of chlorophyll after gastric digestion). Therefore, the results obtained from isothermal titration calorimetry and molecular docking further elucidated that pheophytin could bind to pancreatic lipase with a strong affinity of (4.38 +/- 0.76) x 10(7) M(-1) (K(a)), while the binding site was amino acid residue Trp253. The investigation not only explained why chlorophyll inhibited digestive enzyme activity to reduce lipids digestion but also provided exciting opportunities for developing novel chlorophyll-based healthy products for dietary application in preventing obesity.
ESTHER : Wang_2022_Nutrients_14_
PubMedSearch : Wang_2022_Nutrients_14_
PubMedID: 35565719

Title : Design, synthesis, and biological evaluation of carbamate derivatives of N-salicyloyl tryptamine as multifunctional agents for the treatment of Alzheimer's disease - Liu_2022_Eur.J.Med.Chem_229_114044
Author(s) : Liu D , Zhang H , Wang Y , Liu W , Yin G , Wang D , Li J , Shi T , Wang Z
Ref : Eur Journal of Medicinal Chemistry , 229 :114044 , 2022
Abstract : In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-alpha, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Abeta(1-42). Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation, pharmacokinetics, ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.
ESTHER : Liu_2022_Eur.J.Med.Chem_229_114044
PubMedSearch : Liu_2022_Eur.J.Med.Chem_229_114044
PubMedID: 34923430

Title : A multifunctional anti-AD approach: Design, synthesis, X-ray crystal structure, biological evaluation and molecular docking of chrysin derivatives - Yang_2022_Eur.J.Med.Chem_233_114216
Author(s) : Yang A , Liu C , Zhang H , Wu J , Shen R , Kou X
Ref : Eur Journal of Medicinal Chemistry , 233 :114216 , 2022
Abstract : With the aging of the population intensifying, finding a cure or reasonable treatment for Alzheimer' disease (AD) has become an urgent priority. To target the multi-facets of AD, a class of chrysin derivatives (1-4) were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, which were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis. 1-4 showed inhibitory activities on reactive oxygen species, Abeta(1-42) aggregation (self-, Cu(2+)-induced, AChE-induced). They were also potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with selectivity toward BuChE. Compound 1 as the most promising candidate exhibited the highest selective BuChE inhibition (SI = 15). Furthermore, the kinetic study suggested compound 1 to be a mixed type inhibitor. The results of docking study were consistent with the in vitro results. In addition, compound 1-4 showed favorable blood-brain barrier (BBB) penetration and drug-like property in silico prediction. The corresponding copper complexes of 1-4 have also been synthesized. 1-4 selectively chelated Cu(2+), Fe(2+), Zn(2+) and Al(3+) ions, while had no chelating ability to other biometals. The copper complexes also showed good AChE, BuChE and reactive oxygen species inhibitory activities. Notably, the single crystals of 1-Cu(II) complex [Cu(C(19)H(18)NO(4))(2)] were prepared for the first time and characterized by X-ray single crystal diffraction. X-ray crystallography analysis of 1-Cu(II) complex provided a reliable structure-activity insight at the molecular level about the antioxidative and Abeta(1-42) disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics.
ESTHER : Yang_2022_Eur.J.Med.Chem_233_114216
PubMedSearch : Yang_2022_Eur.J.Med.Chem_233_114216
PubMedID: 35227980

Title : Synthesis and biological evaluation of new series of benzamide derivatives containing urea moiety as sEH inhibitors - Tian_2022_Bioorg.Med.Chem.Lett_70_128805
Author(s) : Tian Y , Li S , Yang P , Su X , Liu J , Lv X , Dong K , Yang T , Duan M , Hu G , Yue H , Sun Y , Zhang H , Du Z , Miao Z , Tong M , Hou Y , Gao Z , Zhao Y
Ref : Bioorganic & Medicinal Chemistry Lett , 70 :128805 , 2022
Abstract : The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC(50) value of 0.03 +/- 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.
ESTHER : Tian_2022_Bioorg.Med.Chem.Lett_70_128805
PubMedSearch : Tian_2022_Bioorg.Med.Chem.Lett_70_128805
PubMedID: 35598794

Title : Three enigmatic BioH isoenzymes are programmed in the early stage of mycobacterial biotin synthesis, an attractive anti-TB drug target - Xu_2022_PLoS.Pathog_18_e1010615
Author(s) : Xu Y , Yang J , Li W , Song S , Shi Y , Wu L , Sun J , Hou M , Wang J , Jia X , Zhang H , Huang M , Lu T , Gan J , Feng Y
Ref : PLoS Pathog , 18 :e1010615 , 2022
Abstract : Tuberculosis (TB) is one of the leading infectious diseases of global concern, and one quarter of the world's population are TB carriers. Biotin metabolism appears to be an attractive anti-TB drug target. However, the first-stage of mycobacterial biotin synthesis is fragmentarily understood. Here we report that three evolutionarily-distinct BioH isoenzymes (BioH1 to BioH3) are programmed in biotin synthesis of Mycobacterium smegmatis. Expression of an individual bioH isoform is sufficient to allow the growth of an Escherichia coli deltabioH mutant on the non-permissive condition lacking biotin. The enzymatic activity in vitro combined with biotin bioassay in vivo reveals that BioH2 and BioH3 are capable of removing methyl moiety from pimeloyl-ACP methyl ester to give pimeloyl-ACP, a cognate precursor for biotin synthesis. In particular, we determine the crystal structure of dimeric BioH3 at 2.27A, featuring a unique lid domain. Apart from its catalytic triad, we also dissect the substrate recognition of BioH3 by pimeloyl-ACP methyl ester. The removal of triple bioH isoforms (deltabioH1/2/3) renders M. smegmatis biotin auxotrophic. Along with the newly-identified Tam/BioC, the discovery of three unusual BioH isoforms defines an atypical 'BioC-BioH(3)' paradigm for the first-stage of mycobacterial biotin synthesis. This study solves a long-standing puzzle in mycobacterial nutritional immunity, providing an alternative anti-TB drug target.
ESTHER : Xu_2022_PLoS.Pathog_18_e1010615
PubMedSearch : Xu_2022_PLoS.Pathog_18_e1010615
PubMedID: 35816546
Gene_locus related to this paper: mycs2-a0r6y0

Title : Employing Engineered Enolase Promoter for Efficient Expression of Thermomyces lanuginosus Lipase in Yarrowia lipolytica via a Self-Excisable Vector - Jiao_2022_Int.J.Mol.Sci_24_
Author(s) : Jiao L , Li W , Li Y , Zhou Q , Zhu M , Zhao G , Zhang H , Yan Y
Ref : Int J Mol Sci , 24 : , 2022
Abstract : Yarrowia lipolytica is progressively being employed as a workhouse for recombinant protein expression. Here, we expanded the molecular toolbox by engineering the enolase promoter (pENO) and developed a new self-excisable vector, and based on this, a combined strategy was employed to enhance the expression of Thermomyces lanuginosus lipase (TLL) in Y. lipolytica. The strength of 11 truncated enolase promoters of different length was first identified using eGFP as a reporter. Seven of the truncated promoters were selected to examine their ability for driving TLL expression. Then, a series of enolase promoters with higher activities were developed by upstream fusing of different copies of UAS1B, and the recombinant strain Po1f/hp16e(100)-tll harboring the optimal promoter hp16e(100) obtained a TLL activity of 447 U/mL. Additionally, a new self-excisable vector was developed based on a Cre/loxP recombination system, which achieved efficient markerless integration in Y. lipolytica. Subsequently, strains harboring one to four copies of the tll gene were constructed using this tool, with the three-copy strain Po1f/3tll showing the highest activity of 579 U/mL. The activity of Po1f/3tll was then increased to 720 U/mL by optimizing the shaking flask fermentation parameters. Moreover, the folding-related proteins Hac1, Pdi, and Kar2 were employed to further enhance TLL expression, and the TLL activity of the optimal recombinant strain Po1f/3tll-hac1-pdi-kar2 reached 1197 U/mL. By using this combined strategy, TLL activity was enhanced by approximately 39.9-fold compared to the initial strain. Thus, the new vector and the combined strategy could be a useful tool to engineer Y. lipolytica for high-level expression of heterologous protein.
ESTHER : Jiao_2022_Int.J.Mol.Sci_24_
PubMedSearch : Jiao_2022_Int.J.Mol.Sci_24_
PubMedID: 36614159

Title : Insight into the Inhibitory Mechanism of Aryl Formyl Piperidine Derivatives on Monoacylglycerol Lipase through Molecular Dynamics Simulations - Liu_2022_Molecules_27_7512
Author(s) : Liu C , Guan S , E J , Yang Z , Zhang X , Ju J , Wang S , Zhang H
Ref : Molecules , 27 :7512 , 2022
Abstract : Monoacylglycerol lipase (MAGL) can regulate the endocannabinoid system and thus becomes a target of antidepressant drugs. In this paper, molecular docking and molecular dynamics simulations, combined with binding free energy calculation, were employed to investigate the inhibitory mechanism and binding modes of four aryl formyl piperidine derivative inhibitors with different 1-substituents to MAGL. The results showed that in the four systems, the main four regions where the enzyme bound to the inhibitor included around the head aromatic ring, the head carbonyl oxygen, the tail amide bond, and the tail benzene ring. The significant conformational changes in the more flexible lid domain of the enzyme were caused by 1-substituted group differences of inhibitors and resulted in different degrees of flipping in the tail of the inhibitor. The flipping led to a different direction of the tail amide bond and made a greater variation in its interaction with some of the charged residues in the enzyme, which further contributed to a different swing of the tail benzene ring. If the swing is large enough, it can weaken the binding strength of the head carbonyl oxygen to its nearby residues, and even the whole inhibitor with the enzyme so that the inhibition decreases.
ESTHER : Liu_2022_Molecules_27_7512
PubMedSearch : Liu_2022_Molecules_27_7512
PubMedID: 36364337

Title : Populus euphratica Phospholipase Ddelta Increases Salt Tolerance by Regulating K(+)\/Na(+) and ROS Homeostasis in Arabidopsis - Zhang_2022_Int.J.Mol.Sci_23_4911
Author(s) : Zhang Y , Yao J , Yin K , Liu Z , Deng C , Liu J , Hou S , Zhang H , Yu D , Zhao N , Zhao R , Chen S
Ref : Int J Mol Sci , 23 :4911 , 2022
Abstract : Phospholipase Dalpha (PLDalpha), which produces signaling molecules phosphatidic acid (PA), has been shown to play a critical role in plants adapting to salt environments. However, it is unclear whether phospholipase Ddelta (PLDdelta) can mediate the salt response in higher plants. PePLDdelta was isolated from salt-resistant Populus euphratica and transferred to Arabidopsis thaliana to testify the salt tolerance of transgenic plants. The NaCl treatment (130 mM) reduced the root growth and whole-plant fresh weight of wild-type (WT) A. thaliana, vector controls (VC) and PePLDdelta-overexpressed lines, although a less pronounced effect was observed in transgenic plants. Under salt treatment, PePLDdelta-transgenic Arabidopsis exhibited lower electrolyte leakage, malondialdehyde content and H(2)O(2) levels than WT and VC, resulting from the activated antioxidant enzymes and upregulated transcripts of genes encoding superoxide dismutase, ascorbic acid peroxidase and peroxidase. In addition, PePLDdelta-overexpressed plants increased the transcription of genes encoding the plasma membrane Na(+)/H(+) antiporter (AtSOS1) and H(+)-ATPase (AtAHA2), which enabled transgenic plants to proceed with Na(+) extrusion and reduce K(+) loss under salinity. The capacity to regulate reactive oxygen species (ROS) and K(+)/Na(+) homeostasis was associated with the abundance of specific PA species in plants overexpressing PePLDdelta. PePLDdelta-transgenic plants retained a typically higher abundance of PA species, 34:2 (16:0-18:2), 34:3 (16:0-18:3), 36:4 (18:2-18:2), 36:5 (18:2-18:3) and 36:6 (18:3-18:3), under control and saline conditions. It is noteworthy that PA species 34:2 (16:0-18:2), 34:3 (16:0-18:3), 36:4 (18:2-18:2) and 36:5 (18:2-18:3) markedly increased in response to NaCl in transgenic plants. In conclusion, we suppose that PePLDdelta-derived PA enhanced the salinity tolerance by regulating ROS and K(+)/Na(+) homeostasis in Arabidopsis.
ESTHER : Zhang_2022_Int.J.Mol.Sci_23_4911
PubMedSearch : Zhang_2022_Int.J.Mol.Sci_23_4911
PubMedID: 35563299

Title : The Effect of Guilingji Capsules on Vascular Mild Cognitive Impairment: A Randomized, Double-Blind, Controlled Trial - Zhang_2022_Evid.Based.Complement.Alternat.Med_2022_4778163
Author(s) : Zhang H , Chen H , Pei H , Wang H , Ma L , Li H
Ref : Evid Based Complement Alternat Med , 2022 :4778163 , 2022
Abstract : Guilingji capsules (GLJC) have been shown to have antiaging effects and improve cognitive function. The aim of this study was to evaluate the clinical efficacy and safety of GLJC for the treatment of vascular mild cognitive impairment (VaMCI). A total of 96 patients with VaMCI (aged 60-85 years) were enrolled in this 24-week, randomized, double-blind, controlled clinical trial. The patients were randomly assigned to a GLJC group (n = 48) or a Ginkgo group (n = 48). Patients in the GLJC group were treated using GLJC, whereas those in the Ginkgo group received Ginkgo extract tablets. We evaluated the participants at baseline and after a 12- and 24-week treatment period using the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Chinese Medicine Symptom Scale (CM-SS). The serum acetylcholine (Ach), acetylcholinesterase (AchE), homocysteine (Hcy), and high-sensitivity C-reactive protein (hs-CRP) serum levels of the patients were measured before and after 24-week treatment. Analysis of the results of both groups showed that both interventions significantly increased the MoCA and MMSE scores of the patients and decreased their ADAS-Cog and CM-SS scores (P < 0.05). The GLJC group showed greater improvement in MoCA, MMSE, and CM-SS scores than the Ginkgo group (P < 0.05). However, both groups showed a significant increase in serum Ach and a decrease in serum AchE, Hcy, and hs-CRP levels (P < 0.05). Furthermore, serum Ach increased and Hcy decreased more significantly in the GLJC group than in the Ginkgo group (P < 0.05). These findings indicate that GLJC can improve the cognitive function, cholinergic system, and inflammatory cytokine levels of patients with VaMCI. Furthermore, this treatment can improve symptoms of syndromes diagnosed according to traditional Chinese medicine practice in patients with VaMCI.
ESTHER : Zhang_2022_Evid.Based.Complement.Alternat.Med_2022_4778163
PubMedSearch : Zhang_2022_Evid.Based.Complement.Alternat.Med_2022_4778163
PubMedID: 35116067

Title : Analysis of transcript-wide profile regulated by microsatellite instability of colorectal cancer - Xu_2022_Ann.Transl.Med_10_169
Author(s) : Xu Y , Wang X , Chu Y , Li J , Wang W , Hu X , Zhou F , Zhang H , Zhou L , Kuai R , Jin Y , Yang D , Peng H
Ref : Ann Transl Med , 10 :169 , 2022
Abstract : BACKGROUND: Microsatellite instability-high (MSI-H) is a form of genomic instability present in 15% of colorectal cancer (CRC) cases. Several differential gene analyses have been conducted on CRC; however, none have specifically explored the differentially expressed genes in MSI-H CRC. Research on the different gene expressions between MSI-H CRC and microsatellite stable (MSS) CRC, and their different patterns of metastasis will provide invaluable insights for diagnosis, prognosis, and treatment. METHODS: In this study, the differential expression of 46,602 genes were analyzed across 613 different tissue samples from The Cancer Genome Atlas (TCGA)-colon adenocarcinoma (COAD) and TCGA-rectum adenocarcinoma (READ) as part of a gene association analysis. R package TCGAbiolinks (version 2.18.0) was used to download the data set, and DESeq2 (version 1.30.1) was used for the differential gene analysis. The resulting genes were then analyzed for shared pathways with R package clusterProfiler (version 3.0.4). RESULTS: A total of 237 significantly differentially expressed genes (P(adj)<0.05) were found between MSI-H and MSS CRC. Differentially expressed genes include insulin like growth factor 2 (IGF2) and fibroblast growth factor 3 (FGF3), and the enriched pathways mostly involve hearing, digestive regulation, and neurogenesis.463 differentially expressed genes were found between metastatic and non-metastatic CRC. Notably differentially expressed genes in metastatic CRC include DEAD-box helicase 53 (DDX53) and adiponectin, C1Q and collagen domain containing (ADIPOQ), and enriched pathways include the immune system, cell adhesion, and cell signaling. For MSI-H CRC, a total of 34 genes were significantly differently expressed between metastatic and non-metastatic CRC. These include notum, palmitoleoyl-protein carboxylesterase (NOTUM), serpin family B member 2 (SERPINB2), and several keratin (KRT) genes, and the pathway analysis showed the major enrichment of the hormonal and secretion and regulation pathways. Of the differentially expressed genes in metastatic CRC, 25 were immunity related and include fatty acid binding protein 4 (FABP4), and the pathway analysis showed the enrichment of humoral immunity and lymphocyte regulation. CONCLUSIONS: Of the biologically plausible differentially expressed genes, the most notable were NOTUM, KRT6A, KRT14, SERPINB2, and serum amyloid A1 (SAA1). NOTUM, KRT6A, and KRT14 are active in the Wnt pathway. All five are also involved in various inflammation pathways.
ESTHER : Xu_2022_Ann.Transl.Med_10_169
PubMedSearch : Xu_2022_Ann.Transl.Med_10_169
PubMedID: 35280417

Title : An alpha\/beta hydrolase family member negatively regulates salt tolerance but promotes flowering through three distinct functions in rice - Xiang_2022_Mol.Plant__
Author(s) : Xiang YH , Yu JJ , Liao B , Shan JX , Ye WW , Dong NQ , Guo T , Kan Y , Zhang H , Yang YB , Li YC , Zhao HY , Yu HX , Lu ZQ , Lin HX
Ref : Mol Plant , : , 2022
Abstract : Ongoing soil salinization drastically threatens crop growth, development, and yield worldwide. It is therefore crucial that we improve salt tolerance in rice by exploiting natural genetic variation. However, many salt-responsive genes confer undesirable phenotypes and therefore cannot be effectively applied to practical agricultural production. Here we successfully identified a quantitative trait locus (QTL) for salt tolerance from the African rice species Oryza glaberrima that we have named STH1. As an integration hub for salt tolerance and heading date, we found that STH1 regulates fatty acid metabolic homeostasis, probably through catalyzing the hydrolytic degradation of fatty acid, which contributes to salt tolerance. Meanwhile, we demonstrated that STH1 forms a protein complex with D3 and a vital regulatory factor in salt tolerance, OsHAL3, to affect the protein abundance of OsHAL3 by ubiquitination pathway. Furthermore, we revealed that STH1 also serves as a co-activator of the floral integrator gene Heading date 1 (Hd1) to balance the expression of the florigen gene Heading date 3a (Hd3a) under different circumstances, thus coordinating the regulation of salt tolerance and heading date. It is worth noting that the allele of STH1 associated with enhanced salt tolerance and high yield is partially found in African rice, but is hardly detected in Asian cultivars. Introgression of the allele of STH1(HP46) from African rice into modern rice cultivars is a desirable approach for boosting grain yield under salt stress. Collectively, our discoveries not only show basic conceptual advances about the mechanism for salt tolerance and synergetic regulation between salt tolerance and flowering time, but also provide strategies to overcome the challenges that result from increasingly serious soil salinization.
ESTHER : Xiang_2022_Mol.Plant__
PubMedSearch : Xiang_2022_Mol.Plant__
PubMedID: 36303433
Gene_locus related to this paper: orysa-q6l556

Title : Conceptual framework for the insect metamorphosis from larvae to pupae by transcriptomic profiling, a case study of Helicoverpa armigera (Lepidoptera: Noctuidae) - Gao_2022_BMC.Genomics_23_591
Author(s) : Gao X , Zhang J , Wu P , Shu R , Zhang H , Qin Q , Meng Q
Ref : BMC Genomics , 23 :591 , 2022
Abstract : BACKGROUND: Insect metamorphosis from larvae to pupae is one of the most important stages of insect life history. Relatively comprehensive information related to gene transcription profiles during lepidopteran metamorphosis is required to understand the molecular mechanism underlying this important stage. We conducted transcriptional profiling of the brain and fat body of the cotton bollworm Helicoverpa armigera (Lepidoptera: Noctuidae) during its transition from last instar larva into pupa to explore the physiological processes associated with different phases of metamorphosis. RESULTS: During metamorphosis, the differences in gene expression patterns and the number of differentially expressed genes in the fat body were found to be greater than those in the brain. Each stage had a specific gene expression pattern, which contributed to different physiological changes. A decrease in juvenile hormone levels at the feeding stage is associated with increased expression levels of two genes (juvenile hormone esterase, juvenile hormone epoxide hydrolase). The expression levels of neuropeptides were highly expressed at the feeding stage and the initiation of the wandering stage and less expressed at the prepupal stage and the initiation of the pupal stage. The transcription levels of many hormone (or neuropeptide) receptors were specifically increased at the initiation of the wandering stage in comparison with other stages. The expression levels of many autophagy-related genes in the fat body were found to be gradually upregulated during metamorphosis. The activation of apoptosis was probably related to enhanced expression of many key genes (Apaf1, IAP-binding motif 1 like, cathepsins, caspases). Active proliferation might be associated with enhanced expression levels in several factors (JNK pathway: jun-D; TGF-beta pathway: decapentaplegic, glass bottom boat; insulin pathway: insulin-like peptides from the fat body; Wnt pathway: wntless, TCF/Pangolin). CONCLUSIONS: This study revealed several vital physiological processes and molecular events of metamorphosis and provided valuable information for illustrating the process of insect metamorphosis from larvae to pupae.
ESTHER : Gao_2022_BMC.Genomics_23_591
PubMedSearch : Gao_2022_BMC.Genomics_23_591
PubMedID: 35963998

Title : Recent advance on pleiotropic cholinesterase inhibitors bearing amyloid modulation efficacy - Zhang_2022_Eur.J.Med.Chem_242_114695
Author(s) : Zhang H , Peng Y , Zhuo L , Wang Y , Zeng G , Wang S , Long L , Li X , Wang Z
Ref : Eur Journal of Medicinal Chemistry , 242 :114695 , 2022
Abstract : Due to the hugely important roles of neurotransmitter acetylcholine (ACh) and amyloid-beta (Abeta) in the pathogenesis of Alzheimer's disease (AD), the development of multi-target directed ligands (MTDLs) focused on cholinesterase (ChE) and Abeta becomes one of the most attractive strategies for combating AD. To date, numerous preclinical studies toward multifunctional conjugates bearing ChE inhibition and anti-Abeta aggregation have been reported. Noteworthily, most of the reported multifunctional cholinesterase inhibitors are carbamate-based compounds due to the initial properties of carbamate moiety. However, because their easy hydrolysis in vivo and the instability of the compound-enzyme conjugate, the mechanism of action of these compounds is rare. Thus, non-carbamate compounds are of great need for developing novel cholinesterase inhibitors. Besides, given that Abeta accumulation begins to occur 10-15 years before AD onset, modulating Abeta is ineffective only in inhibiting its aggregation but not eliminate the already accumulated Abeta if treatment is started when the patient has been diagnosed as AD. Considering the limitation of current Abeta accumulation modulators in ameliorating cognitive deficits and ineffectiveness of ChE inhibitors in blocking disease progression, the development of a practically valuable strategy with multiple pharmaceutical properties including ChE inhibition and Abeta modulation for treating AD is indispensable. In this review, we focus on summarizing the scaffold characteristics of reported non-carbamate cholinesterase inhibitors with Abeta modulation since 2020, and understanding the ingenious multifunctional drug design ideas to accelerate the pace of obtaining more efficient anti-AD drugs in the future.
ESTHER : Zhang_2022_Eur.J.Med.Chem_242_114695
PubMedSearch : Zhang_2022_Eur.J.Med.Chem_242_114695
PubMedID: 36044812

Title : Dwarf and High Tillering1 represses rice tillering through mediating the splicing of D14 pre-mRNA - Liu_2022_Plant.Cell_34_3301
Author(s) : Liu T , Zhang X , Zhang H , Cheng Z , Liu J , Zhou C , Luo S , Luo W , Li S , Xing X , Chang Y , Shi C , Ren Y , Zhu S , Lei C , Guo X , Wang J , Zhao Z , Wang H , Zhai H , Lin Q , Wan J
Ref : Plant Cell , 34 :3301 , 2022
Abstract : Strigolactones (SLs) constitute a class of plant hormones that regulate many aspects of plant development, including repressing tillering in rice (Oryza sativa). However, how SL pathways are regulated is still poorly understood. Here, we describe a rice mutant dwarf and high tillering1 (dht1), which exhibits pleiotropic phenotypes (such as dwarfism and increased tiller numbers) similar to those of mutants defective in SL signaling. We show that DHT1 encodes a monocotyledon-specific hnRNP-like protein that acts as a previously unrecognized intron splicing factor for many precursor mRNAs (pre-mRNAs), including for the SL receptor gene D14. We find that the dht1 (DHT1I232F) mutant protein is impaired in its stability and RNA binding activity, causing defective splicing of D14 pre-mRNA and reduced D14 expression, and consequently leading to the SL signaling-defective phenotypes. Overall, our findings deepen our understanding of the functional diversification of hnRNP-like proteins and establish a connection between posttranscriptional splicing and SL signaling in the regulation of plant development.
ESTHER : Liu_2022_Plant.Cell_34_3301
PubMedSearch : Liu_2022_Plant.Cell_34_3301
PubMedID: 35670739

Title : A Novel Lipase from Lasiodiplodia theobromae Efficiently Hydrolyses C8-C10 Methyl Esters for the Preparation of Medium-Chain Triglycerides' Precursors - Ng_2021_Int.J.Mol.Sci_22_10339
Author(s) : Ng AMJ , Yang R , Zhang H , Xue B , Yew WS , Nguyen GKT
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Medium-chain triglycerides (MCTs) are an emerging choice to treat neurodegenerative disorders such as Alzheimer's disease. They are triesters of glycerol and three medium-chain fatty acids, such as capric (C8) and caprylic (C10) acids. The availability of C8-C10 methyl esters (C8-C10 ME) from vegetable oil processes has presented an opportunity to use methyl esters as raw materials for the synthesis of MCTs. However, there are few reports on enzymes that can efficiently hydrolyse C8-C10 ME to industrial specifications. Here, we report the discovery and identification of a novel lipase from Lasiodiplodia theobromae fungus (LTL1), which hydrolyses C8-C10 ME efficiently. LTL1 can perform hydrolysis over pH ranges from 3.0 to 9.0 and maintain thermotolerance up to 70 degreesC. It has high selectivity for monoesters over triesters and displays higher activity over commercially available lipases for C8-C10 ME to achieve 96.17% hydrolysis within 31 h. Structural analysis by protein X-ray crystallography revealed LTL1's well-conserved lipase core domain, together with a partially resolved N-terminal subdomain and an inserted loop, which may suggest its hydrolytic preference for monoesters. In conclusion, our results suggest that LTL1 provides a tractable route towards to production of C8-C10 fatty acids from methyl esters for the synthesis of MCTs.
ESTHER : Ng_2021_Int.J.Mol.Sci_22_10339
PubMedSearch : Ng_2021_Int.J.Mol.Sci_22_10339
PubMedID: 34638680
Gene_locus related to this paper: 9pezi-a0a5n5dna6

Title : A reverse catalytic triad Asp containing loop shaping a wide substrate binding pocket of a feruloyl esterase from Lactobacillus plantarum - Zhang_2021_Int.J.Biol.Macromol_184_92
Author(s) : Zhang H , Wen B , Liu Y , Du G , Wei X , Khandaker S , Zhou H , Fan S , Wang F , Wang Y , Xin F
Ref : Int J Biol Macromol , 184 :92 , 2021
Abstract : Feruloyl esterase is an indispensable biocatalyst in food processing, pesticide and pharmaceutical industries, catalyzing the cleavage of the ester bond cross-linked between the polysaccharide side chain of hemicellulose and ferulic acid in plant cell walls. LP_0796 from Lactobacillus plantarum was identified as a feruloyl esterase that may have potential applications in the food industry, but the lack of the substrate recognition and catalytic mechanisms limits its application. Here, LP_0796 showed the highest activity towards methyl caffeate at pH 6.6 and 40 degreesC. The crystal structure of LP_0796 was determined at 2.5 A resolution and featured a catalytic triad Asp195-containing loop facing the opposite direction, thus forming a wider substrate binding pocket. Molecular docking simulation and site-directed mutagenesis studies further demonstrated that in addition to the catalytic triad (Ser94, Asp195, His225), Arg125 and Val128 played essential roles in the function of the active site. Our data also showed that Asp mutation of Ala23 and Ile198 increased the catalytic efficiency to 4- and 5-fold, respectively. Collectively, this work provided a better understanding of the substrate recognition and catalytic mechanisms of LP_0796 and may facilitate the future protein design of this important feruloyl esterase.
ESTHER : Zhang_2021_Int.J.Biol.Macromol_184_92
PubMedSearch : Zhang_2021_Int.J.Biol.Macromol_184_92
PubMedID: 34116094
Gene_locus related to this paper: lacpl-LP.0796

Title : Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease - Xuan_2021_ACS.Chem.Neurosci_12_2462
Author(s) : Xuan Z , Gu X , Yan S , Xie Y , Zhou Y , Zhang H , Jin H , Hu S , Mak MSH , Zhou D , Tsim KWK , Carlier PR , Han Y , Cui W
Ref : ACS Chem Neurosci , 12 :2462 , 2021
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and beta-amyloid (Abeta) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Abeta production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Abeta oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Abeta oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Abeta aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.
ESTHER : Xuan_2021_ACS.Chem.Neurosci_12_2462
PubMedSearch : Xuan_2021_ACS.Chem.Neurosci_12_2462
PubMedID: 34156230

Title : The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer's disease with comorbid depression - Li_2021_Eur.J.Med.Chem_229_114045
Author(s) : Li X , Li J , Huang Y , Gong Q , Fu Y , Xu Y , Huang J , You H , Zhang D , Mao F , Zhu J , Wang H , Zhang H
Ref : Eur Journal of Medicinal Chemistry , 229 :114045 , 2021
Abstract : Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT(1A) receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT(1A) receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro, low hERG potassium channel inhibition and acceptable brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression.
ESTHER : Li_2021_Eur.J.Med.Chem_229_114045
PubMedSearch : Li_2021_Eur.J.Med.Chem_229_114045
PubMedID: 34922191

Title : Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE\/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease - Yao_2021_J.Med.Chem__
Author(s) : Yao H , Uras G , Zhang P , Xu S , Yin Y , Liu J , Qin S , Li X , Allen S , Bai R , Gong Q , Zhang H , Zhu Z , Xu J
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC(50) = 51.1 nM; GSK-3beta: IC(50) = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
ESTHER : Yao_2021_J.Med.Chem__
PubMedSearch : Yao_2021_J.Med.Chem__
PubMedID: 34024109

Title : Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease - Tang_2021_ChemMedChem__
Author(s) : Tang W , Zhang H , Wu C , Chen X , Zhang Z , Jiang X , Qin HL
Ref : ChemMedChem , : , 2021
Abstract : Novel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B > series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 microM), which was nicely fallen into Tc AChE via hydrogen interactions between delta-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive ( K i = 7.67 microM) AChE inhibition, nontoxicity and remarkable neuro-protective activity. In vivo studies confirmed that compound B4 significantly ameliorates performances of scopolamine-treated C57BL/6J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD.
ESTHER : Tang_2021_ChemMedChem__
PubMedSearch : Tang_2021_ChemMedChem__
PubMedID: 34036731

Title : Design, synthesis and biological evaluation of naringenin carbamate derivatives as potential multifunctional agents for the treatment of Alzheimer's disease - Wu_2021_Bioorg.Med.Chem.Lett__128316
Author(s) : Wu J , Kou X , Ju H , Zhang H , Yang A , Shen R
Ref : Bioorganic & Medicinal Chemistry Lett , :128316 , 2021
Abstract : A series of naringenin derivatives were designed and synthesized as multifunctional anti-Alzheimer's disease (AD) agents. The results showed that these derivatives displayed moderate-to-good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities at the micromolar range (IC(50), 12.91-62.52 microM for AChE and 0.094-13.72 microM for BuChE). Specifically, compound 1 showed the highest inhibitory activity against BuChE with the IC(50) value of (0.094+/-0.0054) microM. A Lineweaver-Burk plot and molecular docking studies demonstrated that 1 targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of BuChE. Besides, all derivatives showed excellent hydroxyl free radicals (.OH) scavenging ability than vitamin C and cyclic voltammetry results displayed that 1 could effectively scavenge superoxide anion radical (.O(2)(-)). In addition, compound 1 displayed good metal chelating properties and had anti-Abeta aggregation activities. Therefore, compound 1 might be the potential anti-AD agent for further developments.
ESTHER : Wu_2021_Bioorg.Med.Chem.Lett__128316
PubMedSearch : Wu_2021_Bioorg.Med.Chem.Lett__128316
PubMedID: 34391893

Title : Outcomes of juvenile myasthenia gravis: a comparison of robotic thymectomy with medication treatment - Li_2021_Ann.Thorac.Surg__
Author(s) : Li Z , Li F , Zhang H , Swierzy M , Ismail M , Meisel A , Rueckert JC
Ref : Annals of Thoracic surgery , : , 2021
Abstract : BACKGROUND: The study aims to compare the clinical outcomes of patients with juvenile myasthenia gravis (JMG) who underwent robotic thymectomy with that of those who only received medication therapy. METHODS: We retrospectively reviewed patients who visited our institution for the diagnosis or treatment of MG with an age at onset younger than 18 years. Patients who underwent thymectomy comprised the surgical group and those who received only medication therapy comprised the nonsurgical group. The clinical outcomes were assessed according to the Myasthenia Gravis Foundation of America Post Intervention Status. RESULTS: Forty-seven patients (35 female: 12 male) were included as the surgical group and 20 patients (15 female: 5 male) comprised the nonsurgical group. Significant differences were observed between the surgical and nonsurgical groups in antibody against acetylcholinesterase receptor (91.5% versus 65%, p=0.012), disease duration (16 [7-25] months versus 96 [42-480] months, p<0.001) and corticosteroids requirement (53.2% versus 15%, p=0.004) at baseline. Kaplan-Meier analysis showed a higher cumulative probability of complete stable remission (CSR) in the surgical group (p=0.002), compared with that in the nonsurgical group. Moreover, thymectomy (HR 3.842, 95%CI: 1.116-13.230, p=0.033) and age at onset (HR 0.89, 95%CI: 0.80-0.99, p=0.037) were still associated with the achievement of CSR in the multivariable analysis. Furthermore, a significant steroid-sparing effect was only observed in the surgical group, but not in the nonsurgical group. CONCLUSIONS: Robotic thymectomy seems to be more effective than medication therapy on JMG in terms of inducing remission and reducing the use of corticosteroids.
ESTHER : Li_2021_Ann.Thorac.Surg__
PubMedSearch : Li_2021_Ann.Thorac.Surg__
PubMedID: 33482164

Title : The Effects of Repeated Morphine Treatment on the Endogenous Cannabinoid System in the Ventral Tegmental Area - Zhang_2021_Front.Pharmacol_12_632757
Author(s) : Zhang H , Lipinski AA , Liktor-Busa E , Smith AF , Moutal A , Khanna R , Langlais PR , Largent-Milnes TM , Vanderah TW
Ref : Front Pharmacol , 12 :632757 , 2021
Abstract : The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCgamma2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.
ESTHER : Zhang_2021_Front.Pharmacol_12_632757
PubMedSearch : Zhang_2021_Front.Pharmacol_12_632757
PubMedID: 33953672

Title : Phthalimide-(N-alkylbenzylamine) cysteamide hybrids as multifunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation - Zhang_2021_Chem.Biol.Drug.Des__
Author(s) : Zhang H , Song Q , Yu G , Cao Z , Qiang X , Liu X , Deng Y
Ref : Chemical Biology Drug Des , : , 2021
Abstract : The complex pathogenesis of Alzheimer's disease (AD) calls for multi-target approach for disease treatment. Herein, based on the MTDLs strategy, a series of phthalimide-(N-alkylbenzylamine) cysteamide hybrids were designed, synthesized and investigated in vitro for the purpose. Most of the target compounds were found to be potential multi-target agents. In vitro results showed that compound 9e was the representative compound in this series, endowed with high EeAChE and HuAChE inhibitory potency (IC(50) = 1.55microM and 2.23 microM, respectively), good inhibitory activity against self-induced Abeta(1-42) aggregation (36.08% at 25 microM) and moderate antioxidant capacity (ORAC-FL value was 0.68 Trolox equivalents). Molecular docking studies rationalized the binding mode of 9e in both PAS and CAS of AChE. Moreover, 9e displayed excellent ability to against H(2) O(2) -induced PC12 cell injury and penetrate BBB. Overall, these results highlighted that compound 9e was an effective and promising multi-target agent for further anti-AD drug development.
ESTHER : Zhang_2021_Chem.Biol.Drug.Des__
PubMedSearch : Zhang_2021_Chem.Biol.Drug.Des__
PubMedID: 34143938

Title : Genome-Wide Identification of GDSL-Type Esterase\/Lipase Gene Family in Dasypyrum villosum L. Reveals That DvGELP53 Is Related to BSMV Infection - Zhang_2021_Int.J.Mol.Sci_22_
Author(s) : Zhang H , Zhang X , Zhao J , Sun L , Wang H , Zhu Y , Xiao J , Wang X
Ref : Int J Mol Sci , 22 : , 2021
Abstract : GDSL-type esterase/lipase proteins (GELPs) characterized by a conserved GDSL motif at their N-terminus belong to the lipid hydrolysis enzyme superfamily. In plants, GELPs play an important role in plant growth, development and stress response. The studies of the identification and characterization of the GELP gene family in Triticeae have not been reported. In this study, 193 DvGELPs were identified in Dasypyrum villosum and classified into 11 groups (clade A-K) by means of phylogenetic analysis. Most DvGELPs contain only one GDSL domain, only four DvGELPs contain other domains besides the GDSL domain. Gene structure analysis indicated 35.2% DvGELP genes have four introns and five exons. In the promoter regions of the identified DvGELPs, we detected 4502 putative cis-elements, which were associated with plant hormones, plant growth, environmental stress and light responsiveness. Expression profiling revealed 36, 44 and 17 DvGELPs were highly expressed in the spike, the root and the grain, respectively. Further investigation of a root-specific expressing GELP, DvGELP53, indicated it was induced by a variety of biotic and abiotic stresses. The knockdown of DvGELP53 inhibited long-distance movement of BSMV in the tissue of D. villosum. This research provides a genome-wide glimpse of the D. villosum GELP genes and hints at the participation of DvGELP53 in the interaction between virus and plants.
ESTHER : Zhang_2021_Int.J.Mol.Sci_22_
PubMedSearch : Zhang_2021_Int.J.Mol.Sci_22_
PubMedID: 34830200

Title : Plasma cholinesterase activity is influenced by interactive effect between omethoate exposure and CYP2E1 polymorphisms - Wang_2021_J.Environ.Sci.Health.B__1
Author(s) : Wang T , Zhang H , Li L , Zhang W , Wang Q , Wang W
Ref : J Environ Sci Health B , :1 , 2021
Abstract : The aim of this study was to explore the association between metabolizing enzyme gene polymorphisms and the decrease in cholinesterase activity induced by omethoate exposure. A total of 180 workers exposed to omethoate over an extended period were recruited along with 115 healthy controls. Cholinesterase activity in whole blood, erythrocyte, and plasma was detected using acetylthiocholine and the dithio-bis-(nitrobenzoic acid) method. Six polymorphic loci of GSTT1(+/-), GSTM1(+/-), GSTP1 rs1695, CYP2E1 rs6413432, CYP2E1 rs3813867, and PON2 rs12026 were detected by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The gene-environment interactions were analyzed using the generalized linear model method. The cholinesterase activity of erythrocyte and plasma in the exposure group was significantly lower than that in the control group (P < 0.001) in general. The plasma cholinesterase activity in the TT + AT genotype in CYP2E1 rs6413432 was lower than that in the AA genotype in the exposure group (P = 0.016). Interaction between the AA genotype in CYP2E1 rs6413432 and omethoate exposure had a significant effect on plasma cholinesterase activity (P = 0.079). The decrease in plasma cholinesterase activity was associated with interaction between the AA genotypes in rs6413432 and omethoate exposure.
ESTHER : Wang_2021_J.Environ.Sci.Health.B__1
PubMedSearch : Wang_2021_J.Environ.Sci.Health.B__1
PubMedID: 33872129

Title : Immobilized lipase catalytic synthesis of phenolamides and their potential against alpha-glucosidase - Zeng_2021_J.Biotechnol__
Author(s) : Zeng F , Zhang H , Xu M , Huang K , Zhang T , Duan J
Ref : J Biotechnol , : , 2021
Abstract : Although coumaroyltyramine (CT) derivatives are one kind of phenolamides with remarkable biological activities, the low content in plants would inhibit their potential use in food and pharmaceutical industries. Therefore, it is necessary to screen an efficient method to produce CT derivatives. A green and efficient method by using lipase as catalyst to synthesize a series of CT derivatives, was thus proposed. To obtain optimum reaction conditions, the effects of various parameters on conversion rate were firstly evaluated. An in vitro alpha-glucosidase inhibitory assay of synthesized compounds was then carried out, and the structure-activity relationship of these compounds was conducted. Under the optimum conditions (MTBE, Nu/S: 2/1, E/S: 20/1, 50 degreesC and 24 h), the conversion rates of synthesized compounds were above 65%. The bioassay results indicated that N-trans-caffeoyltyramine and N-trans-feruloyltyramine had potent activities against alpha-glucosidase with IC(50) of 30.08 microM and 31.94 microM, respectively. The structure-activity relationship results showed that the presence of -OH or -OCH(3) group at C-3 position could boost the activities of CT derivatives. Meanwhile, the presence of -OH group at C-4 position and double bound on caffeoyl moiety as well as the presence of -OH group at C-4' position was essential for the activities of CT derivatives.
ESTHER : Zeng_2021_J.Biotechnol__
PubMedSearch : Zeng_2021_J.Biotechnol__
PubMedID: 33878390

Title : Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death - Zhang_2021_JCI.Insight_6_e148496
Author(s) : Zhang X , Kellogg AP , Citterio CE , Zhang H , Larkin D , Morishita Y , Targovnik HM , Balbi VA , Arvan P
Ref : JCI Insight , 6 : , 2021
Abstract : Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
ESTHER : Zhang_2021_JCI.Insight_6_e148496
PubMedSearch : Zhang_2021_JCI.Insight_6_e148496
PubMedID: 33914707
Gene_locus related to this paper: human-TG

Title : Zymography for Picogram Detection of Lipase and Esterase Activities - Ng_2021_Molecules_26_
Author(s) : Ng AMJ , Zhang H , Nguyen GKT
Ref : Molecules , 26 : , 2021
Abstract : Lipases and esterases are important catalysts with wide varieties of industrial applications. Although many methods have been established for detecting their activities, a simple and sensitive approach for picogram detection of lipolytic enzyme quantity is still highly desirable. Here we report a lipase detection assay which is 1000-fold more sensitive than previously reported methods. Our assay enables the detection of as low as 5 pg and 180 pg of lipolytic activity by direct spotting and zymography, respectively. Furthermore, we demonstrated that the detection sensitivity was adjustable by varying the buffering capacity, which allows for screening of both high and low abundance lipolytic enzymes. Coupled with liquid chromatography-mass spectrometry, our method provides a useful tool for sensitive detection and identification of lipolytic enzymes.
ESTHER : Ng_2021_Molecules_26_
PubMedSearch : Ng_2021_Molecules_26_
PubMedID: 33799781

Title : Safety and pharmacokinetic interaction between fotagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin in healthy subjects - Ding_2021_Expert.Opin.Drug.Metab.Toxicol_17_725
Author(s) : Ding Y , Zhang H , Li C , Zheng W , Wang M , Li Y , Sun H , Wu M
Ref : Expert Opin Drug Metab Toxicol , 17 :725 , 2021
Abstract : BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have significant clinical efficacy for type 2 diabetes mellitus (T2DM). The combination of fotagliptin (FOT) with metformin (MET) is a promising therapeutic approach in MET-resistant patients. The aim of the present study was to evaluate the pharmacokinetic (PK) interaction between FOT and MET in healthy subjects after multiple-dose administration. METHODS: Eighteen participants received a randomized open-label, three period treatment that included MET 1000 mg alone, co-administration of FOT 24 mg and MET, followed by FOT 24 mg alone. Serial blood samples were collected for PK analysis, which included geometric mean ratios (GMRs) with 90% confidence intervals (CIs), area under the concentration-time curve (AUC), and maximum plasma concentration (C(max)). RESULTS: Analysis results showed that for FOT alone or combination therapy, the 90% CIs of the GMR for AUC(0-24,ss) and C(max,ss) were 102.08% (98.9%, 105.36%) and 110.65% (102.19%, 119.82%), respectively. For MET, they were 113.41% (100.32%, 128.22%) and 97.11% (83.80%, 112.55%) for AUC(0-12,ss) and C(max,ss), respectively. FOT or MET monotherapy and the combination therapy with both drugs were well tolerated. CONCLUSIONS: No PK drug-drug interactions were found in the combination therapy with FOT and MET. Therefore, FOT can be co-administered with MET without dose adjustment. TRIAL REGISTRATION: The trial is registered at http://www.chinadrugtrials.org.cn/(Registration No. CTR20190221).
ESTHER : Ding_2021_Expert.Opin.Drug.Metab.Toxicol_17_725
PubMedSearch : Ding_2021_Expert.Opin.Drug.Metab.Toxicol_17_725
PubMedID: 33899649

Title : Presence of L1014F Knockdown-Resistance Mutation in Anopheles gambiae s.s. From So Tom and Prncipe - Zhang_2021_Front.Cell.Infect.Microbiol_11_633905
Author(s) : Zhang H , Li M , Tan R , Deng C , Huang B , Wu Z , Zheng S , Guo W , Tuo F , Yuan Y , Bandeira CA , Rompao DH , Xu Q , Song J , Wang Q
Ref : Front Cell Infect Microbiol , 11 :633905 , 2021
Abstract : Malaria, one of the most serious parasitic diseases, kills thousands of people every year, especially in Africa. Sao Tome and Prncipe are known to have stable transmission of malaria. Indoor residual spraying (IRS) of insecticides and long-lasting insecticidal nets (LLIN) are considered as an effective malaria control interventions in these places. The resistance status of Anopheles gambiae s.s. from Agua Grande, Caue, and Lemba of Sao Tome and Prncipe to insecticides, such as dichlorodiphenyltrichloroethane (DDT) (4.0%), deltamethrin (0.05%), permethrin (0.75%), fenitrothion (1.0%), and malathion (5.0%), were tested according to the WHO standard protocol. DNA extraction, species identification, as well as kdr and ace-1(R) genotyping were done with the surviving and dead mosquitoes post testing. They showed resistance to cypermethrin with mortality rates ranging from 89.06% to 89.66%. Mosquitoes collected from Agua Grande, Caue, and Lemba displayed resistance to DDT and fenitrothion with mortality rates higher than 90%. No other species were detected in these study localities other than Anopheles gambiae s.s. The frequency of L1014F was high in the three investigated sites, which was detected for the first time in Sao Tome and Prncipe. No ace(-1R) mutation was detected in all investigated sites. The high frequency of L1014F showed that kdr L1014F mutation might be related to insecticide resistance to Anopheles gambiae s.s. populations from Sao Tome and Prncipe. Insecticide resistance status is alarming and, therefore, future malaria vector management should be seriously considered by the government of Sao Tome and Prncipe.
ESTHER : Zhang_2021_Front.Cell.Infect.Microbiol_11_633905
PubMedSearch : Zhang_2021_Front.Cell.Infect.Microbiol_11_633905
PubMedID: 34307185

Title : A strategy to discover selective alpha-glucosidase\/acetylcholinesterase inhibitors from five function-similar citrus herbs through LC-Q-TOF-MS, bioassay and virtual screening - Guo_2021_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1174_122722
Author(s) : Guo H , Chen YH , Wang TM , Kang TG , Sun HY , Pei WH , Song HP , Zhang H
Ref : Journal of Chromatography B Analyt Technol Biomed Life Sciences , 1174 :122722 , 2021
Abstract : The lack of direct connection between traditional herbal medicines and multiple biological targets is a bottleneck in herbal research and quality evaluation. To solve this problem, a strategy for the discovery of active ingredients from function-similar herbal medicines based on multiple biological targets was proposed in this article. The technical route includes chromatographic separation, mass spectrometry analysis, enzymatic activity detection, pharmacophore analysis and molecular docking. Five citrus herbs of Citri Reticulatae Pericarpium (CRP), Citri Exocarpium Rubrum (CER), Citri Grandis Exocarpium (CGE), Aurantii Fructus Immaturus (AFI) and Aurantii Fructus (AF) were used as the research objects. A total of 136 chemical components were identified from above five herbs based on LC-Q-TOF-MS/MS and database matching. The extracts of the five herbs showed obvious inhibitory effects on alpha-glucosidase and acetylcholinesterase in a concentration-dependent manner. Interestingly, the different types of components in the herbs exhibited selectivity for different targets: flavanone glycosides are effective on alpha-glucosidase but ineffective on acetylcholinesterase; polymethoxyflavonoids are effective on acetylcholinesterase but ineffective on alpha-glucosidase. Furthermore, we found for the first time that the components in citrus herbs exhibit opposite structure-activity relationships on the above two targets. For example, the methoxy group can enhance the activity of compounds on acetylcholinesterase but weaken the activity of compounds on alpha-glucosidase. The selective action is a supplement to the "multi-components, multi-targets" system of herbal medicines. Pharmacophore analysis and molecular docking were applied to explore the interaction between active ingredients and biological targets from the perspective of ligands and receptors, respectively. By combining the above multiple technologies, a strong connection among herbal medicines, chemical components and multiple biological targets was established. This work not only helps to understand the similar function of citrus herbs for the treatment of diabetes and Alzheimer's disease, but also provides selective lead compounds for the development of related drugs. This strategy is also helpful to improve the quality evaluation of citrus herbs from the perspective of biological activity.
ESTHER : Guo_2021_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1174_122722
PubMedSearch : Guo_2021_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1174_122722
PubMedID: 33992880

Title : A strategy to discover lead chemome from traditional Chinese medicines based on natural chromatogram-effect correlation (NCEC) and natural structure-effect correlation (NSEC): Mahonia bealei and Mahonia fortunei as a case study - Song_2021_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1181_122922
Author(s) : Song HP , Zhang H , Hu R , Xiao HH , Guo H , Yuan WH , Han XT , Xu XY , Zhang X , Ding ZX , Zhao MY , Kang TG , Sun HY , Chang A , Chen YH , Xie M
Ref : Journal of Chromatography B Analyt Technol Biomed Life Sciences , 1181 :122922 , 2021
Abstract : Lead compound is an important concept for modern drug discovery. In this study, a new concept of lead chemome and an efficient strategy to discover lead chemome were proposed. Compared with the concept of lead compound, lead chemome can provide not only the starting point for drug development, but also the direction for structure optimization. Two traditional Chinese medicines of Mahonia bealei and Mahonia fortunei were used as examples to illustrate the strategy. Based on natural chromatogram-effect correlation (NCEC), berberine, palmatine and jatrorrhizine were discovered as acetylcholinesterase (AchE) inhibitors. Taking the three compounds as template molecules, a lead chemome consisting of 10 structurally related natural compounds were generated through natural structure-effect correlation (NSEC). In the lead chemome, the IC(50) values of jatrorrhizine, berberine, coptisine, palmatine and epiberberine are at nanomolar level, which are comparable to a widely used drug of galantamine. Pharmacophore modeling shows that the positive ionizable group and aromatic rings are important substructures for AchE inhibition. Molecular docking further shows that pi-cation interaction and pi-pi stacking are critical for compounds to maintain nanomolar IC(50) values. The structure-activity information is helpful for drug design and structure optimization. This work also expanded the traditional understanding of "stem is the medicinal part of Mahonia bealei and Mahonia fortunei". Actually, all parts except the leaf of Mahonia bealei exhibited potent AchE-inhibitory activity. This study provides not only a strategy to discover lead chemome for modern drug development, but also a reference for the application of different parts of medicinal plants.
ESTHER : Song_2021_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1181_122922
PubMedSearch : Song_2021_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1181_122922
PubMedID: 34500403

Title : Alpha\/Beta-Hydrolase Domain-Containing 6: Signaling and Function in the Central Nervous System - Zhang_2021_Front.Pharmacol_12_784202
Author(s) : Zhang H , Li X , Liao D , Luo P , Jiang X
Ref : Front Pharmacol , 12 :784202 , 2021
Abstract : Endocannabinoid (eCB) signaling plays an important role in the central nervous system (CNS). alpha/beta-Hydrolase domain-containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes monoacylglycerol (MAG) lipids such as endocannabinoid 2-arachidonoyl glycerol (2-AG). ABHD6 participates in neurotransmission, inflammation, brain energy metabolism, tumorigenesis and other biological processes and is a potential therapeutic target for various neurological diseases, such as traumatic brain injury (TBI), multiple sclerosis (MS), epilepsy, mental illness, and pain. This review summarizes the molecular mechanisms of action and biological functions of ABHD6, particularly its mechanism of action in the pathogenesis of neurological diseases, and provides a theoretical basis for new pharmacological interventions via targeting of ABHD6.
ESTHER : Zhang_2021_Front.Pharmacol_12_784202
PubMedSearch : Zhang_2021_Front.Pharmacol_12_784202
PubMedID: 34925039
Gene_locus related to this paper: human-ABHD6

Title : Chemical and Genetic Studies on the Formation of Pyrrolones During the Biosynthesis of Cytochalasans - Zhang_2021_Chemistry_10_3106
Author(s) : Zhang H , Hantke V , Bruhnke P , Skellam E , Cox RJ
Ref : Chemistry , 10 :3106 , 2021
Abstract : A key step during the biosynthesis of cytochalasans is a proposed Knoevenagel condensation to form the pyrrolone core, enabling the subsequent 4+2 cycloaddition reaction that results in the characteristic octahydroisoindolone motif of all cytochalasans. Here we investigate the role of the highly conserved alpha-beta -hydrolase enzymes PyiE and ORFZ during the biosynthesis of pyrichalasin H and the ACE1 metabolite respectively, using gene knockout and complementation techniques. Using synthetic aldehyde models we demonstrate that the Knoevenagel condensation proceeds spontaneously but results in the 1,3-dihydro-2H-pyrrol-2-one tautomer, rather than the required 1,5-dihydro-2H-pyrrol-2-one tautomer. Taken together our results suggest that the alpha-beta -hydrolase enzymes are essential for first ring cyclisation, but the precise nature of the intermediates remains to be determined .
ESTHER : Zhang_2021_Chemistry_10_3106
PubMedSearch : Zhang_2021_Chemistry_10_3106
PubMedID: 33146923
Gene_locus related to this paper: phano-phmG , aspcl-CCSE , aspfu-psoB , mago7-ORFZB , maggr-pyie

Title : The abundance of mRNA transcripts of bacteroidetal polyethylene terephthalate (PET) esterase genes may indicate a role in marine plastic degradation - Zhang_2021_ResearchSquare__
Author(s) : Zhang H , Dierkes R , Perez-Garcia P , Weigert S , Sternagel S , Hallam S , Schott T , Juergens K , Vollstedt C , Chibani C , Danso D , Buchholz PCF , Pleiss J , Almeida A , Hocker B , Schmitz R , Chow J , Streit WR
Ref : ResearchSquare , : , 2021
Abstract : https://www.researchsquare.com/article/rs-567691/v2 Polyethylene terephthalate (PET) is an important synthetic polymer accumulating in nature 2 and recent studies have identified microorganisms capable of degrading PET. While the majority of 3 known PET hydrolases originate from the Actinobacteria and Proteobacteria, here we describe the 4 first functional PET-active enzymes from the Bacteroidetes phylum. Using a PETase-specific 5 Hidden-Markov-Model (HMM)-based search algorithm we identified two promiscuous and cold6 active esterases derived from Aequorivita sp. (PET27) and Chryseobacterium jeonii (PET30) acting 7 on PET foil and powder. Notably, one of the enzymes (PET30) was able to hydrolyze PET at 8 temperatures between 4 - 30 C with a similar turnover rate compared to the well-known Ideonella 9 sakaiensis enzyme (IsPETase). 10 PET27 and PET30 homologues were detected in metagenomes encompassing a wide range 11 of different global climate zones. Additional transcript abundance mapping of marine samples imply 12 that these promiscuous enzymes and source organisms may play a role in the long-term 13 degradation of microplastic particles and fibers.
ESTHER : Zhang_2021_ResearchSquare__
PubMedSearch : Zhang_2021_ResearchSquare__
Gene_locus related to this paper: flutr-f2ie04 , 9flao-a0a0c1f4u8 , 9flao-kjj39608 , 9flao-a0a1m6f5v0 , 9flao-a0a330mq60

Title : The Bacteroidetes Aequorivita sp. and Kaistella jeonii Produce Promiscuous Esterases With PET-Hydrolyzing Activity - Zhang_2022_Front.Microbiol_12_803896
Author(s) : Zhang H , Perez-Garcia P , Dierkes RF , Applegate V , Schumacher J , Chibani CM , Sternagel S , Preuss L , Weigert S , Schmeisser C , Danso D , Pleiss J , Almeida A , Hocker B , Hallam SJ , Schmitz RA , Smits SHJ , Chow J , Streit WR
Ref : Front Microbiol , 12 :803896 , 2021
Abstract : Certain members of the Actinobacteria and Proteobacteria are known to degrade polyethylene terephthalate (PET). Here, we describe the first functional PET-active enzymes from the Bacteroidetes phylum. Using a PETase-specific Hidden-Markov-Model- (HMM-) based search algorithm, we identified several PETase candidates from Flavobacteriaceae and Porphyromonadaceae. Among them, two promiscuous and cold-active esterases derived from Aequorivita sp. (PET27) and Kaistella jeonii (PET30) showed depolymerizing activity on polycaprolactone (PCL), amorphous PET foil and on the polyester polyurethane Impranil((a)) DLN. PET27 is a 37.8 kDa enzyme that released an average of 174.4 nmol terephthalic acid (TPA) after 120 h at 30 degreesC from a 7 mg PET foil platelet in a 200 microl reaction volume, 38-times more than PET30 (37.4 kDa) released under the same conditions. The crystal structure of PET30 without its C-terminal Por-domain (PET30deltaPorC) was solved at 2.1 A and displays high structural similarity to the IsPETase. PET30 shows a Phe-Met-Tyr substrate binding motif, which seems to be a unique feature, as IsPETase, LCC and PET2 all contain Tyr-Met-Trp binding residues, while PET27 possesses a Phe-Met-Trp motif that is identical to Cut190. Microscopic analyses showed that K. jeonii cells are indeed able to bind on and colonize PET surfaces after a few days of incubation. Homologs of PET27 and PET30 were detected in metagenomes, predominantly aquatic habitats, encompassing a wide range of different global climate zones and suggesting a hitherto unknown influence of this bacterial phylum on man-made polymer degradation.
ESTHER : Zhang_2022_Front.Microbiol_12_803896
PubMedSearch : Zhang_2022_Front.Microbiol_12_803896
PubMedID: 35069509
Gene_locus related to this paper: flutr-f2ie04 , 9flao-a0a0c1f4u8 , 9flao-kjj39608 , 9flao-a0a330mq60

Title : Characterization and genomic analysis of an efficient dibutyl phthalate degrading bacterium Microbacterium sp. USTB-Y - Zhao_2021_World.J.Microbiol.Biotechnol_37_212
Author(s) : Zhao Z , Liu C , Xu Q , Ahmad S , Zhang H , Pang Y , Aikemu A , Liu Y , Yan H
Ref : World J Microbiol Biotechnol , 37 :212 , 2021
Abstract : A promising bacterial strain for biodegrading dibutyl phthalate (DBP) was successfully isolated from activated sludge and characterized as a potential novel Microbacterium sp. USTB-Y based on 16S rRNA sequence analysis and whole genome average nucleotide identity (ANI). Initial DBP of 50 mg/L could be completely biodegraded by USTB-Y both in mineral salt medium and in DBP artificially contaminated soil within 12 h at the optimal culture conditions of pH 7.5 and 30 degC, which indicates that USTB-Y has a strong ability in DBP biodegradation. Phthalic acid (PA) was identified as the end-product of DBP biodegraded by USTB-Y using GC/MS. The draft genome of USTB-Y was sequenced by Illumina NovaSeq and 29 and 188 genes encoding for putative esterase/carboxylesterase and hydrolase/alpha/beta hydrolase were annotated based on NR (non redundant protein sequence database) analysis, respectively. Gene3781 and gene3780 from strain USTB-Y showed 100% identity with dpeH and mpeH from Microbacterium sp. PAE-1. But no phthalate catabolic gene (pht) cluster was found in the genome of strain USTB-Y. The results in the present study are valuable for obtaining a more holistic understanding on diverse genetic mechanisms of PAEs biodegrading Microbacterium sp. strains.
ESTHER : Zhao_2021_World.J.Microbiol.Biotechnol_37_212
PubMedSearch : Zhao_2021_World.J.Microbiol.Biotechnol_37_212
PubMedID: 34738191
Gene_locus related to this paper: 9mico-DpeH , 9mico-MpeH

Title : Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate - Zhou_2021_J.Med.Chem_64_1844
Author(s) : Zhou Y , Fu Y , Yin W , Li J , Wang W , Bai F , Xu S , Gong Q , Peng T , Hong Y , Zhang D , Liu Q , Xu Y , Xu HE , Zhang H , Jiang H , Liu H
Ref : Journal of Medicinal Chemistry , 64 :1844 , 2021
Abstract : The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
ESTHER : Zhou_2021_J.Med.Chem_64_1844
PubMedSearch : Zhou_2021_J.Med.Chem_64_1844
PubMedID: 33570950
Gene_locus related to this paper: human-ACHE

Title : Exploring the global metagenome for plastic-degrading enzymes - Perez-Garcia_2021_Methods.Enzymol_648_137
Author(s) : Perez-Garcia P , Danso D , Zhang H , Chow J , Streit WR
Ref : Methods Enzymol , 648 :137 , 2021
Abstract : Plastics are extensively used in our daily life, but they are also a major pollutant of our biosphere accumulating in both the ocean and the land. In the recent years, few enzymes and microorganisms have been discovered with the ability to degrade even fewer synthetic polymers. Nevertheless, more active species and enzymes need to be discovered and described in order to gain more knowledge about protein adaptation to the degradation of not-naturally-occurring polymers. Within this chapter, we focus on efficient methods to identify novel polyethylene terephthalate-degrading enzymes (PETases) from culturable and non-culturable microorganisms by a combination of sequence- and function-based screening. This protocol can be adapted to discover other plastic hydrolases and in general for other enzymes, for which not many characterized specimens are yet available.
ESTHER : Perez-Garcia_2021_Methods.Enzymol_648_137
PubMedSearch : Perez-Garcia_2021_Methods.Enzymol_648_137
PubMedID: 33579401

Title : Plastics degradation by hydrolytic enzymes: the Plastics-Active Enzymes Database - PAZy - Buchholz_2021_Authorea__
Author(s) : Buchholz PCF , Zhang H , Perez-Garcia P , Nover LL , Chow J , Streit WR , Pleiss J
Ref : Authorea , : , 2021
Abstract : Petroleum based plastics are durable and accumulate in all ecological niches. Knowledge on enzymatic degradation is sparse. Today, less than 50 verified plastics-active enzymes are known. First examples of enzymes acting on the polymers polyethylene terephthalate (PET) and polyurethane (PUR) have been reported together with a detailed biochemical and structural description. Further, very few polyamide (PA) oligomer active enzymes are known. In this paper, the current known enzymes acting on the synthetic polymers PET and PUR are briefly summarized, their published activity data were collected and integrated into a comprehensive open access database. The Plastics-Active Enzymes Database (PAZy) represents an inventory of known and experimentally verified plastics-active enzymes. Almost 3000 homologues of PET-active enzymes were identified by profile hidden Markov models. Over 2000 homologues of PUR-active enzymes were identified by BLAST. Based on multiple sequence alignments, conservation analysis identified the most conserved amino acids, and sequence motifs for PET- and PUR-active enzymes were derived.
ESTHER : Buchholz_2021_Authorea__
PubMedSearch : Buchholz_2021_Authorea__

Title : Discovery of novel reversible monoacylglycerol lipase inhibitors via docking-based virtual screening - Xiong_2021_Bioorg.Med.Chem.Lett__127986
Author(s) : Xiong F , Ding X , Zhang H , Luo X , Chen K , Jiang H , Luo C , Xu H
Ref : Bioorganic & Medicinal Chemistry Lett , :127986 , 2021
Abstract : Monoacylglycerol lipase (MAGL) is the major enzyme that catalyzes the hydrolysis of monoacylglycerols (MAGs). MAGL is responsible for degrading 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain and specific tissues. The inhibition of MAGL could attenuate the inflammatory response. Here, we report a series of reversible non-covalent MAGL inhibitors via virtual screening combined with biochemical analysis. The hit, DC630-8 showed low-micromolar activity against MAGL in vitro, and exhibited significant anti-inflammatory effects.
ESTHER : Xiong_2021_Bioorg.Med.Chem.Lett__127986
PubMedSearch : Xiong_2021_Bioorg.Med.Chem.Lett__127986
PubMedID: 33766770
Gene_locus related to this paper: human-MGLL

Title : Soluble Epoxide Hydrolase in Aged Female Mice and Human Explanted Hearts Following Ischemic Injury - Jamieson_2021_Int.J.Mol.Sci_22_
Author(s) : Jamieson KL , Darwesh AM , Sosnowski DK , Zhang H , Shah S , Zhabyeyev P , Yang J , Hammock BD , Edin ML , Zeldin DC , Oudit GY , Kassiri Z , Seubert JM
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Myocardial infarction (MI) accounts for a significant proportion of death and morbidity in aged individuals. The risk for MI in females increases as they enter the peri-menopausal period, generally occurring in middle-age. Cytochrome (CYP) 450 metabolizes N-3 and N-6 polyunsaturated fatty acids (PUFA) into numerous lipid mediators, oxylipids, which are further metabolised by soluble epoxide hydrolase (sEH), reducing their activity. The objective of this study was to characterize oxylipid metabolism in the left ventricle (LV) following ischemic injury in females. Human LV specimens were procured from female patients with ischemic cardiomyopathy (ICM) or non-failing controls (NFC). Female C57BL6 (WT) and sEH null mice averaging 13-16 months old underwent permanent occlusion of the left anterior descending coronary artery (LAD) to induce myocardial infarction. WT (wild type) mice received vehicle or sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB), in their drinking water ad libitum for 28 days. Cardiac function was assessed using echocardiography and electrocardiogram. Protein expression was determined using immunoblotting, mitochondrial activity by spectrophotometry, and cardiac fibre respiration was measured using a Clark-type electrode. A full metabolite profile was determined by LC-MS/MS. sEH was significantly elevated in ischemic LV specimens from patients, associated with fundamental changes in oxylipid metabolite formation and significant decreases in mitochondrial enzymatic function. In mice, pre-treatment with tAUCB or genetic deletion of sEH significantly improved survival, preserved cardiac function, and maintained mitochondrial quality following MI in female mice. These data indicate that sEH may be a relevant pharmacologic target for women with MI. Although future studies are needed to determine the mechanisms, in this pilot study we suggest targeting sEH may be an effective strategy for reducing ischemic injury and mortality in middle-aged females.
ESTHER : Jamieson_2021_Int.J.Mol.Sci_22_
PubMedSearch : Jamieson_2021_Int.J.Mol.Sci_22_
PubMedID: 33567578

Title : Carboxylesterases from bacterial enrichment culture degrade strobilurin fungicides - Wang_2021_Sci.Total.Environ__152751
Author(s) : Wang W , Zhao Z , Yan H , Zhang H , Li QX , Liu X
Ref : Sci Total Environ , :152751 , 2021
Abstract : Strobilurin fungicides are a class of persistent fungicides frequently detected in the environment. Microbes can effectively degrade strobilurins, but the mechanisms are complex and diverse. Compared with isolated strains, bacterial consortia are more robust in terms of the degradation of multiple pollutants. The enrichment culture XS19 is a group of bacterial strains enriched from soil and degrades six strobilurins at 50 mg/L within 8 d, including azoxystrobin, picoxystrobin, trifloxystrobin, kresoxim-methyl, pyraclostrobin and enestroburin. LC-Q-TOF-MS analysis confirmed that XS19 can demethylate these strobilurins via hydrolysis of the methyl ester group. Analysis of the bacterial communities suggested that Pseudomonas (69.8%), Sphingobacterium (21.2%), Delftia (6.3%), and Achromobacter (1.6%) spp. were highly associated with the removal of strobilurins in the system. Metagenomics-based comprehensive analysis of XS19 suggested that carboxylesterases in Pseudomonas and Sphingobacterium play a central role in the catabolism of strobilurins. Moreover, the carboxylesterase inhibitor bis-p-nitrophenyl phosphate inhibited the degradation activity of strobilurins in XS19. This work proved that XS19 or carboxylesterases can effectively hydrolyze strobilurins, providing a reliable bioremediation paradigm.
ESTHER : Wang_2021_Sci.Total.Environ__152751
PubMedSearch : Wang_2021_Sci.Total.Environ__152751
PubMedID: 34979227

Title : Dammarane Sapogenins Improving Simulated Weightlessness-Induced Depressive-Like Behaviors and Cognitive Dysfunction in Rats - Wang_2021_Front.Psychiatry_12_638328
Author(s) : Wang Q , Dong L , Wang M , Chen S , Li S , Chen Y , He W , Zhang H , Zhang Y , Pires Dias AC , Yang S , Liu X
Ref : Front Psychiatry , 12 :638328 , 2021
Abstract : Background: Our studies demonstrated that the space environment has an impact on the brain function of astronauts. Numerous ground-based microgravity and social isolation showed that the space environment can induce brain function damages in humans and animals. Dammarane sapogenins (DS), an active fraction from oriental ginseng, possesses neuropsychic protective effects and has been shown to improve depression and memory. This study aimed to explore the effects and mechanisms of DS in attenuating depressive-like behaviors and cognitive deficiency induced by simulated weightlessness and isolation [hindlimb suspension and isolation (HLSI)] in rats. Methods: Male rats were orally administered with two different doses of DS (37.5, 75 mg/kg) for 14 days, and huperzine-A (1 mg/kg) served as positive control. Rats were subjected to HLSI for 14 days except the control group during drug administration. The depressive-like behaviors were then evaluated by the open-field test, the novel object recognition test, and the forced swimming test. The spatial memory and working memory were evaluated by the Morris water maze (MWM) test, and the related mechanism was further explored by analyzing the activity of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and superoxide dismutase (SOD) in the hippocampus of rats. Results: The results showed that DS treatment significantly reversed the HLSI-induced depressive-like behaviors in the open-field test, the novel object recognition test, and the forced swimming test and improved the HLSI-induced cognitive impairment in the MWM test. Furthermore, after DS treatment, the ChAT and SOD activities of HLSI rats were increased while AChE activity was significantly suppressed. Conclusions: These findings clearly demonstrated that DS might exert a significant neuropsychic protective effect induced by spaceflight environment, driven in part by the modulation of cholinergic system and anti-oxidation in the hippocampus.
ESTHER : Wang_2021_Front.Psychiatry_12_638328
PubMedSearch : Wang_2021_Front.Psychiatry_12_638328
PubMedID: 33841208

Title : Morphine increases myocardial triacylglycerol through regulating adipose triglyceride lipase S406 phosphorylation - Li_2021_Life.Sci_283_119866
Author(s) : Li L , Wang J , Li D , Zhang H
Ref : Life Sciences , 283 :119866 , 2021
Abstract : AIMS: Morphine, a commonly used drug for anesthesia, affects lipid metabolism in different tissues, but the mechanism is currently unclear. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme responsible for the first step of triglyceride (TG) hydrolysis. Here we aim to investigate whether ATGL phosphorylation is involved in morphine-induced TG accumulation. MAIN METHODS: Oil red O staining and TG content analysis were used to detect the effect of morphine on lipid storage. A series of ATGL phosphoamino acid site mutant plasmids were constructed by gene synthesis and transfected to HL-1 cells to evaluate the phosphorylation levels of ATGL phosphoamino acid in morphine-treated HL-1 cells with immunoprecipitation and immunoblotting assay. KEY FINDINGS: Morphine acute treatment induced excessive accumulation of TG and decreased the phosphorylation level of ATGL Ser406 in HL-1 cells. Of note, the phosphorylation positive mutation of ATGL Ser406 to aspartic acid effectively reversed morphine-induced excessive accumulation of TG in HL-1 cells. SIGNIFICANCE: This discovery will help to fully understand the lipid regulation function of morphine in a new scope. In addition, it will expand the phosphorylation research of ATGL more comprehensively and provide powerful clues for lipid metabolism regulation.
ESTHER : Li_2021_Life.Sci_283_119866
PubMedSearch : Li_2021_Life.Sci_283_119866
PubMedID: 34352257

Title : Ultrasmall Au nanoparticles modified 2D metalloporphyrinic metal-organic framework nanosheets with high peroxidase-like activity for colorimetric detection of organophosphorus pesticides - Yang_2021_Food.Chem_376_131906
Author(s) : Yang H , Sun Z , Qin X , Wu H , Zhang H , Liu G
Ref : Food Chem , 376 :131906 , 2021
Abstract : Ultrasmall Au nanoparticles (UsAuNPs) in the size range of 4.0-7.0 nm was successfully immobilized on the surface of 2D metalloporphyrinic metal-organic framework nanosheets (2D MOF). Firstly, The obtained hybrid nanomaterial, UsAuNPs/2D MOF, was fully characterized by TEM, HRTEM, element mapping images and XPS. Then, the peroxidase-like activity of UsAuNPs/2D MOF was comparatively studied with other hybrid nanozyme to explore the influence of AuNPs size on peroxidase-like activity. Further, UsAuNPs/2D MOF with outstanding peroxidase-like activity was selected to form ternary cascade enzyme reaction with acetylcholinesterase (AChE) and choline oxidase (ChOx). Based on the inhibitory effect of organophosphorus pesticides on AChE, a fast and sensitive colorimetric method was established for trichlorfon detection with the advantages of simple operation, low detection limit (1.7 microM), good linear range (1.7-42.4 microM) and high accuracy (recovery rate of 96.6-105.3%). Finally, this method was applied to visual analysis of trichlorfon concentration in tomatoes, cucumbers and eggplants.
ESTHER : Yang_2021_Food.Chem_376_131906
PubMedSearch : Yang_2021_Food.Chem_376_131906
PubMedID: 34968912

Title : Synthesis, physicochemical properties, and health aspects of structured lipids: A review - Guo_2020_Compr.Rev.Food.Sci.Food.Saf_19_759
Author(s) : Guo Y , Cai Z , Xie Y , Ma A , Zhang H , Rao P , Wang Q
Ref : Compr Rev Food Sci Food Saf , 19 :759 , 2020
Abstract : Structured lipids (SLs) refer to a new type of functional lipids obtained by chemically, enzymatically, or genetically modifying the composition and/or distribution of fatty acids in the glycerol backbone. Due to the unique physicochemical characteristics and health benefits of SLs (for example, calorie reduction, immune function improvement, and reduction in serum triacylglycerols), there is increasing interest in the research and application of novel SLs in the food industry. The chemical structures and molecular architectures of SLs define mainly their physicochemical properties and nutritional values, which are also affected by the processing conditions. In this regard, this holistic review provides coverage of the latest developments and applications of SLs in terms of synthesis strategies, physicochemical properties, health aspects, and potential food applications. Enzymatic synthesis of SLs particularly with immobilized lipases is presented with a short introduction to the genetic engineering approach. Some physical features such as solid fat content, crystallization and melting behavior, rheology and interfacial properties, as well as oxidative stability are discussed as influenced by chemical structures and processing conditions. Health-related considerations of SLs including their metabolic characteristics, biopolymer-based lipid digestion modulation, and oleogelation of liquid oils are also explored. Finally, potential food applications of SLs are shortly introduced. Major challenges and future trends in the industrial production of SLs, physicochemical properties, and digestion behavior of SLs in complex food systems, as well as further exploration of SL-based oleogels and their food application are also discussed.
ESTHER : Guo_2020_Compr.Rev.Food.Sci.Food.Saf_19_759
PubMedSearch : Guo_2020_Compr.Rev.Food.Sci.Food.Saf_19_759
PubMedID: 33325163

Title : The overexpression of three cytochrome P450 genes CYP6CY14, CYP6CY22 and CYP6UN1 contributed to metabolic resistance to dinotefuran in melon\/cotton aphid, Aphis gossypii Glover - Chen_2020_Pestic.Biochem.Physiol_167_104601
Author(s) : Chen A , Zhang H , Shan T , Shi X , Gao X
Ref : Pestic Biochem Physiol , 167 :104601 , 2020
Abstract : Dinotefuran, the third-generation neonicotinoid, has been applied against melon/cotton aphid Aphis gossypii Glover in China. The risk of resistance development, cross-resistance pattern and potential resistance mechanism of dinotefuran in A. gossypii were investigated. A dinotefuran-resistant strain of A. gossypii (DinR) with 74.7-fold resistance was established by continuous selection using dinotefuran. The DinR strain showed a medium level of cross resistance to thiamethoxam (15.2-fold), but no cross resistance to imidacloprid. The synergism assay indicated that piperonyl butoxide and triphenyl phosphate showed synergistic effects on dinotefuran toxicity to the DinR strain with a synergistic ratio of 8.3 and 2.5, respectively, while diethyl maleate showed no synergistic effect. The activities of cytochrome P450 monooxygenase and carboxylesterase were significantly higher in DinR strain than in susceptible strain (SS). Moreover, the gene expression results showed that CYP6CY14, CYP6CY22 and CYP6UN1 were significantly overexpressed in DinR strain compared with SS strain. The expression of CYP6CY14 was 5.8-fold higher in DinR strain than in SS strain. Additionally, the transcription of CYP6CY14, CYP6CY22 and CYP6UN1 in A. gossypii showed dose- and time-dependent responses to dinotefuran exposure. Furthermore, knockdown of CYP6CY14, CYP6CY22 and CYP6UN1 via RNA interference (RNAi) significantly increased mortality of A. gossypii, when A. gossypii was treated with dinotefuran. These results demonstrated the overexpression of CYP6CY14, CYP6CY22 and CYP6UN1 contributed to dinotefuran resistance in A. gossypii.
ESTHER : Chen_2020_Pestic.Biochem.Physiol_167_104601
PubMedSearch : Chen_2020_Pestic.Biochem.Physiol_167_104601
PubMedID: 32527429

Title : Effect of Massa Medicata Fermentata on the Gut Microbiota of Dyspepsia Mice Based on 16S rRNA Technique - Zhang_2020_Evid.Based.Complement.Alternat.Med_2020_7643528
Author(s) : Zhang X , Zhang H , Huang Q , Sun J , Yao R , Wang J
Ref : Evid Based Complement Alternat Med , 2020 :7643528 , 2020
Abstract : Massa Medicata Fermentata (MMF) is a traditional Chinese medicine (TCM) for treating indigestion and its related disorders. This study analyzes the effect of MMF on intestinal microorganisms in dyspepsia mice based on 16S rRNA technology. We take a dyspepsia model caused by a high-protein, high-calorie, high-fat diet. The 60 specific-pathogen free Kunming (SPF KM) mice were randomly divided into a model group (n=12), an MMF group (LSQ group, n=12), a Jianweixiaoshi group (JWXS group, n=12), a domperidone group (DP group, n=12), and a blank group (n=12). On the seventh day of administration, mice were fasted and deprived of water. After 24 h, take the second feces of stress defecation in mice under strict aseptic conditions and quickly transfer them to a sterile cryotube. This study comprehensively evaluates the alpha-diversity, beta-diversity, flora abundance and composition of each group of mice's intestinal microorganisms, and their correlation with functional dyspepsia based on the 16S rRNA gene sequencing technology. After modeling, some dyspepsia reactions, proximal gastric relaxation reduction, and intestinal microflora changes were noted. Dyspepsia mice showed dyspepsia reactions and proximal gastric relaxation reduction, characterized by a significant decrease of contents of gastrin (P < 0.01) and cholinesterase (P < 0.01). MMF can improve dyspepsia symptoms and promote proximal gastric relaxation. Significant intestinal flora disorders were found in dyspepsia mice, including downregulation of Bacteroidetes, Lactobacillus, and Prevotellaceae and upregulation of Proteobacteria, Verrucomicrobia, Epsilonbacteraeota, Firmicutes, Lachnospiraceae NK4A136 group, and Lachnospiraceae. MMF could alleviate intestinal microflora disturbance, and the regulation effect of MMF on Bacteroidetes, Verrucomicrobia, and Epsilonbacteraeota was more reliable than that of Jianweixiaoshi tables and domperidone. The intestinal microflora may be correlated with the promoted digestion of MMF.
ESTHER : Zhang_2020_Evid.Based.Complement.Alternat.Med_2020_7643528
PubMedSearch : Zhang_2020_Evid.Based.Complement.Alternat.Med_2020_7643528
PubMedID: 33029172

Title : Monoterpene indole alkaloids with acetylcholinesterase inhibitory activity from the leaves of Rauvolfia vomitoria - Zhan_2020_Bioorg.Chem_102_104136
Author(s) : Zhan G , Miao R , Zhang F , Chang G , Zhang L , Zhang X , Zhang H , Guo Z
Ref : Bioorg Chem , 102 :104136 , 2020
Abstract : Seventeen monoterpene indole alkaloids, including seven new alkaloids (1-7) and ten known analogues (8-17), were isolated and identified from the leaves of R. vomitoria. The structures of new alkaloids were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Rauvomitorine I (1) represents the first example of an unprecedented C(22) yohimbine-type monoterpene indole alkaloid featuring a carboxymethyl at C-14. The exceedingly rare vobasenal (2-3) and affinisine oxindole (5-6) framework type alkaloids are first reported from the Rauvolfia genus. Most notably, the structure of vobasenal-type alkaloids (2-3) were first determined by single-crystal X-ray diffraction analyses. Alkaloids 1-17 were tested their cytotoxicity against five cancer cell lines, however, none of them showed significant cytotoxicity at a concentration of 40 muM. All the isolated alkaloids were evaluated their acetylcholinesterase (AChE) inhibitory activities. Alkaloid 3 exhibited significant anti-AChE activity with an IC(50) value of 16.39 +/- 1.41 muM and alkaloids 8 and 10 showed moderate anti-AChE activities whereas the others (2, 9, 13, and 17) were weak inhibitors. This is the first report of vobasenal-type alkaloids as AChE inhibitors, indicating this type of alkaloids may be important sources for the discovery of new AChE inhibitors. A preliminary structure-activity relationship for AChE inhibitory activities showed the presence of the N-methyl group in vobasenal-type alkaloids may be essential for anti-AChE activity. Further molecular docking studies of vobasenal-type alkaloids revealed that interaction with Trp133 and Trp86 residues at hydrophobic subsite are necessary for the AChE inhibitory activities. This study not only enriches the chemical diversity of alkaloids in Apocynaceae plants but also provides new potential leading compounds and versatile scaffolds for the design and development of new AChE inhibitors to treat AD.
ESTHER : Zhan_2020_Bioorg.Chem_102_104136
PubMedSearch : Zhan_2020_Bioorg.Chem_102_104136
PubMedID: 32738570

Title : Edaravone at high concentrations attenuates cognitive dysfunctions induced by abdominal surgery under general anesthesia in aged mice - Zhou_2020_Metab.Brain.Dis__
Author(s) : Zhou Y , Wu X , Ye L , Bai Y , Zhang H , Xuan Z , Feng Y , Zhang P , Chen Y , Yan Y , Zhu B , Cui W
Ref : Metabolic Brain Disease , : , 2020
Abstract : Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3beta (pSer9-GSK3beta) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD.
ESTHER : Zhou_2020_Metab.Brain.Dis__
PubMedSearch : Zhou_2020_Metab.Brain.Dis__
PubMedID: 31916204

Title : Correlation between CYP1A1 polymorphisms and susceptibility to glyphosate-induced reduction of serum cholinesterase: A case-control study of a Chinese population - Cai_2020_Pestic.Biochem.Physiol_162_23
Author(s) : Cai W , Zhang F , Zhong L , Chen D , Guo H , Zhang H , Zhu B , Liu X
Ref : Pestic Biochem Physiol , 162 :23 , 2020
Abstract : Glyphosate (GLP) is one of the most common herbicides worldwide. The serum cholinesterase (ChE) may be affected when exposed to glyphosate. Reduction of serum ChE by herbicides is probably related to cytochrome P450 (CYP450) family polymorphisms. We suspect that the abnormal ChE caused by GLP could be correlated with the CYP family members. To determine whether CYP1B1 (rs1056827 and rs1056836) and CYP1A1 (rs1048943) gene polymorphisms and individual susceptibility to GLP-induced ChE abnormalities were interrelated in the Chinese Han population, we performed this genetic association study on a total of 230 workers previously exposed to GLP, including 115 cases with reduced serum ChE and 115 controls with normal serum ChE. Two even groups of cases and controls were enrolled. The CYP1A1 and CYP1B1 polymorphisms in both groups were genotyped using TaqMan. Subjects with the CYP1A1 rs619586 genotypes showed an increased risk of GLP-induced reduction of serum ChE, which was more evident in the following subgroups: female, > 35years old, history of GLP exposure time <10years and >10years, nonsmoker and nondrinker. The results show that CYP1A1 rs619586 was significantly associated with the GLP-induced reduction in serum ChE and could be a biomarker of susceptibility for Chinese GLP exposed workers. Because of a large number of people exposed to glyphosate, this study has a significance in protecting their health.
ESTHER : Cai_2020_Pestic.Biochem.Physiol_162_23
PubMedSearch : Cai_2020_Pestic.Biochem.Physiol_162_23
PubMedID: 31836050

Title : Inhibition of acetylcholinesterase activity and beta-amyloid oligomer formation by 6-bromotryptamine A, a multi-target anti-Alzheimer's molecule - Jin_2020_Oncol.Lett_19_1593
Author(s) : Jin X , Wang M , Shentu J , Huang C , Bai Y , Pan H , Zhang D , Yuan Z , Zhang H , Xiao X , Wu X , Ding L , Wang Q , He S , Cui W
Ref : Oncol Lett , 19 :1593 , 2020
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder characterized by learning and memory impairments. Recent studies have suggested that AD can be induced by multiple factors, such as cholinergic system dysfunction and beta-amyloid (Abeta) neurotoxicity. It was reported that 6-bromo-N-propionyltryptamine could treat neurological diseases, including AD. In the present study, 6-bromotryptamine A, a derivative of 6-bromo-N-propionyltryptamine, was synthesized by the condensation of 2-(6-bromo-1H-indol-3-yl)ethan-1-amine and 2-(4-bromophenyl)acetic acid, and was used as a potential anti-AD molecule. Furthermore, scopolamine can induce impairments of learning and memory, and was widely used to establish AD animal models. The results demonstrated that 6-bromotryptamine A significantly prevented scopolamine-induced short-term cognitive impairments, as revealed by various behavioral tests in mice. Furthermore, an acetylcholinesterase (AChE) activity assay revealed that 6-bromotryptamine A directly inhibited AChE activity. Notably, it was observed that 6-bromotryptamine A blocked the formation of Abeta oligomer, as evaluated by the dot blot assay. All these results suggested that 6-bromotryptamine A may be used to prevent impairments in short-term learning and memory ability possibly via the inhibition of AChE and the blockade of Abeta oligomer formation.
ESTHER : Jin_2020_Oncol.Lett_19_1593
PubMedSearch : Jin_2020_Oncol.Lett_19_1593
PubMedID: 31966085

Title : Characteristics of lipid droplets and the expression of proteins involved in lipolysis in the murine cervix during mid-pregnancy - Tao_2020_Reprod.Fertil.Dev_32_967
Author(s) : Tao L , Zhang H , Wang H , Li L , Huang L , Su F , Yuan X , Luo M , Ge L
Ref : Reprod Fertil Dev , 32 :967 , 2020
Abstract : Lipid droplets (LDs) are reservoirs of arachidonoyl lipids for prostaglandin (PG) E2 synthesis, and progesterone can stimulate PGE2 synthesis; however, the relationship between progesterone and LD metabolism in the murine cervix remains unclear. In the present study we examined LD distribution and changes in the expression of proteins involved in lipolysis and autophagy in the murine cervix during pregnancy, and compared the findings with those in dioestrous mice. During mid-pregnancy, LDs were predominantly distributed in the cervical epithelium. Electron microscopy revealed the transfer of numerous LDs from the basal to apical region in the luminal epithelium, marked catabolism of LDs, an elevated number of LDs and autophagosomes and a higher LD:mitochondrion size ratio in murine cervical epithelial cells (P<0.05). In addition, immunohistochemical and western blotting analyses showed significantly higher cAMP-dependent protein kinase, adipose triglyceride lipase and hormone-sensitive lipase expression, and a higher light chain 3 (LC3) II:LC3I ratio in the stroma and smooth muscles and, particularly, in murine cervical epithelial cells, during mid-pregnancy than late dioestrus. In conclusion, these results suggest that the enhanced lipolysis of LDs and autophagy in murine cervical tissues were closely related to pregnancy and were possibly controlled by progesterone because LD catabolism may be necessary for energy provision and PGE2 synthesis to maintain a closed pregnant cervix.
ESTHER : Tao_2020_Reprod.Fertil.Dev_32_967
PubMedSearch : Tao_2020_Reprod.Fertil.Dev_32_967
PubMedID: 32693909

Title : Acupuncture of the Beishu acupoint participates in regulatory effects of ginsenoside Rg1 on T cell subsets of rats with chronic fatigue syndrome - He_2020_Ann.Palliat.Med_9_3436
Author(s) : He J , Yu Q , Wu C , Sun Z , Wu X , Liu R , Zhang H
Ref : Ann Palliat Med , 9 :3436 , 2020
Abstract : BACKGROUND: There are close relationships between the spleen and limb muscles and thoughts. The study aims to test the effects of ginsenoside Rg1 in combination with acupuncture of the Beishu acupoint on T cell subsets of rats with chronic fatigue syndrome (CFS). METHODS: The model was set up by combining forced cold-water swimming with chronic restraint. The rats were randomly divided into blank control, model, ginsenoside, acupuncture, and ginsenoside plus acupuncture groups (n=10). For the acupuncture group, the Beishu acupoint was acupunctured on the 2nd day after modeling. For the ginsenoside group, the ginsenoside Rg1 solution was injected into the tail vein on the 2nd day after modeling. For the combination group, both processes were conducted. These groups were compared regarding exhausted swimming time, number of struggles, resting time, serum levels of IgA, IgG, IgM, IFN-alpha, IFN-beta, and IFN-gamma, lymphocyte transformation rate, T cell subsets, and skeletal muscle activities of malondialdehyde (MDA), total antioxidative capacity (T-AOC) and acetylcholinesterase (Ache). RESULTS: The exhausted swimming time, number of struggles, and resting time of combination group surpassed those in the ginsenoside and acupuncture groups significantly (P<0.05). The serum levels of IgA, IgG, IgM, IFN-beta, IFN-gamma, T-AOC, and Ache, together with CD3+ and CD8+ T cell percentages of combination groups, were significantly higher than those of ginsenoside and acupuncture groups. However, the IFN-alpha level, MDA activity, and CD4+ T cell percentage were significantly lower (P<0.05). Compared with the model group, the CD4+/CD8+ T cell ratios of acupuncture, ginsenoside, and combination groups decreased significantly (P<0.05). Compared with the combination group, the ratio of the ginsenoside group increased significantly (P<0.05). CONCLUSIONS: Both acupuncture of the Beishu acupoint and intravenous injection of ginsenoside Rg1 have anti-fatigue effects, and their combination works synergistically. This study supplies an experimental basis for joint therapy using acupuncture and drugs to combat fatigue synergistically.
ESTHER : He_2020_Ann.Palliat.Med_9_3436
PubMedSearch : He_2020_Ann.Palliat.Med_9_3436
PubMedID: 33065794

Title : Detoxification enzymes associated with butene-fipronil resistance in Epacromius coerulipes - Jin_2020_Pest.Manag.Sci_76_227
Author(s) : Jin Y , Gao Y , Zhang H , Wang L , Yang K , Dong H
Ref : Pest Manag Sci , 76 :227 , 2020
Abstract : BACKGROUND: Epacromius coerulipes is a widely distributed locust pest species. Chemical control is the main method used to kill locusts; however, this can result in the selection of locusts with resistance to chemical pesticides. Therefore, the study of resistance is of great significance for the sustainable management of locusts. RESULTS: In this study, to investigate the relationship between detoxification enzymes and butene-fipronil resistance in E. coerulipes, resistant strains of the locust were compared with sensitive strains. The synergism of synergistic agents was significantly enhanced, and the activities of multifunctional oxidase, carboxylesterase, and glutathione sulfur transferase were significantly increased. Transcriptome sequencing revealed 226 detoxification enzyme genes and 23 upregulated genes. Neighbor-joining was used to construct a phylogenetic tree of related gene families, which included 59 P450 genes, 52 carboxylesterases (CarE) genes, and 25 glutathione S-transferase (GST) genes. Reverse transcription polymerase chain reaction (RT-PCR) analysis results of overexpressed genes in the resistant population combined with a phylogenetic tree showed that four P450 genes belonged to the CYP6, CYP4, CYP18 and CYP302 families, two CarE genes belonged to Clade A families, and one GST gene belonged to the Sigma family. These family members were annotated as detoxification enzyme genes of metabolic insecticide in the transcriptome databases. CONCLUSIONS: This study showed that P450, CarE and GST together resulted in moderate resistance to butene-fipronil in locusts. The analysis revealed several overexpressed detoxification enzyme genes that will be the focus of future studies on the mechanism of resistance to butene-fipronil. (c) 2019 Society of Chemical Industry.
ESTHER : Jin_2020_Pest.Manag.Sci_76_227
PubMedSearch : Jin_2020_Pest.Manag.Sci_76_227
PubMedID: 31150148

Title : Monoterpene indole alkaloids with diverse skeletons from the stems of Rauvolfia vomitoria and their acetylcholinesterase inhibitory activities - Zhan_2020_Phytochemistry_177_112450
Author(s) : Zhan G , Miao R , Zhang F , Hao X , Zheng X , Zhang H , Zhang X , Guo Z
Ref : Phytochemistry , 177 :112450 , 2020
Abstract : Nine undescribed monoterpene indole alkaloids, rauvomitorine A-I, including an unprecedented C-9-methoxymethylene-sarpagine framework alkaloid, two rare suaveoline framework type alkaloids, and six yohimbine framework type alkaloids, as well as eleven known alkaloids, were isolated from the stems of Rauvolfia vomitoria Afzel. (Apocynaceae). The structures of the unreported alkaloids were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis with Cu Kalpha radiation. Rauvomitorine A with an unreported framework type represents the first example of C-9-methoxymethylene-sarpagine alkaloids and its plausible biosynthetic pathway was proposed. All the isolated alkaloids were evaluated their acetylcholinesterase inhibitory (AChE) activities and cytotoxicity against five cancer cell lines and some of them exhibited potential anti-AChE activities with IC50 values ranging from 49.76 to 186.62 muM. Importantly, this is the first report of the AChE inhibitory activities on suaveoline framework type alkaloids, suggesting this type of alkaloids may be valuable sources for the discovery of AChE inhibitory agents. A preliminary structure-activity relationship for AChE inhibitory activities of the isolated alkaloids is also discussed, providing some clues to designing lead compounds for AChE inhibitors.
ESTHER : Zhan_2020_Phytochemistry_177_112450
PubMedSearch : Zhan_2020_Phytochemistry_177_112450
PubMedID: 32580106

Title : Preparation of DHA-Rich Medium- and Long-Chain Triacylglycerols by Lipase-Catalyzed Acidolysis of Microbial Oil from Schizochytrium sp.with Medium-Chain Fatty Acids - Zou_2020_Appl.Biochem.Biotechnol_191_1294
Author(s) : Zou X , Ye L , He X , Wu S , Zhang H , Jin Q
Ref : Appl Biochem Biotechnol , 191 :1294 , 2020
Abstract : DHA-rich medium- and long-chain triacylglycerols (MLCT) were produced by lipase-catalyzed acidolysis of microbial oil from Schizochytrium sp. with medium-chain fatty acids (MCFA). Four commercial lipases, i.e., NS40086, Novozym 435, Lipozyme RM IM, and Lipozyme TL IM were screened based on their activity and fatty acid specificity. The selected conditions for MLCT synthesis were Lipozyme RM IM as catalyst, reaction time 6 h, lipase load 8 wt%, substrate molar ratio (MCFA/microbial oil) 3:1, and temperature 55 degreeC. Under the selected conditions, the lipase could be reused successively for 17 cycles without significant loss of lipase activity. The obtained product contained 27.53% MCFA, 95.29% at sn-1,3 positions, and 44.70% DHA, 69.77% at sn-2 position. Fifty-nine types of triacylglycerols (TAG) were identified, in which 35 types of TAG contained MCFA, the content accounting for 55.35%. This product enriched with DHA at sn-2 position and MCFA at sn-1,3 positions can improve its digestion and absorption under an infant's digestive system, and thus has potential to be used in infant formula to increase the bioavailability of DHA.
ESTHER : Zou_2020_Appl.Biochem.Biotechnol_191_1294
PubMedSearch : Zou_2020_Appl.Biochem.Biotechnol_191_1294
PubMedID: 32096059

Title : Monoacylglycerol Lipase Knockdown Inhibits Cell Proliferation and Metastasis in Lung Adenocarcinoma - Zhang_2020_Front.Oncol_10_559568
Author(s) : Zhang H , Guo W , Zhang F , Li R , Zhou Y , Shao F , Feng X , Tan F , Wang J , Gao S , Gao Y , He J
Ref : Front Oncol , 10 :559568 , 2020
Abstract : Abnormal metabolism is one of the hallmarks of cancer cells. Monoacylglycerol lipase (MGLL), a key enzyme in lipid metabolism, has emerged as an important regulator of tumor progression. In this study, we aimed to characterize the role of MGLL in the development of lung adenocarcinoma (LUAD). To this end, we used tissue microarrays to evaluate the expression of MGLL in LUAD tissue and assessed whether the levels of this protein are correlated with clinicopathological characteristics of LUAD. We found that the expression of MGLL is higher in LUAD samples than that in adjacent non-tumor tissues. In addition, elevated MGLL expression was found to be associated with advanced tumor progression and poor prognosis in LUAD patients. Functional studies further demonstrated that stable short hairpin RNA (shRNA)-mediated knockdown of MGLL inhibits tumor proliferation and metastasis, both in vitro and in vivo, and mechanistically, our data indicate that MGLL regulates Cyclin D1 and Cyclin B1 in LUAD cells. Moreover, we found that knockdown of MGLL suppresses the expression of matrix metalloproteinase 14 (MMP14) in A549 and H322 cells, and in clinical samples, expression of MMP14 is significantly correlated with MGLL expression. Taken together, our results indicate that MGLL plays an oncogenic role in LUAD progression and metastasis and may serve as a potential biomarker for disease prognosis and as a target for the development of personalized therapies.
ESTHER : Zhang_2020_Front.Oncol_10_559568
PubMedSearch : Zhang_2020_Front.Oncol_10_559568
PubMedID: 33363004

Title : The immunotoxicity and neurobehavioral toxicity of zebrafish induced by famoxadone-cymoxanil - Cheng_2020_Chemosphere_247_125870
Author(s) : Cheng B , Zhang H , Hu J , Peng Y , Yang J , Liao X , Liu F , Guo J , Hu C , Lu H
Ref : Chemosphere , 247 :125870 , 2020
Abstract : As a new protective and therapeutic fungicide, studies on famoxadone-cymoxanil are rare, and its toxicity to aquatic organisms has not been reported. In the present study, zabrafish embryos were exposed to several concentrations of famoxadone-cymoxanil at 10 hpf. Then, the changes of their shape, heart rate, development and function of innate and adaptive immune cells, oxidative stress, apoptosis, the expression of apoptosis-related genes and immune-related genes, the locomotor behavior were observed and detected in acute toxicity of famoxadone-cymoxanil. Our studies showed that, after exposure to famoxadone-cymoxanil, zebrafish embryos had decreased heart rate, shortened body length, swollen yolk sac. Secondly, the number of innate and adaptive immune cells was significantly reduced; and neutrophil migration and retention at the injury area were inhibited, indicating the developmental toxicity and immunotoxicity of famoxadone-cymoxanil on the zebrafish. We also found that the oxidative stress related indicators of embryos were changed significantly, and apoptosis were substantially increased. Further investigation of changes of some key genes in TLR signaling including TLR4, MYD88 and NF-kappaB p65 revealed that the mRNA expression of these genes was up-regulated. Meanwhile, the mRNA expression of some proinflammatory cytokines such as TNF-alpha, IFN-gamma, IL6 and IL-1beta was also up-regulated. In addition, the activity, the total distance, time and average speed were decreased along with the increase of exposure concentration. The absolute turn angle, sinuosity and the enzymatic activity of acetylcholinesterase (AChE) were also increased. These results suggested that famoxadone-cymoxanil can induce developmental toxicity, immunotoxicity and neurobehavioral toxicity in zebrafish larvae.
ESTHER : Cheng_2020_Chemosphere_247_125870
PubMedSearch : Cheng_2020_Chemosphere_247_125870
PubMedID: 31931321

Title : GDSL esterase\/lipases OsGELP34 and OsGELP110\/OsGELP115 are essential for rice pollen development - Zhang_2020_J.Integr.Plant.Biol__
Author(s) : Zhang H , Wang M , Li Y , Yan W , Chang Z , Ni H , Chen Z , Wu J , Xu C , Deng XW , Tang X
Ref : J Integr Plant Biol , : , 2020
Abstract : Pollen exine contains complex biopolymers of aliphatic lipids and phenolics. Abnormal development of pollen exine often leads to plant sterility. Molecular mechanisms regulating exine formation have been studied extensively but remain ambiguous. Here we report the analyses of three GDSL esterase/lipase protein genes, OsGELP34, OsGELP110, and OsGELP115, for rice exine formation. OsGELP34 was identified by cloning of a male sterile mutant gene. OsGELP34 encodes an endoplasmic reticulum protein and was mainly expressed in anthers during pollen exine formation. osgelp34 mutant displayed abnormal exine and altered expression of a number of key genes required for pollen development. OsGELP110 was previously identified as a gene differentially expressed in meiotic anthers. OsGELP110 was most homologous to OsGELP115, and the two genes showed similar gene expression patterns. Both OsGELP110 and OsGELP115 proteins were localized in peroxisomes. Individual knockout of OsGELP110 and OsGELP115 did not affect the plant fertility, but double knockout of both genes altered the exine structure and rendered the plant male sterile. OsGELP34 is distant from OsGELP110 and OsGELP115 in sequence, and osgelp34 and osgelp110/osgelp115 mutants were different in anther morphology despite both were male sterile. These results suggested that OsGELP34 and OsGELP110/OsGELP115 catalyze different compounds for pollen exine development. This article is protected by copyright. All rights reserved.
ESTHER : Zhang_2020_J.Integr.Plant.Biol__
PubMedSearch : Zhang_2020_J.Integr.Plant.Biol__
PubMedID: 32068333

Title : Significant association between the endothelial lipase gene 584C\/T polymorphism and coronary artery disease risk - Wu_2020_Biosci.Rep_40_
Author(s) : Wu YE , Ma L , Zhang H , Chen XR , Xu XY , Hu ZP
Ref : Bioscience Reports , 40 : , 2020
Abstract : Several studies have investigated a potential association between the endothelial lipase gene (LIPG) 584C/T polymorphism and susceptibility to coronary artery disease (CAD), but a uniform conclusion is yet to be reached. To better evaluate the true relationship between the LIPG 584C/T polymorphism and the risk of CAD, a meta-analysis of 14 case-control studies with 9731 subjects was performed. Relevant articles published through August 2020 were searched in the CNKI, PubMed, Embase and Web of Science databases. Thirteen articles, including 14 eligible case-control studies with 4025 cases and 5706 controls, were enrolled in the present meta-analysis. The Newcastle-Ottawa Scale (NOS) scores of the case-control studies ranged from 6 to 8. The pooled results indicated that there is a significant association between the LIPG 584C/T polymorphism and CAD in the homozygote comparison model and the allelic comparison model. Subgroup analyses revealed that the LIPG 584C/T mutation significantly decreased the risk of CAD in the subgroups of African, CAD, hospital-based (HB), and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) populations in some genetic models. No publication bias was found in our meta-analysis, which certifies the robustness of the current meta-analysis. Trial sequential analysis (TSA) also confirmed the stability of our results. The results of our meta-analysis indicate that the LIPG 584C/T polymorphism plays a protective role in the incidence of CAD. More high-quality case-control studies on various ethnicities are needed to confirm our results.
ESTHER : Wu_2020_Biosci.Rep_40_
PubMedSearch : Wu_2020_Biosci.Rep_40_
PubMedID: 32893849
Gene_locus related to this paper: human-LIPG

Title : Biodegradation of bis(2-hydroxyethyl) terephthalate by a newly isolated Enterobacter sp. HY1 and characterization of its esterase properties - Qiu_2020_J.Basic.Microbiol_60_699
Author(s) : Qiu L , Yin X , Liu T , Zhang H , Chen G , Wu S
Ref : J Basic Microbiol , 60 :699 , 2020
Abstract : Bis(2-hydroxyethyl) terephthalate (BHET) is an important compound produced from poly(ethylene terephthalate) (PET) cleavage. It was selected as the representative substance for the study of PET degradation. A bacterial strain HY1 that could degrade BHET was isolated and identified as Enterobacter sp. The optimal temperature and pH for BHET biodegradation were determined to be 30 degreesC and 8.0, respectively. The half-life of degradation was 70.20h at an initial BHET concentration of 1,000mg/L. The results of metabolites' analysis by liquid chromatograph-mass spectrometer revealed that BHET was first converted to mono-(2-hydroxyethyl) terephthalate (MHET) and then to terephthalic acid. Furthermore, an esterase-encoding gene, estB, was cloned from strain HY1, and the expressed enzyme EstB was characterized. The esterase has a molecular mass of approximately 25.13kDa, with an isoelectric point of 4.68. Its optimal pH and temperature were pH 8.0 and 40 degreesC, respectively. The analysis of the enzymatic products showed that EstB could hydrolyze one ester bond of BHET to MHET. To the best of authors' knowledge, this is the first report on the biodegradation characteristics of BHET by a member of the Enterobacter genus.
ESTHER : Qiu_2020_J.Basic.Microbiol_60_699
PubMedSearch : Qiu_2020_J.Basic.Microbiol_60_699
PubMedID: 32510669

Title : Relief of Cadmium-Induced Intestinal Motility Disorder in Mice by Lactobacillus plantarum CCFM8610 - Liu_2020_Front.Immunol_11_619574
Author(s) : Liu Y , Wu J , Xiao Y , Liu Q , Yu L , Tian F , Zhao J , Zhang H , Chen W , Zhai Q
Ref : Front Immunol , 11 :619574 , 2020
Abstract : Cadmium (Cd) is a toxic metal inducing a range of adverse effects on organs including liver and kidneys. However, the underlying molecular mechanisms of Cd-induced intestinal toxicity through dietary intake is poorly studied. This study evaluated the toxic effects of Cd on intestinal physiology and confirmed the effectiveness of the protective mechanism of the probiotic Lactobacillus plantarum CCFM8610 against chronic Cd toxicity. After treatment with Cd, the HT-29 cell line was subjected to iTRAQ analysis, which revealed that changes in the proteomic profiles after Cd exposure were related to pathways involved in the stress response and carbohydrate metabolism. The results of an animal trial also indicated that 10 weeks of Cd exposure decreased the fecal water content and contractile response of colonic muscle strips in mice, and delayed the excretion time of the first black feces. L. plantarum CCFM8610 treatment provided protective effects against these Cd-induced intestinal motility dysfunctions by recovering the levels of neurotransmitters, including substance P, acetyl cholinesterase, vasoactive intestinal peptide, 5-hydroxytryptamine, calcitonin gene-related peptide, and nitric oxide, and suppressing the cellular stress response in mice (e.g., the inhibition of mitogen-activated protein kinase pathways). The administration of this probiotic was also observed to reduce Cd levels in the tissues and blood of the mice. Our results suggest a newly identified protective mechanism of probiotics against Cd toxicity that involves the recovery of intestinal motility and increase in fecal cadmium excretion.
ESTHER : Liu_2020_Front.Immunol_11_619574
PubMedSearch : Liu_2020_Front.Immunol_11_619574
PubMedID: 33362802

Title : Post-exercise Effects and Long-Term Training Adaptations of Hormone Sensitive Lipase Lipolysis Induced by High-Intensity Interval Training in Adipose Tissue of Mice - Liu_2020_Front.Physiol_11_535722
Author(s) : Liu Y , Dong G , Zhao X , Huang Z , Li P , Zhang H
Ref : Front Physiol , 11 :535722 , 2020
Abstract : Although studies have proven that high-intensity interval training (HIIT) shows a comparable effect to moderate-intensity continuous training (MICT) on reducing body fat, especially visceral fat, the mechanism is still unclear. Since MICT consumes more fat during exercise, the mechanism of HIIT weight loss may be related to post-exercise effects, long-term adaptive changes, and hormone sensitive lipase (HSL). The objective of this study was to compare the post-effects of acute exercise, long-term adaptive changes on HSL activity, and catecholamine-induced lipolysis between HIIT and MICT. Following a 14-week high-fat diet (HFD), obese female C57Bl/6 mice were divided into acute exercise groups (one time training, sacrificed at rest and 0, 1, and 12 h after exercise, n = 49), -L groups (12-week long-term training, 12-h fasting, n = 21), and -C groups (12-week training, primary adipocytes were isolated and stimulated by catecholamine in vitro, n = 18). MICT or HIIT treadmill protocols (running distance matched) were carried out during training. Comparison of acute exercise effects by two-way ANOVA showed no time x group interaction effect, however, a significant increase in HSL-Ser563 (at 0 and 1 h) and Ser660 phosphorylation (at 0, 1, and 12 h) in inguinal (subcutaneous) fat was only observed in HIIT mice (p < 0.05 vs. rest), but not in MICT mice. The periuterine (visceral) fat HSL expression and phosphorylation of HIIT mice was similar to or lower than MICT mice. After long-term training, 12-h fasting significantly increased periuterine fat Ser563 phosphorylation in HIIT mice (p < 0.05), but there was no change in MICT mice. Under stimulation of catecholamine in vitro, isolated primary adipocytes from periuterine fat of long-term HIIT mice showed a higher Ser563 increase than that found in MICT mice (p < 0.05). The quantity of triglyceride (TG) lipid bonds (representing lipolysis level) was significantly lower after HIIT than MICT (p < 0.05). The results indicate that (1) acute HIIT can induce an increase of HSL phosphorylation in subcutaneous fat lasting at least 12 h, implying longer post-exercise lipolysis than MICT and (2) long-time HIIT has a better effect on improving catecholamine resistance of visceral adipocytes caused by a HFD, which allows fat to be mobilized more easily when stimulated.
ESTHER : Liu_2020_Front.Physiol_11_535722
PubMedSearch : Liu_2020_Front.Physiol_11_535722
PubMedID: 33324231

Title : Effects of lincomycin hydrochloride on the neurotoxicity of zebrafish - Cheng_2020_Ecotoxicol.Environ.Saf_201_110725
Author(s) : Cheng B , Jiang F , Su M , Zhou L , Zhang H , Cao Z , Liao X , Xiong G , Xiao J , Liu F , Lu H
Ref : Ecotoxicology & Environmental Safety , 201 :110725 , 2020
Abstract : Lincomycin hydrochloride is one of the commonly used drugs in clinic. However, it has many side effects on patients, and its mechanism is still poorly understood. In this study, 6 h post-fertilization (6 hpf) zebrafish embryos were exposed to several concentrations of lincomycin hydrochloride (15, 30, 60 mug/mL) for up to 24 or 96 hpf to detect their developmental toxicity and neurotoxicity, and to 6 days post-fertilization (6 dpf) to detect their behavioral toxicity. Our results showed that lincomycin hydrochloride could lead to embryonic head deformities (unclear ventricles, smaller ventricles, fewer new neurons). The studies showed that the frequency of spontaneous tail flick of zebrafish embryo increased at 24 hpf, and the lincomycin hydrochloride exposed zebrafish embryos showed increased heart rate, shorter body length, and yolk sac edema with severe pericardial edema at 96 hpf. The studies also showed that lincomycin hydrochloride increased oxidative stress level, Acetylcholinesterase (AChE) activity, ATPase activity and apoptosis in zebrafish larvae. In addition, the swimming behavior of zebrafish larvae decreased with the increase of lincomycin hydrochloride concentration, but the angular velocity and meandering degree increased, which might be due to the decreased activity of AChE and ATPase, as well as the decreased expression of genes related to neurodevelopment and neurotransmitter system, leading to the change of their motor behaviors. In summary, we found that lincomycin hydrochloride induced developmental toxicity and neurotoxicity in zebrafish larvae, contributing to a more comprehensive evaluation of the safety of the drug.
ESTHER : Cheng_2020_Ecotoxicol.Environ.Saf_201_110725
PubMedSearch : Cheng_2020_Ecotoxicol.Environ.Saf_201_110725
PubMedID: 32474209

Title : [1,5]-Hydride Shift-Cyclization versus C(sp(2))-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines - Szaloki_2020_Molecules_25_
Author(s) : Szaloki Vargane D , Toth L , Buglyo B , Kiss-Szikszai A , Mandi A , Matyus P , Antus S , Chen Y , Li D , Tao L , Zhang H , Kurtan T
Ref : Molecules , 25 : , 2020
Abstract : Domino cyclization reactions of N-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp(2))-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of N-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7bH-quinolino [1,2-d][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp(3))-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-endo cyclization took place in a complete diastereoselective manner. In two cases, the enantiomers of the chiral condensed new 1,4-benzoxazepine systems were separated by chiral HPLC, HPLC-ECD spectra were recorded, and absolute configurations were determined by time-dependent density functional theory- electronic circular dichroism (TDDFT-ECD) calculations. In contrast, the analogue reaction of the regioisomeric N-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an SEAr reaction [C(sp(2))-H functionalization] resulting in a condensed acridane derivative. The AChE inhibitory assays of the new derivatives revealed that the acridane derivative had a 6.98 muM IC50 value.
ESTHER : Szaloki_2020_Molecules_25_
PubMedSearch : Szaloki_2020_Molecules_25_
PubMedID: 32168821

Title : Cross-resistance and Fitness Cost Analysis of Resistance to Thiamethoxam in Melon and Cotton Aphid (Hemiptera: Aphididae) - Zhang_2020_J.Econ.Entomol__
Author(s) : Zhang H , Chen A , Shan T , Dong W , Shi X , Gao X
Ref : J Econ Entomol , : , 2020
Abstract : The melon/cotton aphid, Aphis gossypii Glover, is a notorious pest in many crops. The neonicotinoid insecticide thiamethoxam is widely used for A. gossypii control. To evaluate thiamethoxam resistance risk, a melon/cotton aphid strain with an extremely high level of resistance to thiamethoxam (>2,325.6-fold) was established after selection with thiamethoxam for 24 generations. Additionally, the cross-resistance pattern to other neonicotinoids and fitness were analyzed. The cross-resistance results showed the thiamethoxam-resistant strain had extremely high levels of cross-resistance against clothianidin (>311.7-fold) and nitenpyram (299.9-fold), high levels of cross-resistance against dinotefuran (142.3-fold) and acetamiprid (76.6-fold), and low cross-resistance against imidacloprid (9.3-fold). Compared with the life table of susceptible strain, the thiamethoxam-resistant strain had a relative fitness of 0.950, with significant decreases in oviposition days and fecundity and prolonged developmental duration. The molecular mechanism for fitness costs was studied by comparing the mRNA expression levels of juvenile hormone acid O-methyltransferase (JHAMT), juvenile hormone-binding protein (JHBP), juvenile hormone epoxide hydrolase (JHEH), ecdysone receptor (EcR), ultraspiracle protein (USP), and Vitellogenin (Vg) in the susceptible and thiamethoxam-resistant strains. Significant overexpression of JHEH and JHBP and downregulation of EcR and Vg expression were found in the thiamethoxam-resistant strain. These results indicate that A. gossypii has the potential to develop extremely high resistance to thiamethoxam after continuous exposure, with a considerable fitness cost and cross-resistance to other neonicotinoids.
ESTHER : Zhang_2020_J.Econ.Entomol__
PubMedSearch : Zhang_2020_J.Econ.Entomol__
PubMedID: 32372079

Title : The relationship of lipoprotein-associated phospholipase A2 activity with the seriousness of coronary artery disease - Zhang_2020_BMC.Cardiovasc.Disord_20_295
Author(s) : Zhang H , Gao Y , Wu D , Zhang D
Ref : BMC Cardiovasc Disord , 20 :295 , 2020
Abstract : BACKGROUND: The level of lipoprotein-associated phospholipase A2 (LP-PLA2) in serum is independently correlated to coronary artery diseases (CAD). The aim of the study was to determine whether LP-PLA2 activity is positively associated with the seriousness of CAD. METHODS: Amount to 1056 patients suspected of having CAD underwent coronary angiography (CAG) to determine the seriousness of CAD. According to the amount of diseased coronary branches, the 1056 patients were split into three groups: single-vessel stenosis group, multiple-vessels stenosis group (> or = 2 diseased coronary branches),and control group (no diseased coronary branches). According to CAG results, electrocardiography, cardiac biomarker, and clinical presentation, all patients were split into four groups: acute myocardial infarction (AMI), unstable angina (UA), stable angina (SA), and control groups (excluding CAD). The activity of LP-PLA2 was compared statistically among the subgroups. Receiver operating characteristic analysis was applied to investigate the role of LP-PLA2 in evaluating the presence and seriousness of CAD. RESULTS: The level of LP-PLA2 increased in line with the number of diseased coronary branches. The levels of LP-PLA2 in the AMI and UA groups were observably higher when compared with the control and SA groups. LP-PLA2 had 75.6% sensitivity and 67.3% specificity for recognizing CAD, and 53.0% sensitivity and 80.3% specificity for recognizing severe coronary artery lesions. CONCLUSION: The activity of LP-PLA2 is positively correlated to the seriousness of CAD.
ESTHER : Zhang_2020_BMC.Cardiovasc.Disord_20_295
PubMedSearch : Zhang_2020_BMC.Cardiovasc.Disord_20_295
PubMedID: 32546193

Title : A De Novo Designed Esterase with p-Nitrophenyl Acetate Hydrolysis Activity - Li_2020_Molecules_25_4658
Author(s) : Li G , Xu L , Zhang H , Liu J , Yan J , Yan Y
Ref : Molecules , 25 :4658 , 2020
Abstract : Esterases are a large family of enzymes with wide applications in the industry. However, all esterases originated from natural sources, limiting their use in harsh environments or newly- emerged reactions. In this study, we designed a new esterase to develop a new protocol to satisfy the needs for better biocatalysts. The ideal spatial conformation of the serine catalytic triad and the oxygen anion hole at the substrate-binding site was constructed by quantum mechanical calculation. The catalytic triad and oxygen anion holes were then embedded in the protein scaffold using the new enzyme protocol in Rosetta 3. The design results were subsequently evaluated, and optimized designs were used for expression and purification. The designed esterase had significant lytic activities towards p-nitrophenyl acetate, which was confirmed by point mutations. Thus, this study developed a new protocol to obtain novel enzymes that may be useful in unforgiving environments or novel reactions.
ESTHER : Li_2020_Molecules_25_4658
PubMedSearch : Li_2020_Molecules_25_4658
PubMedID: 33066055
Gene_locus related to this paper: aspor-cutas , fusso-cutas , hevbr-hnl

Title : Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6\/JAK2\/STAT3 signaling in glioma - Zhou_2020_Cell.Oncol.(Dordr)_43_461
Author(s) : Zhou J , Jiang Y , Zhao J , Zhang H , Fu J , Luo P , Ma Y , Zou D , Gao H , Hu J , Zhang Y , Jing Z
Ref : Cell Oncol (Dordr) , 43 :461 , 2020
Abstract : PURPOSE: The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown. METHODS: Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays. RESULTS: We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling. CONCLUSIONS: Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.
ESTHER : Zhou_2020_Cell.Oncol.(Dordr)_43_461
PubMedSearch : Zhou_2020_Cell.Oncol.(Dordr)_43_461
PubMedID: 32207044
Gene_locus related to this paper: human-NDRG2

Title : An efficient LSPR method to quantitatively detect dimethoate: Development, characterization and evaluation - Li_2020_PLoS.One_15_e0239632
Author(s) : Li D , Zhang Y , Guo Q , Sun X , Zhang H , Wang S , Birech Z , Hu J
Ref : PLoS ONE , 15 :e0239632 , 2020
Abstract : In recent years, there has been growing concern among consumers about pesticide contamination in fruits. Therefore, rapid, reliable, and consistent detection methods for OPPs, especially dimethoate, are crucially needed. The existing quantitative methods for detecting dimethoate are not suitable for rapid measuring system such as the dimethoate samples from two channels. Hence this paper examines the utilization of a dual-channel system for utilize the absorption variations of the Localized Surface Plasmon Resonance (LSPR) bands of gold nanoparticles (AuNPs) were investigate for detection of dimethoate. Under optimized conditions, the relationship between concentrations of dimethoate and absorbance ratios (A(520)/A(640)) was linearly found in the concentration range of 10-100 nM. Result from the experiment shows that both channels exhibit a linear correlation coefficient as high as 0.97 and a limit of detection (LOD) as low as 5.5 nM. This LSPR detection system was characterized by testing the dimethoate in apple samples and the recovery rates were found to be in the range of 85.90% to 107.37%. The proposed dual-channel LSPR system for detecting dimethoate creating a new approach for detecting organophosphate insecticide in agricultural fields. It could lay the foundation for designing a high-throughput analysis of the insecticides using a wavelength division multiplexing switch (WDMS).
ESTHER : Li_2020_PLoS.One_15_e0239632
PubMedSearch : Li_2020_PLoS.One_15_e0239632
PubMedID: 32970749

Title : Transcriptomic analysis of Chlorimuron-ethyl degrading bacterial strain Klebsiella jilinsis 2N3 - Zhang_2019_Ecotoxicol.Environ.Saf_183_109581
Author(s) : Zhang C , Hao Q , Zhang S , Zhang Z , Zhang X , Sun P , Pan H , Zhang H , Sun F
Ref : Ecotoxicology & Environmental Safety , 183 :109581 , 2019
Abstract : Chlorimuron-ethyl is a sulfonylurea herbicide with a long residual period in the field and is toxic to rotational crops. Klebsiella jilinsis 2N3 is a gram-negative bacterium that can rapidly degrade Chlorimuron-ethyl. In this study, the gene expression changes in strain 2N3 during degradation of Chlorimuron-ethyl was analyzed by RNA-Seq. Results showed that 386 genes were up-regulated and 453 genes were down-regulated. KEGG pathway enrichment analysis revealed the highest enrichment ratio in the pathway of sulfur metabolism. On the basis of the functional annotation and gene expression, we predicted that carboxylesterase, monooxygenase, glycosyltransferase, and cytochrome P450 were involved in the metabolism of Chlorimuron-ethyl biodegradation. Results of qRT-PCR showed that the relative mRNA expression levels of these genes were higher in treatment group than those in control group. The cytochrome P450 encoded by Kj-CysJ and the alkanesulfonate monooxygenase encoded by Kj-SsuD were predicted and further experimentally confirmed by gene knockout as the key enzymes in the biodegradation process. Cultured in basal medium containing Chlorimuron-ethyl (5mgL(-1)) in 36h, the strains of DeltaKj-CysJ, DeltaKj-SsuD, and WT reached the highest OD600 values of 0.308, 0.873, and 1.085, and the highest degradation rates of Chlorimuron-ethyl of 11.83%, 96.21%, and 95.62%, respectively.
ESTHER : Zhang_2019_Ecotoxicol.Environ.Saf_183_109581
PubMedSearch : Zhang_2019_Ecotoxicol.Environ.Saf_183_109581
PubMedID: 31446172

Title : Chemical characterization of the main bioactive polyphenols from the roots of Morus australis (mulberry) - Guo_2019_Food.Funct_10_6915
Author(s) : Guo S , Liu L , Zhang S , Yang C , Yue W , Zhao H , Ho CT , Du J , Zhang H , Bai N
Ref : Food Funct , 10 :6915 , 2019
Abstract : Morus species, commonly known as mulberry, is widely distributed in China. The mulberry tree is a high-value plant in agriculture. Morus australis is one of the major Morus species growing in Northern China. However, the biological properties of the main constituents of M. australis roots were not well studied. In the present study, through extensive chromatographic and spectral analysis, 12 phenolic compounds were isolated and identified from the M. australis roots. Compounds 1, 2, 8, 9 and 12 were isolated from M. australis roots for the first time. Antitumor activities of these polyphenols were studied on the A549 cell line. Compounds 1, 5 and 6 exhibited cytotoxicity on A549 cells and induced apoptosis in A549 cells via the intrinsic mitochondrial pathway. They also mediated inhibition of autophagic flux contributed cell death via the PI3k/Akt/mTOR pathway. In order to explore more potential bioactivities of these isolates, alpha-glucosidase, acetylcholinesterase and tyrosinase inhibitory activities were studied, and the results demonstrated that the inhibitory activity of these polyphenols on enzymes was not defined by their basic structural skeletons, but by the substituted position.
ESTHER : Guo_2019_Food.Funct_10_6915
PubMedSearch : Guo_2019_Food.Funct_10_6915
PubMedID: 31588440

Title : Lycodine-type alkaloids from Lycopodiastrum casuarinoides and their acetylcholinesterase inhibitory activity - Feng_2019_Fitoterapia__104378
Author(s) : Feng Z , Chen S , Wang W , Feng L , Dong Y , Zou Y , Ke C , Tang C , Yao S , Zhang H , Gan L , Ye Y , Lin L
Ref : Fitoterapia , :104378 , 2019
Abstract : Five previously undescribed lycodine-type alkaloids, named huperzine Y (1), 8,15-epoxy-N-demethylhuperzinine (2), 7-hydroxyl-huperzinine (3), huperzine Z (4), and huperzine D N-oxide (5), were isolated from the whole plants of Lycopodiastrum casuarinoides (Lycopodiaceae), along with ten known analogues. The structures of the new compounds were elucidated by means of spectroscopic technique (IR, UV, MS and NMR). The absolute configurations of the new compounds were established on the basis of comparison of their experimental and TD-DFT (time-dependent density functional theory) calculated ECD spectra. Moreover, all the isolates were evaluated for acetylcholinesterase (AChE) inhibitory activity. Only huperzine C showed moderate activity, with an IC50 value of 0.525+/-0.140muM, which was comparable with the positive control, huperzine A (IC50=0.143+/-0.029muM).
ESTHER : Feng_2019_Fitoterapia__104378
PubMedSearch : Feng_2019_Fitoterapia__104378
PubMedID: 31676395

Title : Insecticidal effect of aconitine on the rice brown planthoppers - Wei_2019_PLoS.One_14_e0221090
Author(s) : Wei S , Zhang H , Li B , Ji J , Shao X
Ref : PLoS ONE , 14 :e0221090 , 2019
Abstract : The brown planthopper, Nilaparvata lugens (Stal), severely damages rice production and develops high level resistance to several classes of insecticides. To find potential insecticidal resources is always important. As an environmentally friendly compound, aconitine exhibits potential pesticide features. In the present study, the pesticide and knockdown effects of aconitine were first tested on the brown planthopper. The results showed that the knockdown rates for an aconitine concentration of 200 ppm was 83.6%. The insecticidal LD50 was 22.68 ng/pest (95% CI, 17.75-28.99). The molecular mechanisms responding to aconitine application were analyzed through transcriptional sequencing. Compared to that of the knockdown nymphs of the brown planthoppers, the enzymes CYP3A4, UDP-glucuronosyltransferase (UGT), GST, carboxylesterase (EC3.1.1.1), and GABAergic synapse were up-regulated. We inferred that aconitine might be neurotoxic to the brown planthoppers, and the conscious nymphs resist the drug neurotoxicity through the upregulation of CYP3A4, UGT, and GABA receptor mutation. Although aconitine is not safe for mammals, it may be a leading compound to develop novel insecticides.
ESTHER : Wei_2019_PLoS.One_14_e0221090
PubMedSearch : Wei_2019_PLoS.One_14_e0221090
PubMedID: 31426056

Title : Design, synthesis and evaluation of chalcone Mannich base derivatives as multifunctional agents for the potential treatment of Alzheimer's disease - Zhang_2019_Bioorg.Chem_87_395
Author(s) : Zhang X , Song Q , Cao Z , Li Y , Tian C , Yang Z , Zhang H , Deng Y
Ref : Bioorg Chem , 87 :395 , 2019
Abstract : A series of chalcone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease based on the multi-target directed ligands design strategy. In vitro assays demonstrated that most of the derivatives exerted potent selective inhibitory potency on AChE with good multifunctional properties. Among them, representative compound 7c exhibited moderate inhibitory potency for EeAChE (IC50=0.44muM) and MAO-B inhibition (IC50=1.21muM), good inhibitory effect on self-induced Abeta1-42 aggregation (55.0%, at 25muM), biometal chelating property, moderate antioxidant activity with a value 1.93-fold of Trolox. Moreover, both kinetic analysis of AChE inhibition and molecular modeling study revealed that 7c showed a mixed-type inhibition, binding simultaneously to CAS and PAS of AChE. In addition, 7c also displayed high BBB permeability. These properties indicated 7c may be a promising multifunctional agent for the treatment of AD.
ESTHER : Zhang_2019_Bioorg.Chem_87_395
PubMedSearch : Zhang_2019_Bioorg.Chem_87_395
PubMedID: 30921741

Title : Functional Characterization of LIPA (Lysosomal Acid Lipase) Variants Associated With Coronary Artery Disease - Evans_2019_Arterioscler.Thromb.Vasc.Biol_39_2480
Author(s) : Evans TD , Zhang X , Clark RE , Alisio A , Song E , Zhang H , Reilly MP , Stitziel NO , Razani B
Ref : Arterioscler Thromb Vasc Biol , 39 :2480 , 2019
Abstract : OBJECTIVE: LIPA (lysosomal acid lipase) mediates cholesteryl ester hydrolysis, and patients with rare loss-of-function mutations develop hypercholesterolemia and severe disease. Genome-wide association studies of coronary artery disease have identified several tightly linked, common intronic risk variants in LIPA which unexpectedly associate with increased mRNA expression. However, an exonic variant (rs1051338 resulting in T16P) in linkage with intronic variants lies in the signal peptide region and putatively disrupts trafficking. We sought to functionally investigate the net impact of this locus on LIPA and whether rs1051338 could disrupt LIPA processing and function to explain coronary artery disease risk. Approach and Results: In monocytes isolated from a large cohort of healthy individuals, we demonstrate both exonic and intronic risk variants are associated with increased LIPA enzyme activity coincident with the increased transcript levels. To functionally isolate the impact of rs1051338, we studied several in vitro overexpression systems and consistently observed no differences in LIPA expression, processing, activity, or secretion. Further, we characterized a second common exonic coding variant (rs1051339), which is predicted to alter LIPA signal peptide cleavage similarly to rs1051338, yet is not linked to intronic variants. rs1051339 also does not impact LIPA function in vitro and confers no coronary artery disease risk. CONCLUSIONS: Our findings show that common LIPA exonic variants in the signal peptide are of minimal functional significance and suggest coronary artery disease risk is instead associated with increased LIPA function linked to intronic variants. Understanding the mechanisms and cell-specific contexts of LIPA function in the plaque is necessary to understand its association with cardiovascular risk.
ESTHER : Evans_2019_Arterioscler.Thromb.Vasc.Biol_39_2480
PubMedSearch : Evans_2019_Arterioscler.Thromb.Vasc.Biol_39_2480
PubMedID: 31645127
Gene_locus related to this paper: human-LIPA

Title : Structural Basis of Fullerene Derivatives as Novel Potent Inhibitors of Protein Acetylcholinesterase without Catalytic Active Site Interaction: Insight into the Inhibitory Mechanism through Molecular Modeling Studies - Wan_2019_J.Biomol.Struct.Dyn__1
Author(s) : Wan Y , Guan S , Qian M , Huang H , Han F , Wang S , Zhang H
Ref : J Biomol Struct Dyn , :1 , 2019
Abstract : Acetylcholinesterase (AChE) is an important kind of esterase that plays a key biological role in the central and peripheral nervous system. Recent research has demonstrated that some fullerene derivatives serve as a new nanoscale-class of potent inhibitors of AChE, but the specific inhibition mechanism remains unclear. In the present article, several molecular modeling methods, such as molecular docking, molecular dynamics simulations, and molecular mechanics/generalized Born surface area calculations, were used for the investigation of the binding mode and inhibition mechanism of fullerene inhibitions for AChE. Results revealed that fullerene inhibitors block the entrance of substrates by binding with the peripheral anionic site (PAS) region. Thus, fullerene derivatives might mainly serve as competitive inhibitors. The - interactions of a fullerene backbone with AChE are at the same level in different single side chain systems and seem to be related to the length or aromaticity of the side chain. The inhibitor with multi hydroxyl side chains shows an obviously large electrostatic interaction as it forms additional hydrogen bonds with AChE. Moreover, fullerene derivatives might exhibit noncompetitive inhibition partly by affecting some secondary structures around them. Thus, the destructions of these secondary structures can lead to conformational changes in some important regions, such as the catalytic triad and acyl pocket. The investigation is of great importance to the discovery of good fullerene inhibitors.
ESTHER : Wan_2019_J.Biomol.Struct.Dyn__1
PubMedSearch : Wan_2019_J.Biomol.Struct.Dyn__1
PubMedID: 30706763

Title : HFIP-Functionalized Co3 O4 Micro-Nano-Octahedra\/rGO as a Double-Layer Sensing Material for Chemical Warfare Agents - Alali_2019_Chemistry_25_11892
Author(s) : Alali KT , Liu J , Chen R , Liu Q , Zhang H , Li J , Hou J , Li R , Wang J
Ref : Chemistry , 25 :11892 , 2019
Abstract : Semiconductor metal oxides (SMO)-based gas-sensing materials suffer from insufficient detection of a specific target gas. Reliable selectivity, high sensitivity, and rapid response-recovery times under various working conditions are the main requirements for optimal gas sensors. Chemical warfare agents (CWA) such as sarin are fatal inhibitors of acetylcholinesterase in the nerve system. So, sensing materials with high sensitivity and selectivity toward CWA are urgently needed. Herein, micro-nano octahedral Co3 O4 functionalized with hexafluoroisopropanol (HFIP) were deposited on a layer of reduced graphene oxide (rGO) as a double-layer sensing materials. The Co3 O4 micro-nano octahedra were synthesized by direct growth from electrospun fiber templates calcined in ambient air. The double-layer rGO/Co3 O4 -HFIP sensing materials presented high selectivity toward DMMP (sarin agent simulant, dimethyl methyl phosphonate) versus rGO/Co3 O4 and Co3 O4 sensors after the exposure to various gases owing to hydrogen bonding between the DMMP molecules and Co3 O4 -HFIP. The rGO/Co3 O4 -HFIP sensors showed high stability with a response signal around 11.8 toward 0.5 ppm DMMP at 125 degrees C, and more than 75 % of the initial response was maintained under a saturated humid environment (85 % relative humidity). These results prove that these double-layer inorganic-organic composite sensing materials are excellent candidates to serve as optimal gas-sensing materials.
ESTHER : Alali_2019_Chemistry_25_11892
PubMedSearch : Alali_2019_Chemistry_25_11892
PubMedID: 31309626

Title : PMBD: a Comprehensive Plastics Microbial Biodegradation Database - Gan_2019_Database.(Oxford)_2019_bav119
Author(s) : Gan Z , Zhang H
Ref : Database (Oxford) , 2019 :bav119 , 2019
Abstract : Since the invention over a hundred years ago, plastics have been used in many applications, and they are involved in every aspect of our lives. The extensive usage of plastics results in a tremendous amount of waste, which has become a severe burden on the environment. Several degradation approaches exist in nature to cope with ever-increasing plastic waste. Among these approaches, biodegradation by microorganisms has emerged as a natural way, which is favored by many environmentally conscious societies. To facilitate the study on biodegradation of plastics, we developed an online resource, Plastics Microbial Biodegradation Database (PMBD), to gather and present the information about microbial biodegradation of plastics. In this database, 949 microorganisms-plastics relationships and 79 genes involved in the biodegradation of plastics were manually collected and confirmed through literature searching. In addition, more than 8000 automatically annotated enzyme sequences, which were predicted to be involved in the plastics biodegradation, were extracted from the TrEMBL section of the UniProt database. The PMBD database is presented with a website at http://pmbd.genome-mining.cn/home. Data may be accessed through browsing or searching. Also included on the website are a sequence alignment tool and a function prediction tool.
ESTHER : Gan_2019_Database.(Oxford)_2019_bav119
PubMedSearch : Gan_2019_Database.(Oxford)_2019_bav119
PubMedID: 31738435

Title : The genome of broomcorn millet - Zou_2019_Nat.Commun_10_436
Author(s) : Zou C , Li L , Miki D , Li D , Tang Q , Xiao L , Rajput S , Deng P , Peng L , Jia W , Huang R , Zhang M , Sun Y , Hu J , Fu X , Schnable PS , Chang Y , Li F , Zhang H , Feng B , Zhu X , Liu R , Schnable JC , Zhu JK
Ref : Nat Commun , 10 :436 , 2019
Abstract : Broomcorn millet (Panicum miliaceum L.) is the most water-efficient cereal and one of the earliest domesticated plants. Here we report its high-quality, chromosome-scale genome assembly using a combination of short-read sequencing, single-molecule real-time sequencing, Hi-C, and a high-density genetic map. Phylogenetic analyses reveal two sets of homologous chromosomes that may have merged ~5.6 million years ago, both of which exhibit strong synteny with other grass species. Broomcorn millet contains 55,930 protein-coding genes and 339 microRNA genes. We find Paniceae-specific expansion in several subfamilies of the BTB (broad complex/tramtrack/bric-a-brac) subunit of ubiquitin E3 ligases, suggesting enhanced regulation of protein dynamics may have contributed to the evolution of broomcorn millet. In addition, we identify the coexistence of all three C4 subtypes of carbon fixation candidate genes. The genome sequence is a valuable resource for breeders and will provide the foundation for studying the exceptional stress tolerance as well as C4 biology.
ESTHER : Zou_2019_Nat.Commun_10_436
PubMedSearch : Zou_2019_Nat.Commun_10_436
PubMedID: 30683860
Gene_locus related to this paper: panmi-a0a3l6qvl9 , 9poal-a0a2s3hbt0 , panmi-a0a3l6sxg5 , 9poal-a0a2t7cdl4 , panmi-a0a3l6ta96 , panmi-a0a3l6qv47 , panmi-a0a3l6s688 , panmi-a0a3l6tph0

Title : Long noncoding RNA ABHD11-AS1 functions as a competing endogenous RNA to regulate papillary thyroid cancer progression by miR-199a-5p\/SLC1A5 axis - Zhuang_2019_Cell.Death.Dis_10_620
Author(s) : Zhuang X , Tong H , Ding Y , Wu L , Cai J , Si Y , Zhang H , Shen M
Ref : Cell Death Dis , 10 :620 , 2019
Abstract : With the increasing incidence of papillary thyroid cancer (PTC), more attention has been paid to exploring the mechanism of PTC initiation and progression. In addition, ectopic expression of long noncoding RNAs (lncRNAs) is reported to play a pivotal role in multiple human cancers. Based on these findings, we examined lncRNA ABHD11 antisense RNA 1 (ABHD11-AS1) expression and its clinical significance, biological function and mechanism in PTC. First, we analyzed thyroid ABHD11-AS1 expression in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, qRT-PCR was applied to detect the expression in paired PTC tissues and adjacent normal tissues, as well as in PTC cell lines (TPC-1 and K-1) and a normal thyroid follicular epithelium cell line (Nthy-ori3-1). In addition, we validated the relationship between ABHD11-AS1 expression and clinicopathological features by the Pearson X(2) test. The oncogenic role of ABHD11-AS1 and its regulation of miR-199a-5p in PTC were examined by biological assays. Finally, bioinformatics analysis and mechanism assays were used to elucidate the underlying mechanism. We found that ABHD11-AS1 was remarkably overexpressed in PTC, and high expression was related to tumor size, lymph node metastasis, extrathyroidal extension and advanced TNM stage. Moreover, ABHD11-AS1 enhanced the abilities of cell proliferation, migration, and invasion, inhibited apoptosis in vitro, promoted tumorigenesis in vivo via sponging miR-199a-5p and then induced SLC1A5 activation. In addition, rescue assays were performed to confirm the ABHD11-AS1/miR-199a-5p/SLC1A5 axis. Taken together, the data show that ABHD11-AS1 acts as a competing endogenous RNA (ceRNA) to exert malignant properties in PTC through the miR-199a-5p/SLC1A5 axis. Therefore, our study may shed light on PTC diagnosis and therapies.
ESTHER : Zhuang_2019_Cell.Death.Dis_10_620
PubMedSearch : Zhuang_2019_Cell.Death.Dis_10_620
PubMedID: 31409775
Gene_locus related to this paper: human-ABHD11

Title : The Discovery of Fungal Polyene Macrolides via a Postgenomic Approach Reveals a Polyketide Macrocyclization by trans-Acting Thioesterase in Fungi - Morishita_2019_Org.Lett_21_4788
Author(s) : Morishita Y , Zhang H , Taniguchi T , Mori K , Asai T
Ref : Org Lett , 21 :4788 , 2019
Abstract : Heterologous expression of a unique biosynthetic gene cluster (BGC) comprising a highly reducing polyketide synthase and stand-alone thioesterase genes in Aspergillus oryzae enabled us to isolate a novel 34-membered polyene macrolide, phaeospelide A (1). This is the first isolation of a fungal polyene macrolide and the first demonstration of fungal aliphatic macrolide biosynthetic machinery. In addition, sequence similarity network analysis demonstrated the existence of a large number of BGCs for novel fungal macrolides.
ESTHER : Morishita_2019_Org.Lett_21_4788
PubMedSearch : Morishita_2019_Org.Lett_21_4788
PubMedID: 31180682
Gene_locus related to this paper: artpe-apmlb

Title : Soluble epoxide hydrolase inhibitor, TUPS, attenuates isoproterenol\/angiotensin II-induced cardiac hypertrophy through mammalian target of rapamycin-mediated autophagy inhibition - Zhang_2019_J.Pharm.Pharmacol_71_1291
Author(s) : Zhang H , Zhang K , Liang J , Yan W , Wu F , Xu W , Wu Z , Chen Y , Pan R , Wu G
Ref : J Pharm Pharmacol , 71 :1291 , 2019
Abstract : OBJECTIVES: To investigate the potential role and mechanism of TUPS, a soluble epoxide hydrolase inhibitor, in cardiac hypertrophy. METHODS: Rat and H9C2 cell models of cardiac hypertrophy were induced by isoproterenol and angiotensin II, respectively, followed by TUPS treatment. The expression of hypertrophic markers, ANP and BNP, was determined by quantitative real-time PCR. The abundance of Beclin-1, LC3, p-AMPK and phosphorylated-mammalian target of rapamycin (p-mTOR) proteins was analysed by Western blot and immunohistocytology. Cell morphology and viability were evaluated by F-actin staining and MTS. H9C2 cells were transfected with GFP-LC3 to evaluate autophagy flux. KEY FINDINGS: TUPS significantly inhibited rat heart size, heart weight-to-body weight ratio, heart wall thickness, hypertrophic H9C2 cell swelling and viability suppression as well as the expression of ANP and BNP genes in hypertrophic models. In addition, autophagic markers Beclin-1 and LC3 were elevated in both cellular and animal models, which were suppressed by TUPS, with corresponding changes of autophagy flux. The abundance of p-AMPK was increased, while p-mTOR was decreased in hypertrophic cells, which were abolished by TUPS. Rapamycin decreased p-mTOR level, increased Beclin-1 and LC3 expression and induced cell size enlargement and cell viability inhibition in hypertrophic H9C2 cells treated with TUPS. CONCLUSIONS: TUPS inhibits cardiac hypertrophy by regulating mTOR/autophagy axis.
ESTHER : Zhang_2019_J.Pharm.Pharmacol_71_1291
PubMedSearch : Zhang_2019_J.Pharm.Pharmacol_71_1291
PubMedID: 31215026

Title : Rational design of a Yarrowia lipolytica derived lipase for improved thermostability - Zhang_2019_Int.J.Biol.Macromol_137_1190
Author(s) : Zhang H , Sang J , Zhang Y , Sun T , Liu H , Yue R , Zhang J , Wang H , Dai Y , Lu F , Liu F
Ref : Int J Biol Macromol , 137 :1190 , 2019
Abstract : To improve the thermostability of the lipase LIP2 from Yarrowia lipolytica, molecular dynamics (MD) simulations at various temperatures were used to investigate the common fluctuation sites of the protein, which are considered to be thermally weak points. Two of these residues were selected for mutations to improve the enzyme's thermostability, and the variants predicted by MD simulations to have improved thermostability were expressed in Pichia pastoris GS115 for further investigations. According to the proline rule, the high fluctuation site S115 or V213 was replaced with proline residue, the two lipase mutants S115P and V213P were obtained. The mutant V213P exhibited evidently enhanced thermostability with an approximately 70% longer half-life at 50 degrees C than that of the parent LIP2 expressed in P. pastoris. The temperature optimum of V213P was 42 degrees C, which was about 5.0 degrees C higher than that of the parent LIP2, while its specific catalytic activity was comparable to that of the parent and reached 876.5U/mg. The improved thermostability of V213P together with its high catalytic efficiency indicated that the rational design strategy employed here can be efficiently applied for structure optimization of industrially important enzymes.
ESTHER : Zhang_2019_Int.J.Biol.Macromol_137_1190
PubMedSearch : Zhang_2019_Int.J.Biol.Macromol_137_1190
PubMedID: 31299254
Gene_locus related to this paper: yarli-lip2

Title : Molecular and Biochemical Characterization of a Type II Thioesterase From the Zoonotic Protozoan Parasite Cryptosporidium parvum - Guo_2019_Front.Cell.Infect.Microbiol_9_199
Author(s) : Guo F , Zhang H , Eltahan R , Zhu G
Ref : Front Cell Infect Microbiol , 9 :199 , 2019
Abstract : Cryptosporidium parvum is a globally important zoonotic parasite capable of causing severe to deadly diarrhea in humans and animals. Its small genome (~9.1 Mb) encodes not only a highly streamlined metabolism, but also a 25-kb, 3-module fatty acid synthase (CpFAS1) and a 40-kb, 7-module polyketide synthase (CpPKS1). The two megasynthases contain a C-terminal reductase domain to release the final products with predicted chain lengths of >/=C22 for CpFAS1 or C28 to C38 for CpPKS1.The parasite genome also encodes a discrete thioesterase ortholog, suggesting its role to be an alternative tool in releasing the final products from CpFAS1 and/or CpPKS1, or as an editor to remove non-reactive residues or aberrant intermediates, or to control starter units as seen in other parasites. In this study, we have confirmed that this C. parvum thioesterase is a type II thioesterase (thus named as CpTEII). CpTEII contains motifs and a catalytic triad characteristic to the type II thioesterase family. CpTEII is expressed during the entire parasite life cycle stages with the highest levels of expression in the later developmental stages. CpTEII showed the highest hydrolytic activity toward C10:0 decanoyl-CoA, so we speculated that CpTEII may mainly act as an editor to remove non-reactive residues and/or aberrant medium acyl chain from CpFAS1 and/or CpPKS1. However, we cannot rule out the possibility that CpTEII may also participate in the release of final products from CpFAS1 because of its moderate activity on C20:0, C:22:0 and C24:0 acyl-CoA thioesters (i.e., ~20-30% activity vs. decanoyl-CoA).
ESTHER : Guo_2019_Front.Cell.Infect.Microbiol_9_199
PubMedSearch : Guo_2019_Front.Cell.Infect.Microbiol_9_199
PubMedID: 31231619
Gene_locus related to this paper: crypi-q5cyh5

Title : Candida sp. 99-125 lipase-catalyzed synthesis of ergosterol linolenate and its characterization - He_2019_Food.Chem_280_286
Author(s) : He WS , Li L , Zhao J , Xu H , Rui J , Cui D , Li H , Zhang H , Liu X
Ref : Food Chem , 280 :286 , 2019
Abstract : As a major sterol in edible mushroom, ergosterol has gained much attention owing to its potential bioactivities. However, ergosterol has a high melting point, poor oil solubility and stability, which restrict its scope of application. In this study, an ergosterol ester of alpha-linolenic acid was successfully and efficiently prepared using Candida sp. 99-125 lipase as a biocatalyst. The desired product was confirmed to be ergosterol linolenate using MS, FT-IR, and NMR analyses. Using Candida sp. 99-125 lipase, the product conversion exceeded 92% in 12h under the following optimized parameters: 75mmol/L ergosterol, 40g/L lipase, 1:1.25 ergosterol-to-alpha-linolenic acid molar ratio, and 45 degrees C. The results confirmed that Candida sp. 99-125 lipase has good reusability and stability and is also relatively low cost, suggesting its great potential for large-scale production of ergosterol ester. Most importantly, the physiochemical properties (oil solubility and melting point) of ergosterol significantly improved after esterification with alpha-linolenic acid, thus facilitating its application in oil-based systems.
ESTHER : He_2019_Food.Chem_280_286
PubMedSearch : He_2019_Food.Chem_280_286
PubMedID: 30642499

Title : Predicting the Toxicity of Ionic Liquids toward Acetylcholinesterase Enzymes Using Novel QSAR Models - Zhu_2019_Int.J.Mol.Sci_20_
Author(s) : Zhu P , Kang X , Zhao Y , Latif U , Zhang H
Ref : Int J Mol Sci , 20 : , 2019
Abstract : Limited information on the potential toxicity of ionic liquids (ILs) becomes the bottleneck that creates a barrier in their large-scale application. In this work, two quantitative structure-activity relationships (QSAR) models were used to evaluate the toxicity of ILs toward the acetylcholinesterase enzyme using multiple linear regression (MLR) and extreme learning machine (ELM) algorithms. The structures of 57 cations and 21 anions were optimized using quantum chemistry calculations. The electrostatic potential surface area (SEP) and the screening charge density distribution area (Ssigma) descriptors were calculated and used for prediction of IL toxicity. Performance and predictive aptitude between MLR and ELM models were analyzed. Highest squared correlation coefficient (R(2)), and also lowest average absolute relative deviation (AARD%) and root-mean-square error (RMSE) were observed for training set, test set, and total set for the ELM model. These findings validated the superior performance of ELM over the MLR toxicity prediction model.
ESTHER : Zhu_2019_Int.J.Mol.Sci_20_
PubMedSearch : Zhu_2019_Int.J.Mol.Sci_20_
PubMedID: 31052561

Title : The association of the S447X mutation in LPL with Coronary artery disease: a meta-analysis - Sun_2019_Minerva.Cardioangiol_67_246
Author(s) : Sun W , Wu Y , Wen Y , Guo M , Zhang H
Ref : Minerva Cardioangiol , 67 :246 , 2019
Abstract : INTRODUCTION: To investigate the relationships between lipase gene polymorphisms and coronary artery disease (CAD) risk. EVIDENCE ACQUISITION: We searched PubMed, Embase and ISI web of science databases for articles estimated the association of S447X polymorphism with CAD. EVIDENCE SYNTESIS: Twelve-five articles were included in the meta-analysis. We found the G allele S447X polymorphism could reduce CAD risk by approximately 22% (OR=0.78, 95% CI: 0.71-0.84; fixed effects, I2=35.3%, P=0.07). Compared with non-carriers, individuals with two copies of the G allele had approximately 52% risks of CAD (OR=0.48, 95% CI: 0.29-0.68), and the individuals with GG and GC+GG had approximately 19% and 26% risks of CAD compared with those with CC genotype, respectively (GC versus CC: OR=0.81, 95% CI: 0.74-0.88; [GC+GG] versus CC: OR=0.74, 95% CI: 0.68-0.80). The G allelic significantly decreased risk of myocardial infarction (MI) (OR=0.74, 95% CI: 0.57-0.92). We found significant relationship between the variant and AMD in all the genetic models (GG versus CC: OR=0.48, 95% CI: 0.18-0.79; GC versus CC: OR=0.76, 95% CI: 0.57-0.94; [GG+GC] versus CC: OR=0.73, 95% CI: 0.64-0.83). CONCLUSIONS: The results indicated G allelic could significantly decrease CAD and MI risk.
ESTHER : Sun_2019_Minerva.Cardioangiol_67_246
PubMedSearch : Sun_2019_Minerva.Cardioangiol_67_246
PubMedID: 29687697
Gene_locus related to this paper: human-LPL

Title : Safety, efficacy, and pharmacokinetics of pradefovir for the treatment of chronic hepatitis B infection - Zhang_2019_Antiviral.Res__104693
Author(s) : Zhang H , Liu J , Zhu X , Li X , Jin W , Chen H , Wu M , Li C , Liu C , JunqiNiu , Ding Y
Ref : Antiviral Res , :104693 , 2019
Abstract : BACKGROUND & AIMS: Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the tolerability, pharmacokinetics, and antiviral activity of pradefovir in patients with chronic hepatitis B (CHB) virus infection. METHODS: Non-cirrhotic, treatment-naive subjects with CHB were divided into five groups (10 patients each) and randomized within each group in a ratio of 6:2:2 to receive an ascending dose of 30, 60, 75, 90, or 120mg pradefovir, 10mg adefovir dipivoxil (ADV), or 300mg tenofovir disoproxil fumarate (TDF) once a day for 28 days. RESULTS: A total of 51 subjects were randomized and 49 subjects completed the study. The groups were well matched and included 39 males, of whom 71% were hepatitis B e-antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.4-7.16 log10 IU/mL. No subject experienced a serious adverse event or nephrotoxicity. The most frequently reported adverse event was asymptomatic reduction in blood cholinesterase levels in the pradefovir group which recovered without any treatment about 13+/-7 days after drug discontinuation. This adverse event was not observed in the ADV and TDF groups. The mean changes in serum HBV DNA were -2.78, -2.77, -3.08, -3.18, -3.44, -2.34, and -3.07 log10 IU/mL at 30, 60, 75, 90, and 120mg pradefovir, 10mg ADV and 300mg TDF, respectively, with plateau levels reached with 60mg pradefovir. Pradefovir and its metabolite PMEA showed linear pharmacokinetics proportional to the dose. The half-life of PMEA in the pradefovir group was 11.47-17.63h. CONCLUSIONS: Short-term use of pradefovir was well tolerated. A decline in HBV DNA levels was superior to TDF at higher doses of pradefovir. 30-60mg pradefovir is recommended for CHB treatment. CLINICAL TRIAL NUMBER: CTR20150224.
ESTHER : Zhang_2019_Antiviral.Res__104693
PubMedSearch : Zhang_2019_Antiviral.Res__104693
PubMedID: 31838002

Title : Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments - Chen_2019_J.Ginseng.Res_43_499
Author(s) : Chen C , Zhang H , Xu H , Zheng Y , Wu T , Lian Y
Ref : J Ginseng Res , 43 :499 , 2019
Abstract : Background: Ginsenoside Rb1 (Rb1), a dominant component from the extract of Panax ginseng root, exhibits neuroprotective functions in many neurological diseases. This study was intended to investigate whether Rb1 can attenuate cisplatin-induced memory impairments and explore the potential mechanisms. Methods: Cisplatin was injected intraperitoneally with a dose of 5 mg/kg/wk, and Rb1 was administered in drinking water at the dose of 2 mg/kg/d to rats for 5 consecutive wk. The novel objects recognition task and Morris water maze were used to detect the memory of rats. Nissl staining was used to examine the neuron numbers in the hippocampus. The activities of superoxide dismutase, glutathione peroxidase, cholineacetyltransferase, acetylcholinesterase, and the levels of malondialdehyde, reactive oxygen species, acetylcholine, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-10 were measured by ELISA to assay the oxidative stress, cholinergic function, and neuroinflammation in the hippocampus. Results: Rb1 administration effectively ameliorates the memory impairments caused by cisplatin in both novel objects recognition task and Morris water maze task. Rb1 also attenuates the neuronal loss induced by cisplatin in the different regions (CA1, CA3, and dentate gyrus) of the hippocampus. Meanwhile, Rb1 is able to rescue the cholinergic neuron function, inhibit the oxidative stress and neuroinflammation in cisplatin-induced rat brain. Conclusion: Rb1 rescues the cisplatin-induced memory impairment via restoring the neuronal loss by reducing oxidative stress and neuroinflammation and recovering the cholinergic neuron functions.
ESTHER : Chen_2019_J.Ginseng.Res_43_499
PubMedSearch : Chen_2019_J.Ginseng.Res_43_499
PubMedID: 31695559

Title : Lysosomal Acid Lipase in Lipid Metabolism and Beyond - Li_2019_Arterioscler.Thromb.Vasc.Biol_39_850
Author(s) : Li F , Zhang H
Ref : Arterioscler Thromb Vasc Biol , 39 :850 , 2019
Abstract : Lysosomal acid lipase (LAL), encoded by the lipase A ( LIPA) gene, hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell. The essential role of LAL in lipid metabolism has been confirmed in mice and human with LAL deficiency. In humans, loss-of-function mutations of LIPA cause rare lysosomal disorders, Wolman disease and cholesteryl ester storage disease, in which LAL enzyme-replacement therapy has shown significant benefits in a phase 3 clinical trial. Recent studies have revealed the regulatory role of lipolytic products of lysosomal lipid hydrolysis in catabolic, anabolic, and signaling pathways. In vivo studies in mice with knockout of Lipa highlight the systemic impact of Lipa deficiency on metabolic homeostasis and immune cell function. Genome-wide association studies and functional genomic studies have identified LIPA as a risk locus for coronary heart disease, but the causal variants and mechanisms remain to be determined. Future studies will continue to focus on the role of LAL in the crosstalk between lipid metabolism and cellular function in health and diseases including coronary heart disease.
ESTHER : Li_2019_Arterioscler.Thromb.Vasc.Biol_39_850
PubMedSearch : Li_2019_Arterioscler.Thromb.Vasc.Biol_39_850
PubMedID: 30866656

Title : A highly sensitive and low-background fluorescence assay for pesticides residues based on hybridization chain reaction amplification assisted by magnetic separation - Yao_2019_Methods.Appl.Fluoresc_7_035006
Author(s) : Yao Y , Liu Y , Zhang H , Wang X
Ref : Methods Appl Fluoresc , 7 :035006 , 2019
Abstract : Due to the concern over food safety, it is important to detect the pesticides residues in agricultural products. Here, a highly sensitive and low background fluorescent strategy for the detection of pesticides residues has been developed. The fluorescence intensity of N-methyl mesoporphyrin IX (NMM) binding G-quadruplex could be turn off because of inhibiting effect of the pesticides on the acetylcholinesterase (AChE) activity. For that, four single-stranded DNAs (named linker, trigger, H1 and H2, respectively) are rational designed and T-Hg-T mismatches duplex DNAs as a recognizer combined with the separation of magnetic beads. The design of hybridization chain reaction (HCR) amplification strategy assisted by magnetic separation has been adopted to improve the detection sensitivity. In the presence of pesticides, the amount of the thiol group generated by hydrolysis reaction of acetylcholine (ACh) is reduced, lead to release of less trigger DNA. Therefor subsequent HCR process is retarded with decreased fluorescence intensity. The reduced fluorescence intensity has a quantitative relationship with the pesticide concentration. The limit of detection of chlorpyrifos was estimated to be 2.0 ng ml(-1). It has been applied to detect the pesticides residues in real samples.
ESTHER : Yao_2019_Methods.Appl.Fluoresc_7_035006
PubMedSearch : Yao_2019_Methods.Appl.Fluoresc_7_035006
PubMedID: 31042679

Title : Exposure to diclofop-methyl induces immunotoxicity and behavioral abnormalities in zebrafish embryos - Cao_2019_Aquat.Toxicol_214_105253
Author(s) : Cao Z , Zou L , Wang H , Zhang H , Liao X , Xiao J , Zhang S , Lu H
Ref : Aquat Toxicol , 214 :105253 , 2019
Abstract : Diclofop-methyl (DM) is widely used in agriculture and may lead to serious toxicity. However, a limited number of studies have been performed to evaluate the toxicity of DM in the immune and nervous systems of animals. Here, we utilized a good vertebrate model, zebrafish, to evaluate the toxicity of DM during the developmental process. Exposure of zebrafish embryos to 0.1, 0.3 and 0.5mg/l DM from 6h post fertilization (hpf) to 72 hpf induced developmental abnormalities, such as shorter body lengths and yolk sac edemas. The number of immune cells in zebrafish larvae was significantly reduced, but the inflammatory response was not influenced by DM treatment. The expression of immune-related genes were downregulated and the levels of oxidative stress were upregulated by DM exposure. Moreover, locomotor behaviors were inhibited by DM exposure. Therefore, our results suggest that DM has the potential to induce immunotoxicity and cause behavioral changes in zebrafish larvae. This study provides new evidence of the influence of DM exposure on aquatic ecosystems.
ESTHER : Cao_2019_Aquat.Toxicol_214_105253
PubMedSearch : Cao_2019_Aquat.Toxicol_214_105253
PubMedID: 31352076

Title : Reassembly of native components with donepezil to execute dual-missions in Alzheimer's disease therapy - Zhang_2019_J.Control.Release_296_14
Author(s) : Zhang H , Zhao Y , Yu M , Zhao Z , Liu P , Cheng H , Ji Y , Jin Y , Sun B , Zhou J , Ding Y
Ref : J Control Release , 296 :14 , 2019
Abstract : Alzheimer's disease (AD) is a multifaceted and progressive neurodegenerative disease characterized by accumulation of amyloid-beta (Abeta) and deficits of acetylcholine. Accordingly, the intra-/extra-cerebral level of high density lipoprotein (HDL) is crucial on the pathogenesis of AD; and most of all, various HDL-protein subtypes play a double-edged role in AD pathology, of which apolipoprotein A-I (apoA-I) gives protective outcomes. Inspired from "HDL bionics", we proposed biologically reassembled nanodrugs, donepezil-loaded apolipoprotein A-I-reconstituted HDL (rHDL/Do) that concurrently executed dual-missions of Abeta-targeting clearance and acetylcholinesterase (AChE) inhibition in AD therapy. Once prepared, rHDL/Do nanodrug achieved high drug encapsulation efficiency of 90.47%, and mimicked the configurations and properties of natural lipoproteins aiming to significantly enhance BBB penetration and modulate Abeta-induced neuronal damage both in vitro and in vivo. Surface plasmon resonance (SPR) analysis confirmed that rHDL/Do facilitated microglial-mediated Abeta intake and degradation, demonstrating low KD value with Abeta affinity (2.45x10(-8) of Abeta monomer and 2.78x10(-8) of Abeta oligomer). In AD animal models, daily treatment of rHDL/Do efficiently inhibited AChE activity, ameliorated neurologic variation, promoted Abeta clearance, and rescued memory loss at a safe level. The collective findings indicated that the biological nanodrug was provided with the capacities of BBB penetration, Abeta capture and degradation via microglial cells, and cholinergic dysfunction amelioration after controlled donepezil release. In summary, rHDL/Do nanodrugs could offer a promising strategy to synergize both symptom control and disease modification in AD therapy.
ESTHER : Zhang_2019_J.Control.Release_296_14
PubMedSearch : Zhang_2019_J.Control.Release_296_14
PubMedID: 30639387

Title : Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer's Disease - Wang_2019_ACS.Chem.Neurosci_10_852
Author(s) : Wang H , Zhang H
Ref : ACS Chem Neurosci , 10 :852 , 2019
Abstract : Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease-modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence, a lack of persistent treatment, and inappropriate medication times or doses. Here we pinpoint several topics fit for future attention, focusing on the updated cholinergic hypothesis, especially the pleiotropic relationships with key pathogenetic signaling pathways and functions in AD, as well as possible novel therapeutic strategies, including novel ChEIs and cholinesterase inhibition-based innovative multifunctional therapeutic candidates. We intend to strengthen the future value of the precise application of cholinergic drugs, especially novel ChEIs, as a cornerstone pharmacological approach to AD treatment, either alone or in combination with other targets, to relieve symptoms and to modify disease progression.
ESTHER : Wang_2019_ACS.Chem.Neurosci_10_852
PubMedSearch : Wang_2019_ACS.Chem.Neurosci_10_852
PubMedID: 30521323

Title : Purification and characterization of a thermoalkaliphilic esterase from Bacillus cereus WZZ006 for enantioselective resolution of indoxacarb intermediate - Zhang_2019_Int.J.Biol.Macromol_140_358
Author(s) : Zhang H , Xia Y , Zhou M , Zheng J , Wang Z , Zhang Y
Ref : Int J Biol Macromol , 140 :358 , 2019
Abstract : An intracellular esterase (BCE) from Bacillus cereus WZZ006 was purified to homogeneity with an 89.5-fold purification, specific activity of 1.79U/mg, and 26.7% recovery. The estimated molecular weight of BCE was 96kDa which was analyzed by SDS-PAGE and MALDI-TOF-MS. Activity staining denotes that BCE has an unexplored new carboxyl esterase characteristic. BCE enzyme activity was maximum at pH8.5 and also at 50 degrees C with pNP-caproate as a substrate. This indicates that the studied BCE as a thermoalkaliphilic esterase. The kinetic properties like Km, Vmax, kcat and kcat/Km value for BCE was found to be 0.98mM, 0.03mM/min, 69.47min(-1) and 70.89mM(-1)min(-1), respectively. Synthesis of (S)-5-chloro-1-oxo-2,3-dihydro-2-hydroxy-1H-indole-2-carboxylic acid methyl ester ((S)-CODHCM) by BCE can be shortened to 3h compared to 36h with whole-cell catalysis. The e.e.s achieved was 93.83%, and conversion around 52.78% with E being 39.95. These features render BCE as a promising biocatalyst for the synthesis of a key chiral intermediate for indoxacarb.
ESTHER : Zhang_2019_Int.J.Biol.Macromol_140_358
PubMedSearch : Zhang_2019_Int.J.Biol.Macromol_140_358
PubMedID: 31430490

Title : Absolute structure assignment of an iridoid-monoterpenoid indole alkaloid hybrid from Dipsacus asper - Yu_2019_Fitoterapia_135_99
Author(s) : Yu ZP , Wang YY , Yu SJ , Bao J , Yu JH , Zhang H
Ref : Fitoterapia , 135 :99 , 2019
Abstract : Iridoid-monoterpenoid indole alkaloid hybrids (IMIAHs) represent a rare class of natural products reported from only several plants of Rubiaceae and Dipsacaceae families, while their structural assignments remain a very challenging work due to complexity and flexibility. In the current study, a new IMIAH (1) was isolated from the roots of Dipsacus asper and its structure with absolute configuration was unambiguously established by a combination of spectroscopic analyses, chemical degradation and ECD calculation. A new oleanane-type triterpenoid saponin (2) and 15 known co-metabolites were also obtained and structurally characterized. Our biological evaluations showed that compound 2 exhibited moderate inhibition against acetylcholine esterase (AChE) with an IC50 value of 15.8+/-0.56muM, and compound 15 displayed potent cytotoxicity selectively against human A549 and H157 lung cancer cells with IC50 values of 6.94+/-0.24 and 9.06+/-0.12muM, respectively.
ESTHER : Yu_2019_Fitoterapia_135_99
PubMedSearch : Yu_2019_Fitoterapia_135_99
PubMedID: 31051193

Title : Analysis of the SNP rs3747333 and rs3747334 in NLGN4X gene in autism spectrum disorder: a meta-analysis - Sun_2019_Ann.Gen.Psychiatry_18_6
Author(s) : Sun H , Yang Y , Zhang L , Wu H , Zhang H , Li H
Ref : Ann Gen Psychiatry , 18 :6 , 2019
Abstract : Background: The SNP rs3747333 and rs3747334 in Neuroligin 4X (NLGN4X) gene have been demonstrated to be associated with the susceptibility to Autism spectrum disorder (ASDs; MIM 209850), but the results are inconsistent. Therefore, a meta-analysis of eligible studies reporting the association between rs3747333 and rs3747334 and ASD was carried out to enhance the reliability of published results. Methods: A systematic literature search was performed using PubMed, Web of Science, Cochrane Library to search English articles concerning the relation between rs3747333, rs3747334 and ASD up to Sep. 21th, 2017. Summary odds ratios (OR) and 95% confidence interval (CI) were used to evaluate the risk of rs3747333, rs3747334 in the ASD. The heterogeneity and publication bias of the eligible studies were also evaluated. Results: Six eligible studies involving 1284 subjects (735 patients and 549 healthy controls) were included in this meta-analysis. Overall, the results indicated that there was no significant risk elevation between rs3747333, rs3747334 variants and ASD (OR = 0.39, 95% CI 0.10-1.60). Furthermore, sensitivity analysis and publication bias analysis confirmed this result. Conclusions: In conclusion, our meta-analysis suggests that the rs3747333, rs3747334 in NLGN4X gene are not frequent causes of ASD.
ESTHER : Sun_2019_Ann.Gen.Psychiatry_18_6
PubMedSearch : Sun_2019_Ann.Gen.Psychiatry_18_6
PubMedID: 31139237
Gene_locus related to this paper: human-NLGN4X

Title : Whole Genome Sequencing and Analysis of Chlorimuron-Ethyl Degrading Bacteria Klebsiella pneumoniae 2N3 - Zhang_2019_Int.J.Mol.Sci_20_
Author(s) : Zhang C , Hao Q , Zhang Z , Zhang X , Pan H , Zhang J , Zhang H , Sun F
Ref : Int J Mol Sci , 20 : , 2019
Abstract : Klebsiella pneumoniae 2N3 is a strain of gram-negative bacteria that can degrade chlorimuron-ethyl and grow with chlorimuron-ethyl as the sole nitrogen source. The complete genome of Klebsiella pneumoniae 2N3 was sequenced using third generation high-throughput DNA sequencing technology. The genomic size of strain 2N3 was 5.32 Mb with a GC content of 57.33% and a total of 5156 coding genes and 112 non-coding RNAs predicted. Two hydrolases expressed by open reading frames (ORFs) 0934 and 0492 were predicted and experimentally confirmed by gene knockout to be involved in the degradation of chlorimuron-ethyl. Strains of DeltaORF 0934, DeltaORF 0492, and wild type (WT) reached their highest growth rates after 8-10 hours in incubation. The degradation rates of chlorimuron-ethyl by both DeltaORF 0934 and DeltaORF 0492 decreased in comparison to the WT during the first 8 hours in culture by 25.60% and 24.74%, respectively, while strains DeltaORF 0934, DeltaORF 0492, and the WT reached the highest degradation rates of chlorimuron-ethyl in 36 hours of 74.56%, 90.53%, and 95.06%, respectively. This study provides scientific evidence to support the application of Klebsiella pneumoniae 2N3 in bioremediation to control environmental pollution.
ESTHER : Zhang_2019_Int.J.Mol.Sci_20_
PubMedSearch : Zhang_2019_Int.J.Mol.Sci_20_
PubMedID: 31234527
Gene_locus related to this paper: klep7-a6tb98 , klep7-mhpc

Title : Structural Features and Digestive Behavior of Fucosylated Chondroitin Sulfate from Sea Cucumbers Stichopus japonicus - Zhu_2019_J.Agric.Food.Chem_67_10534
Author(s) : Zhu Z , Dong X , Yan C , Ai C , Zhou D , Yang J , Zhang H , Liu X , Song S , Xiao H , Zhu B
Ref : Journal of Agricultural and Food Chemistry , 67 :10534 , 2019
Abstract : Fucosylated chondroitin sulfate from sea cucumber Stichopus japonicus (FCSSJ) has been demonstrated with various biological activities; however, its precise structure is still controversial, and digestive behavior remains poorly understood. FCSSJ was purified, and its detailed structure was elucidated mainly based on the NMR spectroscopic methods. Its main chain was characterized as -->4)-beta-d-GlcA-(1 --> 3)-beta-d-GalNAc-(1--> with GalNAc4S6S:GalNAc4S in a ratio of 1.5:1, and three types of sulfated fucosyl branches attaching C-3 of GlcA, namely, Fucp2S4S, Fucp3S4S, and Fucp4S, were found in a ratio of 2:1.5:1. The digestibility of FCSSJ was investigated in vitro, and the unchanged molecular weight and reducing sugar content indicated that FCSSJ was not broken down under salivary and gastrointestinal digestion. Furthermore, FCSSJ showed a significant inhibitory impact on pancreatic lipase dose-dependently but not on alpha-amylase, indicating that the inhibition of pancreatic lipase by FCSSJ might be a pathway for its hypolipidemic effect. These findings propose a fucosylated chondroitin sulfate and provide insight into the mechanism of its physiological effects in the digestion system.
ESTHER : Zhu_2019_J.Agric.Food.Chem_67_10534
PubMedSearch : Zhu_2019_J.Agric.Food.Chem_67_10534
PubMedID: 31464434

Title : Discovery of new multifunctional selective acetylcholinesterase inhibitors: structure-based virtual screening and biological evaluation - Jiang_2019_J.Comput.Aided.Mol.Des_33_521
Author(s) : Jiang CS , Ge YX , Cheng ZQ , Song JL , Wang YY , Zhu K , Zhang H
Ref : J Comput Aided Mol Des , 33 :521 , 2019
Abstract : Although the mechanism of Alzheimer's disease (AD) is still not fully understood, the development of multifunctional AChE inhibitors remains a research focus for AD treatment. In this study, 48 AChE candidate inhibitors were picked out from SPECS database through a pharmacophore- and molecular docking-based virtual screening. The biological evaluation results indicated that four compounds 7, 29, 41 and 48 with different scaffolds exhibited potent and selective AChE inhibitory activity, with the best IC50 value of 1.62 +/- 0.11 muM obtained for 48. Then their mechanism of action, the inhibition on Abeta aggregation, neurotoxicity, and neuroprotective activity against Abeta-induced nerve cell injury were well studied. The binding mode of 48 with AChE was also proposed. The present bioassay results indicated that these multifunctional AChE inhibitors were worth for further structural derivatization to make them the anti-AD lead compounds.
ESTHER : Jiang_2019_J.Comput.Aided.Mol.Des_33_521
PubMedSearch : Jiang_2019_J.Comput.Aided.Mol.Des_33_521
PubMedID: 30989573

Title : Rational Design of Novel Selective Dual-Target Inhibitors of Acetylcholinesterase and Monoamine Oxidase B as Potential Anti-Alzheimer's Disease Agents - Xu_2019_ACS.Chem.Neurosci_10_482
Author(s) : Xu Y , Zhang J , Wang H , Mao F , Bao K , Liu W , Zhu J , Li X , Zhang H , Li J
Ref : ACS Chem Neurosci , 10 :482 , 2019
Abstract : Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer's disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-4) were designed and synthesized as dual inhibitors of ChEs and MAOs with other functions against AD. Most of these derivatives inhibited ChEs and MAOs with IC50 values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC50 = 0.032 +/- 0.007 muM) and MAO-B (IC50 = 2.117 +/- 0.061 muM), along with the improved blood-brain barrier (BBB) permeability, antioxidant ability, and good copper chelating property in vitro. Animal studies showed that compound 1c.HCl could inhibit the cerebral AChE/MAO-B activities and alleviate scopolamine-induced cognitive impairment in mice. Combined with good oral bioavailability ( F = 45.55%), these findings demonstrated that compound 1c may be a potent brain permeable multifunctional candidate for the treatment of AD.
ESTHER : Xu_2019_ACS.Chem.Neurosci_10_482
PubMedSearch : Xu_2019_ACS.Chem.Neurosci_10_482
PubMedID: 30110536

Title : Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Abeta Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation - Jiang_2019_Molecules_24_
Author(s) : Jiang CS , Ge YX , Cheng ZQ , Wang YY , Tao HR , Zhu K , Zhang H
Ref : Molecules , 24 : , 2019
Abstract : In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Abeta1-42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Abeta1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.
ESTHER : Jiang_2019_Molecules_24_
PubMedSearch : Jiang_2019_Molecules_24_
PubMedID: 31311169

Title : Network pharmacology study on the active components of Pterocypsela elata and the mechanism of their effect against cerebral ischemia - Niu_2019_Drug.Des.Devel.Ther_13_3009
Author(s) : Niu B , Zhang H , Li C , Yan F , Song Y , Hai G , Jiao Y , Feng Y
Ref : Drug Des Devel Ther , 13 :3009 , 2019
Abstract : Objective: The aim of this study was to identify the active anti-ischemic components of Pterocypsela elata (P. elata) using a network pharmacology approach to construct an effective component anti-cerebral ischemic target network and systematically analyze this medicinal material. Methods: Pharmacological studies have shown that P. elata has an obvious effect against cerebral ischemia. To identify the potential targets, 14 components of P. elata were docked to each structural element of the targets in the DRAR-CPI database by reverse docking technology. We then compared the identified potential targets with FDA-approved targets for stroke/cerebral infarction treatment in the DrugBank database and identified the active components of P. elata and their potential targets for stroke/cerebral infarction treatment. The active component-target networks were constructed using Cytoscape 3.5.1 software. The target protein-protein interactions were analyzed using the STRING database. KEGG pathway analysis and gene ontology (GO) enrichment analysis were performed through the Database for Annotation, Visualization and Integrated Discovery (DAVID). Results: There were 14 active components identified from P. elata and 21 potential targets identified for cerebral ischemia treatment, including carbonic anhydrase 2, ribosyldihydronicotinamide dehydrogenase, cholinesterase, and glutathione S-transferase P. The main involved pathways include metabolic pathways, complement and coagulation cascades and steroid hormone biosynthesis. Conclusion: Through a network pharmacology approach, we predicted the active components of P. elata and their potential targets for cerebral ischemia treatment. Our results provide new perspectives and clues for further studies on the anti-cerebral ischemia mechanism of P. elata.
ESTHER : Niu_2019_Drug.Des.Devel.Ther_13_3009
PubMedSearch : Niu_2019_Drug.Des.Devel.Ther_13_3009
PubMedID: 31564827

Title : Screening and determination for potential acetylcholinesterase inhibitory constituents from ginseng stem-leaf saponins using ultrafiltration (UF)-LC-ESI-MS(2) - Yang_2019_Phytochem.Anal_30_26
Author(s) : Yang Y , Liang X , Jin P , Li N , Zhang Q , Yan W , Zhang H , Sun J
Ref : Phytochem Anal , 30 :26 , 2019
Abstract : INTRODUCTION: Previous studies have demonstrated that several ginsenosides have remarkable inhibitory effect on acetylcholinesterase (AChE). In the present study, ginseng stem-leaf saponins (GSLS) can improve learning and memory of Alzheimer's disease patients. However, much comprehensive information regarding AChE inhibition of GSLS and its metabolites is yet unknown. OBJECTIVE: The present study aims to screen and determine the potential of AChE inhibitors (AChEIs) from GSLS. METHODOLOGY: The active fraction of the GSLS detected in vitro AChE inhibition assays was selected as a starting material for the screening of the potential of AChEIs using ultrafiltration liquid chromatography coupled to electrospray ionisation tandem mass spectrometry (UF-LC-ESI-MS(2) ). RESULTS: The results showed that 31 ginsenosides were identified with analysis using rapid resolution liquid chromatography with a diode array detector combined with electrospray ionisation tandem mass spectrometry (RRLC-DAD-ESI-MS(2) ) from the active fraction, and there are 27 compounds with AChE binding activity. Among them, 11 ginsenosides were evaluated and confirmed using in vitro enzymatic assay, and ginsenosides F1 , Rd, Rk3 , 20(S)-Rg3 , F2 and Rb2 were found to possess strong AChE inhibitory activities. CONCLUSION: The proposed UF-LC-ESI-MS(2) method was a powerful tool for the discovery of AChEIs from traditional Chinese medicine (TCM).
ESTHER : Yang_2019_Phytochem.Anal_30_26
PubMedSearch : Yang_2019_Phytochem.Anal_30_26
PubMedID: 30159954

Title : Protective effects of phenformin on zebrafish embryonic neurodevelopmental toxicity induced by X-ray radiation - Gan_2019_Artif.Cells.Nanomed.Biotechnol_47_4202
Author(s) : Gan L , Guo M , Si J , Zhang J , Liu Z , Zhao J , Wang F , Yan J , Li H , Zhang H
Ref : Artif Cells Nanomed Biotechnol , 47 :4202 , 2019
Abstract : Radiotherapy (RT) is a common treatment for head and neck cancers, but central nervous system function can be impaired by clinical radiation doses. This experimental study evaluated the protective efficacy of the anti-hyperglycaemic/anti-neoplastic agent phenformin against radiation-induced developmental toxicity in zebrafish embryos. Zebrafish embryos pre-treated with 25 muM phenformin 1 h before x-ray irradiation were compared to irradiation-only embryos for mortality, hatching rate, morphology, spontaneous movement, heart beat, larval swimming, activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), malondialdehyde content (MDA, a by-product of membrane lipid oxidation), and acetylcholinesterase (AChE) activity. In addition, expression levels of multiple genes related to neural development and apoptosis (sod2, bdnf, ache, p53, bax, and bcl-2) were compared by RT-PCR and associated protein expression levels by western blotting. Pre-treatment with phenformin increased hatching rate, spontaneous movement, heart beat, and larval motor activity, decreased mortality and malformation rate, increased SOD, CAT, and AChE activities, and reduced MDA compared to irradiation-only embryos. The mRNA expression levels of anti-apoptotic sod2, bdnf, ache, and bcl-2 were enhanced while mRNA expression of p53 and pro-apoptotic bax were reduced in the phenformin pre-treatment group. Further, p53, Bax, and gamma-H2AX (a biomarker of DNA damage) were downregulated while Bcl-2 and BDNF were upregulated by phenformin pre-treatment. Taken together, this study supports the protective efficacy of phenformin against radiation toxicity in zebrafish embryos by suppressing oxidative stress and ensuing apoptosis.
ESTHER : Gan_2019_Artif.Cells.Nanomed.Biotechnol_47_4202
PubMedSearch : Gan_2019_Artif.Cells.Nanomed.Biotechnol_47_4202
PubMedID: 31713449

Title : Two new naphthoate derivatives from Morinda officinalis - Zhai_2019_J.Asian.Nat.Prod.Res__1
Author(s) : Zhai HJ , Ye GH , Xue JJ , Yu JH , Zhang YY , Zhang H
Ref : J Asian Nat Prod Res , :1 , 2019
Abstract : Two new naphthoate derivatives, including a symmetrical dimer (1) and a monomer (2), were separated from the roots of Morinda officinalis var. hirsuta. Their structures were characterized on the basis of spectroscopic means especially MS and NMR methods. Biological evaluations revealed that the two compounds did not show inhibition against both cholinesterases AChE and BChE, while the dimer (1) did exhibit moderate growth inhibitory activity toward one human osteosarcoma cell line U2OS with an IC50 value of 18.5 +/- 1.1 muM.
ESTHER : Zhai_2019_J.Asian.Nat.Prod.Res__1
PubMedSearch : Zhai_2019_J.Asian.Nat.Prod.Res__1
PubMedID: 31566431

Title : An ultrasensitive signal-on electrochemiluminescence biosensor based on Au nanoclusters for detecting acetylthiocholine - Zhang_2019_Anal.Bioanal.Chem_411_905
Author(s) : Zhang C , Fan Y , Zhang H , Chen S , Yuan R
Ref : Anal Bioanal Chem , 411 :905 , 2019
Abstract : For improving the sensitivity of the electrochemiluminescent (ECL) detection and extending the applications of luminophore, the development of coreactant accelerator is one of the important ways. In this work, Au nanoclusters (Au NCs) were chosen as the luminescent material, and thiocholine, which was in situ generated by enzymatic reaction, was found to serve as a coreactant accelerator for Au NC-S2O8(2-) ECL system. Based on this discovery, a highly sensitive detection of acetylthiocholine (ATCl) was achieved using the acetylcholinesterase (AChE) biosensor. CeO2 nanowires (CeO2 NWs) were used to improve the stability of Au NCs on the glassy carbon electrode (GCE) due to the large specific surface area and good film-forming properties of CeO2 NWs. ATCl was catalyzed by acetylcholinesterase (AChE) to produce thiocholine, which served as the coreactant accelerator to improve the ECL signal of Au NC-S2O8(2-) system. The biosensor obtained a low detection limit of 0.17 nM. The integration of thiocholine and Au NCs would provide a new ECL platform for bioanalysis. Graphical abstract .
ESTHER : Zhang_2019_Anal.Bioanal.Chem_411_905
PubMedSearch : Zhang_2019_Anal.Bioanal.Chem_411_905
PubMedID: 30565170

Title : Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid\/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Abeta Aggregation Inhibitors - Cheng_2018_Mar.Drugs_16_
Author(s) : Cheng ZQ , Song JL , Zhu K , Zhang J , Jiang CS , Zhang H
Ref : Mar Drugs , 16 : , 2018
Abstract : A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Abeta aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer's disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.
ESTHER : Cheng_2018_Mar.Drugs_16_
PubMedSearch : Cheng_2018_Mar.Drugs_16_
PubMedID: 30134630

Title : Dental malocclusion stimulates neuromuscular circuits associated with temporomandibular disorders - Liu_2018_Eur.J.Oral.Sci_126_466
Author(s) : Liu X , Zhang C , Liu Q , Zhou K , Yin N , Zhang H , Shi M , Wang M
Ref : Eur J Oral Sci , 126 :466 , 2018
Abstract : Unilateral anterior crossbite (UAC) has been demonstrated to cause masseter hyperactivity via the periodontal trigeminal mesencephalic nucleus (Vme)-trigeminal motor nucleus circuit. Here, we studied activation of motor neurons of the facial nucleus (VII), hypoglossal nucleus (XII), nucleus ambiguus (Amb), and spinal nucleus of the accessory nerve (SNA) in rats with UAC via their similar connections with Vme. An anterograde tracer, biotinylated dextran amine (BDA), was injected into the Vme to identify the central axon terminals around the motor neurons of VII, XII, Amb, and SNA. The expression of vesicular glutamate transporter 1 (VGLUT1) in neurons of VII, XII, Amb, and SNA, and the expression of acetylcholinesterase (AChE) were measured in the stapedius, lingualis, palatopharyngeal, and sternocleidomastoid muscles. In BDA-treated rats, many BDA-labeled cell bodies in the Vme and terminals in VII, XII, Amb, and SNA were identified. Compared with control rats, rats with UAC showed higher expression of VGLUT1 in these nuclei, and statistically significantly higher expression of AChE in the stapedius, lingualis, and sternocleidomastoid muscles, but not in the palatopharyngeal muscle. These findings suggest that UAC activates orofacial, head, and cervical multimotor behaviors via connections between the Vme and the corresponding motor nuclei.
ESTHER : Liu_2018_Eur.J.Oral.Sci_126_466
PubMedSearch : Liu_2018_Eur.J.Oral.Sci_126_466
PubMedID: 30341927

Title : Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies - Zhang_2018_Curr.Opin.Lipidol_29_218
Author(s) : Zhang H
Ref : Curr Opin Lipidol , 29 :218 , 2018
Abstract : PURPOSE OF REVIEW: Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome. This review highlights the novel pathophysiological role of LAL, the functional genomic discoveries of LIPA as a risk locus for coronary heart diseases (CHD), and the clinical advance in therapies for LAL deficiency. RECENT FINDINGS: The essential role of LAL in lipid metabolism has been confirmed in human and mice with LAL deficiency. In humans, loss-of-function mutations of LIPA cause rare lysosomal disorders, Wolman disease, and cholesteryl ester storage disease, in which LAL enzyme replacement therapy has shown significant benefits in a phase 3 clinical trial. Recent studies have revealed the role of LAL-mediated lysosomal lipolysis in regulating macrophage M2 polarization, lipid mediator production, VLDL secretion, lysosomal function and autophagy, extracellular degradation of aggregated-LDL, and adipose tissue lipolysis. Genome-wide association studies and functional genomic studies have identified LIPA as a risk locus for CHD, but the causal variants and mechanisms remain to be determined. SUMMARY: Despite years of research, our understanding of LAL is incomplete. Future studies will continue to focus on the key pathophysiological functions of LAL in health and diseases including CHD.
ESTHER : Zhang_2018_Curr.Opin.Lipidol_29_218
PubMedSearch : Zhang_2018_Curr.Opin.Lipidol_29_218
PubMedID: 29547398

Title : Evidence for multiple-insecticide resistance in urban Aedes albopictus populations in southern China - Li_2018_Parasit.Vectors_11_4
Author(s) : Li Y , Xu J , Zhong D , Zhang H , Yang W , Zhou G , Su X , Wu Y , Wu K , Cai S , Yan G , Chen XG
Ref : Parasit Vectors , 11 :4 , 2018
Abstract : BACKGROUND: Aedes albopictus (Skuse) is an invasive mosquito that has become an important vector of chikungunya, dengue and Zika viruses. In the absence of specific antiviral therapy or a vaccine, vector management is the sole method available for reducing Aedes-induced disease morbidity. Determining the resistance status of Ae. albopictus to insecticides and exploring the resistance mechanisms is essential for future vector control planning. METHODS: Aedes albopictus larvae and pupae were sampled from six sites (two sites each from urban, suburban and rural) in Guangzhou. The resistance bioassays were conducted against Bacillus thuringiensis israelensis (Bti): deltamethrin, propoxur and malathion for larvae; and deltamethrin, DDT, propoxur and malathion for adults. P450 monooxygenase (P450s), glutathione S-transferase (GSTs) and carboxylesterase (COEs) activities of adult mosquitoes were measured. Mutations at the knockdown resistance (kdr) gene were analyzed, and the association between kdr mutations and phenotypic resistance was tested. RESULTS: Adult bioassays revealed varied susceptibility against DDT, deltamethrin and propoxur in the six Ae. albopictus populations. Significantly lower mortality rates were found in urban populations than suburban and rural populations. Urban mosquito populations showed resistance against DDT, deltamethrin and propoxur, while one rural population was resistant to DDT. All populations tested were susceptible to malathion. Larval bioassays results indicated that all populations of Ae. albopictus were sensitive to the larvicide Bti and malathion. Resistance to deltamethrin and propoxur was common in larval populations. The F1534S and F1534 L mutations were found to be significantly associated with deltamethrin resistance. Biochemical assays indicated elevated detoxification enzyme activities in the field mosquito populations. CONCLUSIONS: Aedes albopictus populations in Guangzhou, especially in urban areas, have developed resistance to the commonly used insecticides, primarily DDT and deltamethrin. This finding calls for resistance management and developing counter measures to mitigate the spread of resistance.
ESTHER : Li_2018_Parasit.Vectors_11_4
PubMedSearch : Li_2018_Parasit.Vectors_11_4
PubMedID: 29298700

Title : Theoretical Studies on Catalysis Mechanisms of Serum Paraoxonase 1 and Phosphotriesterase Diisopropyl Fluorophosphatase Suggest the Alteration of Substrate Preference from Paraoxonase to DFP - Zhang_2018_Molecules_23_
Author(s) : Zhang H , Yang L , Ma YY , Zhu C , Lin S , Liao RZ
Ref : Molecules , 23 : , 2018
Abstract : The calcium-dependent β-propeller proteins mammalian serum paraoxonase 1 (PON1) and phosphotriesterase diisopropyl fluorophosphatase (DFPase) catalyze the hydrolysis of organophosphorus compounds and enhance hydrolysis of various nerve agents. In the present work, the phosphotriesterase activity development between PON1 and DFPase was investigated by using the hybrid density functional theory method B3LYP. Based on the active-site difference between PON1 and DFPase, both the wild type and the mutant (a water molecule replacing Asn270 in PON1) models were designed. The results indicated that the substitution of a water molecule for Asn270 in PON1 had little effect on the enzyme activity in kinetics, while being more efficient in thermodynamics, which is essential for DFP hydrolysis. Structure comparisons of evolutionarily related enzymes show that the mutation of Asn270 leads to the catalytic Ca(2+) ion indirectly connecting the buried structural Ca(2+) ion via hydrogen bonds in DFPase. It can reduce the plasticity of enzymatic structure, and possibly change the substrate preference from paraoxon to DFP, which implies an evolutionary transition from mono- to dinuclear catalytic centers. Our studies shed light on the investigation of enzyme catalysis mechanism from an evolutionary perspective.
ESTHER : Zhang_2018_Molecules_23_
PubMedSearch : Zhang_2018_Molecules_23_
PubMedID: 29986514

Title : The binding interaction between cadmium-based, aqueous-phase quantum dots with Candida rugosa lipase - Zhao_2018_J.Mol.Recognit__e2712
Author(s) : Zhao L , Hu S , Meng Q , Xu M , Zhang H , Liu R
Ref : J Mol Recognit , :e2712 , 2018
Abstract : As a promising biolabeling biomaterials, quantum dots (QDs) present a great potential. However, the toxicity of QDs to organisms has attracted wide attention. In our research, we introduced an in vitro method to study the molecular mechanisms for the structure and activity alterations of Candida rugosa lipase (CRL) with the binding of 3-mercaptopropionic acid-capped CdTe QDs. Multiple spectroscopic methods, isothermal titration calorimetry, and enzyme activity measurements were used in this paper. QDs statically quenched the intrinsic fluorescence of CRL with the quenching constant decreases from 2.46 x 10(13) to 1.64 x 10(13) L mol(-1) second(-1) (298 to 310 K). It binds to CRL through hydrophobic force with 1 binding site, unfolding and loosening the skeleton and changed its secondary structure. Rather than aggregating on the surface, it enters the pocket of the CRL to interact with Ser-209 (2.43 A) and the residues surrounding Ser-209, making the catalytic triad more exposed. Furthermore, the activity of CRL was inhibited by approximately 15%. This work demonstrates that 3-mercaptopropionic acid-capped CdTe QDs may cause negative effects to CRL and obtains a molecular mechanism on QD-induced toxicity to proteins in vitro.
ESTHER : Zhao_2018_J.Mol.Recognit__e2712
PubMedSearch : Zhao_2018_J.Mol.Recognit__e2712
PubMedID: 29655217

Title : Epidemiology of Dementia in Elderly Chronic Obstructive Pulmonary Disease Patients Living in China's Northwestern High-Elevation Area - Mei_2018_Med.Sci.Monit_24_7742
Author(s) : Mei L , Wu S , Wang D , Li H , Zhang H , Wang M
Ref : Med Sci Monit , 24 :7742 , 2018
Abstract : BACKGROUND The aim of this study was to investigate the effects of oxygen and cholinesterase inhibitor (donepezil) therapy on dementia in patients with age-exacerbated chronic obstructive pulmonary disease (COPD) in China's northwestern high-altitude area. MATERIAL AND METHODS A total of 145 patients with acute exacerbation of COPD admitted to the Gerontology Department of the First People's Hospital of Xining City were initially retrospectively screened. From among these 145 patients, we selected 33 cases with dementia and 33 patients without dementia through use of the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Activities of Daily Living (ADL) Scale evaluated before, 7 days after, and at the end of the treatment after 3 months. Both patient groups received oxygen therapy for 7 days, but patients with dementia in the intervention group were medicated additionally with donepezil (5 mg/day for 1 week, followed by 10 mg/day for another 12 weeks). RESULTS Mild dementia was found in 35 of the 145 COPD patients. ADL, MMSE, and ADAS-Cog scores were all significantly lower in the intervention group before treatment, improved after the first 7 days, and continued to improve significantly until week 12 in the intervention group, but were still significantly lower than in the control group. CONCLUSIONS Dementia in elderly COPD patients was mainly manifested as decreased executive function, attention, language, and delayed recall, while oxygen and donepezil therapy had beneficial effects on the symptoms.
ESTHER : Mei_2018_Med.Sci.Monit_24_7742
PubMedSearch : Mei_2018_Med.Sci.Monit_24_7742
PubMedID: 30372705

Title : Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease - Mao_2018_ACS.Chem.Neurosci_9_328
Author(s) : Mao F , Wang H , Ni W , Zheng X , Wang M , Bao K , Ling D , Li X , Xu Y , Zhang H , Li J
Ref : ACS Chem Neurosci , 9 :328 , 2018
Abstract : Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w.Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.
ESTHER : Mao_2018_ACS.Chem.Neurosci_9_328
PubMedSearch : Mao_2018_ACS.Chem.Neurosci_9_328
PubMedID: 29068218

Title : Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) - Ni_2018_ACS.Chem.Neurosci_9_1625
Author(s) : Ni W , Wang H , Li X , Zheng X , Wang M , Zhang J , Gong Q , Ling D , Mao F , Zhang H , Li J
Ref : ACS Chem Neurosci , 9 :1625 , 2018
Abstract : On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability. Moreover, its citrate (3c.Cit) possessed improved water solubility and good effects against scopolamine-induced cognitive impairment with inhibition of cortical AChE activities and enhancement of cAMP response element-binding protein (CREB) phosphorylation ex vivo.
ESTHER : Ni_2018_ACS.Chem.Neurosci_9_1625
PubMedSearch : Ni_2018_ACS.Chem.Neurosci_9_1625
PubMedID: 29616790

Title : A manually annotated Actinidia chinensis var. chinensis (kiwifruit) genome highlights the challenges associated with draft genomes and gene prediction in plants - Pilkington_2018_BMC.Genomics_19_257
Author(s) : Pilkington SM , Crowhurst R , Hilario E , Nardozza S , Fraser L , Peng Y , Gunaseelan K , Simpson R , Tahir J , Deroles SC , Templeton K , Luo Z , Davy M , Cheng C , McNeilage M , Scaglione D , Liu Y , Zhang Q , Datson P , De Silva N , Gardiner SE , Bassett H , Chagne D , McCallum J , Dzierzon H , Deng C , Wang YY , Barron L , Manako K , Bowen J , Foster TM , Erridge ZA , Tiffin H , Waite CN , Davies KM , Grierson EP , Laing WA , Kirk R , Chen X , Wood M , Montefiori M , Brummell DA , Schwinn KE , Catanach A , Fullerton C , Li D , Meiyalaghan S , Nieuwenhuizen N , Read N , Prakash R , Hunter D , Zhang H , McKenzie M , Knabel M , Harris A , Allan AC , Gleave A , Chen A , Janssen BJ , Plunkett B , Ampomah-Dwamena C , Voogd C , Leif D , Lafferty D , Souleyre EJF , Varkonyi-Gasic E , Gambi F , Hanley J , Yao JL , Cheung J , David KM , Warren B , Marsh K , Snowden KC , Lin-Wang K , Brian L , Martinez-Sanchez M , Wang M , Ileperuma N , Macnee N , Campin R , McAtee P , Drummond RSM , Espley RV , Ireland HS , Wu R , Atkinson RG , Karunairetnam S , Bulley S , Chunkath S , Hanley Z , Storey R , Thrimawithana AH , Thomson S , David C , Testolin R , Huang H , Hellens RP , Schaffer RJ
Ref : BMC Genomics , 19 :257 , 2018
Abstract : BACKGROUND: Most published genome sequences are drafts, and most are dominated by computational gene prediction. Draft genomes typically incorporate considerable sequence data that are not assigned to chromosomes, and predicted genes without quality confidence measures. The current Actinidia chinensis (kiwifruit) 'Hongyang' draft genome has 164 Mb of sequences unassigned to pseudo-chromosomes, and omissions have been identified in the gene models. RESULTS: A second genome of an A. chinensis (genotype Red5) was fully sequenced. This new sequence resulted in a 554.0 Mb assembly with all but 6 Mb assigned to pseudo-chromosomes. Pseudo-chromosomal comparisons showed a considerable number of translocation events have occurred following a whole genome duplication (WGD) event some consistent with centromeric Robertsonian-like translocations. RNA sequencing data from 12 tissues and ab initio analysis informed a genome-wide manual annotation, using the WebApollo tool. In total, 33,044 gene loci represented by 33,123 isoforms were identified, named and tagged for quality of evidential support. Of these 3114 (9.4%) were identical to a protein within 'Hongyang' The Kiwifruit Information Resource (KIR v2). Some proportion of the differences will be varietal polymorphisms. However, as most computationally predicted Red5 models required manual re-annotation this proportion is expected to be small. The quality of the new gene models was tested by fully sequencing 550 cloned 'Hort16A' cDNAs and comparing with the predicted protein models for Red5 and both the original 'Hongyang' assembly and the revised annotation from KIR v2. Only 48.9% and 63.5% of the cDNAs had a match with 90% identity or better to the original and revised 'Hongyang' annotation, respectively, compared with 90.9% to the Red5 models. CONCLUSIONS: Our study highlights the need to take a cautious approach to draft genomes and computationally predicted genes. Our use of the manual annotation tool WebApollo facilitated manual checking and correction of gene models enabling improvement of computational prediction. This utility was especially relevant for certain types of gene families such as the EXPANSIN like genes. Finally, this high quality gene set will supply the kiwifruit and general plant community with a new tool for genomics and other comparative analysis.
ESTHER : Pilkington_2018_BMC.Genomics_19_257
PubMedSearch : Pilkington_2018_BMC.Genomics_19_257
PubMedID: 29661190
Gene_locus related to this paper: actde-CXE3 , actde-CXE5 , actch-a0a2r6p9v4 , actch-a0a2r6phk8 , actch-a0a2r6pty2 , actch-q0zpu6 , actcc-a0a2r6q553 , actcc-a0a2r6quq2 , actcc-a0a2r6q2m9 , actcc-a0a2r6q2n7 , actcc-a0a2r6ru97 , actcc-a0a2r6r3e8 , actcc-a0a2r6qy24 , actcc-a0a2r6pzy5 , actcc-a0a2r6p5n3 , actcc-a0a2r6qdp0 , actcc-a0a2r6qgs9

Title : Rapid Screening and Characterization of Acetylcholinesterase Inhibitors from Yinhuang Oral Liquid Using Ultrafiltration-liquid Chromatography-electrospray Ionization Tandem Mass Spectrometry - Zhang_2018_Pharmacogn.Mag_14_248
Author(s) : Zhang H , Guo Y , Meng L , Sun H , Yang Y , Gao Y , Sun J
Ref : Pharmacogn Mag , 14 :248 , 2018
Abstract : Background: At present, approximately 17-25 million people in the world suffer from Alzheimer's disease (AD). The most efficacious and acceptable therapeutic drug clinically are the acetylcholinesterase inhibitors (AChEIs). Yinhuang oral liquid is a Chinese medicine preparation which contains AChEIs according to the literatures. However, no strategy has been presented for rapid screening and identification of AChEIs from Yinhuang oral liquid. Objective: To develop a method for rapid screening and identification of AChEIs from Yinhuang oral liquid using ultrafiltration-liquid chromatography-electrospray ionization tandem mass spectrometry (UF-LC-ESI-MS/MS). Materials and Methods: In this study, UF incubation conditions such as enzyme concentration, incubation time, and incubation temperature were optimized so as to get better screening results. The AChEIs from Yinhuang oral liquid were identified by high-performance liquid chromatography-ESI-MS and the improved Ellman method was used for the AChE inhibitory activity test in vitro. Results: The results showed that Yinhuang oral liquid can inhibit the activity of AChE. We screened and identified seven compounds with potential AChE inhibitory activity from Yinhuang oral liquid, which provided experimental basis for the treatment and prevention of AD. Conclusion: The current technique was used to directly screen the active ingredients with acetylcholinesterase inhibition from complex traditional Chinese medicine, which was simple, rapid, accurate, and suitable for high-throughput screening of AChEI from complex systems. SUMMARY: A UF-LC-ESI-MS/MS method for rapid screening and identification of AChEIs from Yinhuang oral liquid was developedSeven compounds were screened and identified with potential AChE inhibitory activity from Yinhuang oral liquidIt provided experimental basis of Yinhuang oral liquid for the treating and preventing AD. Abbreviations used: (AD): Alzheimer's disease; (UF-LC-ESI-MS/MS): ultrafiltration-liquid chromatography-electrospray ionization tandem mass spectrometry; (AChEIs): acetylcholinesterase inhibitors.
ESTHER : Zhang_2018_Pharmacogn.Mag_14_248
PubMedSearch : Zhang_2018_Pharmacogn.Mag_14_248
PubMedID: 29720840

Title : Function of C-terminal peptides on enzymatic and interfacial adsorption properties of lipase from Gibberella zeae - Wang_2018_Biochim.Biophys.Acta.Gen.Subj_1862_2623
Author(s) : Wang F , Zhang H , Czarna A , Chen W , Yang B , Wang Y
Ref : Biochimica & Biophysica Acta Gen Subj , 1862 :2623 , 2018
Abstract : BACKGROUND: The crystal structure of lipase from Gibberella zeae (GZEL) indicates that its C-terminal extension is composed of a loop and a alpha-helix. This structure is unique, possibly providing novel evidence on lipase mechanisms. METHODS: Two C-terminally truncated mutants (GZEL-Delta(alpha-helix) and GZEL-Delta(alpha-helix+loop)) were constructed. The role of these secondary structure segments on enzymatic activities and interfacial binding properties of GZEL was investigated by using conventional pH-stat method and monomolecular film techniques. In addition, inactive variants (Ser144Ala) of wild-type GZEL and two truncated mutants were constructed and produced specifically for interfacial binding experiments. RESULTS: Compared to the wild-type GZEL, lipase and phospholipase activities were significantly decreased in the two mutants. Deletion of the alpha-helix had great influence on the lipase activity of GZEL, resulting in residual 7.3% activity; the additional deletion of the loop led to 8.1% lipase activity. As for the phospholipase function, residual activities of 63.0% and 35.4% were maintained for GZEL-Delta(alpha-helix) and GZEL-Delta(alpha-helix+loop), respectively. Findings obtained with monomolecular film experiments further indicated that the reduction in phospholipase activity occurred with the anionic phospholipid as substrate, but was not seen with zwitterionic phospholipid. Results of the maximum insertion pressure, synergy factor and binding kinetic parameters documented that the alpha-helix structure of GZEL strongly influence the binding and insertion of enzyme to the phospholipid monolayer. Moreover, the interfacial binding function of alpha-helix was partly conformed by connecting to the C-terminal of Aspergillus oryzae lipase. GENERAL SIGNIFICANCE: Our results provide important information on the understanding of the structure-function relationship of GZEL.
ESTHER : Wang_2018_Biochim.Biophys.Acta.Gen.Subj_1862_2623
PubMedSearch : Wang_2018_Biochim.Biophys.Acta.Gen.Subj_1862_2623
PubMedID: 30025859

Title : Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE\/BChE inhibitors - Cheng_2018_Bioorg.Chem_83_277
Author(s) : Cheng ZQ , Zhu KK , Zhang J , Song JL , Muehlmann LA , Jiang CS , Liu CL , Zhang H
Ref : Bioorg Chem , 83 :277 , 2018
Abstract : A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer's disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e, displayed potent dual in vitro inhibitory activities against AChE/BChE with IC50 values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a, which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs.
ESTHER : Cheng_2018_Bioorg.Chem_83_277
PubMedSearch : Cheng_2018_Bioorg.Chem_83_277
PubMedID: 30391700

Title : Deglucosylation of zearalenone-14-glucoside in animals and human liver leads to underestimation of exposure to zearalenone in humans - Yang_2018_Arch.Toxicol_92_2779
Author(s) : Yang S , Zhang H , Zhang J , Li Y , Jin Y , Zhang S , De Saeger S , Zhou J , Sun F , De Boevre M
Ref : Archives of Toxicology , 92 :2779 , 2018
Abstract : Zearalenone-14-glucoside (ZEN-14G), the modified mycotoxin of zearalenone (ZEN), has attracted considerable attention due to its high potential to be hydrolyzed into ZEN, which would exert toxicity. It has been confirmed that the microflora could metabolize ZEN-14G to ZEN. However, the metabolic profile of ZEN-14G and whether it could be deglucosidated in the liver are unknown. To thoroughly investigate the metabolism of ZEN-14G, in vitro metabolism including phase I and phase II metabolism was studied using liquid chromatography coupled to high-resolution mass spectrometry. Additionally, in vivo metabolism of ZEN-14G was conducted in model animals, rats, by oral administration. As a result, 29 phase I metabolites and 6 phase II metabolites were identified and significant inter-species metabolic differences were observed as well. What is more, ZEN-14G could be considerably deglucosidated into its free form of ZEN after the incubation with animals and human liver microsomes in the absence of NADPH, which was mainly metabolized by human carboxylesterase CES-I and II. Furthermore, results showed that the major metabolic pathways of ZEN-14G were deglucosylation, hydroxylation, hydrogenation and glucuronidation. Although interspecies differences in the biotransformation of ZEN-14G were observed, ZEN, alpha-ZEL-14G, beta-ZEL-14G, alpha-ZEL, ZEN-14G-16GlcA and ZEN-14GlcA were the major metabolites of ZEN-14G. Additionally, a larger yield of 6-OH-ZEN-14G and 8-OH-ZEN-14G was also observed in human liver microsomes. The obtained data would be of great importance for the safety assessment of modified mycotoxin, ZEN-14G, and provide another perspective for risk assessment of mycotoxin.
ESTHER : Yang_2018_Arch.Toxicol_92_2779
PubMedSearch : Yang_2018_Arch.Toxicol_92_2779
PubMedID: 30019167

Title : Neurotrophins and cholinergic enzyme regulated by calpain-2: New insights into neuronal apoptosis induced by polybrominated diphenyl ether-153 - Zhang_2018_Toxicol.Lett_291_29
Author(s) : Zhang H , Yang X , Li X , Zhang Z , Hou L , Wang Z , Niu Q , Wang T
Ref : Toxicol Lett , 291 :29 , 2018
Abstract : Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons. Neurotrophins and cholinergic enzymes play critical roles in the neuronal survival, maintenance, synaptic plasticity and learning memory, however, their roles in neuronal apoptosis following the BDE-153 treatment remain unclear. In this study, we firstly explored the possible predominant pathway underlying the neuronal apoptotic induced by the BDE-153 treatment in rat cerebral cortex, by measuring expression levels (mRNA and protein) of p53, caspase-3, 8, 9, calpain-1, and calpain-2, detected the levels (protein contents and mRNA) of neurotrophins including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), and measured acetylcholinesterase (AchE) and choline acetyltransferase (ChaT) activities in rat cerebral cortex and primary neurons following BDE-153 treatment with or without pretreatment with inhibitors. Results showed that the neuronal apoptosis induced by BDE-153 was dependent on p53, and dependent on more calpain-2 than caspase-3 in the cerebral cortex of rats. Following the BDE-153 treatment, the protein contents and mRNA levels of BDNF, GDNF, NGF, NT-3, and NT-4, as well as the AchE and ChaT activities were significantly decreased in the cerebral cortex and primary neurons when compared to the untreated group. When pretreated primary neurons with calpain inhibitor PD150606 or cyclin-dependent kinase (cdk5, the downstream complex of calpain) inhibitor Roscovitine, the neurotrophins contents and activities of ChaT and AchE were reverted, along with the improvement of neuron survival compared with BDE-153 treatment alone. We conclude that neurotrophins and cholinergic enzymes were regulated by the calpain-2 activation and its downstream cdk5 pathway, and which was involved in the neuronal apoptosis induced by the BDE-153 treatment.
ESTHER : Zhang_2018_Toxicol.Lett_291_29
PubMedSearch : Zhang_2018_Toxicol.Lett_291_29
PubMedID: 29621559

Title : COX-2\/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin - Wang_2018_Mol.Cancer.Ther_17_474
Author(s) : Wang F , Zhang H , Ma AH , Yu W , Zimmermann M , Yang J , Hwang SH , Zhu D , Lin TY , Malfatti M , Turteltaub KW , Henderson PT , Airhart S , Hammock BD , Yuan J , de Vere White RW , Pan CX
Ref : Mol Cancer Ther , 17 :474 , 2018
Abstract : Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this study was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum-DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner. Mol Cancer Ther; 17(2); 474-83. (c)2017 AACR.
ESTHER : Wang_2018_Mol.Cancer.Ther_17_474
PubMedSearch : Wang_2018_Mol.Cancer.Ther_17_474
PubMedID: 29284644

Title : Activation of Peroxisome Proliferator-Activated Receptor Gamma and Disruption of Progesterone Synthesis of 2-Ethylhexyl Diphenyl Phosphate in Human Placental Choriocarcinoma Cells: Comparison with Triphenyl Phosphate - Hu_2017_Environ.Sci.Technol_51_4061
Author(s) : Hu W , Gao F , Zhang H , Hiromori Y , Arakawa S , Nagase H , Nakanishi T , Hu J
Ref : Environ Sci Technol , 51 :4061 , 2017
Abstract : 2-Ethylhexyl diphenyl phosphate (EHDPP), an organophosphate flame retardant (OPFR), is frequently detected in human blood. In this study, the sensitive dual-luciferase reporter gene assay and molecular docking were used to investigate the activation of EHDPP to human peroxisome proliferator-activated receptor gamma (PPARG). Results show that EHDPP exhibited stronger PPARG activation (EC(20): 2.04 microM) than triphenyl phosphate (TPhP) (EC(20): 2.78 microM). EHDPP upregulated the gene expression of 3beta-hydroxysteroid dehydrogenase type 1 (3beta-HSD1) in human placental choriocarcinoma cells in a dose-dependent manner, and the lowest observable effective concentration was 10 microM, lower than that of TPhP (20 microM). EHDPP significantly altered progesterone secretion at a lower concentration (10 microM) than that of TPhP (20 microM), and both EHDPP and TPhP significantly promoted human chorionic gonadotropin (hCG) production at 20 microM. Furthermore, inactivation of PPARG by either a pharmacological inhibitor (GW9662) or small interfering RNA (siRNA) abolished the change in progesterone secretion and gene expression in the cells exposed to EHDPP, suggesting that the PPARG signaling pathway plays a role in the upregulation of progesterone by the two OPFRs. This is the first report to show that OPFRs can alter the biosynthesis of progesterone in the placenta, which could affect female reproduction and fetal development.
ESTHER : Hu_2017_Environ.Sci.Technol_51_4061
PubMedSearch : Hu_2017_Environ.Sci.Technol_51_4061
PubMedID: 28282128

Title : Novel Double-Potential Electrochemiluminescence Ratiometric Strategy in Enzyme-Based Inhibition Biosensing for Sensitive Detection of Organophosphorus Pesticides - Chen_2017_Anal.Chem_89_2823
Author(s) : Chen H , Zhang H , Yuan R , Chen S
Ref : Analytical Chemistry , 89 :2823 , 2017
Abstract : Generally, electrochemiluminescence (ECL) ratiometric assays were based on the energy transfer (ET) between an emitter and a metal nanomaterial or between two different emitters. The choice of suitable energy donor-acceptor pair and the distance dependence of ET would greatly limit the practical application of ratiometric assays. This work explored a novel double-potential ECL ratiometry without the ET for organophosphorus pesticides (OPs) analysis, in which, reduced graphene oxide-CdTe quantum dots (RGO-CdTe QDs) and carboxyl-conjugated polymer dots (PFO dots) were chosen as cathodic and anodic ECL emitters, and the reactant (dissolved O2) and the product (H2O2) in enzymatic reactions served as their coreactants, respectively. With the occurrence of the enzymatic reactions induced by the acetylcholinesterase (AChE) and choline oxidase (ChOx), the cathodic ECL signal from RGO-CdTe QDs was at "signal off" state due to the consumption of dissolved O2. Meanwhile, the anodic ECL signal from PFO dots was at "signal on" state due to the in situ generation of H2O2. In the presence of OPs, the cathodic ECL signal would increase while the anodic ECL signal would decline correspondingly due to the inhibition of OPs on the activity of AChE. Using the reactant and the product in enzymatic reactions as the coreactants of two different ECL emitters, we conveniently achieved the opposite change trend in two ECL signals for the ratiometric detection of OPs, which exhibited a greatly improved accuracy, reliability and sensitivity, thus, showing a great attraction for developing ECL ratiometric systems for the bioanalysis.
ESTHER : Chen_2017_Anal.Chem_89_2823
PubMedSearch : Chen_2017_Anal.Chem_89_2823
PubMedID: 28192982

Title : Acetylcholinesterase Inhibitory Alkaloids from the Whole Plants of Zephyranthes carinata - Zhan_2017_J.Nat.Prod_80_2462
Author(s) : Zhan G , Zhou J , Liu J , Huang J , Zhang H , Liu R , Yao G
Ref : Journal of Natural Products , 80 :2462 , 2017
Abstract : Eleven new alkaloids (1-11), classified as the 12-acetylplicamine (1), N-deformyl-seco-plicamine (2), plicamine (3-6), 4a-epi-plicamine (7), seco-plicamine (8), and lycorine (9-11) framework types, along with 15 known alkaloids (12-26) were isolated from the whole plants of Zephyranthes carinata. The structures of the new alkaloids 1-11 were established by extensive spectroscopic data interpretation. The absolute configurations of 9 and 10 were defined by single-crystal X-ray diffraction analysis. Zephycarinatines A (1), B (2), and G (7) represent the first examples of 12-acetylplicamine, N-deformyl-seco-plicamine, and 4a-epi-plicamine alkaloids, respectively. Alkaloids 6, 11, 17, and 20-23 exhibited AChE inhibitory activities with IC50 values ranging from 1.21 to 184.05 muM, and a preliminary structure-activity relationship is discussed.
ESTHER : Zhan_2017_J.Nat.Prod_80_2462
PubMedSearch : Zhan_2017_J.Nat.Prod_80_2462
PubMedID: 28898076

Title : CRISPR\/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report - Zhang_2017_Arterioscler.Thromb.Vasc.Biol_37_2156
Author(s) : Zhang H , Shi J , Hachet MA , Xue C , Bauer RC , Jiang H , Li W , Tohyama J , Millar J , Billheimer J , Phillips MC , Razani B , Rader DJ , Reilly MP
Ref : Arterioscler Thromb Vasc Biol , 37 :2156 , 2017
Abstract : OBJECTIVE: To gain mechanistic insights into the role of LIPA (lipase A), the gene encoding LAL (lysosomal acid lipase) protein, in human macrophages. APPROACH AND RESULTS: We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) technology to knock out LIPA in human induced pluripotent stem cells and then differentiate to macrophage (human-induced pluripotent stem cells-derived macrophage [IPSDM]) to explore the human macrophage LIPA loss-of-function phenotypes. LIPA was abundantly expressed in monocyte-derived macrophages and was markedly induced on IPSDM differentiation to comparable levels as in human monocyte-derived macrophage. IPSDM with knockout of LIPA (LIPA(-/-)) had barely detectable LAL enzymatic activity. Control and LIPA(-/-) IPSDM were loaded with [(3)H]-cholesteryl oleate-labeled AcLDL (acetylated low-density lipoprotein) followed by efflux to apolipoprotein A-I. Efflux of liberated [(3)H]-cholesterol to apolipoprotein A-I was abolished in LIPA(-/-) IPSDM, indicating deficiency in LAL-mediated lysosomal cholesteryl ester hydrolysis. In cells loaded with [(3)H]-cholesterol-labeled AcLDL, [(3)H]-cholesterol efflux was, however, not different between control and LIPA(-/-) IPSDM. ABCA1 (ATP-binding cassette, subfamily A, member 1) expression was upregulated by AcLDL loading but to a similar extent between control and LIPA(-/-) IPSDM. In nonlipid loaded state, LIPA(-/-) IPSDM had high levels of cholesteryl ester mass compared with minute amounts in control IPSDM. Yet, with AcLDL loading, overall cholesteryl ester mass was increased to similar levels in both control and LIPA(-/-) IPSDM. LIPA(-/-) did not impact lysosomal apolipoprotein-B degradation or expression of IL1B, IL6, and CCL5. CONCLUSIONS: LIPA(-/-) IPSDM reveals macrophage-specific hallmarks of LIPA deficiency. CRISPR/Cas9 and IPSDM provide important tools to study human macrophage biology and more broadly for future studies of disease-associated LIPA genetic variation in human macrophages.
ESTHER : Zhang_2017_Arterioscler.Thromb.Vasc.Biol_37_2156
PubMedSearch : Zhang_2017_Arterioscler.Thromb.Vasc.Biol_37_2156
PubMedID: 28882870

Title : Recombinant Lipase from Gibberella zeae Exhibits Broad Substrate Specificity: A Comparative Study on Emulsified and Monomolecular Substrate - Wang_2017_Int.J.Mol.Sci_18_
Author(s) : Wang F , Zhang H , Zhao Z , Wei R , Yang B , Wang Y
Ref : Int J Mol Sci , 18 : , 2017
Abstract : Using the classical emulsified system and the monomolecular film technique, the substrate specificity of recombinant Gibberella zeae lipase (rGZEL) that originates from Gibberella zeae was characterized in detail. Under the emulsified reaction system, both phospholipase and glycolipid hydrolytic activities were observed, except for the predominant lipase activity. The optimum conditions for different activity exhibition were also determined. Compared with its lipase activity, a little higher ratio of glycolipid hydrolytic activity (0.06) than phospholipase activity (0.02) was found. rGZEL preferred medium chain-length triglycerides, while lower activity was found for the longer-chain triglyceride. Using the monomolecular film technique, we found that the preference order of rGZEL to different phospholipids was 1,2-diacyl-sn-glycero-3-phospho-l-serine (PS) > 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (PG) > 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) > l-alpha-phosphatidylinositol (PI) > cardiolipin (CL) > 3-sn-phosphatidic acid sodium salt (PA) > l-alpha-phosphatidylethanolamine (PE), while no hydrolytic activity was detected for sphingomyelin (SM). Moreover, rGZEL showed higher galactolipase activity on 1,2-distearoyimonoglactosylglyceride (MGDG). A kinetic study on the stereo- and regioselectivity of rGZEL was also performed by using three pairs of pseudodiglyceride enantiomers (DDGs). rGZEL presented higher preference for distal DDG enantiomers than adjacent ester groups, however, no hydrolytic activity to the sn-2 position of diglyceride analogs was found. Furthermore, rGZEL preferred the R configuration of DDG enantiomers. Molecular docking results were in concordance with in vitro tests.
ESTHER : Wang_2017_Int.J.Mol.Sci_18_
PubMedSearch : Wang_2017_Int.J.Mol.Sci_18_
PubMedID: 28718792
Gene_locus related to this paper: gibze-q6wer3

Title : Discovery of triazole-based uracil derivatives bearing amide moieties as novel dipeptidyl peptidase-IV inhibitors - Deng_2017_Bioorg.Chem_75_357
Author(s) : Deng X , Han L , Zhou J , Zhang H , Li Q
Ref : Bioorg Chem , 75 :357 , 2017
Abstract : Dipeptidyl peptidase-IV (DPP-4) is a validated target for T2DM treatment. We previously reported a novel series of triazole-based uracil derivatives bearing aliphatic carboxylic acids with potent DPP-4 inhibitory activities in vitro, but these compounds showed poor hypoglycemic effects in vivo. Herein we further optimized the triazole moiety by amidation of the carboxylic acid to improve in vivo activities. Two series of compounds 3a-f and 4a-g were designed and synthesized. By screening in DPP-4, compound 4c was identified as a potent DPP-4 inhibitor with the IC(50) value of 28.62 nM. Docking study revealed compound 4c has a favorable binding mode and interpreted the SAR of these analogs. DPP-8 and DPP-9 tests indicated compound 4c had excellent selectivity over DPP-8 and DPP-9. Further in vivo evaluations revealed that compound 4c showed more potent hypoglycemic activity than its corresponding carboxylic acid in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice. The overall results have shown that compound 4c could be a promising lead for further development of novel DPP-4 agents treating T2DM.
ESTHER : Deng_2017_Bioorg.Chem_75_357
PubMedSearch : Deng_2017_Bioorg.Chem_75_357
PubMedID: 29096096

Title : Molecular Basis of ABHD5 Lipolysis Activation - Sanders_2017_Sci.Rep_7_42589
Author(s) : Sanders MA , Zhang H , Mladenovic L , Tseng YY , Granneman JG
Ref : Sci Rep , 7 :42589 , 2017
Abstract : Alpha-beta hydrolase domain-containing 5 (ABHD5), the defective gene in human Chanarin-Dorfman syndrome, is a highly conserved regulator of adipose triglyceride lipase (ATGL)-mediated lipolysis that plays important roles in metabolism, tumor progression, viral replication, and skin barrier formation. The structural determinants of ABHD5 lipolysis activation, however, are unknown. We performed comparative evolutionary analysis and structural modeling of ABHD5 and ABHD4, a functionally distinct paralog that diverged from ABHD5 ~500 million years ago, to identify determinants of ABHD5 lipolysis activation. Two highly conserved ABHD5 amino acids (R299 and G328) enabled ABHD4 (ABHD4 N303R/S332G) to activate ATGL in Cos7 cells, brown adipocytes, and artificial lipid droplets. The corresponding ABHD5 mutations (ABHD5 R299N and ABHD5 G328S) selectively disrupted lipolysis without affecting ATGL lipid droplet translocation or ABHD5 interactions with perilipin proteins and ABHD5 ligands, demonstrating that ABHD5 lipase activation could be dissociated from its other functions. Structural modeling placed ABHD5 R299/G328 and R303/G332 from gain-of-function ABHD4 in close proximity on the ABHD protein surface, indicating they form part of a novel functional surface required for lipase activation. These data demonstrate distinct ABHD5 functional properties and provide new insights into the functional evolution of ABHD family members and the structural basis of lipase regulation.
ESTHER : Sanders_2017_Sci.Rep_7_42589
PubMedSearch : Sanders_2017_Sci.Rep_7_42589
PubMedID: 28211464
Gene_locus related to this paper: mouse-abhd4 , mouse-abhd5

Title : Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation - Li_2017_ACS.Chem.Neurosci_8_2708
Author(s) : Li X , Wang H , Xu Y , Liu W , Gong Q , Wang W , Qiu X , Zhu J , Mao F , Zhang H , Li J
Ref : ACS Chem Neurosci , 8 :2708 , 2017
Abstract : Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC50 = 3.319 +/- 0.708 muM), 5-HT1A agonist (EC50 = 107 +/- 37 nM), and 5-HT reuptake inhibition (IC50 = 76.3 +/- 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e.HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.
ESTHER : Li_2017_ACS.Chem.Neurosci_8_2708
PubMedSearch : Li_2017_ACS.Chem.Neurosci_8_2708
PubMedID: 28872831

Title : Enhancement of methanol resistance of Yarrowia lipolytica lipase 2 using beta-cyclodextrin as an additive: Insights from experiments and molecular dynamics simulation - Cao_2017_Enzyme.Microb.Technol_96_157
Author(s) : Cao H , Jiang Y , Zhang H , Nie K , Lei M , Deng L , Wang F , Tan T
Ref : Enzyme Microb Technol , 96 :157 , 2017
Abstract : The methanol resistance of lipase is a critical parameter in enzymatic biodiesel production. In the present work, the methanol resistance of Yarrowia lipolytica Lipase 2 (YLLIP2) was significantly improved using beta-cyclodextrin (beta-CD) as an additive. According to the results, YLLIP2 with beta-CD exhibited approximately 7000U/mg specific activity in 30wt% methanol for 60min compared with no activity without beta-CD under the same conditions. Molecular dynamics (MD) simulation results indicated that the beta-CD molecules weakened the conformational change of YLLIP2 and maintained a semi-open state of the lid by overcoming the interference caused by methanol molecules. Furthermore, the beta-CD molecule could directly stabilize "pathway" regions (e.g., Asp61-Asp67) and indirectly stabilize "pathway" regions (e.g., Gly44-Phe50) by forming hydrogen bonds with "pathway" regions and nearby "pathway" regions, respectively. The regions stabilized by the beta-CD molecule then prevented the closure of active pockets, thus retaining the enzymatic activity of YLLIP2 with beta-CD in methanol solvent.
ESTHER : Cao_2017_Enzyme.Microb.Technol_96_157
PubMedSearch : Cao_2017_Enzyme.Microb.Technol_96_157
PubMedID: 27871377

Title : Proprioceptive mechanisms in occlusion-stimulated masseter hypercontraction - Liu_2017_Eur.J.Oral.Sci_125_127
Author(s) : Liu X , Zhang C , Wang D , Zhang H , Li J , Wang M
Ref : Eur J Oral Sci , 125 :127 , 2017
Abstract : Neurons in the trigeminal mesencephalic nucleus (Vme) have an axon that branches peripherally to innervate the orofacial region and projects centrally to the trigeminal motor nucleus (Vmo). They function as the primary neurons conveying proprioceptive messages. The present study aimed to demonstrate the presence of a periodontal-Vme-Vmo circuit and to provide evidence for its involvement in an experimental unilateral anterior crossbite (UAC) model, which can induce osteoarthritis in the temporomandibular joint. Cholera toxin B subunit (CTb) was injected into the inferior alveolar nerve of rats to help identify the central axon terminals of Vme neurons in the Vmo. The levels of vesicular glutamate transporter 1 (VGLUT1) expressed in the periodontal region, Vme, Vmo, and masseter, and the level of acetylcholinesterase (AChE) expressed in the masseter, were assessed in UAC rats and controls. In CTb-treated rats, many CTb-labeled cell bodies and endings were identified in the Vme and in the Vmo, respectively. In UAC rats, VGLUT1 was expressed at a statistically significantly higher level in the periodontal ligament, Vme, Vmo, and masseter than it was in control rats. The level of AChE protein was 1.97 times higher in UAC rat masseter compared with control rat masseter. These findings reveal a trigeminal mechanism underlying masseter hyperactivity induced by an altered occlusion.
ESTHER : Liu_2017_Eur.J.Oral.Sci_125_127
PubMedSearch : Liu_2017_Eur.J.Oral.Sci_125_127
PubMedID: 28145597

Title : Biochemical characterization of an enantioselective esterase from Brevundimonas sp. LY-2 - Zhang_2017_Microb.Cell.Fact_16_112
Author(s) : Zhang J , Zhao M , Yu D , Yin J , Zhang H , Huang X
Ref : Microb Cell Fact , 16 :112 , 2017
Abstract : BACKGROUND: Lactofen, a member of the diphenylether herbicides, has high activity and is commonly used to control broadleaf weeds. As a post-emergent herbicide, it is directly released to the environment, and easily caused the pollution. This herbicide is degraded in soil mainly by microbial activity, but the functional enzyme involved in the biodegradation of lactofen is still not clear now.
RESULTS: A novel esterase gene lacH, involved in the degradation of lactofen, was cloned from the strain Brevundimonas sp. LY-2. The gene contained an open reading frame of 921 bp, and a putative signal peptide at the N-terminal was identified with the most likely cleavage site between Ala 28 and Ala 29. The encoded protein, LacH, could catalyze the hydrolysis of lactofen to form acifluorfen. Phylogenetic analysis showed that LacH belong to family V of bacterial lipolytic enzymes. Biochemical characterization analysis showed that LacH was a neutral esterase with an optimal pH of 7.0 and an optimal temperature of 40 degrees C toward lactofen. Besides, the activity of LacH was strongly inhibited by Hg2+ and Zn2+. LacH preferred short chain p-nitrophenyl esters (C2-C6), exhibited maximum activity toward p-nitrophenyl acetate. Furthermore, the enantioselectivity of LacH during lactofen hydrolysis was also studied, and the results show that R-(-)-lactofen was degraded faster than S-(+)-lactofen, indicating the occurrence of enantioselectivity in the enzymatic reaction.
CONCLUSIONS: Our studies characterized a novel esterase involved in the biodegradation of diphenylether herbicide lactofen. The esterase showed enantioselectivity during lactofen degradation, which revealed the occurrence of enzyme-mediated enantioselective degradation of chiral herbicides.
ESTHER : Zhang_2017_Microb.Cell.Fact_16_112
PubMedSearch : Zhang_2017_Microb.Cell.Fact_16_112
PubMedID: 28629408
Gene_locus related to this paper: 9caul-s5rrx5

Title : Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property - Liu_2017_Bioorg.Med.Chem_25_2387
Author(s) : Liu Z , Fang L , Zhang H , Gou S , Chen L
Ref : Bioorganic & Medicinal Chemistry , 25 :2387 , 2017
Abstract : Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Abeta42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Abeta aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2, can be considered as potential therapeutic agents for Alzheimer's disease.
ESTHER : Liu_2017_Bioorg.Med.Chem_25_2387
PubMedSearch : Liu_2017_Bioorg.Med.Chem_25_2387
PubMedID: 28302511

Title : Karyotype Stability and Unbiased Fractionation in the Paleo-Allotetraploid Cucurbita Genomes - Sun_2017_Mol.Plant_10_1293
Author(s) : Sun H , Wu S , Zhang G , Jiao C , Guo S , Ren Y , Zhang J , Zhang H , Gong G , Jia Z , Zhang F , Tian J , Lucas WJ , Doyle JJ , Li H , Fei Z , Xu Y
Ref : Mol Plant , 10 :1293 , 2017
Abstract : The Cucurbita genus contains several economically important species in the Cucurbitaceae family. Here, we report high-quality genome sequences of C. maxima and C. moschata and provide evidence supporting an allotetraploidization event in Cucurbita. We are able to partition the genome into two homoeologous subgenomes based on different genetic distances to melon, cucumber, and watermelon in the Benincaseae tribe. We estimate that the two diploid progenitors successively diverged from Benincaseae around 31 and 26 million years ago (Mya), respectively, and the allotetraploidization happened at some point between 26 Mya and 3 Mya, the estimated date when C. maxima and C. moschata diverged. The subgenomes have largely maintained the chromosome structures of their diploid progenitors. Such long-term karyotype stability after polyploidization has not been commonly observed in plant polyploids. The two subgenomes have retained similar numbers of genes, and neither subgenome is globally dominant in gene expression. Allele-specific expression analysis in the C. maxima x C. moschata interspecific F(1) hybrid and their two parents indicates the predominance of trans-regulatory effects underlying expression divergence of the parents, and detects transgressive gene expression changes in the hybrid correlated with heterosis in important agronomic traits. Our study provides insights into polyploid genome evolution and valuable resources for genetic improvement of cucurbit crops.
ESTHER : Sun_2017_Mol.Plant_10_1293
PubMedSearch : Sun_2017_Mol.Plant_10_1293
PubMedID: 28917590
Gene_locus related to this paper: cucma-a0a6j1jlb1 , cucma-a0a6j1i8e2 , cucma-a0a6j1hwl6

Title : Soluble epoxide hydrolase inhibition Promotes White Matter Integrity and Long-Term Functional Recovery after chronic hypoperfusion in mice - Chen_2017_Sci.Rep_7_7758
Author(s) : Chen Y , Tian H , Yao E , Tian Y , Zhang H , Xu L , Yu Z , Fang Y , Wang W , Du P , Xie M
Ref : Sci Rep , 7 :7758 , 2017
Abstract : Chronic cerebral hypoperfusion induced cerebrovascular white matter lesions (WMLs) are closely associated with cognitive impairment and other neurological deficits. The mechanism of demyelination in response to hypoperfusion has not yet been fully clarified. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids. Inhibition of sEH has been suggested to represent a prototype "combination therapy" targeting multiple mechanisms of stroke injury with a single agent. However, its role in the pathological process after WMLs has not been clarified. The present study was to investigate the role of a potent sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), on multiple elements in white matter of mice brain after chronic hypoperfusion. Adult male C57BL/6 mice were subjected to bilateral carotid artery stenosis (BCAS) to induce WMLs. Administration of TPPU significantly inhibited microglia activation and inflammatory response, increased M2 polarization of microglial cells, enhanced oligodendrogenesis and differentiation of oligodendrocytes, promoted white matter integrity and remyelination following chronic hypoperfusion. Moreover, these cellular changes were translated into a remarkable functional restoration. The results suggest that sEH inhibition could exert multi-target protective effects and alleviate cognitive impairment after chronic hypoperfusion induced WMLs in mice.
ESTHER : Chen_2017_Sci.Rep_7_7758
PubMedSearch : Chen_2017_Sci.Rep_7_7758
PubMedID: 28798352

Title : Repetitive transcranial magnetic stimulation improves cognitive function of Alzheimer's disease patients - Zhao_2017_Oncotarget_8_33864
Author(s) : Zhao J , Li Z , Cong Y , Zhang J , Tan M , Zhang H , Geng N , Li M , Yu W , Shan P
Ref : Oncotarget , 8 :33864 , 2017
Abstract : Repetitive transcranial magnetic stimulation (rTMS) acts as a kind of widely-applied and non-invasive method in the intervention of some neurological disorders. This prospective, randomized, double-blind, placebo-controlled trial investigates the effect of rTMS on 30 cases of Alzheimer's disease (AD) participants, who were classified into mild and moderate groups. Neuropsychological tests were carried out using the AD Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and World Health Organization University of California-Los Angeles, Auditory Verbal Learning Test (WHO-UCLA AVLT) before, immediately after, and 6 weeks after the intervention. In this work, data from 30 AD patients revealed that there was no obvious interaction effect of time-by-group. The ADAS-cog, MMSE and WHO-UCLA AVLT score in the rTMS group was significantly improved compared with baselines at 6 weeks after treatment (all p<0.05). Meanwhile, MoCA scores were also obviously ameliorated in the mild AD patients with rTMS. Besides, subgroup analysis showed that the effect of rTMS on the memory and language of mild AD patients was superior to those of moderate AD patients. In conclusion, our findings suggested that repetitive transcranial magnetic stimulation improves cognitive function, memory and language level of AD patients, especially in the mild stage of AD. Thus, rTMS can be recommended as a promising adjuvant therapy combined with cholinesterase inhibitors at the mild stage of AD patients.
ESTHER : Zhao_2017_Oncotarget_8_33864
PubMedSearch : Zhao_2017_Oncotarget_8_33864
PubMedID: 27823981