Zhao Y

References (212)

Title : Co-Reactive Ligand In Situ Engineered Gold Nanoclusters with Ultra-Bright Near-Infrared Electrochemiluminescence for Ultrasensitive and Label-Free Detection of Carboxylesterase Activity - Guo_2024_Anal.Chem__
Author(s) : Guo W , Xia M , Peng D , Zhao Y , Nie Y , Zhou Y
Ref : Analytical Chemistry , : , 2024
Abstract : Ultrasensitive and accurate monitoring of carboxylesterase (CE) activity is extremely crucial for the early diagnosis of hepatocellular carcinoma (HCC), which is still a considerable challenge. Herein, using a co-reactive ligand engineering strategy, ultra-bright near-infrared (lambda(max) = 830 nm) and self-enhanced electrochemiluminescence (ECL) Au nanoclusters (NCs) were in situ prepared with 2-(diethylamino) ethanethiol (DEAET) as a co-reactive ligand. Remarkably, the co-reactive ligand not only acts as a stabilizer like traditional ligands but also plays a crucial role as a co-reactant to ensure a confinement effect to shorten the charge transfer distance and increase the local concentration, significantly improving the collision efficiency between the electrogenerated free radicals. Consequently, the DEAET Au NCs exhibited a record and stable anodal ECL without the addition of an exogenous co-reactant, dramatically superior to classical Au NCs and Ru(bpy)(3)(2+) with a certain amount of the co-reactant. As a proof of concept, a convenient and label-free CE biosensor was innovatively constructed using 1-naphthyl acetate as a selective substrate, achieving ultrasensitive detection for CE activity with a low limit of detection of 9.1 x 10(-7) U/L. Therefore, this work not only paves a co-reactive ligand engineering strategy for in situ preparation of high-efficiency metal NCs but also provides an ultrasensitive and convenient platform for the early diagnosis of HCC.
ESTHER : Guo_2024_Anal.Chem__
PubMedSearch : Guo_2024_Anal.Chem__
PubMedID: 38310525

Title : The acute neurotoxicity of inorganic mercury in Mactra chinensis philippi - Ma_2024_Aquat.Toxicol_270_106896
Author(s) : Ma B , Zhao X , Zhang X , Yang B , Cai Z , Xing Z , Xu M , Mi L , Zhang J , Wang L , Zhao Y , Liu X
Ref : Aquat Toxicol , 270 :106896 , 2024
Abstract : Inorganic mercury (IHg) is hazardous to marine organisms especially resulting in neurotoxicity, bivalves are sensitive to pollutants as "ocean sentinel", but data on the neurotoxicity of IHg in bivalves are sparse. So we chosed M. chinensis philippi with typical neural structures in bivalves to investigate the neurotoxicity of IHg, which could be helpful to understand the specificity of neural regulation and the response characteristics of bivalves. After acute exposed to IHg (HgCl(2)) for 24 h, the metabolites of ganglion tissues in M. chinensis philippi were evaluated using (1)H-nuclear magnetic resonance based metabolomics; Ca(2+), neurotransmitters (nitric oxide, glutamate, acetylcholine) and related enzymes (calcineurin, nitric oxide synthase and acetylcholinesterase) were measured using biochemical detection. Compared to the control group, the levels of the nitric oxide (81.04 +/- 12.84 micromol/g prot) and acetylcholine (30.93 +/- 12.57 microg/mg prot) in M. chinensis philippi of IHg-treated were decreased, while glutamate (2.11 +/- 0.61 mmol/L) increased significantly; the activity of nitric oxide synthase (679.34 +/- 135.33 U/mg prot) was increased, while acetylcholinesterase (1.39 +/- 0.44 U/mg prot) decreased significantly, and the activity of calcineurin (0.52 +/- 0.02 U/mg prot) had a statistically insignificant increasing tendency. The concentration of Ca(2+) (0.92 +/- 0.46 mmol/g prot) in the IHg-treated group was significantly higher than that in the control group. OPLS-DA was performed to reveal the difference in metabolites between the control and IHg-challenged groups, the metabolites of glucose, glutamine, inosine, succinate, glutamate, homarine, and alanine were sensitive to IHg, subsequently metabolic pathways that were affected including glucose metabolism, glutamine metabolism, nucleotide metabolism, Krebs cycle, amino acid metabolism and osmotic regulation. In our study, IHg interfered with metabolites in M. chinensis philippi, thus the corresponding metabolic pathways were changed, which influenced the neurotransmitters subsequently. Furthermore, Ca(2+)overload affected the synthesis or degradation of the neurotransmitters, and then the altered neurotransmitters involved in changes in metabolic pathways again. Overall, we hypothesized that the neurotoxic effects of IHg on bivalve were in close contact with metabolism, neurotransmitters, related enzymes and Ca(2+), which could be effective neurotoxic biomarkers for marine environmental quality assessment, and also provide effective data for the study of the regulatory mechanism of the nervous system in response to IHg in bivalves.
ESTHER : Ma_2024_Aquat.Toxicol_270_106896
PubMedSearch : Ma_2024_Aquat.Toxicol_270_106896
PubMedID: 38490093

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 : Synthesis and evaluation of a highly selective cannabidiol amide cholinesterase inhibitor - Zhang_2024_Results.Chem_7_101492
Author(s) : Zhang R , Zhao M , Wang D , Zhao Y , Li J , Zhang S , Zhang W , Shi Z
Ref : Results in Chemistry , 7 :101492 , 2024
Abstract : The therapeutic mechanism for the treatment of Alzheimer's disease (AD) is mainly by inhibiting the activity of cholinesterase (ChE) and increasing the transmission of choline and the function of neurons. In this study, two series of ChE inhibitors (CA1CA8 and CB1CB7) were designed and synthesized by the acylation of a cannabinoid (CBD) with bromoacetyl bromide, or the esterification of a CBD with an amino acid. All the synthesized compounds were tested for in vitro activity to evaluate the compounds as AD therapies. Compound CB7 was identified as a potential butyrylcholinesterase (BuChE) inhibitor (IC50=0.310.09microM), which did not display toxicity against HepG2 or PC12 cells at 6.25microM. Compound CB7 showed good antioxidant behavior, effective anti-tyrosinase activity (IC50=0.0370.003microM), and anti-acetylcholinesterase (AChE) activity (IC50=19.730.79microM). Kinetic studies also showed that CB7 can act as a dual inhibitor. These results provide a theoretical basis for the use of the natural product CBD in the design and development of anti-AD drugs.
ESTHER : Zhang_2024_Results.Chem_7_101492
PubMedSearch : Zhang_2024_Results.Chem_7_101492

Title : Improvement of plant resistance to geminiviruses via protein de-S-acylation - Zhao_2024_Stress.Biol_4_23
Author(s) : Zhao Y , Li Z , Wang Z , Huang L , Li G , Liu X , Yuan M , Huang W , Ling L , Yang C , He Z , Lai J
Ref : Stress Biol , 4 :23 , 2024
Abstract : Geminiviruses are an important group of viruses that infect a variety of plants and result in heavy agricultural losses worldwide. The homologs of C4 (or L4) in monopartite geminiviruses and AC4 (or AL4) in bipartite geminiviruses are critical viral proteins. The C4 proteins from several geminiviruses are the substrates of S-acylation, a dynamic post-translational modification, for the maintenance of their membrane localization and function in virus infection. Here we initiated a screening and identified a plant protein ABAPT3 (Alpha/Beta Hydrolase Domain-containing Protein 17-like Acyl Protein Thioesterase 3) as the de-S-acylation enzyme of C4 encoded by BSCTV (Beet severe curly top virus). Overexpression of ABAPT3 reduced the S-acylation of BSCTV C4, disrupted its plasma membrane localization, inhibited its function in pathogenesis, and suppressed BSCTV infection. Because the S-acylation motifs are conserved among C4 from different geminiviruses, we tested the effect of ABAPT3 on the C4 protein of ToLCGdV (Tomato leaf curl Guangdong virus) from another geminivirus genus. Consistently, ABAPT3 overexpression also disrupted the S-acylation, subcellular localization, and function of ToLCGdV C4, and inhibited ToLCGdV infection. In summary, we provided a new approach to globally improve the resistance to different types of geminiviruses in plants via de-S-acylation of the viral C4 proteins and it can be extendedly used for suppression of geminivirus infection in crops.
ESTHER : Zhao_2024_Stress.Biol_4_23
PubMedSearch : Zhao_2024_Stress.Biol_4_23
PubMedID: 38662136
Gene_locus related to this paper: arath-At5g14390

Title : Depletion of ApoA5 aggravates spontaneous and diet-induced nonalcoholic fatty liver disease by reducing hepatic NR1D1 in hamsters - Guo_2024_Theranostics_14_2036
Author(s) : Guo J , Miao G , Zhang W , Shi H , Lai P , Xu Y , Zhang L , Chen G , Han Y , Zhao Y , Liu G , Wang Y , Huang W , Xian X
Ref : Theranostics , 14 :2036 , 2024
Abstract : Background: ApoA5 mainly synthesized and secreted by liver is a key modulator of lipoprotein lipase (LPL) activity and triglyceride-rich lipoproteins (TRLs). Although the role of ApoA5 in extrahepatic triglyceride (TG) metabolism in circulation has been well documented, the relationship between ApoA5 and nonalcoholic fatty liver disease (NAFLD) remains incompletely understood and the underlying molecular mechanism still needs to be elucidated. Methods: We used CRISPR/Cas9 gene editing to delete Apoa5 gene from Syrian golden hamster, a small rodent model replicating human metabolic features. Then, the ApoA5-deficient (ApoA5(-/-)) hamsters were used to investigate NAFLD with or without challenging a high fat diet (HFD). Results: ApoA5(-/-) hamsters exhibited hypertriglyceridemia (HTG) with markedly elevated TG levels at 2300 mg/dL and hepatic steatosis on a regular chow diet, accompanied with an increase in the expression levels of genes regulating lipolysis and small adipocytes in the adipose tissue. An HFD challenge predisposed ApoA5(-/-) hamsters to severe HTG (sHTG) and nonalcoholic steatohepatitis (NASH). Mechanistic studies in vitro and in vivo revealed that targeting ApoA5 disrupted NR1D1 mRNA stability in the HepG2 cells and the liver to reduce both mRNA and protein levels of NR1D1, respectively. Overexpression of human NR1D1 by adeno-associated virus 8 (AAV8) in the livers of ApoA5(-/-) hamsters significantly ameliorated fatty liver without affecting plasma lipid levels. Moreover, restoration of hepatic ApoA5 or activation of UCP1 in brown adipose tissue (BAT) by cold exposure or CL316243 administration could significantly correct sHTG and hepatic steatosis in ApoA5(-/-) hamsters. Conclusions: Our data demonstrate that HTG caused by ApoA5 deficiency in hamsters is sufficient to elicit hepatic steatosis and HFD aggravates NAFLD by reducing hepatic NR1D1 mRNA and protein levels, which provides a mechanistic link between ApoA5 and NAFLD and suggests the new insights into the potential therapeutic approaches for the treatment of HTG and the related disorders due to ApoA5 deficiency in the clinical trials in future.
ESTHER : Guo_2024_Theranostics_14_2036
PubMedSearch : Guo_2024_Theranostics_14_2036
PubMedID: 38505614

Title : Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling of cetagliptin in patients with type 2 diabetes mellitus - Zhou_2024_Front.Endocrinol.(Lausanne)_15_1359407
Author(s) : Zhou C , Zhou S , Wang J , Xie L , Lv Z , Zhao Y , Wang L , Luo H , Xie D , Shao F
Ref : Front Endocrinol (Lausanne) , 15 :1359407 , 2024
Abstract : AIMS: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients. MATERIALS AND METHODS: 32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix. RESULTS: Following multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (<=80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC(0-24h) increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-E(max) model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V(2)), and V(2) increased with the increase of TBIL. CONCLUSIONS: Cetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.
ESTHER : Zhou_2024_Front.Endocrinol.(Lausanne)_15_1359407
PubMedSearch : Zhou_2024_Front.Endocrinol.(Lausanne)_15_1359407
PubMedID: 38529396

Title : Protective Effects of Myricetin and Morin on Neurological Damage in Abeta(1-42)\/Al(3+) -induced Alzheimer's Disease Model of Rats - Guo_2024_J.Chem.Neuroanat__102404
Author(s) : Guo L , Zhao Y , Kong Z , Liu R , Liu P
Ref : Journal of Chemical Neuroanatomy , :102404 , 2024
Abstract : Alzheimer's disease (AD) is a degenerative neurological disorder with unclear pathogenesis. Single-target drugs have very limited efficacy in treating AD, but synthetic multi-target drugs have poor efficacy and safety. Therefore, finding suitable natural multi-target drugs against AD is of great interest for research studies. We chose two flavonols, myricetin and morin, for the relevant study. In this study, we used microinjection of Abeta(1-42) oligomers into the CA1 region of rat hippocampus, combined with gavage of Aluminum chloride hexahydrate (AlCl(3).6H(2)O) solution to establish AD rat models, and myricetin and morin were selected as intervening drugs to explore the protective effects against neurological impairment. Experimental results showed that myricetin or morin could reduce the production of Abeta, Tubulin-associated unit (Tau), and Phosphorylated tubulin-associated unit (p-Tau), down-regulate the expression of relevant inflammatory factors, reduce hippocampal cell apoptosis in rats. There was a significant increase in the activity of adenosine triphosphatase, catalase, total superoxide dismutase, and the content of glutathione in the brain tissue. However, the content of malondialdehyde, inducible nitric oxide synthase, and the activity of acetylcholinesterase were decreased in the brain tissue. These two flavonols can regulate the imbalance of monoamine and amino acid neurotransmitter levels. In conclusion, Myricetin or morin can effectively improve learning and memory dysfunction in AD rats induced by Abeta(1-42)/Al(3+) through anti-oxidative stress and anti-apoptotic features.
ESTHER : Guo_2024_J.Chem.Neuroanat__102404
PubMedSearch : Guo_2024_J.Chem.Neuroanat__102404
PubMedID: 38423257

Title : Optimizing drug-like properties of selective butyrylcholinesterase inhibitors for cognitive improvement: Enhancing aqueous solubility by disrupting molecular plane - Xing_2024_Eur.J.Med.Chem_268_116289
Author(s) : Xing S , Tang X , Wang L , Wang J , Lv B , Wang X , Guo C , Zhao Y , Feng F , Liu W , Chen Y , Sun H
Ref : Eur Journal of Medicinal Chemistry , 268 :116289 , 2024
Abstract : Most recently, worldwide interest in butyrylcholinesterase (BChE) as a potential target for treating Alzheimer's disease (AD) has increased. In this study, the previously obtained selective BChE inhibitors with benzimidazole-oxadiazole scaffold were further structurally modified to increase their aqueous solubility and pharmacokinetic (PK) characteristics. S16-1029 showed improved solubility (3280 microM, upgraded by 14 times) and PK parameters, including plasma exposure (AUC(0-inf) = 1729.95 ng/mL*h, upgraded by 2.6 times) and oral bioavailability (F(po) = 48.18%, upgraded by 2 times). S16-1029 also displayed weak or no inhibition against Cytochrome P450 (CYP450) and human ether a-go-go related gene (hERG) potassium channel. In vivo experiments on tissue distribution revealed that S16-1029 could cross the blood-brain barrier (BBB) and reach the central nervous system (CNS). In vivo cognitive improvement efficacy and good in vitro target inhibitory activity (eqBChE IC(50) = 11.35 +/- 4.84 nM, hBChE IC(50) = 48.1 +/- 11.4 nM) were also assured. The neuroprotective effects against several AD pathology characteristics allowed S16-1029 to successfully protect the CNS of progressed AD patients. According to the findings of this study, altering molecular planarity might be a viable strategy for improving the drug-like property of CNS-treating drugs.
ESTHER : Xing_2024_Eur.J.Med.Chem_268_116289
PubMedSearch : Xing_2024_Eur.J.Med.Chem_268_116289
PubMedID: 38452730

Title : Metabolic engineering of Saccharomyces cerevisiae for de novo production of odd-numbered medium-chain fatty acids - Dong_2024_Metab.Eng__
Author(s) : Dong G , Zhao Y , Ding W , Xu S , Zhang Q , Zhao H , Shi S
Ref : Metab Eng , : , 2024
Abstract : Odd-numbered fatty acids (FAs) have been widely used in nutrition, agriculture, and chemical industries. Recently, some studies showed that they could be produced from bacteria or yeast, but the products are almost exclusively odd-numbered long-chain FAs. Here we report the design and construction of two biosynthetic pathways in Saccharomyces cerevisiae for de novo production of odd-numbered medium-chain fatty acids (OMFAs) via ricinoleic acid and 10-hydroxystearic acid, respectively. The production of OMFAs was enabled by introducing a hydroxy fatty acid cleavage pathway, including an alcohol dehydrogenase from Micrococcus luteus, a Baeyer-Villiger monooxygenase from Pseudomonas putida, and a lipase from Pseudomonas fluorescens. These OMFA biosynthetic pathways were optimized by eliminating the rate-limiting step, generating heptanoic acid, 11-hydroxyundec-9-enoic acid, nonanoic acid, and 9-hydroxynonanoic acid at 7.83 mg/L, 9.68 mg/L, 9.43 mg/L and 13.48 mg/L, respectively. This work demonstrates the biological production of OMFAs in a sustainable manner in S. cerevisiae.
ESTHER : Dong_2024_Metab.Eng__
PubMedSearch : Dong_2024_Metab.Eng__
PubMedID: 38325640

Title : Perilipin1 deficiency prompts lipolysis in lipid droplets and aggravates the pathogenesis of persistent immune activation in Drosophila - Wang_2023_J.Innate.Immun__
Author(s) : Wang L , Lin J , Yang K , Wang W , Lv Y , Zeng X , Zhao Y , Yu J , Pan L
Ref : J Innate Immun , : , 2023
Abstract : Lipid droplets (LDs) are highly dynamic intracellular organelles, which are involved in lots of biological processes. However, the dynamic morphogenesis and functions of intracellular LDs during persistent innate immune responses remain obscure. In this study, we induce long-term systemic immune activation in Drosophila through genetic manipulation. Then, the dynamic pattern of LDs is traced in the Drosophila fat body. We find that deficiency of Plin1, a key regulator of LDs' reconfiguration, blocks LDs minimization at the initial stage of immune hyperactivation but enhances LDs breakdown at the later stage of sustained immune activation via recruiting the lipase Brummer (Bmm, homologous to human ATGL). The high wasting in LDs shortens the lifespan of flies with high-energy-cost immune hyperactivation. Therefore, these results suggest a critical function of LDs during long-term immune activation and provide a potential treatment for the resolution of persistent inflammation.
ESTHER : Wang_2023_J.Innate.Immun__
PubMedSearch : Wang_2023_J.Innate.Immun__
PubMedID: 37742619

Title : Transcriptome-based analyses reveal venom diversity in two araneomorph spiders, Psechrus triangulus and Hippasa lycosina - Yin_2023_Comp.Biochem.Physiol.Part.D.Genomics.Proteomics_47_101101
Author(s) : Yin WH , You YM , Tembrock LR , Ding LJ , Zhang CG , Zhao Y , Yang ZZ
Ref : Comparative Biochemistry & Physiology Part D Genomics Proteomics , 47 :101101 , 2023
Abstract : The spiders Psechrus triangulus and Hippasa lycosina are widely distributed in Yunnan Province, China, and are important natural enemies of agricultural pests, yet studies regarding the composition of their venom are lacking. In this study, cDNA libraries were constructed from venom gland tissue of P. triangulus and H. lycosina and used for transcriptomic analysis. From the analysis, 39 and 31 toxin-like sequences were predicted for P. triangulus and H. lycosina, respectively. The predicted neurotoxin sequences were categorized according to cysteine sequence motifs, and the predicted neurotoxin sequences of P. triangulus and H. lycosina could be classified into 9 and 6 toxin families, respectively. In addition, potential acetylcholinesterase, hyaluronidase, and astaxanthin-like metalloproteinases were identified through annotation. In summary, transcriptomic techniques were invaluable in mining the gene expression information from these two spider species to explore the toxin composition of their venom and determine how they differ. Studies of this type provide essential baseline data for studying the evolution and physiological activities of spider toxins and for the potential development of medicinal compounds.
ESTHER : Yin_2023_Comp.Biochem.Physiol.Part.D.Genomics.Proteomics_47_101101
PubMedSearch : Yin_2023_Comp.Biochem.Physiol.Part.D.Genomics.Proteomics_47_101101
PubMedID: 37352672

Title : Research Progress on Effects of Ginsenoside Rg2 and Rh1 on Nervous System and Related Mechanisms - Liu_2023_Molecules_28_
Author(s) : Liu C , Zheng P , Wang H , Wei Y , Wang C , Hao S , Liu S , Chen W , Zhao Y , Zong Y , Li J , He Z
Ref : Molecules , 28 : , 2023
Abstract : Neurological-related disorders are diseases that affect the body's neurons or peripheral nerve tissue, such as Parkinson's disease (PD) and Alzheimer's disease (AD). The development of neurological disorders can cause serious harm to the quality of life and functioning of the patient. The use of traditional therapeutic agents such as dopamine-promoting drugs, anticholinergic drugs, cholinesterase inhibitors, and NMDA receptor antagonists is often accompanied by a series of side effects such as drug resistance, cardiac arrhythmia, liver function abnormalities, and blurred vision. Therefore, there is an urgent need to find a therapeutic drug with a high safety profile and few side effects. Herbal medicines are rich in active ingredients that are natural macromolecules. Ginsenoside is the main active ingredient of ginseng, which has a variety of pharmacological effects and is considered to have potential value in the treatment of human diseases. Modern pharmacological studies have shown that ginsenosides Rg2 and Rh1 have strong pharmacological activities in the nervous system, with protective effects on nerve cells, improved resistance to neuronal injury, modulation of neural activity, resistance to cerebral ischemia/reperfusion injury, improvement of brain damage after eclampsia hemorrhage, improvement of memory and cognitive deficits, treatment of AD and vascular dementia, alleviation of anxiety, pain, and inhibition of ionic-like behavior. In this article, we searched the pharmacological research literature of Rg2 and Rh1 in the field of neurological diseases, summarized the latest research progress of the two ginsenosides, and reviewed the pharmacological effects and mechanisms of Rg2 and Rh1, which provided a new way of thinking for the research of the active ingredients in ginseng anti-neurological diseases and the development of new drugs.
ESTHER : Liu_2023_Molecules_28_
PubMedSearch : Liu_2023_Molecules_28_
PubMedID: 36677589 || 38067664

Title : Efficient decolorization of melanoidin in raw molasses wastewater by thermophilic esterase in actual extreme conditions - Zhang_2023_Bioresour.Technol_382_129191
Author(s) : Zhang Z , Hu W , Xie Q , Shi Y , Zhao Y , Deng Y , He J , Wu X , Zhang Y , Zhang W , Liu P , Yang H , Wang W
Ref : Bioresour Technol , 382 :129191 , 2023
Abstract : This work was developed to explore the versatility of thermophilic esterase for decolorizing raw molasses wastewater at high temperature and acidic pH. Combining covalent crosslinking method with deep eutectic solvent, a thermophilic esterase from Pyrobaculum calidifontis was immobilized on chitosan/macroporous resin composite carrier. The application of this immobilized thermophilic esterase eliminated 92.35% of colorants in raw molasses wastewater, achieving maximal decolorization efficiency across all the enzymes tested. Strikingly, this immobilized thermophilic esterase was capable of engaging in continuous activity for a 5-day period while removing 76.23% of pigments from samples. It effectively and continuously eliminated BOD(5) and COD, effectively and directly facilitating raw molasses wastewater decolorization under extreme conditions more readily than control group. In addition, this thermophilic esterase was believed to achieve decolorization through an addition reaction that disrupted conjugated system of melanoidins. Together, these results highlight an efficient and practical means of achieving enzyme-based molasses wastewater decolorization.
ESTHER : Zhang_2023_Bioresour.Technol_382_129191
PubMedSearch : Zhang_2023_Bioresour.Technol_382_129191
PubMedID: 37196742

Title : Nanoplasmonic biosensors for multicolor visual analysis of acetylcholinesterase activity and drug inhibitor screening in point-of-care testing - Li_2023_Biosens.Bioelectron_247_115912
Author(s) : Li Y , Chen L , Li CY , Zhang J , Zhao Y , Yang YH , Yang T
Ref : Biosensors & Bioelectronics , 247 :115912 , 2023
Abstract : The monitoring of acetylcholinesterase (AChE) activity and the screening of its inhibitors are significance of the diagnosis and drug therapy of nervous diseases. A metal ions-mediated signal amplification strategy was developed for the highly sensitive and multicolor assay of AChE activity and visually screening its drug inhibitors. After the specific reaction between AChE and acetylthiocholine (ATCh), the hydrolysis product thiocholine (TCh) can directly and decompose the alpha-FeOOH nanorods (NRs) to release amounts of Fe(2+), which was regarded as Fenton reagent to efficiently catalyze H(2)O(2) to produce .OH. Then, the as-formed .OH can further largely shorten the gold nanobipyramids (Au NBPs), generating a series of palpable color variations. The linear range for AChE activity was 0.01-500.0 U/L with the limit of detection as low as 0.0074 U/L. The vivid visual effects could be easily distinguished for the multicolor assay of AChE activity by naked eye in visible light. To achieve the point-of-care testing, Au NBPs were further assembled on polymeric electrospun nanofibrous films (ENFs) surface as test strips for the easy-to-use test of AChE activity by RGB values with a smartphone. Fascinatingly, this proposed strategy can be used for the visual screening AChE inhibitors or non-inhibitors. Comparing with the clinical drugs (rivastigmine tartrate, and donepezil), some natural alkaloids such as evodiamine, caffeine, camptothecin, and berberine hydrochloride were selected as inhibitor modes to confirm the drug screening capability of this method. This proposed strategy may have great potential in the other disease-related enzymatic biomarkers assay and the rapid screening of drug therapy.
ESTHER : Li_2023_Biosens.Bioelectron_247_115912
PubMedSearch : Li_2023_Biosens.Bioelectron_247_115912
PubMedID: 38096721

Title : Design, synthesis and biological evaluation of new multi-target scutellarein hybrids for treatment of Alzheimer's disease - Luo_2023_Bioorg.Chem_138_106596
Author(s) : Luo K , Chen J , Li H , Wu D , Du Y , Zhao S , Liu T , Li L , Dai Z , Li Y , Zhao Y , Tang L , Fu X
Ref : Bioorg Chem , 138 :106596 , 2023
Abstract : Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC(50) values of 6.72 +/- 0.09 and 8.91 +/- 0.08 microM, respectively. In addition, compound 11e displayed not only excellent inhibition of self- and Cu(2+)-induced Abeta(1-42) aggregation (91.85% and 85.62%, respectively) but also induced disassembly of self- and Cu(2+)-induced Abeta fibrils (84.54% and 83.49% disaggregation, respectively). Moreover, 11e significantly reduced tau protein hyperphosphorylation induced by Abeta(25-35), and also exhibited good inhibition of platelet aggregation. A neuroprotective assay demonstrated that pre-treatment of PC12 cells with 11e significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax and caspase-3) and inhibited RSL3-induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 11e would have optimal blood-brain barrier and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11e significantly attenuated learning and memory impairment in an AD mice model. Toxicity experiments with the compound did not reveal any safety concerns. Notably, 11e significantly reduced beta-amyloid precursor protein (APP) and beta-site APP cleaving enzyme-1 (BACE-1) protein expression in brain tissue of scopolamine-treated mice. Taken together, these outstanding properties qualified compound 11e as a promising multi-target candidate for AD therapy, worthy of further studies.
ESTHER : Luo_2023_Bioorg.Chem_138_106596
PubMedSearch : Luo_2023_Bioorg.Chem_138_106596
PubMedID: 37186997

Title : Artificial Esterase for Cooperative Catalysis of Ester Hydrolysis at pH 7 - Bose_2023_Mater.Today.Chem_30_
Author(s) : Bose I , Bahrami F , Zhao Y
Ref : Mater Today Chem , 30 : , 2023
Abstract : Ester is one of the most prevalent functional groups in natural and man-made products. Natural esterases hydrolyze nonactivated alkyl esters readily but artificial esterases generally use highly activated p-nitrophenyl esters as substrates. We report synthetic esterases constructed through molecular imprinting in cross-linked micelles. The water-soluble nanoparticle catalysts contain a thiouronium cation to mimic the oxyanion hole and a nearby base to assist the hydrolysis. Whereas this catalytic motif readily affords large rate acceleration for the hydrolysis of p-nitrophenyl hexanoate, nonactivated cyclopentyl hexanoate demands catalytic groups that can generate a strong nucleophile (hydroxide) in the active site. The hydroxide is stabilized by the protonated base when the external solution is at pH 7, enabling the hydrolysis of activated and nonactivated esters under neutral conditions.
ESTHER : Bose_2023_Mater.Today.Chem_30_
PubMedSearch : Bose_2023_Mater.Today.Chem_30_
PubMedID: 37997572

Title : Effects and mechanism of extracts rich in phenylpropanoids-polyacetylenes and polysaccharides from Codonopsis Radix on improving scopolamine-induced memory impairment of mice - Xie_2023_J.Ethnopharmacol__117106
Author(s) : Xie Q , Hu X , Zhao X , Xiang Z , Chen Q , Xie Z , Wang H , Zhao Y , Cheng X , Wang C
Ref : J Ethnopharmacol , :117106 , 2023
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a progressive developmental neurodegenerative disease that primarily develops in old age. Memory impairment is an important manifestation of AD. It has been demonstrated that inflammation and oxidative stress are important mediators in the development and progression of AD. Codonopsis Radix (CR) has a long history of consumption, exhibiting lots of beneficial health effects, including anti-ageing, antioxidant, and anti-inflammatory properties. However, studies on the effects of CR on scopolamine-induced amnesia have rarely been reported. AIM OF THE STUDY: The aim of this study was to investigate the ameliorative effect of macromolecular portion (polysaccharides, POL) and small molecule portion (fine extract rich in phenylpropanoids-polyacetylenes, EPP) from CR on improving scopolamine-induced memory impairment and to elucidate the potential mechanism of action. MATERIALS AND METHODS: C57BL/6 mice were pretreated with EPP (0.2, 0.4, and 0.6 g/kg), POL (0.3, 0.6, and 0.9 g/kg), and donepezil (5 mg/kg) by gavage for 7 days, followed by intraperitoneal injection of scopolamine (1 mg/kg) to induce memory impairment. The 16S rRNA gene sequencing, histopathological, western blotting, and biochemical analysis (various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation) were performed to further elucidate the mechanism of action. Moreover, the acetylcholinesterase (AChE) inhibitory activities of POL, EPP, and its main compounds tangshenoside I, lobetyol, lobetyolin, and lobetyolinin were evaluated. RESULTS: Experiments have confirmed that both POL and EPP from CR could improve scopolamine-induced spatial learning memory deficits. Both of them could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities. They also could enhance antioxidant defense via increasing the activities of superoxide dismutase and glutathione peroxidase, and anti-inflammatory function through suppressing inflammatory factors (nitric oxide, TNF-alpha, and IL-6) and regulating gut flora. Besides, in vitro experiments demonstrated that four monomeric compounds and EPP, except POL, exhibited inhibition of AChE activity. CONCLUSION: EPP and POL from CR exert a beneficial effect on learning and memory processes in mice with scopolamine-induced memory impairment. CR may be a promising medicine for preventing and improving learning memory.
ESTHER : Xie_2023_J.Ethnopharmacol__117106
PubMedSearch : Xie_2023_J.Ethnopharmacol__117106
PubMedID: 37652198

Title : Lp-PLA2 silencing ameliorates inflammation and autophagy in nonalcoholic steatohepatitis through inhibiting the JAK2\/STAT3 pathway - Yao_2023_PeerJ_11_e15639
Author(s) : Yao J , Zhao Y
Ref : PeerJ , 11 :e15639 , 2023
Abstract : BACKGROUND: Nonalcoholic steatohepatitis (NASH), a common cause of liver-related morbidity and mortality worldwide, is characterized by inflammation and hepatocellular injury. Our research focuses on lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammation-related biomarker that has recently garnered interest in the context of NASH due to its potential roles in disease pathogenesis and progression. METHODS: We established a NASH mouse model using a high-fat diet (HFD) and treated it with sh-Lp-PLA2 and/or rapamycin (an mTOR inhibitor). Lp-PLA2 expression in NASH mice was detected by qRT-PCR. Serum levels of liver function parameters and inflammatory cytokines were detected using corresponding assay kits. We examined pathological changes in liver using hematoxylin-eosin, oil red O, and Masson staining, and observed autophagy through transmission electron microscopy. The protein levels of Lp-PLA2, mTOR, light chain 3 (LC3) II/I, phosphorylated Janus kinase 2 (p-JAK2)/JAK2, and phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/STAT3 were determined by western blotting. Kupffer cells extracted from C57BL/6J mice were treated to replicate NASH conditions and treated with sh-Lp-PLA2, rapamycin, and/or a JAK2-inhibitor to further verify the roles and mechanisms of Lp-PLA2 in NASH. RESULTS: Our data indicate an upregulation of Lp-PLA2 expression in HFD-induced NASH mice. Silencing Lp-PLA2 in NASH mice reduced liver damage and inflammation markers (aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides (TG), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6)), while increasing IL-10 levels, an anti-inflammatory cytokine. Additionally, Lp-PLA2 silencing decreased lipid and collagen accumulation and promoted autophagy. The beneficial effects of sh-Lp-PLA2 on NASH were enhanced by rapamycin. Furthermore, Lp-PLA2 silencing resulted in the downregulation of the expression of p-JAK2/JAK2 and p-STAT3/STAT3 in NASH mice. Similar results were observed in Kupffer cells treated under NASH conditions; Lp-PLA2 silencing promoted autophagy and repressed inflammation, effects which were potentiated by the addition of rapamycin or a JAK2-inhibitor. CONCLUSION: Our findings suggest that silencing Lp-PLA2 promotes autophagy via deactivating the JAK2/STAT3 signaling pathway, thereby restraining NASH progression. This highlights the potential therapeutic value of targeting Lp-PLA2, adding a new dimension to our understanding of NASH pathogenesis and treatment strategies.
ESTHER : Yao_2023_PeerJ_11_e15639
PubMedSearch : Yao_2023_PeerJ_11_e15639
PubMedID: 37397012
Gene_locus related to this paper: human-PLA2G7

Title : In-situ growth of SnO(2) nanoparticles on Nb(2)CT(x) nanosheets as highly sensitive electrochemical sensing platform for organophosphorus pesticide detection - Guo_2023_Colloids.Surf.B.Biointerfaces_224_113238
Author(s) : Guo W , Liang L , Zhao Y , Zhao C , Lu X , Cao Y , Gao F
Ref : Colloids Surf B Biointerfaces , 224 :113238 , 2023
Abstract : In this study, the SnO(2)/Nb(2)CT(x) MXene nanocomposite containing 0D/2D interfaces was prepared by situ growth strategy of one-step hydrothermal method. A SnO(2)/Nb(2)CT(x) MXene based acetylcholinesterase (AChE) biosensor was constructed for pesticide detection. Highly conductive Nb(2)CT(x) MXene, acting as substrate material, restrained the agglomeration of nanoparticles (NPs) and accelerated electron migration due to the confinement effect and well-known accordion-like layered structure. In addition, SnO(2) anchored on both sides of the Nb(2)CT(x) MXene nanosheets effectively provided a large surface area, abundant surface groups and active sites, which preserved numbers of electrons at the interface of the heterojunction. The SnO(2)/Nb(2)CT(x) MXene hybrids with outstanding conductivity, good biocompatibility and structural stability were beneficial for AChE immobilization. Under the optimized conditions, as-fabricated electrochemical biosensor demonstrated superior performance with linear detection range of 5.1 x 10(-14) - 5.1 x 10(-7) M for chlorpyrifos, along with the limit of detection (LOD) down to 5.1 x 10(-14) M (calculated for 10% inhibition). Furthermore, it is highly expected that this biosensor can be applied for the detection of other organophosphorus pesticides in the environment, providing an effective nanoplatform in biosensing field.
ESTHER : Guo_2023_Colloids.Surf.B.Biointerfaces_224_113238
PubMedSearch : Guo_2023_Colloids.Surf.B.Biointerfaces_224_113238
PubMedID: 36870270

Title : Hyperglycemia disrupted the integrity of the blood-brain barrier following diffuse axonal injury through the sEH\/NF-B pathway - Wei_2023_Immun.Inflamm.Dis_11_e1105
Author(s) : Wei X , Xing Z , Huang T , Zhang M , Song J , Zhao Y
Ref : Immun Inflamm Dis , 11 :e1105 , 2023
Abstract : OBJECTIVES: We aimed to investigate the role of soluble epoxide hydrolase for hyperglycemia induced-disruption of blood-brain barrier (BBB) integrity after diffuse axonal injury (DAI). METHODS: Rat DAI hyperglycemia model was established by a lateral head rotation device and intraperitoneal injection of 50% glucose. Glial fibrillary acidic protein, ionized calcium-binding adapter molecule-1, beta-amyloid precursor protein, neurofilament light chain, and neurofilament heavy chain was detected by immunohistochemistry. Cell apoptosis was examined by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay. The permeability of blood-brain barrier (BBB) was assessed by expression of tight junction proteins, leakage of Evans blue and brain water content. The soluble epoxide hydrolase (sEH) pathway was inhibited by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) and the nuclear transcription factor kappa B (NF-kappaB) pathway was inhibited by pyrrolidine dithiocarbamate and activated by phorbol-12-myristate-13-acetate in vivo and/or vitro, respectively. The inflammatory factors were detected by enzyme-linked immunosorbent assay. RESULTS: Hyperglycemia could exacerbate axonal injury, aggravate cell apoptosis and glial activation, worsen the loss of BBB integrity, increase the release of inflammatory factors, and upregulate the expression of sEH and NF-kappaB. Inhibition of sEH could reverse all these damages and protect BBB integrity by upregulating the expression of tight junction proteins and downregulating the levels of inflammatory factors in vivo and vitro, while the agonist of NF-kappaB pathway abrogated the protective effects of TPPU on BBB integrity in vitro. CONCLUSIONS: sEH was involved in mediating axonal injury induced by hyperglycemia after DAI by disrupting BBB integrity through inducing inflammation via the NF-kappaB pathway.
ESTHER : Wei_2023_Immun.Inflamm.Dis_11_e1105
PubMedSearch : Wei_2023_Immun.Inflamm.Dis_11_e1105
PubMedID: 38156378

Title : Polystyrene nanoplastics induce lipid metabolism disorder and alter fatty acid composition in the hepatopancreas of Pacific whiteleg shrimp (Litopenaeus vannamei) - Li_2023_Sci.Total.Environ__167616
Author(s) : Li Y , Ye Y , Rihan N , Zhu B , Jiang Q , Liu X , Zhao Y , Che X
Ref : Sci Total Environ , :167616 , 2023
Abstract : The impact of nanoplastics (NPs) on environmental pollution and aquatic organisms has gradually attracted attention, but there are relatively few reports of the effects of NPs on the lipid metabolism of crustaceans. In this study, we exposed Pacific whiteleg shrimp (Litopenaeus vannamei) to different concentrations of polystyrene NPs (0, 0.1, 1, 5, and 10 mg/L) for 28 days. We then evaluated the effects of NP exposure on metabolite content, histology, lipid metabolism-related enzyme activity, and gene expression. Our results showed that with increasing NPs concentrations and exposure time, (1) the crude protein and crude fat content decreased and fatty acid composition changed; (2) the tissue structure was destroyed and the number of lipid droplets increased in the hepatopancreas; (3) the activities of acetyl-CoA carboxylase, fatty acid synthase, carnitine palmitoyl transferase-1, pyruvate kinase and low-density lipoprotein content tended to decrease and that of lipase and high-density lipoprotein content first increased and then decreased; the content of triglycerides and total carbohydrate first decreased and then increased; (4) the expression of fatty acid synthesis-related genes (Fas, SREBP, and FAD), fatty acid transport-related genes (FATP, FABP, and ACBP), and fatty acid decomposition-related genes (Ampk and lip1) first increased and then decreased. These results indicate that exposure to NPs can cause physiological disorders of fat metabolism in L. vannamei and that high concentrations of NPs have a negative impact on lipid metabolism. These results of this study provide valuable ecotoxicological data for better interpretation of the mechanism of action of NPs in crustaceans.
ESTHER : Li_2023_Sci.Total.Environ__167616
PubMedSearch : Li_2023_Sci.Total.Environ__167616
PubMedID: 37832676

Title : In vivo and in silico toxicity assessment of four common liquid crystal monomers to Daphnia magna: Novel endocrine disrupting chemicals in crustaceans? - He_2023_Sci.Total.Environ__168757
Author(s) : He S , He J , Wu F , Zhao Y , Jin X , Martyniuk CJ
Ref : Sci Total Environ , :168757 , 2023
Abstract : Liquid crystal monomers (LCMs) are widely used in liquid crystal displays (LCDs) and are proposed to be a new generation of environmentally persistent, bioaccumulative and toxic (PBT) substances that are increasingly detected in rivers and seas. However, there is a lack of in vivo data that characterize adverse responses and toxic mechanisms of LCMs on aquatic organisms. The aim of this study was to comprehensively investigate the effect of four typical LCMs on the lethality, growth, molting, and reproductive capacity of Daphnia magna (D. magna), a highly studied aquatic species in environmental toxicology. Whole body and enzymatic biomarkers (i.e., body length, chitobiase, acetylcholinesterase, antioxidant defense) were measured to assess the toxicity of LCMs. The 48 h mortality rate and observations of disrupted thorax development and inhibition of ecdysis indicate that D. magna are sensitive to LCMs exposure. Oxidative stress, impaired neurotransmission, and disruptions in molting were observed in short-term biomarker tests using LCMs. A 21 day exposure of D. magna to LCMs resulted in reduced growth, reproduction, and population intrinsic growth rate. In addition, chitobiase and 20-hydroxyecdysone, enzymes important for the molting process, were altered at 7, 14 and 21 d. This is hypothesized to be related to endocrine imbalance resulting from LCM exposure. Based on molecular docking simulations, there is evidence that LCMs bind directly to ecdysteroid receptors; this may explain the observed endocrine disrupting effects of LCMs. These data support the hypothesis that LCMs are endocrine disrupting chemicals in aquatic species, impacting the process of molting. This may subsequently lead to lower reproduction and unbalanced population dynamics.
ESTHER : He_2023_Sci.Total.Environ__168757
PubMedSearch : He_2023_Sci.Total.Environ__168757
PubMedID: 38008309

Title : Patatin-like phospholipase domain-containing 3 gene (PNPLA3) polymorphic (rs738409) single nucleotide polymorphisms and susceptibility to nonalcoholic fatty liver disease: A meta-analysis of twenty studies - Zhao_2023_Medicine.(Baltimore)_102_e33110
Author(s) : Zhao Y , Zhao W , Ma J , Toshiyoshi M
Ref : Medicine (Baltimore) , 102 :e33110 , 2023
Abstract : BACKGROUND: To investigate the correlation between rs738409 polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (encoding I148m) and genetic susceptibility to nonalcoholic fatty liver disease (NAFLD). METHODS: Web of Science, Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform databases were subjected to study retrieving, from the earliest records to November 2022. International databases were searched using the key words (PNPLA3 gene or PNPLA3 polymorphism or patatin-like phospholipase domain-containing pro-tein3) and (nonalcoholic fatty liver disease or NAFLD or nonalcoholic steatohepatitis) and their possible combination. There was no limitation to language. Ethnicity and country restrictions were not applied. Hardy-Weinberg equilibrium about the genotype frequencies of rs738,409 polymorphism in group of controls was assessed using a chi-square goodness-of-fit test (P > .05). A chi-square-based Q test was applied to assess heterogeneity among studies. The random-effect model (DerSimonian-Laird method) was used when a probability value of P < .10, I2 > 50%. If not, the fixed-effect model (Mantel-Haenszel method) was adopted. The current meta-analysis was done by using STATA 16.0. RESULTS: Twenty studies are selected for this meta-analysis, which includes totally 3240 patients in the treatment group and 5210 patients in the control group. These studies demonstrated a significant increased association between rs738,409 and NAFLD under 5 models: allelic contrast (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.65-2.37, Pheterogeneity = 0.000, Z = 7.346, P = .000), homozygote comparison (OR = 3.59, 95% CI = 2.56-5.04, Pheterogeneity = 0.000, Z = 7.416, P = .000), heterozygote comparison (OR = 1.93, 95% CI = 1.63-2.30, Pheterogeneity = 0.002, Z = 7.507, P = .000), the dominant allele model (OR = 2.33, 95% CI = 1.89-2.88, Pheterogeneity = 0.000, Z = 7.856, P = .000), and the recessive allele model (OR = 2.56, 95% CI = 1.96-3.35, Pheterogeneity = 0.000, Z = 6.850, P = .000). Subgroup analysis shows that the rs738,409 polymorphism of PNPLA3 gene in Caucasians and those with a sample size of < 300 is significantly associated with the susceptibility to nonalcoholic fatty liver. Sensitivity analysis shows that the results of meta-analysis are stable. CONCLUSION: PNPLA3 rs738,409 may play a significant role in increasing risk of NAFLD.
ESTHER : Zhao_2023_Medicine.(Baltimore)_102_e33110
PubMedSearch : Zhao_2023_Medicine.(Baltimore)_102_e33110
PubMedID: 36897668

Title : Acetylcholinesterase inhibitory activity of sesquiterpenoids isolated from Laggera pterodonta - Li_2023_Front.Plant.Sci_14_1074184
Author(s) : Li J , Li F , Wu G , Gui F , Li H , Xu L , Hao X , Zhao Y , Ding X , Qin X
Ref : Front Plant Sci , 14 :1074184 , 2023
Abstract : Plant-derived natural products are important resources for pesticide discovery. Acetylcholinesterase (AChE) is a well-validated pesticide target, and inhibiting AChE proves fatal for insects. Recent studies have shown that the potential of various sesquiterpenoids as AChE inhibitors. However, few studies have been conducted with eudesmane-type sesquiterpenes with AChE inhibitory effects. Therefore, in this research, we isolated two new sesquiterpenes, laggeranines A (1) and B (2), along with six known eudesmane-type sesquiterpenes (3-8) from Laggera pterodonta, and characterized their structures and the inhibitory effect they exerted on AChE. The results showed that these compounds had certain inhibitory effects on AChE in a dose-dependent manner, of which compound 5 had the best inhibitory effect with IC50 of 437.33 +/- 8.33 mM. As revealed by the Lineweaver-Burk and Dixon plots, compound 5 was observed to suppress AChE activity reversibly and competitively. Furthermore, all compounds exhibited certain toxicity levels on C. elegans. Meanwhile, these compounds had good ADMET properties. These results are significant for the discovery of new AChE targeting compounds, and also enrich the bioactivity activity repertoire of L. pterodonta.
ESTHER : Li_2023_Front.Plant.Sci_14_1074184
PubMedSearch : Li_2023_Front.Plant.Sci_14_1074184
PubMedID: 36844064

Title : Rutin hydrate relieves neuroinflammation in zebrafish models: Involvement of NF-kB pathway as a central network - Hu_2023_Fish.Shellfish.Immunol_141_109062
Author(s) : Hu Y , Jia K , Zhou Y , Chen L , Wang F , Yi X , Huang Y , Ge Y , Chen X , Liao D , Peng Y , Meng Y , Liu Y , Luo Q , Cheng B , Zhao Y , Lu H , Yuan W
Ref : Fish Shellfish Immunol , 141 :109062 , 2023
Abstract : Neuroinflammation is prevalent in multiple brain diseases and may also lead to dementia, cognitive impairment, and impaired spatial memory function associated with neurodegenerative diseases. A neuroprotective and antioxidant flavonoid, rutin hydrate (RH), was evaluated for the anti-neuroinflammatory activity mediated by copper sulfate (CuSO(4)) solution and lipopolysaccharide (LPS) in zebrafish. The results showed that 100 mg/L RH significantly reduced the ratio of neutrophil mobility in caudal hematopoietic tissue (CHT) region caused by CuSO(4) and the number of neutrophils co-localized with facial peripheral nerves. In the LPS model, RH co-injection significantly diminished neutrophil and macrophage migration. Therefore, RH exhibited a significant rescue effect on both models. In addition, RH treatment remarkably reduced the effects of neuroinflammation on the locomotor ability, expression levels of genes associated with behavioral disorders, and acetylcholinesterase (AChE) activity. Furthermore, network pharmacology techniques were employed to investigate the potential mechanisms, and the associated genes and enzyme activities were validated in order to elucidate the underlying mechanisms. Network pharmacological analysis and zebrafish model indicated that RH regulated the expressions of NF-kappaB pathway-related targets (Toll-like receptor 9 (tlr9), nuclear factor kappa B subunit 1 (nfkb1), RELA proto-oncogene (RelA), nitric oxide synthase 2a, inducible (nos2a), tumour necrosis factor alpha-like (tnfalpha), interleukin 6 (il6), interleukin 1beta (il1beta), chemokine 8 (cxcl8), and macrophage migration inhibitory factor (mif)) as well as six key factors (arachidonic acid 4 alpha-lipoxygenase (alox4a), arachidonate 5-lipoxygenase a (alox5), prion protein a (prnpa), integrin, beta 2 (itgb2), catalase (CAT), and alkaline phosphatase (ALP) enzymes). Through this study, a thorough understanding of the mechanism underlying the therapeutic effects of RH in neuroinflammation has been achieved, thereby establishing a solid foundation for further research on the potential therapeutic applications of RH in neuroinflammatory disorders.
ESTHER : Hu_2023_Fish.Shellfish.Immunol_141_109062
PubMedSearch : Hu_2023_Fish.Shellfish.Immunol_141_109062
PubMedID: 37678480

Title : Characterization of a PBAT Degradation Carboxylesterase from Thermobacillus composti KWC4 - Wu_2023_Catalysts_13_340
Author(s) : Wu P , Li Z , Gao J , Zhao Y , Wang H , Qin H , Gu Q , Wei R , Liu W , Han X
Ref : Catalysts , 13 :340 , 2023
Abstract : The large amount of waste synthetic polyester plastics has complicated waste management and also endangering the environment due to improper littering. In this study, a novel carboxylesterase from Thermobacillus composti KWC4 (Tcca) was identified, heterologously expressed in Escherichia coli, purified and characterized with various plastic substrates. Irregular grooves were detected on polybutylene adipate terephthalate (PBAT) film by scanning electron microscopy (SEM) after Tcca treatment, and Tcca can also hydrolyze short-chain diester bis(hydroxyethyl) terephthalate (BHET). The optimal pH and temperature for Tcca were 7.0 and 40 C, respectively. In order to explore its catalytic mechanism and improve its potential for plastic hydrolysis, we modeled the protein structure of Tcca and compared it with its homologous structures, and we identified positions that might be crucial for the binding of substrates. We generated a variety of Tcca variants by mutating these key positions; the variant F325A exhibited a more than 1.4-fold improvement in PBAT hydrolytic activity, and E80A exhibited a more than 4.1-fold increase in BHET activity when compared to the wild type. Tcca and its variants demonstrated future applicability for the recycling of bioplastic waste containing a PBAT fraction.
ESTHER : Wu_2023_Catalysts_13_340
PubMedSearch : Wu_2023_Catalysts_13_340
Gene_locus related to this paper: theck-l0ef70

Title : Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors - Yang_2023_Chem.Biol.Interact_378_110501
Author(s) : Yang Y , Xiong Y , Zhu G , Sun M , Zou K , Zhao Y , Zhang Y , Xu Z , Li Y , Zhu W , Jia Q , Li B , Ge G
Ref : Chemico-Biological Interactions , 378 :110501 , 2023
Abstract : Human carboxylesterase 2A (hCES2A) is a key serine hydrolase responsible for the metabolic clearance of large number of compounds bearing the ester- or amide-bond(s). Inhibition of hCES2A can relieve the chemotherapy-induced toxicity and alter the pharmacokinetic bahaviors of some orally administrate esters-containing agents. However, most of the hCES2A inhibitors show poor cell-membrane permeability and poor specificity. Herein, guided by the structure activity relationships (SAR) of fifteen natural alkaloids against hCES2A, fifteen new seven-membered ring berberine analogues were designed and synthesized, and their anti-hCES2A activities were evaluated. Among all tested compounds, compound 28 showed potent anti-hCES2A effect (IC(50) = 1.66 microM) and excellent selectivity over hCES1A (IC(50) > 100 microM). The SAR analysis revealed that the seven-membered ring of these berberine analogues was a crucial moiety for hCES2A inhibition, while the secondary amine group of the ring-C is important for improving their specificity over other serine hydrolases. Inhibition kinetic analyses and molecular dynamic simulation demonstrated that 28 strongly inhibited hCES2A in a mixed-inhibition manner, with an estimated K(i) value of 1.035 microM. Moreover, 28 could inhibit intracellular hCES2A in living HepG2 cells and exhibited suitable metabolic stability. Collectively, the SAR of seven-membered ring berberine analogues as hCES2A inhibitors were studied, while compound 28 acted as a promising candidate for developing highly selective hCES2A inhibitors.
ESTHER : Yang_2023_Chem.Biol.Interact_378_110501
PubMedSearch : Yang_2023_Chem.Biol.Interact_378_110501
PubMedID: 37080375

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 : CES1-Triggered Liver-Specific Cargo Release of CRISPR\/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration - Zhao_2023_Adv.Sci.(Weinh)__e2300502
Author(s) : Zhao Y , Li Y , Wang F , Gan X , Zheng T , Chen M , Wei L , Chen J , Yu C
Ref : Adv Sci (Weinh) , :e2300502 , 2023
Abstract : The broad application of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing tools is hindered by challenges in the efficient delivery of its two components into specific cells and intracytoplasmic release. Herein, a novel copolymer for delivery of Cas9-mRNA/ single-guide RNA (Cas9-mRNA/sgRNA) in vitro and vivo, using carboxylesterase-responsive cationic triadic copolymeric nanoparticles targeted proprotein convertase subtilisin/kexin type 9 (PCSK9) for hyperlipidemia amelioration is reported. A dimethyl biguanide derivative is designed and synthesized to form cationic block, and copolymerization onto prepolymer with propyl methacrylate, to fabricate a triadic copolymer mPEG-b-P(Met/n-PMA). The copolymer can self-assemble with Cas9-mRNA/sgRNA, indicating the excellent potential of nanoparticles to form a delivery carrier. This vehicle can efficiently release RNA in response to the hepatocytes carboxylesterase for genome editing. It was demonstrated that the mPEG-b-P(Met/n-PMA)/Cas9 mRNA/sgRNA nanoparticles effectively accumulated in hepatocytes, lead to the inhibition of PCSK9, and lowered the levels of Low-density lipoprotein cholesterol and total cholesterol in mouse serum down 20% of nontreatment. Interestingly, the nanoparticles even enable multiple functions in the regulation of blood glucose and weight. This study establishes a novel method to achieve complex CRISPR components stable loading, safe delivery, and fixed-point release, which expand the application of CRISPR delivery systems.
ESTHER : Zhao_2023_Adv.Sci.(Weinh)__e2300502
PubMedSearch : Zhao_2023_Adv.Sci.(Weinh)__e2300502
PubMedID: 37083231

Title : Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene - Chen_2023_Front.Pharmacol_14_1105702
Author(s) : Chen X , Zuo X , Zhao Y , Huang Y , Lv C
Ref : Front Pharmacol , 14 :1105702 , 2023
Abstract : Introduction: In clinical practice, warfarin is often combined with Compound Danshen dripping pill (CDDP) for the treatment of cardiovascular diseases. However, warfarin has a narrow therapeutic index, wide interindividual variability (genetic and non-genetic factors), and is susceptible to drug-drug interactions. Our previous study indicated that CDDP might interact with warfarin in individuals with the epoxide hydrolase gene (EPHX1; single-nucleotide polymorphism: rs2292566) A/A subtype. We sought to clarify the interaction between CDDP and warfarin associated with EPHX1 in a comprehensive and accurate manner. Methods: Here, EPHX1 A and EPHX1 G cell lines were established. Expression of microsomal epoxide hydrolase (mEH), vitamin K epoxide reductase (VKOR), and vitamin K-dependent clotting factors (FII, FVII, FIX, FX) was measured by western blotting upon incubation with CDDP and warfarin. mEH activity was evaluated by measuring the transformation of epoxyeicosatrienoic acids into dihydroxyeicosatrienoic acids. Then, healthy volunteers (HVs) with the EPHX1 A/A genotype were recruited and administered warfarin and CDDP to investigate the pharmacokinetics and pharmacodynamics of warfarin. Results: CDDP combined with warfarin could decrease expression of mEH and VKOR, and increase protein expression of FII, FVII, FIX, and FX, in EPHX1 A cells. CDDP could slightly influence the pharmacokinetics/pharmacodynamics of warfarin in HVs with the EPHX1 A/A genotype. Discussion: Rational combination of CDDP and warfarin was safe with no risk of bleeding, but the therapeutic management is also needed. The clinical study is posted in the China Clinical Trial Registry (ChiCTR190002434).
ESTHER : Chen_2023_Front.Pharmacol_14_1105702
PubMedSearch : Chen_2023_Front.Pharmacol_14_1105702
PubMedID: 37214448

Title : Nde1 promotes Lis1-mediated activation of dynein - Zhao_2023_Nat.Commun_14_7221
Author(s) : Zhao Y , Oten S , Yildiz A
Ref : Nat Commun , 14 :7221 , 2023
Abstract : Cytoplasmic dynein drives the motility and force generation functions towards the microtubule minus end. The assembly of dynein with dynactin and a cargo adaptor in an active transport complex is facilitated by Lis1 and Nde1/Ndel1. Recent studies proposed that Lis1 relieves dynein from its autoinhibited conformation, but the physiological function of Nde1/Ndel1 remains elusive. Here, we investigate how human Nde1 and Lis1 regulate the assembly and subsequent motility of mammalian dynein using in vitro reconstitution and single molecule imaging. We find that Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated assembly of dynein-dynactin adaptor complexes. Nde1 can compete with the alpha2 subunit of platelet activator factor acetylhydrolase 1B (PAF-AH1B) for the binding of Lis1, which suggests that Nde1 may disrupt PAF-AH1B recruitment of Lis1 as a noncatalytic subunit, thus promoting Lis1 binding to dynein. Before the initiation of motility, the association of dynactin with dynein triggers the dissociation of Nde1 from dynein by competing against Nde1 binding to the dynein intermediate chain. Our results provide a mechanistic explanation for how Nde1 and Lis1 synergistically activate the dynein transport machinery.
ESTHER : Zhao_2023_Nat.Commun_14_7221
PubMedSearch : Zhao_2023_Nat.Commun_14_7221
PubMedID: 37940657

Title : Monovalent SARS-COV-2 mRNA vaccine using optimal UTRs and LNPs is highly immunogenic and broadly protective against Omicron variants - Ye_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2311752120
Author(s) : Ye Z , Bonam SR , McKay LGA , Plante JA , Walker J , Zhao Y , Huang C , Chen J , Xu C , Li Y , Liu L , Harmon J , Gao S , Song D , Zhang Z , Plante KS , Griffiths A , Hu H , Xu Q
Ref : Proc Natl Acad Sci U S A , 120 :e2311752120 , 2023
Abstract : The emergence of highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that are resistant to the current COVID-19 vaccines highlights the need for continued development of broadly protective vaccines for the future. Here, we developed two messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines, TU88mCSA and ALCmCSA, using the ancestral SARS-CoV-2 spike sequence, optimized 5' and 3' untranslated regions (UTRs), and LNP combinations. Our data showed that these nanocomplexes effectively activate CD4(+) and CD8(+) T cell responses and humoral immune response and provide complete protection against WA1/2020, Omicron BA.1 and BQ.1 infection in hamsters. Critically, in Omicron BQ.1 challenge hamster models, TU88mCSA and ALCmCSA not only induced robust control of virus load in the lungs but also enhanced protective efficacy in the upper respiratory airways. Antigen-specific immune analysis in mice revealed that the observed cross-protection is associated with superior UTRs [Carboxylesterase 1d (Ces1d)/adaptor protein-3beta (AP3B1)] and LNP formulations that elicit robust lung tissue-resident memory T cells. Strong protective effects of TU88mCSA or ALCmCSA against both WA1/2020 and VOCs suggest that this mRNA-LNP combination can be a broadly protective vaccine platform in which mRNA cargo uses the ancestral antigen sequence regardless of the antigenic drift. This approach could be rapidly adapted for clinical use and timely deployment of vaccines against emerging and reemerging VOCs.
ESTHER : Ye_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2311752120
PubMedSearch : Ye_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2311752120
PubMedID: 38134199

Title : Soluble Epoxide Hydrolase Inhibitor TPPU Alleviates Nab-Paclitaxel-Induced Peripheral Neuropathic Pain via Suppressing NF-B Signalling in the Spinal Cord of a Rat - Wei_2023_Pain.Res.Manag_2023_9058774
Author(s) : Wei X , Jia L , Zhou Y , Li W , Shan C , Zhang S , Zhao Y
Ref : Pain Res Manag , 2023 :9058774 , 2023
Abstract : OBJECTIVE: Paclitaxel-induced peripheral neuropathy (PIPN) is a debilitating and difficult-to-treat side effect of paclitaxel. Soluble epoxide hydrolase (sEH) can rapidly metabolize the endogenous anti-inflammatory mediators' epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. This study aimed to assess whether the sEH inhibitor N-(1-(1-oxopropy)-4-piperidinyl]-N'-(trifluoromethoxy) phenyl)-urea (TPPU) plays a critical role in PIPN of rats and provides a new target for treatment. METHODS: A Sprague-Dawley male rat model of PIPN induced by nab-paclitaxel was established. Rats were randomly divided into a control group, nab-paclitaxel group, and nab-paclitaxel + TPPU (sEH inhibitor) group, with 36 rats in each group. The effects of the sEH inhibitor TPPU on behavioural assays, apoptosis, glial activation, axonal injury, microstructure, and permeability of the blood-spinal cord barrier were detected, and the underlying mechanisms were explored by examining the expression of NF-kappaB signalling pathways, inflammatory cytokines, and oxidative stress. RESULTS: The results showed that the mechanical and thermal pain thresholds of rats were decreased after nab-paclitaxel treatment, accompanied by an increased expression of axonal injury-related proteins, enhanced cell apoptosis, aggravated destruction of vascular permeability, intense glial responses, and elevated inflammatory cytokines and oxidative stress in the L4-L6 spinal cord. TPPU restored the mechanical and thermal thresholds, decreased cell apoptosis, alleviated axonal injury and glial responses, and protected vascular permeability by increasing the expression of tight junction proteins. TPPU relieved PIPN by inhibiting the activation of the sEH and NF-kappaB signalling pathways by decreasing the levels of inflammatory cytokines and oxidative stress. CONCLUSION: These findings support a role for sEH in PIPN and suggest that the inhibition of sEH represents a potential new therapeutic target for PIPN.
ESTHER : Wei_2023_Pain.Res.Manag_2023_9058774
PubMedSearch : Wei_2023_Pain.Res.Manag_2023_9058774
PubMedID: 36819745

Title : Targeting soluble epoxide hydrolase promotes osteogenic-angiogenic coupling via activating SLIT3\/HIF-1alpha signalling pathway - Gao_2023_Cell.Prolif__e13403
Author(s) : Gao L , Chen W , Li L , Li J , Kongling W , Zhang Y , Yang X , Zhao Y , Bai J , Wang F
Ref : Cell Prolif , :e13403 , 2023
Abstract : Type H vessels have recently been identified to modulate osteogenesis. Epoxyeicostrioleic acids (EETs) have an essential contribution to vascular homeostasis. However, whether increased EETs with soluble epoxide hydrolase (sEH) inhibitor TPPU enhance the coupling of angiogenesis and osteogenesis remains largely unknown. The effects of TPPU on cross-talk between co-cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs), and on long bone growth and calvarial defect repair in mice were investigated in vitro and in vivo. TPPU enhanced osteogenic differentiation of co-cultured HUVECs and hDPSCs in vitro and increased type H vessels, and long bone growth and bone repair of calvarial defect. Mechanistically, TPPU promoted cell proliferation and angiogenesis, reclined cell apoptosis, and significantly increased CD31(hi) EMCN(hi) endothelial cells (ECs) and SLIT3 and HIF-1alpha expression levels in co-cultured HUVECs and hDPSCs. Knockdown of Slit3 in hDPSCs or Hif-1alpha in HUVECs impaired the formation of CD31(hi) EMCN(hi) ECs and reversed TPPU-induced osteogenesis. We defined a previously unidentified effect of TPPU coupling angiogenesis and osteogenesis. TPPU induced type H vessels by upregulating the expression of hDPSCs-derived SLIT3, which resulted in the activation of ROBO1/YAP1/HIF-1alpha signalling pathway in ECs. Targeting metabolic pathways of EETs represents a new strategy to couple osteogenesis and angiogenesis, sEH is a promising therapeutic target for bone regeneration and repair.
ESTHER : Gao_2023_Cell.Prolif__e13403
PubMedSearch : Gao_2023_Cell.Prolif__e13403
PubMedID: 36636821

Title : Molecular Machinery of Lipid Droplet Degradation and Turnover in Plants - Qin_2023_Int.J.Mol.Sci_24_
Author(s) : Qin Z , Wang T , Zhao Y , Ma C , Shao Q
Ref : Int J Mol Sci , 24 : , 2023
Abstract : Lipid droplets (LDs) are important organelles conserved across eukaryotes with a fascinating biogenesis and consumption cycle. Recent intensive research has focused on uncovering the cellular biology of LDs, with emphasis on their degradation. Briefly, two major pathways for LD degradation have been recognized: (1) lipolysis, in which lipid degradation is catalyzed by lipases on the LD surface, and (2) lipophagy, in which LDs are degraded by autophagy. Both of these pathways require the collective actions of several lipolytic and proteolytic enzymes, some of which have been purified and analyzed for their in vitro activities. Furthermore, several genes encoding these proteins have been cloned and characterized. In seed plants, seed germination is initiated by the hydrolysis of stored lipids in LDs to provide energy and carbon equivalents for the germinating seedling. However, little is known about the mechanism regulating the LD mobilization. In this review, we focus on recent progress toward understanding how lipids are degraded and the specific pathways that coordinate LD mobilization in plants, aiming to provide an accurate and detailed outline of the process. This will set the stage for future studies of LD dynamics and help to utilize LDs to their full potential.
ESTHER : Qin_2023_Int.J.Mol.Sci_24_
PubMedSearch : Qin_2023_Int.J.Mol.Sci_24_
PubMedID: 38003229

Title : Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase - Zhao_2023_Bioorg.Med.Chem_91_117413
Author(s) : Zhao Y , Zhang M , Hou X , Han J , Qin X , Yang Y , Song Y , Liu Z , Zhang Y , Xu Z , Jia Q , Li Y , Chen K , Li B , Zhu W , Ge G
Ref : Bioorganic & Medicinal Chemistry , 91 :117413 , 2023
Abstract : Obesity is a growing global health problem and is associated with increased prevalence of many metabolic disorders, including diabetes, hypertension and cardiovascular disease. Pancreatic lipase (PL) has been validated as a key target for developing anti-obesity agents, owing to its crucial role in lipid digestion and absorption. In the past few decades, porcine PL (pPL) is always used as the enzyme source for screening PL inhibitors, which generate numerous pPL inhibitors but the potent inhibitors against human PL (hPL) are rarely reported. Herein, a series of salicylanilide derivatives were designed and synthesized, while their anti-hPL effects were assayed by a fluorescence-based biochemical approach. To investigate the structure-activity relationships of salicylanilide derivatives as hPL inhibitors in detail, structural modifications on three rings (A, B and C) of the salicylanilide skeleton were performed. Among all tested compounds, 2t and 2u were found possessing the most potent anti-PL activity, showing IC(50) values of 1.86 microM and 1.63 microM, respectively. Inhibition kinetic analyses suggested that both 2t and 2u could effectively inhibit hPL in a non-competitive manner, with the k(i) value of 1.67 microM and 1.70 microM, respectively. Fluorescence quenching assays suggested that two inhibitors could quench the fluorescence of hPL via a static quenching procedure. Molecular docking simulations suggested that 2t and 2u could tightly bind on an allosteric site of hPL. Collectively, the structure-activity relationships of salicylanilide derivatives as hPL inhibitors were carefully investigated, while two newly identified reversible hPL inhibitors (2t and 2u) could be used as promising lead compounds to develop novel anti-obesity drugs.
ESTHER : Zhao_2023_Bioorg.Med.Chem_91_117413
PubMedSearch : Zhao_2023_Bioorg.Med.Chem_91_117413
PubMedID: 37490786

Title : Green biosynthesis of DHA-phospholipids in tailor-made supersaturated DHA aqueous solution and catalytic mechanism study - Zhang_2023_Food.Chem_431_137164
Author(s) : Zhang T , Wang J , Zhao Y , Wang Z , Hu D , Liu Y , Zhang X , Li H , Zhao B , Li B
Ref : Food Chem , 431 :137164 , 2023
Abstract : Docosahexaenoic acid-phospholipids (DHA-PLs) were prepared via lipase-mediated transesterification of DHA donor and phosphatidylcholine (PC) in a purely aqueous solution. Pre-existing carriers would play the role as "artificial interfaces" to adsorb water-insoluble PC and made them disperse in water. DHA donors were concentrated by a pH-responsive method and presented as supersaturated salt solutions. 153 triacylglycerol lipase structures were analyzed and screened in silico. Transesterification was carried out to further evaluate the six lipase candidates. Lipase B from Candida antarctica (CALB) was the best biocatalyst with 34.8% of DHA incorporation and 80.0% of PLs yields (involving 38.1% PC and 41.9% sn-1 lyso-PC). Toxic organic solvents were avoided. Six possible microunits of our aqueous system consisting of three PLs donors (PC, lyso-PC, sn-glycero-3-PC) and two DHA donors (DHA and DHA salts), were simulated by molecular dynamics (MD) to illustrate the enzymatic mechanism based on diffusional channels, competitive bindings, and enzymatic structures.
ESTHER : Zhang_2023_Food.Chem_431_137164
PubMedSearch : Zhang_2023_Food.Chem_431_137164
PubMedID: 37607420

Title : Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity - Atkinson_2023_Eur.J.Med.Chem_251_115132
Author(s) : Atkinson BN , Willis NJ , Zhao Y , Patel C , Frew S , Costelloe K , Magno L , Svensson F , Jones EY , Fish PV
Ref : Eur Journal of Medicinal Chemistry , 251 :115132 , 2023
Abstract : N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.
ESTHER : Atkinson_2023_Eur.J.Med.Chem_251_115132
PubMedSearch : Atkinson_2023_Eur.J.Med.Chem_251_115132
PubMedID: 36934521
Gene_locus related to this paper: human-NOTUM

Title : Identification of the first selective bioluminescent probe for real-time monitoring of carboxylesterase 2 in vitro and in vivo - Chen_2023_Analyst__
Author(s) : Chen Z , Yu J , Sun K , Song J , Chen L , Jiang Y , Wang Z , Chen Y , Zhao T , Miao Z , Huang T , Chen M , Zhao Y , Hai A , Qi Q , Feng P , Li M , Ke B
Ref : Analyst , : , 2023
Abstract : Carboxylesterase (CES), a main hydrolysis enzyme family in the human body, plays a crucial role in drug metabolism. Among them, CES1 and CES2 are the primary subtypes, and each exhibits distinct distribution and functions. However, convenient and non-invasive methods for distinguishing them and the real-time monitoring of CES2 are relatively rare, hindering the further understanding of physiological functions and underlying mechanisms. In this study, we have designed, synthesized, and evaluated the first selective bioluminescent probe (CBP 1) for CES2 with high sensitivity, high specificity and rapid reactivity. This probe offers a promising approach for the real-time detection of CES2 and its dynamic fluctuations both in vitro and in vivo.
ESTHER : Chen_2023_Analyst__
PubMedSearch : Chen_2023_Analyst__
PubMedID: 36661088 || 38078792

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 : A novel skeleton alkaloid from Portulaca oleracea L. and its bioactivities - Lan_2023_Fitoterapia__105608
Author(s) : Lan X , Guo S , Zhao Y , Zhang M , Zhang D , Leng A , Ying X
Ref : Fitoterapia , :105608 , 2023
Abstract : A novel skeleton alkaloid was obtained from Portulaca oleracea L., which was identified as 10,11-dihydroxybenzo[5',6'] pentaleno[1',2':3,4]pyrrolo[2,1-b]oxazol-7(11bH)-one, named oleracone M, and its structure was determined using UHPLC-ESI-QTOF/MS, 1D NMR and 2D NMR spectroscopy, and circular dichroism. Then the bioactivities of the compound were investigated including the anti-inflammatory, anti-acetylcholinesterase and antioxidant activities. The results showed that the novel skeleton alkaloid exhibited the potent effect on inhibiting the secretion of IL-1beta at 10 microM, anticholinesterase activity with IC(50) value of 49.58 microM, and antioxidant activity with IC(50) value of 66.43 microM.
ESTHER : Lan_2023_Fitoterapia__105608
PubMedSearch : Lan_2023_Fitoterapia__105608
PubMedID: 37453700

Title : Organophosphate Level Evaluation for the Poisoning Treatment by Enzyme Activation Regeneration Strategy with Oxime-Functionalized ZIF-8 Nanoparticles - Shen_2023_Anal.Chem__
Author(s) : Shen A , Hao X , Li M , Zhao Y , Li Z , Hou L , Duan R , Zhang P , Zhang L , Yang Y
Ref : Analytical Chemistry , : , 2023
Abstract : In this work, two nanometal-organic frameworks (NMOFs) of ZIF-8-1 and ZIF-8-2 were designed and synthesized with a "missing linker" defects strategy by using Oxime-1 and Oxime-2 as coligands, respectively. ZIF-8-2 exhibited an excellent performance in comparison to that of ZIF-8-1 in activating and regenerating the activity of BChE suppressed by demeton-S-methyl (DSM) and could rapidly detoxify DSM in poisoned serum samples within 24 min. Additionally, the synthesized fluorescence probe of IND-BChE with high quantum yields, large Stokes shifts, and superior water solubility could be used for the detection of both butyrylcholinesterase (BChE) and DSM in a lower LOD of 0.63 mU/mL (BChE) and 0.086 microg/mL (DSM). By the difference in fluorescent intensity of IND-BChE with and without ZIF-8-2, a highly linear relationship of IND-BChE with DSM concentration was found (R(2) = 0.9889), and the LOD was 0.073 microg/mL. In addition, an intelligent detection platform of ZIF-8-2@IND-BChE@agarose hydrogel combined with a smartphone formed a point-of-care test for DSM -poisoned serum samples and also realized satisfactory results. Unlike other detection methods of nerve agents, this assay first combined an NMOF reactivator for detoxification and detection of BChE enzyme activity and then quantification of OP nerve agents, which was of great significance in treatment of organophosphate poisoning.
ESTHER : Shen_2023_Anal.Chem__
PubMedSearch : Shen_2023_Anal.Chem__
PubMedID: 37358141

Title : Improving the Efficiency of Precise Genome Editing with CRISPR\/Cas9 to Generate Goats Overexpressing Human Butyrylcholinesterase - Wang_2023_Cells_12_
Author(s) : Wang JH , Wu SJ , Li Y , Zhao Y , Liu ZM , Deng SL , Lian ZX
Ref : Cells , 12 : , 2023
Abstract : The CRISPR/Cas9 system is widely used for genome editing in livestock production, although off-target effects can occur. It is the main method to produce genome-edited goats by somatic cell nuclear transfer (SCNT) of CRISPR/Cas9-mediated genome-edited primary goat fetal fibroblast cells (GFFs). Improving the double-strand break (DSB) efficiency of Cas9 in primary cells would improve the homologous repair (HR) efficiency. The low efficiency of HR remains a major hurdle in CRISPR/Cas9-mediated precise genome editing, increasing the work required to screen the genome-edited primary cell clones. In this study, we modified several essential parameters that affect the efficiency of the CRISPR/Cas9-mediated knock-in GFF cloning system, including establishing a high-efficiency transfection system for primary cells via nucleofection and optimizing homology arm (HA) length during HR. Here, we specifically inserted a recombinant human butyrylcholinesterase gene (rhBChE) into the goat fibroblast growth factor (FGF)-5 locus through the CRISPR/Cas9 system, thereby achieving simultaneous rhBChE insertion and FGF5 knock-out. First, this study introduced the Cas9, FGF5 knock-out small guide RNA, and rhBChE knock-in donors into GFFs by electroporation and obtained positive cell clones without off-target effects. Then, we demonstrated the expression of rhBChE in GFF clones and verified its function. Finally, we obtained a CRISPR/Cas9-mediated rhBChE-overexpression goat.
ESTHER : Wang_2023_Cells_12_
PubMedSearch : Wang_2023_Cells_12_
PubMedID: 37508483

Title : Nanoclusterzyme for Dual Colorimetric Sensings: A Case Study on [Au(14) (Dppp)(5) I(4) ](2) - Zhao_2023_Small__e2207936
Author(s) : Zhao H , You Q , Zhu W , Li J , Deng H , Li MB , Zhao Y , Wu Z
Ref : Small , :e2207936 , 2023
Abstract : The enzymatic activity of atomically precise metal nanoclusters has recently been recognized; however, the number of nanoclusterzymes is very small. Besides, the applications of nanoclusterzyme wait to be explored. Herein, a novel nanoclusterzyme is synthesized and its structure is majorly resolved by single-crystal X-ray diffraction and mass spectrometry, which reveal that the nanocluster consists of an Au(13) icosahedron capped by an exterior shell including four I, three Dppp (1,3-bis(diphenylphosphino) propane) ligands, and a rarely reported Dppp-Au-Dppp handle staple, which contributes a lot to the enzyme activity of [Au(14) (Dppp)(5) I(4) ](2+) nanocluster. The as-obtained nanocluster can catalyze oxygen to O(2) (-) under visible light irradiation with a specific activity up to 0.182 U.mg(-1) and lead to the blue color of 3,3',5,5'-tetramethylbenzidine (TMB) in both solution and solid states. With the addition of acetylcholinesterase (AChE), the blue color of (Au(14) + TMB) solution system disappears due to the nanoclusterzyme activity inhibition, but the further addition of organophosphorus pesticides (OPs) into the above mixture can restore the nanoclusterzyme and recover the blue color. Based on the color turn-off and on, the various nanoclusterzyme-containing systems are used to colorimetrically sense AChE and OPs with the detection limits reaching 0.04 mU.mL(-1) and 0.02 ng.mL(-1) , respectively.
ESTHER : Zhao_2023_Small__e2207936
PubMedSearch : Zhao_2023_Small__e2207936
PubMedID: 37060229

Title : The porous hollow cobalt-based oxides encapsulated with bimetallic PdAu Nanoparticles of electrochemical biosensor for highly sensitive pesticides detection - Zhao_2023_Nanotechnology__
Author(s) : Zhao Y , Liang L , Guo W , Lu X , Zhao C , Gao F
Ref : Nanotechnology , : , 2023
Abstract : Efficient and portable electrochemical biosensors are received to evaluation of pesticides in the environment, which can make great significance for food safety. In this study, the Co-based oxides with a kind of hierarchical porous hollow and nanocages were constructed, in which the materials (Co3O4-NC) were encapsulated with PdAu nanoparticles (NPs). Due to the unique porous structure, the changeable valence state of cobalt and the synergistic effect of bimetallic PdAuNPs, PdAu@Co3O4-NC possessed excellent electron pathways, and showed more exposed active sites. Accordingly, the porous Co-based oxides have been applied to construct an acetylcholinesterase (AChE) electrochemical biosensor, which showed good performance for organophosphorus pesticides (OPs) detection. The optimum biosensing platform based on nanocomposites was applied to exhibit highly sensitive determination of omethoate and chlorpyrifos, with the relative low detection limit of 6.125 x 10-15 M and 5.10 x 10-13 M, respectively. And a wide detection range of 6.125 x 10-15 ~ 6.125 x 10-6 M and 5.10 x 10-13 ~ 5.10 x 10-6 M for these two pesticides were achieved. Therefore, the PdAu@Co3O4-NC may represent a powerful tool for ultrasensitive sensing of OPs, and have great potential application.
ESTHER : Zhao_2023_Nanotechnology__
PubMedSearch : Zhao_2023_Nanotechnology__
PubMedID: 37054697

Title : Selection and Identification of an ssDNA Aptamer for Fibroblast Activation Protein - Zhang_2023_Molecules_28_
Author(s) : Zhang X , Yang G , Zhao Y , Dai X , Liu W , Qu F , Huang Y
Ref : Molecules , 28 : , 2023
Abstract : As a type II transmembrane serine protease, fibroblast activation protein (FAP) is specifically expressed on the surface of fibroblasts associated with a variety of epithelial-derived malignancies such as pancreatic cancer, breast cancer, and colon cancer. It participates in the processes of tumorigenesis, progression, and immunosuppression. FAP constitutes an important target for tumor treatment; however, the current studies on FAP are mainly related to structural characteristics, enzymatic properties, and biological functions, and aptamers of FAP have not been investigated. In this work, by using recombinant human FAP as the target, five candidate aptamers, which are AptFAP-A1, AptFAP-A2, AptFAP-A3, AptFAP-A4, and AptFAP-A5, were selected by capillary electrophoresis-systematic evolution of ligands by exponential enrichment (CE-SELEX), and their secondary structures were predicted to be mainly stem-loop. Moreover, the CE-laser-induced fluorescence (LIF) method was used to determine the equilibrium dissociation constant K(D) values between the FAP protein and candidate aptamers, and the K(D) value was in the low molar range. Finally, Cy5-labeled aptamers were co-incubated with human pancreatic cancer-associated fibroblasts highly expressing FAP protein, and confocal microscopy imaging showed that aptamer AptFAP-A4 had the highest affinities with the cells. The FAP aptamers screened in this study provide a promising direction for the development of rapid tumor diagnosis and targeted therapy.
ESTHER : Zhang_2023_Molecules_28_
PubMedSearch : Zhang_2023_Molecules_28_
PubMedID: 36838669

Title : Network pharmacology combined with an animal model to reveal the material basis and mechanism of Amomum villosum in alleviating constipation in mice - Liu_2023_Gene_897_148064
Author(s) : Liu S , Zhao Y , Li S , Li Y , Liu L , Sheng J , Tian Y , Gao X
Ref : Gene , 897 :148064 , 2023
Abstract : Constipation is a prevalent gastrointestinal disorder, with its prevalence showing an annual upward trend. There are many factors involved in the occurrence of constipation, such as abnormal smooth muscle contraction and disorders of gastrointestinal hormone secretion. Amomum villosum (A. villosum) has been proven to be effective in improving digestive system diseases, but there is no report on improving constipation. Therefore, we used network pharmacology prediction combined with animal experiments to explore the key active components of A. villosum and their pharmacological mechanisms. The results of network pharmacological prediction showed that beta-sitosterol was the key laxative compound of A. villosum, which may play a laxative role by activating the adrenoceptor alpha 1 A-myosin light chain (ADRA1A-MLC) pathway. Further animal experiments showed that beta-sitosterol could significantly shorten the time to first black stool; increase faecal weight, faecal number, and faecal water content; and promote gastrointestinal motility. beta-sitosterol may promote intestinal motility by upregulating the expression of ADRA1A and myosin light chain 9 (Myl9) mRNA and protein in the colon, thereby activating the ADRA1A-MLC signalling pathway. In addition, it is possible to improve constipation symptoms by regulating serum neurotransmitters and gastrointestinal motility-related factors, such as the serum content of 5-hydroxytryptamine (5-HT) and acetylcholinesterase (AchE) and the mRNA expression of 5-hydroxytryptamine receptor 4 (5-HT4), stem cell factor (SCF), stem cell factor receptor (c-Kit) and smooth muscle myosin light chain kinase (smMLCK) in the colon. These results lay a foundation for the application of A. villosum and beta-sitosterol in constipation.
ESTHER : Liu_2023_Gene_897_148064
PubMedSearch : Liu_2023_Gene_897_148064
PubMedID: 38065427

Title : Static Binding and Dynamic Transporting-Based Design of Specific Ring-Chain-Ring Acetylcholinesterase Inhibitor: From Galantamine to Natural Product - Zhang_2023_Chemistry__e202203363
Author(s) : Zhang Z , Lv J , Wang Y , Yu H , Guo B , Zhai J , Wang C , Zhao Y , Fan F , Luo W
Ref : Chemistry , :e202203363 , 2023
Abstract : Acetylcholinesterase (AChE) is a key target for the current symptomatic treatment of Alzheimer's disease, and galantamine is a clinical anticholinesterase drug with transiently acting characteristic and good selectivity for AChE. The present theoretical-experimental work improves the drug's residence time without reducing inhibition effect, thus provides crucial breakthrough for modifying the inhibitor of AChE with better-kinetic behavior. The static binding and dynamic delivery properties acquired from atomic view reveal that the galantamine simply occupies catalytic anionic site, and its release from AChE needs only ~ 8.6 kcal/mol. Both of them may cause the short residence time of galantamine. The hotspots and most favorable transport mechanism are identified, and the hydrogen bond and aromatic stacking interactions are observed to play crucial roles for galantamine binding and release in AChE. The typical peripheral anionic site arisen at the delivery process would provide another key occupation to enhance the anti-release ability for inhibitors. The compound with "specific-ring-chain-ring" framework with detail beneficial modify scheme is summarized, which may improve the residence time of inhibitor in AChE. The thermodynamic and dynamic properties of galantamine derivatives are also studied. Based on dictamnine, a natural alkaloid, two novel eligible derivatives are designed, synthesized and evaluated, which verifies our prediction. Multiple computational approaches and experiment combination probably provide a train of thought from static and dynamic view to modify or design appropriate inhibitor on the basis of specific binding and transportation features.
ESTHER : Zhang_2023_Chemistry__e202203363
PubMedSearch : Zhang_2023_Chemistry__e202203363
PubMedID: 36826395

Title : Ormosianines A-P, Structurally Diverse Quinolizidine Alkaloids with AChE Inhibitory Effects from Ormosia yunnanensis - Jin_2023_J.Nat.Prod__
Author(s) : Jin Q , Qin XJ , Sun WJ , Ding X , Zhao Y , Wang CB , Tao XY , Luo XD
Ref : Journal of Natural Products , : , 2023
Abstract : Sixteen new quinolizidine alkaloids (QAs), named ormosianines A-P (1-16), and 18 known congeners (17-34) were isolated from the stems and leaves of Ormosia yunnanensis. The structures were elucidated based on spectroscopic analyses and electron circular dichroism (ECD) calculations. Structurally, ormosianines A (1) and B (2) are the first examples of cytisine and Ormosia-type alkaloids with the cleavage of the piperidine ring. Results of the acetylcholinesterase (AChE) inhibitory assay revealed that the pentacycline Ormosia-type QAs, including 1, 16, 24, and 27-29, are good AChE inhibitors. Ormosianine A (1) exhibited more potent AChE inhibitory activity with an IC(50) value of 1.55 microM. Molecular docking revealed that 1 might bind to the protein 1DX4, forming two hydrogen bonds with residues SER-238 and HIS-480.
ESTHER : Jin_2023_J.Nat.Prod__
PubMedSearch : Jin_2023_J.Nat.Prod__
PubMedID: 37589667

Title : Ultrasensitivity Detecting AChE through "\;Covalent Assembly"\; and Signal Amplification Strategic Approaches and Applied to Screen Its Inhibitor - Zhao_2023_Anal.Chem__
Author(s) : Zhao Y , Shen A , Hao X , Li M , Hou L , Li Z , Duan R , Du M , Li X , Wang X , Zhao X , Yang Y
Ref : Analytical Chemistry , : , 2023
Abstract : An ultrasensitivity detecting assay for acetylcholinesterase (AChE) activity was developed based on "covalent assembly" and signal amplification strategic approaches. After hydrolyzing thioacetylcholine by AChE and participation of thiol in a self-inducing cascade accelerated by the Meldrum acid derivatives of 2-[bis(methylthio) methylene] malonitrile (CA-2), mercaptans triggered an intramolecular cyclization assembly by the probe of 2-(2,2-dicyanovinyl)-5-(diethylamino) phenyl 2,4-dinitrobenzenesulfonate (Sd-I) to produce strong fluorescence. The limit of detection for AChE activity was as low as 0.0048 mU/mL. The detection system also had a good detecting effect on AChE activity in human serum and could also be used to screen its inhibitors. By constructing a Sd-I@agarose hydrogel with a smartphone, a point-of-care detection of AChE activity was achieved again.
ESTHER : Zhao_2023_Anal.Chem__
PubMedSearch : Zhao_2023_Anal.Chem__
PubMedID: 36812425

Title : Gut microbiome helps honeybee (Apis mellifera) resist the stress of toxic nectar plant (Bidens pilosa) exposure: Evidence for survival and immunity - Tang_2023_Environ.Microbiol__
Author(s) : Tang Q , Li W , Wang Z , Dong Z , Li X , Li J , Huang Q , Cao Z , Gong W , Zhao Y , Wang M , Guo J
Ref : Environ Microbiol , : , 2023
Abstract : Honeybee (Apis mellifera) ingestion of toxic nectar plants can threaten their health and survival. However, little is known about how to help honeybees mitigate the effects of toxic nectar plant poisoning. We exposed honeybees to different concentrations of Bidens pilosa flower extracts and found that B. pilosa exposure significantly reduced honeybee survival in a dose-dependent manner. By measuring changes in detoxification and antioxidant enzymes and the gut microbiome, we found that superoxide dismutase, glutathione-S-transferase and carboxylesterase activities were significantly activated with increasing concentrations of B. pilosa and that different concentrations of B. pilosa exposure changed the structure of the honeybee gut microbiome, causing a significant reduction in the abundance of Bartonella (p < 0.001) and an increase in Lactobacillus. Importantly, by using Germ-Free bees, we found that colonization by the gut microbes Bartonella apis and Apilactobacillus kunkeei (original classification as Lactobacillus kunkeei) significantly increased the resistance of honeybees to B. pilosa and significantly upregulated bee-associated immune genes. These results suggest that honeybee detoxification systems possess a level of resistance to the toxic nectar plant B. pilosa and that the gut microbes B. apis and A. kunkeei may augment resistance to B. pilosa stress by improving host immunity.
ESTHER : Tang_2023_Environ.Microbiol__
PubMedSearch : Tang_2023_Environ.Microbiol__
PubMedID: 37291689

Title : FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis - Du_2022_Cell.Death.Dis_13_488
Author(s) : Du Q , Liu P , Zhang C , Liu T , Wang W , Shang C , Wu J , Liao Y , Chen Y , Huang J , Tan H , Zhao Y , Xia M , Liu J , Yao S
Ref : Cell Death Dis , 13 :488 , 2022
Abstract : Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.
ESTHER : Du_2022_Cell.Death.Dis_13_488
PubMedSearch : Du_2022_Cell.Death.Dis_13_488
PubMedID: 35597782

Title : Cymbopogon citratus (DC.) Stapf aqueous extract ameliorates loperamide-induced constipation in mice by promoting gastrointestinal motility and regulating the gut microbiota - Gao_2022_Front.Microbiol_13_1017804
Author(s) : Gao X , Hu Y , Tao Y , Liu S , Chen H , Li J , Zhao Y , Sheng J , Tian Y , Fan Y
Ref : Front Microbiol , 13 :1017804 , 2022
Abstract : Slow transit constipation (STC) is the most common type of functional constipation. Drugs with good effects and few side effects are urgently needed form the treatment of STC. Cymbopogon citratus (DC.) Stapf (CC) is an important medicinal and edible spice plant. The wide range of biological activities suggested that CC may have laxative effects, but thus far, it has not been reported. In this study, the loperamide-induced STC mouse model was used to evaluate the laxative effect of the aqueous extract of CC (CCAE), and the laxative mechanism was systematically explored from the perspectives of the enteric nervous system (ENS), neurotransmitter secretion, gastrointestinal motility factors, intestinal inflammation, gut barrier and gut microbiota. The results showed that CCAE not only decreased the serum vasoactive intestinal polypeptide (VIP), induced nitric oxide synthases (iNOS), and acetylcholinesterase (AchE) in STC mice but also increased the expression of gastrointestinal motility factors in colonic interstitial cells of Cajal (ICCs) and smooth muscle cells (SMCs), thereby significantly shortening the defecation time and improving the gastrointestinal transit rate. The significantly affected gastrointestinal motility factors included stem cell factor receptor (c-Kit), stem cell factor (SCF), anoctamin 1 (Ano1), ryanodine receptor 3 (RyR3), smooth muscle myosin light chain kinase (smMLCK) and Connexin 43 (Cx43). Meanwhile, CCAE could repair loperamide-induced intestinal inflammation and intestinal barrier damage by reducing the expression of the pro-inflammatory factor IL-1beta and increasing the expression of the anti-inflammatory factor IL-10, chemical barrier (Muc-2) and mechanical barrier (Cldn4, Cldn12, Occludin, ZO-1, and ZO-2). Interestingly, CCAE could also partially restore loperamide-induced gut microbial dysbiosis in various aspects, such as microbial diversity, community structure and species composition. Importantly, we established a complex but clear network between gut microbiota and host parameters. Muribaculaceae, Lachnospiraceae and UCG-010 showed the most interesting associations with the laxative phenotypes; several other specific taxa showed significant associations with serum neurotransmitters, gastrointestinal motility factors, intestinal inflammation, and the gut barrier. These findings suggested that CCAE might promote intestinal motility by modulating the ENS-ICCs-SMCs network, intestinal inflammation, intestinal barrier and gut microbiota. CC may be an effective and safe therapeutic choice for STC.
ESTHER : Gao_2022_Front.Microbiol_13_1017804
PubMedSearch : Gao_2022_Front.Microbiol_13_1017804
PubMedID: 36267178

Title : Bioaccumulation and toxicity of terbuthylazine in earthworms (Eisenia fetida) - Li_2022_Environ.Toxicol.Pharmacol_97_104016
Author(s) : Li S , Yuan Y , Wang X , Cai L , Wang J , Zhao Y , Jiang L , Yang X
Ref : Environ Toxicol Pharmacol , 97 :104016 , 2022
Abstract : Terbuthylazine is an effective and widely used s-triazine herbicide. However, limited data exists on its toxicity and bioaccumulation in earthworms (Eisenia fetida). In this study, we investigated the bioaccumulation, antioxidant enzyme activity, detoxification enzyme activity, and DNA damage in earthworms when exposed to terbuthylazine. The results indicated that terbuthylazine in soil had low bioaccumulation in earthworms and the biota-soil accumulation factors of terbuthylazine declined with an increasing soil terbuthylazine concentration. In the enzyme activity assays, the superoxide dismutase (SOD), catalase (CAT), and glutathione-S-transferase (GST) activities showed upward trends when compared with the control. The carboxylesterase (CarE) activity increased on day 21. The 8-hydroxy-2-deoxyguanosine (8-OHdG) content, a DNA damage bioindicator, was higher than that of the control on day 21. Combined with the integrated biological response index version 2 analysis, these results can provide a comprehensive evaluation of the toxicological effects that terbuthylazine has on earthworms and soil ecosystems.
ESTHER : Li_2022_Environ.Toxicol.Pharmacol_97_104016
PubMedSearch : Li_2022_Environ.Toxicol.Pharmacol_97_104016
PubMedID: 36435387

Title : Toxin diversity revealed by de novo transcriptome assembly for venom gland in two species of spiders (Trichonephila clavata and Sinopoda pengi) - Ding_2022_Comp.Biochem.Physiol.Part.D.Genomics.Proteomics_42_100984
Author(s) : Ding LJ , Wu XM , Zhang CG , Gao PF , Zhang Y , Yang ZZ , Zhao Y
Ref : Comparative Biochemistry & Physiology Part D Genomics Proteomics , 42 :100984 , 2022
Abstract : During long-term predator-prey coevolution, spiders have generated a vast diversity of toxins. Trichonephila clavata is a web-spinning spider whose large, well-constructed webs and venomous arsenal facilitate prey capture. In contrast, Sinopoda pengi is an ambush predator with agile locomotion and strong chelicerae for hunting. In this study, transcriptomic analysis was performed to describe the predicted toxins of S. pengi and T. clavata. A total of 43 and 47 of these unigenes from S. pengi and T. clavata, respectively, were predicted to have toxin activity. Putative neurotoxins were classified to the family level according to cysteine arrangement; 4 and 6 toxin families were produced by S. pengi and T. clavata, respectively. In addition, potential metalloproteases, acetylcholinesterases, serine proteases, hyaluronidases and phospholipases were found by annotation in databases. In summary, molecular templates with potential application value for medical and biological fields were obtained by classifying and characterizing presumed venom components, which established a foundation for further study of venom.
ESTHER : Ding_2022_Comp.Biochem.Physiol.Part.D.Genomics.Proteomics_42_100984
PubMedSearch : Ding_2022_Comp.Biochem.Physiol.Part.D.Genomics.Proteomics_42_100984
PubMedID: 35462116

Title : Antifeedant Mechanism of Dodonaea viscosa Saponin A Isolated from the Seeds of Dodonaea viscosa - Yu_2022_Molecules_27_4464
Author(s) : Yu H , Li J , Wu G , Tang Q , Duan X , Liu Q , Lan M , Zhao Y , Hao X , Qin X , Ding X
Ref : Molecules , 27 :4464 , 2022
Abstract : Dodonaea viscosa is a medicinal plant which has been used to treat various diseases in humans. However, the anti-insect activity of extracts from D. viscosa has not been evaluated. Here, we found that the total saponins from D. viscosa (TSDV) had strong antifeedant and growth inhibition activities against 4th-instar larvae of Spodoptera litura. The median antifeeding concentration (AFC(50)) value of TSDV on larvae was 1621.81 microg/mL. TSDV affected the detoxification enzyme system of the larvae and also exerted antifeedant activity possibly through targeting the gamma-aminobutyric acid (GABA) system. The AFC(50) concentration, the carboxylesterase activity, glutathione S-transferases activity, and cytochrome P450 content increased to 258%, 205%, and 215%, respectively, and likewise the glutamate decarboxylase activity and GABA content to 195% and 230%, respectively, in larvae which fed on TSDV. However, D. viscosa saponin A (DVSA) showed better antifeedant activity and growth inhibition activity in larvae, compared to TSDV. DVSA also exerted their antifeedant activity possibly through targeting the GABA system and subsequently affected the detoxification enzyme system. Further, DVSA directly affected the medial sensillum and the lateral sensillum of the 4th-instar larvae. Stimulation of Spodoptera litura. with DVSA elicited clear, consistent, and robust excitatory responses in a single taste cell.
ESTHER : Yu_2022_Molecules_27_4464
PubMedSearch : Yu_2022_Molecules_27_4464
PubMedID: 35889337

Title : The adverse effects of fluxapyroxad on the neurodevelopment of zebrafish embryos - Yu_2022_Chemosphere_307_135751
Author(s) : Yu H , Zhang J , Chen Y , Chen J , Qiu Y , Zhao Y , Li H , Xia S , Chen S , Zhu J
Ref : Chemosphere , 307 :135751 , 2022
Abstract : Fluxapyroxad (Flu), one of the succinate dehydrogenase-inhibited (SDHI) fungicides, has been extensively used in crop fungal disease control. Despite its increasing use in modern agriculture and long-term retention in the environment, the potentially toxic effects of Flu in vivo, especially on neurodevelopment, remain under-evaluated. In this study, zebrafish embryos were exposed to Flu at concentrations of 0.5, 0.75, and 1 mg/L for 96 h to evaluate the neurotoxicity of Flu. The results showed that Flu caused concentration-dependent malformations, including shorter body length, smaller head and eyes, and yolk sac edema. After exposure to Flu, larval zebrafish exhibited severe motor aberrations. Flu at a concentration of 1 mg/L significantly decreased dopamine level and notably altered acetylcholinesterase (AChE) activity and acetylcholine (ACh) content. Abnormal central nervous system (CNS) neurogenesis and disordered motor neuron development were observed in Tg (HUC-GFP) and Tg (hb9-GFP) zebrafish in Flu-treated groups. The expression of key genes involved in neurotransmission and neurodevelopment further proved that Flu impaired the zebrafish nervous system. This work contributes to our understanding of the neurotoxic effects and mechanisms induced by Flu in zebrafish and may help us take precautions against the neurotoxicity of Flu.
ESTHER : Yu_2022_Chemosphere_307_135751
PubMedSearch : Yu_2022_Chemosphere_307_135751
PubMedID: 35863420

Title : Design, synthesis and evaluation of novel scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as potential multifunctional therapeutics for Alzheimer's disease - Wu_2022_Bioorg.Chem_122_105760
Author(s) : Wu D , Chen J , Luo K , Li H , Liu T , Li L , Dai Z , Li Y , Zhao Y , Fu X
Ref : Bioorg Chem , 122 :105760 , 2022
Abstract : In this study, we designed, synthesized and evaluated a series of scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds containing scutellarein as the parent nucleus (6a-l) had good inhibitory activity against acetyl cholinesterase (AChE), with compound 6 h exhibiting the most potent inhibition of electric eel AChE and human AChE enzymes with IC(50) values of 6.01 +/- 1.66 and 7.91 +/- 0.49 microM, respectively. In addition, compound 6 h displayed not only excellent inhibition of self- and Cu(2+)-induced Abeta(1-42) aggregation (89.17% and 86.19% inhibition) but also induced disassembly of self- and Cu(2+)-induced Abeta fibrils (84.25% and 78.73% disaggregation). Moreover, a neuroprotective assay demonstrated that pre-treatment of PC12 cells with 6 h significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax, and caspase-3) and inhibited RSL3 induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 6 h would have optimal blood-brain barrier and intestinal absorption characteristics. The in vivo experimental data suggested that 6 h ameliorated learning and memory impairment in mice by decreasing AChE activity, increasing ACh levels and alleviating pathological damage of hippocampal tissue cells. These multifunctional properties highlight compound 6 h as a promising candidate for development as a multifunctional drug against AD.
ESTHER : Wu_2022_Bioorg.Chem_122_105760
PubMedSearch : Wu_2022_Bioorg.Chem_122_105760
PubMedID: 35349945

Title : New insights into the function of plant tannase with promiscuous acyltransferase activity - Chen_2022_Plant.J__
Author(s) : Chen Y , Jiang C , Yin S , Zhuang J , Zhao Y , Zhang L , Jiang X , Liu Y , Gao L , Xia T
Ref : Plant J , : , 2022
Abstract : Plant tannases (TAs) or tannin acyl hydrolases, a class of recently reported carboxylesterase (CXE) in tannin-rich plants, are involved in the degalloylation of two important secondary metabolites: flavan-3-ol gallates and hydrolyzable tannins (HTs). In this paper, we have made a new progress on the function of Camellia sinensis (Cs) TA-it is a hydrolase with promiscuous acyltransferase activity in vitro and in vivo experiments and promotes the synthesis of simple galloyl glucoses and flavan-3-ols gallates in plants. We gained the new understanding to the functions of CsTA through enzyme analysis, protein mass spectrometry identification, metabolic analysis of plants by genetic modification. Firstly, CsTA was proved that it is not only a hydrolase but also an acyltransferase. In the two-step covalent catalytic reaction, when CsTA hydrolyzes the galloylated compounds epigallocatechin-3-gallate (EGCG) or 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) into their degalloylated forms, a long-lived Ser159-linked galloyl-enzyme covalent intermediate is also formed. Under nucleophilic attack, the galloyl group on the intermediate is transferred to the nucleophilic acyl acceptors (including water, methanol, flavan-3-ols and simple galloyl glucoses). Then, metabolic analysis suggested that transiently overexpression of TAs in young strawberry fruits, young leaves of tea plants and young leaves of Chinese bayberry actually increased the total content of simple galloyl glucoses and flavan-3-ol gallates. Overall, these findings provide new insights into the promiscuous acyltransferase activity of plant tannase.
ESTHER : Chen_2022_Plant.J__
PubMedSearch : Chen_2022_Plant.J__
PubMedID: 36534122
Gene_locus related to this paper: camsi-CsTA

Title : Insights into acylation mechanisms: co-expression of serine carboxypeptidase-like acyltransferases and their non-catalytic companion paralogs - Yao_2022_Plant.J_111_117
Author(s) : Yao S , Liu Y , Zhuang J , Zhao Y , Dai X , Jiang C , Wang Z , Jiang X , Zhang S , Qian Y , Tai Y , Wang Y , Wang H , Xie DY , Gao L , Xia T
Ref : Plant J , 111 :117 , 2022
Abstract : Serine carboxypeptidase-like acyltransferases (SCPL-ATs) play a vital role in the diversification of plant metabolites. Galloylated flavan-3-ols highly accumulate in tea (Camellia sinensis), grape (Vitis vinifera), and persimmon (Diospyros kaki). To date, the biosynthetic mechanism of these compounds remains unknown. Herein, we report that two SCPL-AT paralogs are involved in galloylation of flavan-3-ols: CsSCPL4, which contains the conserved catalytic triad S-D-H, and CsSCPL5, which has the alternative triad T-D-Y. Integrated data from transgenic plants, recombinant enzymes, and gene mutations showed that CsSCPL4 is a catalytic acyltransferase, while CsSCPL5 is a non-catalytic companion paralog (NCCP). Co-expression of CsSCPL4 and CsSCPL5 is likely responsible for the galloylation. Furthermore, pull-down and co-immunoprecipitation assays showed that CsSCPL4 and CsSCPL5 interact, increasing protein stability and promoting post-translational processing. Moreover, phylogenetic analyses revealed that their homologs co-exist in galloylated flavan-3-ol- or hydrolyzable tannin-rich plant species. Enzymatic assays further revealed the necessity of co-expression of those homologs for acyltransferase activity. Evolution analysis revealed that the mutations of the CsSCPL5 catalytic residues may have taken place about 10 million years ago. These findings show that the co-expression of SCPL-ATs and their NCCPs contributes to the acylation of flavan-3-ols in the plant kingdom.
ESTHER : Yao_2022_Plant.J_111_117
PubMedSearch : Yao_2022_Plant.J_111_117
PubMedID: 35437852
Gene_locus related to this paper: dioka-dkSCPL1 , camsi-SCPL5 , camsi-SCPL4

Title : Engineering an Ag\/Au bimetallic nanoparticle-based acetylcholinesterase SERS biosensor for in situ sensitive detection of organophosphorus pesticide residues in food - Xu_2022_Anal.Bioanal.Chem__
Author(s) : Xu S , Li M , Li X , Jiang Y , Yu L , Zhao Y , Wen L , Xue Q
Ref : Anal Bioanal Chem , : , 2022
Abstract : Developing simple, efficient, and inexpensive method for trace amount organophosphorus pesticides' (OPs) detection with high sensitivity and specificity is of significant importance for guaranteeing food safety. Herein, an Ag/Au bimetallic nanoparticle-based acetylcholinesterase (AChE) surface-enhanced Raman scattering (SERS) biosensor was constructed for in situ simple and sensitive detection of pesticide residues in food. The principle of this biosensor exploited 4-mercaptophenylboronic acid (4-MPBA)-modified Ag/Au bimetallic nanoprobes as SERS signal probe to improve sensitivity and stability. The combination of AChE and choline oxidase (CHO) can hydrolyze acetylcholine (ATCh) to generate H(2)O(2). The product of H(2)O(2) selectively oxidizes the boronate ester of 4-MPBA, decreasing the Raman intensity of the B-O symmetric stretching. In the presence of OPs, it could inhibit the production of H(2)O(2) by destroying the AChE activity, so the reduction of the SERS signal was also alleviated. Based on the principle, an Ag/Au bimetallic nanoparticle-based AChE SERS sensor was established without any complicated pretreatments. Benefiting from the synergistic effects of Ag/Au bimetallic hybrids, a linear detection range from 5x10(-9) to 5x10(-4) M was achieved with a limit of detection down to 1.7x10(-9) M using parathion-methyl (PM) as the representative model of OPs. Moreover, the SERS biosensor uses readily available reagents and is simple to implement. Importantly, the proposed SERS biosensor was used to quantitatively analyze OP residues in apple peels. The levels of OPs detected in real samples by this method were consistent with those obtained using gas chromatography-mass spectrometry (GC-MS), suggesting the proposed assay has great potential applications for OPs in situ detection in food safety fields.
ESTHER : Xu_2022_Anal.Bioanal.Chem__
PubMedSearch : Xu_2022_Anal.Bioanal.Chem__
PubMedID: 36333614

Title : Nematicidal activity of tirotundin and parthenolide isolated from Tithonia diversifolia and Chrysanthemum parthenium - Lan_2022_J.Environ.Sci.Health.B__1
Author(s) : Lan M , Gao X , Duan X , Li H , Yu H , Li J , Zhao Y , Hao X , Ding X , Wu G
Ref : J Environ Sci Health B , :1 , 2022
Abstract : Acetylcholinesterase (AChE) is an enzyme that catalyzes acetylcholine into choline and acetic acid. Conventional pesticides, including organophosphates and carbamates target and inhibit the activity of AChE. To obtain more pesticide precursors that meet the safety requirements, more than 200 compounds were screened. Tirotundin and parthenolide identified as potential neurotoxins to nematodes were isolated from Tithonia diversifolia and Chrysanthemum parthenium, respectively. Their IC(50) values were 6.89 +/- 0.30 and 5.51 +/- 0.23 microg/mL, respectively against the AChE isolated from Caenorhabditis elegans. AChE was inhibited in a dose-dependent manner using the two compounds. And the Lineweaver-Burk and Dixon plots indicated that tirotundin and parthenolide were reversible inhibitors against AChE, both inhibiting AChE in a mixed-type competitive manner and demonstrating these compounds may possess dual binding site AChE inhibitors. LC(50) values of tirotundin and parthenolide against C. elegans were 9.16 +/- 0.21 and 7.23 +/- 0.48 microg/mL, respectively. These results provide a certain theoretical basis for the development and utilization of novel pesticides.
ESTHER : Lan_2022_J.Environ.Sci.Health.B__1
PubMedSearch : Lan_2022_J.Environ.Sci.Health.B__1
PubMedID: 34983315

Title : A stable enzyme sensor via embedding enzymes into zeolitic imidazolate frameworks for pesticide determination - Zhao_2022_Anal.Biochem__114628
Author(s) : Zhao Y , Lu X , Gao F
Ref : Analytical Biochemistry , :114628 , 2022
Abstract : The stability of biosensors is of significant importance for practical applications, and the natural biomineralization processes in living organisms have inspired us from a new perspective. In this work, acetylcholinesterase (AChE) was embedded into zeolitic imidazolate framework-8 carriers (with negligible cytotoxicity) via biomimetic mineralization, being demonstrated to be a stable strategy for enzyme immobilization. When further coupled with the conductive and catalytic Au nanoparticles, the biocomposites were explored as electrochemical pesticide detection biosensor, which showed favorable analytical performance, and improved stability comparing with other biosensors. This work provides a new strategy for the reasonable design of stable biosensors for different analytes monitoring.
ESTHER : Zhao_2022_Anal.Biochem__114628
PubMedSearch : Zhao_2022_Anal.Biochem__114628
PubMedID: 35257680

Title : Phytochemical profiling and antioxidant, enzyme-inhibitory, and toxic activities of extracts from Adonis ramosa Franch - Guo_2022_Nat.Prod.Res__1
Author(s) : Guo X , Chen M , He X , Zhao Y , Yu J , Zhu J , Li L , Xia G , Zang H
Ref : Nat Prod Res , :1 , 2022
Abstract : This study investigated the content and biological activity of three solvent extracts of Adonis ramosa Franch (AR), which contains 12 types of phytochemicals. The overall yield and total protein content of the aqueous extract were the highest, and it exhibited the highest hydroxyl and superoxide radical-scavenging abilities, copper chelating abilities, and cupric reducing antioxidant capacity. Ethanol extract had the highest total phenolic, flavonoid, and carbohydrate contents, and it showed the highest iron chelating activity, and HClO- and nitrite-scavenging abilities. Methanol AR extract contained the highest total steroid and tannin contents; it also demonstrated high radical- and reactive oxygen species-scavenging abilities and had the best ferric reducing antioxidant power, which allowed it to effectively prevent beta-carotene bleaching. Methanol extract also showed good stability and low toxicity. All tested solvent extracts of AR exhibited weak enzyme-inhibitory activities for four enzymes (alpha-glucosidase, alpha-amylase, acetylcholinesterase and butyrylcholinesterase). Overall, AR can serve as a natural antioxidant.
ESTHER : Guo_2022_Nat.Prod.Res__1
PubMedSearch : Guo_2022_Nat.Prod.Res__1
PubMedID: 35045779

Title : Biodegradation of polybutylene adipate-co-terephthalate by Priestia megaterium, Pseudomonas mendocina, and Pseudomonas pseudoalcaligenes following incubation in the soil - Wei_2022_Chemosphere__135700
Author(s) : Wei S , Zhao Y , Zhou R , Lin J , Su T , Tong H , Wang Z
Ref : Chemosphere , :135700 , 2022
Abstract : Soil that contained polybutylene adipate-co-terephthalate (PBAT) was incubated with Priestia megaterium, Pseudomonas mendocina, and Pseudomonas pseudoalcaligenes to improve the biodegradative process of this polymer. The mixture of Pr. megaterium and Ps. mendocina was highly effective at biodegrading the PBAT, and after eight weeks of soil incubation, approximately 84% of the PBAT film weight was lost. Mixtures of the other two species also positively affected the synergistic degradation of PBAT film in the soil, but the mixture of three species had a negative effect. The residual PBAT film microstructure clearly demonstrated the degradation of PBAT, and the degree of degradation was related to the different species. Cleavage of the PBAT film ester bond after soil microbial action affected its properties. The incubation of PBAT in soil that contained these species affected soil dehydrogenase and soil lipase in particular. The secretion of lipase by these species could play an important role in the degradation of PBAT in the soil.
ESTHER : Wei_2022_Chemosphere__135700
PubMedSearch : Wei_2022_Chemosphere__135700
PubMedID: 35850225

Title : The suppression of pancreatic lipase-related protein 2 ameliorates experimental hepatic fibrosis in mice - Ding_2022_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1867_159102
Author(s) : Ding Z , Cheng R , Liu J , Zhao Y , Ge W , Yang Y , Xu X , Wang S , Zhang J
Ref : Biochimica & Biophysica Acta Molecular & Cellular Biology Lipids , 1867 :159102 , 2022
Abstract : Quiescent hepatic stellate cells (HSCs) store vitamin A as lipid droplets in the cytoplasm. When activated, these cells lose vitamin A and exhibit an increased capacity for proliferation, mobility, contractility, and the synthesis of collagen and other components of the extracellular matrix. Our previous work demonstrated that the lipid hydrolytic gene pancreatic lipase-related protein 2 (mPlrp2) is involved in the hydrolysis of retinyl esters (REs) in the liver. Here, we showed that bile duct ligation (BDL)-induced liver injury triggered the conditional expression of mPlrp2 in livers and describe evidence of a strong relationship between the expression of mPlrp2 and Acta-2, a marker for activated HSCs. RNA interference targeting mPlrp2 inhibited HSC activation and ameliorated hepatic fibrosis induced by BDL in mice. Liver BDL markedly reduced the adenosine level and increased the ratio between S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH). Chromatin immunoprecipitation (ChIP) analysis demonstrated an increase in trimethylated histone H3K4 at the mPlrp2 promoter in BDL mice, which was associated with the conditional expression of mPlrp2 in the liver. SAM, a well-known hepatoprotective substance, inhibited mPlrp2 expression and reduced RE hydrolysis in mice with hepatic fibrosis induced by chronic CCl(4) treatment. Liver fibrosis induced by CCl(4) or BDL was improved in Plrp2(-/-) mice. Our results reveal that mPlrp2 suppression is a potential approach for treating hepatic fibrosis.
ESTHER : Ding_2022_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1867_159102
PubMedSearch : Ding_2022_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1867_159102
PubMedID: 34995790
Gene_locus related to this paper: mouse-LIPR2

Title : Mutation in BrGGL7 gene encoding a GDSL esterase \/ lipase causes male sterility in Chinese cabbage (Brassica rapa L. ssp. pekinensis) - Zhao_2022_Theor.Appl.Genet_135_3323
Author(s) : Zhao Y , Huang S , Zou J , Dong S , Wang N , Feng H
Ref : Theor Appl Genet , _135 :3323 , 2022
Abstract : MutMap and KASP analyses revealed that the BrGGL7 gene is responsible for the male-sterile trait of ftms1 in Chinese cabbage, with functional verification in Arabidopsis. The application of a male-sterile line is an ideal approach of hybrid seed production in Chinese cabbage. In this study, we obtained a male-sterile mutant (ftms1) from the double haploid line 'FT' using ethyl methane sulfonate (EMS) mutagenesis. The mutant was completely sterile due to abnormal enlargement and vacuolization of the tapetum cells. A single recessive nuclear gene was found to control male sterility in the mutant, while MutMap and KASP analyses identified BraA05g022470.3C (BrGGL7), which encodes a GDSL esterase / lipase, as the candidate mutant gene. A single nucleotide substitution from C to T occurred within the domain of BrGGL7 in ftms1, resulting in premature translation termination in the fourth exon. Meanwhile, qRT-PCR analysis indicated that BrGGL7 was prominently expressed in the anothers, and expression was greater in the wild-type 'FT' than ftms1. Genetic complementation of the orthologous Arabidopsis ggl7 mutant further confirmed the role of BrGGL7 in pollen development. These findings suggest that BrGGL7 plays a fundamental role in pollen formation, providing important insight into the molecular mechanisms underlying male sterility in Chinese cabbage.
ESTHER : Zhao_2022_Theor.Appl.Genet_135_3323
PubMedSearch : Zhao_2022_Theor.Appl.Genet_135_3323
PubMedID: 35840736

Title : Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress - Liu_2022_Nat.Cancer__
Author(s) : Liu X , Viswanadhapalli S , Kumar S , Lee TK , Moore A , Ma S , Chen L , Hsieh M , Li M , Sareddy GR , Parra K , Blatt EB , Reese TC , Zhao Y , Chang A , Yan H , Xu Z , Pratap UP , Liu Z , Roggero CM , Tan Z , Weintraub ST , Peng Y , Tekmal RR , Arteaga CL , Lippincott-Schwartz J , Vadlamudi RK , Ahn JM , Raj GV
Ref : Nat Cancer , : , 2022
Abstract : Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.
ESTHER : Liu_2022_Nat.Cancer__
PubMedSearch : Liu_2022_Nat.Cancer__
PubMedID: 35654861
Gene_locus related to this paper: human-LIPA

Title : Structural and Mechanistic Insights into Chain Release of the Polyene PKS Thioesterase Domain - Zhou_2022_ACS.Catal_12_762
Author(s) : Zhou Y , Tao W , Qi Z , Wei J , Shi T , Kang Q , Zheng J , Zhao Y , Bai L
Ref : ACS Catal , 12 :762 , 2022
Abstract : Polyketides serve as rich source of therapeutically relevant drug leads. The manipulation of polyketide synthases (PKSs) for generating derivatives with improved activities usually results in substantially reduced yields. Growing evidence suggests that type I PKS thioesterase (TE) domains are key bottlenecks in the biosynthesis of polyene antibiotics, such as pimaricin and amphotericin, and their unnatural derivatives. Herein, we elucidate the structure of the 26-membered macrolide-complexed TE domain from the pimaricin pathway (Pim TE), which specifies a spacious bifunnel-shaped substrate channel with a highly hydrophobic cleft proximal to the catalytic triad and a hydrophilic loop I region specific for the cyclization of amphiphilic polyene macrolide. Notably, the natural intermediate with C12-COOH is stabilized by a hydrogen-bond network, as well as by interactions between the polyene moiety and the hydrophobic cleft. Moreover, the bottleneck in processing the unnatural intermediate with C12-CH3 is attributed to the unstable and mismatched docking of the curved substrate in the channel. Aided by an in vitro assay with a fully elongated linear polyene intermediate as the substrate, multiple strategies were adopted, herein, to engineer Pim TE, including introducing H-bond donors, enhancing hydrophobic interactions, and modifying the catalytic center. Efficient TE mutations with increased substrate conversion up to 39.2% in vitro were further conducted in vivo, with a titer increase as high as 37.1% for the less toxic decarboxylated pimaricin derivatives with C12-CH3. Our work uncovers the mechanism of TE-catalyzed polyene macrolide formation and highlights TE domains as targets for PKS manipulation for titer increases in engineered unnatural polyketide derivatives.
ESTHER : Zhou_2022_ACS.Catal_12_762
PubMedSearch : Zhou_2022_ACS.Catal_12_762
Gene_locus related to this paper: 9actn-f1cla7

Title : Ternary heterostructures of 1D\/2D\/2D CuCo(2)S(4)\/CuS\/Ti(3)C(2) MXene: Boosted amperometric sensing for chlorpyrifos - Mi_2022_J.Hazard.Mater_438_129419
Author(s) : Mi Y , Zhao Y , Chen J , Li X , Yang Y , Gao F
Ref : J Hazard Mater , 438 :129419 , 2022
Abstract : Multicomponent heterogeneous Ti(3)C(2) transition metal carbide (MXene)-based materials are receiving extensive research attention due to their interesting synergistic interactions and catalytic properties. However, the morphology-controllable synthesis of heterostructures as structural stabilizers for Ti(3)C(2) MXene remains a challenge owing the complicated synthesis procedure. In this work, a kind of ternary heterogeneous nanomaterials CuCo(2)S(4)/CuS/Ti(3)C(2) MXene with a nanorod/nanoplate/nanosheet hybrid architecture is constructed through a one-step low-temperature solvothermal method. The well-designed ternary one-dimensional (1D)/two-dimensional (2D)/2D CuCo(2)S(4)/CuS/Ti(3)C(2) MXene heteromaterials exhibit synergistic improvements in substrate-catalyzed reactions for electrochemical acetylcholinesterase (AChE) biosensor. The Michaelis-Menten constant for the Nafion/AChE/CuCo(2)S(4)/CuS/Ti(3)C(2) MXene/GCE biosensor is 228 microM, which is smaller than ones reported in previous literatures, indicating a higher affinity of the fabricated enzyme biosensor to acetylthiocholine chloride. The biosensor exhibits a well linear relationship with chlorpyrifos concentration ranging from 2.852 x 10(-12) M to 2.852 x 10(-6) M. The multicomponent 1D/2D/2D CuCo(2)S(4)/CuS/Ti(3)C(2) MXene heteromaterial may shine a light in more electrochemical applications.
ESTHER : Mi_2022_J.Hazard.Mater_438_129419
PubMedSearch : Mi_2022_J.Hazard.Mater_438_129419
PubMedID: 35780734

Title : Molecular and Biochemical Differences of the Tandem and Cold-Adapted PET Hydrolases Ple628 and Ple629, Isolated From a Marine Microbial Consortium - Meyer-Cifuentes_2022_Front.Bioeng.Biotechnol_10_930140
Author(s) : Meyer-Cifuentes IE , Wu P , Zhao Y , Liu W , Neumann-Schaal M , Pfaff L , Barys J , Li Z , Gao J , Han X , Bornscheuer UT , Wei R , Ozturk B
Ref : Front Bioeng Biotechnol , 10 :930140 , 2022
Abstract : Polybutylene adipate terephthalate (PBAT) is a biodegradable alternative to polyethylene and can be broadly used in various applications. These polymers can be degraded by hydrolases of terrestrial and aquatic origin. In a previous study, we identified tandem PETase-like hydrolases (Ples) from the marine microbial consortium I1 that were highly expressed when a PBAT blend was supplied as the only carbon source. In this study, the tandem Ples, Ple628 and Ple629, were recombinantly expressed and characterized. Both enzymes are mesophilic and active on a wide range of oligomers. The activities of the Ples differed greatly when model substrates, PBAT-modified polymers or PET nanoparticles were supplied. Ple629 was always more active than Ple628. Crystal structures of Ple628 and Ple629 revealed a structural similarity to other PETases and can be classified as member of the PETases IIa subclass, alpha/beta hydrolase superfamily. Our results show that the predicted functions of Ple628 and Ple629 agree with the bioinformatic predictions, and these enzymes play a significant role in the plastic degradation by the consortium.
ESTHER : Meyer-Cifuentes_2022_Front.Bioeng.Biotechnol_10_930140
PubMedSearch : Meyer-Cifuentes_2022_Front.Bioeng.Biotechnol_10_930140
PubMedID: 35935485
Gene_locus related to this paper: 9zzzz-Ple628 , 9zzzz-Ple629

Title : Structural insight and engineering of a plastic degrading hydrolase Ple629 - Li_2022_Biochem.Biophys.Res.Commun_626_100
Author(s) : Li Z , Zhao Y , Wu P , Wang H , Li Q , nGao J , Qin HM , Wei H , Bornscheuer UT , Han X , Wei R , Liu W
Ref : Biochemical & Biophysical Research Communications , 626 :100 , 2022
Abstract : Polyethylene terephthalate (PET) is one of the most abundantly produced synthetic polyesters. The vast number of waste plastics including PET has challenged the waste management sector while also posing a serious threat to the environment due to improper littering. Recently, enzymatic PET degradation has been shown to be a viable option for a circular plastic economy, which can mitigate the plastic pollution. While protein engineering studies on specific PET degradation enzymes such as leaf-branch compost cutinase (LCC), Thermobifida sp. cutinases and Ideonella sakaiensis PETase (IsPETase) have been extensively published, other homologous PET degrading enzymes have received less attention. Ple629 is a polyester hydrolase identified from marine microbial consortium having activity on PET and the bioplastic polybutylene adipate terephthalate (PBAT). In order to explore its catalytic mechanism and improve its potential for PET hydrolysis, we solved its crystal structure in complex with a PET monomer analogue, and validated its structural and mechanistic similarity to known PET hydrolases. By structural comparisons, we identified some hot spot positions described in previous research on protein engineering of PET hydrolases. We substitute these amino acid residues in Ple629, and obtained variants with improved activity and thermo-stability. The most promising variant D226A/S279A exhibited a more than 5.5-fold improved activity on PET nanoparticles than the wild-type enzyme, suggesting its potential applicability in the biotechnological plastic recycling.
ESTHER : Li_2022_Biochem.Biophys.Res.Commun_626_100
PubMedSearch : Li_2022_Biochem.Biophys.Res.Commun_626_100
PubMedID: 35981419
Gene_locus related to this paper: 9zzzz-Ple629

Title : Structural Analysis and Development of Notum Fragment Screening Hits - Zhao_2022_ACS.Chem.Neurosci_13_2060
Author(s) : Zhao Y , Mahy W , Willis NJ , Woodward HL , Steadman D , Bayle ED , Atkinson BN , Sipthorp J , Vecchia L , Ruza RR , Harlos K , Jeganathan F , Constantinou S , Costa A , Kjaer S , Bictash M , Salinas PC , Whiting P , Vincent JP , Fish PV , Jones EY
Ref : ACS Chem Neurosci , 13 :2060 , 2022
Abstract : The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 microM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC(50) 0.0067 microM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.
ESTHER : Zhao_2022_ACS.Chem.Neurosci_13_2060
PubMedSearch : Zhao_2022_ACS.Chem.Neurosci_13_2060
PubMedID: 35731924
Gene_locus related to this paper: human-NOTUM

Title : Transport, Stability, and In Vivo Hypoglycemic Effect of a Broccoli-Derived DPP-IV Inhibitory Peptide VPLVM - Pei_2022_J.Agric.Food.Chem__
Author(s) : Pei J , Liu Z , Pan D , Zhao Y , Dang Y , Gao X
Ref : Journal of Agricultural and Food Chemistry , : , 2022
Abstract : Diabetes is a major metabolic disease that requires long-term pharmacotherapy. Bioactive peptides have unique advantages such as higher potency, selectivity, and safety over small molecules and have achieved great success in the treatment of diabetes. We previously isolated a dipeptidyl peptidase-IV (DPP-IV) inhibitory peptide VPLVM with IC(50) = 99.68 microM from the protein hydrolysates of broccoli stems and leaves. Here, we evaluated the interaction with DPP-IV, transport, stability, and in vivo hypoglycemic effects of VPLVM. VPLVM interacted closely and steadily with DPP-IV at S1 and S2 pockets. VPLVM had a good gastrointestinal enzyme resistance and was transported through the Caco-2 cell monolayer via paracellular diffusion and by the PepT1 with a P(app) of 6.96 x 10(-7) cm/s. VPLVM has a t(1/2) of 12.56 +/- 0.41 min in vitro plasma stability. In the oral glucose tolerance test, VPLVM showed an excellent hypoglycemic effect at 30 min after administration. VPLVM has potential as a candidate for the treatment of hyperglycemia.
ESTHER : Pei_2022_J.Agric.Food.Chem__
PubMedSearch : Pei_2022_J.Agric.Food.Chem__
PubMedID: 35436096

Title : Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity - Steadman_2022_J.Med.Chem_65_562
Author(s) : Steadman D , Atkinson BN , Zhao Y , Willis NJ , Frew S , Monaghan A , Patel C , Armstrong E , Costelloe K , Magno L , Bictash M , Jones EY , Fish PV , Svensson F
Ref : Journal of Medicinal Chemistry , 65 :562 , 2022
Abstract : Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC(50) < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/beta-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.
ESTHER : Steadman_2022_J.Med.Chem_65_562
PubMedSearch : Steadman_2022_J.Med.Chem_65_562
PubMedID: 34939789
Gene_locus related to this paper: human-NOTUM

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 : Design of a potent, selective and brain penetrant inhibitor of Wnt-deactivating enzyme Notum by optimization of a crystallographic fragment hit - Willis_2022_J.Med.Chem_65_7212
Author(s) : Willis NJ , Mahy W , Sipthorp J , Zhao Y , Woodward HL , Atkinson BN , Bayle ED , Svensson F , Frew S , Jeganathan F , Monaghan A , Benvegnu S , Jolly S , Vecchia L , Ruza RR , Kjaer S , Howell SA , Snidjers AP , Bictash M , Salinas PC , Vincent JP , Jones EY , Whiting P , Fish PV
Ref : Journal of Medicinal Chemistry , 65 :7212 , 2022
Abstract : Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human disease such as colorectal cancer and Alzheimer'ss disease supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we describe the discovery and profile of 8l (ARUK3001185) as a potent, selective and brain pentrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identifed 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases and drug targets.
ESTHER : Willis_2022_J.Med.Chem_65_7212
PubMedSearch : Willis_2022_J.Med.Chem_65_7212
PubMedID: 35536179
Gene_locus related to this paper: human-NOTUM

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 : Transcriptome analysis and the identification of genes involved in the metabolic pathways of fenoxaprop-P-ethyl in rice treated with isoxadifen-ethyl hydrolysate - Zhao_2022_Pestic.Biochem.Physiol_183_105057
Author(s) : Zhao Y , Li W , Sun L , Xu H , Su W , Xue F , Wu R , Lu C
Ref : Pestic Biochem Physiol , 183 :105057 , 2022
Abstract : Fenoxaprop-P-ethyl (FE) is a highly effective weed control agent for rice fields, but it causes phytotoxicity in crops. A whole-plant bioassay has revealed that isoxadifen-ethyl hydrolysate (IH) can significantly improve the tolerance of rice to FE, but the molecular mechanisms underlying this phenomenon are still unclear. In this study, we performed RNA-Seq analysis using rice seedlings treated with FE and IH to determine the IH-regulated candidate genes involved in metabolic resistance to FE. We also analyzed spatiotemporal expression using quantitative reverse transcription polymerase chain reaction to reveal the expression patterns of these genes under different treatments. The results showed that genes encoding metabolic enzymes, such as cytochrome P450 monooxygenases, glutathione-s-transferases, UDP-glycosyltransferase, carboxylesterase, and ATP-binding cassette transporter, were influenced by the application of IH. Most of these genes were upregulated, and their products were involved in various stages of FE metabolism. Tolerance to FE was primarily mediated by CarE15, CYP86A1, GSTU6, GST4, UGT13248, UGT79, and ABCC4, all of which played a vital role in regulating the detoxification process of FE. Our findings elucidated the protective mechanisms of IH, which can help alleviate the phytotoxic effects of FE and expand its potential for application in agriculture.
ESTHER : Zhao_2022_Pestic.Biochem.Physiol_183_105057
PubMedSearch : Zhao_2022_Pestic.Biochem.Physiol_183_105057
PubMedID: 35430061

Title : Digging and identification of novel microorganisms from the soil environments with high methanol-tolerant lipase production for biodiesel preparation - Tan_2022_Environ.Res_212_113570
Author(s) : Tan Z , Chen G , Zhao Y , Shi H , Wang S , Bilal M , Li D , Li X
Ref : Environ Research , 212 :113570 , 2022
Abstract : Converting renewable biomass into carbon-neutral biofuels is one of the most effective strategies to achieve zero carbon emissions and contribute to environmental protection. Microorganisms from the soil were primarily screened on the rhodamine B-plate for highly-active lipase producing strains and re-screened on a tributyrin-methanol plate using crude lipases produced from the initially screened-out strains. The lipase-producing strains with higher methanol-tolerant lipase were identified based on morphological characteristics and 16S rDNA sequencing. The crude lipases with much higher methanol-tolerance from screened top-4 strains, Stenotrophomonas maltophilia D18, Lysinibacillus fusiformis B23, Acinetobacter junii C69, and A. pittii C95 showed temperature optima of 25 degreesC, 35 degreesC, 30 degreesC, and 30 degreesC at pH 7.0, respectively, while their pH optima were 8.0, 7.0, 7.5, and 7.5 at each optimum temperature, respectively. After 24-h incubation, they retained more than 85% of their original activities in 25%, 15%, 20%, and 20% of methanol, respectively. They catalyzed the conversion of soybean oil into biodiesel by yields of 63.1%, 35.4%, 74.6%, and 78.5% after 24-h reactions, respectively. In conclusion, the as-isolated microorganisms producing high methanol-tolerant lipase are considered promising to provide robust biocatalyst for efficient biodiesel preparation and other industrial applications.
ESTHER : Tan_2022_Environ.Res_212_113570
PubMedSearch : Tan_2022_Environ.Res_212_113570
PubMedID: 35671798

Title : Mycobacterium tuberculosis puromycin hydrolase displays a prolyl oligopeptidase fold and an acyl aminopeptidase activity - Zhao_2021_Proteins__
Author(s) : Zhao Y , Feng Q , Zhou X , Zhang Y , Lukman M , Jiang J , Ruiz-Carrillo D
Ref : Proteins , : , 2021
Abstract : Puromycin-hydrolizing peptidases have been described as members of the prolyl oligopeptidase peptidase family. These enzymes are present across all domains of life but still little is known of the homologs found in the pathogenic bacterium Mycobacterium tuberculosis. The crystal structure of a M. tuberculosis puromycin hydrolase peptidase has been determined at 3 Angstrom resolution, revealing a conserved prolyl oligopeptidase fold, defined by alpha/beta-hydrolase and beta-propeller domains with two distinctive loops that occlude access of large substrates to the active site. The enzyme displayed amino peptidase activity with a substrate specificity preference for hydrophobic residues in the decreasing order of phenylalanine, leucine, alanine and proline. The enzyme's active site is lined by residues Glu564 for the coordination of the substrates amino terminal moiety and His561, Val608, Tyr78, Trp306, Phe563 and Ty567 for the accommodation of hydrophobic substrates. The availability of a crystal structure for puromycin hydrolase of M. tuberculosis shall facilitate the development of inhibitors with therapeutic applications. This article is protected by copyright. All rights reserved.
ESTHER : Zhao_2021_Proteins__
PubMedSearch : Zhao_2021_Proteins__
PubMedID: 33426726
Gene_locus related to this paper: myctu-CNE19725

Title : Magnetic covalent organic framework immobilized gold nanoparticles with high-efficiency catalytic performance for chemiluminescent detection of pesticide triazophos - Ma_2021_Talanta_235_122798
Author(s) : Ma Y , Zhao Y , Xu X , Ding S , Li Y
Ref : Talanta , 235 :122798 , 2021
Abstract : Covalent organic frameworks (COFs) are considered to be a promising support material for catalyst due to their highly ordered porous structure. Here, a core-shell structured Fe(3)O(4) magnetic covalent organic framework (Fe(3)O(4)@COF) was synthesized and employed to provide basic sites for immobilization of gold nanoparticles (AuNPs). The AuNPs was in-situ immobilized on the shell of Fe(3)O(4)@COF via a citrate reducing method. The Fe(3)O(4)@COF-AuNP had convenient magnetic separability and exhibited excellent mimicking peroxidase-like activity in catalyzing chemiluminescence (CL) reaction of luminol with hydrogen peroxide (H(2)O(2)). With acetylcholine chloride (ACh) as substrate of acetylcholinesterase (AChE), a CL method was exploited for sensitive detection of organophosphorus pesticide triazophos due to its irreversible inhibiting effect on the AChE activity and subsequently influences the production of H(2)O(2) under the condition of choline oxidase (ChOx). This method gave a good linearity for triazophos in the range of 5.0-300.0 nmol L(-1), and a limit of detection (LOD) of 1 nmol L(-1) was acquired. The applicability of this method was verified by the determination of triazophos in different spiked vegetable samples.
ESTHER : Ma_2021_Talanta_235_122798
PubMedSearch : Ma_2021_Talanta_235_122798
PubMedID: 34517656

Title : Enteral Nutrition Combined with Improved-Sijunzi Decoction Shows Positive Effect in Precachexia Cancer Patients: A Retrospective Analysis - Li_2021_Evid.Based.Complement.Alternat.Med_2021_7357521
Author(s) : Li Y , Chen Y , Zeng Y , Dong J , Li C , Jia Y , Zhao Y , Wang K
Ref : Evid Based Complement Alternat Med , 2021 :7357521 , 2021
Abstract : BACKGROUND: Cancer has been considered as the leading cause of death in the world. In patients with cancer, up to 80% display a cachectic period after diagnosis. Cachexia is known to have a negative impact on function, treatment tolerance, higher rates of hospitalizations, and mortality. Anorexia is often used as a warning sign of precachexia. Long-term anorexia may lead to malnutrition and, then, accelerate the occurrence of cachexia. A safe and effective treatment, which can both improve appetite and assist nutritional support for precachexia cancer patients shows its particular important role. METHODS: A retrospective analysis comparing the different therapeutic effects on precachexia cancer patients with anorexia-malnutrition. We recorded 46 patients with the improved-Sijunzi decoction combined with enteral nutrition emulsion (ISJZ group) and 35 patients with single enteral nutrition emulsion (SEN group). The different therapeutic effects of the two groups were observed by recording indicators before and 2 weeks after treatment, including patient-generated subjective global assessment score, quality of life score, Karnofsky performance status scale, Eastern cooperative oncology group scale standard and traditional Chinese medicine syndrome, daily total dietary intake, red blood cells, hemoglobin, prealbumin, albumin, total protein cholinesterase, C-reactive protein, leukocytes, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea nitrogen, and creatinine. RESULTS: ISJZ group exhibited prominent improvement of traditional Chinese medicine syndrome (TCMS), nutritional condition, and quality of life compared with the SEN group (QOL: p=0.0001, PG-SGA: p=0.019, dietary intake: p=0.0001, TCMS: p=0.0001). The levels of HGB (p=0.006), PAlb (p=0.001), Alb (p=0.0001), TP (p=0.008), and ChE (p=0.0001) in the ISJZ group were higher than the SEN group after treatment. Moreover, the ratios of CRP/ALB (p=0.028) and CRP/PALB (p=0.005) in the two groups have obvious differences; they were lower for the ISJZ group than the SEN group. CONCLUSIONS: Enteral nutrition combined with ISJZ decoction is an effective treatment in precachexia cancer patients for the prevention of cachexia. This treatment therapy can alleviate the inflammatory response, improve malnutrition state, and promote the performance status. Tianjin Medical University Cancer Institute and Hospital approved this study (Trial No. 1913).
ESTHER : Li_2021_Evid.Based.Complement.Alternat.Med_2021_7357521
PubMedSearch : Li_2021_Evid.Based.Complement.Alternat.Med_2021_7357521
PubMedID: 34603476

Title : 4D-QSAR Molecular Modeling and Analysis of Flavonoid Derivatives as Acetylcholinesterase Inhibitors - Wang_2021_Biol.Pharm.Bull_44_999
Author(s) : Wang Y , Zhao Y , Wei C , Tian N , Yan H
Ref : Biol Pharm Bull , 44 :999 , 2021
Abstract : Flavonoids are potential strikingly natural compounds with antioxidant activity and acetylcholinesterase (AChE) inhibitory activity for treating Alzheimer's disease (AD). In present study, in line with our interests in flavonoid derivatives as AChE inhibitors, a four-dimensional quantitative structure-activity relationship (4D-QSAR) molecular model was proposed. The data required to perform 4D-QSAR analysis includes 52 compounds reported in the literature, usually analogs, and their measured biological activities in a common assay. The model was generated by a complete set of 4D-QSAR program which was written by our group. The best model was found after trying multiple experiments. It had a good predictive ability with the cross-validation correlation coefficient Q(2) = 0.77, the internal validation correlation coefficient R(2) = 0.954, and the external validation correlation coefficient R(2)(pred) = 0.715. The molecular docking analysis was also carried out to understand exceedingly the interactions between flavonoids and the AChE targets, which was in good agreement with the 4D-QSAR model. Based on the information provided by the 4D-QSAR model and molecular docking analysis, the idea for optimizing the structures of flavonoids as AChE inhibitors was put forward which maybe provide theoretical guidance for the research and development of new AChE inhibitors.
ESTHER : Wang_2021_Biol.Pharm.Bull_44_999
PubMedSearch : Wang_2021_Biol.Pharm.Bull_44_999
PubMedID: 34193695

Title : Astilbin ameliorates oxidative stress and apoptosis in D-galactose-induced senescence by regulating the PI3K\/Akt\/m-TOR signaling pathway in the brains of mice - Zhang_2021_Int.Immunopharmacol_99_108035
Author(s) : Zhang Y , Ding C , Cai Y , Chen X , Zhao Y , Liu X , Zhang J , Sun S , Liu W
Ref : Int Immunopharmacol , 99 :108035 , 2021
Abstract : An increasing amount of evidence has shown that injection of D-galactose (D-gal) can mimic natural aging that typically is associated with brain injury. Oxidative stress and apoptosis has been shown to play an essential role in aging process. The purpose of this study was to investigate the protective effectsof astilbin (ASB) on D-Gal-induced agingin miceand to further explore the underlying mechanisms. We randomly divided 50 mice into 5 groups.To establish this model of aging, 40micewere intraperitoneally administered D-Gal (500 mg/kg). The mice in the treatmentgroupswere intragastricaly administratedASB at doses of 40 and 80 mg/kg. H&E and TUNEL staining were used to determine the effect of ASB on the number of apoptotic cells in the brain. Furthermore, biochemical indices of serum, oxidative stress factors, and apoptosis factors were determined to clarify the underlying mechanism using reagent test kits and western blotting. The results showed that varying doses of ASB could improve D-Gal-induced histopathological damageand significantly alleviatedthe aging induced by D-Galin mice. ASB remarkably decreased the activities of malondialdehyde (MDA)(p < 0.01)and Acetyl cholinesterase (AChE)(p < 0.05) and markedlyincreased the content of catalase (CAT)(p < 0.01)and superoxide dismutase (SOD)(p < 0.01), respectively. In addition, Western blotting revealed thatASB treatment (40 mg/kg)attenuated the D-gal-induced Bax and Caspase 3 protein expression(p < 0.01) and reversed the increase in Bcl-2protein expressionin brain. Moreover, ASB treatment significantly upregulated the protein expression ofp-PI3K/PI3K and altered the p-Akt/Akt ratio (p < 0.05), while inhibiting the expression of p-m-TOR relative to m-TOR(p < 0.05). Moreover, the expression of P53 tended to decreasein the low ASB treatmentgroup (40 mg/kg), whereas no change was observed in the high ASB treatmentgroup (80 mg/kg). In the intestinal flora, the richness of the normal group and the ASB group was higher than that of the D-Gal group. Heat map analysis also showed that ASB promoted Lactobacillus and other probiotics and also confirmed the advantages of ASB. The observed changes in intestinal flora further verified the efficacy of ASB.
ESTHER : Zhang_2021_Int.Immunopharmacol_99_108035
PubMedSearch : Zhang_2021_Int.Immunopharmacol_99_108035
PubMedID: 34435579

Title : Attenuation of virulence in multiple serotypes (M1, M3, and M28) of Group A Streptococcus after the loss of secreted esterase - Zhang_2021_J.Microbiol.Immunol.Infect__
Author(s) : Zhang X , Zhao Y , Wang Y , Cai M , Song Y , Zhu H
Ref : J Microbiol Immunol Infect , : , 2021
Abstract : INTRODUCTION: Group A Streptococcus (GAS) can produce streptococcal secreted esterase (Sse), which inhibits neutrophil recruitment to the site of infection and is crucial for GAS pathogenesis. As an effective esterase, Sse hydrolyzes the sn-2 ester bond of human platelet-activating factor, inactivating it and abolishing its ability to recruit neutrophils. OBJECTIVES: The purpose of this study was to investigate the effects of sse deletion on the virulence of multiple serotypes of GAS. METHODS: Isogenic strains that lack the sse gene (deltasse) were derived from the parent strains MGAS5005 (serotype M1, CovRS mutant), MGAS2221 (serotype M1, wild-type CovRS), MGAS315 (serotype M3, CovRS mutant) and MGAS6180 (serotype M28, wild-type CovRS) and were used to study the differences in virulence and pathogenicity of GAS serotypes. RESULTS: In a subcutaneous infection model, mice infected with MGAS5005(deltasse) exhibited higher survival rates but decreased dissemination to the organs compared with mice infected with MGAS5005. When mice were infected with the four deltasse mutants, the MPO activity and IFN-gamma, TNF-alpha, IL-2 and IL-6 levels increased, but the skin lesion sizes decreased. In an intraperitoneal infection model, the absence of Sse significantly reduced the virulence of GAS, leading to increased mouse survival rates and decreased GAS burdens in the organs in most of the challenge experiments. In addition, the numbers of the four deltasse mutants were greatly reduced 60 min after incubation with isolated rat neutrophils. CONCLUSION: Our results suggest that Sse participates in the pathogenesis of multiple GAS serotypes (MGAS5005, MGAS2221, MGAS315 and MGAS6180), particularly the hypervirulent CovS mutant strains MGAS5005 and MGAS315. These strain differences were positively correlated with the virulence of the serotype.
ESTHER : Zhang_2021_J.Microbiol.Immunol.Infect__
PubMedSearch : Zhang_2021_J.Microbiol.Immunol.Infect__
PubMedID: 34674958

Title : Phosphatidylserine-specific phospholipase A1: A friend or the devil in disguise - Zhao_2021_Prog.Lipid.Res_83_101112
Author(s) : Zhao Y , Hasse S , Bourgoin SG
Ref : Prog Lipid Res , 83 :101112 , 2021
Abstract : Various human tissues and cells express phospholipase A1 member A (PLA1A), including the liver, lung, prostate gland, and immune cells. The enzyme belongs to the pancreatic lipase family. PLA1A specifically hydrolyzes sn-1 fatty acid of phosphatidylserine (PS) or 1-acyl-lysophosphatidylserine (1-acyl-lysoPS). PS externalized by activated cells or apoptotic cells or extracellular vesicles is a potential source of substrate for the production of unsaturated lysoPS species by PLA1A. Maturation and functions of many immune cells, such as T cells, dendritic cells, macrophages, and mast cells, can be regulated by PLA1A and lysoPS. Several lysoPS receptors, including GPR34, GPR174 and P2Y10, have been identified. High serum levels and high PLA1A expression are associated with autoimmune disorders such as Graves' disease and systemic lupus erythematosus. Increased expression of PLA1A is associated with metastatic melanomas. PLA1A may contribute to cardiometabolic disorders through mediating cholesterol transportation and producing lysoPS. Furthermore, PLA1A is necessary for hepatitis C virus assembly and can play a role in the antivirus innate immune response. This review summarizes recent findings on PLA1A expression, lysoPS and lysoPS receptors in autoimmune disorders, cancers, cardiometabolic disorders, antivirus immune responses, as well as regulations of immune cells.
ESTHER : Zhao_2021_Prog.Lipid.Res_83_101112
PubMedSearch : Zhao_2021_Prog.Lipid.Res_83_101112
PubMedID: 34166709

Title : Detection of carboxylesterase 1 and carbamates with a novel fluorescent protein chromophore based probe - Dai_2021_Dyes.Pigments_192_109444
Author(s) : Dai J , Zhao Y , Hou Y , Zhong G , Gao R , Wu J , Shen B , Zhang X
Ref : Dyes and Pigments , 192 :109444 , 2021
Abstract : An aggregation-induced emission (AIE) fluorescent protein chromophore-based probe (CBZ-FP) for detection of human carboxylesterases (CESs) was designed and synthesized. CBZ -FP exhibited good cell permeability with a large stokes shift (116snm) and can be applied to reveal the actual activities of CES1 in living cells associated with pesticide s detoxification process. CBZ-FP can also serve as a fluorescence indicator of pesticide exposure in the way of hydrolyzing the carboxylic acid ester group in CBZ-FP. There fore, CBZ-FP has high selectivity for CESs and can detect real-time activity of CES1 in biological samples. Molecular docking study was used to explore the binding of CESs and CBZ-FP. Finding that only one specific activity site of CESs can bind with probe. In view of the fact that, the biotransformation of drugs and poisons containing ester groups can carry out normally depending on CESs, Carboxylesterase probes are expected to contribute to the characterization of relevant disease.
ESTHER : Dai_2021_Dyes.Pigments_192_109444
PubMedSearch : Dai_2021_Dyes.Pigments_192_109444

Title : Molecular and behavioral responses of zebrafish embryos\/larvae after sertraline exposure - Yang_2021_Ecotoxicol.Environ.Saf_208_111700
Author(s) : Yang H , Liang X , Zhao Y , Gu X , Mao Z , Zeng Q , Chen H , Martyniuk CJ
Ref : Ecotoxicology & Environmental Safety , 208 :111700 , 2021
Abstract : Sertraline (SER) is one of the most frequently detected antidepressant drugs in aquatic environments. However, knowledge regarding SER-induced behavioral alterations in fish is insufficient, as well as the mechanisms underlying SER-induced toxicity. The present study aimed to determine behavioral and molecular responses in larval fish following SER exposure with a focus on its mode of action. Zebrafish embryos (~6 h-post-fertilization, hpf) were exposed to one of three concentrations of SER (1, 10, 100 microg/L) for 6 days, respectively. Evaluated parameters included development, behavior, transcripts related to serotonin signaling, serotonin levels, and acetylcholinesterase activity. Accelerated hatching of zebrafish embryos was observed for those fish exposed to 100 microg/L SER at 54 hpf. Locomotor activity (e.g. distance moved and mobile cumulative duration) was significantly reduced in larval zebrafish following exposure to 10 and 100 microg/L SER. Conversely, larval fish showed increased dark-avoidance after exposure to 1-100 microg/L SER. Of the measured transcripts related to serotonin signaling, only serotonin transporter (serta) and serotonin receptor 2c (5-ht2c) mRNA levels were increased in fish in response to 10 microg/L SER treatment. However, serotonin levels were unaltered in larvae exposed to SER. There were no differences among groups in acetylcholinesterase activity at any concentration tested. Taking together, the results evidenced that exposure to SER alters behavioral responses in early-staged zebrafish, which may be related to the abnormal expression of 5-ht2c. This study elucidates molecular responses to SER and characterizes targets that may be sensitive to antidepressant pharmaceuticals in larval fish.
ESTHER : Yang_2021_Ecotoxicol.Environ.Saf_208_111700
PubMedSearch : Yang_2021_Ecotoxicol.Environ.Saf_208_111700
PubMedID: 33396031

Title : Fluorescent and colorimetric dual-response sensor based on copper (II)-decorated graphitic carbon nitride nanosheets for detection of toxic organophosphorus - Chen_2021_Food.Chem_345_128560
Author(s) : Chen Y , Zhu Y , Zhao Y , Wang J
Ref : Food Chem , 345 :128560 , 2021
Abstract : An efficient and convenient detection method for organophosphorus pesticide (OP) residues is needed because of their high neurotoxicity and severe threat to food safety. OPs effectively reduce the production of thiocholine in the acetylcholinesterase/acetylthiocholine reaction by inhibiting the activity of acetylcholinesterase. Therefore, we developed a feasible and convenient fluorescent and colorimetric dual-response sensor based on the competitive complexation of Cu(2+) between graphitic carbon nitride nanosheets and thiocholine for the rapid detection of OPs with high sensitivity. Malathion was used as a model OP, and a linear range of 70-800 nM with a detection limit of 6.798 nM for a fluorescent signaling platform and 2.5-25 nM with a detection limit of 1.204 nM for a colorimetric probe were attained. The constructed probe was successfully applied to determine OP in actual samples of cabbages leaves and tap water. The results indicated that the dual-response probe was reliable and sensitive to actual samples.
ESTHER : Chen_2021_Food.Chem_345_128560
PubMedSearch : Chen_2021_Food.Chem_345_128560
PubMedID: 33601648

Title : First-in-Human, Single-Ascending Dose and Food Effect Studies to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Cetagliptin, a Dipeptidyl Peptidase-4 Inhibitor for the Treatment of Type 2 Diabetes Mellitus - Wang_2021_Clin.Drug.Investig_41_999
Author(s) : Wang L , Lu J , Zhou S , Zhao Y , Xie L , Zhou C , Chen J , Ding S , Xie D , Ding J , Yu Q , Shen H , Hao G , Shao F
Ref : Clin Drug Investig , 41 :999 , 2021
Abstract : BACKGROUND AND OBJECTIVES: Cetagliptin is a highly selective dipeptidyl peptidase-4 inhibitor under development to treat type 2 diabetes mellitus. This first-in-human study was conducted to characterise the pharmacokinetics, pharmacodynamics and tolerability of single-ascending oral doses of cetagliptin in healthy subjects. In addition, the effect of food on pharmacokinetics was evaluated. METHODS: Study 1 enrolled 66 healthy subjects in a double-blind, randomised, placebo-controlled, single-dose escalation study; sitagliptin was employed as a positive open-label control. Forty-four subjects were assigned to seven cohorts (cetagliptin 12.5, 25, 50, 100, 200, 300 or 400 mg); 12 subjects were assigned to the placebo group. The remaining ten subjects received sitagliptin 100 mg as the positive control. Blood, urine and faeces were collected for the pharmacokinetic analysis and determination of plasma dipeptidyl peptidase-4 inhibition, active glucagon-like peptide-1, glucose and insulin levels. In Study 2, 14 healthy subjects were assigned to a randomised, open-label, two-period crossover study, and received a single oral dose of cetagliptin 100 mg in the fasted state or after a high-fat meal, with a 14-day washout period between treatments. Blood samples were collected to evaluate the effects of food on the pharmacokinetics of cetagliptin. RESULTS: Following administration of a single oral dose, cetagliptin was rapidly absorbed, presenting a median time to maximum concentration of 1.0-3.25 h. The terminal half-life ranged between 25.8 and 41.3 h, which was considerably longer than that of sitagliptin. The area under the plasma concentration-time curve was approximately dose proportional between 25 mg and 400 mg, and the increase in maximum concentration was greater than dose proportional. The unchanged drug was mainly excreted in the urine (27.2-46.2% of dose) and minimally via the faeces (1.4% of dose). Dipeptidyl peptidase-4 inhibition, an increase in active glucagon-like peptide-1 and a slight decrease in blood glucose were observed, whereas insulin was not significantly altered when compared with placebo. The weighted average dipeptidyl peptidase-4 inhibition by cetagliptin 100 mg was higher than that mediated by sitagliptin 100 mg. Cetagliptin was well tolerated up to a single oral dose of 400 mg. No food effects were noted. CONCLUSIONS: Cetagliptin inhibited plasma dipeptidyl peptidase-4 activity, increased levels of active glucagon-like peptide-1 and was well tolerated at single doses up to 400 mg, eliciting no dose-limiting toxicity in healthy volunteers. Food did not affect the pharmacokinetics of cetagliptin. CLINICAL TRIAL REGISTRATION: The studies were registered at http://www.chinadrugtrials.org.cn (Nos. CTR20180167 and CTR20181331).
ESTHER : Wang_2021_Clin.Drug.Investig_41_999
PubMedSearch : Wang_2021_Clin.Drug.Investig_41_999
PubMedID: 34655432

Title : Portable electrochemical biosensor based on laser-induced graphene and MnO(2) switch-bridged DNA signal amplification for sensitive detection of pesticide - Liu_2021_Biosens.Bioelectron_199_113906
Author(s) : Liu X , Cheng H , Zhao Y , Wang Y , Li F
Ref : Biosensors & Bioelectronics , 199 :113906 , 2021
Abstract : Developing portable, quantitative, and user-friendly analytical tools for sensitive pesticide assay is of significant importance for guaranteeing food safety. Herein, a novel electrochemical biosensor was constructed by integrating laser-induced graphene (LIG) electrode on polyimide (PI) foil and MnO(2) nanosheets loaded on the paper for point-of-care test (POCT) of organophosphorus (OPs) residues. The principle of this biosensor relied on acetylcholinesterase (AChE)-catalyzed hydrolytic product-triggered disintegration of MnO(2) nanosheets for releasing assistant DNA to initiate nicking enzyme-aided recycling amplification. In the presence of OPs, the activity of AChE was inhibited and could not initiate the cleavage of the electroactive molecules-labeled hairpin probe on the electrode, resulting in the maintenance of the electrochemical response to realize a "sign-on" determination of OPs. The proposed biosensor exhibited satisfactory analytical performance for OPs assay with a linear range from 3 to 4000 ng/mL and a limit of detection down to 1.2 ng/mL. Moreover, the biosensor was useful for evaluating the residual level of pesticides in the vegetables. Therefore, this novel biosensor holds great promise for OPs assay and opens a new avenue on the development of higher-performance POCT device for sensing applications in the environment and food safety fields.
ESTHER : Liu_2021_Biosens.Bioelectron_199_113906
PubMedSearch : Liu_2021_Biosens.Bioelectron_199_113906
PubMedID: 34968952

Title : A highly sensitive acetylcholinesterase electrochemical biosensor based on Au-Tb alloy nanospheres for determining organophosphate pesticides - Yang_2021_Nanotechnology__
Author(s) : Yang Y , Zhao Y , Liu Q , You T , Gao Y , Chen H , Yin P
Ref : Nanotechnology , : , 2021
Abstract : Accurately detect the residues of organophosphate pesticides(OPs) in food and environment is critical to our daily lives. In this study, we developed a novel acetylcholinesterase (AChE) biosensor based on Au-Tb alloy nanospheres (NSs) for rapid and sensitive detection of OPs for the first time. Au-Tb alloy nanospheres that with good conductivity and biocompatibility were produced with a mild hydrothermal. Under optimal conditions, the AChE biosensor was obtained by a simple assembly process, with a big linear range (10-13 M - 10-7 M) and the limit of detection was 2.51 x 10-14 M for the determination of methyl parathion. Moreover, the determination of methyl parathion with the prepared biosensor presented a high sensitivity, outstanding repeatability and superior stability compared with other reported biosensors. Through the determination of tap water and Yanming lake samples, it was proved that the modified biosensor with satisfactory recoveries (96.76 %-108.6 %), and are realizable in the determination of OPs in real samples.
ESTHER : Yang_2021_Nanotechnology__
PubMedSearch : Yang_2021_Nanotechnology__
PubMedID: 34256363

Title : Structural Insights into Notum Covalent Inhibition - Zhao_2021_J.Med.Chem_64_11354
Author(s) : Zhao Y , Svensson F , Steadman D , Frew S , Monaghan A , Bictash M , Moreira T , Chalk R , Lu W , Fish PV , Jones EY
Ref : Journal of Medicinal Chemistry , 64 :11354 , 2021
Abstract : The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer's disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.
ESTHER : Zhao_2021_J.Med.Chem_64_11354
PubMedSearch : Zhao_2021_J.Med.Chem_64_11354
PubMedID: 34292747
Gene_locus related to this paper: human-NOTUM

Title : Neuroprotective effects of NDEELNK from sea cucumber ovum against scopolamine-induced PC12 cell damage through enhancing energy metabolism and upregulation of the PKA\/BDNF\/NGF signaling pathway - Zhao_2021_Food.Funct__
Author(s) : Zhao Y , Dong Y , Ge Q , Cui P , Sun N , Lin S
Ref : Food Funct , : , 2021
Abstract : The aim of the study was to evaluate the neuroprotective function of sea cucumber ovum peptide-derived NDEELNK and explore the underlying molecular mechanisms. NDEELNK exerted the neuroprotective effect by improving the acetylcholine (ACh) level and reducing the acetylcholinesterase (AChE) activity in PC12 cells. By molecular docking, we confirmed that the NDEELNK backbone and AChE interacted through hydrophobic and hydrogen bonds in contact with the amino acid residues of the cavity wall. NDEELNK increased superoxide dismutase (SOD) activity and decreased reactive oxygen species (ROS) production, thereby reducing mitochondrial dysfunction and enhancing energy metabolism. Our results demonstrated that NDEELNK supplementation alleviated scopolamine-induced PC12 cell damage by improving the cholinergic system, increasing energy metabolism and upregulating the expression of phosphorylated protein kinase A (p-PKA), brain-derived neurotrophic factor (BNDF) and nerve growth factor (NGF) signaling proteins in in vitro experiments. These results demonstrated that the sea cucumber ovum peptide-derived NDEELNK might play a protective role in PC12 cells.
ESTHER : Zhao_2021_Food.Funct__
PubMedSearch : Zhao_2021_Food.Funct__
PubMedID: 34259275

Title : Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation -
Author(s) : Cui Z , Li B , Zhang Y , He J , Shi X , Wang H , Zhao Y , Yao L , Ai D , Zhang X , Zhu Y
Ref : Hypertension , 78 :1527 , 2021
PubMedID: 34601968

Title : Small-molecule inhibitors of carboxylesterase Notum - Zhao_2021_Future.Med.Chem__
Author(s) : Zhao Y , Jolly S , Benvegnu S , Jones EY , Fish PV
Ref : Future Med Chem , : , 2021
Abstract : Notum has recently been identified as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group from Wnt proteins. There are emerging reports that Notum plays a role in human disease, with published data suggesting that targeting Notum could represent a new therapeutic approach for treating cancer, osteoporosis and neurodegenerative disorders. Complementary hit-finding strategies have been applied with successful approaches that include high-throughput screening, activity-based protein profiling, screening of fragment libraries and virtual screening campaigns. Structural studies are accelerating the discovery of new inhibitors of Notum. Three fit-for-purpose examples are LP-922056, ABC99 and ARUK3001185. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease.
ESTHER : Zhao_2021_Future.Med.Chem__
PubMedSearch : Zhao_2021_Future.Med.Chem__
PubMedID: 33882714
Gene_locus related to this paper: human-NOTUM

Title : Notum Deacylates Octanoylated Ghrelin - Zhao_2021_Mol.Metab__101201
Author(s) : Zhao Y , Schuhmacher LN , Roberts M , Kakugawa S , Bineva-Todd G , Howell S , O'Reilly N , Perret C , Snijders AP , Vincent JP , Jones EY
Ref : Mol Metab , :101201 , 2021
Abstract : OBJECTIVES: The only proteins known to be modified by O-linked lipidation are Wnts and ghrelin, and enzymatic removal of this post-translational modification inhibits ligand activity. Indeed, the Wnt-deacylase activity of Notum is the basis of its ability to act as a feedback inhibitor of Wnt signalling. Whether Notum also deacylates ghrelin has not been determined. METHODS: We used mass-spectrometry to assay ghrelin deacylation by Notum and co-crystallisation to reveal enzyme-substrate interactions at the atomic level. CRISPR/Cas technology was used to tag endogenous Notum and assess its localisation in mice while liver-specific Notum knock-out mice allowed us to investigate the physiological role of Notum in modulating the level of ghrelin deacylation. RESULTS: Mass-spectrometry detected the removal of octanoyl from ghrelin by purified active Notum, but not by an inactive mutant. The 2.2 A resolution crystal structure of the Notum-ghrelin complex shows the octanoyl lipid is accommodated in the hydrophobic pocket of Notum. The knock-in allele expressing HA-tagged Notum reveals that Notum is produced in the liver and present in the bloodstream, albeit at a low level. Liver-specific inactivation of Notum in animals fed with a high fat diet leads to a small but significant increase in acylated ghrelin in the circulation, while no such increase is seen in wildtype animals on the same diet. CONCLUSIONS: Overall our data demonstrate Notum can act as a ghrelin deacylase, and that this may be physiologically relevant under high fat diet conditions. Our work therefore adds Notum to the list of enzymes, including butylcholineasterase and other carboxylesterases, that modulate the acylation state of ghrelin. The contribution of multiple enzymes could help tune the activity of this important hormone to a wide range of physiological conditions.
ESTHER : Zhao_2021_Mol.Metab__101201
PubMedSearch : Zhao_2021_Mol.Metab__101201
PubMedID: 33647468
Gene_locus related to this paper: human-NOTUM

Title : Effects of exogenous GR24 on biogas upgrading and nutrient removal by co-culturing microalgae with fungi under mixed LED light wavelengths - Zhang_2021_Chemosphere_281_130791
Author(s) : Zhang W , Zhao C , Liu J , Sun S , Zhao Y , Wei J
Ref : Chemosphere , 281 :130791 , 2021
Abstract : To realize the synchronous purification of raw biogas and biogas slurry, the algal-fungal symbiont pellets were cultivated by supplementing strigolactone (GR24) under different mixed LED light wavelengths. The optimal light intensity was proved to be red and blue in the ratio of 5:5. The symbionts treated with 10(-9) M GR24 had the highest growth rate and mean daily productivity. The extracellular carbonic anhydrase activity and the content of chlorophyll were also affected by GR24 concentrations and mixed light wavelengths. With the induction of 10(-9) M GR24, the maximum removal efficiency of chemical oxygen demand, total nitrogen, and total phosphorus reached 76.35 +/- 6.87%, 78.77 +/- 7.13% and 79.49 +/- 7.43%, respectively. Besides, the CO(2) removal efficiency reached 59.32 +/- 5.19% when the concentration of GR24 was 10(-7) M. This work will be beneficial for large-scale biogas slurry purification and biogas upgrading using co-cultivation of microalgae and fungi.
ESTHER : Zhang_2021_Chemosphere_281_130791
PubMedSearch : Zhang_2021_Chemosphere_281_130791
PubMedID: 34020195

Title : Androgen-dependent miR-125a-5p targets LYPLA1 and regulates global protein palmitoylation level in late-onset hypogonadism males - Qu_2021_J.Cell.Physiol_236_4738
Author(s) : Qu M , Zhao Y , Qing X , Zhang X , Li H
Ref : Journal of Cellular Physiology , 236 :4738 , 2021
Abstract : Late-onset hypogonadism (LOH) is defined as a clinical and biochemical syndrome with multiple symptoms caused by testosterone deficiency in aging males. An in-depth exploration of the molecular mechanism underlying LOH development is insufficient. We previously identified miR-125a-5p as a dysregulated microRNA in LOH patients and potential diagnostic biomarker for LOH. The present study demonstrated that plasma miR-125a-5p was upregulated after testosterone supplementation in both LOH patients and castrated mice, and positively associated with the testosterone concentrations, suggesting direct regulation of miR-125a-5p expression by testosterone. Androgen response element in the promoter of miR-125a-5p was subsequently identified. Target gene screening and confirmation verified that LYPLA1, encoding acyl-protein thioesterase 1 which catalyzed protein depalmitoylation process, was a target gene of miR-125a-5p. Furthermore, in cells cultured with testosterone deprivation and organs from castrated mice, testosterone deficiency led to decreased global protein palmitoylation level. In aging males, global protein palmitoylation in peripheral blood showed a notable decline in LOH patients contrast to the normal elderly males. And the palmitoylation level was positively correlative with serum testosterone concentrations. Our results suggested that testosterone could regulate global palmitoylation level through miR-125a-5p/LYPLA1 signaling pathway. Given that protein palmitoylation is pivotal for protein function and constitutes the pathogenesis of various diseases, testosterone/miR-125a-5p/LYPLA1 may contribute to the molecular mechanism underlying multiple symptoms caused by testosterone deficiency in LOH patients, and aberrant global palmitoylation could be a potential biomarker for LOH.
ESTHER : Qu_2021_J.Cell.Physiol_236_4738
PubMedSearch : Qu_2021_J.Cell.Physiol_236_4738
PubMedID: 33284463

Title : Synthesis and Structure-Activity Relationships of 3-Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors - Zhao_2021_ChemMedChem_16_388
Author(s) : Zhao Y , Xiong Y , Dong S , Guan X , Song Y , Yang Y , Zou K , Li Z , Zhang Y , Fang S , Li B , Zhu W , Chen K , Jia Q , Ge G
Ref : ChemMedChem , 16 :388 , 2021
Abstract : Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3-arylisoquinolones 3h [3-(4-(benzyloxy)-3-methoxyphenyl)-7,8-dimethoxyisoquinolin-1(2H)-one] and 4a [3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-dimethoxyisoquinolin-1(2H)-one] were found to have potent inhibitory effects on hCES2A (IC(50) =0.68microM, K(i) =0.36microM) and excellent specificity (more than 147.05-fold over hCES1A). Moreover, 4a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3h, with an IC(50) value of 0.41microM. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3h and 4a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure-activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.
ESTHER : Zhao_2021_ChemMedChem_16_388
PubMedSearch : Zhao_2021_ChemMedChem_16_388
PubMedID: 32935462

Title : An ABHD17-like hydrolase screening system to identify de-S-acylation enzymes of protein substrates in plant cells - Liu_2021_Plant.Cell__
Author(s) : Liu X , Li M , Li Y , Chen Z , Zhuge C , Ouyang Y , Zhao Y , Lin Y , Xie Q , Yang C , Lai J
Ref : Plant Cell , : , 2021
Abstract : Protein S-acylation is an important post-translational modification in eukaryotes, regulating the subcellular localization, trafficking, stability, and activity of substrate proteins. The dynamic regulation of this reversible modification is mediated inversely by protein S-acyltransferases and de-S-acylation enzymes, but the de-S-acylation mechanism remains unclear in plant cells. Here we characterized a group of putative protein de-S-acylation enzymes in Arabidopsis thaliana, including 11 members of ABHD17 (Alpha/Beta Hydrolase Domain-containing Protein 17)-like Acyl Protein Thioesterases (ABAPTs). A robust system was then established for the screening of de-S-acylation enzymes of protein substrates in plant cells, based on the effects of substrate localization and confirmed via the protein S-acylation levels. Using this system, the ABAPTs, which specifically reduced the S-acylation levels and disrupted the plasma membrane localization of five immunity-related proteins, were identified respectively in Arabidopsis. Further results indicated that the de-S-acylation of RIN4 (RPM1 Interacting Protein 4), which was mediated by ABAPT8, resulted in an increase of cell death in Arabidopsis and Nicotiana benthamiana, supporting the physiological role of the ABAPTs in plants. Collectively, our current work provides a powerful and reliable system to identify the pairs of plant protein substrates and de-S-acylation enzymes for further studies on the dynamic regulation of plant protein S-acylation.
ESTHER : Liu_2021_Plant.Cell__
PubMedSearch : Liu_2021_Plant.Cell__
PubMedID: 34338800
Gene_locus related to this paper: arath-AT1G66900 , arath-AT2G24320 , arath-AT4G31020 , arath-AT5G20520 , arath-AT5G38220 , arath-F3C3.3 , arath-AT1G13610 , arath-At5g14390 , arath-F22K18.40 , arath-At3g01690 , arath-Q9LI62

Title : Congenital myasthenic syndrome in China: genetic and myopathological characterization - Zhao_2021_Ann.Clin.Transl.Neurol__
Author(s) : Zhao Y , Li Y , Bian Y , Yao S , Liu P , Yu M , Zhang W , Wang Z , Yuan Y
Ref : Ann Clin Transl Neurol , : , 2021
Abstract : OBJECTIVE: We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes. METHODS: The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up. RESULTS: Thirty-five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb-girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha-dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long-term use in patients with COLQ or AGRN mutations. INTERPRETATION: The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb-girdle myasthenic syndrome, tubular aggregates, and decreased alpha-dystroglycan were indicative of the specific subtypes. Based on the follow-up findings, we suggest cautious evaluation of the long-term efficacy of therapeutic agents in congenital myasthenic syndrome.
ESTHER : Zhao_2021_Ann.Clin.Transl.Neurol__
PubMedSearch : Zhao_2021_Ann.Clin.Transl.Neurol__
PubMedID: 33756069

Title : Inhibition of soluble epoxide hydrolase (sEH) protects hippocampal neurons and reduces cognitive decline in type 2 diabetic mice - Wu_2021_Eur.J.Neurosci__
Author(s) : Wu J , Fan Z , Zhao Y , Chen Q , Xiao Q
Ref : European Journal of Neuroscience , : , 2021
Abstract : Diabetes mellitus is a metabolic disorder that can lead to cognitive dysfunction. The hippocampus plays an important role in the cognitive function. Research has identified correlations between hippocampal impairment and diabetes, yet their intermediate remains unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects by suppressing inflammation, apoptosis and oxidative stress. In this study, under diabetic conditions both hippocampal injury, and cognitive decline are accompanied by upregulation of sEH. Moreover, the sEH inhibitor trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) prevents cognitive dysfunction and decreased ROS accumulation and apoptosis in the diabetic hippocampus. t-AUCB treatment restored neuronal synaptic plasticity by restoring the expression of the postsynaptic proteins Postsynaptic density protein-95 (PSD95) and N-methyl-d-aspartate receptor subunit 2B (NR2B), the levels of which were positively correlated with Proline-rich tyrosine kinase 2 (Pyk2) levels under diabetic conditions. Thus, we suggest that hippocampal protection via sEH inhibition might be a potential therapeutic approach to attenuate the progression of cognitive decline in diabetes.
ESTHER : Wu_2021_Eur.J.Neurosci__
PubMedSearch : Wu_2021_Eur.J.Neurosci__
PubMedID: 33595911

Title : Red ginseng has stronger anti-aging effects compared to ginseng possibly due to its regulation of oxidative stress and the gut microbiota - Peng_2021_Phytomedicine_93_153772
Author(s) : Peng X , Hao M , Zhao Y , Cai Y , Chen X , Chen H , Zhang Y , Dong L , Liu X , Ding C , Liu W , Yang M , Luo Y
Ref : Phytomedicine , 93 :153772 , 2021
Abstract : BACKGROUND: Panax ginseng (PG) and red ginseng (RG) are considered to be effective anti-aging treatments. However, evidence of their therapeutic mechanisms and difference in anti-aging effects is lacking. PURPOSE: To explore the potential therapeutic mechanisms of RG and PG in brain damage in D-Gal-induced aging mice, and evaluate the difference in anti-aging effects caused by their compositional differences. METHODS: We first tested the chemical components in PG and RG. In D-Gal aging mouse model, RG and PG (800 mg/kg) were orally administered for 9 weeks. The mice performed the Radial Arm Maze (RAM) behavior test. We collected blood, brain tissue, and fecal samples and performed biochemical analysis, histological examination, western blot, and Illumina MiSeq sequencing analysis. RESULTS: The results of component analysis showed that the total polyphenols and rare ginsenosides were present in RG in 3.2, and 2.2 fold greater concentrations, respectively, compared to PG, while the proportion of non-starch polysaccharides in the crude polysaccharides of RG was 1.94 fold greater than that of PG. In D-Gal-induced aging mice, both PG and RG could prevent the increase in acetylcholinesterase (AChE), and malondialdehyde (MDA) levels, and improved the expression of superoxide dismutase (SOD), and catalase (CAT) in the serum. Meanwhile, both PG and RG could ameliorate brain tissue architecture and behavioral trial. In addition, the D-Gal-induced translocation of nuclear factor-kappaB (NF-kappaB), as well as activation of the pro-apoptotic factors Caspase-3 and the PI3K/Akt pathways were inhibited by PG and RG. Overall, both PG and RG exerted anti-aging effects, with RG stronger than PG. Finally, although both PG and RG regulated the diversity of gut microbes, RG appeared to aggravate the increase in probiotics, such as Bifidobacterium and Akkermania, and the decrease in inflammatory bacteria to a greater extent compared to PG. CONCLUSION: Our results suggest that RG is more conducive to delay the D-Gal-induced aging process than PG, with possible mechanisms including beneficial changes in brain structure, cognitive functions, oxidative stress inhibition, and gut microbiome structure and diversity than PG, These mechanisms may rely on the presence of more total polyphenols, rare ginsenosides and non-starch polysaccharides in RG.
ESTHER : Peng_2021_Phytomedicine_93_153772
PubMedSearch : Peng_2021_Phytomedicine_93_153772
PubMedID: 34753028

Title : Soluble epoxide hydrolase inhibitor protects against blood-brain barrier dysfunction in a mouse model of type 2 diabetes via the AMPK\/HO-1 pathway - Wu_2020_Biochem.Biophys.Res.Commun__
Author(s) : Wu J , Zhao Y , Fan Z , Chen Q , Chen J , Sun Y , Jiang X , Xiao Q
Ref : Biochemical & Biophysical Research Communications , : , 2020
Abstract : Diabetes mellitus is a metabolic disorder that can lead to blood-brain barrier (BBB) disruption and cognitive decline. However, the mechanisms of BBB breakdown in diabetes are still unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects on vascular structure and functions. In the current study, we showed increased vascular permeability of the BBB, which was accompanied by upregulation of sEH and downregulation of 14,15-EET. Moreover, the sEH inhibitor t-AUCB restored diabetic BBB integrity in vivo, and 14,15-EET prevented ROS accumulation and MEC injury in vitro. t-AUCB or 14,15-EET treatment provoked AMPK/HO-1 activation under diabetic conditions in vivo and in vitro. Thus, we suggest that decreased EET degradation by sEH inhibition might be a potential therapeutic approach to attenuate the progression of BBB injury in diabetic mice via AMPK/HO-1 pathway activation.
ESTHER : Wu_2020_Biochem.Biophys.Res.Commun__
PubMedSearch : Wu_2020_Biochem.Biophys.Res.Commun__
PubMedID: 32001002

Title : Inhibitory activities of flavonoids from Eupatorium adenophorum against acetylcholinesterase - Li_2020_Pestic.Biochem.Physiol_170_104701
Author(s) : Li M , Gao X , Lan M , Liao X , Su F , Fan L , Zhao Y , Hao X , Wu G , Ding X
Ref : Pestic Biochem Physiol , 170 :104701 , 2020
Abstract : Fifteen flavonoids isolated from the Eupatorium adenophorum showed inhibitory activities against acetylcholinesterase (AChE) isolated from Caenorhabditis elegans and Spodoptera litura. Their IC(50) values ranged from 12.54 to 89.06mug/mL and 12.08 to 86.01mug/mL, respectively against the AChE isolated from the nematode and insect species. AChE was inhibited in a dose-dependent manner by all tested flavonoids, The isolated compound quercetagetin-7-O-(6-O-caffeoyl-beta-D-glucopyranoside) displayed the highest inhibitory effect against AChE from C. elegans and S. litura, with IC(50) values of 12.54 mug/mL and 12.58 mug/mL, respectively. The structure-activity relationship of flavonoids on the inhibitory activities indicated that additional phenolic hydroxyl groups in the glucose were favorable for their inhibitory effects and the degree of increase in inhibitory activity also depended on the number of phenolic hydroxyl groups. The Lineweaver-Burk and Dixon plots indicated that quercetagetin-7-O-(6-O-caffeoyl-beta-d-glucopyranoside) is a reversible inhibitor against AChE. Quercetagetin-7-O-(6-O-caffeoyl-beta-d-glucopyranoside), 5,4'-Dihydroxytlavone and quercetin-3-O-beta-d-glucopyranoside inhibited AChE in a mixed-type competitive manner and these compounds might be the dual binding site AChE inhibitors. Further, nine compounds showed poisonous effects against C. elegans and inhibitory effects on the growth and development of S. litura.
ESTHER : Li_2020_Pestic.Biochem.Physiol_170_104701
PubMedSearch : Li_2020_Pestic.Biochem.Physiol_170_104701
PubMedID: 32980054

Title : Myasthenia Gravis Coexisting With Primary Sjogren's Syndrome: Report of Three Cases and Literature Review - Li_2020_Front.Neurol_11_939
Author(s) : Li X , Zhao Y , Liao Q , Da Y
Ref : Front Neurol , 11 :939 , 2020
Abstract : Objective: The coexistence of myasthenia gravis (MG) and primary Sjogren's syndrome (pSS) is rarely reported. This study aims to describe the clinical features, treatment and outcome of MG coexisting with pSS. Materials and Methods: Herein we reported three cases with the two coexisting diseases, and also searched the PubMed, Medline databases, and China Wanfang databases for the relevant case reports written in English, Chinese, or Japanese with detailed data. Results: We reviewed a total of 17 patients with both diseases. Fifteen patients were female. The median age at onset was 48 years (range 28-78 years). MG was the initial disease in nine of 17 cases. The median interval between the onsets of the two diseases was 30 months (range 7 months to 20 years). The symptoms of MG included fatigable ptosis (64.7%), bulbar symptoms (58.8%), muscle fatigability (64.7%), diplopia (64.7%), dyspnea (23.5%), and facial paralysis (5.9%). Anti-acetylcholine receptor antibody was positive in 70.6% patients. All the patients had sicca symptoms. Manifestations of pSS also included swollen exocrine glands (23.5%), joint pain (23.5%), hair loss (11.8%), leukopenia (11.8%), recurrent oral ulcers (5.9%), Raynaud phenomenon (5.9%), and fever (5.9%). ANA positivity was present in 70.6% patients, anti-SSA positivity in 47.1%, and double positivity of anti-SSA and anti-SSB in 17.6%. There were 12 patients (70.6%) with two autoimmune diseases (pSS and MG), and five patients with more than two autoimmune diseases. Cholinesterase inhibitors were the most commonly prescribed drugs (82.4%). Seven patients received thymectomy and one patient improved after the operation. Two patients were given intravenous methylprednisolone pulse therapy, and four patients oral steroids combined with immunosuppressants initially. Intravenous immunoglobulin and plasma exchange were used in two patients, respectively, for the respiratory failure. All the patients improved following treatment except one patient who died of MG crisis due to medication withdrawal. Conclusion: The coexistence of SS with MG is quite rare. The onset of MG may occur before or after the diagnosis of SS. Co-morbidity with MG does not seem to adversely affect the course of SS. Thus, controlling the progress of MG is the critical aspect of treatment.
ESTHER : Li_2020_Front.Neurol_11_939
PubMedSearch : Li_2020_Front.Neurol_11_939
PubMedID: 32982946

Title : Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease - Sang_2020_Eur.J.Med.Chem_194_112265
Author(s) : Sang Z , Wang K , Bai P , Wu A , Shi J , Liu W , Zhu G , Wang Y , Lan Y , Chen Z , Zhao Y , Qiao Z , Wang C , Tan Z
Ref : Eur Journal of Medicinal Chemistry , 194 :112265 , 2020
Abstract : A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 muM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 muM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Abeta aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl3-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Abeta1-40. PET-CT imaging demonstrated that [(11)C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease.
ESTHER : Sang_2020_Eur.J.Med.Chem_194_112265
PubMedSearch : Sang_2020_Eur.J.Med.Chem_194_112265
PubMedID: 32240904

Title : Coronavirus Disease 2019 versus Influenza A in Children: An Observational Control Study in China - Zhao_2020_Biomed.Environ.Sci_33_614
Author(s) : Zhao Y , Sun L , Bouchard HC , Zhang XX , Wan G , Hao YW , He SX , Jiang YY , Pang L
Ref : Biomedical & Environmental Sciences , 33 :614 , 2020
Abstract : This study aimed to understand the differences in clinical, epidemiological, and laboratory features between the new coronavirus disease 2019 (COVID-2019) and influenza A in children. Data of 23 hospitalized children with COVID-19 (9 boys, 5.7 +/- 3.8 years old) were compared with age- and sex-matched 69 hospitalized and 69 outpatient children with influenza A from a hospital in China. The participants' epidemiological history, family cluster, clinical manifestations, and blood test results were assessed. Compared with either inpatients or outpatients with influenza A, children with COVID-19 showed significantly more frequent family infections and higher ratio of low fever (< 37.3 degC), but shorter cough and fever duration, lower body temperature, and lower rates of cough, fever, high fever (> 39 degC), nasal congestion, rhinorrhea, sore throat, vomiting, myalgia or arthralgia, and febrile seizures. They also showed higher counts of lymphocytes, T lymphocyte CD8, and platelets and levels of cholinesterase, aspartate aminotransferase, lactate dehydrogenase, and lactic acid, but lower serum amyloid, C-reactive protein, and fibrinogen levels and erythrocyte sedimentation rate, and shorter prothrombin time. The level of alanine aminotransferase in children with COVID-19 is lower than that in inpatients but higher than that in outpatients with influenza A. Pediatric COVID-19 is associated with more frequent family infection, milder symptoms, and milder immune responses relative to pediatric influenza A.
ESTHER : Zhao_2020_Biomed.Environ.Sci_33_614
PubMedSearch : Zhao_2020_Biomed.Environ.Sci_33_614
PubMedID: 32933613

Title : Decreased T-cell mediated hepatic injury in concanavalin A-treated PLRP2-deficient mice - Ge_2020_Int.Immunopharmacol_85_106604
Author(s) : Ge W , Gao Y , Zhao Y , Yang Y , Sun Q , Yang X , Xu X , Zhang J
Ref : Int Immunopharmacol , 85 :106604 , 2020
Abstract : Concanavalin A (Con A) activates innate immunity and causes liver damage mediated by cytotoxic T lymphocytes (CTL) in mice. The Pancreatic lipase-related protein 2 (PLRP2) is induced by interleukin (IL)-4 in vitro in CTLs and associated with CTL functions. We examined the role of PLRP2 in a mouse model of Con A-induced T cell-mediated hepatitis. PLRP2-knockout and wild-type (WT) mice were inoculated with 20 mg/kg Con A. Mice lacking PLRP2 reduced Con A-induced hepatitis, which was manifested by a decrease in serum aminotransferase and histopathological assessment. The expression and secretion of cytokines including tumor necrosis factor-alpha (TNF-alpha), interferon (IFN)-gamma, IL-6, and IL-1beta were suppressed in Con A-treated PLRP2-knockout mice. In PLRP2 knockout mice, Con A-induced liver chemokines and adhesion molecules (such as MIP-1alpha, MIP-1beta, ICAM-1 and MCP-1) were also down regulated. In the WT liver treated with Con A, the number of T cells (CD4(+) and CD8(+)) and macrophages (CD11b(+) F4/80(+)) increased significantly, while the lack of PLRP2 reduced the number of T cells in the liver, but had no effect on macrophages. The shift of the metabolic profiles was impaired in Con A-treated PLRP2-knockout mice compared to WT mice. In conclusion, these results indicate that PLRP2 deficiency reduces T-cell mediated Con A-induced hepatitis, and suggest PLRP2 is a potential target of anti-inflammatory and immunomodulatory drugs to treat immune-mediated hepatitis.
ESTHER : Ge_2020_Int.Immunopharmacol_85_106604
PubMedSearch : Ge_2020_Int.Immunopharmacol_85_106604
PubMedID: 32428799
Gene_locus related to this paper: mouse-LIPR2

Title : Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis - Tu_2020_Nat.Commun_11_971
Author(s) : Tu L , Su P , Zhang Z , Gao L , Wang J , Hu T , Zhou J , Zhang Y , Zhao Y , Liu Y , Song Y , Tong Y , Lu Y , Yang J , Xu C , Jia M , Peters RJ , Huang L , Gao W
Ref : Nat Commun , 11 :971 , 2020
Abstract : Triptolide is a trace natural product of Tripterygium wilfordii. It has antitumor activities, particularly against pancreatic cancer cells. Identification of genes and elucidation of the biosynthetic pathway leading to triptolide are the prerequisite for heterologous bioproduction. Here, we report a reference-grade genome of T. wilfordii with a contig N50 of 4.36 Mb. We show that copy numbers of triptolide biosynthetic pathway genes are impacted by a recent whole-genome triplication event. We further integrate genomic, transcriptomic, and metabolomic data to map a gene-to-metabolite network. This leads to the identification of a cytochrome P450 (CYP728B70) that can catalyze oxidation of a methyl to the acid moiety of dehydroabietic acid in triptolide biosynthesis. We think the genomic resource and the candidate genes reported here set the foundation to fully reveal triptolide biosynthetic pathway and consequently the heterologous bioproduction.
ESTHER : Tu_2020_Nat.Commun_11_971
PubMedSearch : Tu_2020_Nat.Commun_11_971
PubMedID: 32080175
Gene_locus related to this paper: triwf-a0a7j7c8l4

Title : Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase - Zhang_2020_Front.Chem_8_730
Author(s) : Zhang Z , Fan F , Luo W , Zhao Y , Wang C
Ref : Front Chem , 8 :730 , 2020
Abstract : Butyrylcholinesterase (BChE) is a non-specific enzyme with clinical pharmacological and toxicological significance, which was a renewed interest as therapeutic target in Alzheimer's disease (AD) nowadays. Here, all-atom molecular dynamics simulations of butyrylcholinesterase with tacrine complex were designed to characterize inhibitor binding modes, strengths, and the hydrogen-bond dependent non-covalent release mechanism. Four possible release channels were identified, and the most favorable channel was determined by random acceleration molecular dynamics molecular dynamics (RAMD MD) simulations. The thermodynamic and dynamic properties as well as the corresponding Detour-forward delivery mechanism were determined according to the classical molecular dynamics (MD) simulations accompanied with umbrella sampling. The free energy barrier of the tacrine release process for the most beneficial pathway is about 10.95 kcal/mol, which is related to the non-covalent interactions from the surrounding residues, revealing the specific binding characteristics in the active site. The residues including Asp70, Ser79, Trp82, Gly116, Thr120, Tyr332, and His438 were identified to play major roles in the stabilization of tacrine in the pocket of BChE, where hydrogen bonding and Pi-Pi interactions are significant factors. Tyr332 and Asp70, which act as gate keepers, play crucial roles in the substrate delivery. The present results provide a basic understanding for the ligand transport mechanism depending on the BChE enzymatic environment, which is useful for the design of BChE inhibitors in the future.
ESTHER : Zhang_2020_Front.Chem_8_730
PubMedSearch : Zhang_2020_Front.Chem_8_730
PubMedID: 33195011

Title : Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I \/ II) - Ye_2020_Trials_21_520
Author(s) : Ye Q , Wang H , Xia X , Zhou C , Liu Z , Xia ZE , Zhang Z , Zhao Y , Yehenala J , Wang S , Zhou G , Hu K , Wu B , Wu CT , He Y
Ref : Trials , 21 :520 , 2020
Abstract : OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. INCLUSION CRITERIA: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: 1)Adults aged 18-65 years;2)Voluntarily participate in this clinical trial and sign the "informed consent form" or have consent from a legal representative.3)Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg).4)COVID-19 featured lung lesions in chest X-ray image. EXCLUSION CRITERIA: Patients will be excluded from the study if they meet any of the following criteria. 1.Patients have received other experimental treatment for COVID-19 within the last 30 days;2.Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit);3.Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m(2)) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis;4.Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses;5.Female patients who have no sexual protection in the last 30 days prior to the screening assessment;6.Pregnant or lactating women or women using estrogen contraception;7.Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period;8.Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: GradeDescriptionGrade 1:Discharged of patient;Grade 2:Hospitalized without oxygen supplement;Grade 3:Hospitalized, oxygen supplement is required, but NIV / HFNC is not required;Grade 4:Hospitalized in intensive care unit, and NIV / HFNC treatment is required;Grade 5:Hospitalized in intensive care unit, requiring ECMO and/or IMV;Grade 6:Death. ABBREVIATIONS: NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h +/- 30min, 24h +/- 30min after the injection) and follow-up period D90 +/- 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h +/- 30min, 24h +/- 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 +/- 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 +/- 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 beta, IL-2, TNF-a, ITN-gamma), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood beta-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 +/- 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h +/- 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient's randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16(th) April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
ESTHER : Ye_2020_Trials_21_520
PubMedSearch : Ye_2020_Trials_21_520
PubMedID: 32532356

Title : Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects - Han_2020_Eur.J.Med.Chem__113028
Author(s) : Han Y , Huang D , Xu S , Li L , Tian Y , Li S , Chen C , Li Y , Sun Y , Hou Y , Qin M , Gong P , Gao Z , Zhao Y
Ref : Eur Journal of Medicinal Chemistry , :113028 , 2020
Abstract : Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC(50) value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a "prodrug". In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.
ESTHER : Han_2020_Eur.J.Med.Chem__113028
PubMedSearch : Han_2020_Eur.J.Med.Chem__113028
PubMedID: 33248848

Title : 5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit - Mahy_2020_J.Med.Chem_63_12942
Author(s) : Mahy W , Willis NJ , Zhao Y , Woodward HL , Svensson F , Sipthorp J , Vecchia L , Ruza RR , Hillier J , Kjr S , Frew S , Monaghan A , Bictash M , Salinas PC , Whiting P , Vincent JP , Jones EY , Fish PV
Ref : Journal of Medicinal Chemistry , 63 :12942 , 2020
Abstract : Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.
ESTHER : Mahy_2020_J.Med.Chem_63_12942
PubMedSearch : Mahy_2020_J.Med.Chem_63_12942
PubMedID: 33124429
Gene_locus related to this paper: human-NOTUM

Title : The botanical origin and antioxidant, anti-BACE1 and antiproliferative properties of bee pollen from different regions of South Korea - Zou_2020_BMC.Complement.Med.Ther_20_236
Author(s) : Zou Y , Hu J , Huang W , Zhu L , Shao M , Dordoe C , Ahn YJ , Wang D , Zhao Y , Xiong Y , Wang X
Ref : BMC Complement Med Ther , 20 :236 , 2020
Abstract : BACKGROUND: Bee pollen (BP) has been used as a traditional medicine and food diet additive due to its nutritional and biological properties. The potential biological properties of bee pollen vary greatly with the botanical and geographical origin of the pollen grains. This study was conducted to characterize the botanical origin and assess the antioxidant effects of ethanol extracts of 18 different bee pollen (EBP) samples from 16 locations in South Korea and their inhibitory activities on human beta-amyloid precursor cleavage enzyme (BACE1), acetylcholinesterase (AChE), human intestinal bacteria, and 5 cancer cell lines. METHODS: The botanical origin and classification of each BP sample was evaluated using palynological analysis by observing microscope slides. We measured the biological properties, including antioxidant capacity, inhibitory activities against human BACE1, and AChE, and antiproliferative activities toward five cancer cell lines, of the 18 EBPs. In addition, the growth inhibitory activities on four harmful intestinal bacteria, six lactic acid-producing bacteria, two nonpathogenic bacteria, and an acidulating bacterium were also assessed. RESULTS: Four samples (BP3, BP4, BP13 and BP15) were found to be monofloral and presented four dominant pollen types: Quercus palustris, Actinidia arguta, Robinia pseudoacacia, and Amygdalus persica. One sample (BP12) was found to be bifloral, and the remaining samples were considered to be heterofloral. Sixteen samples showed potent antioxidant activities with EC(50) from 292.0 to 673.9 microg/mL. Fourteen samples presented potent inhibitory activity against human BACE1 with EC(50) from 236.0 to 881.1 microg/mL. All samples showed antiproliferative activity toward the cancer cell lines PC-3, MCF-7, A549, NCI-H727 and AGS with IC(50) from 2.7 to 14.4mG/Ml, 0.9 to 12.7mG/Ml, 5.0 to > 25mG/Ml, 2.7 to 17.7mG/Ml, and 2.4 to 8.7mG/Ml, respectively. In addition, total phenol and flavonoid contents had no direct correlation with antioxidant, anti-human BACE1, or antiproliferative activities. CONCLUSION: Fundamentally, Korean bee pollen-derived preparations could be considered a nutritional addition to food to prevent various diseases related to free radicals, neurodegenerative problems, and cancers. The botanical and geographical origins of pollen grains could help to establish quality control standards for bee pollen consumption and industrial production.
ESTHER : Zou_2020_BMC.Complement.Med.Ther_20_236
PubMedSearch : Zou_2020_BMC.Complement.Med.Ther_20_236
PubMedID: 32711521

Title : Caffeine inhibits Notum activity by binding at the catalytic pocket - Zhao_2020_Commun.Biol_3_555
Author(s) : Zhao Y , Ren J , Hillier J , Lu W , Jones EY
Ref : Commun Biol , 3 :555 , 2020
Abstract : Notum inhibits Wnt signalling via enzymatic delipidation of Wnt ligands. Restoration of Wnt signalling by small molecule inhibition of Notum may be of therapeutic benefit in a number of pathologies including Alzheimer's disease. Here we report Notum activity can be inhibited by caffeine (IC(50) 19 microM), but not by demethylated caffeine metabolites: paraxanthine, theobromine and theophylline. Cellular luciferase assays show Notum-suppressed Wnt3a function can be restored by caffeine with an EC(50) of 46 microM. The dissociation constant (K(d)) between Notum and caffeine is 85 microM as measured by surface plasmon resonance. High-resolution crystal structures of Notum complexes with caffeine and its minor metabolite theophylline show both compounds bind at the centre of the enzymatic pocket, overlapping the position of the natural substrate palmitoleic lipid, but using different binding modes. The structural information reported here may be of relevance for the design of more potent brain-accessible Notum inhibitors.
ESTHER : Zhao_2020_Commun.Biol_3_555
PubMedSearch : Zhao_2020_Commun.Biol_3_555
PubMedID: 33033363
Gene_locus related to this paper: human-NOTUM

Title : Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity - Mahy_2020_J.Med.Chem_63_9464
Author(s) : Mahy W , Patel M , Steadman D , Woodward HL , Atkinson BN , Svensson F , Willis NJ , Flint A , Papatheodorou D , Zhao Y , Vecchia L , Ruza RR , Hillier J , Frew S , Monaghan A , Costa A , Bictash M , Walter MW , Jones EY , Fish PV
Ref : Journal of Medicinal Chemistry , 63 :9464 , 2020
Abstract : The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
ESTHER : Mahy_2020_J.Med.Chem_63_9464
PubMedSearch : Mahy_2020_J.Med.Chem_63_9464
PubMedID: 32787107
Gene_locus related to this paper: human-NOTUM

Title : Imaging Sarcoplasmic Reticulum Ca(2+) Signaling in Intact Cardiac Myocytes -
Author(s) : Lu F , Zhao Y , Xie W , Guo Q , Wang SQ , Wang X , Cheng H
Ref : Circulation , 142 :1503 , 2020
PubMedID: 33044861

Title : Development and Molecular Investigation into the Effects of Carbamazepine Exposure in the Zebrafish (Danio rerio) - Chen_2020_Int.J.Environ.Res.Public.Health_17_
Author(s) : Chen H , Yang H , Zhao Y , Gu X , Martyniuk CJ
Ref : Int J Environ Research Public Health , 17 : , 2020
Abstract : Concerns regarding environmental exposures and the impacts of pharmaceuticals on non-target aquatic organisms continue to increase. The antiepileptic drug carbamazepine (CBZ) is often detected as an aquatic contaminant and can disrupt various behaviors of fishes. However, there are few reports which investigate the mechanism of CBZ action in fish. The aim of the current study was to evaluate the effects of CBZ on embryonic development (i.e., hatching rate, heart rate, and body length) and early spontaneous movement. Moreover, we sought to investigate potential mechanisms by focusing on the gamma-aminobutyric acid (GABA) neurotransmitter system in zebrafish 6 days after of exposure. The results show that CBZ exposure did not cause significant effects on embryo development (hatching rate, heart rate, nor body length) at the test concentrations. However, the early spontaneous movement of embryos was inhibited following 10 g/L CBZ exposure at 28-29 h post-fertilization (hpf). In addition, acetylcholinesterase (AChE) activity and GABA concentrations were increased with exposure, whereas glutamate (Glu) concentrations were decreased in larval zebrafish. Gene expression analysis revealed that GABA and glutamate metabolic pathways in zebrafish larvae were altered following exposure to CBZ. GABA transaminase (abat) and glutamic acid decarboxylase (gad1b) decreased to 100 microg/L, and glutamate receptor, ionotropic, N-methyl D-aspartate 1b (grin1b) as well as the glutamate receptor, ionotropic, alpha-amino-3hydroxy-5methylisoxazole-4propionic 2b (gria2b) were down-regulated with exposure to 1 microg/L CBZ. Our study suggests that CBZ, which can act as an agonist of the GABA(A) receptor in humans, can also induce alterations in the GABAergic system in fish. Overall, this study improves understanding of the neurotoxicity and behavioral toxicity of zebrafish exposed to CBZ and generates data to be used to understand mechanisms of action that may underlie antiepileptic drug exposures.
ESTHER : Chen_2020_Int.J.Environ.Res.Public.Health_17_
PubMedSearch : Chen_2020_Int.J.Environ.Res.Public.Health_17_
PubMedID: 33260372

Title : Karrikin Signaling Acts Parallel to and Additively with Strigolactone Signaling to Regulate Rice Mesocotyl Elongation in Darkness - Zheng_2020_Plant.Cell_32_2780
Author(s) : Zheng J , Hong K , Zeng L , Wang L , Kang S , Qu M , Dai J , Zou L , Zhu L , Tang Z , Meng X , Wang B , Hu J , Zeng D , Zhao Y , Cui P , Wang Q , Qian Q , Wang Y , Li J , Xiong G
Ref : Plant Cell , 32 :2780 , 2020
Abstract : Seedling emergence in monocots depends mainly on mesocotyl elongation, requiring coordination between developmental signals and environmental stimuli. Strigolactones (SLs) and karrikins are butenolide compounds that regulate various developmental processes; both are able to negatively regulate rice (Oryza sativa) mesocotyl elongation in the dark. Here, we report that a karrikin signaling complex, DWARF14-LIKE (D14L)-DWARF3 (D3)-O. sativa SUPPRESSOR OF MAX2 1 (OsSMAX1) mediates the regulation of rice mesocotyl elongation in the dark. We demonstrate that D14L recognizes the karrikin signal and recruits the SCF(D3) ubiquitin ligase for the ubiquitination and degradation of OsSMAX1, mirroring the SL-induced and D14- and D3-dependent ubiquitination and degradation of D53. Overexpression of OsSMAX1 promoted mesocotyl elongation in the dark, whereas knockout of OsSMAX1 suppressed the elongated-mesocotyl phenotypes of d14l and d3 OsSMAX1 localizes to the nucleus and interacts with TOPLESS-RELATED PROTEINs, regulating downstream gene expression. Moreover, we showed that the GR24 enantiomers GR24(5DS) and GR24 (ent-5DS) specifically inhibit mesocotyl elongation and regulate downstream gene expression in a D14- and D14L-dependent manner, respectively. Our work revealed that karrikin and SL signaling play parallel and additive roles in modulating downstream gene expression and negatively regulating mesocotyl elongation in the dark.
ESTHER : Zheng_2020_Plant.Cell_32_2780
PubMedSearch : Zheng_2020_Plant.Cell_32_2780
PubMedID: 32665307

Title : An update on T-2 toxin and its modified forms: metabolism, immunotoxicity mechanism, and human exposure assessment - Wu_2020_Arch.Toxicol_94_3645
Author(s) : Wu Q , Qin Z , Kuca K , You L , Zhao Y , Liu A , Musilek K , Chrienova Z , Nepovimova E , Oleksak P , Wu W , Wang X
Ref : Archives of Toxicology , 94 :3645 , 2020
Abstract : T-2 toxin is the most toxic trichothecene mycotoxin, and it exerts potent toxic effects, including immunotoxicity, neurotoxicity, and reproductive toxicity. Recently, several novel metabolites, including 3',4'-dihydroxy-T-2 toxin and 4',4'-dihydroxy-T-2 toxin, have been uncovered. The enzymes CYP3A4 and carboxylesterase contribute to T-2 toxin metabolism, with 3'-hydroxy-T-2 toxin and HT-2 toxin as the corresponding primary products. Modified forms of T-2 toxin, including T-2-3-glucoside, exert their immunotoxic effects by signaling through JAK/STAT but not MAPK. T-2-3-glucoside results from hydrolyzation of the corresponding parent mycotoxin and other metabolites by the intestinal microbiota, which leads to enhanced toxicity. Increasing evidence has shown that autophagy, hypoxia-inducible factors, and exosomes are involved in T-2 toxin-induced immunotoxicity. Autophagy promotes the immunosuppression induced by T-2 toxin, and a complex crosstalk between apoptosis and autophagy exists. Very recently, "immune evasion" activity was reported to be associated with this toxin; this activity is initiated inside cells and allows pathogens to escape the host immune response. Moreover, T-2 toxin has the potential to trigger hypoxia in cells, which is related to activation of hypoxia-inducible factor and the release of exosomes, leading to immunotoxicity. Based on the data from a series of human exposure studies, free T-2 toxin, HT-2 toxin, and HT-2-4-glucuronide should be considered human T-2 toxin biomarkers in the urine. The present review focuses on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 toxin and its modified forms. In particular, the immunotoxicity mechanisms of T-2 toxin and the toxicity mechanism of its modified form, as well as human T-2 toxin biomarkers, are discussed. This work will contribute to an improved understanding of the immunotoxicity mechanism of T-2 toxin and its modified forms.
ESTHER : Wu_2020_Arch.Toxicol_94_3645
PubMedSearch : Wu_2020_Arch.Toxicol_94_3645
PubMedID: 32910237

Title : Design, synthesis and biological evaluation of novel carboline-cinnamic acid hybrids as multifunctional agents for treatment of Alzheimer's disease - Liao_2020_Bioorg.Chem_99_103844
Author(s) : Liao Q , Li Q , Zhao Y , Jiang P , Yan Y , Sun H , Liu W , Feng F , Qu W
Ref : Bioorg Chem , 99 :103844 , 2020
Abstract : Alzheimer's disease (AD) is a complex neurodegenerative disease with multiple pathological features. Multifunctional compounds able to simultaneously interact with several pathological components have been considered as a solution to treat the complex pathologies of neurodegenerative diseases. beta-carboline and cinnamic acid have been extensively studied for their widespread biological effects in treatment of AD, further application is limited due to its poor solubility and high toxicity. Herein, a series of carboline-cinnamic acid hybrids was designed and synthesized to obtain new multifunctional molecules with low toxicity and good physicochemical properties. In particular, e3 and e12 exhibited significant inhibition of Abeta aggregation (inhibitory rate at 25 M: 65% and 72% respectively), moderate BuChE inhibition, excellent neuroprotective effects and low neurotoxicity. Furthermore, in the AD mice model, e3 and e12 could restore learning and memory function to a comparable level to that of the control and did not exhibit any acute toxicity in vivo at a relatively high dose of 600 mg/kg. Thus, these new compounds can be further studied as multifunctional molecules for AD.
ESTHER : Liao_2020_Bioorg.Chem_99_103844
PubMedSearch : Liao_2020_Bioorg.Chem_99_103844
PubMedID: 32325336

Title : Down-Regulation of Essential Synaptic Components by GI-Tract Microbiome-Derived Lipopolysaccharide (LPS) in LPS-Treated Human Neuronal-Glial (HNG) Cells in Primary Culture: Relevance to Alzheimer's Disease (AD) - Zhao_2019_Front.Cell.Neurosci_13_314
Author(s) : Zhao Y , Sharfman NM , Jaber VR , Lukiw WJ
Ref : Front Cell Neurosci , 13 :314 , 2019
Abstract : Trans-synaptic neurotransmission of both electrical and neurochemical information in the central nervous system (CNS) is achieved through a highly interactive network of neuron-specific synaptic proteins that include pre-synaptic and post-synaptic elements. These elements include a family of several well-characterized integral- and trans-membrane synaptic core proteins necessary for the efficient operation of this complex signaling network, and include the pre-synaptic proteins: (i) neurexin-1 (NRXN-1); (ii) the synaptosomal-associated phosphoprotein-25 (SNAP-25); (iii) the phosphoprotein synapsin-2 (SYN-2); and the post-synaptic elements: (iv) neuroligin (NLGN), a critical cell adhesion protein; and (v) the SH3-ankyrin repeat domain, proline-rich cytoskeletal scaffolding protein SHANK3. All five of these pre- and post-synaptic proteins have been found to be significantly down-regulated in primary human neuronal-glial (HNG) cell co-cultures after exposure to Bacteroides fragilis lipopolysaccharide (BF-LPS). Interestingly, LPS has also been reported to be abundant in Alzheimer's disease (AD) affected brain cells where there are significant deficits in this same family of synaptic components. This "Perspectives" paper will review current research progress and discuss the latest findings in this research area. Overall these experimental results provide evidence (i) that gastrointestinal (GI) tract-derived Gram-negative bacterial exudates such as BF-LPS express their neurotoxicity in the CNS in part through the directed down-regulation of neuron-specific neurofilaments and synaptic signaling proteins; and (ii) that this may explain the significant alterations in immune-responses and cognitive deficits observed after bacterial-derived LPS exposure to the human CNS.
ESTHER : Zhao_2019_Front.Cell.Neurosci_13_314
PubMedSearch : Zhao_2019_Front.Cell.Neurosci_13_314
PubMedID: 31354434

Title : Pharmacokinetics, excretion and metabolites analysis of DL0410, a dualacting cholinesterase inhibitor and histamine3 receptor antagonist - Pang_2019_Mol.Med.Rep_20_1103
Author(s) : Pang X , Zhao Y , Song J , Kang , Wu S , Wang L , Liu A , Du G
Ref : Mol Med Rep , 20 :1103 , 2019
Abstract : DL0410, a dualaction cholinesterase inhibitor and histamine3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method for the measurement of DL0410 in rat plasma, brain, bile, urine and feces samples, and identification of its primary metabolites. The pharmacokinetic properties of DL0410 were analyzed by liquid chromatographymass spectrometry at oral doses of 25, 50 and 100 mg/kg and intravenous dose of 5 mg/kg. The investigation of the excretion and metabolism of DL0410 was determined following liquidliquid extraction for biliary, urinary and fecal samples. Finally, the cytochrome (CY)P450 isoforms involved in the production of DL0410 metabolites with recombinant human cytochrome P450 enzymes were characterized. The results suggested that DL0410 was not well absorbed; however, was distributed to the entorhinal cortex and hippocampus of the brain. A total of two common metabolites of the reduction of DL0140 in the bile, urine and feces were identified and CYP2D6 was involved in this reaction. The pharmacokinetic results of DL0410 provided information for the illustration of its pharmacodynamic properties, mechanism of action and promoted its continued evaluation as a therapeutic agent for AD treatment.
ESTHER : Pang_2019_Mol.Med.Rep_20_1103
PubMedSearch : Pang_2019_Mol.Med.Rep_20_1103
PubMedID: 31173186

Title : Role of XIAP gene overexpressed bone marrow mesenchymal stem cells in the treatment of cerebral injury in rats with cerebral palsy - Deng_2019_Cancer.Cell.Int_19_273
Author(s) : Deng W , Fan C , Fang Y , Zhao Y , Wei Y , Li M , Teng J
Ref : Cancer Cell Int , 19 :273 , 2019
Abstract : Background: This study is performed to investigate the effects of adenovirus-mediated X-linked inhibitor of apoptosis protein (XIAP) overexpressed bone marrow mesenchymal stem cells (BMSCs) on brain injury in rats with cerebral palsy (CP). Methods: Rat's BMSCs were cultured and identified. The XIAP gene of BMSCs was modified by adenovirus expression vector Ad-XIAP-GFP. The rat model of CP with ischemia and anoxia was established by ligating the left common carotid artery and anoxia for 2 h, and BMSCs were intracerebroventricularly injected to the modeled rats. The mRNA and protein expression of XIAP in brain tissue of rats in each group was detected by RT-qPCR and western blot analysis. The neurobehavioral situation, content of acetylcholine (Ach), activity of acetylcholinesterase (AchE), brain pathological injury, apoptosis of brain nerve cells and the activation of astrocytes in CP rats were determined via a series of assays. Results: Rats with CP exhibited obvious abnormalities, increased Ach content, decreased AchE activity, obvious pathological damage, increased brain nerve cell apoptosis, as well as elevated activation of astrocyte. XIAP overexpressed BMSCs improved the neurobehavioral situation, decreased Ach content and increased AchE activity, attenuated brain pathological injury, inhibited apoptosis of brain nerve cells and the activation of astrocytes in CP rats. Conclusion: Our study demonstrates that XIAP overexpressed BMSCs can inhibit the apoptosis of brain nerve cells and the activation of astrocytes, increase AchE activity, and inhibit Ach content, so as to lower the CP caused by cerebral ischemia and hypoxia in rats.
ESTHER : Deng_2019_Cancer.Cell.Int_19_273
PubMedSearch : Deng_2019_Cancer.Cell.Int_19_273
PubMedID: 31660045

Title : ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield - Ou_2019_Nat.Commun_10_1078
Author(s) : Ou J , Peng Y , Yang W , Zhang Y , Hao J , Li F , Chen Y , Zhao Y , Xie X , Wu S , Zha L , Luo X , Xie G , Wang L , Sun W , Zhou Q , Li J , Liang H
Ref : Nat Commun , 10 :1078 , 2019
Abstract : The efficacy of Fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance. Autophagy has been implicated in chemoresistance, but the role of selective autophagic degradation in regulating chemoresistance remains unknown. In this study, we revealed a critical role of ABHD5 in charging CRC sensitivity to FU via regulating autophagic uracil yield. We demonstrated that ABHD5 localizes to lysosome and interacts with PDIA5 to prevent PDIA5 from interacting with RNASET2 and inactivating RNASET2. ABHD5 deficiency releases PDIA5 to directly interact with RNASET2 and leave RNASET2 in an inactivate state, which impairs RNASET2-mediated autophagic uracil yield and promotes CRC cells to uptake FU as an exogenous uracil, thus increasing their sensitivity to FU. Our findings for the first time reveal a novel role of ABHD5 in regulating lysosome function, highlighting the significance of ABHD5 as a compelling biomarker predicting the sensitivity of CRCs to FU-based chemotherapy.
ESTHER : Ou_2019_Nat.Commun_10_1078
PubMedSearch : Ou_2019_Nat.Commun_10_1078
PubMedID: 30842415
Gene_locus related to this paper: human-ABHD5

Title : Improvement of the alkali stability of Penicillium cyclopium lipase by error-prone PCR, - Huang_2018_Electron.J.Biotechnol_39_91
Author(s) : Huang L , Zheng D , Zhao Y , Ma J , Li Y , Xu Z , Shan M , Shao S , Guo Q , Zhang J , Fuping Lu F , Yihan Liu Y
Ref : Electronic Journal of Biotechnology , 39 :91 , 2019
Abstract : Background Lipases are extensively exploited in lots of industrial fields; cold-adapted lipases with alkali-resistance are especially desired in detergent industry. Penicillium cyclopium lipase I (PCL) might be suitable for applications of detergent industry due to its high catalytic efficiency at low temperature and relatively good alkali stability. In this study, to better meet the requirements, the alkali stability of PCL was further improved via directed evolution with error-prone PCR. Results The mutant PCL (N157F) with an improved alkali stability was selected based on a high-throughput activity assay. After incubating at pH11.0 for 120min, N157F retained 70% of its initial activity, which was 23% higher than that of wild type PCL. Combined with the three-dimensional structure analysis, N157F exhibited an improved alkali stability under the high pH condition due to the interactions of hydrophilicity and -strand propensity. Conclusions This work provided the theoretical foundation and preliminary data for improving alkali stability of PCL to meet the industrial requirements, which is also beneficial to improving alkali-tolerance ability of other industrial enzymes via molecular modification. How to cite: Huang L, Zheng D, Zhao Y, et al. Improvement of the alkali stability of Penicillium cyclopium lipase by error-prone PCR.
ESTHER : Huang_2018_Electron.J.Biotechnol_39_91
PubMedSearch : Huang_2018_Electron.J.Biotechnol_39_91
Gene_locus related to this paper: penex-Q9HFW6

Title : Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen - Atkinson_2019_Medchemcomm_10_1361
Author(s) : Atkinson BN , Steadman D , Zhao YG , Sipthorp J , Vecchia L , Ruza RR , Jeganathan F , Lines G , Frew S , Monaghan A , Kjaer S , Bictash M , Jones Y , Fish PV , Zhao Y , Jones EY
Ref : Medchemcomm , 10 :1361 , 2019
Abstract : NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 muM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0.032 muM) and isoquinoline 45 (IC50 0.085 muM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to 3. However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.
ESTHER : Atkinson_2019_Medchemcomm_10_1361
PubMedSearch : Atkinson_2019_Medchemcomm_10_1361
PubMedID: 31534655
Gene_locus related to this paper: human-NOTUM

Title : Seawater acidification increases copper toxicity: A multi-biomarker approach with a key marine invertebrate, the Pacific Oyster Crassostrea gigas - Cao_2019_Aquat.Toxicol_210_167
Author(s) : Cao R , Zhang T , Li X , Zhao Y , Wang Q , Yang D , Qu Y , Liu H , Dong Z , Zhao J
Ref : Aquat Toxicol , 210 :167 , 2019
Abstract : Ocean acidification (OA) has been found to increase the release of free Cu(2+) in seawater. However, only a handful of studies have investigated the influence of OA on Cu accumulation and cellular toxicity in bivalve species. In this study, Pacific oysters, Crassostrea gigas, were exposed to 25 mug/L Cu(2+) at three pH levels (8.1, 7.8 and 7.6) for 14 and 28 days. Physiological and histopathological parameters [(clearance rate (CR), respiration rate (RR), histopathological damage and condition index (CI)), oxidative stress and neurotoxicity biomarkers [superoxide dismutase (SOD) and glutathione transferase (GST) activities, lipid peroxidation (LPO) and acetylcholinesterase (AChE) activity], combined with glycolytic enzyme activities [pyruvate kinase (PK) and hexokinase (HK)] were investigated in C. gigas. The bioconcentration of Cu was increased in soft tissues of Cu-exposed oysters under OA. Our results suggest that both OA and Cu could lead to physiological disturbance, oxidative stress, cellular damage, disturbance in energy metabolism and neurotoxicity in oysters. The inhibited CR, increased glycolytic enzymes activities and decreased CI suggested that the energy metabolism strategy adopted by oysters was not sustainable in the long term. Furthermore, integrated biomarker response (IBR) results found that OA and Cu exposure lead to severe stress to oysters, and co-exposure was the most stressful condition. Results from this study highlight the need to include OA in future environmental assessments of pollutants and hazardous materials to better elucidate the risks of those environmental perturbations.
ESTHER : Cao_2019_Aquat.Toxicol_210_167
PubMedSearch : Cao_2019_Aquat.Toxicol_210_167
PubMedID: 30870663

Title : Kinetic model of the enzymatic Michael addition for synthesis of mitomycin analogs catalyzed by immobilized lipase from T. laibacchii - Zhang_2019_Mol.Catal_466_146
Author(s) : Zhang Y , Zhao Y , Gao X , Jiang W , Li Z , Yao Q , Yang F , Wang F , Liu J
Ref : Molecular Catalysis , 466 :146 , 2019
Abstract : The present study investigates the kinetic model of the enzymatic Michael addition of butylamine to 2-methyl-1,4-benzoquinone to form 2-methyl-3-n-butylaminoyl-1-hydro-4-quinone in citrate buffer solution (pH 7.0). The yield of the product of 98% was achieved, mainly due to the excellent regioselectivity of immobilized lipase from T. laibacchii. The immobilized preparation used here was obtained by a method of purification and in situ immobilization. Through the purification using a PEG 4000/ K2HPO4 aqueous two-phase system (ATPS), the T. laibacchii lipase was partitioned predominantly in the PEG-rich top phase where diatomite was added to achieve in situ immobilization via interfacial activation on the hydrophobic support. A proposed reaction mechanism of the Michael addition involves (1) the oxyanion hole polarizes the alpha,beta-unsaturated carbonyl of 2-methyl-1,4 -benzoquinone, increasing its electrophilic ability, (2) the catalytic histidine deprotonates the nucleophile n-butyl amine. A modified sequential mechanism including ordered and random sequential bi-bi was proposed for the first, and it is beneficial to add these modification mechanisms to the family of enzyme complex reaction mechanism because the mechanism is partly expanded. The kinetic parameters were directly obtained by combining the numerical integration toolbox ode45 to solve differential equations and the nonlinear optimization toolbox fmincon for error minimizing objective function. A very satisfactory agreement between experimental data and model results was obtained based on the modified random bi-bi mechanism, implying that the enzymatic Michael addition may follow the modified random bi-bi mechanism. The mass transfer limitations were investigated, and it is found that both internal and external mass transfer limitations could be ignored.
ESTHER : Zhang_2019_Mol.Catal_466_146
PubMedSearch : Zhang_2019_Mol.Catal_466_146

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 : Transformation pathway and toxicity assessment of malathion in aqueous solution during UV photolysis and photocatalysis - Li_2019_Chemosphere_234_204
Author(s) : Li W , Zhao Y , Yan X , Duan J , Saint CP , Beecham S
Ref : Chemosphere , 234 :204 , 2019
Abstract : In drinking water treatment, complete mineralization of organophosphorus pesticides (OPPs) by UV-based advanced oxidation processes (UV AOPs) is rarely achieved. The formation of intermediate oxidation byproducts would likely have some profound effects on toxicity of the reaction solutions. This study investigated the intermediate oxidation byproducts, transformation pathway and toxicity of malathion solutions during the treatment processes of UV alone, UV/H2O2, UV/TiO2 and UV/Fenton. The main intermediate oxidation byproducts were derived using ultra-performance liquid chromatography - electrospray - time-of-flight mass spectrometry. Thereby the transformation pathway for each of these treatment processes was proposed. The results indicate that in UV photolysis, the transformation pathway of malathion proceeded initially via cleavage of the phosphorus-sulfur bonds while in photocatalysis, the desulfurization from a PS bond to a PO bond was the primary degradation pathway. Interestingly, only in the UV/TiO2 process a small fraction of malathion was found decomposed via a demethylation reaction. At the same time, a toxicity assessment of the treated solutions was conducted by both luminescence inhibition of Vibrio fischeri and inhibition of acetylcholinesterase (AChE). It was found that after UV AOP treatment, the toxicity of the malathion aqueous solution increased sharply. In contrast, no increase in toxicity was observed for the malathion aqueous solution after UV alone treatment. This study demonstrates that the high removal efficiency achieved by OPPs does not imply that detoxification of the water solution has been achieved. On the contrary, the toxicity of the treated solutions by OPPs may be increased significantly depending on the selected treatment processes.
ESTHER : Li_2019_Chemosphere_234_204
PubMedSearch : Li_2019_Chemosphere_234_204
PubMedID: 31220654

Title : Graphene oxide disrupts the protein-protein interaction between Neuroligin\/NLG-1 and DLG-1 or MAGI-1 in nematode Caenorhabditis elegans - Zhao_2019_Sci.Total.Environ_700_134492
Author(s) : Zhao Y , Chen H , Yang Y , Wu Q , Wang D
Ref : Sci Total Environ , 700 :134492 , 2019
Abstract : Graphene oxide (GO) is a carbon-based engineered nanomaterial (ENM). Using Caenorhabditis elegans as an animal model, we investigated the effect of GO exposure on protein-protein interactions. In nematodes, NLG-1/Neuroligin, a postsynaptic protein, acted only in the neurons to regulate the GO toxicity. In the neurons, DLG-1, a PSD-95 protein, and MAGI-1, a S-SCAM protein, were identified as the downstream targets of NLG-1 in the regulation of GO toxicity. PKC-1, a serine/threonine protein kinase C, further acted downstream of neuronal DLG-1 and MAGI-1 to regulate the GO toxicity. Co-immunoprecipitation analysis demonstrated the protein-protein interaction between NLG-1 and DLG-1 or MAGI-1. After GO expression, this protein-protein interaction between NLG-1 and DLG-1 or MAGI-1 was significantly inhibited. Therefore, our data raised the evidence to suggest the potential of GO exposure in disrupting protein-protein interactions in organisms.
ESTHER : Zhao_2019_Sci.Total.Environ_700_134492
PubMedSearch : Zhao_2019_Sci.Total.Environ_700_134492
PubMedID: 31627046
Gene_locus related to this paper: caeel-NLGN1 , human-NLGN1

Title : Structural Insights into the Substrate Specificity of Acyltransferases from Salinomycin Polyketide Synthase - Zhang_2019_Biochemistry_58_2978
Author(s) : Zhang F , Shi T , Ji H , Ali I , Huang S , Deng Z , Min Q , Bai L , Zhao Y , Zheng J
Ref : Biochemistry , 58 :2978 , 2019
Abstract : Salinomycin with antibacterial and anticoccidial activities is a commercial polyether polyketide widely used in animal husbandry as a food additive. Malonyl-CoA (MCoA), methylmalonyl-CoA (MMCoA), and ethylmalonyl-CoA (EMCoA) are used as extension units in its biosynthesis. To understand how the salinomycin modular polyketide synthase (PKS) strictly discriminates among these extension units, the acyltransferase (AT) domains selecting MCoA, MMCoA, and EMCoA were structurally characterized. Molecular dynamics simulations of the AT structures helped to reveal the key interactions involved in enzyme-substrate recognitions, which enabled the engineering of AT mutants with switched specificity. The catalytic efficiencies ( kcat/ Km) of these AT mutants are comparable with those of the wild-type AT domains. These results set the stage for engineering the AT substrate specificity of modular PKSs.
ESTHER : Zhang_2019_Biochemistry_58_2978
PubMedSearch : Zhang_2019_Biochemistry_58_2978
PubMedID: 31199122

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 : Lipase-catalyzed synthesis of ethyl (R)-2-benzyloxy-2-isopropylhydrogenmalonate: a useful combination of chemical synthesis with enzymatic methods - Ding_2019_Biosci.Biotechnol.Biochem__1
Author(s) : Ding J , Yang Z , Zhao Y , Fang W , Lu Q
Ref : Biosci Biotechnol Biochem , :1 , 2019
Abstract : Ethyl (R)-2-benzyloxy-2-isopropylhydrogenmalonate is a key intermediate for the synthesis of the side chain in ergopeptines. In this work, we adopted a method to prepare enantiomerically pure title monoester via immobilized Candida antarctica lipase B (Novozym 435)-catalyzed hydrolysis of the corresponding diester.
ESTHER : Ding_2019_Biosci.Biotechnol.Biochem__1
PubMedSearch : Ding_2019_Biosci.Biotechnol.Biochem__1
PubMedID: 30654732

Title : Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum - Zhao_2019_J.Pineal.Res__e12630
Author(s) : Zhao Y , Ren J , Hillier J , Jones M , Lu W , Jones EY
Ref : J Pineal Res , :e12630 , 2019
Abstract : The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/beta-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin, came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high resolution structures (<= 1.5 A) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid; and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 microM), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which up-regulation of Wnt signalling may be beneficial.
ESTHER : Zhao_2019_J.Pineal.Res__e12630
PubMedSearch : Zhao_2019_J.Pineal.Res__e12630
PubMedID: 31876313
Gene_locus related to this paper: human-NOTUM

Title : MicroRNA-98 reduces amyloid beta-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice - Chen_2019_Int.J.Mol.Med_43_91
Author(s) : Chen FZ , Zhao Y , Chen HZ
Ref : Int J Mol Med , 43 :91 , 2019
Abstract : Alzheimer's disease (AD) is a chronic neurodegenerative disease that often occurs at a slow pace yet deteriorates with time. MicroRNAs (miRs) have been demonstrated to offer novel therapeutic hope for disease treatment. The aim of the present study was to investigate the effect of miR98 on amyloid beta (Abeta)protein production, oxidative stress and mitochondrial dysfunction through the Notch signaling pathway by targeting hairy and enhancer of split (Hes)related with YRPW motif protein 2 (HEY2) in mice with AD. A total of 70 Kunming mice were obtained and subjected to behavioral assessment. The levels of oxidative stressrelated proteins glutathione peroxidase, reduced glutathione, superoxide dismutase, malondialdehyde, acetylcholinesterase and Na+K+ATP were measured. Morphological changes in brain tissue, HEY2positivity levels, neuronal apoptotic index (AI) and neuron mitochondrial DNA (mtDNA) levels were also determined. Subsequently, the levels of miR98 and the mRNA and protein levels of HEY2, Jagged1, Notch1, Hes1, Hes5, betaamyloid precursor protein, Bcell lymphoma 2 (Bcl2) and Bcl2associated X protein in tissues and hippocampal neurons were determined by reverse transcriptionquantitative polymerase chain reaction and western blot analyses, respectively. Finally, hippocampal neuron viability and apoptosis were determined using an MTT assay and flow cytometry, respectively. The levels of miR98targeted HEY2 and miR98 were low and the levels of HEY2 were high in the AD mice. The AD mice exhibited poorer learning and memory abilities, oxidative stress function, and morphological changes of pyramidal cells in the hippocampal CA1 region. Furthermore, the AD mice exhibited increased protein levels of HEY2 and AI in the CA1 region of brain tissues with reduced mtDNA levels and dysfunctional neuronal mitochondria. miR98 suppressed hippocampal neuron apoptosis and promoted hippocampal neuron viability by inactivating the Notch signaling pathway via the inhibition of HEY2. In conclusion, the results demonstrated that miR98 reduced the production of Abeta and improved oxidative stress and mitochondrial dysfunction through activation of the Notch signaling pathway by binding to HEY2 in AD mice.
ESTHER : Chen_2019_Int.J.Mol.Med_43_91
PubMedSearch : Chen_2019_Int.J.Mol.Med_43_91
PubMedID: 30365070

Title : Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors - Atkinson_2019_Bioorg.Med.Chem.Lett__126751
Author(s) : Atkinson BN , Steadman D , Mahy W , Zhao Y , Sipthorp J , Bayle ED , Svensson F , Papageorgiou G , Jeganathan F , Frew S , Monaghan A , Bictash M , Jones EY , Fish PV
Ref : Bioorganic & Medicinal Chemistry Lett , :126751 , 2019
Abstract : The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.
ESTHER : Atkinson_2019_Bioorg.Med.Chem.Lett__126751
PubMedSearch : Atkinson_2019_Bioorg.Med.Chem.Lett__126751
PubMedID: 31862412
Gene_locus related to this paper: human-NOTUM

Title : The Structures and Bioactivities of Fatty Acid Synthase Inhibitors - Jiang_2019_Curr.Med.Chem_26_7081
Author(s) : Jiang H , Gan T , Zhang J , Ma Q , Liang Y , Zhao Y
Ref : Curr Med Chem , 26 :7081 , 2019
Abstract : BACKGROUND: Fatty Acid Synthase (FAS or FASN) is a vital enzyme which catalyzes the de novo synthesis of long chain fatty acids. A number of studies have recently been reported that FAS was combined targets for the discovery of anti-obesity and anti-cancer drugs. Great interest has been developed in finding novel FAS inhibitors, and result in more than 200 inhibitors being reported. METHODS: The reported research literature about the FAS inhibitors was collected and analyzedsised through major databases including Web of Science, and PubMed. Then the chemical stractures, FAS inhibitory activities, and Structure-Activity Relationships (SAR) were summarized focused on all these reported FAS inhibitors. RESULTS: The 248 FAS inhibitors, which were reported during the past 20 years, could be divided into thiolactone, butyrolactone and butyrolactam, polyphenols, alkaloids, terpenoids, and other structures, in view of their structure characteristics. And the SAR of high inhibitory structures of each type was proposed in this paper. CONCLUSION: A series of synthetic quinolinone derivatives show strongest inhibitory activity in the reported FAS inhibitors. Natural polyphenols, existing in food and herbs, show more adaptive in medicine exploration because of their safety and efficiency. Moreover, screening the FAS inhibitors from microorganism and marine natural products could be the hot research directions in the future.
ESTHER : Jiang_2019_Curr.Med.Chem_26_7081
PubMedSearch : Jiang_2019_Curr.Med.Chem_26_7081
PubMedID: 31538883

Title : LncRNA ABHD11-AS1 promotes the development of endometrial carcinoma by targeting cyclin D1 - Liu_2018_J.Cell.Mol.Med_22_3955
Author(s) : Liu Y , Wang LL , Chen S , Zong ZH , Guan X , Zhao Y
Ref : J Cell Mol Med , 22 :3955 , 2018
Abstract : To investigate the expression, role and mechanism of action of long non-coding RNA (lncRNA) ABHD11-AS1 in endometrial carcinoma. The expression of lncRNA ABHD11-AS1 was quantified by qRT-PCR in human endometrial carcinoma (n = 89) and normal endometrial tissues (n = 27). LncRNA ABHD11-AS1 was stably overexpressed or knocked-down in endometrial carcinoma cell lines to examine the cellular phenotype and expression of related molecules. Compared to normal endometrial tissue, lncRNA ABHD11-AS1 was significantly overexpressed in endometrial carcinoma. Overexpression of lncRNA ABHD11-AS1 promoted the proliferation, G1-S progression, invasion and migration of endometrial cancer cells; inhibited apoptosis; up-regulated cyclin D1, CDK1, CDK2, CDK4, Bcl-xl and VEGFA; and down-regulated p16, while ABHD11-AS1 down-regulation has the opposite effect. RNA pull down demonstrated that lncRNA ABHD11-AS1 binds directly to cyclin D1. Knockdown of cyclin D1 can reverse the effect of ABHD11-AS1. Overexpression of lncRNA ABHD11-AS1 increased the tumorigenicity and up-regulated cyclin D1 in an in vivo model of endometrial cancer in nude mice. LncRNA ABHD11-AS1 functions as an oncogene to promote cell proliferation and invasion in endometrial carcinoma by positively targeting cyclin D1.
ESTHER : Liu_2018_J.Cell.Mol.Med_22_3955
PubMedSearch : Liu_2018_J.Cell.Mol.Med_22_3955
PubMedID: 29799152
Gene_locus related to this paper: human-ABHD11

Title : Sublethal effects of chlorfenapyr on the life table parameters, nutritional physiology and enzymatic properties of Bradysia odoriphaga (Diptera: Sciaridae) - Zhao_2018_Pestic.Biochem.Physiol_148_93
Author(s) : Zhao Y , Wang Q , Ding J , Wang Y , Zhang Z , Liu F , Mu W
Ref : Pestic Biochem Physiol , 148 :93 , 2018
Abstract : Bradysia odoriphaga (Diptera: Sciaridae) is the major pest affecting Chinese chive production. Chlorfenapyr is a halogenated pyrrole-based pro-insecticide that is currently used to control insects and mites on a variety of crops. In the present study, fourth-instar larvae of B. odoriphaga were exposed to chlorfenapyr at LC1, LC20 and LC50 concentrations. The developmental duration of the treated larvae was not significantly different, but fecundity was significantly increased in the LC1 and LC20 treatment groups compared with the control group. The population parameters of the LC1 treatment group were increased significantly, whereas those of the LC50 treatment group were reduced significantly compared with the control. The food consumption by larvae and pupal weight were significantly increased under the LC1 treatment and decreased under the LC50 treatment compared with the control. Moreover, chlorfenapyr decreased the lipid, carbohydrate and trehalose contents significantly, whereas the total protein content was increased compared with the control. Additionally, the activities of protease, lipase and trehalase were significantly decreased. Chlorfenapyr treatment for 24h also induced the activities of glutathione S-transferase (GST), carboxylesterase (CarE) and O-demethylation. The results of this study suggest that low lethal concentrations of chlorfenapyr can affect oviposition, population development, the activities of digestion and detoxification enzymes, and nutrient accumulation in B. odoriphaga. This study provides valuable information for the assessment and rational application of chlorfenapyr for effective control of this pest.
ESTHER : Zhao_2018_Pestic.Biochem.Physiol_148_93
PubMedSearch : Zhao_2018_Pestic.Biochem.Physiol_148_93
PubMedID: 29891384

Title : Precision Electrophile Tagging in Caenorhabditis elegans - Long_2018_Biochemistry_57_216
Author(s) : Long MJC , Urul DA , Chawla S , Lin HY , Zhao Y , Haegele JA , Wang Y , Aye Y
Ref : Biochemistry , 57 :216 , 2018
Abstract : Adduction of an electrophile to privileged sensor proteins and the resulting phenotypically dominant responses are increasingly appreciated as being essential for metazoan health. Functional similarities between the biological electrophiles and electrophilic pharmacophores commonly found in covalent drugs further fortify the translational relevance of these small-molecule signals. Genetically encodable or small-molecule-based fluorescent reporters and redox proteomics have revolutionized the observation and profiling of cellular redox states and electrophile-sensor proteins, respectively. However, precision mapping between specific redox-modified targets and specific responses has only recently begun to be addressed, and systems tractable to both genetic manipulation and on-target redox signaling in vivo remain largely limited. Here we engineer transgenic Caenorhabditis elegans expressing functional HaloTagged fusion proteins and use this system to develop a generalizable light-controlled approach to tagging a prototypical electrophile-sensor protein with native electrophiles in vivo. The method circumvents issues associated with low uptake/distribution and toxicity/promiscuity. Given the validated success of C. elegans in aging studies, this optimized platform offers a new lens with which to scrutinize how on-target electrophile signaling influences redox-dependent life span regulation.
ESTHER : Long_2018_Biochemistry_57_216
PubMedSearch : Long_2018_Biochemistry_57_216
PubMedID: 28857552

Title : Development and validation of a novel score for fibrosis staging in patients with chronic hepatitis B - Wu_2018_Liver.Int_38_1930
Author(s) : Wu D , Rao Q , Chen W , Ji F , Xie Z , Huang K , Chen E , Zhao Y , Ouyang X , Zhang S , Jiang Z , Zhang L , Xu L , Gao H , Li L
Ref : Liver Int , 38 :1930 , 2018
Abstract : BACKGROUND & AIMS: Non-invasive assessment methods for liver fibrosis are urgently needed. The present study aimed to develop a novel diagnostic model for fibrosis staging in patients with chronic hepatitis B. METHODS: A cross-sectional set of 417 chronic hepatitis B patients who underwent liver biopsy was enrolled and the METAVIR score was adopted as the reference of fibrosis staging. RESULTS: Among thyroid hormones, only the level of free tetraiodothyronine (FT4) decreased gradually with the METAVIR fibrosis score (P < .001). FibroStage, a novel diagnosis model that incorporates data on FT4, platelets, cholinesterase, gamma-glutamyl transpeptidase, and age, was developed using the deriving set (n = 219). For the diagnosis of significant fibrosis, the FibroStage model had a significantly higher area under the receiver operating curve than did the FibroIndex, Forn, and Lok models (all of P < .01) and tended to better than the fibrosis-4 (P = .0791) but comparable with the aspartate transaminase-to-platelet ratio index model (P = .1694). For the diagnosis of advanced fibrosis, FibroStage had a higher area under the receiver operating curve than did the aspartate transaminase-to-platelet ratio index, FibroIndex, Forn, and Lok models (all of P < .05) and had a comparable area under the receiver operating curve with the fibrosis-4 model (P = .2109). For the diagnosis of cirrhosis, the area under the receiver operating curve of FibroStage was higher than those of the aspartate transaminase-to-platelet ratio index, fibrosis-4, FibroIndex, and Lok (all of P < .05) models and was comparable with Forn (P = .1649). These results was validated by a validation set (n = 198). CONCLUSION: FT4 may be an indicator for fibrosis staging in chronic hepatitis B patients. FibroStage is a better model than aspartate transaminase-to-platelet ratio index, fibrosis-4, FibroIndex, Forn, and Lok for the comprehensively diagnosis of significant and advanced fibrosis and cirrhosis.
ESTHER : Wu_2018_Liver.Int_38_1930
PubMedSearch : Wu_2018_Liver.Int_38_1930
PubMedID: 29654711

Title : Novel Method of Preparation and Activity Research on Arctigenin from Fructus Arctii - Cai_2018_Pharmacogn.Mag_14_87
Author(s) : Cai E , Han J , Yang L , Zhang W , Zhao Y , Chen Q , Guo M , He X
Ref : Pharmacogn Mag , 14 :87 , 2018
Abstract : Background: Arctigenin has many pharmacological activities with clinical significance and is derived from Arctium lappa L. However, the present extraction method is inefficient and does not have meaningful industrial production. Objective: A new method to directly prepare arctigenin was established by combining enzyme-assisted extraction and central composite design. Arctigenin's further pharmacological activity was also surveyed in vitro. Materials and Methods: beta-D-Glucosidase, a food-grade enzyme, was added directly to the fruits of A. lappa L. to hydrolyze the arctiin to arctigenin, and the obtained samples were subsequently subjected to ethanol (30%, v/v) extraction. The pharmacological activity of the extraction and arctigenin was determined by inhibiting acetylcholinesterase (AChE) and scavenging nitrite. Results: The factors investigated include the enzyme concentration (0.5%-2.5%), ultrasound time (10 min(-3) 0 min), and extraction temperature (30 degrees C-50 degrees C). From the analysis of the results by Design-Expert (V8.0.6), the optimal extraction conditions were obtained: enzyme concentration (1.4%), ultrasound time (25 min), and extraction temperature (45 degrees C). The highest yield of arctigenin, obtained under the optimal conditions was 6.39%, representing an increase of 28.15% compared to the reference extraction without enzyme processing. The IC50 values of the extraction and arctigenin, respectively, for inhibiting AChE were 0.572 mg/ml and 0.462 mg/ml, and those for nitrite-scavenging were 34.571 mg/ml and 17.49 mg/ml. Conclusions: The results demonstrate that using an enzyme directly in the production is an effective means for extracting arctigenin from Fructus arctii. The extraction has the activities of inhibiting AChE and scavenging nitrite, probably because there has arctigenin in it. It is implied that the extraction and arctigenin could contribute to human health in clinical applications. SUMMARY: The new method of adding enzyme directly to the preparation of arctigenin was carried out instead of preparing arctigenin by two-step methodThree factors affecting the efficiency of preparation were analyzed and discussed include the enzyme concentration, ultrasound time, and extraction temperature by central composite designThis new method of preparing arctigenin improved the yield significantly than other methodsArctigenin has remarkable pharmacological activities of inhibiting acetylcholinesterase and scavenging nitrite. Abbreviations used: AChE: Acetylcholinesterase, CCD: Central composite design, TCM: Traditional Chinese medicines, AD.
ESTHER : Cai_2018_Pharmacogn.Mag_14_87
PubMedSearch : Cai_2018_Pharmacogn.Mag_14_87
PubMedID: 29576707

Title : Accumulation of polystyrene microplastics in juvenile Eriocheir sinensis and oxidative stress effects in the liver - Yu_2018_Aquat.Toxicol_200_28
Author(s) : Yu P , Liu Z , Wu D , Chen M , Lv W , Zhao Y
Ref : Aquat Toxicol , 200 :28 , 2018
Abstract : As a widespread and ubiquitous pollutant of marine ecosystems, microplastic has the potential to become an emerging global threat for aquatic organisms. The present study aims to elucidate the effects of microplastics on the growth, accumulation and oxidative stress response in the liver of Eriocheir sinensis. Fluorescent microplastic particles (diameter=0.5mum) accumulated in the gill, liver and gut tissues of E. sinensis were investigated when crabs were exposed to a concentration of 40000mug/L for 7days. A 21day toxicity test suggested that the rate of weight gain, specific growth rate, and hepatosomatic index of E. sinensis decreased with increasing microplastic concentration (0mug/L, 40mug/L, 400mug/L, 4000mug/L and 40000mug/L). The activities of AChE and GPT in crabs exposed to microplastics were lower than those in control group. GOT activity increased significantly after exposure to a low concentration of microplastics and then decreased continuously with increasing microplastic concentrations. The activities of superoxide dismutase (SOD), aspartate transaminase (GOT), glutathione (GSH), and glutathione peroxidase (GPx) increased in specimens exposed to low concentrations of microplastics (40 and 400mug/L) compared to the control and decreased in organisms exposed to high concentrations (4000 and 40000mug/L). In contrast, the activities of acetylcholinesterase, catalase (CAT), and alanine aminotransferase were significantly lower in the organisms exposed to microplastics compared to control animals. Upon exposure to increasing microplastic concentrations, the expression of genes encoding the antioxidants SOD, CAT, GPx and glutathione S-transferase in the liver decreased after first increasing. Exposure to microplastics increased the expression of the gene encoding p38 in the MAPK signaling pathway and significantly decreased the expressions of genes encoding ERK, AKT, and MEK. The results of this study demonstrate that microplastics can accumulate in the tissues of E. sinensis and negatively affect growth. In addition, exposure to microplastics causes damage and induces oxidative stress in the hepatopancreas of E. sinensis. The findings provide basic biological data for environmental and human risk assessments of microplastics of high concern.
ESTHER : Yu_2018_Aquat.Toxicol_200_28
PubMedSearch : Yu_2018_Aquat.Toxicol_200_28
PubMedID: 29709883

Title : Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits - Zhang_2018_Cardiovasc.Diabetol_17_160
Author(s) : Zhang X , Zhang Z , Yang Y , Suo Y , Liu R , Qiu J , Zhao Y , Jiang N , Liu C , Tse G , Li G , Liu T
Ref : Cardiovasc Diabetol , 17 :160 , 2018
Abstract : BACKGROUND: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. METHODS: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-beta1, NF-kappaB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. RESULTS: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1alpha/NRF1/Tfam signaling pathway. CONCLUSIONS: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.
ESTHER : Zhang_2018_Cardiovasc.Diabetol_17_160
PubMedSearch : Zhang_2018_Cardiovasc.Diabetol_17_160
PubMedID: 30591063

Title : Use of low-dose neostigmine intravenously in the treatment of thyroid storm-induced severe tachycardia in patient during huge pelvic mass resection: A case report and review of literature - Zhang_2018_Medicine.(Baltimore)_97_e0300
Author(s) : Zhang X , Jiang H , Li S , Luo A , Zhao Y
Ref : Medicine (Baltimore) , 97 :e0300 , 2018
Abstract : RATIONALE: Thyroid storm is a rare and life-threatening metabolic crisis because of an emergent release of excess thyroid hormone. Sinus tachycardia induced by excess thyroid hormone may result in congestive heart failure due to decreased diastolic filling time. PATIENT CONCERNS: A controlled hyperthyroidism patient with severe sinus tachycardia. DIAGNOSES: A controlled hyperthyroidism patient was induced thyroid storm during huge pelvic mass resection. INTERVENTIONS: Application of low-dose neostigmine and beta-antagonist esmolol to control the heart rate (HR) avoided hemodynamic collapse. OUTCOMES: The patient improved dramatically following application of low-dose neostigmine instead of esmolol to control the HR avoided hemodynamic collapse. LESSONS: Our case suggests that neostigmine, an acetylcholinesterase inhibitor, may warrant further investigation in patients with thyroid storm-induced severe sinus tachycardia.
ESTHER : Zhang_2018_Medicine.(Baltimore)_97_e0300
PubMedSearch : Zhang_2018_Medicine.(Baltimore)_97_e0300
PubMedID: 29620652

Title : Di-branched triphenylamine dye sensitized TiO2 nanocomposites with good photo-stability for sensitive photoelectrochemical detection of organophosphate pesticides - Song_2018_Anal.Chim.Acta_1001_24
Author(s) : Song J , Wu S , Xing P , Zhao Y , Yuan J
Ref : Anal Chim Acta , 1001 :24 , 2018
Abstract : Herein, a di-branched di-anchoring dye, T(TA)2, with triphenylamine as electron donor, thiophene as electron transfer pi-bridge, and acrylic acid as both acceptor and anchoring groups, was synthesized and coupled with TiO2 nanoparticles for the highly sensitive photoelectrochemical (PEC) assay of organophosphate pesticides (OPs). The T(TA)2 exhibited good anchoring stability to TiO2 nanoparticles in neutral buffer solutions. Under 2h continual irradiation, the T(TA)2-TiO2 nanocomposites respectively kept 99.7% and 85.9% of their initial photocurrents in neutral Tris-HCl and phosphate buffer solutions. Neither degradation nor desorption of T(TA)2 from TiO2 nanoparticles was observed during the continual irradiation in the Tris-HCl solutions. The stability was not only superior to its analogues either possessing one branch, with cyanoacrylic acid as anchoring groups, or without thiophene in the pi-bridge, but also better than the Ru(II) complex N719 and the porphyrin dye sensitized TiO2 nanocomposites. The nanocomposites also showed highly photocatalytic ability towards the oxidation of ascorbic acid and thiocholine (TCh). Since the latter is the enzymatic hydrolysis product of acetylcholinesterase (AChE) and the activity of AChE can be inhibited by OPs, the T(TA)2-TiO2/FTO was further used for PEC assay of OPs. Using parathion as a model analyte, the PEC method showed a wide linear range from 2x10(-12)-4x10(-6)gmL(-1) and an extremely low limit of detection of 5.6x10(-13)gmL(-1). Regarding these good analytical performances, this study may provide some guidance and pave the way for the applications of dye-TiO2 nanocomposites in a lot of PEC devices required to be performed in aqueous solutions.
ESTHER : Song_2018_Anal.Chim.Acta_1001_24
PubMedSearch : Song_2018_Anal.Chim.Acta_1001_24
PubMedID: 29291803

Title : Tea saponin reduces the damage of Ectropis obliqua to tea crops, and exerts reduced effects on the spiders Ebrechtella tricuspidata and Evarcha albaria compared to chemical insecticides - Zeng_2018_PeerJ_6_e4534
Author(s) : Zeng C , Wu L , Zhao Y , Yun Y , Peng Y
Ref : PeerJ , 6 :e4534 , 2018
Abstract : Background: Tea is one of the most economically important crops in China. However, the tea geometrid (Ectropis obliqua), a serious leaf-feeding pest, causes significant damage to tea crops and reduces tea yield and quality. Spiders are the most dominant predatory enemies in the tea plantation ecosystem, which makes them potentially useful biological control agents of E. obliqua. These highlight the need for alternative pest control measures. Our previous studies have shown that tea saponin (TS) exerts insecticidal activity against lepidopteran pests. Here, we investigate whether TS represents a potentially new alternative insecticide with no harm to spiders. Methods: We investigated laboratory bioactivities and the field control properties of TS solution against E. obliqua. (i) A leaf-dip bioassay was used to evaluate the toxicity of TS to 3rd-instar E. obliqua larvae and effects of TS on the activities of enzymes glutathione-S-transferase (GST), acetylcholinesterase (AChE), carboxylesterase (CES) and peroxidase (POD) of 3rd-instar E. obliqua larvae in the laboratory. (ii) Topical application was used to measure the toxicity of 30% TS (w/v) and two chemical insecticides (10% bifenthrin EC and 50% diafenthiuron SC) to two species of spider, Ebrechtella tricuspidata and Evarcha albaria. (iii) Field trials were used to investigate the controlling efficacy of 30% TS against E. obliqua larvae and to classify the effect of TS to spiders in the tea plantation. Results: The toxicity of TS to 3rd-instar E. obliqua larvae occurred in a dose-dependent manner and the LC50 was 164.32 mg/mL. Activities of the detoxifying-related enzymes, GST and POD, increased in 3rd-instar E. obliqua larvae, whereas AChE and CES were inhibited with time by treatment with TS. Mortalities of E. tricuspidata and E. albaria after 48 h with 30% TS treatment (16.67% and 20%, respectively) were significantly lower than those with 10% bifenthrin EC (80% and 73.33%, respectively) and 50% diafenthiuron EC (43.33% and 36.67%, respectively). The highest controlling efficacy of 30% TS was 77.02% at 5 d after treatment, which showed no difference to 10% bifenthrin EC or 50% diafenthiuron SC. 30% TS was placed in the class N (harmless or slightly harmful) of IOBC (International Organization of Biological Control) categories for natural enemies, namely spiders. Conclusions: Our results indicate that TS is a botanical insecticide that has a good controlling efficacy in E. obliqua larvae, which suggests it has promise as application in the integrated pest management (IPM) envisaged for tea crops.
ESTHER : Zeng_2018_PeerJ_6_e4534
PubMedSearch : Zeng_2018_PeerJ_6_e4534
PubMedID: 29576988

Title : Chronic brain toxicity response of juvenile Chinese rare minnows (Gobiocypris rarus) to the neonicotinoid insecticides imidacloprid and nitenpyram - Tian_2018_Chemosphere_210_1006
Author(s) : Tian X , Yang W , Wang D , Zhao Y , Yao R , Ma L , Ge C , Li X , Huang Z , He L , Jiao W , Lin A
Ref : Chemosphere , 210 :1006 , 2018
Abstract : Imidacloprid and nitenpyram are widely used neonicotinoid pesticides worldwide and were observed to adversely affect non-target aquatic organisms. In this study, the toxic effect of imidacloprid and nitenpyram on the brain of juvenile Chinese rare minnows (Gobiocypris rarus) was investigated by determining the oxidative stress, 8-hydroxy-2-deoxyguanosine (8-OHdG) content and acetylcholinesterase (AChE) activity. The superoxide dismutase (SOD) activities did not significantly change after long-term exposure to imidacloprid and nitenpyram. A noticeable increase of catalase (CAT) activities was observed on the brain tissues under 0.1mg/L imidacloprid and under all nitenpyram treatments (p<0.05). The malondialdehyde (MDA) content increased markedly under 2.0mg/L imidacloprid and 0.1mg/L nitenpyram treatments (p<0.05). The glutathione (GSH) content in the brain significantly increased under 0.5 and 2.0mg/L imidacloprid (p<0.05). A significant decrease was observed in the mRNA levels of Cu/Zn-sod under 2.0mg/L imidacloprid and those of cat under 0.1 and 0.5mg/L nitenpyram (p<0.05). The mRNA levels of gpx1 clearly decreased under 2.0mg/L imidacloprid and under 0.1mg/L nitenpyram (p<0.05). The treatments of 0.1 and 0.5mg/L nitenpyram decreased cat expression levels markedly (p<0.05). 2.0mg/L imidacloprid raised the 8-OHdG content. The AChE activities increased markedly under 0.5 and 2.0mg/L imidacloprid while clearly decreasing under 2.0mg/L nitenpyram (p<0.05). Therefore, our results indicate that imidacloprid and nitenpyram might cause adverse effects on juvenile Chinese rare minnows brain. Notably, imidacloprid had greater impacts on juvenile rare minnows compared to nitenpyram.
ESTHER : Tian_2018_Chemosphere_210_1006
PubMedSearch : Tian_2018_Chemosphere_210_1006
PubMedID: 30208524

Title : Online screening of acetylcholinesterase inhibitors in natural products using monolith-based immobilized capillary enzyme reactors combined with liquid chromatography-mass spectrometry - Wang_2018_J.Chromatogr.A_1563_135
Author(s) : Wang L , Zhao Y , Zhang Y , Zhang T , Kool J , Somsen GW , Wang Q , Jiang Z
Ref : Journal of Chromatography A , 1563 :135 , 2018
Abstract : In order to develop a direct and reliable method for discovering lead compounds from traditional Chinese medicines (TCMs), a comparative online ligand fishing platform was developed using immobilized capillary enzyme reactors (ICERs) in combination with liquid chromatography-mass spectrometry (LC-MS). Methacrylate-based monolithic capillaries (400mum I.D.x10cm) containing epoxy reactive groups were used as support to immobilize the target enzyme acetylcholinesterase (AChE). The activity and kinetic parameters of the AChE-ICER were investigated using micro-LC-UV. Subsequently, ligand fishing and identification from mixtures was carried out using the complete AChE-ICER-LC-MS platform. For efficient distinction of true actives from false positives, highly automated comparative analyses were run alternatingly using AChE-ICERs and negative control-ICERs, both online installed in the system. After washing unbound compounds to the waste, bound ligands were eluted from the AChE-ICER to a trapping loop using a denaturing solution. The trapped ligands were further separated and identified using LC-MS. Non-specific binding to the monolith support or non-functional sites of the immobilized enzyme was investigated by exposing analytes to the negative control-ICER. The specificity of the proposed approach was verified by analyzing a known AChE inhibitor in the presence of an inactive compound. The platform was applied to screen for AChE inhibitors in extracts of Corydalis yanhusuo. Eight compounds (columbamine, jatrorrhizine, coptisine, palmatine, berberine, dehydrocorydaline, tetrahydropalmatine and corydaline) with AChE binding affinity were detected and identified, and their AChE inhibitory activities were further verified by an in vitro enzymatic inhibition assay. Experimental results show that the proposed comparative online ligand fishing platform is suitable for rapid screening and mass-selective detection of AChE inhibitors in complex mixtures.
ESTHER : Wang_2018_J.Chromatogr.A_1563_135
PubMedSearch : Wang_2018_J.Chromatogr.A_1563_135
PubMedID: 29866504

Title : A Nanozyme- and Ambient Light-Based Smartphone Platform for Simultaneous Detection of Dual Biomarkers from Exposure to Organophosphorus Pesticides - Zhao_2018_Anal.Chem_90_7391
Author(s) : Zhao Y , Yang M , Fu Q , Ouyang H , Wen W , Song Y , Zhu C , Lin Y , Du D
Ref : Analytical Chemistry , 90 :7391 , 2018
Abstract : A transparent, lateral-flow test strip coupled with a smartphone-based ambient light sensor was first proposed for detecting enzymatic inhibition and phosphorylation. The principle of the platform is based on the simultaneous measurement of the total amount of the enzyme and enzyme activity to biomonitor exposure to organophosphorus (OP) pesticides. In this study, butyrylcholinesterase (BChE) was adopted as the model enzyme and ethyl paraoxon was chosen as an analyte representing OP pesticides. The total amount of BChE was quantified by a sensitive colorimetric signal originating from a sandwich immunochromatographic assay utilizing PtPd nanoparticles as a colorimetric probe, which exhibited excellent catalytic activity for phenols. In the sandwich immunoassay, only one antibody against BChE was simultaneously utilized as the recognition antibody and the labeling antibody due to the tetrameric structure of native BChE. The BChE activity was estimated by another colorimetric signal using the Ellman assay. Both colorimetric signals on two separated test strips were detected by the smartphone-based ambient light sensor. The proposed sensor operated with an LED in a 3D-printed substrate, which emitted excitation light and transmitted it through a transparent, lateral-flow test strip. With the increase in the colorimetric signal in the test line of the test strip, the intensity of the transmitted light decreased. The smartphone-based sensor showed excellent linear responses for assaying the total amount of BChE and active BChE ranging from 0.05 to 6.4 nM and from 0.1 to 6.4 nM, respectively. A high portability and low detection limit were simultaneously realized in the common smartphone-based device. This low-cost, portable, easy-operation, and sensitive immunoassay strategy shows great potential for online detection of OP exposure and monitoring other disease biomarkers.
ESTHER : Zhao_2018_Anal.Chem_90_7391
PubMedSearch : Zhao_2018_Anal.Chem_90_7391
PubMedID: 29792679

Title : Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent - Pang_2017_Molecules_22_2
Author(s) : Pang X , Wang L , Kang , Zhao Y , Wu S , Liu AL , Du GH
Ref : Molecules , 22 : , 2017
Abstract : In our study, we attempted to investigate the influences of P-glycoprotein (P-gp) on DL0410, a novel synthetic molecule for Alzheimer's disease (AD) treatment, for intestinal absorption and blood-brain barrier permeability in vitro and related binding mechanisms in silico. Caco-2, MDCK, and MDCK-MDR1 cells were utilized for transport studies, and homology modelling of human P-gp was built for further docking study to uncover the binding mode of DL0410. The results showed that the apparent permeability (Papp) value of DL0410 was approximately 1 x 10(-6) cm/s, indicating the low permeability of DL0410. With the presence of verapamil, the directional transport of DL0410 disappeared in Caco-2 and MDCK-MDR1 cells, suggesting that DL0410 should be a substrate of P-gp, which was also confirmed by P-gp ATPase assay. In addition, DL0410 could competitively inhibit the transport of Rho123, a P-gp known substrate. According to molecular docking, we also found that DL0410 could bind to the drug binding pocket (DBP), but not the nucleotide binding domain (NBD). In conclusion, DL0410 was a substrate as well as a competitive inhibitor of P-gp, and P-gp had a remarkable impact on the intestine and brain permeability of DL0410, which is of significance for drug research and development.
ESTHER : Pang_2017_Molecules_22_2
PubMedSearch : Pang_2017_Molecules_22_2
PubMedID: 28757552

Title : Role of the lncRNA ABHD11-AS(1) in the tumorigenesis and progression of epithelial ovarian cancer through targeted regulation of RhoC - Wu_2017_Mol.Cancer_16_138
Author(s) : Wu DD , Chen X , Sun KX , Wang LL , Chen S , Zhao Y
Ref : Mol Cancer , 16 :138 , 2017
Abstract : BACKGROUND: There is increasing evidence in support of the role of lncRNAs in tumor cell proliferation, differentiation and apoptosis. METHODS: We examined the expression of the lncRNA ABHD11-AS(1) in epithelial ovarian cancer (EOC) tissues and normal ovarian tissues by real-time quantitative PCR (qRT-PCR). After inducing ABHD11-AS(1) downregulation by small interfering RNA (siRNA) or ABHD11-AS(1) overexpression by plasmid transfection, we examined the EOC cell phenotypes and expression of related molecules. RESULTS: Expression of the lncRNA ABHD11-AS(1) in EOC tissues was higher than that in normal ovarian tissue. It was positively associated with the tumor stage (stage I/II vs. stage III/IV), and it was lower in the well-differentiated group than in the poorly/moderately differentiated group. Overexpression of ABHD11-AS(1) in the ovarian cancer cell lines A2780 and OVCAR3 promoted ovarian cancer cell proliferation, invasion and migration, and inhibited apoptosis. Silencing of ABHD11-AS(1) had the opposite effect. Subcutaneous injection of tumor cells in nude mice showed that ABHD11-AS(1) could significantly promote tumor growth. In addition, intraperitoneal injection of tumor cells in the nude mice resulted in an increase in the metastatic ability of the tumor. Further, overexpression of ABHD11-AS(1) upregulated the expression of RhoC and its downstream molecules P70s6k, MMP2 and BCL-xL. Silencing of ABHD11-AS(1) had the opposite effect. The RNA pull-down assay showed that ABHD11-AS(1) can combine directly with RhoC. Silencing of RhoC was found to inhibit the cancer-promoting effects of lncRNA ABHD11-AS(1). Thus, it seems that RhoC is a major target of the lncRNA ABHD11-AS(1). CONCLUSIONS: This is the first study to demonstrate the role of RhoC in the tumor-promoting effects of the lncRNA ABHD11-AS(1). The present findings shed light on new therapeutic targets for ovarian cancer treatment.
ESTHER : Wu_2017_Mol.Cancer_16_138
PubMedSearch : Wu_2017_Mol.Cancer_16_138
PubMedID: 28818073
Gene_locus related to this paper: human-ABHD11

Title : The Inhibitory Effect of alpha\/beta-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors - Wei_2017_Front.Mol.Neurosci_10_55
Author(s) : Wei M , Jia M , Zhang J , Yu L , Zhao Y , Chen Y , Ma Y , Zhang W , Shi YS , Zhang C
Ref : Front Mol Neurosci , 10 :55 , 2017
Abstract : The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are major excitatory receptors that mediate fast neurotransmission in the mammalian brain. The surface expression of functional AMPARs is crucial for synaptic transmission and plasticity. AMPAR auxiliary subunits control the biosynthesis, membrane trafficking, and synaptic targeting of AMPARs. Our previous report showed that alpha/beta-hydrolase domain-containing 6 (ABHD6), an auxiliary subunit for AMPARs, suppresses the membrane delivery and function of GluA1-containing receptors in both heterologous cells and neurons. However, it remained unclear whether ABHD6 affects the membrane trafficking of glutamate receptor subunits, GluA2 and GluA3. Here, we examine the effects of ABHD6 overexpression in HEK293T cells expressing GluA1, GluA2, GluA3, and stargazin, either alone or in combination. The results show that ABHD6 suppresses the glutamate-induced currents and the membrane expression of AMPARs when expressing GluA2 or GluA3 in the HEK293T cells. We generated a series of GluA2 and GluA3 C-terminal deletion constructs and confirm that the C-terminus of GluAs is required for ABHD6's inhibitory effects on glutamate-induced currents and surface expression of GluAs. Meanwhile, our pull-down experiments reveal that ABHD6 binds to GluA1-3, and deletion of the C-terminal domain of GluAs abolishes this binding. These findings demonstrate that ABHD6 inhibits the AMPAR-mediated currents and its surface expression, independent of the type of AMPAR subunits, and this inhibitor's effects are mediated through the binding with the GluAs C-terminal regions.
ESTHER : Wei_2017_Front.Mol.Neurosci_10_55
PubMedSearch : Wei_2017_Front.Mol.Neurosci_10_55
PubMedID: 28303090

Title : Simultaneous detection of dual biomarkers from humans exposed to organophosphorus pesticides by combination of immunochromatographic test strip and ellman assay - Yang_2017_Biosens.Bioelectron_104_39
Author(s) : Yang M , Zhao Y , Wang L , Paulsen M , Simpson CD , Liu F , Du D , Lin Y
Ref : Biosensors & Bioelectronics , 104 :39 , 2017
Abstract : A novel sandwich immunoassay based immunochromatographic test strip (ICTS) has been developed for simultaneously measuring both butyrylcholinesterase (BChE) activity and the total amount of BChE (including inhibited and active enzyme) from 70 muLpost-exposure human plasma sample. The principle of this method is based on the BChE monoclonal antibody (MAb) capable of acting as both capture antibody and detection antibody. The BChE MAb which was immobilized on the test line was able to recognize both organophosphorus BChE adducts (OP-BChE) and BChE and provided equal binding affinity, permitting detection of the total enzyme amount in post-exposure human plasma samples. The formed immunocomplexes on the test line can further be excised from the test-strip for subsequent off-line measurement of BChE activity using the Ellman assay. Therefore, dual biomarkers of BChE activity and phosphorylation (OP-BChE) will be obtained simultaneously. The whole sandwich-immunoassay was performed on one ICTS, greatly reducing analytical time. The ICTS sensor showed excellent linear responses for assaying total amount of BChE and active BChE ranging from 0.22 to 3.58nM and 0.22-7.17nM, respectively. Both the signal detection limits are 0.10nM. We validated the practical application of the proposed method to measure 124 human plasma samples from orchard workers and cotton farmers with long-term exposure to organophosphorus pesticides (OPs). The results were in highly agreement with LC/MS/MS which verified our method is extremely accurate. Combining the portability and rapidity of test strip and the compatibility of BChE MAb as both capture antibody and detection antibody, the developed method provides a baseline-free, low-cost and rapid tool for in-field monitoring of OP exposures.
ESTHER : Yang_2017_Biosens.Bioelectron_104_39
PubMedSearch : Yang_2017_Biosens.Bioelectron_104_39
PubMedID: 29306031

Title : The North American bullfrog draft genome provides insight into hormonal regulation of long noncoding RNA - Hammond_2017_Nat.Commun_8_1433
Author(s) : Hammond SA , Warren RL , Vandervalk BP , Kucuk E , Khan H , Gibb EA , Pandoh P , Kirk H , Zhao Y , Jones M , Mungall AJ , Coope R , Pleasance S , Moore RA , Holt RA , Round JM , Ohora S , Walle BV , Veldhoen N , Helbing CC , Birol I
Ref : Nat Commun , 8 :1433 , 2017
Abstract : Frogs play important ecological roles, and several species are important model organisms for scientific research. The globally distributed Ranidae (true frogs) are the largest frog family, and have substantial evolutionary distance from the model laboratory Xenopus frog species. Unfortunately, there are currently no genomic resources for the former, important group of amphibians. More widely applicable amphibian genomic data is urgently needed as more than two-thirds of known species are currently threatened or are undergoing population declines. We report a 5.8 Gbp (NG50 = 69 kbp) genome assembly of a representative North American bullfrog (Rana [Lithobates] catesbeiana). The genome contains over 22,000 predicted protein-coding genes and 6,223 candidate long noncoding RNAs (lncRNAs). RNA-Seq experiments show thyroid hormone causes widespread transcriptional change among protein-coding and putative lncRNA genes. This initial bullfrog draft genome will serve as a key resource with broad utility including amphibian research, developmental biology, and environmental research.
ESTHER : Hammond_2017_Nat.Commun_8_1433
PubMedSearch : Hammond_2017_Nat.Commun_8_1433
PubMedID: 29127278
Gene_locus related to this paper: litct-a0a2g9rgn1 , litct-a0a2g9sm06

Title : Pharmacokinetics and tolerability of oral dosage forms of huperzine a in healthy Chinese male volunteers: a randomized, single dose, three-period, six-sequence crossover study - Wu_2017_J.Huazhong.Univ.Sci.Technolog.Med.Sci_37_795
Author(s) : Wu SL , Gan J , Rao J , He SJ , Zhu WW , Zhao Y , Lv YN , Huang JG , Liu YN
Ref : J Huazhong Univ Sci Technolog Med Sci , 37 :795 , 2017
Abstract : Huperzine A is a potent, reversible, and blood-brain barrier permeable acetylcholinesterase inhibitor. The aim of this study was to compare the pharmacokinetics, tolerability, and bioavailability of two formulations with the established reference formulation of huperzine A in a fasting, healthy Chinese male population. This was a randomized, single-dose, 3-period, 6-sequence crossover study. The plasma concentrations of huperzine A were determined by liquid chromatography tandem mass spectrometry. Tolerability was assessed based on subject interview, vital sign monitoring, physical examination, and routine blood and urine tests. The mean (SD) pharmacokinetic parameters of the reference drug were Cmax, 1.550 (0.528) ng/mL; t1/2, 12.092 (1.898) h; AUC0-72h, 17.550 (3.794) ng.h/mL. Those of the test formulation A and test formulation B were Cmax, 1.412 (0.467), 1.521 (0.608) ng/mL; t1/2, 12.073 (2.068), 12.271 (1.678) h; AUC0-72h, 15.286 (3.434) ng.h/mL, 15.673 (3.586) ng.h/mL. The 90% confidence intervals for the AUC0-72h and Cmax were between 0.80 and 1.25. No adverse events were reported by the subjects or found with results of clinical laboratory test. The test and reference products met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. All three formulations appeared to be well tolerated.
ESTHER : Wu_2017_J.Huazhong.Univ.Sci.Technolog.Med.Sci_37_795
PubMedSearch : Wu_2017_J.Huazhong.Univ.Sci.Technolog.Med.Sci_37_795
PubMedID: 29058298

Title : Differential physiological effects of neonicotinoid insecticides on honey bees: A comparison between Apis mellifera and Apis cerana - Li_2017_Pestic.Biochem.Physiol_140_1
Author(s) : Li Z , Li M , He J , Zhao X , Chaimanee V , Huang WF , Nie H , Zhao Y , Su S
Ref : Pestic Biochem Physiol , 140 :1 , 2017
Abstract : Acute toxicities (LD50s) of imidacloprid and clothianidin to Apis mellifera and A. cerana were investigated. Changing patterns of immune-related gene expressions and the activities of four enzymes between the two bee species were compared and analyzed after exposure to sublethal doses of insecticides. Results indicated that A. cerana was more sensitive to imidacloprid and clothianidin than A. mellifera. The acute oral LD50 values of imidacloprid and clothianidin for A. mellifera were 8.6 and 2.0ng/bee, respectively, whereas the corresponding values for A. cerana were 2.7 and 0.5ng/bee. The two bee species possessed distinct abilities to mount innate immune response against neonicotinoids. After 48h of imidacloprid treatment, carboxylesterase (CCE), prophenol oxidase (PPO), and acetylcholinesterase (AChE) activities were significantly downregulated in A. mellifera but were upregulated in A. cerana. Glutathione-S-transferase (GST) activity was significantly elevated in A. mellifera at 48h after exposure to imidacloprid, but no significant change was observed in A. cerana. AChE was downregulated in both bee species at three different time points during clothianidin exposure, and GST activities were upregulated in both species exposed to clothianidin. Different patterns of immune-related gene expression and enzymatic activities implied distinct detoxification and immune responses of A. cerana and A. mellifera to imidacloprid and clothianidin.
ESTHER : Li_2017_Pestic.Biochem.Physiol_140_1
PubMedSearch : Li_2017_Pestic.Biochem.Physiol_140_1
PubMedID: 28755688

Title : Surfactant-activated lipase hybrid nanoflowers with enhanced enzymatic performance - Cui_2016_Sci.Rep_6_27928
Author(s) : Cui J , Zhao Y , Liu R , Zhong C , Jia S
Ref : Sci Rep , 6 :27928 , 2016
Abstract : Increasing numbers of materials have been extensively used as platforms for enzyme immobilization to improve catalytic performance. However, activity of the most of the enzymes was declined after immobilization. Here, we develop a surfactant-activated lipase-inorganic flowerlike hybrid nanomaterials with rational design based on interfacial activation and self-assembly. The resulting surfactant-activated lipase-inorganic hybird nanoflower (activated hNF-lipase) exhibited 460% and 200% higher activity than native lipase and conventional lipase-inorganic hybird nanoflower (hNF-lipase). Furthermore, the activated hNF-lipase displayed good reusability due to its monodispersity and mechanical properties, and had excellent long-time stability. The superior catalytic performances were attributed to both the conformational modulation of surfactants and hierarchical structure of nanoflowers, which not only anchored lipases in an active form, but also decreased the enzyme-support negative interaction and mass-transfer limitations. This new biocatalytic system is promising to find widespread use in applications related to biomedicine, biosensor, and biodiesel.
ESTHER : Cui_2016_Sci.Rep_6_27928
PubMedSearch : Cui_2016_Sci.Rep_6_27928
PubMedID: 27297609

Title : Donepezil delays photoreceptor apoptosis induced by N-methyl-N-nitrosourea in mice - Wu_2016_Exp.Ther.Med_11_2446
Author(s) : Wu L , Xu M , Liu S , Chen G , Zhang F , Zhao Y , Yi J
Ref : Exp Ther Med , 11 :2446 , 2016
Abstract : Retinitis pigmentosa (RP) is a group of inherited retinal degeneration diseases characterized by photoreceptor cell death that causes visual disturbances and eventual blindness. Intraperitoneal injection of N-methyl-N-nitrosourea (MNU) causes photoreceptor loss, and is used to create an animal model for investigating the mechanisms that cause retinal degeneration diseases. Donepezil is an acetylcholinesterase inhibitor that has a protective effect on retinal ganglion cells in vitro and in vivo, and it is understood that donepezil increases the expression of a heat shock protein 70 (Hsp70), which serves to protect neurons. Hsp70 functions as a chaperone molecule that protects cells from protein aggregation and assists in the refolding of denatured proteins. In the present study, the effects of donepezil on photoreceptor survival in mice was investigated. It was observed that donepezil upregulates the expression of Hsp70, to increase resistance to MNU-induced photoreceptor cell apoptosis by using its anti-apoptotic properties. In addition, the present study observed that Hsp70 promotes photoreceptor cell survival by upregulating the expression levels of B-cell lymphoma 2 (Bcl-2). In conclusion, the results of the present study indicate that donepezil has the potential to be used as a treatment for retinal degenerative diseases.
ESTHER : Wu_2016_Exp.Ther.Med_11_2446
PubMedSearch : Wu_2016_Exp.Ther.Med_11_2446
PubMedID: 27284332

Title : Design, synthesis and biological evaluation of coumarin derivatives as novel acetylcholinesterase inhibitors that attenuate H2O2-induced apoptosis in SH-SY5Y cells - Yao_2016_Bioorg.Chem_68_112
Author(s) : Yao D , Wang J , Wang G , Jiang Y , Shang L , Zhao Y , Huang J , Yang S , Yu Y
Ref : Bioorg Chem , 68 :112 , 2016
Abstract : A novel series of coumarin derivatives were designed, synthesized and investigated for inhibition of cholinesterase, including acetyl cholinesterase (AChE) and butyrylcholinesterase (BuChE). This biological study showed that these compounds containing piperazine ring had significant inhibition activities on AChE rather than BuChE. Further study suggested that 9x, as one of this kind of structure derivative, showed the strongest inhibition activity on AChE with an IC50 value of 34nM. Moreover, molecular docking, flow cytometry (FCM), and western blot assay suggested that 9x could induce cytoprotective autophagy to attenuate H2O2-induced cell death in human neuroblastoma SH-SY5Y cells. These findings highlight a new approach for the development of a novel potential neuroprotective compound targeting AChE with autophagy-inducing activity in future Alzheimer's disease (AD) therapy.
ESTHER : Yao_2016_Bioorg.Chem_68_112
PubMedSearch : Yao_2016_Bioorg.Chem_68_112
PubMedID: 27479541

Title : Lipoprotein lipase deficiency leads to alpha-synuclein aggregation and ubiquitin C-terminal hydrolase L1 reduction - Yang_2015_Neurosci_290_1
Author(s) : Yang H , Zhou T , Wang H , Liu T , Ueda K , Zhan R , Zhao L , Tong Y , Tian X , Zhang T , Jin Y , Han X , Li Z , Zhao Y , Guo X , Xiao W , Fan D , Liu G , Chui D
Ref : Neuroscience , 290 :1 , 2015
Abstract : We have previously reported that presynaptic dysfunction and cognitive decline have been found in lipoprotein lipase (LPL) deficient mice, but the mechanism remains to be elucidated. Accumulating evidence supported that alpha-synuclein (alpha-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study, we found that alpha-syn aggregated and the expression of UCHL1 decreased in the brain of LPL deficient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore, deficiency of LPL increased ubiquitination of alpha-syn. These results indicated that aggregation of alpha-syn and reduction of UCHL1 expression in LPL-deficient mice may affect synaptic function.
ESTHER : Yang_2015_Neurosci_290_1
PubMedSearch : Yang_2015_Neurosci_290_1
PubMedID: 25595992

Title : Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis - Wang_2015_Hepatology_61_870
Author(s) : Wang C , Zhao Y , Gao X , Li L , Yuan Y , Liu F , Zhang L , Wu J , Hu P , Zhang X , Gu Y , Xu Y , Wang Z , Li Z , Zhang H , Ye J
Ref : Hepatology , 61 :870 , 2015
Abstract : Abnormal metabolism of nonesterified fatty acids (NEFAs) and their derivatives has been reported to be the main cause of intracellular lipotoxic injury. Normally, NEFAs are stored in lipid droplets (LDs) in the form of triglyceride (TG), which could reduce the lipotoxicity of cytosolic NEFAs. Previous studies have implicated that Perilipin 5 (Plin5), an LD-binding protein, regulates the storage and hydrolysis of TG in LD. However, its roles and underlying mechanisms in the liver remain unknown. Here we found that Plin5 expression was increased in steatotic livers. Using Plin5 knockout mice, we found that Plin5 deficiency resulted in reduced hepatic lipid content and smaller-sized LDs, which was due to the elevated lipolysis rate and fatty acid utilization. Plin5-deficient hepatocytes showed increased mitochondria proliferation, which could be explained by the increased expression and activity of PPARalpha stimulated by the increased NEFA levels. Meanwhile, Plin5-deficient livers also exhibited enhanced mitochondrial oxidative capacity. We also found that Plin5 deficiency induces lipotoxic injury in hepatocytes, attributed to lipid peroxidation. Mechanistically, we found that Plin5 blocks adipose triglyceride lipase (ATGL)-mediated lipolysis by competitively binding to comparative gene identification-58 (CGI-58) and disrupting the interaction between CGI-58 and ATGL. CONCLUSION: Plin5 is an important protective factor against hepatic lipotoxicity induced by NEFAs generated from lipolysis. This provides an important new insight into the regulation of hepatic lipid storage and relation between lipid storage and lipotoxicity.
ESTHER : Wang_2015_Hepatology_61_870
PubMedSearch : Wang_2015_Hepatology_61_870
PubMedID: 25179419

Title : Effects of Total Ginsenosides on the Feeding Behavior and Two Enzymes Activities of Mythimna separata (Walker) Larvae - Zhang_2015_Evid.Based.Complement.Alternat.Med_2015_451828
Author(s) : Zhang AH , Tan SQ , Zhao Y , Lei FJ , Zhang LX
Ref : Evid Based Complement Alternat Med , 2015 :451828 , 2015
Abstract : Ginsenosides, the main effective components of Panax ginseng C.A. Meyer and Panax quinquefolius L., are important allelochemicals of ginseng. Although many studies have targeted the pharmacological, chemical, and clinical properties of ginsenosides, little is known about their ecological role in ginseng population adaptation and evolution. Pests rarely feed on ginseng, and it is not known why. This study investigated the effects of total ginsenosides on feeding behavior and activities of acetylcholinesterase (AChE) and glutathione s-transferase (GST) in Mythimna separata (Walker) larvae. The results showed that the total ginsenosides had significant antifeeding activity against M. separata larvae, determined by nonselective and selective antifeeding bioassays. In addition, the total ginsenosides had inhibitory effects on the activities of GST and AChE. The antifeeding ratio was the highest at 8 h, then decreased, and was the lowest at 16 h. Both GST and AChE activities decreased from 0 h to 48 h in all total ginsenosides treatments but increased at 72 h. Total ginsenosides had antifeeding activity against M. separata larvae and inhibitory effects on the activities of GST and AChE.
ESTHER : Zhang_2015_Evid.Based.Complement.Alternat.Med_2015_451828
PubMedSearch : Zhang_2015_Evid.Based.Complement.Alternat.Med_2015_451828
PubMedID: 26074991

Title : Transgenic mouse milk expressing human bile salt-stimulated lipase improves the survival and growth status of premature mice - Wang_2015_Mol.Biotechnol_57_287
Author(s) : Wang Y , Sheng Z , Li Q , Gao Y , Dai Y , Liu G , Zhao Y , Li N
Ref : Mol Biotechnol , 57 :287 , 2015
Abstract : The lactating human mammary gland and the pancreas both produce bile salt-stimulated lipase (BSSL), a lipolytic enzyme acting on a wide range of substrates, including triglyceride, cholesterol esters, and fat-soluble vitamins esters. Breast milk BSSL has a particularly important role in the digestion of milk fat by newborn infants. We report the generation of transgenic mice that harbored a human BSSL gene controlled by a mammary gland-specific promoter. BSSL levels in transgenic mouse milk were raised to 376.8 mug/ml, corresponding to an activity of 9.15 U/ml. Premature wild-type neonates nursed by transgenic dams exhibited significantly higher survival rate than did the control neonates nursed by wild dams (95 vs. 83.3 % and, P < 0.05). They also showed 43.8 % greater body weight gain and 33.3 % lesser fecal crude fat levels than did the controls. This study provides significant evidence that increased levels of BSSL in milk may reduce mortality and improve the growth and fat absorption in premature mice during neonatal development.
ESTHER : Wang_2015_Mol.Biotechnol_57_287
PubMedSearch : Wang_2015_Mol.Biotechnol_57_287
PubMedID: 25385005

Title : Organelle-Specific Nitric Oxide Detection in Living Cells via HaloTag Protein Labeling - Wang_2015_PLoS.One_10_e0123986
Author(s) : Wang J , Zhao Y , Wang C , Zhu Q , Du Z , Hu A , Yang Y
Ref : PLoS ONE , 10 :e0123986 , 2015
Abstract : Nitric oxide (NO) is a membrane-permeable signaling molecule that is constantly produced, transferred, and consumed in vivo. NO participates and plays important roles in multiple biological processes. However, spatiotemporal imaging of NO in living cells is challenging. To fill the gap in currently used techniques, we exploited the versatility of HaloTag technology and synthesized a novel organelle-targetable fluorescent probe called HTDAF-2DA. We demonstrate the utility of the probe by monitoring subcellular NO dynamics. The developed strategy enables precise determination of local NO function.
ESTHER : Wang_2015_PLoS.One_10_e0123986
PubMedSearch : Wang_2015_PLoS.One_10_e0123986
PubMedID: 25923693

Title : Flavisolibacter ginsenosidimutans sp. nov., with ginsenoside-converting activity isolated from soil used for cultivating ginseng - Zhao_2015_Int.J.Syst.Evol.Microbiol_65_4868
Author(s) : Zhao Y , Liu Q , Kang MS , Jin F , Yu H , Im WT
Ref : Int J Syst Evol Microbiol , 65 :4868 , 2015
Abstract : A Gram-reaction-negative, aerobic, non-motile and rod-shaped bacterial strain designated Gsoil 636T was isolated from soil of a ginseng cultivation field in Pocheon Province, South Korea and its taxonomic position was investigated using a polyphasic approach. Gsoil 636T grew at 18-30 degreesC and at pH 6.0-8.0 on R2A medium. Gsoil 636T possessed beta-glucosidase activity, which was responsible for its ability to transform ginsenoside Rb1 (ones of the dominant active components of ginseng) to F2. On the basis of 16S rRNA gene sequence similarity, Gsoil 636T was shown to belong to the family Chitinophagaceae and to be related to Flavisolibacter ginsengiterrae Gsoil 492T (96.7 % sequence similarity), Flavisolibacter ginsengisoli Gsoil 643T (96.6 %) and Flavisolibacter rigui 02SUJ3T (96.6 %). The G+C content of the genomic DNA was 48.9 %. The predominant respiratory quinone was MK-7 and the major fatty acids were iso-C15 : 0, summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c) and iso-C17 : 0 3-OH. DNA and chemotaxonomic data supported the affiliation of Gsoil 636T to the genus Flavisolibacter. Gsoil 636T could be differentiated genotypically and phenotypically from the species of the genus Flavisolibacter with validly published names. The isolate therefore represents a novel species, for which the name Flavisolibacter ginsenosidimutans sp. nov. is proposed, with the type strain Gsoil 636T (KCTC 22818T = JCM 18197T = KACC 14277T).
ESTHER : Zhao_2015_Int.J.Syst.Evol.Microbiol_65_4868
PubMedSearch : Zhao_2015_Int.J.Syst.Evol.Microbiol_65_4868
PubMedID: 26442990
Gene_locus related to this paper: 9bact-a0a5b8uge7

Title : M1 muscarinic acetylcholine receptor in Alzheimer's disease - Jiang_2014_Neurosci.Bull_30_295
Author(s) : Jiang S , Li Y , Zhang C , Zhao Y , Bu G , Xu H , Zhang YW
Ref : Neurosci Bull , 30 :295 , 2014
Abstract : The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer's disease (AD). Muscarinic acetylcholine receptors (mAChRs) mediate acetylcholine-induced neurotransmission and five mAChR subtypes (M1-M5) have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists for AD treatment.
ESTHER : Jiang_2014_Neurosci.Bull_30_295
PubMedSearch : Jiang_2014_Neurosci.Bull_30_295
PubMedID: 24590577

Title : Whole-genome sequence of a flatfish provides insights into ZW sex chromosome evolution and adaptation to a benthic lifestyle - Chen_2014_Nat.Genet_46_253
Author(s) : Chen S , Zhang G , Shao C , Huang Q , Liu G , Zhang P , Song W , An N , Chalopin D , Volff JN , Hong Y , Li Q , Sha Z , Zhou H , Xie M , Yu Q , Liu Y , Xiang H , Wang N , Wu K , Yang C , Zhou Q , Liao X , Yang L , Hu Q , Zhang J , Meng L , Jin L , Tian Y , Lian J , Yang J , Miao G , Liu S , Liang Z , Yan F , Li Y , Sun B , Zhang H , Zhu Y , Du M , Zhao Y , Schartl M , Tang Q , Wang J
Ref : Nat Genet , 46 :253 , 2014
Abstract : Genetic sex determination by W and Z chromosomes has developed independently in different groups of organisms. To better understand the evolution of sex chromosomes and the plasticity of sex-determination mechanisms, we sequenced the whole genomes of a male (ZZ) and a female (ZW) half-smooth tongue sole (Cynoglossus semilaevis). In addition to insights into adaptation to a benthic lifestyle, we find that the sex chromosomes of these fish are derived from the same ancestral vertebrate protochromosome as the avian W and Z chromosomes. Notably, the same gene on the Z chromosome, dmrt1, which is the male-determining gene in birds, showed convergent evolution of features that are compatible with a similar function in tongue sole. Comparison of the relatively young tongue sole sex chromosomes with those of mammals and birds identified events that occurred during the early phase of sex-chromosome evolution. Pertinent to the current debate about heterogametic sex-chromosome decay, we find that massive gene loss occurred in the wake of sex-chromosome 'birth'.
ESTHER : Chen_2014_Nat.Genet_46_253
PubMedSearch : Chen_2014_Nat.Genet_46_253
PubMedID: 24487278
Gene_locus related to this paper: cynse-a0a3p8wch2 , cynse-a0a3p8vd14 , cynse-a0a3p8w747 , cynse-a0a3p8wq40 , cynse-a0a3p8wul3 , cynse-a0a3p8vqr4 , cynse-a0a3p8vmz4

Title : A full picture of enzymatic catalysis by hydroxynitrile lyases from Hevea brasiliensis: protonation dependent reaction steps and residue-gated movement of the substrate and the product - Zhao_2014_Phys.Chem.Chem.Phys_16_26864
Author(s) : Zhao Y , Chen N , Mo Y , Cao Z
Ref : Phys Chem Chem Phys , 16 :26864 , 2014
Abstract : Hydroxynitrile lyases (HNLs) defend plants from herbivores and microbial attack by releasing cyanide from hydroxynitriles. The reverse process has been productively applied to bioorganic syntheses of pharmaceuticals and agrochemicals. To improve our understanding of the catalytic mechanism of HNLs, extensive ab initio QM/MM and classical MM molecular dynamics simulations have been performed to explore the catalytic conversion of cyanohydrins into aldehyde (or ketone) and HCN by hydroxynitrile lyases from Hevea brasiliensis (HbHNLs). It was found that the catalytic reaction approximately follows a two-stage mechanism. The first stage involves two fast processes including the proton abstraction of the substrate through a double-proton transfer and the C-CN bond cleavage, while the second stage concerns HCN formation and is rate-determining. The complete free energy profile exhibits a peak of approximately 18 kcal mol(-1). Interestingly, the protonation state of Lys236 influences the efficiency of the enzyme only to some extent, but it changes the entire catalytic mechanism. The dynamical behaviors of substrate delivery and HCN release are basically modulated by the gate movement of Trp128. The remarkable exothermicity of substrate binding and the facile release of HCN may drive the enzyme-catalyzed reaction to proceed along the substrate decomposition efficiently. Computational mutagenesis reveals the key residues which play an important role in the catalytic process.
ESTHER : Zhao_2014_Phys.Chem.Chem.Phys_16_26864
PubMedSearch : Zhao_2014_Phys.Chem.Chem.Phys_16_26864
PubMedID: 25375265

Title : Cloning, homology modeling, and reaction mechanism analysis of a novel cis-epoxysuccinate hydrolase from Klebsiella sp - Cheng_2014_Biotechnol.Lett_36_2537
Author(s) : Cheng Y , Pan H , Bao W , Sun W , Xie Z , Zhang J , Zhao Y
Ref : Biotechnol Lett , 36 :2537 , 2014
Abstract : The gene encoding a novel cis-epoxysuccinate hydrolase, which hydrolyzes cis-epoxysuccinate to L (+)-tartaric acid, was cloned from Klebsiella sp. BK-58 and expressed in Escherichia coli. The ORF was 825 bp encoding a mature protein of 274 amino acids with a molecular mass of 30.1 kDa. Multiple sequence alignment showed that the enzyme belonged to the haloacid dehalogenase-like super family. Homology modeling and site-directed mutagenesis were performed to investigate the structural characteristics of the enzyme. Its overall structure consisted of a core domain formed by six-stranded parallel beta-sheets flanked by seven alpha-helices and a subdomain that had a four helix bundle structure. Residues D48, T52, R85, N165, K195, Y201, A219, H221, and D224 were catalytically important forming the active pocket between the two domains. An (18)O-labeling study suggested that the catalytic reaction of the enzyme proceeded through a two-step mechanism.
ESTHER : Cheng_2014_Biotechnol.Lett_36_2537
PubMedSearch : Cheng_2014_Biotechnol.Lett_36_2537
PubMedID: 25216644

Title : Genome sequencing of the high oil crop sesame provides insight into oil biosynthesis - Wang_2014_Genome.Biol_15_R39
Author(s) : Wang L , Yu S , Tong C , Zhao Y , Liu Y , Song C , Zhang Y , Zhang X , Wang Y , Hua W , Li D , Li F , Yu J , Xu C , Han X , Huang S , Tai S , Wang J , Xu X , Li Y , Liu S , Varshney RK
Ref : Genome Biol , 15 :R39 , 2014
Abstract : BACKGROUND: Sesame, Sesamum indicum L., is considered the queen of oilseeds for its high oil content and quality, and is grown widely in tropical and subtropical areas as an important source of oil and protein. However, the molecular biology of sesame is largely unexplored. RESULTS: Here, we report a high-quality genome sequence of sesame assembled de novo with a contig N50 of 52.2 kb and a scaffold N50 of 2.1 Mb, containing an estimated 27,148 genes. The results reveal novel, independent whole genome duplication and the absence of the Toll/interleukin-1 receptor domain in resistance genes. Candidate genes and oil biosynthetic pathways contributing to high oil content were discovered by comparative genomic and transcriptomic analyses. These revealed the expansion of type 1 lipid transfer genes by tandem duplication, the contraction of lipid degradation genes, and the differential expression of essential genes in the triacylglycerol biosynthesis pathway, particularly in the early stage of seed development. Resequencing data in 29 sesame accessions from 12 countries suggested that the high genetic diversity of lipid-related genes might be associated with the wide variation in oil content. Additionally, the results shed light on the pivotal stage of seed development, oil accumulation and potential key genes for sesamin production, an important pharmacological constituent of sesame. CONCLUSIONS: As an important species from the order Lamiales and a high oil crop, the sesame genome will facilitate future research on the evolution of eudicots, as well as the study of lipid biosynthesis and potential genetic improvement of sesame.
ESTHER : Wang_2014_Genome.Biol_15_R39
PubMedSearch : Wang_2014_Genome.Biol_15_R39
PubMedID: 24576357
Gene_locus related to this paper: sesin-a0a6i9snr9

Title : Cognitive Enhancing Treatment with a PPARgamma Agonist Normalizes Dentate Granule Cell Presynaptic Function in Tg2576 APP Mice - Nenov_2014_J.Neurosci_34_1028
Author(s) : Nenov MN , Laezza F , Haidacher SJ , Zhao Y , Sadygov RG , Starkey JM , Spratt H , Luxon BA , Dineley KT , Denner L
Ref : Journal of Neuroscience , 34 :1028 , 2014
Abstract : Hippocampal network hyperexcitability is considered an early indicator of Alzheimer's disease (AD) memory impairment. Some AD mouse models exhibit similar network phenotypes. In this study we focused on dentate gyrus (DG) granule cell spontaneous and evoked properties in 9-month-old Tg2576 mice that model AD amyloidosis and cognitive deficits. Using whole-cell patch-clamp recordings, we found that Tg2576 DG granule cells exhibited spontaneous EPSCs that were higher in frequency but not amplitude compared with wild-type mice, suggesting hyperactivity of DG granule cells via a presynaptic mechanism. Further support of a presynaptic mechanism was revealed by increased I-O relationships and probability of release in Tg2576 DG granule cells. Since we and others have shown that activation of the peroxisome proliferator-activated receptor gamma (PPARgamma) axis improves hippocampal cognition in mouse models for AD as well as benefitting memory performance in some humans with early AD, we investigated how PPARgamma agonism affected synaptic activity in Tg2576 DG. We found that PPARgamma agonism normalized the I-O relationship of evoked EPSCs, frequency of spontaneous EPSCs, and probability of release that, in turn, correlated with selective expression of DG proteins essential for presynaptic SNARE function that are altered in patients with AD. These findings provide evidence that DG principal cells may contribute to early AD hippocampal network hyperexcitability via a presynaptic mechanism, and that hippocampal cognitive enhancement via PPARgamma activation occurs through regulation of presynaptic vesicular proteins critical for proper glutamatergic neurotransmitter release, synaptic transmission, and short-term plasticity.
ESTHER : Nenov_2014_J.Neurosci_34_1028
PubMedSearch : Nenov_2014_J.Neurosci_34_1028
PubMedID: 24431460

Title : Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions - Zhang_2014_Int.J.Mol.Sci_15_14396
Author(s) : Zhang R , Zhang J , Fang L , Li X , Zhao Y , Shi W , An L
Ref : Int J Mol Sci , 15 :14396 , 2014
Abstract : Alzheimer's disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and d-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics.
ESTHER : Zhang_2014_Int.J.Mol.Sci_15_14396
PubMedSearch : Zhang_2014_Int.J.Mol.Sci_15_14396
PubMedID: 25196440

Title : Enhanced therapeutic efficacy of combined use of sorafenib and transcatheter arterial chemoembolization for treatment of advanced hepatocellular carcinoma - Zhou_2014_Jpn.J.Clin.Oncol_44_711
Author(s) : Zhou L , Li J , Ai DL , Fu JL , Peng XM , Zhang LZ , Wang JY , Zhao Y , Yang B , Yu Q , Liu CZ , Wang HM
Ref : Japanese Journal of Clinical Oncology , 44 :711 , 2014
Abstract : OBJECTIVE: Clinical trials suggest that combining transcatheter arterial chemoembolization with sorafenib in patients with advanced hepatocellular carcinoma shows a superior safety and tolerability profile. Our study aimed to retrospectively analyze the utility and prognostic factors of this combined therapy in these patients.
METHODS: Patients with advanced hepatocellular carcinoma, treated by transcatheter arterial chemoembolization and sorafenib subsequently, between February 2010 and September 2012 in our hospital, were retrospectively analyzed. After sorafenib treatment for 12 weeks, abdominal enhanced computed tomography or magnetic resonance imaging was used to evaluate short-term outcomes and clinical benefit rate. Overall survival and adverse events were recorded during follow-up. Univariate and multivariate analyses were used to identify relationships between baseline characteristics and overall survival.
RESULTS: Fifty-one advanced hepatocellular carcinoma patients were included. Common adverse events for sorafenib were hand-foot skin reaction, alopecia, diarrhea, anorexia and fatigue. The clinical benefit rate was 64% and the median survival time was 7.5 months. Median survival of patients with and without portal vein tumor thrombi was 6.0 months and 10.3 months (P < 0.001), respectively. Median survival of patients with cholinesterase >/=5000 U/l and < 5000 U/l was 10.6 months and 6.1 months (P < 0.001), respectively. Multivariate analysis identified the presence of portal vein tumor thrombi and low cholinesterase level as independent negative predictors of survival.
CONCLUSIONS: Combining sorafenib and transcatheter arterial chemoembolization was safe and effective for advanced hepatocellular carcinoma patients with extrahepatic spread but without portal vein tumor thrombi. Portal vein tumor thrombi and cholinesterase level are independent predictors of prognosis following this combined therapy.
ESTHER : Zhou_2014_Jpn.J.Clin.Oncol_44_711
PubMedSearch : Zhou_2014_Jpn.J.Clin.Oncol_44_711
PubMedID: 24855686

Title : A novel oriented immobilized lipase on magnetic nanoparticles in reverse micelles system and its application in the enrichment of polyunsaturated fatty acids - Liu_2013_Bioresour.Technol_132C_99
Author(s) : Liu T , Zhao Y , Wang X , Li X , Yan Y
Ref : Bioresour Technol , 132C :99 , 2013
Abstract : A novel oriented immobilized lipase was derived from Yarrowia lipolytica lipase LIP2 covalently immobilized on functionalized Fe(3)O(4) magnetic nanoparticles (MNPs) in reverse micelles system (RMS). The activity recovery reached 382% compared with 29% in aqueous phase, and further ran up to 1425% under optimum conditions. (3-Aminopropyl) triethoxysilane (APTES) coated Fe(3)O(4) nanoparticles were characterized by Fourier transform infrared (FT-IR) and X-ray diffraction (XRD). A significant alteration in the secondary structure of the lipase in RMS with a 15.5% increase of alpha-helix content and a 12.5% decrease of beta-sheet content was detected by circular dichroism (CD). The immobilized lipase was employed to enrich polyunsaturated fatty acids in fish oil, a 90% increase of DHA content was obtained after 12h, and after 20 cycles of successive usage, it still remained over 80% of relative hydrolysis degree, which shows a good recyclability.
ESTHER : Liu_2013_Bioresour.Technol_132C_99
PubMedSearch : Liu_2013_Bioresour.Technol_132C_99
PubMedID: 23395761

Title : Casuarinines A-J, Lycodine-Type Alkaloids from Lycopodiastrum casuarinoides - Tang_2013_J.Nat.Prod_76_1475
Author(s) : Tang Y , Fu Y , Xiong J , Li M , Ma GL , Yang GX , Wei BG , Zhao Y , Zhang HY , Hu JF
Ref : Journal of Natural Products , 76 :1475 , 2013
Abstract : Ten new lycodine-type alkaloids, named casuarinines A-J (1-10), along with eight known analogues (11-18), were isolated from the whole plant of Lycopodiastrum casuarinoides . The new structures were established by spectroscopic methods and chemical transformations. Casuarinines A-D (1-4) and J (10) are common lycodine alkaloids possessing four connected six-membered rings, while tricyclic casuarinines E-H (5-8) are the piperidine ring cleavage products. In particular, casuarinine I (9) has an unprecedented five-membered tetrahydropyrrole ring instead of the piperidine ring. A plausible biosynthetic pathway to 9 is proposed. Among the compounds reported, casuarinine H (8) exhibited significant neuroprotective effect against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells, while casuarinines C (3) and I (9) showed moderate inhibitory activity against acetylcholinesterase (AChE).
ESTHER : Tang_2013_J.Nat.Prod_76_1475
PubMedSearch : Tang_2013_J.Nat.Prod_76_1475
PubMedID: 23941108

Title : Investigating the Antioxidant and Acetylcholinesterase Inhibition Activities of Gossypium herbaceam - Zhao_2013_Molecules_18_951
Author(s) : Zhao Y , Dou J , Wu T , Aisa HA
Ref : Molecules , 18 :951 , 2013
Abstract : Our previous research showed that standardized extract from the flowers of the Gossypium herbaceam labeled GHE had been used in clinical trials for its beneficial effects on brain functions, particularly in connection with age-related dementia and Alzheimer's disease (AD). The aim of this work was to determine the components of this herb and the individual constituents of GHE. In order to better understand this herb for AD treatment, we investigated the acetylcholinesterase (AChE) inhibition and antioxidant activity of GHE as well as the protective effects to PC12 cells against cytotoxicity induced by tertiary butyl hydroperoxide (tBHP) using in vitro assays. The antioxidant activities were assessed by measuring their capabilities for scavenging 1,1-diphenyl-2-picylhydrazyl (DPPH) and 2-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical as well as in inhibiting lipid peroxidation. Our data showed that GHE exhibited certain activities against AChE and also is an efficient free radical scavenger, which may be helpful in preventing or alleviating patients suffering from AD.
ESTHER : Zhao_2013_Molecules_18_951
PubMedSearch : Zhao_2013_Molecules_18_951
PubMedID: 23344203

Title : Choline acetate enhanced the catalytic performance of Candida rogusa lipase in AOT reverse micelles - Xue_2013_Colloids.Surf.B.Biointerfaces_105C_81
Author(s) : Xue L , Zhao Y , Yu L , Sun Y , Yan K , Li Y , Huang X , Qu Y
Ref : Colloids Surf B Biointerfaces , 105C :81 , 2013
Abstract : Choline acetate is an ionic liquid composed of a kosmotropic anion and a chaotropic cation. According to Hofmeister series, a kosmotropic anion and/or a chaotropic cation could stabilize an enzyme, thereby facilitating the retention of the catalytic activity of the enzyme. In this work, we first report the influence of choline acetate on the activity and stability of lipase in AOT/water/isooctane reverse micelles. The indicator reaction is the lipase-catalyzed hydrolysis of 4-nitrophenyl butyrate. The results show that a low level of choline acetate does not affect the microstructure of the AOT reverse micelles, but the ionic liquid can improve the catalytic efficiency of lipase. Fluorescence spectra show that a high level of choline acetate has an impact on the conformation of lipase, so the activation is mainly due to the influence of choline acetate on the nucleophilicity of water. Infrared spectra demonstrate that choline acetate can form stronger hydrogen bonds with water surrounding lipase, and therefore enhance the nucleophilicity of the water, which makes it easier to attack the acyl enzyme intermediate, thereby increasing the activity of the lipase-catalyzed hydrolysis of the ester. A study on the stability of lipase in AOT reverse micelles indicates that the ionic liquid is able to maintain the activity of lipase to a certain extent. The effect of choline acetate is consistent with that predicted based on Hofmeister series.
ESTHER : Xue_2013_Colloids.Surf.B.Biointerfaces_105C_81
PubMedSearch : Xue_2013_Colloids.Surf.B.Biointerfaces_105C_81
PubMedID: 23352950

Title : The duck genome and transcriptome provide insight into an avian influenza virus reservoir species - Huang_2013_Nat.Genet_45_776
Author(s) : Huang Y , Li Y , Burt DW , Chen H , Zhang Y , Qian W , Kim H , Gan S , Zhao Y , Li J , Yi K , Feng H , Zhu P , Li B , Liu Q , Fairley S , Magor KE , Du Z , Hu X , Goodman L , Tafer H , Vignal A , Lee T , Kim KW , Sheng Z , An Y , Searle S , Herrero J , Groenen MA , Crooijmans RP , Faraut T , Cai Q , Webster RG , Aldridge JR , Warren WC , Bartschat S , Kehr S , Marz M , Stadler PF , Smith J , Kraus RH , Ren L , Fei J , Morisson M , Kaiser P , Griffin DK , Rao M , Pitel F , Wang J , Li N
Ref : Nat Genet , 45 :776 , 2013
Abstract : The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A viruses. We present the duck genome sequence and perform deep transcriptome analyses to investigate immune-related genes. Our data indicate that the duck possesses a contractive immune gene repertoire, as in chicken and zebra finch, and this repertoire has been shaped through lineage-specific duplications. We identify genes that are responsive to influenza A viruses using the lung transcriptomes of control ducks and ones that were infected with either a highly pathogenic (A/duck/Hubei/49/05) or a weakly pathogenic (A/goose/Hubei/65/05) H5N1 virus. Further, we show how the duck's defense mechanisms against influenza infection have been optimized through the diversification of its beta-defensin and butyrophilin-like repertoires. These analyses, in combination with the genomic and transcriptomic data, provide a resource for characterizing the interaction between host and influenza viruses.
ESTHER : Huang_2013_Nat.Genet_45_776
PubMedSearch : Huang_2013_Nat.Genet_45_776
PubMedID: 23749191
Gene_locus related to this paper: anapl-BCHE , anapl-r0lw36 , anapl-r0m5n4 , anapl-thioe , anapl-u3iqr9 , anapl-r0l4n7 , anapl-u3j4v8 , anapl-u3icy5 , anapl-u3ivv9 , anapl-u3j4g1 , anapl-u3j4i2 , anapl-u3j4v5 , anapl-r0kv25 , anapl-u3ild2 , anapl-u3imh5 , anapl-b6dzk9 , anapl-u3imp7 , anapl-u3i5h5 , anapl-u3id17 , anapl-r0m1y3 , anapl-r0lhc4 , anapl-r0ktn0 , anapl-r0l8l1 , anapl-r0lin6 , anapl-r0jhf3

Title : 3-Hydroxybutyrate methyl ester as a potential drug against Alzheimer's disease via mitochondria protection mechanism - Zhang_2013_Biomaterials_34_7552
Author(s) : Zhang J , Cao Q , Li S , Lu X , Zhao Y , Guan JS , Chen JC , Wu Q , Chen GQ
Ref : Biomaterials , 34 :7552 , 2013
Abstract : Alzheimer's disease (AD) is induced by many reasons, including decreased cellular utilization of glucose and brain cell mitochondrial damages. Degradation product of microbially synthesized polyhydroxybutyrate (PHB), namely, 3-hydroxybutyrate (3HB), can be an alternative to glucose during sustained hypoglycemia. In this study, the derivative of 3HB, 3-hydroxybutyrate methyl ester (HBME), was used by cells as an alternative to glucose. HBME inhibited cell apoptosis under glucose deprivation, rescued activities of mitochondrial respiratory chain complexes that were impaired in AD patients and decreased the generation of ROS. Meanwhile, HBME stabilized the mitochondrial membrane potential. In vivo studies showed that HBME crossed the blood brain barrier easier compared with charged 3HB, resulting in a better bioavailability. AD mice treated with HBME performed significantly better (p < 0.05) in the Morris water maze compared with other groups, demonstrating that HBME has a positive in vivo pharmaceutical effect to improve the spatial learning and working memory of mice. A reduced amyloid-beta deposition in mouse brains after intragastric administration of HBME was also observed. Combined with the in vitro and in vivo results, HBME was proposed to be a drug candidate against AD, its working mechanism appeared to be mediated by various effects of protecting mitochondrial damages.
ESTHER : Zhang_2013_Biomaterials_34_7552
PubMedSearch : Zhang_2013_Biomaterials_34_7552
PubMedID: 23849878

Title : Draft genome of the mountain pine beetle, Dendroctonus ponderosae Hopkins, a major forest pest - Keeling_2013_Genome.Biol_14_R27
Author(s) : Keeling CI , Yuen MM , Liao NY , Roderick Docking T , Chan SK , Taylor GA , Palmquist DL , Jackman SD , Nguyen A , Li M , Henderson H , Janes JK , Zhao Y , Pandoh P , Moore R , Sperling FA , DP WH , Birol I , Jones SJ , Bohlmann J
Ref : Genome Biol , 14 :R27 , 2013
Abstract : BACKGROUND: The mountain pine beetle, Dendroctonus ponderosae Hopkins, is the most serious insect pest of western North American pine forests. A recent outbreak destroyed more than 15 million hectares of pine forests, with major environmental effects on forest health, and economic effects on the forest industry. The outbreak has in part been driven by climate change, and will contribute to increased carbon emissions through decaying forests.
RESULTS: We developed a genome sequence resource for the mountain pine beetle to better understand the unique aspects of this insect's biology. A draft de novo genome sequence was assembled from paired-end, short-read sequences from an individual field-collected male pupa, and scaffolded using mate-paired, short-read genomic sequences from pooled field-collected pupae, paired-end short-insert whole-transcriptome shotgun sequencing reads of mRNA from adult beetle tissues, and paired-end Sanger EST sequences from various life stages. We describe the cytochrome P450, glutathione S-transferase, and plant cell wall-degrading enzyme gene families important to the survival of the mountain pine beetle in its harsh and nutrient-poor host environment, and examine genome-wide single-nucleotide polymorphism variation. A horizontally transferred bacterial sucrose-6-phosphate hydrolase was evident in the genome, and its tissue-specific transcription suggests a functional role for this beetle.
CONCLUSIONS: Despite Coleoptera being the largest insect order with over 400,000 described species, including many agricultural and forest pest species, this is only the second genome sequence reported in Coleoptera, and will provide an important resource for the Curculionoidea and other insects.
ESTHER : Keeling_2013_Genome.Biol_14_R27
PubMedSearch : Keeling_2013_Genome.Biol_14_R27
PubMedID: 23537049
Gene_locus related to this paper: denpd-j3jwt7 , denpd-j3jt98 , denpd-j3jtm4 , denpd-j3jub5 , denpd-j3juf0 , denpd-j3jun6 , denpd-j3jvv1 , denpd-j3jw22 , denpd-j3jwb0 , denpd-j3jwv2 , denpd-j3jwv4 , denpd-j3jwz8 , denpd-j3jx26 , denpd-j3jx34 , denpd-j3jxh9 , denpd-j3jxv6 , denpd-j3jy62 , denpd-j3jy79 , denpd-j3jyn7 , denpd-j3jz59 , denpd-j3jzj2 , denpd-n6umq8 , denpd-j3jyt2 , denpd-u4upn0.1 , denpd-n6t493 , denpd-u4up38 , denpd-n6uaj3 , denpd-u4umd6 , denpd-u4u438 , denpd-n6ue67.1 , denpd-n6ue67.2 , denpd-u4uj02 , denpd-u4ux57 , denpd-n6uar4 , denpd-n6uu12 , denpd-n6trb6 , denpd-u4u8e2 , denpd-j3jv02

Title : Complete Genome Sequence of the Industrial Strain Gluconobacter oxydans H24 - Ge_2013_Genome.Announc_1_e00003
Author(s) : Ge X , Zhao Y , Hou W , Zhang W , Chen W , Wang J , Zhao N , Lin J , Wang W , Chen M , Wang Q , Jiao Y , Yuan Z , Xiong X
Ref : Genome Announc , 1 : , 2013
Abstract : Gluconobacter oxydans is characterized by its ability to incompletely oxidize carbohydrates and alcohols. The high yields of its oxidation products and complete secretion into the medium make it important for industrial use. We report the finished genome sequence of Gluconobacter oxydans H24, an industrial strain with high l-sorbose productivity.
ESTHER : Ge_2013_Genome.Announc_1_e00003
PubMedSearch : Ge_2013_Genome.Announc_1_e00003
PubMedID: 23472221
Gene_locus related to this paper: gluth-t1e0l0 , gluoy-k7si88 , gluoy-k7smm7

Title : Protection of salvianolic acid A on rat brain from ischemic damage via soluble epoxide hydrolase inhibition - Wang_2012_J.Asian.Nat.Prod.Res_14_1084
Author(s) : Wang SB , Pang XB , Zhao Y , Wang YH , Zhang L , Yang XY , Fang LH , Du GH
Ref : J Asian Nat Prod Res , 14 :1084 , 2012
Abstract : Epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH) have been associated with ischemic stroke. Salvianolic acid A (SAA) is proved to display potent cerebroprotection. However, little information is available about the link between them. This study aimed to investigate whether SAA exhibits its protective effects in rats subjected to middle cerebral artery occlusion (MCAO) through sEH and EETs. The results showed that SAA treatment ameliorated neurological deficits and reduced infarct volume. Notably, the beneficial effects of SAA were attenuated by co-administration of (14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE)), a putative selective EETs antagonist. Furthermore, SAA increased the 14,15-EET levels in the blood and brain of sham and MCAO rats. Assay for hydrolase activity showed that 1 and 3 mg/kg of SAA significantly diminished brain sEH activity of MCAO rats. A fluorescent assay in vitro indicated that SAA could inhibit recombinant human sEH activity in a concentration-dependent manner (IC(50) = 1.62 mumol/l). Immunohistochemical analysis showed that SAA at the doses of 1 and 3 mg/kg significantly decreased sEH protein expression in hippocampus CA1 region of MCAO rats. In conclusion, cerebral protection of SAA is mediated, at least in part, via inhibiting sEH to increase EETs levels.
ESTHER : Wang_2012_J.Asian.Nat.Prod.Res_14_1084
PubMedSearch : Wang_2012_J.Asian.Nat.Prod.Res_14_1084
PubMedID: 23106500

Title : CutA divalent cation tolerance homolog (Escherichia coli) (CUTA) regulates beta-cleavage of beta-amyloid precursor protein (APP) through interacting with beta-site APP cleaving protein 1 (BACE1) - Zhao_2012_J.Biol.Chem_287_11141
Author(s) : Zhao Y , Wang Y , Hu J , Zhang X , Zhang YW
Ref : Journal of Biological Chemistry , 287 :11141 , 2012
Abstract : Accumulation of the neurotoxic beta-amyloid (Abeta) peptide in the brain is central to the pathogenesis of Alzheimer disease. Abeta is derived from the beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases, and the production of Abeta is greatly affected by the subcellular localization of these factors. CUTA, the mammalian CutA divalent cation tolerance homolog (E. coli), has been proposed to mediate acetylcholinesterase activity and copper homeostasis, which are important in Alzheimer disease pathology. However, the exact function of CUTA remains largely unclear. Here we show that human CUTA has several variants that differ in their N-terminal length and are separated as heavy (H) and light (L) components. The H component has the longest N terminus and is membrane-associated, whereas the L component is N-terminally truncated at various sites and localized in the cytosol. Importantly, we demonstrate that the H component of CUTA interacts through its N terminus with the transmembrane domain of beta-site APP cleaving enzyme 1 (BACE1), the putative beta-secretase, mainly in the Golgi/trans-Golgi network. Overexpression and RNA interference knockdown of CUTA can reduce and increase BACE1-mediated APP processing/Abeta secretion, respectively. RNA interference of CUTA decelerates intracellular trafficking of BACE1 from the Golgi/trans-Golgi network to the cell surface and reduces the steady-state level of cell surface BACE1. Our results identify the H component of CUTA as a novel BACE1-interacting protein that mediates the intracellular trafficking of BACE1 and the processing of APP to Abeta.
ESTHER : Zhao_2012_J.Biol.Chem_287_11141
PubMedSearch : Zhao_2012_J.Biol.Chem_287_11141
PubMedID: 22351782

Title : Pan-genomic analysis provides insights into the genomic variation and evolution of Salmonella Paratyphi A - Liang_2012_PLoS.One_7_e45346
Author(s) : Liang W , Zhao Y , Chen C , Cui X , Yu J , Xiao J , Kan B
Ref : PLoS ONE , 7 :e45346 , 2012
Abstract : Salmonella Paratyphi A (S. Paratyphi A) is a highly adapted, human-specific pathogen that causes paratyphoid fever. Cases of paratyphoid fever have recently been increasing, and the disease is becoming a major public health concern, especially in Eastern and Southern Asia. To investigate the genomic variation and evolution of S. Paratyphi A, a pan-genomic analysis was performed on five newly sequenced S. Paratyphi A strains and two other reference strains. A whole genome comparison revealed that the seven genomes are collinear and that their organization is highly conserved. The high rate of substitutions in part of the core genome indicates that there are frequent homologous recombination events. Based on the changes in the pan-genome size and cluster number (both in the core functional genes and core pseudogenes), it can be inferred that the sharply increasing number of pseudogene clusters may have strong correlation with the inactivation of functional genes, and indicates that the S. Paratyphi A genome is being degraded.
ESTHER : Liang_2012_PLoS.One_7_e45346
PubMedSearch : Liang_2012_PLoS.One_7_e45346
PubMedID: 23028950

Title : Complete genome sequence of the bacterium Methylovorus sp. strain MP688, a high-level producer of pyrroloquinolone quinone - Xiong_2011_J.Bacteriol_193_1012
Author(s) : Xiong XH , Zhi JJ , Yang L , Wang JH , Zhao Y , Wang X , Cui YJ , Dong F , Li MX , Yang YX , Wei N , An JJ , Du BH , Liang L , Zhang JS , Zhou W , Cheng SF , He T , Wang L , Chen HP , Liu DS , Zhang WC
Ref : Journal of Bacteriology , 193 :1012 , 2011
Abstract : Methylotrophic bacteria are widespread microbes which can use one carbon compound as their only carbon and energy sources. Here we report the finished, annotated genome sequence of the methylotrophic bacterium Methylovorus sp. strain MP688, which was isolated from soil for high-level production of pyrroloquinolone quinone (PQQ) in our lab.
ESTHER : Xiong_2011_J.Bacteriol_193_1012
PubMedSearch : Xiong_2011_J.Bacteriol_193_1012
PubMedID: 21148725
Gene_locus related to this paper: mets6-e4qna9 , mets6-e4qnd9 , metsd-c6xa50

Title : Genome sequence analyses of Pseudomonas savastanoi pv. glycinea and subtractive hybridization-based comparative genomics with nine pseudomonads - Qi_2011_PLoS.One_6_e16451
Author(s) : Qi M , Wang D , Bradley CA , Zhao Y
Ref : PLoS ONE , 6 :e16451 , 2011
Abstract : Bacterial blight, caused by Pseudomonas savastanoi pv. glycinea (Psg), is a common disease of soybean. In an effort to compare a current field isolate with one isolated in the early 1960s, the genomes of two Psg strains, race 4 and B076, were sequenced using 454 pyrosequencing. The genomes of both Psg strains share more than 4,900 highly conserved genes, indicating very low genetic diversity between Psg genomes. Though conserved, genome rearrangements and recombination events occur commonly within the two Psg genomes. When compared to each other, 437 and 163 specific genes were identified in B076 and race 4, respectively. Most specific genes are plasmid-borne, indicating that acquisition and maintenance of plasmids may represent a major mechanism to change the genetic composition of the genome and even acquire new virulence factors. Type three secretion gene clusters of Psg strains are near identical with that of P. savastanoi pv. phaseolicola (Pph) strain 1448A and they shared 20 common effector genes. Furthermore, the coronatine biosynthetic cluster is present on a large plasmid in strain B076, but not in race 4. In silico subtractive hybridization-based comparative genomic analyses with nine sequenced phytopathogenic pseudomonads identified dozens of specific islands (SIs), and revealed that the genomes of Psg strains are more similar to those belonging to the same genomospecies such as Pph 1448A than to other phytopathogenic pseudomonads. The number of highly conserved genes (core genome) among them decreased dramatically when more genomes were included in the subtraction, suggesting the diversification of pseudomonads, and further indicating the genome heterogeneity among pseudomonads. However, the number of specific genes did not change significantly, suggesting these genes are indeed specific in Psg genomes. These results reinforce the idea of a species complex of P. syringae and support the reclassification of P. syringae into different species.
ESTHER : Qi_2011_PLoS.One_6_e16451
PubMedSearch : Qi_2011_PLoS.One_6_e16451
PubMedID: 21304594
Gene_locus related to this paper: pse14-q48cb3 , pse14-q48ck7 , pse14-q48e33 , pse14-q48ji2 , pse14-q48nt0 , pse14-q48pq2 , psesy-PIP , psesy-PSPTO3135 , pseu2-q4zwv7 , psesg-e7p3i0

Title : Acetylcholinesterase, a key prognostic predictor for hepatocellular carcinoma, suppresses cell growth and induces chemosensitization - Zhao_2011_Hepatology_53_493
Author(s) : Zhao Y , Wang X , Wang T , Hu X , Hui X , Yan M , Gao Q , Chen T , Li J , Yao M , Wan D , Gu J , Fan J , He X
Ref : Hepatology , 53 :493 , 2011
Abstract : UNLABELLED: Acetylcholinesterase (ACHE) plays important roles in the cholinergic system, and its dysregulation is involved in a variety of human diseases. However, the roles and implications of ACHE in hepatocellular carcinoma (HCC) remain elusive. Here we demonstrate that ACHE was significantly down-regulated in the cancerous tissues of 69.2% of HCC patients, and the low ACHE expression in HCC was correlated with tumor aggressiveness, an elevated risk of postoperative recurrence, and a low survival rate. Both the recombinant ACHE protein and the enhanced expression of ACHE significantly inhibited HCC cell growth in vitro and tumorigenicity in vivo. Further study showed that ACHE suppressed cell proliferation via its enzymatic activity of acetylcholine catalysis and degradation. Moreover, ACHE could inactivate mitogen-activated protein kinase and phosphatidyl inositol-3'-phosphate kinase/protein kinase B pathways in HCC cells and thereby increase the activation of glycogen synthase kinase 3beta and lead to beta-catenin degradation and cyclin D1 suppression. In addition, increased ACHE expression could remarkably sensitize HCC cells to chemotherapeutic drugs (i.e., adriamycin and etoposide). CONCLUSION: For the first time, we describe the function of ACHE as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways, and the drug sensitivity of HCC cells. ACHE is a promising independent prognostic predictor for HCC recurrence and the survival of HCC patients. These findings provide new insights into potential strategies for drug discovery and improved HCC treatment.
ESTHER : Zhao_2011_Hepatology_53_493
PubMedSearch : Zhao_2011_Hepatology_53_493
PubMedID: 21274871

Title : Neuroprotection against excitotoxic and ischemic insults by bis(12)-hupyridone, a novel anti-acetylcholinesterase dimer, possibly via acting on multiple targets - Zhao_2011_Brain.Res_1421_100
Author(s) : Zhao Y , Dou J , Luo J , Li W , Chan HH , Cui W , Zhang H , Han R , Carlier PR , Zhang X , Han Y
Ref : Brain Research , 1421 :100 , 2011
Abstract : The activation of N-methyl-d-aspartate (NMDA) receptors by excessive release of glutamate is involved in the pathogenesis of ischemic stroke. Thus the NMDA receptor has become an attractive therapeutic target for the development of neuroprotectants, especially from antagonists with moderate to low affinity. In the current study, NMDA receptor blockage and neuroprotective effects of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase inhibitor derived from a naturally occurring monomeric analog huperzine A, were investigated in vitro and in vivo. In primary rat cerebellar granule neurons, B12H (0.1 nM to 1 muM) prevented glutamate-induced apoptosis in a concentration- and time-dependent manner. Receptor-ligand binding analysis showed that B12H competed with [(3)H]MK801 with a K(i) value of 7.7 muM. In the 2-hour middle cerebral artery occlusion rat model, B12H (0.4 and 0.8 mg/kg, 30 min before-ischemia and 15 min post-ischemia, i.p.) significantly attenuated ischemia-induced apoptosis in the penumbra region, improved neurological behavior impairment, and decreased cerebral infarct volume, cerebral edema and neuronal apoptosis in the stroke model. Together, these results showed that B12H moderately blocks NMDA receptors at MK801 site and exerts neuroprotection against excitotoxic and ischemic insults in vitro and in vivo. Combined with our previous publications, we conjecture that B12H might exert neuroprotection via acting on multiple targets.
ESTHER : Zhao_2011_Brain.Res_1421_100
PubMedSearch : Zhao_2011_Brain.Res_1421_100
PubMedID: 21978549

Title : In vivo toxicity and immunogenicity of wheat germ agglutinin conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal delivery to the brain - Liu_2011_Toxicol.Appl.Pharmacol_251_79
Author(s) : Liu Q , Shao X , Chen J , Shen Y , Feng C , Gao X , Zhao Y , Li J , Zhang Q , Jiang X
Ref : Toxicol Appl Pharmacol , 251 :79 , 2011
Abstract : Biodegradable polymer-based nanoparticles have been widely studied to deliver therapeutic agents to the brain after intranasal administration. However, knowledge as to the side effects of nanoparticle delivery system to the brain is limited. The aim of this study was to investigate the in vivo toxicity and immunogenicity of wheat germ agglutinin (WGA) conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (WGA-NP) after intranasal instillation. Sprague-Dawley rats were intranasally given WGA-NP for 7 continuous days. Amino acid neurotransmitters, lactate dehydrogenase (LDH) activity, reduced glutathione (GSH), acetylcholine, acetylcholinesterase activity, tumor necrosis factor alpha (TNF-alpha) and interleukin-8 (IL-8) in rat olfactory bulb (OB) and brain were measured to estimate the in vivo toxicity of WGA-NP. Balb/C mice were intranasally immunized by WGA-NP and then WGA-specific antibodies in serum and nasal wash were detected by indirect ELISA. WGA-NP showed slight toxicity to brain tissue, as evidenced by increased glutamate level in rat brain and enhanced LDH activity in rat OB. No significant changes in acetylcholine level, acetylcholinesterase activity, GSH level, TNF-alpha level and IL-8 level were observed in rat OB and brain for the WGA-NP group. WGA-specific antibodies in mice serum and nasal wash were not increased after two intranasal immunizations of WGA-NP. These results demonstrate that WGA-NP is a safe carrier system for intranasal delivery of therapeutic agents to the brain.
ESTHER : Liu_2011_Toxicol.Appl.Pharmacol_251_79
PubMedSearch : Liu_2011_Toxicol.Appl.Pharmacol_251_79
PubMedID: 21163285

Title : Complete genome sequence of Bacillus thuringiensis subsp. chinensis strain CT-43 - He_2011_J.Bacteriol_193_3407
Author(s) : He J , Wang J , Yin W , Shao X , Zheng H , Li M , Zhao Y , Sun M , Wang S , Yu Z
Ref : Journal of Bacteriology , 193 :3407 , 2011
Abstract : Bacillus thuringiensis has been widely used as an agricultural biopesticide for a long time. As a producing strain, B. thuringiensis subsp. chinensis strain CT-43 is highly toxic to lepidopterous and dipterous insects. It can form various parasporal crystals consisting of Cry1Aa3, Cry1Ba1, Cry1Ia14, Cry2Aa9, and Cry2Ab1. During fermentation, it simultaneously generates vegetative insecticidal protein Vip3Aa10 and the insecticidal nucleotide analogue thuringiensin. Here, we report the finished, annotated genome sequence of B. thuringiensis strain CT-43.
ESTHER : He_2011_J.Bacteriol_193_3407
PubMedSearch : He_2011_J.Bacteriol_193_3407
PubMedID: 21551307
Gene_locus related to this paper: bacan-BA3703 , bacan-BA5009 , bacan-DHBF , bacce-BC0192 , bacce-BC0968 , bacce-BC1788 , bacce-BC2141 , bacce-BC4854 , bacce-BC4862 , bacce-PHAC , baccr-pepx

Title : Isoflurane-induced spatial memory impairment in mice is prevented by the acetylcholinesterase inhibitor donepezil - Su_2011_PLoS.One_6_e27632
Author(s) : Su D , Zhao Y , Wang B , Xu H , Li W , Chen J , Wang X
Ref : PLoS ONE , 6 :e27632 , 2011
Abstract : Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg) or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2%) for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE), choline acetylase (ChAT) and alpha7 nicotinic receptor (alpha7-nAChR) were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or alpha7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.
ESTHER : Su_2011_PLoS.One_6_e27632
PubMedSearch : Su_2011_PLoS.One_6_e27632
PubMedID: 22114680

Title : Over-expression of human lipoprotein lipase in mouse mammary glands leads to reduction of milk triglyceride and delayed growth of suckling pups - Wang_2011_PLoS.One_6_e20895
Author(s) : Wang Y , Tong J , Li S , Zhang R , Chen L , Zheng M , Wang M , Liu G , Dai Y , Zhao Y , Li N
Ref : PLoS ONE , 6 :e20895 , 2011
Abstract : BACKGROUND: The mammary gland is a conserved site of lipoprotein lipase expression across species and lipoprotein lipase attachment to the luminal surface of mammary gland vascular endothelial cells has been implicated in the direction of circulating triglycerides into milk synthesis during lactation. PRINCIPAL FINDINGS: Here we report generation of transgenic mice harboring a human lipoprotein lipase gene driven by a mammary gland-specific promoter. Lipoprotein lipase levels in transgenic milk was raised to 0.16 mg/ml, corresponding to an activity of 8772.95 mU/ml. High lipoprotein lipase activity led to a significant reduction of triglyceride concentration in milk, but other components were largely unchanged. Normal pups fed with transgenic milk showed inferior growth performances compared to those fed with normal milk. CONCLUSION: Our study suggests a possibility to reduce the triglyceride content of cow milk using transgenic technology.
ESTHER : Wang_2011_PLoS.One_6_e20895
PubMedSearch : Wang_2011_PLoS.One_6_e20895
PubMedID: 21698114

Title : Preventing H(2)O(2)-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2\/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone - Cui_2011_Brain.Res_1394_14
Author(s) : Cui W , Li W , Zhao Y , Mak SH , Gao Y , Luo J , Zhang H , Liu Y , Carlier PR , Rong J , Han YF
Ref : Brain Research , 1394 :14 , 2011
Abstract : Oxidative stress-induced apoptosis plays a critical role in the pathogenesis of various neurodegenerative disorders. In this study, the neuroprotective properties of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase (AChE) inhibitor modified from a naturally occurring monomeric analogue, huperzine A, on H(2)O(2)-induced neurotoxicity were investigated in cerebellar granule neurons (CGNs). Exposure of CGNs to H(2)O(2) resulted in apoptosis which could be attenuated by the pre-treatment of B12H (0.3-5 nM) in a concentration-dependent manner. Moreover, tacrine and neostigmine failed to prevent neurotoxicity, indicating that the neuroprotection of B12H might not be due to its inhibitory property of AChE enzymatic activity. Increased activation of extracellular signal-regulated kinase (ERK) and decreased activation of glycogen synthase kinase (GSK) 3beta were observed after H(2)O(2) exposure, and B12H reversed the altered activation of GSK3beta, but not that of ERK. Furthermore, using vascular endothelial growth factor (VEGF), phospho-VEGF receptor-2 (VEGFR-2) antibody, a specific VEGFR-2 inhibitor (PTK787/ZK222584) and specific phosphoinositide 3-kinase inhibitors (LY294002 and wortmannin), it was found that VEGF prevented H(2)O(2)-induced neuronal loss from activating the VEGF/VEGFR-2 system and that the observed B12H neuroprotective effects might share the same signaling pathway. These findings strongly suggest that B12H prevents H(2)O(2)-induced neuronal apoptosis independent of inhibiting AChE, but through regulating VEGFR-2/Akt/GSK3beta signaling pathway.
ESTHER : Cui_2011_Brain.Res_1394_14
PubMedSearch : Cui_2011_Brain.Res_1394_14
PubMedID: 21315693

Title : Retinoblastoma-binding proteins 4 and 9 are important for human pluripotent stem cell maintenance - O'Connor_2011_Exp.Hematol_39_866
Author(s) : O'Connor MD , Wederell E , Robertson G , Delaney A , Morozova O , Poon SS , Yap D , Fee J , Zhao Y , McDonald H , Zeng T , Hirst M , Marra MA , Aparicio SA , Eaves CJ
Ref : Experimental Hematology , 39 :866 , 2011
Abstract : OBJECTIVE: The molecular mechanisms that maintain human pluripotent stem (PS) cells are not completely understood. Here we sought to identify new candidate PS cell regulators to facilitate future improvements in their generation, expansion, and differentiation. MATERIALS AND METHODS: We used bioinformatic analyses of multiple serial-analysis-of-gene-expression libraries (generated from human PS cells and their differentiated derivatives), together with small interfering RNA (siRNA) screening to identify candidate pluripotency regulators. Validation of candidate regulators involved promoter analyses, Affymetrix profiling, real-time PCR, and immunoprecipitation. RESULTS: Promoter analysis of genes differentially expressed across multiple serial-analysis-of-gene-expression libraries identified E2F motifs in the promoters of many PS cell-specific genes (e.g., POU5F1, NANOG, SOX2, FOXD3). siRNA analyses identified two retinoblastoma binding proteins (RBBP4, RBBP9) as required for maintenance of multiple human PS cell types. Both RBBPs were bound to RB in human PS cells, and E2F motifs were present in the promoters of genes whose expression was altered by decreasing RBBP4 and RBBP9 expression. Affymetrix and real-time PCR studies of siRNA-treated human PS cells showed that reduced RBBP4 or RBBP9 expression concomitantly decreased expression of POU5F1, NANOG, SOX2, and/or FOXD3 plus certain cell cycle genes (e.g., CCNA2, CCNB1), while increasing expression of genes involved in organogenesis (particularly neurogenesis). CONCLUSIONS: These results reveal new candidate positive regulators of human PS cells, providing evidence of their ability to regulate expression of pluripotency, cell cycle, and differentiation genes in human PS cells. These data provide valuable new leads for further elucidating mechanisms of human pluripotency.
ESTHER : O'Connor_2011_Exp.Hematol_39_866
PubMedSearch : O'Connor_2011_Exp.Hematol_39_866
PubMedID: 21689726
Gene_locus related to this paper: human-RBBP9

Title : Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders - Zhao_2010_Mol.Psychiatry_15_286
Author(s) : Zhao Y , Fung C , Shin D , Shin BC , Thamotharan S , Sankar R , Ehninger D , Silva A , Devaskar SU
Ref : Mol Psychiatry , 15 :286 , 2010
Abstract : Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.
ESTHER : Zhao_2010_Mol.Psychiatry_15_286
PubMedSearch : Zhao_2010_Mol.Psychiatry_15_286
PubMedID: 19506559

Title : Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin - Luo_2010_J.Biol.Chem_285_19947
Author(s) : Luo J , Li W , Zhao Y , Fu H , Ma DL , Tang J , Li C , Peoples RW , Li F , Wang Q , Huang P , Xia J , Pang Y , Han Y
Ref : Journal of Biological Chemistry , 285 :19947 , 2010
Abstract : Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and gamma-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [(3)H]MK-801 with a K(i) value of 0.27 mum, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.
ESTHER : Luo_2010_J.Biol.Chem_285_19947
PubMedSearch : Luo_2010_J.Biol.Chem_285_19947
PubMedID: 20404346

Title : Genomic analyses of the microsporidian Nosema ceranae, an emergent pathogen of honey bees - Cornman_2009_PLoS.Pathog_5_e1000466
Author(s) : Cornman RS , Chen YP , Schatz MC , Street C , Zhao Y , Desany B , Egholm M , Hutchison S , Pettis JS , Lipkin WI , Evans JD
Ref : PLoS Pathog , 5 :e1000466 , 2009
Abstract : Recent steep declines in honey bee health have severely impacted the beekeeping industry, presenting new risks for agricultural commodities that depend on insect pollination. Honey bee declines could reflect increased pressures from parasites and pathogens. The incidence of the microsporidian pathogen Nosema ceranae has increased significantly in the past decade. Here we present a draft assembly (7.86 MB) of the N. ceranae genome derived from pyrosequence data, including initial gene models and genomic comparisons with other members of this highly derived fungal lineage. N. ceranae has a strongly AT-biased genome (74% A+T) and a diversity of repetitive elements, complicating the assembly. Of 2,614 predicted protein-coding sequences, we conservatively estimate that 1,366 have homologs in the microsporidian Encephalitozoon cuniculi, the most closely related published genome sequence. We identify genes conserved among microsporidia that lack clear homology outside this group, which are of special interest as potential virulence factors in this group of obligate parasites. A substantial fraction of the diminutive N. ceranae proteome consists of novel and transposable-element proteins. For a majority of well-supported gene models, a conserved sense-strand motif can be found within 15 bases upstream of the start codon; a previously uncharacterized version of this motif is also present in E. cuniculi. These comparisons provide insight into the architecture, regulation, and evolution of microsporidian genomes, and will drive investigations into honey bee-Nosema interactions.
ESTHER : Cornman_2009_PLoS.Pathog_5_e1000466
PubMedSearch : Cornman_2009_PLoS.Pathog_5_e1000466
PubMedID: 19503607
Gene_locus related to this paper: nosce-c4v7s6 , nosce-c4vae8

Title : An organophosphorus hapten used in the preparation of monoclonal antibody and as an active immunization vaccine in the detoxication of soman poisoning - Jia_2009_Toxicol.Lett_187_45
Author(s) : Jia P , Wang Y , Yu M , Wu J , Yang R , Zhao Y , Zhou L
Ref : Toxicol Lett , 187 :45 , 2009
Abstract : Soman is an organophosphorus neurotoxin which inhibits the activity of acetylcholinesterase (AChE). The goal of this work was to find out whether antibodies against an organophosphorus hapten could protect mice from soman toxicity. An organophosphorus hapten P6 was synthesized. Its chemical conjugates with limulus polyphemus hemocyanin and bovine serum albumin were used as immune antigen (P6-LPH) and detection antigen (P6-BSA), respectively. Eight hybridoma cell lines secreting monoclonal antibodies (Mabs) were established. The binding reactivities of Mabs with P6 and soman were determined by competitive inhibition enzyme immunoassay (CIEIA). All antibodies recognized P6 and four of them (2C10, 3G1, 3B9 and 3C11) combined with soman. The IC(50) was 10(-6.5) to 10(-5.3)mol/l for P6 and 10(-5) to 10(-3.5)mol/l for soman. Furthermore, Mab 3G1 reduced the inhibition of AChE activity by soman in vitro. When soman was pre-incubated with Mabs before being injected into mice, soman potency was reduced, indicating that Mabs could protect mice from soman toxicity. In an active immunization regimen, mice immunized with P6-LPH and challenged with 0.15mg/kg soman injected subcutaneously, had fewer signs of intoxication and a higher survival rate compared with control mice. These results demonstrate that the anti-soman antibodies have proper characteristics as scavengers in the detoxication of soman poisoning.
ESTHER : Jia_2009_Toxicol.Lett_187_45
PubMedSearch : Jia_2009_Toxicol.Lett_187_45
PubMedID: 19429243

Title : The measurement of serum cholinesterase activities by an integration strategy with expanded linear ranges and negligible substrate-activation - Liao_2009_Clin.Biochem_42_926
Author(s) : Liao F , Yang D , Tang J , Yang X , Liu B , Zhao Y , Zhao L , Liao H , Yu M
Ref : Clinical Biochemistry , 42 :926 , 2009
Abstract : OBJECTIVES: To measure serum cholinesterase (SCHE) with an integration strategy. DESIGN AND METHODS: At 54.0 micromol/L butyrylthiolcholine, SCHE initial rates were calculated with 50.0 micromol/L butyrylthiolcholine and maximal rates via an improved integrated method if substrate consumptions within 5.0 min were over 60%, or were determined by the classical initial rate method. RESULTS: The linear range was from 16 to 1560 nkat/L, and SCHE in clinic sera showed negligible substrate-activation. CONCLUSION: This strategy was effective.
ESTHER : Liao_2009_Clin.Biochem_42_926
PubMedSearch : Liao_2009_Clin.Biochem_42_926
PubMedID: 19101530

Title : Construction of the pharmacophore model of acetylcholinesterase inhibitor - Zhu_2008_Yao.Xue.Xue.Bao_43_267
Author(s) : Zhu Y , Tong XY , Zhao Y , Chen H , Jiang FC
Ref : Yao Xue Xue Bao , 43 :267 , 2008
Abstract : Based on ninety three acetylcholinesterase inhibitors (AChEIs) which have the same mechanism of action but are different in structural characteristics, the pharmacophore model for acetylcholinesterase inhibitor was constructed by the CATALYST system. The optimal pharmacophore model with three hydrophobic units, a ring aromatic unit and a hydrogen-bond acceptor unit were confirmed (Weight = 3.29, RMS = 0.53, total cost-null cost = 62.75, Correl = 0.93, Config = 19.05). This pharmacophore model will act on the double active site of acetylcholinesterase and is able to predict the activity of known acetylcholinesterase inhibitors that are used for clinical treatment of Alzheimer's disease (AD), and can be further used to identify structurally diverse compounds that have higher activity treating with Alzheimer's disease (AD) by virtual screening.
ESTHER : Zhu_2008_Yao.Xue.Xue.Bao_43_267
PubMedSearch : Zhu_2008_Yao.Xue.Xue.Bao_43_267
PubMedID: 18630262

Title : Genome sequence of Aedes aegypti, a major arbovirus vector - Nene_2007_Science_316_1718
Author(s) : Nene V , Wortman JR , Lawson D , Haas B , Kodira C , Tu ZJ , Loftus B , Xi Z , Megy K , Grabherr M , Ren Q , Zdobnov EM , Lobo NF , Campbell KS , Brown SE , Bonaldo MF , Zhu J , Sinkins SP , Hogenkamp DG , Amedeo P , Arensburger P , Atkinson PW , Bidwell S , Biedler J , Birney E , Bruggner RV , Costas J , Coy MR , Crabtree J , Crawford M , Debruyn B , Decaprio D , Eiglmeier K , Eisenstadt E , El-Dorry H , Gelbart WM , Gomes SL , Hammond M , Hannick LI , Hogan JR , Holmes MH , Jaffe D , Johnston JS , Kennedy RC , Koo H , Kravitz S , Kriventseva EV , Kulp D , LaButti K , Lee E , Li S , Lovin DD , Mao C , Mauceli E , Menck CF , Miller JR , Montgomery P , Mori A , Nascimento AL , Naveira HF , Nusbaum C , O'Leary S , Orvis J , Pertea M , Quesneville H , Reidenbach KR , Rogers YH , Roth CW , Schneider JR , Schatz M , Shumway M , Stanke M , Stinson EO , Tubio JM , Vanzee JP , Verjovski-Almeida S , Werner D , White O , Wyder S , Zeng Q , Zhao Q , Zhao Y , Hill CA , Raikhel AS , Soares MB , Knudson DL , Lee NH , Galagan J , Salzberg SL , Paulsen IT , Dimopoulos G , Collins FH , Birren B , Fraser-Liggett CM , Severson DW
Ref : Science , 316 :1718 , 2007
Abstract : We present a draft sequence of the genome of Aedes aegypti, the primary vector for yellow fever and dengue fever, which at approximately 1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae. Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of approximately 4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster. Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of approximately 2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.