Liu W


Full name : Liu Weidong

First name : Weidong

Mail : Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine 1-1 Mokogawacho, Nishinomiya, Hyogo 663-8501

Zip Code :

City :

Country : Japan

Email :

Phone : +81-798-456472

Fax : +81-798-456474

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References (236)

Title : Exploring new galaxies: Perspectives on the discovery of novel PET-degrading enzymes - Mican_2024_Appl.Catal.B.Environmental_342_123404
Author(s) : Mican J , Jaradat DMM , Liu W , Weber G , Mazurenko S , Bornscheuer UT , Damborsky J , Wei R , Bednar D
Ref : Applied Catalysis B: Environmental , 342 :123404 , 2024
Abstract : Polyethylene terephthalate (PET) is a widely used polyester due to its beneficial material properties and low cost. However, PET contributes significantly to the growing problem of plastic waste pollution. Enzymatic PET recycling has emerged as a promising alternative to conventional mechanical and chemical recycling methods. While many PET hydrolases belonging to the a/-hydrolase fold superfamily have been discovered, the wild-type enzymes obtained from natural sources are not optimal for industrial conditions and need to be optimized through rational design or directed evolution to improve their efficiency and stability. This Perspective summarizes case studies of engineered PET hydrolases and proposes a workflow that tightly integrates a variety of in silico and high-throughput approaches for biochemical and structural characterization to accelerate the discovery of PET-degrading enzymes, also with novel structural scaffolds. These biocatalysts could be candidates for developing further innovative plastic recycling techniques.
ESTHER : Mican_2024_Appl.Catal.B.Environmental_342_123404
PubMedSearch : Mican_2024_Appl.Catal.B.Environmental_342_123404

Title : Inhibiting PLA2G7 reverses the immunosuppressive function of intratumoral macrophages and augments immunotherapy response in hepatocellular carcinoma - Zhang_2024_J.Immunother.Cancer_12_e008094
Author(s) : Zhang F , Liu W , Meng F , Jiang Q , Tang W , Liu Z , Lin X , Xue R , Zhang S , Dong L
Ref : J Immunother Cancer , 12 : , 2024
Abstract : BACKGROUND: Hepatocellular carcinoma (HCC) is an exceptionally immunosuppressive malignancy characterized by limited treatment options and a dismal prognosis. Macrophages constitute the primary and heterogeneous immune cell population within the HCC microenvironment. Our objective is to identify distinct subsets of macrophages implicated in the progression of HCC and their resistance to immunotherapy. METHODS: Intratumoral macrophage-specific marker genes were identified via single-cell RNA sequencing analyses. The clinical relevance of phospholipase A2 Group VII (PLA2G7), a pivotal enzyme in phospholipid metabolism, was assessed in patients with HCC through immunohistochemistry and immunofluorescence. Flow cytometry and an in vitro co-culture system were used to elucidate the specific role of PLA2G7 in macrophages. Orthotopic and subcutaneous HCC mouse models were employed to evaluate the potential of the PLA2G7 inhibitor in complementing immune checkpoint blockade (ICB) therapy. RESULTS: Single-cell RNA sequencing analyses disclosed predominant PLA2G7 expression in intratumoral macrophages within the HCC microenvironment. The macrophage-specific PLA2G7 was significantly correlated with poorer prognosis and immunotherapy resistance in patients with HCC. PLA2G7(high) macrophages represent a highly immunosuppressive subset and impede CD8 T-cell activation. Pharmacological inhibition of PLA2G7 by darapladib improved the therapeutic efficacy of anti-programmed cell death protein 1 antibodies in the HCC mouse models. CONCLUSIONS: Macrophage-specific PLA2G7 serves as a novel biomarker capable of prognosticating immunotherapy responsiveness and inhibiting PLA2G7 has the potential to enhance the efficacy of ICB therapy for HCC.
ESTHER : Zhang_2024_J.Immunother.Cancer_12_e008094
PubMedSearch : Zhang_2024_J.Immunother.Cancer_12_e008094
PubMedID: 38272562
Gene_locus related to this paper: human-PLA2G7

Title : Soil microbiome of shiro reveals the symbiotic relationship between Tricholoma bakamatsutake and Quercus mongolica - Guo_2024_Front.Microbiol_15_1361117
Author(s) : Guo H , Liu W , Xie Y , Wang Z , Huang C , Yi J , Yang Z , Zhao J , Yu X , Sibirina LA
Ref : Front Microbiol , 15 :1361117 , 2024
Abstract : Tricholoma bakamatsutake is a delicious and nutritious ectomycorrhizal fungus. However, its cultivation is hindered owing to limited studies on its symbiotic relationships. The symbiotic relationship between T. bakamatsutake and its host is closely related to the shiro, a complex network composed of mycelium, mycorrhizal roots, and surrounding soil. To explore the symbiotic relationship between T. bakamatsutake and its host, soil samples were collected from T. bakamatsutake shiro (Tb) and corresponding Q. mongolica rhizosphere (CK) in four cities in Liaoning Province, China. The physicochemical properties of all the soil samples were then analyzed, along with the composition and function of the fungal and bacterial communities. The results revealed a significant increase in total potassium, available nitrogen, and sand in Tb soil compared to those in CK soil, while there was a significant decrease in pH, total nitrogen, total phosphorus, available phosphorus, and silt. The fungal community diversity in shiro was diminished, and T. bakamatsutake altered the community structure of its shiro by suppressing other fungi, such as Russula (ectomycorrhizal fungus) and Penicillium (phytopathogenic fungus). The bacterial community diversity in shiro increased, with the aggregation of mycorrhizal-helper bacteria, such as Paenibacillus and Bacillus, and plant growth-promoting bacteria, such as Solirubrobacter and Streptomyces, facilitated by T. bakamatsutake. Microbial functional predictions revealed a significant increase in pathways associated with sugar and fat catabolism within the fungal and bacterial communities of shiro. The relative genetic abundance of carboxylesterase and gibberellin 2-beta-dioxygenase in the fungal community was significantly increased, which suggested a potential symbiotic relationship between T. bakamatsutake and Q. mongolica. These findings elucidate the microbial community and relevant symbiotic environment to better understand the relationship between T. bakamatsutake and Q. mongolica.
ESTHER : Guo_2024_Front.Microbiol_15_1361117
PubMedSearch : Guo_2024_Front.Microbiol_15_1361117
PubMedID: 38601932

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

Title : Genome-wide association studies of egg production traits by whole genome sequencing of Laiwu Black chicken - Lei_2024_Poult.Sci_103_103705
Author(s) : Lei Q , Zhang S , Wang J , Qi C , Liu J , Cao D , Li F , Han H , Liu W , Li D , Tang C , Zhou Y
Ref : Poult Sci , 103 :103705 , 2024
Abstract : Compared to high-yield commercial laying hens, Chinese indigenous chicken breeds have poor egg laying capacity due to the lack of intensive selection. However, as these breeds have not undergone systematic selection, it is possible that there is a greater abundance of genetic variations related to egg laying traits. In this study, we assessed 5 egg number (EN) traits at different stages of the egg-laying period: EN1 (from the first egg to 23 wk), EN2 (from 23 to 35 wk), EN3 (from 35 to 48 wk), EN4 (from the first egg to 35 wk), and EN5 (from the first egg to 48 wk). To investigate the molecular mechanisms underlying egg number traits in a Chinese local chicken breed, we conducted a genome-wide association study (GWAS) using data from whole-genome sequencing (WGS) of 399 Laiwu Black chickens. We obtained a total of 3.01 Tb of raw data with an average depth of 7.07 x per individual. A total of 86 genome-wide suggestive or significant single-nucleotide polymorphisms (SNP) contained within a set of 45 corresponding candidate genes were identified and found to be associated with stages EN1-EN5. The genes vitellogenin 2 (VTG2), lipase maturation factor 1 (LMF1), calcium voltage-gated channel auxiliary subunit alpha2delta 3 (CACNA2D3), poly(A) binding protein cytoplasmic 1 (PABPC1), programmed cell death 11 (PDCD11) and family with sequence similarity 213 member A (FAM213A) can be considered as the candidate genes associated with egg number traits, due to their reported association with animal reproduction traits. Noteworthy, results suggests that VTG2 and PDCD11 are not only involved in the regulation of EN3, but also in the regulation of EN5, implies that VTG2 and PDCD11 have a significant influence on egg production traits. Our study offers valuable genomic insights into the molecular genetic mechanisms that govern egg number traits in a Chinese indigenous egg-laying chicken breed. These findings have the potential to enhance the egg-laying performance of chickens.
ESTHER : Lei_2024_Poult.Sci_103_103705
PubMedSearch : Lei_2024_Poult.Sci_103_103705
PubMedID: 38598913

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 : A rare case of anti-DPPX encephalitis combined with neuroleptospirosis - Jin_2024_BMC.Neurol_24_34
Author(s) : Jin Y , Lan W , Chen X , Liu W , Luo W , Chen S
Ref : BMC Neurol , 24 :34 , 2024
Abstract : BACKGROUND: Neuroleptospirosis and anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis are both very rare and have only been reported in the form of respective case reports. There are no reports of anti-DPPX encephalitis combined with neuroleptospirosis in the literature. We reported the first case of neuroleptospirosis combined with elevated DPPX antibodies in serum and cerebrospinal fluid (CSF). CASE PRESENTATION: A previously healthy 53-year-old Chinese male farmer with a history of drinking raw stream water and flood sewage exposure was brought to the hospital due to an acute onset of neuropsychiatric symptoms. No fever or meningeal irritation signs were detected on physical examination. Routine laboratory investigations, including infection indicators, leukocyte and protein in CSF, electroencephalogram and gadolinium-enhanced magnetic resonance imaging of the brain, all revealed normal. While metagenomic next-generation sequencing (mNGS) identified the DNA genome of Leptospira interrogans in the CSF. Anti-DPPX antibody was detected both in blood and in CSF. A diagnosis of neuroleptospirosis combined with autoimmune encephalitis associated with DPPX-Ab was eventually made. He resolved completely after adequate amount of penicillin combined with immunotherapy. CONCLUSION: We highlight that in patients with acute or subacute behavioral changes, even in the absence of fever, if the most recent freshwater exposure is clear, physicians should pay attention to leptospirosis. Due to the low sensitivity of routine microscopy, culture, polymerase chain reaction and antibody testing, mNGS may have more advantages in diagnosing neuroleptospirosis. As autoimmune encephalitis can be triggered by various infections, neuroleptospirosis may be one of the causes of autoimmune encephalitis. Since neuronal antibody measurements themselves are not that common in neuroleptospirosis, future studies are needed to determine whether the detection of anti-DPPX antibodies is a rare event in leptospirosis. Early identification of autoimmune encephalitis and timely administration of immunotherapy may lead to a better outcome.
ESTHER : Jin_2024_BMC.Neurol_24_34
PubMedSearch : Jin_2024_BMC.Neurol_24_34
PubMedID: 38243162
Gene_locus related to this paper: human-DPP6

Title : Discovery of 4-benzylpiperazinequinoline BChE inhibitor that suppresses neuroinflammation for the treatment of Alzheimer's disease - Chen_2024_Eur.J.Med.Chem_272_116463
Author(s) : Chen Y , Zhang W , Li Q , Xie H , Xing S , Lu X , Lyu W , Xiong B , Wang Y , Qu W , Liu W , Chi H , Zhang X , Feng F , Sun H
Ref : Eur Journal of Medicinal Chemistry , 272 :116463 , 2024
Abstract : Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with beta-amyloid (Abeta) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE inhibitor S21-1011 (eqBChE IC(50) = 0.059 +/- 0.006 microM, hBChE IC(50) = 0.162 +/- 0.069 microM), which presented satisfactory druggability and therapeutic efficacy in AD models. In pharmacokinetics (PK) studies, S21-1011 showed excellent blood-brain barrier (BBB) permeability, metabolism stability and high oral-bioavailability. In pharmacodynamic (PD) studies, it protected neural cells from toxicity and inflammation stimulation in vitro. Besides, it also exerted anti-inflammatory effect and alleviated cognitive impairment in mice models induced by lipopolysaccharides (LPS) and Abeta. Generally, this compound has been confirmed to function as a neuroprotector and cognition improver in various AD pathology-like models. Therefore, S21-1011, a novel potent BChE inhibitor, could be considered as a potential anti-AD candidate worthy of more profound investigation.
ESTHER : Chen_2024_Eur.J.Med.Chem_272_116463
PubMedSearch : Chen_2024_Eur.J.Med.Chem_272_116463
PubMedID: 38704944

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

Title : Characterization of Recombinantly-Expressed Hydrolytic Enzymes from Chinese Hamster Ovary Cells: Identification of Host Cell Proteins that Degrade Polysorbate - Kovner_2023_J.Pharm.Sci__
Author(s) : Kovner D , Yuk IH , Shen A , Li H , Graf T , Gupta S , Liu W , Tomlinson A
Ref : J Pharm Sci , : , 2023
Abstract : Enzymatic hydrolysis of polysorbate in drug products is a major challenge for the biopharmaceutical industry. Polysorbate hydrolysis caused by host cell proteins (HCPs) co-purified during bioprocessing can reduce the protective effects of the surfactant for the active pharmaceutical ingredient and cause the accumulation of low-solubility degradation products over the long-term storage. The identities of such HCPs are elusive due to their extremely low concentrations after the efficient purification processes of most biopharmaceuticals. In this work, 20 enzymes-selected for their known or putative hydrolytic activity and potential to degrade polysorbate-were recombinantly expressed, purified, and characterized via orthogonal methods. First, these recombinant HCPs were assessed for hydrolytic activity against a fluorogenic esterase substrate in a recently-developed, high-throughput assay. Second, these HCPs were screened for hydrolytic activity against polysorbate in a representative mAb formulation. Third, HCPs that displayed hydrolytic activities in the first two assays were subjected to more detailed characterization of their enzyme kinetics against polysorbates. Finally, these HCPs were evaluated for substrate specificity towards different sub-species of polysorbates. This work provides critical new insights for targeted LC-MS/MS approaches for identification of relevant polysorbate-degrading enzymes and supports improvements to remove such HCPs, including knockouts or targeted removal during purification.
ESTHER : Kovner_2023_J.Pharm.Sci__
PubMedSearch : Kovner_2023_J.Pharm.Sci__
PubMedID: 36646283

Title : Ameliorative effect of scopolamine-induced cognitive dysfunction by Fufangmuniziqi formula: The roles of alkaloids, saponins, and flavonoids - Zhao_2023_J.Ethnopharmacol__116792
Author(s) : Zhao X , Hu X , Xie Q , Qi S , Xiang Z , Sun X , Xie Z , Dang R , Zhou L , Liu W , Cheng X , Wang C
Ref : J Ethnopharmacol , :116792 , 2023
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Fufangmuniziqi formula (FFMN), a traditional Uyghur medicine used in China, is derived from an ancient Uyghur medical book and consists of 13 herbs. The herbs of FFMN, such as Peganum harmala L., Glycyrrhiza uralensis Fisch., and Nigella glandulifera, have been demonstrated to have acetylcholinesterase (AChE) inhibitory, anti-neuroinflammatory, or antioxidant effects. Therefore, FFMN may have a good anti-Alzheimer's disease (AD) effect, but its specific action and mechanism need to be further proven. AIM OF THE STUDY: This study aims to investigate the anti-AD effects of FFMN and the role played by alkaloids, flavonoids, and saponins in anti-AD. MATERIALS AND METHODS: The alkaloids, flavonoids, and saponins fractions of FFMN were prepared by macroporous resin chromatography. The absorbed ingredients in the drug-containing serum were identified by UPLC-Q-TOF-MS. An AD mouse model was established by intraperitoneal injection of scopolamine (SCO). The role of different fractions of FFMN in the anti-AD process was examined by Morris water maze (MWM), in-vitro cell, and AChE inhibition assay. RESULTS: A total of 20 ingredients were identified in the serum samples collected after oral administration of FFMN, and seven compounds were selected as candidate active compounds. MWM experiments showed that different fractions of FFMN could significantly improve SCO-induced learning memory impairment in mice. The alkaloids fraction (ALK) regulated cholinergic function by inhibiting AChE activity, activating choline acetyltransferase activity, and protein expression. Flavonoids and saponins were more potent than the ALK in downregulating pro-inflammatory factors or inflammatory mediators, such as TNF-alpha, MPO, and nitric oxide. Western blot results further confirmed that flavonoids and saponins attenuated neuroinflammation by inhibiting the phosphorylation of IkappaB and NF-kappaB p65. This result was also verified by in-vitro cellular assays. FFMN enhanced antioxidant defense by increasing the activity of superoxide dismutase and reducing the production of MDA. Combined with cellular experiments, flavonoids and saponins were proven more protective against oxidative damage. CONCLUSION: FFMN improved cognitive and memory impairment in the SCO-induced AD mouse model. ALK mainly enhanced the function of the cholinergic system. Flavonoid and saponin fractions mainly attenuated neuroinflammation and oxidative stress by modulating the NF-kappaB pathway. All these findings strongly suggested that the combination of alkaloid, flavonoid, and saponin fractions derived from FFMN is a promising anti-AD agent that deserves further development.
ESTHER : Zhao_2023_J.Ethnopharmacol__116792
PubMedSearch : Zhao_2023_J.Ethnopharmacol__116792
PubMedID: 37356745

Title : Development of novel salicylic acid-donepezil-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease - Zhou_2023_J.Enzyme.Inhib.Med.Chem_38_2231661
Author(s) : Zhou Y , He Y , Teng X , Mi J , Yang J , Wei R , Liu W , Ma Q , Tan Z , Sang Z
Ref : J Enzyme Inhib Med Chem , 38 :2231661 , 2023
Abstract : Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid-donepezil-rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC(50) = 0.53 microM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD.
ESTHER : Zhou_2023_J.Enzyme.Inhib.Med.Chem_38_2231661
PubMedSearch : Zhou_2023_J.Enzyme.Inhib.Med.Chem_38_2231661
PubMedID: 37414563

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 : Clinical and genetic characteristics of CEL-MODY (MODY8): a literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes - Sun_2023_Endocrine__
Author(s) : Sun S , Gong S , Li M , Wang X , Wang F , Cai X , Liu W , Luo Y , Zhang S , Zhang R , Zhou L , Zhu Y , Ma Y , Ren Q , Zhang X , Chen J , Chen L , Wu J , Gao L , Zhou X , Li Y , Zhong L , Han X , Ji L
Ref : Endocrine , : , 2023
Abstract : OBJECTIVE: CEL-related maturity-onset diabetes of the young (CEL-MODY, MODY8) is a special type of monogenetic diabetes caused by mutations in the carboxyl-ester lipase (CEL) gene. This study aimed to summarize the genetic and clinical characteristics of CEL-MODY patients and to determine the prevalence of the disease among Chinese patients with early-onset type 2 diabetes (EOD). METHODS: We systematically reviewed the literature associated with CEL-MODY in PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Wanfang Data to analyze the features of patients with CEL-MODY. We screened and evaluated rare variants of the CEL gene in a cohort of 679 Chinese patients with EOD to estimate the prevalence of CEL-MODY in China. RESULTS: In total, 21 individuals reported in previous studies were diagnosed with CEL-MODY based on the combination of diabetes and pancreatic exocrine dysfunction as well as frameshift mutations in exon 11 of the CEL gene. CEL-MODY patients were nonobese and presented with exocrine pancreatic affection (e.g., chronic pancreatitis, low fecal elastase levels, pancreas atrophy and lipomatosis) followed by insulin-dependent diabetes. No carriers of CEL missense mutations were reported with exocrine pancreatic dysfunction. Sequencing of CEL in Chinese EOD patients led to the identification of the variant p.Val736Cysfs*22 in two patients. However, these patients could not be diagnosed with CEL-MODY because there were no signs that the exocrine pancreas was afflicted. CONCLUSION: CEL-MODY is a very rare disease caused by frameshift mutations affecting the proximal VNTR segments of the CEL gene. Signs of exocrine pancreatic dysfunction provide diagnostic clues for CEL-MODY, and genetic testing is vital for proper diagnosis. Further research in larger cohorts is needed to investigate the characteristics and prevalence of CEL-MODY in the Chinese population.
ESTHER : Sun_2023_Endocrine__
PubMedSearch : Sun_2023_Endocrine__
PubMedID: 37726640

Title : A rationally engineered specific near-infrared fluorogenic substrate of human pancreatic lipase for functional imaging and inhibitor screening - Hou_2023_Analyst__
Author(s) : Hou FB , Zhang N , Hou XD , Liu W , Fan YF , Zhu GH , Wu Y , Sun MR , Zhao B , Ge GB , Wang P
Ref : Analyst , : , 2023
Abstract : Obesity, now widespread all over the world, is frequently associated with several chronic diseases. Human pancreatic lipase (hPL) is a crucial digestive enzyme responsible for the digestion of dietary lipids in humans, and the inhibition of hPL is effective in reducing triglyceride intake and thus preventing and treating obesity. In this work, a practical sequential screening strategy was developed to construct a highly selective near-infrared fluorogenic substrate 7-STCFC for hPL. Under physiological conditions, 7-STCFC can be rapidly hydrolyzed by hPL to form 7-HTCFC, which triggers 254-fold NIR signal enhancement at 670 nm. 7-STCFC was successfully applied for the sensing and imaging of endogenous PL in living systems (including living cells, tissues and organs) with low cytotoxicity and high imaging resolution. Moreover, a high-throughput screening platform was established using 7-STCFC, and the inhibitory effects of 94 kinds of herbs toward hPL were evaluated. Among them, Pu-erh tea stood out with outstanding hPL inhibitory effects, and the inhibitory ingredients and involved inhibitory mechanism were further revealed, which strongly facilitates the discovery of novel anti-obesity agents targeting hPL. Collectively, these findings suggested that our strategy was practical to develop an isoform-specific fluorogenic substrate for a target enzyme, and 7-STCFC was a powerful tool for monitoring PL activity in complex biological systems with value for exploring physiological functions and rapid screening of inhibitors.
ESTHER : Hou_2023_Analyst__
PubMedSearch : Hou_2023_Analyst__
PubMedID: 37092796

Title : Enzyme-mediated Ru@UiO-66@MnO(2) NSs\/thiamine-based ratiometric fluorescence sensor for visual detection of organophosphorus pesticide residues - Tong_2023_Food.Chem_429_136945
Author(s) : Tong F , Yang Z , Wang Z , Liu W , Jiang W , Zhu L , Wang L , Zheng M , Hou R , Zhou Y , Liu Y
Ref : Food Chem , 429 :136945 , 2023
Abstract : In view of the potential hazards of organophosphorus pesticides (OPs), this paper constructed a ratiometric fluorescent probe utilizing a functionalized metal-organic framework to detect OPs. Ru(bpy)(3)Cl(2) was encapsulated inside UiO-66 as a reference signal, and MnO(2) nanosheets (MnO(2) NSs) were grown on the surface to obtain Ru@UiO-66@MnO(2) NSs. Acetylcholinesterase catalyzed the decomposition of acetylcholine into reductive thiocholine, which consumed MnO(2) NSs, thus restoring the Ru@UiO-66 fluorescence. Due to the enzymatic inhibition of OPs and the redox reaction between MnO(2) NSs and thiamine, this probe emitted blue fluorescence in the presence of OPs. The probe achieved linear responses to dichlorvos and chlorpyrifos with LODs of 9.99 x 10(-6) microg mL(-1) and 9.99 x 10(-5) microg mL(-1). The probe exhibited a satisfactory recovery rate for OPs in green tea. Furthermore, a hydrogel detection platform was developed by embedding the probe into sodium alginate. Overall, this work provides a visual approach to detect OPs in agricultural products.
ESTHER : Tong_2023_Food.Chem_429_136945
PubMedSearch : Tong_2023_Food.Chem_429_136945
PubMedID: 37487398

Title : Single and Combined Effects of Chlorpyrifos and Glyphosate on the Brain of Common Carp: Based on Biochemical and Molecular Perspective - Zhang_2023_Int.J.Mol.Sci_24_
Author(s) : Zhang D , Ding W , Liu W , Li L , Zhu G , Ma J
Ref : Int J Mol Sci , 24 : , 2023
Abstract : Chlorpyrifos (CPF) and glyphosate (GLY) are the most widely used organophosphate insecticide and herbicide worldwide, respectively; co-occurrence of CPF and GLY in aquatic environments occurs where they inevitably have potential hazards to fish. However, the potential mechanisms of CPF and GLY to induce toxicity have not been fully explored. To identify the adverse impacts of CPF and GLY on fish, either alone or in combination (MIX), CPF (25 microg/L) and GLY (3.5 mg/L) were set up according to an environmentally relevant concentration to expose to common carp for 21 days. After exposure, CPF and GLY decreased the activities of acetylcholinesterase and Na(+)/K(+)-ATPase, altered monoamine oxidase levels, decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione S-transferase and glutamic reductase), and induced the accumulation of malondialdehyde in the carp brain. The parameters in the MIX groups had a greater impact compared to that in the CPF or GLY group, suggesting that both single and combined exposure could affect neurological signaling systems and cause oxidative stress and lipid peroxidation damage in carp brains, and that MIX exposure increases the impact of each pollutant. RNA-seq results showed that single or combined exposure to CPF and GLY induced global transcriptomic changes in fish brains, and the number of differentially expressed genes in MIX-treated carp brains were globally increased compared to either the CPF or GLY groups, suggesting that the effects of co-exposure were greater than single exposure. Further analysis results revealed that the global transcriptomic changes participated in oxidative stress, immune dysfunction, and apoptosis of fish brains, and identified that the P13k-Akt signaling pathway participates in both single and combined exposure of CPF- and GLY-induced toxicity. Taken together, our results demonstrated that the interaction of CPF and GLY might be synergic and provided novel insights into the molecular mechanisms of fish brains coping with CPF and GLY.
ESTHER : Zhang_2023_Int.J.Mol.Sci_24_
PubMedSearch : Zhang_2023_Int.J.Mol.Sci_24_
PubMedID: 37629125

Title : Attack Site Density of a Highly-efficient PET Hydrolases - Li_2023_Protein.Pept.Lett__
Author(s) : Li Q , Liu W , Jing N , Yang K , Yao J , Wang X
Ref : Protein Pept Lett , : , 2023
Abstract : INTRODUCTION: Poly (ethylene terephthalate) (PET) is one of the most abundant polyester materials used in daily life and it is also one of the main culprits of environmental pollution. ICCG (F243I/D238C/S283C/Y127G) is enzyme with four modifications of leaf-branch compost cutinase (LCC) that display outstanding performance in hydrolyzing PET and hold a great potential in further applications. METHOD: Here, we used ICCG to degrade PET particles of various sizes and use the density of attack sites (attack) and kinetic parameters to evaluate the effect of particle size on enzyme degradation efficiency. We are surprised to observe that there is a certain relationship between Km and attack. In order to further confirm the relationship, we obtained three different enzymes (Y95K, M166S and H218S) by site-directed mutagenesis on the basis of ICCG. RESULT: The results confirmed that there was a negative correlation between Km and attack. In addition, we also found that increasing the affinity between the enzyme and the substrate does not necessarily lead to the increase of degradation rate. CONCLUSION: These findings show that the granulation of PET and the selection of appropriate particle size are helpful to improve its industrial application value. At the same time, additional protein engineering to increase ICCG performance is realistic, but it can't be limited to enhance the affinity between enzyme and substrate.
ESTHER : Li_2023_Protein.Pept.Lett__
PubMedSearch : Li_2023_Protein.Pept.Lett__
PubMedID: 37165591
Gene_locus related to this paper: 9bact-g9by57

Title : N-Amidation of Nitrogen-Containing Heterocyclic Compounds: Can We Apply Enzymatic Tools? - Yang_2023_Bioengineering.(Basel)_10_
Author(s) : Yang A , Miao X , Yang L , Xu C , Liu W , Xian M , Zou H
Ref : Bioengineering (Basel) , 10 : , 2023
Abstract : Amide bond is often seen in value-added nitrogen-containing heterocyclic compounds, which can present promising chemical, biological, and pharmaceutical significance. However, current synthesis methods in the preparation of amide-containing N-heterocyclic compounds have low specificity (large amount of by-products) and efficiency. In this study, we focused on reviewing the feasible enzymes (nitrogen acetyltransferase, carboxylic acid reductase, lipase, and cutinase) for the amidation of N-heterocyclic compounds; summarizing their advantages and weakness in the specific applications; and further predicting candidate enzymes through in silico structure-functional analysis. For future prospects, current enzymes demand further engineering and improving for practical industrial applications and more enzymatic tools need to be explored and developed for a broader range of N-heterocyclic substrates.
ESTHER : Yang_2023_Bioengineering.(Basel)_10_
PubMedSearch : Yang_2023_Bioengineering.(Basel)_10_
PubMedID: 36829716

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 : Cisplatin increases carboxylesterases through increasing PXR mediated by the decrease of DEC1 - Xu_2023_J.Biomed.Res__431
Author(s) : Xu M , Zhang L , Lin L , Qiang Z , Liu W , Yang J
Ref : J Biomed Res , :431 , 2023
Abstract : cis-Diamminedichloroplatinum (CDDP) is widely used for the treatment of various solid cancers. Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2), along with the upregulation of pregnane X receptor (PXR) and the downregulation of differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in human hepatoma cells, primary mouse hepatocytes, mouse liver and intestine. The overexpression or knockdown of PXR alone upregulated or downregulated the CES1 and CES2 expression, respectively. The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PXR knockdown or overexpression, implying that CDDP induces carboxylesterases through the activation of PXR. Likewise, the overexpression or knockdown of DEC1 alone significantly decreased or increased PXR and its targets. Moreover, the increases of PXR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1. The overexpression or knockdown of DEC1 affected the response of PXR to CDDP, but not vice versa, suggesting that CDDP increases carboxylesterases by upregulating PXR mediated by the decrease of DEC1. In addition, CDDP did not increase DEC1 mRNA degradation but suppressed DEC1 promoter reporter activity, indicating that it suppresses DEC1 transcriptionally. The combined use of CDDP and irinotecan had a synergistic effect on two cell lines, especially when CDDP was used first.
ESTHER : Xu_2023_J.Biomed.Res__431
PubMedSearch : Xu_2023_J.Biomed.Res__431
PubMedID: 37990879

Title : KARRIKIN UP-REGULATED F-BOX 1 (KUF1) imposes negative feedback regulation of karrikin and KAI2 ligand metabolism in Arabidopsis thaliana - Sepulveda_2022_Proc.Natl.Acad.Sci.U.S.A_119_e2112820119
Author(s) : Sepulveda C , Guzman MA , Li Q , Villaecija-Aguilar JA , Martinez SE , Kamran M , Khosla A , Liu W , Gendron JM , Gutjahr C , Waters MT , Nelson DC
Ref : Proc Natl Acad Sci U S A , 119 :e2112820119 , 2022
Abstract : Significance: Karrikins are chemicals in smoke that stimulate regrowth of many plants after fire. However, karrikin responses are not limited to species from fire-prone environments and can affect growth after germination. Putatively, this is because karrikins mimic an unknown signal in plants, KAI2 ligand (KL). Karrikins likely require modification in plants to become bioactive. We identify a gene, KUF1, that appears to negatively regulate biosynthesis of KL and metabolism of a specific karrikin. KUF1 expression increases in response to karrikin or KL signaling, thus forming a negative feedback loop that limits further activation of the signaling pathway. This discovery will advance understanding of how karrikins are perceived and how smoke-activated germination evolved. It will also aid identification of the elusive KL.
ESTHER : Sepulveda_2022_Proc.Natl.Acad.Sci.U.S.A_119_e2112820119
PubMedSearch : Sepulveda_2022_Proc.Natl.Acad.Sci.U.S.A_119_e2112820119
PubMedID: 35254909

Title : Structural Insights into (Tere)phthalate-Ester Hydrolysis by a Carboxylesterase and Its Role in Promoting PET Depolymerization - von Haugwitz_2022_ACS.Catal_12_15259
Author(s) : von Haugwitz G , Han X , Pfaff L , Li Q , Wei H , Gao J , Methling K , Ao Y , Brack Y , Jan Mican J , Feiler CG , Weiss MS , Bednar D , Palm GJ , Lalk M , Lammers M , Damborsky J , Weber G , Liu W , Bornscheuer UT , Wei R
Ref : ACS Catal , 12 :15259 , 2022
Abstract : TfCa, a promiscuous carboxylesterase from Thermobifida fusca, was found to hydrolyze polyethylene terephthalate (PET) degradation intermediates such as bis(2-hydroxyethyl) terephthalate (BHET) and mono-(2-hydroxyethyl)-terephthalate (MHET). In this study, we elucidated the structures of TfCa in its apo form, as well as in complex with a PET monomer analogue and with BHET. The structurefunction relationship of TfCa was investigated by comparing its hydrolytic activity on various ortho- and para-phthalate esters of different lengths. Structure-guided rational engineering of amino acid residues in the substrate-binding pocket resulted in the TfCa variant I69W/V376A (WA), which showed 2.6-fold and 3.3-fold higher hydrolytic activity on MHET and BHET, respectively, than the wild-type enzyme. TfCa or its WA variant was mixed with a mesophilic PET depolymerizing enzyme variant [Ideonella sakaiensis PETase (IsPETase) PM] to degrade PET substrates of various crystallinity. The dual enzyme system with the wild-type TfCa or its WA variant produced up to 11-fold and 14-fold more terephthalate (TPA) than the single IsPETase PM, respectively. In comparison to the recently published chimeric fusion protein of IsPETase and MHETase, our system requires 10% IsPETase and one-fourth of the reaction time to yield the same amount of TPA under similar PET degradation conditions. Our simple dual enzyme system reveals further advantages in terms of cost-effectiveness and catalytic efficiency since it does not require time-consuming and expensive cross-linking and immobilization approaches.
ESTHER : von Haugwitz_2022_ACS.Catal_12_15259
PubMedSearch : von Haugwitz_2022_ACS.Catal_12_15259
PubMedID: 36570084
Gene_locus related to this paper: thefu-1831

Title : Effect of alcohol exposure on the efficacy and safety of tenofovir alafenamide fumarate, a major medicine against human immunodeficiency virus - Liu_2022_Biochem.Pharmacol_204_115224
Author(s) : Liu W , Yu S , Yan B
Ref : Biochemical Pharmacology , 204 :115224 , 2022
Abstract : Human immunodeficiency virus (HIV) continues to be a major health concern. AIDS-related deaths (acquired immunodeficiency syndrome) have decreased recently, but chronic liver disease is now a major cause of mortality among HIV patients. Widespread alcohol use is recognized to be a major contributing factor. Tenofovir alafenamide fumarate (TAF), one of the most used HIV drugs, requires hydrolysis followed by phosphorylation to produce tenofovir diphosphate, the ultimate anti-HIV metabolite. Carboxylesterase-1 (CES1), established to hydrolyze TAF, is known to catalyze transesterification in the presence of ethanol. The aim of the study was to test the hypothesis that metabolism-based interactions between TAF and ethanol negatively impact both efficacy and safety of TAF. To test this hypothesis, the metabolism of TAF was determined in human primary hepatocytes and with a large number of human liver samples (S9 fractions) in the presence or absence of ethanol. The metabolism was monitored by LC-MS/MS (liquid chromatography with tandem mass spectrometry) and the level of CES1 or CES2 was determined by Western blotting. Consistent with the hypothesis, TAF underwent transesterification in the presence of ethanol accompanied by decreased hydrolysis. The formation of tenofovir diphosphate (the therapeutically active metabolite) was significantly decreased. In addition, TAF but not its hydrolytic metabolite, was found to increase intracellular lipid retention, and the increase was enhanced by ethanol. These findings conclude that alcohol consumption, beyond commonly accepted poor adherence to HIV medications, directly impacts the efficacy and safety of TAF.
ESTHER : Liu_2022_Biochem.Pharmacol_204_115224
PubMedSearch : Liu_2022_Biochem.Pharmacol_204_115224
PubMedID: 36007574

Title : Peroxidase-like activity of Ru-N-C nanozymes in colorimetric assay of acetylcholinesterase activity - Yan_2022_Anal.Chim.Acta_1191_339362
Author(s) : Yan B , Wang F , He S , Liu W , Zhang C , Chen C , Lu Y
Ref : Anal Chim Acta , 1191 :339362 , 2022
Abstract : Herein, the Ru-N-C nanozymes with abundant active Ru-N(x) sites have been successfully prepared by pyrolyzing Ru(acac)(3) trapped zeolitic-imidazolate-frameworks (Ru(acac)(3)@ZIF-8). Taking advantages of the remarkable peroxidase-mimicking activity, outstanding stability and reusability of Ru-N-C nanozymes, a novel biosensing system with explicit mechanism is strategically fabricated for sensitively determining acetylcholinesterase (AChE) and tacrine. The limit of detection for AChE activity can achieve as low as 0.0433 mU mL(-1), and the IC(50) value of tacrine for AChE is about 0.190 micromol L(-1). The robust analytical performance in serums test verifies the great application potential of this assay in real matrix. Furthermore, "INH" and "IMPLICATION-AND" logic gates are rationally constructed based on the proposed colorimetric sensor. This work not only provides one sustainable and effective avenue to fabricate Ru-N-C-based peroxidase mimic with high catalytic performance, and also gives new impetuses for developing novel biosensors by applying Ru-N-C-based enzyme mimics as substitutes for the natural enzyme.
ESTHER : Yan_2022_Anal.Chim.Acta_1191_339362
PubMedSearch : Yan_2022_Anal.Chim.Acta_1191_339362
PubMedID: 35033267

Title : Impaired sweating in patients with cholinergic urticaria is linked to low expression of acetylcholine receptor CHRM3 and acetylcholine esterase in sweat glands - Wang_2022_Front.Immunol_13_955161
Author(s) : Wang Y , Scheffel J , Vera CA , Liu W , Gunzel D , Terhorst-Molawi D , Maurer M , Altrichter S
Ref : Front Immunol , 13 :955161 , 2022
Abstract : BACKGROUND: Cholinergic urticaria (CholU), a frequent form of chronic inducible urticaria, is characterized by itchy wheals and angioedema in response to sweating. As of now, the rate and pathophysiological relevance of impaired sweating in patients with CholU are ill-defined. AIM: To assess in CholU patients the rate and extent of impaired sweating and its links to clinical and pathophysiological features of CholU. PATIENTS AND METHODS: We assessed sweating in patients with CholU (n = 13) subjected to pulse-controlled ergometry (PCE) provocation testing. Pre- and post-PCE biopsies of lesional (L) and non-lesional (NL) skin were analyzed for the expression of acetylcholine receptor M3 (CHRM3) and acetylcholine esterase (ACh-E) by quantitative histomorphometry and compared to those of healthy control subjects (HCs). CholU patients were assessed for disease duration and severity as well as other clinical features. RESULTS: Of the 13 patients with CholU, 10 showed reduced sweating in response to PCE provocation, and 3 had severely reduced sweating. Reduced sweating was linked to long disease duration and high disease severity. CholU patients with impaired sweating responses showed reduced sweat gland epithelial expression of CHRM3 and ACh-E. CONCLUSION: Reduced sweating is common in CholU patients, especially in those with long-standing and severe disease, and it can be severe. Reduced expression of CHRM3 and ACh-E may be the cause or consequence of CholU in patients with impaired sweating, and this should be explored by further studies.
ESTHER : Wang_2022_Front.Immunol_13_955161
PubMedSearch : Wang_2022_Front.Immunol_13_955161
PubMedID: 35967390

Title : Flavin-enabled reductive and oxidative epoxide ring opening reactions - De_Nat.Commun_13_4896
Author(s) : De BC , Zhang W , Yang C , Mandi A , Huang C , Zhang L , Liu W , Ruszczycky MW , Zhu Y , Ma M , Bashiri G , Kurtan T , Liu Hw , Zhang C
Ref : Nat Commun , 13 :4896 , 2022
Abstract : Epoxide ring opening reactions are common and important in both biological processes and synthetic applications and can be catalyzed in a non-redox manner by epoxide hydrolases or reductively by oxidoreductases. Here we report that fluostatins (FSTs), a family of atypical angucyclines with a benzofluorene core, can undergo nonenzyme-catalyzed epoxide ring opening reactions in the presence of flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NADH). The 2,3-epoxide ring in FST C is shown to open reductively via a putative enol intermediate, or oxidatively via a peroxylated intermediate with molecular oxygen as the oxidant. These reactions lead to multiple products with different redox states that possess a single hydroxyl group at C-2, a 2,3-vicinal diol, a contracted five-membered A-ring, or an expanded seven-membered A-ring. Similar reactions also take place in both natural products and other organic compounds harboring an epoxide adjacent to a carbonyl group that is conjugated to an aromatic moiety. Our findings extend the repertoire of known flavin chemistry that may provide new and useful tools for organic synthesis.
ESTHER : De_Nat.Commun_13_4896
PubMedSearch : De_Nat.Commun_13_4896
PubMedID: 35986005

Title : Recent Advances on the Role of ATGL in Cancer - Zhang_2022_Front.Oncol_12_944025
Author(s) : Zhang R , Meng J , Yang S , Liu W , Shi L , Zeng J , Chang J , Liang B , Liu N , Xing D
Ref : Front Oncol , 12 :944025 , 2022
Abstract : The hypoxic state of the tumor microenvironment leads to reprogramming lipid metabolism in tumor cells. Adipose triglyceride lipase, also known as patatin-like phospholipase= domain-containing protein 2 and Adipose triglyceride lipase (ATGL), as an essential lipid metabolism-regulating enzyme in cells, is regulated accordingly under hypoxia induction. However, studies revealed that ATGL exhibits both tumor-promoting and tumor-suppressing effects, which depend on the cancer cell type and the site of tumorigenesis. For example, elevated ATGL expression in breast cancer is accompanied by enhanced fatty acid oxidation (FAO), enhancing cancer cells' metastatic ability. In prostate cancer, on the other hand, tumor activity tends to be negatively correlated with ATGL expression. This review outlined the regulation of ATGL-mediated lipid metabolism pathways in tumor cells, emphasizing the Hypoxia-inducible factors 1 (HIF-1)/Hypoxia-inducible lipid droplet-associated (HIG-2)/ATGL axis, peroxisome proliferator-activated receptor (PPAR)/G0/G1 switch gene 2 (G0S2)/ATGL axis, and fat-specific protein 27 (FSP-27)/Early growth response protein 1 (EGR-1)/ATGL axis. In the light of recent research on different cancer types, the role of ATGL on tumorigenesis, tumor proliferation, and tumor metastasis was systemically reviewed.
ESTHER : Zhang_2022_Front.Oncol_12_944025
PubMedSearch : Zhang_2022_Front.Oncol_12_944025
PubMedID: 35912266

Title : Multiple Substrate Binding Mode-Guided Engineering of a Thermophilic PET Hydrolase - Pfaff_2022_ACS.Catalysis_12_9790
Author(s) : Pfaff L , Gao J , Li Z , Jackering A , Weber G , Mican J , Chen Y , Dong W , Han X , Feiler CG , Ao YF , Badenhorst CPS , Bednar D , Palm GJ , Lammers M , Damborsky J , Strodel B , Liu W , Bornscheuer UT , Wei R
Ref : ACS Catal , 12 :9790 , 2022
Abstract : Thermophilic polyester hydrolases (PES-H) have recently enabled biocatalytic recycling of the mass-produced synthetic polyester polyethylene terephthalate (PET), which has found widespread use in the packaging and textile industries. The growing demand for efficient PET hydrolases prompted us to solve high-resolution crystal structures of two metagenome-derived enzymes (PES-H1 and PES-H2) and notably also in complex with various PET substrate analogues. Structural analyses and computational modeling using molecular dynamics simulations provided an understanding of how product inhibition and multiple substrate binding modes influence key mechanistic steps of enzymatic PET hydrolysis. Key residues involved in substratebinding and those identified previously as mutational hotspots in homologous enzymes were subjected to mutagenesis. At 72 C, the L92F/Q94Y variant of PES-H1 exhibited 2.3-fold and 3.4-fold improved hydrolytic activity against amorphous PET films and pretreated real-world PET waste, respectively. The R204C/S250C variant of PES-H1 had a 6.4 C higher melting temperature than the wild-type enzyme but retained similar hydrolytic activity. Under optimal reaction conditions, the L92F/Q94Y variant of PES-H1 hydrolyzed low-crystallinity PET materials 2.2-fold more efficiently than LCC ICCG, which was previously the most active PET hydrolase reported in the literature. This property makes the L92F/ Q94Y variant of PES-H1 a good candidate for future applications in industrial plastic r"cycling processes.
ESTHER : Pfaff_2022_ACS.Catalysis_12_9790
PubMedSearch : Pfaff_2022_ACS.Catalysis_12_9790
PubMedID: 35966606
Gene_locus related to this paper: 9firm-PHL7

Title : N-Benzyl Benzamide Derivatives as Selective Sub-Nanomolar Butyrylcholinesterase Inhibitors for Possible Treatment in Advanced Alzheimer's Disease - Du_2022_J.Med.Chem__
Author(s) : Du C , Wang L , Guan Q , Yang H , Chen T , Liu Y , Li Q , Lyu W , Lu X , Chen Y , Liu H , Feng F , Liu W , Liu Z , Li W , Sun H
Ref : Journal of Medicinal Chemistry , : , 2022
Abstract : Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC(50) from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar K(D) value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Abeta(1-42). The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.
ESTHER : Du_2022_J.Med.Chem__
PubMedSearch : Du_2022_J.Med.Chem__
PubMedID: 35969197

Title : Design, synthesis and biological evaluation of novel coumarin derivatives as multifunctional ligands for the treatment of Alzheimer's disease - Liu_2022_Eur.J.Med.Chem_242_114689
Author(s) : Liu W , Wu L , Tian L , Chen H , Wu Z , Wang N , Liu X , Qiu J , Feng X , Xu Z , Jiang X , Zhao Q
Ref : Eur Journal of Medicinal Chemistry , 242 :114689 , 2022
Abstract : Multi-targeted directed ligands (MTDLs) are emerging as promising Alzheimer's disease (AD) therapeutic possibilities. Coumarin is a multifunctional backbone with extensive bioactivity that has been utilized to develop innovative anti-neurodegenerative properties and is a desirable starting point for the construction of MTDLs. Herein, we explored and synthesized a series of novel coumarin derivatives and assessed their inhibitory effects on cholinesterase (AChE, BuChE), GSK-3beta, and BACE1. Among these compounds, compound 30 displayed the multifunctional profile of targeting the AChE (IC(50) = 1.313 +/- 0.099 microM) with a good selectivity over BuChE (SI = 24.623), GSK-3beta (19.30% inhibition at 20 microM), BACE1 (IC(50) = 1.227 +/- 0.112 microM), along with moderate HepG2 cytotoxicity, SH-SY5Y cytotoxicity, low HL-7702 cytotoxicity, as well as good blood-brain barrier (BBB) permeability. Kinetic and docking studies indicated that compound 30 was a competitive AChE inhibitor. Furthermore, acute toxicity experiments revealed that it was non-toxic at a dosage of 1000 mg/kg. The ADME prediction results indicate that 30 has acceptable physicochemical properties. Collectively, these findings demonstrated that compound 30 would be a potential multifunctional candidate for AD therapy.
ESTHER : Liu_2022_Eur.J.Med.Chem_242_114689
PubMedSearch : Liu_2022_Eur.J.Med.Chem_242_114689
PubMedID: 36007469

Title : The role of butyrylcholinesterase in the regulation of cognitive dysfunction in minimal hepatic encephalopathy: A potential blood marker of disease evolution - Yang_2022_Front.Neurol_13_900997
Author(s) : Yang X , Dang P , Liu W , Ma W , Ge X , Zhu K , Wang M , Huang X , Ding X , Wang X
Ref : Front Neurol , 13 :900997 , 2022
Abstract : BACKGROUND AND AIMS: Patients with cirrhosis commonly experience minimal hepatic encephalopathy (MHE), and alterations in neurotransmitters have been thought to be related to cognitive function. However, the relationship between alterations in peripheral and central butyrylcholinesterase (BuChE) with MHE disease progression remains unknown. As such, this study was designed to investigate potential changes in peripheral and central BuChE activity and their effects on cognitive function in the context of MHE. MATERIALS AND METHODS: We enrolled 43 patients with cirrhosis secondary to hepatitis B, 20 without MHE and 23 with MHE, and 25 with healthy controls (HC). All the selected subjects underwent resting-state functional MRI, and the original images were processed to obtain the regional homogeneity (ReHo) brain maps. Thereafter, the correlation of BuChE activity with ReHo, number connection test of type A (NCT-A), and digital symbol test (DST) scores with MHE patients were analyzed using Person correlation analysis. Meanwhile, we purchased 12 Sprague-Dawley (SD) rats and divided them into an experimental group (n = 6) and a control group (n = 6). The rats in the experimental group were intraperitoneally injected with thioacetamide (TAA) to prepare MHE model rats. After modeling, we used the Morris water maze (MWM) and elevated plus maze (EPM) to assess the cognition function and exploratory behavior of all rats. The activity of serum, hippocampus, and frontal lobe tissue BuChE was detected by ELISA. RESULTS: BuChE activity gradually decreased among the HC, patients with cirrhosis, and MHE groups (all P < 0.01). We observed a linear correlation between serum BuChE and NCT-A and DST scores in MHE patients (all P < 0.01). We noted that BuChE activity can negatively correlate with ReHo values in the left middle temporal gyrus and left inferior temporal gyrus, and positively correlate with ReHo values in the right inferior frontal gyrus, and also found that the peripheral BuChE activity of MHE rats was significantly lower than their control counterparts, and the BuChE activity in frontal lobe extracts was significantly higher than the control rats (all P < 0.05). CONCLUSION: The altered activity of BuChE may contribute to cognitive impairment in MHE patients, which may be a potential biomarker of disease evolution in the context of MHE.
ESTHER : Yang_2022_Front.Neurol_13_900997
PubMedSearch : Yang_2022_Front.Neurol_13_900997
PubMedID: 36341087

Title : Discovery of novel beta-carboline-1,2,3-triazole hybrids as AChE\/GSK-3beta dual inhibitors for Alzheimer's disease treatment - Liu_2022_Bioorg.Chem_129_106168
Author(s) : Liu W , Tian L , Wu L , Chen H , Wang N , Liu X , Zhao C , Wu Z , Jiang X , Wu Q , Xu Z , Zhao Q
Ref : Bioorg Chem , 129 :106168 , 2022
Abstract : Alzheimer's disease (AD) is characterized by progressive cognitive impairment and mental behavior. The combination inhibition of two essential AD targets, acetylcholinesterase (AChE) and glycogen synthase kinase-3beta (GSK-3beta), might be a breakthrough in the discovery of therapeutic success. Herein, 17 beta-carboline-1,2,3-triazole hybrids were designed, synthesized, and evaluated for their AChE and GSK-3beta inhibitory potential. The results indicated that compound 21 has the most potent inhibition against eeAChE (IC(50) = 0.20 +/- 0.02 microM), hAChE (IC(50) = 0.34 +/- 0.01 microM) and GSK-3beta (IC(50) = 1.14 +/- 0.05 microM) among these compounds. In addition, it inhibited hAChE in a mixed type manner and could occupy the binding pocket forming diverse interactions with the target of AChE and GSK-3beta. Moreover, compound 21 showed low cytotoxicity against SH-SY5Y and HepG2 cell lines and good BBB permeability. Compound 21 also attenuated the tau hyperphosphorylation in the Tau (P301L) 293T cell model. The ADME projection exhibited that compound 21 has acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and GSK-3beta dual inhibition as a promising strategy for AD treatment.
ESTHER : Liu_2022_Bioorg.Chem_129_106168
PubMedSearch : Liu_2022_Bioorg.Chem_129_106168
PubMedID: 36191431

Title : Development of naringenin-O-carbamate derivatives as multi-target-directed liagnds for the treatment of Alzheimer's disease - Mi_2022_Bioorg.Med.Chem.Lett_60_128574
Author(s) : Mi J , He Y , Yang J , Zhou Y , Zhu G , Wu A , Liu W , Sang Z
Ref : Bioorganic & Medicinal Chemistry Lett , 60 :128574 , 2022
Abstract : In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC(50) = 9.7 microM) inhibitor. In addition, compound 3c significantly inhibited self-induced Abeta(1-42) aggregation, and it could activate UPS degradation pathway in HT22 cells and clear the aggregated proteins associated with AD. Moreover, compound 3c was a selective metal chelator, and it significantly inhibited and disaggregated Cu(2+)-mediated Abeta(1-42) aggregation. Furthermore, compound 3c displayed remarkable neuroprotective effect and anti-inflammatory property. Interestingly, compound 3c displayed good hepatoprotective effect by its antioxidant activity. More importantly, compound 3c demonstrated favourable blood-brain barrier penetration in vitro and drug-like property. Therefore, compound 3c was a promising multifunctional agent for the treatment of AD.
ESTHER : Mi_2022_Bioorg.Med.Chem.Lett_60_128574
PubMedSearch : Mi_2022_Bioorg.Med.Chem.Lett_60_128574
PubMedID: 35065231

Title : Esterase-Activated Precipitating Strategy to Achieve Highly Specific Detection and Long-Term Imaging of Calcium Ions by Aggregation-Induced Phosphorescence Probe - Wang_2022_Anal.Chem__
Author(s) : Wang Z , Xiong Z , Liu W , Zhu Q , Zhang X , Ding Y , Huang C , Feng H , Zhang K , Zhu E , Qian Z
Ref : Analytical Chemistry , : , 2022
Abstract : Spatial and temporal monitoring of bioactive targets such as calcium ions is vitally significant for their essential roles in physiological and biochemical functions. Herein, we proposed an esterase-activated precipitating strategy to achieve highly specific identification and long-term bioimaging of calcium ions via lighting up the calcium ions by precipitation using a water-soluble aggregation-induced phosphorescence (AIP) probe. The designed probe CaP2 has an AIP behavior and can be efficiently aggregated by calcium ions through the coupling coordination of carboxylic acid and cyanide groups, which enables it to light up Ca(2+) by precipitating-triggered phosphorescence. Four hydrophilic groups of tetraethylene glycol were introduced to endow the resulting probe CaP3 with extraordinary water solubility as well as excellent cellular penetration. Only when the probe CaP3 penetrates inside the live cells the existing esterase in cells can activate the probe to be transformed active CaP2 probe selectively binding with calcium ion in the surroundings. The probe was used to further evaluate the imaging of intracellular calcium ions in model organisms. The excellent imaging performance of CaP3 in Arabidopsis thaliana seedling roots demonstrates that CaP3 has the excellent capability of monitoring calcium ions in live-cell imaging, and furthermore CaP3 exhibits much better photostability and thereby greater potential in long-term imaging. This work established a general esterase-activated precipitating strategy to achieve specific detection and bioimaging in situ triggered by esterase in live cells, and established a water-soluble aggregation-induced phosphorescence probe with high selectivity to achieve specific sensing and long-term imaging of calcium ions in live cells.
ESTHER : Wang_2022_Anal.Chem__
PubMedSearch : Wang_2022_Anal.Chem__
PubMedID: 35315662

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 : A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease - Liu_2022_Ageing.Neurodegener.Dis__
Author(s) : Liu W , Wang Y , Youdim MB
Ref : Ageing and Neurodegenerative Diseases , : , 2022
Abstract : The current novel therapeutic approach suggests that multi-targeted compounds, with diverse biological activities but a single set of bioavailability and pharmacokinetics, will be significantly more advantageous in the treatment of the complex pathology of Parkinsons diseases (PD) than traditional therapies. This review introduces a novel cholinesterase (ChE)-monoamine oxidase (MAO) inhibitor, namely MT-031, which was designed by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor and neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the methylamino position of the ChE inhibitor anti-AD drug, rivastigmine. MT-031 possesses neuroprotective, cognition enhancing, anti-depressant, and anti-inflammatory properties both in vitro and in vivo. Altogether, these findings suggest that MT-031 may be a potential treatment for combating PD and associated dementia and depression.
ESTHER : Liu_2022_Ageing.Neurodegener.Dis__
PubMedSearch : Liu_2022_Ageing.Neurodegener.Dis__

Title : Covalent CES2 Inhibitors Protect against Reduced Formation of Intestinal Organoids by the Anticancer Drug Irinotecan - Eades_2022_Curr.Drug.Metab__
Author(s) : Eades W , Liu W , Shen Y , Shi Z , Yan B
Ref : Curr Drug Metab , : , 2022
Abstract : BACKGROUND: Irinotecan is widely used to treat various types of solid and metastatic cancer. It is an ester prodrug and its hydrolytic metabolite (SN-38) exerts potent anticancer activity. Irinotecan is hydrolyzed primarily by carboxylesterase-2 (CES2), a hydrolase abundantly present in the intestine such as the duodenum. We have identified several potent and covalent CES2 inhibitors such as remdesivir and sofosbuvir. Remdesivir is the first small molecule drug approved for COVID-19, whereas sofosbuvir is a paradigm-shift medicine for hepatitis C viral infection. Irinotecan is generally well-tolerated but associated with severe/life-threatening diarrhea due to intestinal accumulation of SN-38. OBJECTIVE: This study was to test the hypothesis that remdesivir and sofosbuvir protect against irinotecan-induced epithelial injury associated with gastrointestinal toxicity. METHODS: To test this hypothesis, formation of organoids derived from mouse duodenal crypts, a robust cellular model for intestinal regeneration, was induced in the presence or absence of irinotecan +/- pretreatment with a CES2 drug inhibitor. RESULTS: Irinotecan profoundly inhibited the formation of intestinal organoids and the magnitude of the inhibition was greater with female crypts than their male counterparts. Consistently, crypts from female mice had significantly higher hydrolytic activity toward irinotecan. Critically, remdesivir and sofosbuvir both reduced irinotecan hydrolysis and reversed irinotecan-reduced formation of organoids. Human duodenal samples robustly hydrolyzed irinotecan, stable CES2 transfection induced cytotoxicity and the cytotoxicity was reduced by CES2 drug inhibitor. CONCLUSION: These findings establish a therapeutic rationale to reduce irinotecan-gastrointestinal injury and serve as a cellular foundation to develop oral formulations of irinotecan with high safety.
ESTHER : Eades_2022_Curr.Drug.Metab__
PubMedSearch : Eades_2022_Curr.Drug.Metab__
PubMedID: 36515038

Title : Substrate-Binding Mode of a Thermophilic PET Hydrolase and Engineering the Enzyme to Enhance the Hydrolytic Efficacy - Zeng_2022_ACS.Catal_12_3033
Author(s) : Zeng W , Li X , Yang Y , Min J , Huang JW , Liu W , Niu D , Yang X , Han X , Zhang L , Dai L , Chen CC , Guo RT
Ref : ACS Catal , 12 :3033 , 2022
Abstract : Polyethylene terephthalate (PET) is among the most extensively produced plastics, but huge amounts of PET wastes that have accumulated in the environment have become a serious threat to the ecosystem. Applying PET hydrolytic enzymes to depolymerize PET is an attractive measure to manage PET pollution, and searching for more effective enzymes is a prerequisite to achieve this goal. A thermostable cutinase that originates from the leaf-branch compost termed ICCG is the most effective PET hydrolase reported so far. Here, we illustrated the crystal structure of ICCG in complex with the PET analogue, mono(2-hydroxyethyl)terephthalic acid, to reveal the enzyme-substrate interaction network. Furthermore, we applied structure-based engineering to modify ICCG and screened for variants that exhibit higher efficacy than the parental enzyme. As a result, several variants with the measured melting temperature approaching 99 C and elevated PET hydrolytic activity were obtained. Finally, crystallographic analyses were performed to reveal the structural stabilization effects mediated by the introduced mutations. These results are of importance in the context of understanding the mechanism of action of the thermostable PET hydrolytic enzyme and shall be beneficial to the development of PET biodegradation platforms.
ESTHER : Zeng_2022_ACS.Catal_12_3033
PubMedSearch : Zeng_2022_ACS.Catal_12_3033
Gene_locus related to this paper: 9bact-g9by57

Title : Design, synthesis and evaluation of fused hybrids with acetylcholinesterase inhibiting and Nrf2 activating functions for Alzheimer's disease - Wang_2022_Eur.J.Med.Chem_244_114806
Author(s) : Wang Y , Xiong B , Lin H , Li Q , Yang H , Qiao Y , Xu Z , Lyu W , Qu W , Liu W , Chen Y , Feng F , Sun H
Ref : Eur Journal of Medicinal Chemistry , 244 :114806 , 2022
Abstract : Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory (eeAChE IC(50) = 0.07 +/- 0.01 microM; hAChE IC(50) = 0.38 +/- 0.04 microM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H(2)O(2) and Abeta(1-42) aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and Abeta(1-42). At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.
ESTHER : Wang_2022_Eur.J.Med.Chem_244_114806
PubMedSearch : Wang_2022_Eur.J.Med.Chem_244_114806
PubMedID: 36223681

Title : Evodiamine-A Privileged Structure with Broad-Ranging Biological Activities - Li_2022_Mini.Rev.Med.Chem__
Author(s) : Li D , Li Y , Jiang X , Liu W , Zhao Q
Ref : Mini Rev Med Chem , : , 2022
Abstract : Evodiamine (EVO) is a natural quinolone alkaloid firstly isolated from the fruit of Evodia rutaecarpa, which is one of the most frequently used traditional Chinese herb for treating a variety of ailments including headaches, abdominal pain, vomiting, diarrhea, amenorrhea difficult menstruation, postpartum hemorrhage, and other diseases. Latest pharmacological studies showed that EVO possesses a broad spectrum of pharmacological activities through different mechanisms. However, its moderate activities and poor physicochemical properties hampered its clinical application. In this regard, the modification of EVO aiming at seeking derivatives with more potency and better physicochemical properties has been extensively emerging. These derivatives exhibit diverse biological activities including antitumor, anti-Alzheimer's disease, anti-pulmonary hypertension, anti-fungi, and thermogenic activities via a variety of mechanisms. Moreover, they were described to act as single, dual, or multiple inhibitors or agonists of many proteins such as topoisomerase I, topoisomerase II, tubulin, histone deacetylase, sirtuins, butyrylcholinesterase, phosphodiesterase 5, and transient receptor potential vanilloid 1. However, hitherto, there is no comprehensive review to systematically summarize the derivatives of EVO. In this perspective, this paper aims to provide a comprehensive description of them focused on their diverse biological activities. For each biological activity, the mechanisms and the main structure-activity relationships (SARs) will be presented in cases where adequate information is available. Finally, future directions of this class of compounds will be discussed. This review will be helpful in understanding and encouraging further exploration of EVO.
ESTHER : Li_2022_Mini.Rev.Med.Chem__
PubMedSearch : Li_2022_Mini.Rev.Med.Chem__
PubMedID: 35379148

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

Title : Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property - Liu_2022_Bioorg.Chem_126_105875
Author(s) : Liu W , Wu L , Li D , Huang Y , Liu M , Tian C , Liu X , Jiang X , Hu X , Gao X , Xu Z , Lu H , Zhao Q
Ref : Bioorg Chem , 126 :105875 , 2022
Abstract : Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI(50) = 0.029 microM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD(50)) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC(50) = 0.002 microM) and good selectivity over CDK2 (IC(50) = 0.054 microM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.
ESTHER : Liu_2022_Bioorg.Chem_126_105875
PubMedSearch : Liu_2022_Bioorg.Chem_126_105875
PubMedID: 35623141

Title : A highly effective and stable butyrylcholinesterase inhibitor with multi-faceted neuroprotection and cognition improvement - Li_2022_Eur.J.Med.Chem_239_114510
Author(s) : Li Q , Xiong B , Wang Y , Lyu W , Xing S , Chen Y , Liao Q , He S , Feng F , Liu W , Sun H
Ref : Eur Journal of Medicinal Chemistry , 239 :114510 , 2022
Abstract : Butyrylcholinesterase (BChE) has been more and more attractive for treating neurodegenerative diseases, especially Alzheimer's disease (AD). In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC(50) values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC(50) = 2.94 nM, hBChE IC(50) = 34.6 nM, and 20, eqBChE IC(50) = 0.15 nM, hBChE IC(50) = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments. Two candidates exhibited remarkable neuroprotective properties and cognition improving activity, by benefiting cholinergic system, reducing the total Abeta amount and increasing the ghrelin content. Simultaneous modulation in the center and periphery greatly improves the efficiency of BChE inhibitors. Considering the regulation on ghrelin level, BChE inhibition could improve not only symptoms but also nutritional status of AD patients.
ESTHER : Li_2022_Eur.J.Med.Chem_239_114510
PubMedSearch : Li_2022_Eur.J.Med.Chem_239_114510
PubMedID: 35728508

Title : Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease - Lu_2022_Eur.J.Med.Chem_243_114729
Author(s) : Lu X , Qin N , Liu Y , Du C , Feng F , Liu W , Chen Y , Sun H
Ref : Eur Journal of Medicinal Chemistry , 243 :114729 , 2022
Abstract : Butyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, neurotoxicity assay and neuroprotective effects assay indicated two optimal compounds 17c and 19c. Both compounds showed selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 microM), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from Abeta(1-42) induced damage. It also demonstrated that 17c and 19c were able to restore cognitive impairment in vivo test. These data suggest that 17c and 19c represent promising candidate for follow-up in the drug-discovery process against AD.
ESTHER : Lu_2022_Eur.J.Med.Chem_243_114729
PubMedSearch : Lu_2022_Eur.J.Med.Chem_243_114729
PubMedID: 36084535

Title : Development and structure-activity relationship of tacrine derivatives as highly potent CDK2\/9 inhibitors for the treatment of cancer - Wu_2022_Eur.J.Med.Chem_242_114701
Author(s) : Wu L , Liu W , Huang Y , Zhu C , Ma Q , Wu Q , Tian L , Feng X , Liu M , Wang N , Xu X , Liu X , Xu C , Qiu J , Xu Z , Zhao Q
Ref : Eur Journal of Medicinal Chemistry , 242 :114701 , 2022
Abstract : CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI(50) = 0.006 microM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC(50) = 0.011 microM, CDK9: IC(50) = 0.002 microM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC(50) = 19.023 microM) and butyrylcholinesterase (BuChE, IC(50) = 2.768 microM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD(50)) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.
ESTHER : Wu_2022_Eur.J.Med.Chem_242_114701
PubMedSearch : Wu_2022_Eur.J.Med.Chem_242_114701
PubMedID: 36054949

Title : Mechanism-Based Design of Efficient PET Hydrolases - Wei_2022_ACS.Catal_12_3382
Author(s) : Wei R , von Haugwitz G , Pfaff L , Mican J , Badenhorst CPS , Liu W , Weber G , Austin HP , Bednar D , Damborsky J , Bornscheuer UT
Ref : ACS Catal , 12 :3382 , 2022
Abstract : Polyethylene terephthalate (PET) is the most widespread synthetic polyester, having been utilized in textile fibers and packaging materials for beverages and food, contributing considerably to the global solid waste stream and environmental plastic pollution. While enzymatic PET recycling and upcycling have recently emerged as viable disposal methods for a circular plastic economy, only a handful of benchmark enzymes have been thoroughly described and subjected to protein engineering for improved properties over the last 16 years. By analyzing the specific material properties of PET and the reaction mechanisms in the context of interfacial biocatalysis, this Perspective identifies several limitations in current enzymatic PET degradation approaches. Unbalanced enzyme-substrate interactions, limited thermostability, and low catalytic efficiency at elevated reaction temperatures, and inhibition caused by oligomeric degradation intermediates still hamper industrial applications that require high catalytic efficiency. To overcome these limitations, successful protein engineering studies using innovative experimental and computational approaches have been published extensively in recent years in this thriving research field and are summarized and discussed in detail here. The acquired knowledge and experience will be applied in the near future to address plastic waste contributed by other mass-produced polymer types (e.g., polyamides and polyurethanes) that should also be properly disposed by biotechnological approaches.
ESTHER : Wei_2022_ACS.Catal_12_3382
PubMedSearch : Wei_2022_ACS.Catal_12_3382
PubMedID: 35368328

Title : FAM135B sustains the reservoir of Tip60-ATM assembly to promote DNA damage response - Zhang_2022_Clin.Transl.Med_12_e945
Author(s) : Zhang K , Wu Q , Liu W , Wang Y , Zhao L , Chen J , Liu H , Liu S , Li J , Zhang W , Zhan Q
Ref : Clin Transl Med , 12 :e945 , 2022
Abstract : BACKGROUND: Recently, the mechanism by which cells adapt to intrinsic and extrinsic stresses has received considerable attention. Tat-interactive protein 60-kDa/ataxia-telangiectasia-mutated (TIP60/ATM) axis-mediated DNA damage response (DDR) is vital for maintaining genomic integrity. METHODS: Protein levels were detected by western blot, protein colocalisation was examined by immunofluorescence (IF) and protein interactions were measured by co-immunoprecipitation, proximity ligation assay and GST pull-down assays. Flow cytometry, comet assay and IF assays were used to explore the biological functions of sequence similarity 135 family member B (FAM135B) in DDR. Xenograft tumour, FAM135B transgenic mouse models and immunohistochemistry were utilised to confirm in vitro observations. RESULTS: We identified a novel DDR regulator FAM135B which could protect cancer cells from genotoxic stress in vitro and in vivo. The overexpression of FAM135B promoted the removal of gammaH2AX and 53BP1 foci, whereas the elimination of FAM135B attenuated these effects. Consistently, our findings revealed that FAM135B could promote homologous recombination and non-homologous end-joining repairs. Further study demonstrated that FAM135B physically bound to the chromodomain of TIP60 and improved its histone acetyltransferase activity. Moreover, FAM135B enhanced the interactions between TIP60 and ATM under resting conditions. Intriguingly, the protein levels of FAM135B dramatically decreased following DNA damage stress but gradually increased during the DNA repair period. Thus, we proposed a potential DDR mechanism where FAM135B sustains a reservoir of pre-existing TIP60-ATM assemblies under resting conditions. Once cancer cells suffer DNA damage, FAM135B is released from TIP60, and the functioning pre-assembled TIP60-ATM complex participates in DDR. CONCLUSIONS: We characterised FAM135B as a novel DDR regulator and further elucidated the role of the TIP60-ATM axis in response to DNA damage, which suggests that targeting FAM135B in combination with radiation therapy or chemotherapy could be a potentially effective approach for cancer treatment.
ESTHER : Zhang_2022_Clin.Transl.Med_12_e945
PubMedSearch : Zhang_2022_Clin.Transl.Med_12_e945
PubMedID: 35979619
Gene_locus related to this paper: human-FAM135B

Title : A carboxylesterase-activatable near-infrared phototheranostic probe for tumor fluorescence imaging and photodynamic therapy - Li_2022_RSC.Adv_12_35477
Author(s) : Li L , Zhang Q , Li J , Tian Y , Liu W , Diao H
Ref : RSC Adv , 12 :35477 , 2022
Abstract : Phototheranostic probes have been proven to be a promising option for cancer diagnosis and treatment. However, near-infrared phototheranostic probes with specific tumor microenvironment responsiveness are still in demand. In this paper, a carboxylesterase (CES)-responsive near-infrared phototheranostic probe was developed by incorporating 6-acetamidohexanoic acid into a hemicyanine dye through an ester bond. The probe exhibits highly sensitive and selective fluorescence enhancement towards CES because CES-catalyzed cleavage of the ester bond leads to the release of the fluorophore. By virtue of its near-infrared analytical wavelengths and high sensitivity, the probe has been employed for endogenous CES activatable fluorescence imaging of tumor cells. Moreover, under 660 nm laser irradiation, the probe can generate toxic reactive oxygen species and efficiently kill tumor cells, with low cytotoxicity in dark. As far as we know, the probe was the first CES-responsive phototheranostic probe with both near-infrared analytical wavelengths and photosensitive capacity, which may be useful in the real-time and in situ imaging of CES as well as imaging-guided photodynamic therapy of tumors. Therefore, the proposed probe may have wide application prospect in cancer theranostics.
ESTHER : Li_2022_RSC.Adv_12_35477
PubMedSearch : Li_2022_RSC.Adv_12_35477
PubMedID: 36540215

Title : The Covid-19 oral drug Molnupiravir is a CES2 substrate: potential drug-drug interactions and impact of CES2 genetic polymorphism in vitro - Shen_2022_Drug.Metab.Dispos__
Author(s) : Shen Y , Eades W , Liu W , Yan B
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , : , 2022
Abstract : Molnupiravir is one of the two COVID-19 oral drugs that were recently granted the emergency use authorization by the Food and Drug Administration (FDA). Molnupiravir is an ester and requires hydrolysis to exert antiviral activity. Carboxylesterases constitute a class of hydrolases with high catalytic efficiency. Humans express two major carboxylesterases (CES1 and CES2) that differ in substrate specificity. Based on the structural characteristics of molnupiravir, this study was performed to test the hypothesis that molnupiravir is preferably hydrolyzed by CES2. Several complementary approaches were used to test this hypothesis. As many as 24 individual human liver samples were tested and the hydrolysis of molnupiravir was significantly correlated with the level of CES2 but not CES1. Microsomes from the intestine, kidney and liver but not lung all rapidly hydrolyzed molnupiravir and the magnitude of hydrolysis was related closely to the level of CES2 expression among these organs. Importantly, recombinant CES2 but not CES1 hydrolyzed molnupiravir, collectively establishing that molnupiravir is a CES2-selective substrate. In addition, several CES2 polymorphic variants (e.g., R180H) differed from the wild-type CES2 in the hydrolysis of molnupiravir. Molecular docking revealed that wild-type CES2 and its variant R180H used different sets of amino acids to interact with molnupiravir. Furthermore, molnupiravir hydrolysis was significantly inhibited by remdesivir, the first COVID-19 drug granted the full approval by the FDA. The results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation. Significance Statement COVID-19 remains a global health crisis, and molnupiravir is one of the two recently approved oral COVID-19 therapeutics. In this study, we have shown that molnupiravir is hydrolytically activated by CES2, a major hydrolase whose activity is impacted by genetic polymorphic variants, disease mediators, and many potentially co-administered medicines. these results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation.
ESTHER : Shen_2022_Drug.Metab.Dispos__
PubMedSearch : Shen_2022_Drug.Metab.Dispos__
PubMedID: 35790245

Title : Silencing of MsD14 Resulted in Enhanced Forage Biomass through Increasing Shoot Branching in Alfalfa (Medicago sativa L.) - Ma_2022_Plants.(Basel)_11_
Author(s) : Ma L , Zhang Y , Wen H , Liu W , Zhou Y , Wang X
Ref : Plants (Basel) , 11 : , 2022
Abstract : Branching is one of the key determinants of plant architecture that dramatically affects crop yield. As alfalfa is the most important forage crop, understanding the genetic basis of branching in this plant can facilitate breeding for a high biomass yield. In this study, we characterized the strigolactone receptor gene MsD14 in alfalfa and demonstrated that MsD14 was predominantly expressed in flowers, roots, and seedpods. Furthermore, we found that MsD14 expression could significantly respond to strigolactone in alfalfa seedlings, and its protein was located in the nucleus, cytoplasm, and cytomembrane. Most importantly, transformation assays demonstrated that silencing of MsD14 in alfalfa resulted in increased shoot branching and forage biomass. Significantly, MsD14 could physically interact with AtMAX2 and MsMAX2 in the presence of strigolactone, suggesting a similarity between MsD14 and AtD14. Together, our results revealed the conserved D14-MAX2 module in alfalfa branching regulation and provided candidate genes for alfalfa high-yield molecular breeding.
ESTHER : Ma_2022_Plants.(Basel)_11_
PubMedSearch : Ma_2022_Plants.(Basel)_11_
PubMedID: 35406919

Title : Synthesis, Characterization and Biological Evaluation of Benzothiazole-Isoquinoline Derivative - Liu_2022_Molecules_27_9062
Author(s) : Liu W , Zhao D , He Z , Hu Y , Zhu Y , Zhang L , Jin L , Guan L , Wang S
Ref : Molecules , 27 :9062 , 2022
Abstract : Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi-target-directed ligands (MTDLs), we synthesized a series of (R)-N-(benzo[d]thiazol-2-yl)-2-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl) acetamides with substituted benzothiazoles and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory potency against monoamine oxidase B (MAO-B) and butyrylcholinesterase (BuChE). Among them, six compounds (4b-4d, 4f, 4g and 4i) displayed excellent activity. The classical antidepressant forced swim test (FST) was used to verify the in vitro results, revealing that six compounds reduced the immobility time significantly, especially compound 4g. The cytotoxicity of the compounds was assessed by the MTT method and Acridine Orange (AO) staining, with cell viability found to be above 90% at effective compound concentrations, and not toxic to L929 cells reversibility, kinetics and molecular docking studies were also performed using compound 4g, which showed the highest MAO-B and BuChE inhibitory activities. The results of these studies showed that compound 4g binds to the primary interaction sites of both enzymes and has good blood-brain barrier (BBB) penetration. This study provides new strategies for future research on neurodegenerative diseases complicated by depression.
ESTHER : Liu_2022_Molecules_27_9062
PubMedSearch : Liu_2022_Molecules_27_9062
PubMedID: 36558194

Title : Synthesis and activity of miconazole derivatives as dual BChE\/IDO1 inhibitors for the treatment of Alzheimer's disease - Lu_2021_Future.Med.Chem_13_1105
Author(s) : Lu X , Liu Y , Qin N , Yang H , Qiao Y , Jiang X , Chen Y , Feng F , Liu W , Zhou Y , Sun H
Ref : Future Med Chem , 13 :1105 , 2021
Abstract : Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.
ESTHER : Lu_2021_Future.Med.Chem_13_1105
PubMedSearch : Lu_2021_Future.Med.Chem_13_1105
PubMedID: 33960203

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 : Identification and Characterization of Polysorbate-Degrading Enzymes in a Monoclonal Antibody Formulation - Graf_2021_J.Pharm.Sci__
Author(s) : Graf T , Tomlinson A , Yuk IH , Kufer R , Spensberger B , Falkenstein R , Shen A , Li H , Duan D , Liu W , Wohlrab S , Edelmann F , Leiss M
Ref : J Pharm Sci , : , 2021
Abstract : Degradation of polysorbate (PS) by hydrolytically active host cell proteins (HCPs) in drug products may impair the protein-stabilizing properties of PS and lead to the formation of particles due to the accumulation of poorly soluble free fatty acids upon long-term storage. The identification of the causative enzymes is challenging due to their low-abundance even when using state-of-the-art instrumentation and workflows. To overcome these challenges, we developed a rigorous enrichment strategy for HCPs, utilizing both Protein A and anti-HCP affinity chromatography, which facilitated the in-depth characterization of the HCP population in a monoclonal antibody formulation prone to PS hydrolysis. Based on the HCPs identified by liquid chromatography coupled to tandem mass spectrometry, a number of enzymes annotated as hydrolases were recombinantly expressed and characterized in terms of polysorbate degradation. Among the selected candidates, Lipoprotein Lipase, Lysosomal Acid Lipase (LIPA) and Palmitoyl-Protein Thioesterase 1 (PPT1) exhibited notable activity towards PS. To our knowledge, this is the first report to identify LIPA and PPT1 as residual HCPs that can contribute to PS degradation in a biological product.
ESTHER : Graf_2021_J.Pharm.Sci__
PubMedSearch : Graf_2021_J.Pharm.Sci__
PubMedID: 34224732

Title : Combined use of GABA and sitagliptin promotes human beta-cell proliferation and reduces apoptosis - Liu_2021_J.Endocrinol_248_133
Author(s) : Liu W , Lau HK , Son DO , Jin T , Yang Y , Zhang Z , Li Y , Prud'homme GJ , Wang Q
Ref : J Endocrinol , 248 :133 , 2021
Abstract : gamma-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent beta-cell survival and function. In human beta-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic beta-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human beta-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human beta-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ beta-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of alpha-Klotho, a protein with protective and stimulatory effects on beta cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of beta-cell proliferation and a decrease in apoptosis.
ESTHER : Liu_2021_J.Endocrinol_248_133
PubMedSearch : Liu_2021_J.Endocrinol_248_133
PubMedID: 33258801

Title : Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection - Li_2021_J.Med.Chem__
Author(s) : Li Q , Chen Y , Xing S , Liao Q , Xiong B , Wang Y , Lu W , He S , Feng F , Liu W , Sun H
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Abeta deposit. Here, we identified S06-1011 (hBChE IC(50) = 16 nM) and S06-1031 (hBChE IC(50) = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Abeta(1-42) peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
ESTHER : Li_2021_J.Med.Chem__
PubMedSearch : Li_2021_J.Med.Chem__
PubMedID: 33973470

Title : General features to enhance enzymatic activity of poly(ethylene terephthalate) hydrolysis - Chen_2021_Nat.Catal_4_425
Author(s) : Chen CC , Han X , Li X , Jiang P , Niu D , Ma L , Liu W , Li S , Qu Y , Hu H , Min J , Yang Y , Zhang L , Zeng W , Huang JW , Dai L , Guo RT , Chen, CC
Ref : Nature Catalysis , 4 :425 , 2021
Abstract : Poly(ethylene terephthalate) (PET) is the most abundant polyester plastic and a major contributor to plastic pollution. IsPETase, from the PET-assimilating bacterium Ideonella sakaiensis, is a unique PET-hydrolytic enzyme that shares high sequence identity to canonical cutinases, but shows substrate preference towards PET and exhibits higher PET-hydrolytic activity at ambient temperature. Structural analyses suggest that IsPETase harbours a substrate-binding residue, W185, with a wobbling conformation and a highly flexible W185-locating beta6-beta7 loop. Here, we show that these features result from the presence of S214 and I218 in IsPETase, whose equivalents are strictly His and Phe, respectively, in all other homologous enzymes. We found that mutating His/Phe residues to Ser/Ile could enhance the PET-hydrolytic activity of several IsPETase-like enzymes. In conclusion, the Ser/Ile mutations should provide an important strategy to improve the activity of potential PET-hydrolytic enzymes with properties that may be useful for various applications.
ESTHER : Chen_2021_Nat.Catal_4_425
PubMedSearch : Chen_2021_Nat.Catal_4_425
Gene_locus related to this paper: 9burk-a0a1f4jxw8 , idesa-peth

Title : Enhancement of Fear Extinction Memory and Resistance to Age-Related Cognitive Decline in Butyrylcholinesterase Knockout Mice and (R)-Bambuterol Treated Mice - Liu_2021_Biology.(Basel)_10_
Author(s) : Liu W , Cao Y , Lin Y , Tan KS , Zhao H , Guo H , Tan W
Ref : Biology (Basel) , 10 : , 2021
Abstract : Butyrylcholinesterase (BChE) is detected in plaques preferentially in Alzheimer's disease (AD) and may be associated with stress disorders. However, the physiological function of BChE in the central nervous system remains to be further investigated. BChE knockout (KO) mice and wild-type (WT) mice with orally or intranasal administration of (R)-bambuterol were used to explore the effect of BChE on behavior changes. (R)-bambuterol is a specific and reversible inhibitor of BChE. The behavior changes were evaluated and compared among 3-10 month old mice. Our finding showed that BChE KO and (R)-bambuterol administration enhanced episodic memory, including fear conditioning memory and fear extinction memory in fear conditioning and fear extinction test. BChE KO and (R)-bambuterol administered mice rescued age-related spatial memory and general activity in the water maze test and open field test. The brain metabolomics were imaged using a desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The image of DESI-MS demonstrated that glutamine content increased in the brain of BChE KO mice. In conclusion, this study found that inhibition of BChE ameliorated episodic and spatial memories. This study also suggested that (R)-bambuterol as a BChE inhibitor has the potential application in the treatment of post-traumatic stress disorder (PTSD) and early cognitive decline.
ESTHER : Liu_2021_Biology.(Basel)_10_
PubMedSearch : Liu_2021_Biology.(Basel)_10_
PubMedID: 34062954

Title : Discovery of novel beta-carboline derivatives as selective AChE inhibitors with GSK-3beta inhibitory property for the treatment of Alzheimer's disease - Liu_2021_Eur.J.Med.Chem_229_114095
Author(s) : Liu W , Liu X , Gao Y , Wu L , Huang Y , Chen H , Li D , Zhou L , Wang N , Xu Z , Jiang X , Zhao Q
Ref : Eur Journal of Medicinal Chemistry , 229 :114095 , 2021
Abstract : The natural product harmine, a representative beta-carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti-acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC(50) = 0.27 microM) and selective BChE inhibition (IC(50) = 20.82 microM), as well as acceptable glycogen synthase kinase-3 (GSK-3beta) inhibition (IC(50) = 6.78 microM). Molecular docking studies and molecular dynamics simulations indicated that ZLWH-23 could form stable interaction with AChE and GSK-3beta. Gratifyingly, ZLWH-23 exhibited good selectivity for GSK-3beta over multi-kinases and very low cytotoxicity towards SH-SY5Y, HEK-293T, HL-7702, and HepG2 cell lines. Importantly, ZLWH-23 displayed efficient reduction against tau hyperphosphorylation on Ser-396 site in Tau (P301L) 293T cell model. Collectively, harmine-based derivatives could be considered as possible drug leads for the development of AD therapies.
ESTHER : Liu_2021_Eur.J.Med.Chem_229_114095
PubMedSearch : Liu_2021_Eur.J.Med.Chem_229_114095
PubMedID: 34995924

Title : Synthesis and bio-evaluation of a novel selective butyrylcholinesterase inhibitor discovered through structure-based virtual screening - Xing_2021_Int.J.Biol.Macromol_166_1352
Author(s) : Xing S , Chen Y , Xiong B , Lu W , Li Q , Wang Y , Jiao M , Feng F , Liu W , Sun H
Ref : Int J Biol Macromol , 166 :1352 , 2021
Abstract : In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schrodinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513-4169 displayed the highest inhibitory activity and selectivity against BChE (eeAChE IC(50) > 10 microM, eqBChE IC(50) = 3.73 +/- 1.90 microM). Molecular dynamic (MD) simulation validated the binding pattern of 2513-4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513-4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513-4169 against toxic Abeta(1)(-)(42). In vivo behavioral study further confirmed the great efficacy of 2513-4169 on reversing Abeta(1)(-)(42)-induced cognitive impairment of mice and clearing the toxic Abeta(1)(-)(42) in brains. Moreover, 2513-4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513-4169 is a promising lead compound for future optimization to discover anti-AD treating agents.
ESTHER : Xing_2021_Int.J.Biol.Macromol_166_1352
PubMedSearch : Xing_2021_Int.J.Biol.Macromol_166_1352
PubMedID: 33161083

Title : Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer's disease, and fat metabolism - Xing_2021_Med.Res.Rev_41_858
Author(s) : Xing S , Li Q , Xiong B , Chen Y , Feng F , Liu W , Sun H
Ref : Med Res Rev , 41 :858 , 2021
Abstract : Structural information of butyrylcholinesterase (BChE) and its variants associated with several diseases are discussed here. Pure human BChE has been proved safe and effective in treating organophosphorus (OPs) poisoning and has completed Phase 1 and 2 pharmacokinetic (PK) and safety studies. The introduction of specific mutations into native BChE to endow it a self-reactivating property has gained much progress in producing effective OPs hydrolases. The hydrolysis ability of native BChE on cocaine has been confirmed but was blocked to clinical application due to poor PK properties. Several BChE mutants with elevated cocaine hydrolysis activity were published, some of which have shown safety and efficiency in treating cocaine addiction of human. The increased level of BChE in progressed Alzheimer's disease patients made it a promising target to elevate acetylcholine level and attenuate cognitive status. A variety of selective BChE inhibitors with high inhibitory activity published in recent years are reviewed here. BChE could influence the weight and insulin secretion and resistance of BChE knockout (KO) mice through hydrolyzing ghrelin. The BChE-ghrelin pathway could also regulate aggressive behaviors of BChE-KO mice.
ESTHER : Xing_2021_Med.Res.Rev_41_858
PubMedSearch : Xing_2021_Med.Res.Rev_41_858
PubMedID: 33103262

Title : Triglyceride-Mimetic Structure-Gated Prodrug Nanoparticles for Smart Cancer Therapy - Tian_2021_J.Med.Chem__
Author(s) : Tian C , Guo J , Miao Y , Zheng S , Sun B , Sun M , Ye Q , Liu W , Zhou S , Kamei KI , He Z , Sun J
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles bioactivated under tumor-specific conditions are one of the effective strategies to achieve on-demand drug release and effective tumor accumulation. Herein, stimuli-activable prodrugs are designed yielding smart tumor delivery by combination of the triglyceride-mimic (TG-mimetic) prodrug structure and disulfide bond. Surprisingly, these prodrugs can self-assemble into uniform nanoparticles (NPs) with a high drug loading (over 40%) and accumulate in tumor sites specifically. The super hydrophobic TG structure can act as a gate that senses lipase to selectively control over NP dissociation and affect the glutathione-triggered prodrug activation. In addition, the impacts of the double bonds in the prodrug NPs on parent drug release and the following cytotoxicity, pharmacokinetics, and antitumor efficiency are further demonstrated. Our findings highlight the promising potential of TG-mimetic structure-gated prodrug nanoparticles for tumor-specific drug delivery.
ESTHER : Tian_2021_J.Med.Chem__
PubMedSearch : Tian_2021_J.Med.Chem__
PubMedID: 34723524

Title : Effect of Chitosan Coatings with Cinnamon Essential Oil on Postharvest Quality of Mangoes - Yu_2021_Foods_10_
Author(s) : Yu K , Xu J , Zhou L , Zou L , Liu W
Ref : Foods , 10 : , 2021
Abstract : Mango (Mangifera indica Linn.) is a famous climacteric fruit containing abundant flavor and nutrients in the tropics, but it is prone to decay without suitable postharvest preservation measures. In this study, the chitosan (CH)-cinnamon essential oil (CEO) Pickering emulsion (CH-PE) coating was prepared, with cellulose nanocrystals as the emulsifier, and applied to harvested mangoes at the green stage of maturity. It was compared with a pure CH coating and a CH-CEO emulsion (CH-E) coating, prepared with the emulsifier Tween 80. Results showed that the CH-PE coating had a lower water solubility and water vapor permeability than the other coatings, which was mainly due to electrostatic interactions, and had a better sustained-release performance for CEO than the CH-E coating. During mango storage, the CH-PE coating effectively improved the appearance of mangoes at 25 degreesC for 12 d by reducing yellowing and dark spots, and delayed water loss. Hardness was maintained and membrane lipid peroxidation was reduced by regulating the activities of pectin methyl esterase, polygalacturonase, and peroxidase. In addition, the nutrient quality was improved by the CH-PE coating, with higher contents of total soluble solid, titratable acid, and ascorbic acid. Therefore, the CH-PE coating is promising to comprehensively maintain the postharvest quality of mangoes, due to its enhanced physical and sustained-release properties.
ESTHER : Yu_2021_Foods_10_
PubMedSearch : Yu_2021_Foods_10_
PubMedID: 34945553

Title : Electro-Acupuncture Improve the Early Pattern Separation in Alzheimer's Disease Mice via Basal Forebrain-Hippocampus Cholinergic Neural Circuit - Li_2021_Front.Aging.Neurosci_13_770948
Author(s) : Li L , Li J , Dai Y , Yang M , Liang S , Wang Z , Liu W , Chen L , Tao J
Ref : Front Aging Neurosci , 13 :770948 , 2021
Abstract : OBJECTIVES: To explore the effect of electro-acupuncture (EA) treatment on pattern separation and investigate the neural circuit mechanism involved in five familial mutations (5 x FAD) mice. METHODS: Five familial mutations mice were treated with EA at Baihui (DU20) and Shenting (DU24) acupoints for 30 min each, lasting for 4 weeks. Cognitive-behavioral tests were performed to evaluate the effects of EA treatment on cognitive functions. (1)H-MRS, Nissl staining, immunohistochemistry, and immunofluorescence were performed to examine the cholinergic system alteration. Thioflavin S staining and 6E10 immunofluorescence were performed to detect the amyloid-beta (Abeta). Furthermore, hM4Di designer receptors exclusively activated by designer drugs (DREADDs) virus and long-term clozapine-N-oxide injection were used to inhibit the medial septal and vertical limb of the diagonal band and dentate gyrus (MS/VDB-DG) cholinergic neural circuit. Cognitive-behavioral tests and immunofluorescence were performed to investigate the cholinergic neural circuit mechanism of EA treatment improving cognition in 5 x FAD mice. RESULTS: Electro-acupuncture treatment significantly improved spatial recognition memory and pattern separation impairment, regulated cholinergic system via reduction neuron loss, upregulation of choline/creatine, choline acetyltransferase, vesicular acetylcholine transporter, and downregulation of enzyme acetylcholinesterase in 5 x FAD mice. Abeta deposition was reduced after EA treatment. Subsequently, the monosynaptic hM4Di DREADDs virus tracing and inhibiting strategy showed that EA treatment activates the MS/VDB-DG cholinergic neural circuit to improve the early pattern separation. In addition, EA treatment activates this circuit to upregulating M1 receptors positive cells and promoting hippocampal neurogenesis in the dentate gyrus (DG). CONCLUSION: Electro-acupuncture could improve the early pattern separation impairment by activating the MS/VDB-DG cholinergic neural circuit in 5 x FAD mice, which was related to the regulation of the cholinergic system and the promotion of neurogenesis by EA treatment.
ESTHER : Li_2021_Front.Aging.Neurosci_13_770948
PubMedSearch : Li_2021_Front.Aging.Neurosci_13_770948
PubMedID: 35185516

Title : Longitudinal Profile of Laboratory Parameters and Their Application in the Prediction for Fatal Outcome Among Patients Infected With SARS-CoV-2: A Retrospective Cohort Study - Zeng_2021_Clin.Infect.Dis_72_626
Author(s) : Zeng HL , Lu QB , Yang Q , Wang X , Yue DY , Zhang LK , Li H , Liu W , Li HJ
Ref : Clin Infect Dis , 72 :626 , 2021
Abstract : BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) experience a wide clinical spectrum, with over 2% developing fatal outcome. The prognostic factors for fatal outcome remain sparsely investigated. METHODS: A retrospective cohort study was performed in a cohort of patients with confirmed COVID-19 in one designated hospital in Wuhan, China, from 17 January-5 March 2020. The laboratory parameters and a panel of cytokines were consecutively evaluated until patients' discharge or death. The laboratory features that could be used to predict fatal outcome were identified. RESULTS: Consecutively collected data on 55 laboratory parameters and cytokines from 642 patients with COVID-19 were profiled along the entire disease course, based on which 3 clinical stages (acute stage, days 1-9; critical stage, days 10-15; and convalescence stage, day 15 to observation end) were determined. Laboratory findings based on 75 deceased and 357 discharged patients revealed that, at the acute stage, fatality could be predicted by older age and abnormal lactate dehydrogenase (LDH), urea, lymphocyte count, and procalcitonin (PCT) level. At the critical stage, the fatal outcome could be predicted by age and abnormal PCT, LDH, cholinesterase, lymphocyte count, and monocyte percentage. Interleukin 6 (IL-6) was remarkably elevated, with fatal cases having a more robust production than discharged cases across the whole observation period. LDH, PCT, lymphocytes, and IL-6 were considered highly important prognostic factors for COVID-19-related death. CONCLUSIONS: The identification of predictors that were routinely tested might allow early identification of patients at high risk of death for early aggressive intervention.
ESTHER : Zeng_2021_Clin.Infect.Dis_72_626
PubMedSearch : Zeng_2021_Clin.Infect.Dis_72_626
PubMedID: 33048116

Title : Discovery of 2-(cyclopropanecarboxamido)-N-(5-((1-(4-fluorobenzyl)piperidin-4-yl)methoxy)pyridin-3-yl)isonicotinamide as a potent dual AChE\/GSK3beta inhibitor for the treatment of Alzheimer's disease: Significantly increasing the level of acetylcholine in the brain without affecting that in intestine - Jiang_2021_Eur.J.Med.Chem_223_113663
Author(s) : Jiang X , Liu C , Zou M , Xie H , Lin T , Lyu W , Xu J , Li Y , Feng F , Sun H , Liu W
Ref : Eur Journal of Medicinal Chemistry , 223 :113663 , 2021
Abstract : Acetylcholinesterase (AChE) inhibitors are currently the first-line drugs approved by the FDA for the treatment of Alzheimer's disease (AD). However, a short effective-window limits their therapeutic benefits. Clinical studies have confirmed that the combination of AChE inhibitors and neuroprotective agents exhibits better anti-AD effects. We have previously reported that the dual AChE/GSK3beta (Glycogen synthase kinase 3beta) modulators have both neuroprotective effects and cognitive impairment-improvement effects. In this study, we characterized a new backbone of the AChE/GSK3beta inhibitor 11c. It was identified as a highly potent AChE inhibitor and was found superior to donepezil, the first-line drug for the treatment of AD. In vivo studies confirmed that 11c significantly inhibited the activity of AChE in the brain but had little effect on the activity of AChE in the intestine. This advantage of 11c was expected to reduce the peripheral side effects caused by donepezil. Furthermore, biomarker studies have shown that 11c also improved the levels of acetylcholine and synaptophysin in the brain and exhibited neuroprotective effects. Preliminary in vivo and in vitro research results underline the exciting potential of compound 11c in the treatment of AD.
ESTHER : Jiang_2021_Eur.J.Med.Chem_223_113663
PubMedSearch : Jiang_2021_Eur.J.Med.Chem_223_113663
PubMedID: 34198150

Title : Discovery of potent glycogen synthase kinase 3\/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer's disease - Jiang_2021_Bioorg.Med.Chem_30_115940
Author(s) : Jiang X , Wang Y , Liu C , Xing C , Lyu W , Wang S , Li Q , Chen T , Chen Y , Feng F , Liu W , Sun H
Ref : Bioorganic & Medicinal Chemistry , 30 :115940 , 2021
Abstract : In the present work, a novel series of pyridinethiazole bearing benzylpiperidine hybrids were designed and synthesized as dual-target inhibitors of GSK-3beta/AChE. Among them, GD29 was the most promising candidate, with an IC(50) value of 0.3 M for hAChE and an IC(50) value of 0.003 M for hGSK-3beta, respectively. The compounds exhibited good drug-like properties with optimal inhibitory enzyme activities. Moreover, GD29 showed anti-inflammatory properties at micromolar concentrations and displayed interesting neuroprotective profiles in an in vitro model of oxidative stress-induced neuronal death. Notably, the compounds also exhibited good permeability across the blood-brain-barrier (BBB) both in vitro. Central cholinomimetic activity was confirmed using a scopolamine-induced cognition impairment model in Institute of Cancer Research (ICR) mice upon oral administration. The current work identified optimized compounds and explored the therapeutic potential of glycogen synthase kinase 3/cholinesterase inhibition for the treatment of AD.
ESTHER : Jiang_2021_Bioorg.Med.Chem_30_115940
PubMedSearch : Jiang_2021_Bioorg.Med.Chem_30_115940
PubMedID: 33340937

Title : Structural analysis of PET-degrading enzymes PETase and MHETase from Ideonella sakaiensis - Graf_2021_Methods.Enzymol_648_337
Author(s) : Graf LG , Michels EAP , Yew Y , Liu W , Palm GJ , Weber G
Ref : Methods Enzymol , 648 :337 , 2021
Abstract : The concept of biocatalytic PET degradation for industrial recycling processes had made a big step when the bacterium Ideonella sakaiensis was discovered to break PET down to its building blocks at ambient temperature. This process involves two enzymes: cleavage of ester bonds in PET by PETase and in MHET, the resulting intermediate, by MHETase. To understand and further improve this unique capability, structural analysis of the involved enzymes was aimed at from early on. We describe a repertoire of methods to this end, including protein expression and purification, crystallization of apo and substrate-bound enzymes, and modeling of PETase complexed with a ligand.
ESTHER : Graf_2021_Methods.Enzymol_648_337
PubMedSearch : Graf_2021_Methods.Enzymol_648_337
PubMedID: 33579411
Gene_locus related to this paper: idesa-mheth , idesa-peth

Title : Colorimetric detection of acetylcholinesterase and its inhibitor based on thiol-regulated oxidase-like activity of 2D palladium square nanoplates on reduced graphene oxide - Yan_2021_Mikrochim.Acta_188_162
Author(s) : Yan B , Liu W , Duan G , Ni P , Jiang Y , Zhang C , Wang B , Lu Y , Chen C
Ref : Mikrochim Acta , 188 :162 , 2021
Abstract : A convenient and sensitive colorimetric assay for acetylcholinesterase (AChE) and its inhibitor has been designed based on the oxidase-like activity of {100}-faceted Pd square nanoplates which are grown in situ on reduced graphene oxide (PdSP@rGO). PdSP@rGO can effectively catalyze the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) without the assistance of H(2)O(2) to generate blue oxidized TMB (oxTMB) with a characteristic absorption peak at 652 nm. In the presence of AChE, acetylthiocholine (ATCh), a typical AChE substrate, is hydrolyzed to thiocholine (TCh). The generated TCh can effectively inhibit the PdSP@rGO-triggered chromogenic reaction of TMB via cheating with Pd, resulting in color fading and decrease in absorbance. Thus, a sensitive probe for AChE activity is constructed with a working range of 0.25-5 mU mL(-1) and a limit of detection (LOD) of 0.0625 mU mL(-1). Furthermore, because of the inhibition effect of tacrine on AChE, tacrine is also detected through the colorimetric AChE assay system within the concentrations range 0.025-0.4 microM with a LOD of 0.00229 microM. Hence, a rapid and facile colorimetric procedure to sensitively detect AChE and its inhibitor can be anticipated through modulating the oxidase-like activity of PdSP@rGO. Colorimetric method for detection of AChE and its inhibitor is established by modulating the oxidase mimetic activity of {100}-faceted Pd square nanoplates on reduced graphene oxide (PdSP@rGO).
ESTHER : Yan_2021_Mikrochim.Acta_188_162
PubMedSearch : Yan_2021_Mikrochim.Acta_188_162
PubMedID: 33839958

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 : Structure of a gut microbial diltiazem-metabolizing enzyme suggests possible substrate binding mode - Zhou_2020_Biochem.Biophys.Res.Commun__
Author(s) : Zhou S , Ko TP , Huang JW , Liu W , Zheng Y , Wu S , Wang Q , Xie Z , Liu Z , Chen CC , Guo RT
Ref : Biochemical & Biophysical Research Communications , : , 2020
Abstract : When administrated orally, the vasodilating drug diltiazem can be metabolized into diacetyl diltiazem in the presence of Bacteroides thetaiotaomicron, a human gut microbe. The removal of acetyl group from the parent drug is carried out by the GDSL/SGNH-family hydrolase BT4096. Here the crystal structure of the enzyme was solved by mercury soaking and single-wavelength anomalous diffraction. The protein folds into two parts. The N-terminal part comprises the catalytic domain which is similar to other GDSL/SGNH hydrolases. The flanking C-terminal part is made up of a beta-barrel subdomain and an alpha-helical subdomain. Structural comparison shows that the catalytic domain is most akin to acetyl-xylooligosaccharide esterase and allows a plausible binding mode of diltiazem to be proposed. The beta-barrel subdomain is similar in topology to the immunoglobulin-like domains, including some carbohydrate-binding modules, of various bacterial glycoside hydrolases. Consequently, BT4096 might originally function as an oligosaccharide deacetylase with additional subdomains that could enhance substrate binding, and it acts on diltiazem just by accident.
ESTHER : Zhou_2020_Biochem.Biophys.Res.Commun__
PubMedSearch : Zhou_2020_Biochem.Biophys.Res.Commun__
PubMedID: 32423809

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 : LPL deletion is associated with poorer response to ibrutinib-based treatments and overall survival in TP53-deleted chronic lymphocytic leukemia - Liu_2020_Ann.Hematol_99_2343
Author(s) : Liu W , Burger JA , Xu J , Tang Z , Toruner G , Khanlari M , Medeiros LJ , Tang G
Ref : Ann Hematol , 99 :2343 , 2020
Abstract : Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p<0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p<0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.
ESTHER : Liu_2020_Ann.Hematol_99_2343
PubMedSearch : Liu_2020_Ann.Hematol_99_2343
PubMedID: 32833105

Title : Transcription Factor CfSte12 of Colletotrichum fructicola Is a Key Regulator of Early Apple Glomerella Leaf Spot Pathogenesis - Liu_2020_Appl.Environ.Microbiol_87_
Author(s) : Liu W , Liang X , Gleason ML , Cao M , Zhang R , Sun G
Ref : Applied Environmental Microbiology , 87 : , 2020
Abstract : Glomerella leaf spot (GLS), caused by Colletotrichum fructicola, is a rapidly emerging disease leading to defoliation, fruit spot, and storage fruit rot on apple in China. Little is known about the mechanisms of GLS pathogenesis. Early transcriptome analysis revealed that expression of the zinc finger transcription factor Ste12 gene in C. fructicola (CfSte12) was upregulated in appressoria and leaf infection. To investigate functions of CfSte12 during pathogenesis, we constructed gene deletion mutants (deltaCfSte12) by homologous recombination. Phenotypic analysis revealed that CfSte12 was involved in pathogenesis of nonwounded apple fruit and leaf, as well as wounded apple fruit. Subsequent histological studies revealed that loss of pathogenicity by deltaCfSte12 on apple leaf was expressed as defects of conidium germination, appressorium development, and appressorium-mediated penetration. Further RNA sequencing-based transcriptome comparison revealed that CfSte12 modulates the expression of genes related to appressorium function (e.g., genes for the tetraspanin PLS1, Gas1-like proteins, cutinases, and melanin biosynthesis) and candidate effectors likely involved in plant interaction. In sum, our results demonstrated that CfSte12 is a key regulator of early apple GLS pathogenesis in C. fructicola In addition, CfSte12 is also needed for sexual development of perithecia and ascospores.IMPORTANCE Glomerella leaf spot (GLS) is an emerging fungal disease of apple that causes huge economic losses in Asia, North America, and South America. The damage inflicted by GLS manifests in rapid necrosis of leaves, severe defoliation, and necrotic spot on the fruit surface. However, few studies have addressed mechanisms of GLS pathogenesis. In this study, we identified and characterized a key pathogenicity-related transcription factor, CfSte12, of Colletotrichum fructicola that contributes to GLS pathogenesis. We provide evidence that the CfSte12 protein regulates many important pathogenic processes of GLS, including conidium germination, appressorium formation, appressorium-mediated penetration, and colonization. CfSte12 also impacts development of structures needed for sexual reproduction which are vital for the GLS disease cycle. These results reveal a key pathogenicity-related transcription factor, CfSte12, in C. fructicola that causes GLS.
ESTHER : Liu_2020_Appl.Environ.Microbiol_87_
PubMedSearch : Liu_2020_Appl.Environ.Microbiol_87_
PubMedID: 33067192

Title : Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor - Li_2020_J.Med.Chem_63_10030
Author(s) : Li Q , Xing S , Chen Y , Liao Q , Xiong B , He S , Lu W , Liu Y , Yang H , Feng F , Liu W , Sun H
Ref : Journal of Medicinal Chemistry , 63 :10030 , 2020
Abstract : To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC(50) = 0.18 +/- 0.03 M, hBChE IC(50) = 0.32 +/- 0.07 M) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Abeta(1-42) (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Abeta(1-42) total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T(1/2), and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.
ESTHER : Li_2020_J.Med.Chem_63_10030
PubMedSearch : Li_2020_J.Med.Chem_63_10030
PubMedID: 32787113

Title : Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease - Li_2020_Acta.Pharm.Sin.B_10_646
Author(s) : Li X , Lu J , Xu Y , Wang J , Qiu X , Fan L , Li B , Liu W , Mao F , Zhu J , Shen X , Li J
Ref : Acta Pharm Sin B , 10 :646 , 2020
Abstract : Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting beta-amyloid (Abeta) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.
ESTHER : Li_2020_Acta.Pharm.Sin.B_10_646
PubMedSearch : Li_2020_Acta.Pharm.Sin.B_10_646
PubMedID: 32322468

Title : Efficacy and safety of DBPR108 monotherapy in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled, phase II clinical trial - Wang_2020_Curr.Med.Res.Opin_36_1107
Author(s) : Wang W , Yao J , Guo X , Guo Y , Yan C , Liu K , Zhang Y , Wang X , Li H , Wen Z , Li S , Xiao X , Liu W , Li Z , Zhang L , Shao S , Ye S , Qin G , Li Y , Li F , Zhang X , Li X , Peng Y , Deng H , Xu X , Zhou L , Huang Y , Cao M , Xia X , Shi M , Dou J , Yuan J
Ref : Curr Med Res Opin , 36 :1107 , 2020
Abstract : Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 +/- 0.77 in placebo group, -0.51 +/- 0.71, -0.75 +/- 0.73, and -0.57 +/- 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c >=7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program.
ESTHER : Wang_2020_Curr.Med.Res.Opin_36_1107
PubMedSearch : Wang_2020_Curr.Med.Res.Opin_36_1107
PubMedID: 32338063

Title : Reasonably activating Nrf2: A long-term, effective and controllable strategy for neurodegenerative diseases - Li_2020_Eur.J.Med.Chem_185_111862
Author(s) : Li Q , Xing S , Chen Y , Liao Q , Liu Y , He S , Feng F , Zhang J , Liu W , Guo Q , Sun Y , Sun H
Ref : Eur Journal of Medicinal Chemistry , 185 :111862 , 2020
Abstract : Neurodegenerative diseases are a variety of debilitating and fatal disorder in central nervous system (CNS). Besides targeting neuronal activity by influencing neurotransmitters or their corresponding receptors, modulating the underlying processes that lead to cell death, such as oxidative stress and mitochondrial dysfunction, should also be emphasized as an assistant strategy for neurodegeneration therapy. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been closely verified to be related to anti-inflammation and oxidative stress, rationally regulating its belonging pathway and activating Nrf2 is emphasized to be a potential treatment approach. There have existed multiple Nrf2 activators with different mechanisms and diverse structures, but those applied for neuro-disorders are still limited. On the basis of research arrangement and compound summary, we put forward the limitations of existing Nrf2 activators for neurodegenerative diseases and their future developing directions in enhancing the blood-brain barrier permeability to make Nrf2 activators function in CNS and designing Nrf2-based multi-target-directed ligands to affect multiple nodes in pathology of neurodegenerative diseases.
ESTHER : Li_2020_Eur.J.Med.Chem_185_111862
PubMedSearch : Li_2020_Eur.J.Med.Chem_185_111862
PubMedID: 31735576

Title : AChR myasthenia gravis switching to MuSK or double antibody positive myasthenia gravis in two children and literature review - Lu_2020_Neuromuscul.Disord__
Author(s) : Lu Y , Ran H , Yang W , Ma Q , Qiu L , Ou C , Chen P , Lin Z , Liu W
Ref : Neuromuscular Disorders , : , 2020
Abstract : Muscle-specific tyrosine kinase antibody (MuSK-Ab) and acetylcholine receptor antibody (AChR-Ab) coexistence in myasthenia gravis (MG) is very rare. In this report, two children with AChR-Ab switching to double antibody positive MG (DP-MG) or MuSK-Ab positive MG (MuSK-MG) are described. Six similar cases were found in the literature via online database search. Therefore, this study describes eight patients in total, six female and two male. The average age of onset was 7.25 +/- 5.95 years. Four AChR-MG patients switched to DP-MG with no known precipitating factor and four switched after thymectomy (two to MuSK-MG and two to DP-MG). After the serological switch, the patients transitioned to the phenotype of MuSK-MG and responded poorly to cholinesterase inhibitors and well to corticosteroids and plasma exchange.
ESTHER : Lu_2020_Neuromuscul.Disord__
PubMedSearch : Lu_2020_Neuromuscul.Disord__
PubMedID: 32387283

Title : Complete metabolic study by dibutyl phthalate degrading Pseudomonas sp. DNB-S1 - Yu_2020_Ecotoxicol.Environ.Saf_194_110378
Author(s) : Yu H , Wang L , Lin Y , Liu W , Tuyiringire D , Jiao Y , Zhang L , Meng Q , Zhang Y
Ref : Ecotoxicology & Environmental Safety , 194 :110378 , 2020
Abstract : The primary purpose of this study was to systematically explore the complete metabolic pathway and tolerance mechanism of strain DNB-S1 to dibutyl phthalate (DBP), and the effect of DBP on energy metabolism of DNB-S1. Here, DNB-S1, a strain of Pseudomonas sp. that was highly effective in degrading DBP, was identified, and differentially expressed metabolites and metabolic networks of DBP were studied. The results showed that the differentially expressed metabolites were mainly aromatic compounds and lipid compounds, with only a few toxic intermediate metabolites. It speculated that phthalic acid, salicylic acid, 3-hydroxybenzoate acid, 3-Carboxy-cis, cis-muconate, fumarypyravate were intermediate metabolites of DBP. Their up-regulation indicated that there were two metabolic pathways in the degradation of DBP (protocatechuate pathway and gentisate pathway), which had been verified by peak changes at 290 nm, 320 nm, 330 nm, and 375 nm in the enzymatic method. Also, aspartate, GSH, and other metabolites were up-regulation, indicating that DNB-S1 had a high tolerance to DBP and maintained cell homeostasis, which was also one of the essential reasons to ensure the efficient degradation of DBP. Altogether, this study firstly proposed two pathways to degrade DBP and comprehensively explored the effect of DBP on the metabolic function of DNB-S1, which enriched the study of microbial metabolism of organic pollutants, and which provided a basis for the application of metabolomics.
ESTHER : Yu_2020_Ecotoxicol.Environ.Saf_194_110378
PubMedSearch : Yu_2020_Ecotoxicol.Environ.Saf_194_110378
PubMedID: 32146194

Title : Rational design and biological evaluation of a new class of thiazolopyridyl tetrahydroacridines as cholinesterase and GSK-3 dual inhibitors for Alzheimer's disease - Jiang_2020_Eur.J.Med.Chem_207_112751
Author(s) : Jiang X , Zhou J , Wang Y , Chen L , Duan Y , Huang J , Liu C , Chen Y , Liu W , Sun H , Feng F , Qu W
Ref : Eur Journal of Medicinal Chemistry , 207 :112751 , 2020
Abstract : A key factor in the success of the MTDLs drug discovery approach is the selection of suitable target proteins. Based on the results of our previous research regarding dual-target inhibitors of AChE/GSK-3beta and analysis of target proteins, in the current study, 28 hybrids were designed and synthesized. Docking studies allowed us to rationalize the binding mode of the synthesized compounds in both targets. In vitro enzyme inhibition studies identified compound GT15 as a lead molecule with preferential AChE/GSK-3beta inhibition (hAChE IC(50) = 1.2 +/- 0.1 nM; hGSK-3beta IC(50) = 22.2 +/- 1.4 nM). In addition, GT15 showed high kinase selectivity for GSK-3, except for DYRK1, with inhibition rate of 83.69% and 67.94% against DYRK1alpha and DYRK1beta at a concentration of 20 muM. The compound also exhibited good permeability across the blood-brain-barrier and ability to inhibit the phosphorylation of tau protein. Upon oral administration, GT15 exhibited promising cognitive improvement in the scopolamine-induced cognitive deficit mice in the Morris water maze model. These results suggest that AChE and GSK-3 based multitargeted approach have therapeutic potential for Alzheimer's disease.
ESTHER : Jiang_2020_Eur.J.Med.Chem_207_112751
PubMedSearch : Jiang_2020_Eur.J.Med.Chem_207_112751
PubMedID: 32950908

Title : Sensitive and reversible perylene derivative-based fluorescent probe for acetylcholinesterase activity monitoring and its inhibitor - Chen_2020_Anal.Biochem__113835
Author(s) : Chen Y , Liu W , Zhang B , Suo Z , Xing F , Feng L
Ref : Analytical Biochemistry , :113835 , 2020
Abstract : A reversible fluorescence probe for acetylcholinesterase activity detection was developed based on water soluble perylene derivative, N,N'-di(2-aspartic acid)-perylene-3,4,9,10-tetracarboxylic diimide (PASP). Based on the photo-induced electron transfer (PET), PASP fluorescence in aqueous is quenched after combining with copper ions (Cu(2+)). Acetylcholinesterase (AChE) is well known to catalyze the hydrolysis of acetylcholine (ATCh) to produce thiocholine, whose affinity is strong enough to capture Cu(2+) by thiol (-SH) group from the complex PASP-Cu, resulting in the fluorescence signal of PASP recovers up to 90%. This optical switch is highly sensitive depended on the coordination and dissociation between PASP and Cu(2+). We proposed its application for AChE activity detection, as well as its inhibitor screening. According to the change of fluorescence intensity, quantifying the detection limit of AChE was 1.78 mU.mL(-1). Classical inhibitors, tacrine and organophosphate pesticide diazinon, were further evaluated for drug screening. The IC(50) value of tacrine was calculated to be 0.43 muM, and the detection limit of diazinon was 0.22 muM. Both of these performances were much better than previous results, revealing our probe is sensitive and reversible for screening applications.
ESTHER : Chen_2020_Anal.Biochem__113835
PubMedSearch : Chen_2020_Anal.Biochem__113835
PubMedID: 32739347

Title : Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease - Mo_2020_J.Enzyme.Inhib.Med.Chem_35_330
Author(s) : Mo J , Chen T , Yang H , Guo Y , Li Q , Qiao Y , Lin H , Feng F , Liu W , Chen Y , Liu Z , Sun H
Ref : J Enzyme Inhib Med Chem , 35 :330 , 2020
Abstract : Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer's disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 +/- 0.11 microM; 15j, eqBChE IC50 = 0.16 +/- 0.04 microM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.
ESTHER : Mo_2020_J.Enzyme.Inhib.Med.Chem_35_330
PubMedSearch : Mo_2020_J.Enzyme.Inhib.Med.Chem_35_330
PubMedID: 31856607

Title : Applanaic acids A-C, three new highly oxygenated lanostane triterpenoids from the fruiting bodies of Ganoderma applanatum - Chen_2020_Nat.Prod.Res__1
Author(s) : Chen Y , Gao J , Chen Q , Liu W , Qi Y , Aisa HA , Yuan T
Ref : Nat Prod Res , :1 , 2020
Abstract : Three new highly oxygenated lanostane triterpenoids, applanaic acids A-C (1-3), were isolated from the fruiting bodies of the basidiomycete Ganoderma applanatum. Among them, applanaic acid B (2) possessed the Delta(17(20))-double bond connection between the side chain and the tetracyclic skeleton, which was not common in the natural lanostane triterpenoids. Their structures were determined by 1D, 2D NMR and HRESIMS spectroscopic analysis. Compound 3 showed a weak acetylcholinesterase (AchE) inhibitory activity with 33.5% inhibition rate at 50 muM.
ESTHER : Chen_2020_Nat.Prod.Res__1
PubMedSearch : Chen_2020_Nat.Prod.Res__1
PubMedID: 32252566

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 : Circulating lncRNA ABHD11-AS1 serves as a biomarker for early pancreatic cancer diagnosis - Liu_2019_J.Cancer_10_3746
Author(s) : Liu Y , Feng W , Liu W , Kong X , Li L , He J , Wang D , Zhang M , Zhou G , Xu W , Chen W , Gong A , Xu M
Ref : J Cancer , 10 :3746 , 2019
Abstract : Background: Recent studies have shown that circulating long noncoding RNAs (lncRNAs) could be stably detectable in the blood of cancer patients and play important roles in the diagnosis of many different cancers. However, the value of lncRNAs in the diagnosis of pancreatic cancer (PC) has not been fully explored. Methods: Eleven PC-related lncRNAs were selected by analyzing bioinformatics databases. The expression levels of the lncRNAs were further analyzed in a small set of plasma samples from a training group including 30 noncancer samples (15 healthy and 15 chronic pancreatitis (CP) subjects) and 15 PC samples. Then, the candidate lncRNAs were validated with data from 46 healthy controls, 97 CP patients and 114 PC patients. Receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic performance of the identified lncRNAs. Results: After selection and validation, three characteristic plasma candidate lncRNAs, ABHD11-AS1, LINC00176 and SNHG11, were identified, and their levels were significantly higher in PC patients than in normal controls. We found that among the three candidate lncRNAs, ABHD11-AS1 showed the best diagnostic performance for the detection of PC. Furthermore, ABHD11-AS1 had a higher area under the ROC curve (AUC) than CEA, CA199 and CA125 for early PC diagnosis, while the combination of ABHD11-AS1 and CA199 was more effective than ABHD11-AS1 alone. Conclusions: Plasma ABHD11-AS1 could serve as a potential biomarker for detecting PC, and the combination of ABHD11-AS1 and CA199 was more efficient for the diagnosis of PC than ABHD11-AS1 alone, particularly for early tumor screening.
ESTHER : Liu_2019_J.Cancer_10_3746
PubMedSearch : Liu_2019_J.Cancer_10_3746
PubMedID: 31333792
Gene_locus related to this paper: human-ABHD11

Title : Structural and functional analyses of the lipase CinB from Enterobacter asburiae - Shang_2019_Biochem.Biophys.Res.Commun_519_274
Author(s) : Shang F , Lan J , Liu W , Chen Y , Wang L , Zhao J , Chen J , Gao P , Ha NC , Quan C , Nam KH , Xu Y
Ref : Biochemical & Biophysical Research Communications , 519 :274 , 2019
Abstract : Lipases are widely present in various plants, animals and microorganisms, constituting a large category of enzymes. They have the ability to catalyze the cleavage of ester bonds. The lipase CinB from Enterobacter asburiae (E. asburiae) is an acetyl esterase. The primary amino acid sequence suggests that the EaCinB protein belongs to the alpha/beta-hydrolase (ABH) superfamily of the esterase/lipase superfamily. However, its molecular functions have not yet been determined. Here, we report the crystal structure of E. asburiae CinB at a 1.45A resolution. EaCinB contains a signal peptide, cap domain and catalytic domain. The active site of EaCinB contains the catalytic triad (Ser180-His307-Asp277) on the catalytic domain. The oxyanion hole is composed of Gly106 and Gly107 within the conserved sequence motif HGGG (amino acid residues 106-109). The substrate is accessible between the alpha1 and alpha2 helices or the alpha1 helix and catalytic domain. Narrow substrate pockets are formed by the alpha2 helix of the cap domain. Site-directed mutagenesis showed that EaCinB-W208H exhibits a higher catalytic ability than EaCinB-WT by approximately nine times. Our results provide insight into the molecular function of EaCinB.
ESTHER : Shang_2019_Biochem.Biophys.Res.Commun_519_274
PubMedSearch : Shang_2019_Biochem.Biophys.Res.Commun_519_274
PubMedID: 31493870
Gene_locus related to this paper: entas-cinB

Title : Effects of Picrasma quassioides and its active constituents on Alzheimer's disease in vitro and in vivo - Guo_2019_Bioorg.Chem_92_103258
Author(s) : Guo E , Hu Y , Du T , Zhu H , Chen L , Qu W , Zhang J , Xie N , Liu W , Feng F , Xu J
Ref : Bioorg Chem , 92 :103258 , 2019
Abstract : Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Abeta25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-beta peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Abeta1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six beta-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four beta-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE).
ESTHER : Guo_2019_Bioorg.Chem_92_103258
PubMedSearch : Guo_2019_Bioorg.Chem_92_103258
PubMedID: 31520892

Title : The Effector AGLIP1 in Rhizoctonia solani AG1 IA Triggers Cell Death in Plants and Promotes Disease Development Through Inhibiting PAMP-Triggered Immunity in Arabidopsis thaliana - Li_2019_Front.Microbiol_10_2228
Author(s) : Li S , Peng X , Wang Y , Hua K , Xing F , Zheng Y , Liu W , Sun W , Wei S
Ref : Front Microbiol , 10 :2228 , 2019
Abstract : Rhizoctonia solani, one of the most detrimental necrotrophic pathogens, causes rice sheath blight and poses a severe threat to production. Focus on the function of effectors secreted by necrotrophic pathogens during infection has grown rapidly in recent years. However, little is known about the virulence and mechanisms of these proteins. In this study, we performed functional studies on putative effectors in R. solani and revealed that AGLIP1 out of 13 putative effectors induced cell death in Nicotiana benthamiana. AGLIP1 was also demonstrated to trigger cell death in rice protoplasts. The predicted lipase active sites and signal peptide (SP) of this protein were required for the cell death-inducing ability. AGLIP1 was greatly induced during R. solani infection in rice sheath. The AGLIP1's virulence function was further demonstrated by transgenic technology. The pathogenesis-related genes induced by pathogen-associated molecular pattern and bacteria were remarkably inhibited in AGLIP1-expressing transgenic Arabidopsis lines. Ectopic expression of AGLIP1 strongly facilitated disease progression in Arabidopsis caused by the type III secretion system-defective mutant from Pseudomonas syringae pv. tomato DC3000. Collectively, these results indicate that AGLIP1 is a possible effector that plays a significant role in pathogen virulence through inhibiting basal defenses and promoting disease development in plants.
ESTHER : Li_2019_Front.Microbiol_10_2228
PubMedSearch : Li_2019_Front.Microbiol_10_2228
PubMedID: 31611861
Gene_locus related to this paper: 9agam-a0a8h2wbw6

Title : In vivo and in vitro metabolism and pharmacokinetics of cholinesterase inhibitor deoxyvasicine from aerial parts of Peganum harmala Linn in rats via UPLC-ESI-QTOF-MS and UPLC-ESI-MS\/MS - Deng_2019_J.Ethnopharmacol_236_288
Author(s) : Deng G , Liu W , Ma C , Rong X , Zhang Y , Wang Y , Wu C , Cao N , Ding W , Guan H , Cheng X , Wang C
Ref : J Ethnopharmacol , 236 :288 , 2019
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Peganum harmala Linn are a Uighur traditional medicinal herb in China used to treat amnesia, bronchial asthma, and cough. Deoxyvasicine (DVAS), a potent cholinesterase inhibitor exhibiting anti-senile dementia activity, is one of the chief active ingredients in aerial parts of P. harmala and plays a key role in mediating the pharmacological effects of P. harmala. However, the metabolic profiling and in vivo pharmacokinetic characteristics of DVAS still remain unknown. AIM OF THE STUDY: The aim of this present study was to investigate the metabolism and pharmacokinetic properties of DVAS in rats by using ultra-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-QTOF-MS) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method. MATERIALS AND METHODS: The metabolic profiling of DVAS was evaluated in vitro and in vivo by rat liver microsomes (RLMs) incubation and by rat bio-specimens, such as urine, feces, plasma, and bile, after the oral administration of 45mg/kg DVAS. An efficient and sensitive UPLC-ESI-MS/MS method was developed and validated to simultaneously determine DVAS and its major four metabolites, namely, vasicine, deoxyvasicinone, vasicinone, and 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-beta-D-glucuronide in rat plasma. For pharmacokinetic studies, 32 Sprague-Dawley rats were randomly divided into four groups, namely, intravenous dosage group (2mg/kg DVAS) and three oral dosage groups (5, 15, and 45mg/kg DVAS). In addition, the activity of the components in plasma after intravenous administration of DVAS was evaluated by in vitro anti-butyrylcholinesterase (BChE) assays. RESULTS: A total of 23 metabolites were found in RLMs, plasma, urine, feces, and bile by UPLC-ESI-QTOF-MS. The metabolic pathway of DVAS in vivo and in vitro mainly involved hydroxylation, dehydrogenation, acetylation, methylation, glucuronidation, and O-sulphate conjugation, and the C-3 and C-9 sites were the main metabolic soft spots. All 23 metabolites were detected in the urine sample, and 13, 8, 22, and 6 metabolites were identified from rat feces, plasma, bile, and RLMs, respectively. The standard curves of DVAS and four metabolites in rat plasma showed good linearity in the concentration range of 0.82-524.00ng/mL with acceptable selectivity, precision, accuracy, recovery, and stability. DVAS exhibited linear dose-proportional pharmacokinetics at doses of 5, 15, and 45mg/kg after oral administration, and the average oral absolute bioavailability of DVAS was 47.46%. The in vitro anti-BChE assays implied that the inhibitive activities were mainly due to the different concentrations of prototype DVAS. CONCLUSIONS: DVAS can be rapidly absorbed and excreted by blood, and it is also extensively metabolized in vivo, and the anti-BChE activity in blood is mainly attributed to DVAS. These findings can lay a foundation for new drug development for DVAS.
ESTHER : Deng_2019_J.Ethnopharmacol_236_288
PubMedSearch : Deng_2019_J.Ethnopharmacol_236_288
PubMedID: 30872168

Title : Design, synthesis, biological evaluation, and molecular modeling studies of quinoline-ferulic acid hybrids as cholinesterase inhibitors - Mo_2019_Bioorg.Chem_93_103310
Author(s) : Mo J , Yang H , Chen T , Li Q , Lin H , Feng F , Liu W , Qu W , Guo Q , Chi H , Chen Y , Sun H
Ref : Bioorg Chem , 93 :103310 , 2019
Abstract : A series of quinoline-ferulic acid hybrids has been designed, synthesized, and evaluated as cholinesterase inhibitors. Most of the compounds showed good inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 10f was found to be the most potent inhibitor against AChE (IC50=0.62+/-0.17mum), and 14 was the most potent inhibitor against BChE (IC50=0.10+/-0.01mum). Representative compounds, such as 10f and 12g, act in a competitive manner when they inhibit AChE or BChE. Molecular docking and dynamic simulation revealed that the synthesized compounds bind to the target by simultaneously interacting with the catalytic active site (CAS) and the peripheral anionic site (PAS) of both AChE and BChE. The U-shaped confirmation was preferred when 12g bound to BChE, which was different from the linear conformation of 10f bound to AChE. Cell-based assays have confirmed the moderate neuroprotective effects of compounds 10f and 12g against H2O2-induced oxidative damage towards PC12 cells. Moreover, the hepatotoxicity of 12g was lower than that of tacrine, indicating its potential safety as an anti-Alzheimer's agent. In summary, we report a new chemotype of multifunctional hybrid, which may be further modified to develop new anti-Alzheimer's agents.
ESTHER : Mo_2019_Bioorg.Chem_93_103310
PubMedSearch : Mo_2019_Bioorg.Chem_93_103310
PubMedID: 31586704

Title : Design, Synthesis, and Evaluation of Novel Ferulic Acid Derivatives as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease - Sang_2019_ACS.Chem.Neurosci_10_1008
Author(s) : Sang Z , Wang K , Han X , Cao M , Tan Z , Liu W
Ref : ACS Chem Neurosci , 10 :1008 , 2019
Abstract : A novel series of ferulic acid derivatives was designed and synthesized on the basis of the multi-target-directed ligands strategy for the treatment of Alzheimer's disease (AD). In vitro results revealed that all the target compounds were highly effective and selective butyrylcholinesterase (BuChE) inhibitors. In particular, compound TM-10 showed the best BuChE inhibitory activity, with IC(50) = 8.9 nM, and remarkable monoamine oxidase A and B inhibitory potency, with IC(50) = 6.3 and 8.6 microM, respectively. TM-10 could inhibit (53.9%) and disaggregate (43.8%) self-induced amyloid-beta peptide (Abeta) aggregation. In addition, TM-10 exhibited potent antioxidant activity (ORAC = 0.52 equiv) and neuroprotective effect against Abeta(1-42)-mediated SH-SY5Y neurotoxicity, and it acted as an autophagic activator. TM-10 also showed good blood-brain barrier penetration. Furthermore, TM-10 exhibited a favorable dyskinesia recovery rate and response efficiency on an AlCl(3)-induced zebrafish AD model and a potent neuroprotective effect on Abeta(1-40)-induced zebrafish vascular injury. Further, in vivo assays demonstrated that TM-10 showed low acute toxicity, and the step-down passive avoidance test indicated that this compound could improve scopolamine-induced memory deficit in mice. Therefore, the present study displays evidence that TM-10 is a potent, multi-functional agent against AD and could be a promising lead candidate for anti-Alzheimer's disease drug development.
ESTHER : Sang_2019_ACS.Chem.Neurosci_10_1008
PubMedSearch : Sang_2019_ACS.Chem.Neurosci_10_1008
PubMedID: 30537804

Title : Maltol (3-Hydroxy-2-methyl-4-pyrone) Slows d-Galactose-Induced Brain Aging Process by Damping the Nrf2\/HO-1-Mediated Oxidative Stress in Mice - Sha_2019_J.Agric.Food.Chem_67_10342
Author(s) : Sha JY , Zhou YD , Yang JY , Leng J , Li JH , Hu JN , Liu W , Jiang S , Wang YP , Chen C , Li W
Ref : Journal of Agricultural and Food Chemistry , 67 :10342 , 2019
Abstract : Maltol, a maillard reaction product from ginseng (Panax ginseng C. A. Meyer), has been confirmed to inhibit oxidative stress in several animal models. Its beneficial effect on oxidative stress related brain aging is still unclear. In this study, the mouse model of d-galactose (d-Gal)-induced brain aging was employed to investigate the therapeutic effects and potential mechanisms of maltol. Maltol treatment significantly restored memory impairment in mice as determined by the Morris water maze tests. Long-term d-Gal treatment reduced expression of cholinergic regulators, i.e., the cholineacetyltransferase (ChAT) (0.456 +/- 0.10 vs 0.211 +/- 0.03 U/mg prot), the acetylcholinesterase (AChE) (36.4 +/- 5.21 vs 66.5 +/- 9.96 U/g). Maltol treatment prevented the reduction of ChAT and AChE in the hippocampus. Maltol decreased oxidative stress levels by reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production in the brain and by elevating antioxidative enzymes. Furthermore, maltol treatment minimized oxidative stress by increasing the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1). The above results clearly indicate that supplementation of maltol diminishes d-Gal-induced behavioral dysfunction and neurological deficits via activation of the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in brain. Maltol might become a potential drug to slow the brain aging process and stimulate endogenous antioxidant defense capacity. This study provides the novel evidence that maltol may slow age-associated brain aging.
ESTHER : Sha_2019_J.Agric.Food.Chem_67_10342
PubMedSearch : Sha_2019_J.Agric.Food.Chem_67_10342
PubMedID: 31461273

Title : The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease - Zhu_2019_Bioorg.Med.Chem.Lett_29_126625
Author(s) : Zhu G , Wang K , Shi J , Zhang P , Yang D , Fan X , Zhang Z , Liu W , Sang Z
Ref : Bioorganic & Medicinal Chemistry Lett , 29 :126625 , 2019
Abstract : A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC(50) value of 2.9 microM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu(2+) complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC(50) = 6.8 microM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease.
ESTHER : Zhu_2019_Bioorg.Med.Chem.Lett_29_126625
PubMedSearch : Zhu_2019_Bioorg.Med.Chem.Lett_29_126625
PubMedID: 31444085

Title : Structural insight into the carboxylesterase BioH from Klebsiella pneumoniae - Wang_2019_Biochem.Biophys.Res.Commun_520_538
Author(s) : Wang L , Chen Y , Shang F , Liu W , Lan J , Gao P , Ha NC , Nam KH , Dong Y , Quan C , Xu Y
Ref : Biochemical & Biophysical Research Communications , 520 :538 , 2019
Abstract : The BioH carboxylesterase which is a typical alpha/beta-hydrolase enzyme involved in biotin synthetic pathway in most bacteria. BioH acts as a gatekeeper and blocks the further elongation of its substrate. In the pathogen Klebsiella pneumoniae, BioH plays a critical role in the biosynthesis of biotin. To better understand the molecular function of BioH, we determined the crystal structure of BioH from K. pneumoniae at 2.26A resolution using X-ray crystallography. The structure of KpBioH consists of an alpha-beta-alpha sandwich domain and a cap domain. B-factor analysis revealed that the alpha-beta-alpha sandwich domain is a rigid structure, while the loops in the cap domain shows the structural flexibility. The active site of KpBioH contains the catalytic triad (Ser82-Asp207-His235) on the interface of the alpha-beta-alpha sandwich domain, which is surrounded by the cap domain. Size exclusion chromatography shows that KpBioH prefers the monomeric state in solution, whereas two-fold symmetric dimeric formation of KpBioH was observed in the asymmetric unit, the conserved Cys31-based disulfide bonds can maintain the irreversible dimeric formation of KpBioH. Our study provides important structural insight for understanding the molecular mechanisms of KpBioH and its homologous proteins.
ESTHER : Wang_2019_Biochem.Biophys.Res.Commun_520_538
PubMedSearch : Wang_2019_Biochem.Biophys.Res.Commun_520_538
PubMedID: 31615653
Gene_locus related to this paper: klep3-bioh

Title : Ameliorative effect of deoxyvasicine on scopolamine-induced cognitive dysfunction by restoration of cholinergic function in mice - Deng_2019_Phytomedicine_63_153007
Author(s) : Deng G , Wu C , Rong X , Li S , Ju Z , Wang Y , Ma C , Ding W , Guan H , Cheng X , Liu W , Wang C
Ref : Phytomedicine , 63 :153007 , 2019
Abstract : BACKGROUND: Aerial parts of Peganum harmala Linn is used as a traditional medical herb for treatment of amnesia in Uighur medicine in China. Deoxyvasicine (DVAS) is one of the chief active ingredients in P. harmala, it possesses strong acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in vitro, but the therapeutic effect and mechanisms on amnesia in vivo are unclear. PURPOSE: The objective of this study was to investigate the improvement effect of DVAS from P. harmala in learning and memory deficits of scopolamine-induced mice and elucidate the underlying mechanisms involved. METHODS: Mice were pretreated with DVAS (5, 15 and 45mg/kg) and huperzine-A (0.2mg/kg) by gavage for 7 days, and subsequently were daily intraperitoneally injected with scopolamine (1mg/kg) to induce learning and memory deficits and behavioral performance was assessed by Morris water maze. To further evaluate the potential mechanisms of DVAS in improving learning and memory capabilities, pathological change, levels of various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation were examined. RESULTS: The results showed that DVAS could alleviate learning and memory deficits in scopolamine-treated mice. DVAS could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities and protein expressions. DVAS could induce brain-derived neurotrophic factor and protect hippocampal pyramidal cells against neuronal damage. DVAS also enhanced antioxidant defense via increasing the antioxidant enzyme level and activity of glutathione peroxidase, and anti-inflammatory function through suppressing tumor necrosis factor-alpha. Additionally, DVAS could regulate the neurotransmitters by elevating acetylcholine, 5-hydroxytryptamine, gamma-aminobutyric acid and reducing 5-hydroxyindole-3-acetic acid and glutamic acid. CONCLUSION: Results illustrated that DVAS may be a promising candidate compound against amnesia via restoration of cholinergic function, regulating neurotransmitters, attenuating neuroinflammation and oxidative stress.
ESTHER : Deng_2019_Phytomedicine_63_153007
PubMedSearch : Deng_2019_Phytomedicine_63_153007
PubMedID: 31301537

Title : Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing beta-oxidation of fatty acid in mice - Yao_2019_Am.J.Physiol.Gastrointest.Liver.Physiol_316_G527
Author(s) : Yao L , Cao B , Cheng Q , Cai W , Ye C , Liang J , Liu W , Tan L , Yan M , Li B , He J , Hwang SH , Zhang X , Wang C , Ai D , Hammock BD , Zhu Y
Ref : American Journal of Physiology Gastrointest Liver Physiol , 316 :G527 , 2019
Abstract : Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 for the animal model and 1 muM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), as evidenced by elevated beta-oxidation of fatty acids and the expression of PPAR-alpha target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-alpha activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-alpha. Of note, 11,12-EET ligand dependently activated PPAR-alpha. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-alpha was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.
ESTHER : Yao_2019_Am.J.Physiol.Gastrointest.Liver.Physiol_316_G527
PubMedSearch : Yao_2019_Am.J.Physiol.Gastrointest.Liver.Physiol_316_G527
PubMedID: 30789748

Title : Changes in Neuroimmune and Neuronal Death Markers after Adolescent Alcohol Exposure in Rats are Reversed by Donepezil - Swartzwelder_2019_Sci.Rep_9_12110
Author(s) : Swartzwelder HS , Healey KL , Liu W , Dubester K , Miller KM , Crews FT
Ref : Sci Rep , 9 :12110 , 2019
Abstract : Adolescent intermittent ethanol (AIE) exposure diminishes neurogenesis and dendritic spine density in the dentate gyrus. The cholinesterase inhibitor, donepezil (Aricept), reverses AIE effects on dendritic spines, possibly by interacting with inflammatory and/or epigenetic mediators after AIE exposure. This study tests the hypothesis that donepezil reverses AIE-induced neuroimmune, and epigenetic changes in the adult dentate gyrus. Adolescent Sprague-Dawley male rats (PD30-43) were given 10 intermittent, intragastric doses of ethanol (5.0 g/kg) or isovolumetric water (AIW). Twenty-one days later half of the animals from each group were treated with either donepezil or isovolumetric water (i.g.) once daily for four days. Two hours after the last donepezil or water dose animals were sacrificed and brains prepared for immunohistochemical analyses. AIE reduced immunoreactivity for doublecortin (DCX) and increased immunoreactivity for activated caspase-3 and death receptor-3 in adulthood, suggesting an enduring attenuation of neurogenesis and an increase in progenitor death. These effects were reversed by donepezil treatment in adulthood. AIE also increased immunoreactivity for the inflammatory signaling molecules HMGB1 and RAGE, as well as the activated phosphorylated transcription factor pNFkappaB p65, and the gene silencing marker dimethylated histone H3K9. All of these AIE effects were also reversed by donepezil, with the exception of HMGB1.
ESTHER : Swartzwelder_2019_Sci.Rep_9_12110
PubMedSearch : Swartzwelder_2019_Sci.Rep_9_12110
PubMedID: 31431637

Title : Shen-Yuan-Dan Capsule Attenuates Atherosclerosis and Foam Cell Formation by Enhancing Autophagy and Inhibiting the PI3K\/Akt\/mTORC1 Signaling Pathway - Zhou_2019_Front.Pharmacol_10_603
Author(s) : Zhou M , Ren P , Zhang Y , Li S , Li M , Li P , Shang J , Liu W , Liu H
Ref : Front Pharmacol , 10 :603 , 2019
Abstract : Background and Aim: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a crucial role in autophagy and inflammation. Our previous studies demonstrated that Shen-Yuan-Dan Capsule (SYDC), a Chinese medicine used for treating angina pectoris, has anti-atherosclerotic and anti-inflammatory effects in mice. However, its effects on autophagy and the PI3K/Akt/mTORC1 signaling pathway remain unclear. This study aimed to explore the effects of SYDC on autophagy and PI3K/Akt/mTORC1 signaling in the apolipoprotein E knockout (ApoE(-/-)) mouse model and in macrophage-derived foam cells to delineate the underlying mechanism. Methods: After 6 weeks of high-fat diet, ApoE(-/-) mice were randomly grouped into control, Lipitor, low-SYDC (SYDC-L), middle-SYDC (SYDC-M), and high-SYDC (SYDC-H) groups (n = 10). The mice were intragastrically administered the respective treatment for 6 weeks. Murine RAW264.7 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) (80 microg/ml) for 24 h and then pretreated with SYDC freeze-dried powder for another 24 h. Cells treated with SYDC were co-cultured for 24 h with LY294002, tricirbine, and rapamycin to investigate the effects on the PI3K/Akt/mTORC1 signaling pathway. Results: SYDC ameliorated blood lipid levels, reduced the atherosclerotic index and plaque areas in the aortic root in mice, and inhibited total cholesterol (TC) levels and cholinesterase (ChE)/TC ratios in ox-LDL stimulated macrophages. Moreover, SYDC up-regulated Beclin1 and LC3II/I proteins in mice and in the ox-LDL-stimulated macrophages. Moreover, SYDC inhibited AKT phosphorylation at Ser473 and mTOR phosphorylation at Ser2448 in mice and in ox-LDL-stimulated macrophages. Furthermore, SYDC's inhibitory of ChE/TC ratios in ox-LDL-stimulated macrophages was not changed by selective inhibition of the PI3K/Akt/mTORC1 pathway. Conclusions: Our results highlight that SYDC treatment attenuates foam cell formation by promoting autophagy via inhibiting activation of the PI3K/Akt/mTORC1 signaling pathway. This study provides new insights into the molecular mechanism underlying SYDC's therapeutic potential for treating atherosclerosis.
ESTHER : Zhou_2019_Front.Pharmacol_10_603
PubMedSearch : Zhou_2019_Front.Pharmacol_10_603
PubMedID: 31214032

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

Title : Molecular footprints of inshore aquatic adaptation in Indo-Pacific humpback dolphin (Sousa chinensis) - Ming_2019_Genomics_111_1034
Author(s) : Ming Y , Jian J , Yu F , Yu X , Wang J , Liu W
Ref : Genomics , 111 :1034 , 2019
Abstract : The Indo-Pacific humpback dolphin, Sousa chinensis, being a member of cetaceans, had fully adapted to inshore waters. As a threatened marine mammal, little molecular information available for understanding the genetic basis of ecological adaptation. We firstly sequenced and obtained the draft genome map of S. chinensis. Phylogenetic analysis in this study, based on the single copy orthologous genes of the draft genome, is consistent with traditional phylogenetic classification. The comparative genomic analysis indicated that S. chinensis had 494 species-specific gene families, which involved immune, DNA repair and sensory systems associated with the potential adaption mechanism. We also identified the expansion and positive selection genes in S. chinensis lineage to investigate the potential adaptation mechanism. Our study provided the potential insight into the molecular bases of ecological adaptation in Indo-Pacific humpback dolphin and will be also valuable for future understanding the ecological adaptation and evolution of cetaceans at the genomic level.
ESTHER : Ming_2019_Genomics_111_1034
PubMedSearch : Ming_2019_Genomics_111_1034
PubMedID: 30031902
Gene_locus related to this paper: delle-a0a2y9mw48

Title : Discovery, molecular dynamic simulation and biological evaluation of structurally diverse cholinesterase inhibitors with new scaffold through shape-based pharmacophore virtual screening - Yang_2019_Bioorg.Chem_92_103294
Author(s) : Yang H , Du C , Li Q , Chen T , Lu X , Feng F , Chen Y , Liu W , Sun H
Ref : Bioorg Chem , 92 :103294 , 2019
Abstract : Designing small molecule inhibitors targeting cholinesterases (ChEs) is considered as an efficient strategy for the treatment of Alzheimer's disease (AD). In the present study, based on a shaped-based pharmacophore (SBP) model that we reported previously, virtual screening was performed on four commercial compound databases, from which eight small molecules containing new structurally scaffolds were retained and evaluated. In general, six of these potential hits were identified to be selective ChEs inhibitors. Three compounds exhibited IC50 values and Ki values in micromolar range on acetylcholinesterase (AChE), the most active compound 4 showed IC50 value of 6.31+/-2.68muM and Ki value of 4.76muM. Other three compounds displayed IC50 values and Ki values in micromolar range on butyrylcholinesterase (BChE) with high target selectivity, the most active compound 1 showed IC50 value of 3.87+/-2.48muM and Ki value of 1.52muM. Multiple biological evaluations were performed to determine their cytotoxicity, cyto-protective effects, antioxidant effect as well as druglike properties. These compounds provide new cores for the further design and optimization, with the aim to discover new ChEs inhibitors for the treatment of AD.
ESTHER : Yang_2019_Bioorg.Chem_92_103294
PubMedSearch : Yang_2019_Bioorg.Chem_92_103294
PubMedID: 31557623

Title : Expansion of the scaffold diversity for the development of highly selective butyrylcholinesterase (BChE) inhibitors: Discovery of new hits through the pharmacophore model generation, virtual screening and molecular dynamics simulation - Lu_2019_Bioorg.Chem_85_117
Author(s) : Lu X , Yang H , Li Q , Chen Y , Zhou Y , Feng F , Liu W , Guo Q , Sun H
Ref : Bioorg Chem , 85 :117 , 2018 || 2019
Abstract : Butyrylcholinesterase (BChE) is recently considered as a new target for the treatment of Alzheimer's disease (AD). There is an increasing interest in the development of BChE inhibitors. In the present study, a set of pharmacophore models for BChE was developed and validated. Based on the models, virtual screening was performed on five compound collections, from which seventeen potential hits were retained for biological investigation. In total, eight of these seventeen potential hits showed selective BChE inhibitory activity. Moreover, four compounds displayed IC50 values in sub-micromolar range on eqBChE and three displayed IC50 values <2muM on huBChE. The diverse scaffolds of the active compounds provided good starting point further development of selective BChE inhibitors. As far as we concerned, here we disclose the first selective pharmacophore model targeting BChE. The high rate of the model in the identification of active hits indicates it is a valuable tool for the development of selective BChE inhibitors, which may benefit the treatment of AD.
ESTHER : Lu_2019_Bioorg.Chem_85_117
PubMedSearch : Lu_2019_Bioorg.Chem_85_117
PubMedID: 30605885

Title : Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer's Disease - Wu_2018_Molecules_23_
Author(s) : Wu W , Liang X , Xie G , Chen L , Liu W , Luo G , Zhang P , Yu L , Zheng X , Ji H , Zhang C , Yi W
Ref : Molecules , 23 : , 2018
Abstract : A series of novel ligustrazine derivatives 8a(-)r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer's disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 x 10(6); for 8r, IC50 BuChE/IC50 AChE = 1.32 x 10(7)). Of note, 8q and 8r also presented potent inhibitory activities against Abeta aggregation, with IC50 values of 17.36 microM and 49.14 microM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 muM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.
ESTHER : Wu_2018_Molecules_23_
PubMedSearch : Wu_2018_Molecules_23_
PubMedID: 30301153

Title : Stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic pharmacodynamics, and toxic properties of vasicine enantiomers in vitro and in vivo - Zhu_2018_Eur.J.Pharm.Sci_123_459
Author(s) : Zhu Y , Liu W , Qi S , Wang H , Wang Y , Deng G , Zhang Y , Li S , Ma C , Cheng X , Wang C
Ref : Eur J Pharm Sci , 123 :459 , 2018
Abstract : Vasicine (VAS) is a potential natural cholinesterase inhibitor for treatment of Alzheimer's disease. Due to one chiral centre (C-3) presenting in molecule, VAS has two enantiomers, d-vasicine (d-VAS) and l-vasicine (l-VAS). The study was undertaken to investigate the stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic effect and acute toxicity of VAS enantiomers. In results, the glucuronidation metabolic rate of l-VAS was faster than d-VAS in human liver microsomes and isoenzymes tests, and it was proved that the UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B15 were the major metabolic enzymes for glucuronidation of l-VAS, while only UGT1A9 for d-VAS, which take responsibility of the significantly less metabolic affinity of d-VAS than l-VAS in HLM and rhUGT1A9. The plasma exposure of d-VAS in rats was 1.3-fold and 1.6-fold higher than that of l-VAS after intravenous and oral administration of d-VAS and l-VAS, respectively. And the plasma exposure of the major glucuronidation metabolite d-VASG was one of tenth of l-VASG or more less, no matter by intravenous or oral administration. Both d-VAS and l-VAS were exhibited promising acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, and the BChE inhibitory activity of d-VAS with IC50 of 0.03+/-0.001muM was significantly stronger than that of l-VAS with IC50 of 0.98+/-0.19muM. The molecular docking results indicated that d-VAS and l-VAS could bind to the catalytic active site (CAS position) either of human AChE and BChE, and the BChE combing ability of d-VAS (the score of GBI/WAS dG -7.398) was stronger than that of l-VAS (the score of GBI/WAS dG -7.135). Both d-VAS and l-VAS could improving the learning and memory on scopolamine-induced memory deficits in mice. The content of acetylcholine (ACh) after oral administration d-VAS increased more than that of l-VAS in mice cortex, through inhibiting cholinesterase (ChE) and increasing choline acetyltransferase (ChAT). In addition, the LD50 value of d-VAS ( was slight lower than l-VAS ( These results indicated that VAS enantiomers displayed significantly stereoselective metabolic, pharmacokinetics, anti-amnesic effect and toxic properties in vitro and in vivo. The d-VAS might be the dominant configuration for treating Alzheimer's disease.
ESTHER : Zhu_2018_Eur.J.Pharm.Sci_123_459
PubMedSearch : Zhu_2018_Eur.J.Pharm.Sci_123_459
PubMedID: 30077712

Title : Analogous beta-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice - Li_2018_Front.Pharmacol_9_346
Author(s) : Li SP , Wang YW , Qi SL , Zhang YP , Deng G , Ding WZ , Ma C , Lin QY , Guan HD , Liu W , Cheng XM , Wang CH
Ref : Front Pharmacol , 9 :346 , 2018
Abstract : The analogous beta-carboline alkaloids, harmaline (HAL) and harmine (HAR), possess a variety of biological properties, including acetylcholinesterase (AChE) inhibitory activity, antioxidant, anti-inflammatory, and many others, and have great potential for treating Alzheimer's disease (AD). However, studies have showed that the two compounds have similar structures and in vitro AChE inhibitory activities but with significant difference in bioavailability. The objective of this study was to comparatively investigate the effects of HAL and HAR in memory deficits of scopolamine-induced mice. In the present study, mice were pretreated with HAL (2, 5, and 10 mg/kg), HAR (10, 20, and 30 mg/kg) and donepezil (5 mg/kg) by intragastrically for 7 days, and were daily intraperitoneal injected with scopolamine (1 mg/kg) to induce memory deficits and then subjected to behavioral evaluation by Morris water maze. To further elucidate the underlying mechanisms of HAL and HAR in improving learning and memory, the levels of various biochemical factors and protein expressions related to cholinergic function, oxidative stress, and inflammation were examined. The results showed that HAL and HAR could effectively ameliorate memory deficits in scopolamine-induced mice. Both of them exhibited an enhancement in cholinergic function by inhibiting AChE and inducing choline acetyltransferase (ChAT) activities, and antioxidant defense via increasing the antioxidant enzymes activities of superoxide dismutase and glutathione peroxidase, and reducing maleic diadehyde production, and anti-inflammatory effects through suppressing myeloperoxidase, tumor necrosis factor alpha, and nitric oxide as well as modulation of critical neurotransmitters such as acetylcholine (ACh), choline (Ch), L-tryptophan (L-Trp), 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (gamma-GABA), and L-glutamic acid (L-Glu). Furthermore, the regulations of HAL on cholinergic function, inflammation, and neurotransmitters were more striking than those of HAR, and HAL manifested a comparable antioxidant capacity to HAR. Remarkably, the effective dosage of HAL (2 mg/kg) was far lower than that of HAR (20 mg/kg), which probably due to the evidently differences in the bioavailability and metabolic stability of the two analogs. Taken together, all these results revealed that HAL may be a promising candidate compound with better anti-amnesic effects and pharmacokinetic characteristics for the treatments of AD and related diseases.
ESTHER : Li_2018_Front.Pharmacol_9_346
PubMedSearch : Li_2018_Front.Pharmacol_9_346
PubMedID: 29755345

Title : IL-6 release of Rv0183 antigen-stimulated whole blood is a potential biomarker for active tuberculosis patients - Liu_2018_J.Infect_76_376
Author(s) : Liu Y , Li X , Liu W , Zhong Z , Wang L , Ge S , Zhang J , Xia N
Ref : J Infect , 76 :376 , 2018
Abstract : OBJECTIVE: New tests for diagnosing active tuberculosis (aTB) are urgently needed, and TB antigen-specific cell-mediated immunity can be expected to develop new testing methods of aTB. MATERIALS AND METHODS: Rv0183 protein, the only monoglyceride lipase identified in mycobacteria, was used to stimulate freshly heparin-treated whole blood. The Rv0183-specific cytokines/chemokines response associated with aTB was screened firstly with 4 aTB patients and 4 LTBIs, and further evaluated in 192 suspected aTB patients and 372 healthy individuals. RESULTS: Out of 71 cytokines/chemokines, the response of IL-6 against Rv0183 protein was found to be associated with aTB. The Rv0183-specific IL-6 response was significantly higher in aTB patients (n = 128) than in those with non-TB lung disease (n = 64) and in healthy individuals (n = 327) (p < 0.0001), and not affected by latent TB infection. In IGRA+ suspected active TB patients, the sensitivity, specificity, PPV and NPV of IL-6 response (with cutoff of 235.2 pg/ml) were 85.7%, 100%, 100% and 51.5% for diagnosing aTB, respectively. While in IGRA- ones, they were 87.5%, 80.5%, 60.9% and 95.0% with 174.2 pg/ml IL-6 response as cutoff, respectively. CONCLUSIONS: These results clearly show that the Rv0183 antigen-specific IL-6 response has the potential to be used as an immune-diagnosis test for active TB in clinical practice.
ESTHER : Liu_2018_J.Infect_76_376
PubMedSearch : Liu_2018_J.Infect_76_376
PubMedID: 29174965
Gene_locus related to this paper: myctu-rv0183

Title : Efficient resolution of (R,S)-1-(1-naphthyl)ethylamine by Candida antarctica lipase B in ionic liquids - Wang_2018_Mol.Catal_448_116
Author(s) : Wang B , Zhang C , He Q , Qin H , Liang G , Liu W
Ref : Molecular Catalysis , 448 :116 , 2018
Abstract : The resolution of (R,S)-1-(1-naphthyl)ethylamine ((R,S)-NEA) by Candida antarctica lipase B (CALB) in ionic liquids (ILs) containing 1-alkyl-3-methylimidazolium cations ([Cnmim]+) and [Tf2N]-, [BF4]-, and [PF6]- anions was investigated. When the alkyl chain on the cation contained less than six carbons, the lipase activity corresponded with the hydrophobicity of the ILs, but further increase in the chain length suppressed the enzyme activity. The enzyme activity decreased depending on the anion, where [Tf2N]- > [PF6]- > [BF4]-. The effects of acyl donors, pH, temperature, water activity, and substrate concentration on the resolution were determined. Under the optimal conditions, the conversion of (R,S)-NEA and enantiomer excess of (R)-n-octyl acyl-NEA was 49.3% and 99.2%, respectively. The resolution kinetics of (R,S)-NEA by CALB in [C6mim][Tf2N] were studied and a ping-pong mechanism with a two substrate inhibition model was selected. The kinetic parameters of the fitting results were as follows: Michaelis constant of (R,S)-NEA Kma, 461.8 mmol/L; Michaelis constant of vinyl n-octanoateKmb, 262.1 mmol/L; inhibition constant of (R,S)-NEA Kia, 8737.2 mmol/L; inhibition constant of vinyl n-octanoateKib, 62336.8 mmol/L; maximum reaction rate rmax, 0.352 mmol/(mg min). Moreover, circular dichroism revealed that incubation of CALB in [C6mim][Tf2N] resulted in increased beta-sheet content; its secondary structure was stable.
ESTHER : Wang_2018_Mol.Catal_448_116
PubMedSearch : Wang_2018_Mol.Catal_448_116

Title : Dual effects of insect nAChR chaperone RIC-3 on hybrid receptor: Promoting assembly on endoplasmic reticulum but suppressing transport to plasma membrane on Xenopus oocytes - Bao_2018_Neurochem.Int_115_24
Author(s) : Bao H , Xu X , Liu W , Yu N , Liu Z
Ref : Neurochem Int , 115 :24 , 2018
Abstract : Resistance to inhibitors of cholinesterase (RIC) -3 promotes the maturation (folding and assembly) of neuronal nicotinic acetylcholine receptors (nAChRs) as a molecular chaperone. The modulation effects of RIC-3 on homomeric alpha7 nAChRs are always positive, but its effects on heteromeric subtypes are inconsistent among reports. In this study, five RIC-3 isoforms were identified from Locusta migratoria. Four isoforms showed obvious effects on hybrid receptor Localpha1/rbeta2 expressed in Xenopus oocytes. As a representative, the co-expression of RIC-3v4 exhibited the decreased agonist responses (Imax) on oocytes, lower specific [(3)H]epibatidine binding (Bmax) on plasma membrane protein (PMP), and reduced subunit levels in PMP, which showed that the mature Localpha1/rbeta2 on the plasma membrane was decreased by the co-expression of RIC-3. In contrast, the [(3)H]epibatidine binding and mature Localpha1/rbeta2 levels in the endoplasmic reticulum membrane protein (ERMP) were much increased when co-expressing with RIC-3v4. The [(3)H]epibatidine binding and mature Localpha1/rbeta2 levels in total membrane protein (TMP) gave the similar results as that in ERMP. Taking data together, the results showed that the co-expression of RIC-3 increased the mature Localpha1/rbeta2 receptor levels on ER of Xenopus oocytes, but these mature receptors were mostly kept on ER and suppressed to transport to plasma membrane.
ESTHER : Bao_2018_Neurochem.Int_115_24
PubMedSearch : Bao_2018_Neurochem.Int_115_24
PubMedID: 29032010

Title : The molecular basis for lipase stereoselectivity - Chen_2018_Appl.Microbiol.Biotechnol_102_3487
Author(s) : Chen H , Meng X , Xu X , Liu W , Li S
Ref : Applied Microbiology & Biotechnology , 102 :3487 , 2018
Abstract : Lipases are among the most applied biocatalysts in organic synthesis to catalyze the kinetic resolution of a wide range of racemic substrates to yield optically pure compounds. Due to the rapidly increased demands for optically pure compounds, deep understanding of the molecular basis for lipase stereoselectivity and how to obtain lipases with excellent asymmetric selectivity have become one of primary research goals in this field. This review is focused on the molecular factors that have impacts on the stereoselectivity of lipases including the steric complementarity between the lipase topological structure and its substrate, the regional structural flexibility, the hydrogen bonds between the residues around the catalytic site and the tetrahedral intermediates, and the electrostatic interactions between surface residues. Moreover, the synergistic effects of these structural factors on the catalytic properties including stereoselectivity, activity, and stability are also discussed.
ESTHER : Chen_2018_Appl.Microbiol.Biotechnol_102_3487
PubMedSearch : Chen_2018_Appl.Microbiol.Biotechnol_102_3487
PubMedID: 29500755

Title : [Effects of tenofovir and telbivudine on HBV RNA in pregnant women with different genotypes of HBeAg-positive hepatitis B in Guizhou Province] - Zhang_2018_Zhonghua.Yi.Xue.Za.Zhi_98_3503
Author(s) : Zhang BF , Cheng ML , Lu S , Wu J , Wu YY , Liu Q , Zhao XK , Li YY , Hu YX , Liu W
Ref : Zhonghua Yi Xue Za Zhi , 98 :3503 , 2018
Abstract : Objective: To investigate whether HBV genotype influences HBV DNA and RNA responses to tenofovir(TDF) and telbivudine(LDT) in pregnant women with HBeAg-positive in Guizhou. Methods: This was a retrospective analysis of 75 pregnant women hepatitis B with HBsAg and HBeAg double-positive(19-38 years old, median age 26 years old), who were enrolled in the Department of Infectious Diseases and Obstetrics Clinic of the Affiliated Hospital of Guizhou Medical University from May 2016 to July 2017.Blood samples were collected at 12-24, 28-32 and 36-40 weeks of pregnancy for analyses of genotype, including hepatitis B surface antigen(HBsAg), hepatitis B e antigen (HBeAg), HBV DNA, HBV RNA and liver function, alanine transaminase(ALT), aspartate transaminase(AST), total bilirubin(TBiL), total bile acids(TBA), cholinesterase(CHE), alkaline phosphatase (ALP). Continuous variable was adopted by means of mean+/-standard deviation, and categorical variables were used for statistical analysis. Results: The HBV genotype was B in 64.0%(48/75)and C in 36.0%(27/75). The TDF and LDT groups showed no differences in demographic and clinical characteristics, including liver function tests, HBsAg, HBeAg, log(10)HBV DNA and log(10)HBV RNA.TDF groups, pre-treatment: HBV DNA (4.8+/-2.0), HBV RNA (6.4+/-1.1); at 4 weeks of treatment: HBV DNA (4.0+/-0.8), HBV RNA (6.0+/-0.9); at the end of treatment: HBV DNA (3.1+/-0.7), HBV RNA (5.5+/-0.8). LDT groups, pre-treatment HBV DNA (5.1+/-2.0), HBV RNA(6.5+/-0.9); at 4 weeks of treatment: HBV DNA (4.4+/-1.2), HBV RNA(6.5+/-0.8); at the end of treatment: HBV DNA(3.5+/-1.2), HBV RNA (6.1+/-0.7). Compared with pre-treatment (12-24 weeks), the TDF and LDT group showed significant reductions in log(10)(HBV DNA) and log(10)(HBV RNA) at 36-40 weeks ( P<0.05). Under the influence of excluding other variables, the genotype had a certain influence on the HBV RNA load.That was, HBV RNA in patients with the C genome decreased by 0.54 units(log(10)) at the end of the treatment compared to patients with the B genome, and the P value was less than 0.05. Conclusion: B and C genotypes are predominant in pregnant women with hepatitis B in Guizhou Province. B-type viruses are more easily controlled when different genotypes are treated with nucleotide analogues.
ESTHER : Zhang_2018_Zhonghua.Yi.Xue.Za.Zhi_98_3503
PubMedSearch : Zhang_2018_Zhonghua.Yi.Xue.Za.Zhi_98_3503
PubMedID: 30481899

Title : Structural studies reveal the molecular mechanism of PETase - Chen_2018_FEBS.J_285_3717
Author(s) : Chen CC , Han X , Ko TP , Liu W , Guo RT
Ref : Febs J , 285 :3717 , 2018
Abstract : Poly(ethylene terephthalate) (PET) is a class of plastic material widely used in modern society, but large amounts of PET waste cause severe environmental problems. Obtained from a PET-consuming bacterium Ideonella sakaiensis, the enzyme PETase exhibits superb hydrolytic activity and substrate preference toward PET. Here, we summarize some recent advances in the crystallographic analysis of PETase. These reports uncover structural features of PETase that are involved in its catalytic activity. In comparison to homologous enzymes, PETase contains an additional disulfide bond as well as an extended beta8-alpha6 loop. More importantly, the crystal structures of PETase in complex with substrate and product analogs provide critical information for understanding the mechanism of action of PETase. In particular, the wobbling conformation of W156 is closely related to the binding of substrate and product. These new findings are of great importance for further in-depth research and engineering development of PETase, and should advance the implementation of plastic biodegradation strategy.
ESTHER : Chen_2018_FEBS.J_285_3717
PubMedSearch : Chen_2018_FEBS.J_285_3717
PubMedID: 30048043

Title : Thiolation Protein-Based Transfer of Indolyl to a Ribosomally Synthesized Polythiazolyl Peptide Intermediate during the Biosynthesis of the Side-Ring System of Nosiheptide - Qiu_2017_J.Am.Chem.Soc_139_18186
Author(s) : Qiu Y , Du Y , Zhang F , Liao R , Zhou S , Peng C , Guo Y , Liu W
Ref : Journal of the American Chemical Society , 139 :18186 , 2017
Abstract : Nosiheptide, a potent bicyclic member of the family of thiopeptide antibiotics, possesses a distinctive l-Trp-derived indolyl moiety. The way in which this moiety is incorporated into a ribosomally synthesized and post-translationally modified thiopeptide remains poorly understood. Here, we report that NosK, an alpha/beta-hydrolase fold protein, mediates the transfer of indolyl from NosJ, a discrete thiolation protein, to a linear pentathiazolyl peptide intermediate rather than its genetically encoded untreated precursor. This intermediate results from enzymatic processing of the peptide precursor, in which five of the six l-Cys residues are transformed into thiazoles but Cys4 selectively remains unmodified for indolyl substitution via a thioester exchange. Determining the timing of indolyl incorporation, which expands the chemical space of a thiopeptide framework, facilitates mechanistic access to the unusual logic of post-translational modifications in the biosynthesis of nosiheptide-type thiopeptide members that share a similar compact side-ring system.
ESTHER : Qiu_2017_J.Am.Chem.Soc_139_18186
PubMedSearch : Qiu_2017_J.Am.Chem.Soc_139_18186
PubMedID: 29200275
Gene_locus related to this paper: stras-c6fx50

Title : Involvement of pregnane X receptor in the suppression of carboxylesterases by metformin in vivo and in vitro, mediated by the activation of AMPK and JNK signaling pathway - Shan_2017_Eur.J.Pharm.Sci_102_14
Author(s) : Shan E , Zhu Z , He S , Chu D , Ge D , Zhan Y , Liu W , Yang J , Xiong J
Ref : Eur J Pharm Sci , 102 :14 , 2017
Abstract : Type 2 diabetes mellitus (T2D) is a complex metabolic disorder requiring polypharmacy treatment in clinic, with metformin being widely used antihyperglycemic drug. However, the mechanisms of metformin as a perpetrator inducing potential drug-drug interactions and adverse drug reactions are scarcely known to date. Carboxylesterases (CESs) are major hydrolytic enzymes highly expressed in the liver, including mouse carboxylesterase 1d (Ces1d) and Ces1e. In the present study, experiments are designed to investigate the effects and mechanisms of metformin on Ces1d and Ces1e in vivo and in vitro. In results, metformin suppresses the expression and activity of Ces1d and Ces1e in a dose- and time-dependent manner. The decreased expression of nuclear receptor PXR and its target gene P-gp indicates the involvements of PXR in the suppressed expression of carboxylesterases by metformin. Furthermore, metformin significantly suppresses the phosphorylation of AMPK and JNK, and the suppression of carboxylesterases induced by metformin is repeatedly abolished by AMPK inhibitor Compound C and JNK inhibitor SP600125. It implies that the activation of AMPK and JNK pathways mediates the suppression of carboxylesterases by metformin. The findings deserve further elucidation including clinical trials and have a potential to make contribution for the rational medication in the treatment of T2D patients.
ESTHER : Shan_2017_Eur.J.Pharm.Sci_102_14
PubMedSearch : Shan_2017_Eur.J.Pharm.Sci_102_14
PubMedID: 28238946

Title : Expression of family with sequence similarity 172 member A and nucleotide-binding protein 1 is associated with the poor prognosis of colorectal carcinoma - Liu_2017_Oncol.Lett_14_3587
Author(s) : Liu W , Wang S , Qian K , Zhang J , Zhang Z , Liu H
Ref : Oncol Lett , 14 :3587 , 2017
Abstract : In our previous studies, a functionally unknown gene, family with sequence similarity 172, member A (FAM172A), was identified. High levels of FAM172A suppressed the cell cycle process, arresting HepG2 cells in G1/S and inhibiting cell proliferation. The present study aimed to confirm the expression levels of FAM172A and nucleotide-binding protein 1 (NUBP1) in colorectal cancer (CRC) tissues and normal colorectal tissues. The impact of FAM172A and NUBP1 on the prognosis of patients with CRC was also analyzed. Immunohistochemical staining for FAM172A and NUBP1 was performed on 180 cancerous tissues and 60 normal paraffin-embedded tissues from patients with CRC. In total, 85 and 83% of 180 patients revealed positive expression of FAM172A and NUBP1, respectively. FAM172A expression level was associated with Tumor-Node-Metastasis (TNM) staging (P<0.001), the levels of serum carcinoembryonic antigen (CEA; P=0.023) and carbohydrate antigen 19-9 (CA19-9; P=0.016), lymph node involvement (P=0.004), tissue type (P=0.016), Dukes' staging (P<0.001) and NUBP1 (P=0.026). Furthermore, the expression level of NUBP1 was also markedly associated with the levels of serum CEA (P=0.006) and CA19-9 (P=0.001), TNM staging (P<0.001), lymph node involvement (P=0.005), histological typing (P=0.024) and Dukes' stage (P<0.001). Results of the univariate analysis demonstrated that there was a negative correlation between the expression level of FAM172A and overall survival (OS) and relapse-free survival (RFS) (P=0.013 and P=0.012, respectively), and there was also a negative correlation between NUBP1 expression level and OS and RFS (P<0.001 and P<0.001, respectively). With regards to OS and RFS, multivariate analysis revealed that expression levels of FAM172A and NUBP1 and tumor stage may be independent prognostic factors Thus, the present study suggested that FAM172A and NUBP1 may be prognostic makers for CRC.
ESTHER : Liu_2017_Oncol.Lett_14_3587
PubMedSearch : Liu_2017_Oncol.Lett_14_3587
PubMedID: 28927116

Title : Structural insight into catalytic mechanism of PET hydrolase - Han_2017_Nat.Commun_8_2106
Author(s) : Han X , Liu W , Huang JW , Ma J , Zheng Y , Ko TP , Xu L , Cheng YS , Chen CC , Guo RT
Ref : Nat Commun , 8 :2106 , 2017
Abstract : PET hydrolase (PETase), which hydrolyzes polyethylene terephthalate (PET) into soluble building blocks, provides an attractive avenue for the bioconversion of plastics. Here we present the structures of a novel PETase from the PET-consuming microbe Ideonella sakaiensis in complex with substrate and product analogs. Through structural analyses, mutagenesis, and activity measurements, a substrate-binding mode is proposed, and several features critical for catalysis are elucidated.
ESTHER : Han_2017_Nat.Commun_8_2106
PubMedSearch : Han_2017_Nat.Commun_8_2106
PubMedID: 29235460
Gene_locus related to this paper: idesa-peth

Title : Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase\/monoamine oxidase inhibitors for the treatment of Alzheimer's disease - Sang_2017_Bioorg.Med.Chem_25_3006
Author(s) : Sang Z , Pan W , Wang K , Ma Q , Yu L , Liu W
Ref : Bioorganic & Medicinal Chemistry , 25 :3006 , 2017
Abstract : A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC50 values of 0.56muM, 2.3muM, 0.3muM and 1.4muM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM-33 could cross the blood-brain barrier (BBB) in vitro, and abided by Lipinski's rule of five. The results suggest that compound TM-33, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
ESTHER : Sang_2017_Bioorg.Med.Chem_25_3006
PubMedSearch : Sang_2017_Bioorg.Med.Chem_25_3006
PubMedID: 28487125

Title : Juvenile hormone regulates the differential expression of putative juvenile hormone esterases via methoprene-tolerant in non-diapause-destined and diapause-destined adult female beetle - Zhu_2017_Gene_627_373
Author(s) : Zhu L , Yin TY , Sun D , Liu W , Zhu F , Lei CL , Wang XP
Ref : Gene , 627 :373 , 2017
Abstract : Juvenile hormone (JH) plays an essential role in regulating molting, metamorphosis, reproduction, and diapause (dormancy), in many insects and crustaceans. JH esterases (JHEs) can control JH titer by regulating JH degradation. Although the biochemistry and structure of JHEs have been well studied, regulation of their expression remains unclear. We identified three putative JHEs (JHE1, JHE2, JHE3) in the cabbage beetle Colaphellus bowringi, and investigated the regulation of their expression by JH signaling in non-diapause-destined (NDD, reproductive) and diapause-destined (DD) female adults. Sequence and phylogenetic tree analyses indicate that the three putative JHEs shared conserved motifs with the JHEs of other insects and one crustacean, and were similar to Coleopteran, Dipteran, Orthopteran, Hymenopteran, and Decapodan JHEs. They were, however, less closely related to Hemipteran and Lepidopteran JHEs. JHEs were more highly expressed in NDD female adults than in DD female adults. JH analog induction in DD female adults significantly upregulated the expression of JHE1 and JHE2, but had no effect on the expression of JHE3. Knockdown of the JH candidate receptor methoprene-tolerant (Met) in NDD female adults downregulated the expression of all three JHEs. These results suggest that JHE expression is positively correlated with JH signaling, and that Met may be involved in the JH-mediated differential expression of JHE in DD and NDD adult female C. bowringi.
ESTHER : Zhu_2017_Gene_627_373
PubMedSearch : Zhu_2017_Gene_627_373
PubMedID: 28679117

Title : Combined Oral Administration of GABA and DPP-4 Inhibitor Prevents Beta Cell Damage and Promotes Beta Cell Regeneration in Mice - Liu_2017_Front.Pharmacol_8_362
Author(s) : Liu W , Son DO , Lau HK , Zhou Y , Prud'homme GJ , Jin T , Wang Q
Ref : Front Pharmacol , 8 :362 , 2017
Abstract : gamma-aminobutyric acid (GABA) or glucagon-like peptide-1 based drugs, such as sitagliptin (a dipeptidyl peptidase-4 inhibitor), were shown to induce beta cell regenerative effects in various diabetic mouse models. We propose that their combined administration can bring forth an additive therapeutic effect. We tested this hypothesis in a multiple low-dose streptozotocin (STZ)-induced beta cell injury mouse model (MDSD). Male C57BL/6J mice were assigned randomly into four groups: non-treatment diabetic control, GABA, sitagliptin, or GABA plus sitagliptin. Oral drug administration was initiated 1 week before STZ injection and maintained for 6 weeks. GABA or sitagliptin administration decreased ambient blood glucose levels and improved the glucose excursion rate. This was associated with elevated plasma insulin and reduced plasma glucagon levels. Importantly, combined use of GABA and sitagliptin significantly enhanced these effects as compared with each of the monotherapies. An additive effect on reducing water consumption was also observed. Immunohistochemical analyses revealed that combined GABA and sitagliptin therapy was superior in increasing beta cell mass, associated with increased small-size islet numbers, Ki67+ and PDX-1+ beta cell counts; and reduced Tunel+ beta cell counts. Thus, beta cell proliferation was increased, whereas apoptosis was reduced. We also noticed a suppressive effect of GABA or sitagliptin on alpha cell mass, which was not significantly altered by combining the two agents. Although either GABA or sitagliptin administration delays the onset of MDSD, our study indicates that combined use of them produces superior therapeutic outcomes. This is likely due to an amelioration of beta cell proliferation and a decrease of beta cell apoptosis.
ESTHER : Liu_2017_Front.Pharmacol_8_362
PubMedSearch : Liu_2017_Front.Pharmacol_8_362
PubMedID: 28676760

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

Title : Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease - Sang_2017_Bioorg.Med.Chem.Lett_27_5053
Author(s) : Sang Z , Wang K , Wang H , Yu L , Ma Q , Ye M , Han X , Liu W
Ref : Bioorganic & Medicinal Chemistry Lett , 27 :5053 , 2017
Abstract : A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2muM, 3.8muM and 2.6muM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
ESTHER : Sang_2017_Bioorg.Med.Chem.Lett_27_5053
PubMedSearch : Sang_2017_Bioorg.Med.Chem.Lett_27_5053
PubMedID: 29033232

Title : miR27a promotes proliferation, migration, and invasion of colorectal cancer by targeting FAM172A and acts as a diagnostic and prognostic biomarker - Liu_2017_Oncol.Rep_37_3554
Author(s) : Liu W , Qian K , Wei X , Deng H , Zhao B , Chen Q , Zhang J , Liu H
Ref : Oncol Rep , 37 :3554 , 2017
Abstract : Accumulating evidence shows that mircroRNAs (miRNAs) play a crucial role in the development of colorectal cancer. In our previous study, FAM172A was demonstrated to be a novel tumor suppressor gene in CRC. Therefore, the aim of the present study was to identify whether the miR27a could be a diagnostic and prognostic marker and the regulatory relationships between miR27a and FAM172A. We demonstrated high levels of miR27a expression in tissues of patients with CRC as well as in CRC cell lines. There was a positive correlation between the levels of miR27a and the poor overall survival of patients with CRC. Furthermore, elevated levels of miR27a expression were associated with TNM stage and distant metastasis. Increased expression or inhibition of miR27a promoted or inhibited the metastasis of CRC cell lines, respectively. Moreover, we showed that miR27a directly targets the 3'-untranslated region of FAM172A mRNA by using a dual-luciferase assay. Increased or decreased expression of FAM172A expression was observed when miR27a expression was inhibited or elevated in the CRC cells, respectively. In summary, our study showed that miR27a expression is a diagnostic and prognostic marker and correlates with overall survival of patients with CRC. Therefore, it may be a therapeutic approach for preventing metastasis of CRC to inhibit expression of miR27a or increase expression of FAM172A.
ESTHER : Liu_2017_Oncol.Rep_37_3554
PubMedSearch : Liu_2017_Oncol.Rep_37_3554
PubMedID: 28440497
Gene_locus related to this paper: human-f172a

Title : A new facet of NDRG1 in pancreatic ductal adenocarcinoma: Suppression of glycolytic metabolism - Liu_2017_Int.J.Oncol_50_1792
Author(s) : Liu W , Zhang B , Hu Q , Qin Y , Xu W , Shi S , Liang C , Meng Q , Xiang J , Liang D , Ji S , Liu J , Hu P , Liu L , Liu C , Long J , Ni Q , Yu X , Xu J
Ref : Int J Oncol , 50 :1792 , 2017
Abstract : N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1alpha level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1alpha, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC.
ESTHER : Liu_2017_Int.J.Oncol_50_1792
PubMedSearch : Liu_2017_Int.J.Oncol_50_1792
PubMedID: 28350132

Title : Dietary phosphatidylcholine impacts on growth performance and lipid metabolism in adult Genetically Improved Farmed Tilapia (GIFT) strain of Nile tilapia Oreochromis niloticus - Tian_2017_Br.J.Nutr__1
Author(s) : Tian J , Wen H , Lu X , Liu W , Wu F , Yang CG , Jiang M , Yu LJ
Ref : British Journal of Nutrition , :1 , 2017
Abstract : This study aimed to determine the effects of supplementing the diet of adult Nile tilapia Oreochromis niloticus with phosphatidylcholine (PC) on growth performance, body composition, fatty acid composition and gene expression. Genetically Improved Farmed Tilapia fish with an initial body weight of 83.1 (sd 2.9) g were divided into six groups. Each group was hand-fed a semi-purified diet containing 1.7 (control diet), 4.0, 6.5, 11.5, 21.3 or 41.0 g PC/kg diet for 68 d. Supplemental PC improved the feed efficiency rate, which was highest in the 11.5 g PC/kg diet. Weight gain and specific growth rate were unaffected. Dietary PC increased PC content in the liver and decreased crude fat content in the liver, viscera and body. SFA and MUFA increased and PUFA decreased in muscle with increasing dietary PC. Cytoplasmic phospholipase A 2 and secreted phospholipase A 2 mRNA expression were up-regulated in the brain and heart in PC-supplemented fish. PC reduced fatty acid synthase mRNA expression in the liver and visceral tissue but increased expression in muscle. Hormone-sensitive lipase and lipoprotein lipase expression increased in the liver with increasing dietary PC. Growth hormone mRNA expression was reduced in the brain and insulin-like growth factor-1 mRNA expression in liver reduced with PC above 6.5 g/kg. Our results demonstrate that dietary supplementation with PC improves feed efficiency and reduces liver fat in adult Nile tilapia, without increasing weight gain, representing a novel dietary approach to reduce feed requirements and improve the health of Nile tilapia.
ESTHER : Tian_2017_Br.J.Nutr__1
PubMedSearch : Tian_2017_Br.J.Nutr__1
PubMedID: 29227215

Title : Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE\/BuChE inhibitor in scopolamine mouse model and inflammatory cells - Liu_2017_Neuropharmacol_113_445
Author(s) : Liu W , Rabinovich A , Nash Y , Frenkel D , Wang Y , Youdim MB , Weinreb O
Ref : Neuropharmacology , 113 :445 , 2017
Abstract : Previous study demonstrated that the novel multitarget compound, MT-031 preserved in one molecule entity the beneficial properties of its parent drugs, rasagiline and rivastigmine, and exerted high dual potencies of monoamine oxidase-A (MAO-A) and cholinesterase (ChE) inhibition in acute-treated mice and neuroprotective effects against H2O2-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. The present study aimed to further investigate the anti-inflammatory and protective effects of MT-031 in scopolamine mouse model and inflammatory cell cultures. Our findings demonstrated that once daily chronic administration of MT-031 (5-10 mg/kg) to mice antagonized scopolamine-induced memory and cognitive impairments, displayed brain selective MAO-A and AChE/BuChE inhibition, increased the levels of striatal dopamine (DA), serotonin (5-HT) and norepinephrine and prevented the metabolism of DA and 5-HT. In addition, MT-031 upregulated mRNA expression levels of Bcl-2, the neurotrophic factors, (e.g., brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF)), the antioxidant enzyme catalase and the anti-inflammatory cytokine, neurotrophic tyrosine kinase receptor (Ntrk), and down-regulated the mRNA expression levels of the pro-inflammatory interleukin (IL)-6 in scopolamine-induced mice. In accordance, MT-031 was shown to reduce reactive oxygen species accumulation, increase the levels of anti-inflammatory cytokines, IL-10 and decrease the levels of the pro-inflammatory cytokines, IL-1beta, IL-6, IL-17 and interferon-gamma (IFN-gamma) in activated mouse splenocytes and microglial cells. Taken together, these pharmacological properties of MT-031 can be of clinical importance for developing this novel multitarget compound as a novel drug candidate for the treatment of Alzheimer's disease.
ESTHER : Liu_2017_Neuropharmacol_113_445
PubMedSearch : Liu_2017_Neuropharmacol_113_445
PubMedID: 27984078

Title : Anti-amnesic effect of extract and alkaloid fraction from aerial parts of Peganum harmala on scopolamine-induced memory deficits in mice - Liu_2017_J.Ethnopharmacol_204_95
Author(s) : Liu W , Zhu Y , Wang Y , Qi S , Ma C , Li S , Jiang B , Cheng X , Wang Z , Xuan Z , Wang C
Ref : J Ethnopharmacol , 204 :95 , 2017
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Peganum harmala Linn (APP) is used as traditional medical herb for treatment of forgetfulness in Uighur medicine in China. But, the active ingredients and underlying mechanisms are unclear. AIM OF THE STUDY: The present study was undertaken to investigate the improvement effects of extract and alkaloid fraction from APP on scopolamine-induced cognitive dysfunction and to elucidate their underlying mechanisms of action, and to support its folk use with scientific evidence, and lay a foundation for its further researches. MATERIALS AND
METHODS: The acetylcholinesterase (AChE) inhibitory activities of extract (EXT), alkaloid fraction (ALK) and flavonoid fraction (FLA) from APP were evaluated in normal male C57BL/6 mice. The anti-amnesic effects of EXT and ALK from APP were measured in scopolamine-induced memory deficits mice by the Morris water maze (MWM) tasks. The levels of biomarkers, enzyme activity and protein expression of cholinergic system were determined in brain tissues.
RESULTS: The AChE activity was significantly decreased and the content of neurotransmitter acetylcholine (ACh) was significantly increased in normal mice cortex and hippocampus by treatment with donepezil at dosage of 8mg/kg, EXT at dosages of 183, 550, 1650mg/kg and ALK at dosages of 10, 30, 90mg/kg (P<0.05), and the AChE activity and the content of ACh were not significantly changed in cortex and hippocampus after treatment with FLA at dosages of 10, 30, 90mg/kg (P>0.05). In the MWM task, scopolamine-induced a decrease in both the swimming time within the target zone and the number of crossings where the platform had been placed were significantly reversed by treatment with EXT at dosages of 550, 1650mg/kg and ALK at dosages of 30, 90mg/kg (P<0.05). Moreover, the activity and protein expression of AChE was significantly decreased and the content of neurotransmitter ACh was significantly increased in cerebral cortex of scopolamine-induced mice by treatment with EXT at dosages of 183, 550, 1650mg/kg and ALK at dosages of 10, 30, 90mg/kg (P<0.05), compared with scopolamine-treated group.
CONCLUSIONS: EXT and ALK from APP exert beneficial effect on learning and memory processes in mice with scopolamine-induced memory impairment. APP is an effective traditional folk medicine and the ALK fraction is proved to be the main effective components for the treatment of forgetfulness. The ALK may be valuable source for lead compounds discovery and drug development for treatment of memory impairment such as in Alzheimer's disease.
ESTHER : Liu_2017_J.Ethnopharmacol_204_95
PubMedSearch : Liu_2017_J.Ethnopharmacol_204_95
PubMedID: 28442406

Title : Characterization and crystal structure of a novel zearalenone hydrolase from Cladophialophora bantiana - Hui_2017_Acta.Crystallogr.F.Struct.Biol.Commun_73_515
Author(s) : Hui R , Hu X , Liu W , Zheng Y , Chen Y , Guo RT , Jin J , Chen CC
Ref : Acta Crystallographica F Struct Biol Commun , 73 :515 , 2017
Abstract : Zearalenone (ZEN) is a mycotoxin which causes huge economic losses in the food and animal feed industries. The lactonase ZHD101 from Clonostachys rosea, which catalyzes the hydrolytic degradation of ZEN, is the only known ZEN-detoxifying enzyme. Here, a protein homologous to ZHD101, denoted CbZHD, from Cladophialophora batiana was expressed and characterized. Sequence alignment indicates that CbZHD possesses the same catalytic triad and ZEN-interacting residues as found in ZHD101. CbZHD exhibits optimal enzyme activity at 35 degrees C and pH 8, and is sensitive to heat treatment. The crystal structure of apo CbZHD was determined to 1.75 A resolution. The active-site compositions of CbZHD and ZHD101 were analyzed.
ESTHER : Hui_2017_Acta.Crystallogr.F.Struct.Biol.Commun_73_515
PubMedSearch : Hui_2017_Acta.Crystallogr.F.Struct.Biol.Commun_73_515
PubMedID: 28876230
Gene_locus related to this paper: xylba-a0a0d2h023

Title : Screening of a natural compound library identifies emodin, a natural compound from Rheum palmatum Linn that inhibits DPP4 - Wang_2017_PeerJ_5_e3283
Author(s) : Wang Z , Yang L , Fan H , Wu P , Zhang F , Zhang C , Liu W , Li M
Ref : PeerJ , 5 :e3283 , 2017
Abstract : Historically, Chinese herbal medicines have been widely used in the treatment of hyperglycemia, but the mechanisms underlying their effectiveness remain largely unknown. Here, we screened a compound library primarily comprised of natural compounds extracted from herbs and marine organisms. The results showed that emodin, a natural compound from Rheum palmatum Linn, inhibited DPP4 activity with an in vitro IC50 of 5.76 microM without inhibiting either DPP8 or DPP9. A docking model revealed that emodin binds to DPP4 protein through Glu205 and Glu206, although with low affinity. Moreover, emodin treatment (3, 10 and 30 mg/kg, P.O.) in mice decreased plasma DPP4 activity in a dose-dependent manner. Our study suggests that emodin inhibits DPP4 activity and may represent a novel therapeutic for the treatment of type 2 diabetes.
ESTHER : Wang_2017_PeerJ_5_e3283
PubMedSearch : Wang_2017_PeerJ_5_e3283
PubMedID: 28507818

Title : Design, synthesis and evaluation of novel ferulic acid-O-alkylamine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease - Sang_2017_Eur.J.Med.Chem_130_379
Author(s) : Sang Z , Pan W , Wang K , Ma Q , Yu L , Yang Y , Bai P , Leng C , Xu Q , Li X , Tan Z , Liu W
Ref : Eur Journal of Medicinal Chemistry , 130 :379 , 2017
Abstract : A series of novel ferulic acid-O-alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced beta-amyloid (Abeta) aggregation and acted as potential antioxidants. Particularly, compound 7f, one of the most potent BuChE inhibitor (IC50 value of 0.021 muM for equine serum BuChE, 8.63 muM for ratBuChE and 0.07 muM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC50 = 2.13 muM for electric eel AChE, 1.8 muM for ratAChE and 3.82 muM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced Abeta1-42 aggregation (50.8 +/- 0.82%) and was found to disaggregate self-induced Abeta1-42 aggregation (38.7 +/- 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H2O2-induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro. Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of AD.
ESTHER : Sang_2017_Eur.J.Med.Chem_130_379
PubMedSearch : Sang_2017_Eur.J.Med.Chem_130_379
PubMedID: 28279845

Title : Development of a neuroprotective potential algorithm for medicinal plants - Liu_2016_Neurochem.Int_100_164
Author(s) : Liu W , Ma H , DaSilva NA , Rose KN , Johnson SL , Zhang L , Wan C , Dain JA , Seeram NP
Ref : Neurochem Int , 100 :164 , 2016
Abstract : Medicinal plants are promising candidates for Alzheimer's disease (AD) research but there is lack of systematic algorithms and procedures to guide their selection and evaluation. Herein, we developed a Neuroprotective Potential Algorithm (NPA) by evaluating twenty-three standardized and chemically characterized Ayurvedic medicinal plant extracts in a panel of bioassays targeting oxidative stress, carbonyl stress, protein glycation, amyloid beta (Abeta) fibrillation, acetylcholinesterase (AChE) inhibition, and neuroinflammation. The twenty-three herbal extracts were initially evaluated for: 1) total polyphenol content (Folin-Ciocalteu assay), 2) free radical scavenging capacity (DPPH assay), 3) ferric reducing antioxidant power (FRAP assay), 4) reactive carbonyl species scavenging capacity (methylglyoxal trapping assay), 5) anti-glycative effects (BSA-fructose, and BSA-methylglyoxal assays) and, 6) anti-Abeta fibrillation effects (thioflavin-T assay). Based on assigned index scores from the initial screening, twelve extracts with a cumulative NPA score >/=40 were selected for further evaluation for their: 1) inhibitory effects on AChE activity, 2) in vitro anti-inflammatory effects on murine BV-2 microglial cells (Griess assay measuring levels of lipopolysaccharide-induced nitric oxide species), and 3) in vivo neuroprotective effects on Caenorhabditis elegans post induction of Abeta1-42 induced neurotoxicity and paralysis. Among these, four extracts had a cumulative NPA score >/=60 including Phyllanthus emblica (amla; Indian gooseberry), Mucuna pruriens (velvet bean), Punica granatum (pomegranate) and Curcuma longa (turmeric; curcumin). These extracts also showed protective effects on H2O2 induced cytotoxicity in differentiated cholinergic human neuronal SH-SY5Y and murine BV-2 microglial cells and reduced tau protein levels in the SH-SY5Y neuronal cells. While published animal data support the neuroprotective effects of several of these Ayurvedic medicinal plant extracts, some remain unexplored for their anti-AD potential. Therefore, the NPA may be utilized, in part, as a strategy to help guide the selection of promising medicinal plant candidates for future AD-based research using animal models.
ESTHER : Liu_2016_Neurochem.Int_100_164
PubMedSearch : Liu_2016_Neurochem.Int_100_164
PubMedID: 27693453

Title : Clinical Outcomes of Thymectomy in Myasthenia Gravis Patients with a History of Crisis - Liu_2016_World.J.Surg_40_2681
Author(s) : Liu Z , Lai Y , Yao S , Feng H , Zou J , Liu W , Lei Y , Zhu H , Cheng C
Ref : World J Surg , 40 :2681 , 2016
Abstract : BACKGROUND: The use of thymectomy in myasthenia gravis (MG) patients with a history of myasthenic crisis (MC) has not been well established. Here, we determined the efficacy of thymectomy by assessing the long-term clinical outcomes and reviewed thymectomy reports on MC patients.
METHODS: Subjects included 31 patients who suffered at least one crisis before surgery, with a cumulative total 73 episodes of MC in Southern China between May 2000 and December 2010. Long-term follow-up was performed and clinical outcomes were evaluated. We used complete stable remission (CSR), termed an asymptomatic status without medication for at least 12 months; general complete remission (GCR), termed an asymptomatic status with or without some form of therapy excluding cholinesterase inhibitors, to assess patient outcomes.
RESULTS: All patients underwent thymectomy with an overall complication rate of 16.1 % and a perioperative mortality rate of 3.2 %. Long-term follow-up occurred between 12.6 and 177 months, at which point 18 (58.1 %) patients experienced improved status, including one patient who achieved CSR; 13 (41.9 %) patients achieved GCR; 6 (19.4 %) showed unchanged status and one worse (3.2 %) status. The remaining 6 patients died, with 3 due to MG-related causes. Using a multivariate Cox regression analysis of GCR by characteristics, patients with better response to medical treatments before thymectomy were positively associated with GCR rates (p = 0.028).
CONCLUSIONS: Extended transsternal thymectomy is a feasible and effective therapy for MG patients with crisis history, especially for those patients who have shown positive signs of remission after exhausting conventional medical treatments.
ESTHER : Liu_2016_World.J.Surg_40_2681
PubMedSearch : Liu_2016_World.J.Surg_40_2681
PubMedID: 27312319

Title : FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter - Qian_2016_Oncol.Rep_35_1273
Author(s) : Qian K , Zhang J , Lu J , Liu W , Yao X , Chen Q , Lu S , Xiang G , Liu H
Ref : Oncol Rep , 35 :1273 , 2016
Abstract : In our previous study, low expression of FAM172A protein was found in colon cancer tissues. This research was planned to explore the functions of FAM172A gene and examine the mechanisms of its transcriptional regulation. Firstly, flow cytometry showed that FAM172A inhibited proliferation and promoted apoptosis and differentiation of colon cancer cells. Then through continuous truncation, we identified the minimal functional promoter region of FAM172A. Subsequently, we found that STAT1, as a transcription factor, could bind to the minimal FAM172A promoter, as evaluated using Chromatin immunoprecipitation (ChIP) and Electrophoreticmobility shift assay (EMSA). The results of Western blot analysis and qRT-PCR indicated that STAT1 was able to upregulate the expression of FAM172A. Our results showed that FAM172A could suppress proliferation of colon cancer cells, and STAT1 could bind to the minimum promoter region of FAM172A and upregulated the expression of FAM172A. These results may provide advanced insights into the functions of FAM172A and its regulatory mechanisms.
ESTHER : Qian_2016_Oncol.Rep_35_1273
PubMedSearch : Qian_2016_Oncol.Rep_35_1273
PubMedID: 26676844
Gene_locus related to this paper: human-f172a

Title : Fluoxetine reduces CES1, CES2, and CYP3A4 expression through decreasing PXR and increasing DEC1 in HepG2 cells - Shang_2016_Xenobiotica_46_393
Author(s) : Shang W , Liu J , Chen R , Ning R , Xiong J , Liu W , Mao Z , Hu G , Yang J
Ref : Xenobiotica , 46 :393 , 2016
Abstract : 1. This study investigated the mechanisms of the decreases of carboxylesterases (CES) and cytochrome P4503A4 (CYP3A4) and the enzymatic activities induced by fluoxetine (FLX) in HepG2 cells. We found that FLX decreased the carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) expression and the hydrolytic activity. 2. FLX decreased the pregnane X receptor (PXR) expression which regulated the target genes such as CYP3A4, whereas increased the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) expression. 3. FLX repressed the PXR at transcriptional level. 4. Overexpression of PXR alone increased the expression of CES1, CES2, and CYP3A4 and attenuated the decreases of CES1, CES2, and CYP3A4 induced by FLX. On the contrary, knockdown of PXR alone decreased the expression of CES1, CES2, and CYP3A4 and almost abolished the decreases of CES1, CES2, and CYP3A4 induced by FLX. 5. Knockdown of DEC1 alone increased the expression of PXR and CYP3A4 and almost abolished the decreases of CES1, CES2, and CYP3A4 induced by FLX. 6. Taken together, the decreases of CES and CYP3A4 expression and enzymatic activities induced by FLX are through decreasing PXR and increasing DEC1 in HepG2 cells.
ESTHER : Shang_2016_Xenobiotica_46_393
PubMedSearch : Shang_2016_Xenobiotica_46_393
PubMedID: 26340669
Gene_locus related to this paper: human-CES1

Title : Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer's disease - Pan_2016_Bioorg.Med.Chem.Lett_26_2539
Author(s) : Pan W , Hu K , Bai P , Yu L , Ma Q , Li T , Zhang X , Chen C , Peng K , Liu W , Sang Z
Ref : Bioorganic & Medicinal Chemistry Lett , 26 :2539 , 2016
Abstract : A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7muM) and self-induced beta-amyloid (Abeta1-42) aggregation (30.8-39.1%, 25muM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50=3.2muM), and Abeta1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Abeta aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.
ESTHER : Pan_2016_Bioorg.Med.Chem.Lett_26_2539
PubMedSearch : Pan_2016_Bioorg.Med.Chem.Lett_26_2539
PubMedID: 27072909

Title : Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer's disease - Liu_2016_Neuropharmacol_109_376
Author(s) : Liu W , Lang M , Youdim MB , Amit T , Sun Y , Zhang Z , Wang Y , Weinreb O
Ref : Neuropharmacology , 109 :376 , 2016
Abstract : Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the "N-methyl" position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo. Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H2O2-induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD.
ESTHER : Liu_2016_Neuropharmacol_109_376
PubMedSearch : Liu_2016_Neuropharmacol_109_376
PubMedID: 27318273

Title : Enhanced alpha-Zearalenol Hydrolyzing Activity of a Mycoestrogen-Detoxifying Lactonase by Structure-Based Engineering - Xu_2016_ACS.Catal_6_7657
Author(s) : Xu Z , Liu W , Chen CC , Li Q , Huang JW , Ko TP , Liu G , Peng W , Cheng YS , Chen Y , Jin J , Li H , Zheng Y , Guo RT
Ref : ACS Catal , 6 :7657 , 2016
Abstract : The enzyme ZHD101 from Clonostachys rosea hydrolyzes and deactivates the mycotoxin zearalenone (ZEN) and its zearalenol (ZOL) derivatives. ZHD101 prefers ZEN to ZOL as its substrate, but ZOL, especially the -form, shows higher estrogenic toxicity than ZEN. To enhance alpha-ZOL selectivity, we solved the complex structures of ZHD101 with both ZOLs and modified several lactone-surrounding residues. Among the mutants, V153H maintained activity for ZEN but showed a 3.7-fold increase in specific activity against alpha-ZOL, with an 2.7-fold reduction in substrate affinity but a 5.2-fold higher turnover rate. We then determined two V153H/ZOL complex structures. Here, the alpha-ZOL lactone ring is hydrogen-bonded to the H153 side chain, yielding a larger space for H242 to reconstitute the catalytic triad. In conclusion, structure-based engineering was successfully employed to improve the ZHD101 activity toward the more toxic alpha-ZOL, with great potential in further industrial applications.
ESTHER : Xu_2016_ACS.Catal_6_7657
PubMedSearch : Xu_2016_ACS.Catal_6_7657
Gene_locus related to this paper: biooc-ZHD101

Title : Gambogic acid potentiates clopidogrel-induced apoptosis and attenuates irinotecan-induced apoptosis through down-regulating human carboxylesterase 1 and -2 - Ning_2016_Xenobiotica__1
Author(s) : Ning R , Wang XP , Zhan YR , Qi Q , Huang XF , Hu G , Guo QL , Liu W , Yang J
Ref : Xenobiotica , :1 , 2016
Abstract : 1. In this study, we report that gambogic acid (GA), a promising anticancer agent, potentiates clopidogrel-induced apoptosis and attenuates CPT-11-induced apoptosis by down-regulating human carboxylesterase (CES) 1 and -2 via ERK and p38 MAPK pathway activation, which provides a molecular explanation linking the effect of drug combination directly to the decreased capacity of hydrolytic biotransformation. 2. The expression levels of CES1 and CES2 decreased significantly in a concentration- and time-dependent manner in response to GA in Huh7 and HepG2 cells; hydrolytic activity was also reduced. 3. The results showed that pretreatment with GA potentiated clopidogrel-induced apoptosis by down-regulating CES1. Moreover, the GA-mediated repression of CES2 attenuated CPT-11-induced apoptosis. 4. Furthermore, the ERK and p38 MAPK pathways were involved in the GA-mediated down-regulation of CES1 and CES2. 5. Taken together, our data suggest that GA is a potent repressor of CES1 and CES2 and that combination with GA will affect the metabolism of drugs containing ester bonds.
ESTHER : Ning_2016_Xenobiotica__1
PubMedSearch : Ning_2016_Xenobiotica__1
PubMedID: 26750665

Title : An alpha\/beta-hydrolase fold protein in the biosynthesis of thiostrepton exhibits a dual activity for endopeptidyl hydrolysis and epoxide ring opening\/macrocyclization - Zheng_2016_Proc.Natl.Acad.Sci.U.S.A_113_14318
Author(s) : Zheng Q , Wang S , Duan P , Liao R , Chen D , Liu W
Ref : Proc Natl Acad Sci U S A , 113 :14318 , 2016
Abstract : Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of the QA moiety, i.e., by fluorination or methylation, we have recently designed and biosynthesized biologically more active TSR analogs. Using these analogs as chemical probes, we uncovered an unusual indirect mechanism of TSR-type thiopeptides, which are able to act against intracellular pathogens through host autophagy induction in addition to direct targeting of bacterial ribosome. Herein, we report the accumulation of 6'-fluoro-7', 8'-epoxy-TSR, a key intermediate in the preparation of the analog 6'-fluoro-TSR. This unexpected finding led to unveiling of the TSR maturation process, which involves an unusual dual activity of TsrI, an alpha/beta-hydrolase fold protein, for cascade C-N bond cleavage and formation during side-ring system construction. These two functions of TsrI rely on the same catalytic triad, Ser72-His200-Asp191, which first mediates endopeptidyl hydrolysis that occurs selectively between the residues Met-1 and Ile1 for removal of the leader peptide and then triggers epoxide ring opening for closure of the QA-containing side-ring system in a regio- and stereo-specific manner. The former reaction likely requires the formation of an acyl-Ser72 enzyme intermediate; in contrast, the latter is independent of Ser72. Consequently, C-6' fluorination of QA lowers the reactivity of the epoxide intermediate and, thereby, allows the dissection of the TsrI-associated enzymatic process that proceeds rapidly and typically is difficult to be realized during TSR biosynthesis.
ESTHER : Zheng_2016_Proc.Natl.Acad.Sci.U.S.A_113_14318
PubMedSearch : Zheng_2016_Proc.Natl.Acad.Sci.U.S.A_113_14318
PubMedID: 27911800
Gene_locus related to this paper: strlu-c0l0l7

Title : Dietary lipid levels impact lipoprotein lipase, hormone-sensitive lipase, and fatty acid synthetase gene expression in three tissues of adult GIFT strain of Nile tilapia, Oreochromis niloticus - Tian_2015_Fish.Physiol.Biochem_41_1
Author(s) : Tian J , Wu F , Yang CG , Jiang M , Liu W , Wen H
Ref : Fish Physiol Biochem , 41 :1 , 2015
Abstract : The objective of this study was to assess the effects of dietary lipids on growth performance, body composition, serum parameters, and expression of genes involved in lipid metabolism in adult genetically improved farmed tilapia (GIFT strain) of Nile tilapia, Oreochromis niloticus. We randomly assigned adult male Nile tilapia (average initial body weight = 220.00 +/- 9.54 g) into six groups consisting of four replicates (20 fish per replicate). Fish in each group were hand-fed a semi-purified diets containing different lipid levels [3.3 (the control group), 28.4, 51.4, 75.4, 101.9, and 124.1 g kg(-1)] for 8 weeks. The results indicated that there was no obvious effect in feeding rate among all groups (P > 0.05). The highest weight gain, specific growth rate, and protein efficiency ratio in 75.4 g kg(-1) diet group were increased by 23.31, 16.17, and 22.02 % than that of fish in the control group (P < 0.05). Protein retention ratio was highest in 51.4 g kg(-1) diet group. The results revealed that the optimum dietary lipid level for maximum growth performance is 76.6-87.9 g kg(-1). Increasing dietary lipid levels contributed to increased tissue and whole body lipid levels. Saturated and monounsaturated fatty acids (MUFAs) decreased, and polyunsaturated fatty acids increased with increasing dietary lipid levels. With the exception of MUFAs, the fatty acid profiles of liver and muscle were similar. Dietary lipid levels were negatively correlated with low-density lipoprotein- cholesterol content and positively with triacylglycerol and glucose contents. In the lipid-fed groups, there was a significant down-regulation of fatty acid synthase (FAS) mRNA in liver, muscle, and visceral adipose tissues. There was a rapid up-regulation of lipoprotein lipase (LPL) mRNA in muscle and liver with increasing dietary lipid levels. In visceral adipose tissue, LPL mRNA was significantly down-regulated in the lipid-fed groups. Dietary lipids increased hormone-sensitive lipase (HSL) mRNA expression levels in the three tissues. These results strongly suggested that moderate dietary lipid levels were beneficial for adult tilapia growth performance and feed efficiency. However, excessive dietary lipid levels contributed to lipid deposition. Additionally, excessive dietary lipids may induce a competition between lipolysis and lipogenesis. FAS did not have tissue-specific regulation; however, the regulation of dietary lipids on LPL expression is tissue specific. FAS was a negative feedback regulator on fat deposition, and HSL was an indicator of fat content in tilapia.
ESTHER : Tian_2015_Fish.Physiol.Biochem_41_1
PubMedSearch : Tian_2015_Fish.Physiol.Biochem_41_1
PubMedID: 25347968

Title : Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP\/PS1 transgenic mice and scopolamine-induced memory impairment mice - He_2015_Eur.J.Pharmacol_768_96
Author(s) : He D , Wu H , Wei Y , Liu W , Huang F , Shi H , Zhang B , Wu X , Wang C
Ref : European Journal of Pharmacology , 768 :96 , 2015
Abstract : Harmine, a beta-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that harmine (20mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL/6 mice impaired by intraperitoneal injection of scopolamine (1mg/kg). Meanwhile, long-term consumption of harmine (20mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency.
ESTHER : He_2015_Eur.J.Pharmacol_768_96
PubMedSearch : He_2015_Eur.J.Pharmacol_768_96
PubMedID: 26526348

Title : In vitro and in vivo metabolism and inhibitory activities of vasicine, a potent acetylcholinesterase and butyrylcholinesterase inhibitor - Liu_2015_PLoS.One_10_e0122366
Author(s) : Liu W , Shi X , Yang Y , Cheng X , Liu Q , Han H , Yang B , He C , Wang Y , Jiang B , Wang Z , Wang C
Ref : PLoS ONE , 10 :e0122366 , 2015
Abstract : Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer's disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-beta-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity.
ESTHER : Liu_2015_PLoS.One_10_e0122366
PubMedSearch : Liu_2015_PLoS.One_10_e0122366
PubMedID: 25849329

Title : Potent AChE and BChE inhibitors isolated from seeds of Peganum harmala Linn by a bioassay-guided fractionation - Yang_2015_J.Ethnopharmacol_168_279
Author(s) : Yang Y , Cheng X , Liu W , Chou G , Wang Z , Wang C
Ref : J Ethnopharmacol , 168 :279 , 2015
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Seeds of Peganum harmala Linn are traditionally used as folk medical herb in Uighur medicine in China to treat disorders of hemiplegia and amnesia. Previously studies have proved that dominating alkaloids in P. harmala show significant inhibitory activities on the cholinesterase. AIM OF THE STUDY: The aim of the present study is to isolate trace ingredients from seeds of P. harmala and evaluate its inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). MATERIALS AND
METHODS: For sake of screening effective cholinesterase inhibitors, trace compounds were isolated from seeds of P. harmala through a bioassay-guided fractionation and their structures were determined via detailed spectral analysis. The inhibitory activities on AChE and BChE were assessed using an improved Ellman method by UPLC-ESI-MS/MS to determine the common final product choline.
RESULTS: The activity-guided fractionation led to the isolation of two new alkaloids 2-aldehyde-tetrahydroharmine (10), 2-carboxyl-3,4-dihydroquinazoline (19), one syringin structure analog 1-O-beta-D-xylopyranose sinapyl alcohol (22), and along with 19 known compounds. Compounds acetylnorharmine (6), harmic acid methy ester (7), harmine N-oxide (13), 6-methoxyindoline (14), syringin (21) were first found from genus Peganum and compounds 3-hydroxylated harmine (4), 1-hydroxy-7-methoxy-beta-carboline (5) were new natural products. The results showed that the 2-aldehyde-tetrahydroharmine (10) has a potential inbibitive effect on both AChE and BChE with IC50 values of 12.35+/-0.24 and 5.51+/-0.33microM, respectively. Deoxyvasicine (15) and vasicine (16) showed the strongest BChE inhibitory activity with IC50 values of 0.04+/-0.01 and 0.1+/-0.01microM. The analysis of the structure-activity relationship indicated that the saturation of pyridine ring and the presence of substitution at indole ring, C-1, C-3, C-7 and N-2, for beta-carbolines, were essential for effective inhibition of both AChE and BChE and the five-membered ring between C-2 and N-3 as well as the substituent groups sited at C-4 and C-9, for quinazolines, were important to both the AChE/BChE-inhibitory activity.
CONCLUSIONS: Bioassay-guided fractionation has led to the isolation of AChE and BChE inhibitors from the seeds of P. harmala. These results are in agreement with the traditional uses of the seeds of P. harmala.
ESTHER : Yang_2015_J.Ethnopharmacol_168_279
PubMedSearch : Yang_2015_J.Ethnopharmacol_168_279
PubMedID: 25862961

Title : Conversion of inhibition biosensing to substrate-like biosensing for quinalphos selective detection - Yang_2015_Anal.Chem_87_5270
Author(s) : Yang L , Han J , Liu W , Li J , Jiang L
Ref : Analytical Chemistry , 87 :5270 , 2015
Abstract : Since all of the organophosphorus pesticides (OPP) inhibit the cholinesterases with a common mechanism, it is still challenging to detect OPP selectively with inhibition-based biosensors. This study focuses on the conversion of a typical inhibition biosensing to a selective substrate-like biosensing. The interaction of quinalphos with plant-esterase involves not only a decrease in enzyme activity but also a heterolytic bond cleavage of quinalphos. The leaving group eliminated from quinalphos is an ideal biomarker due to its specificity in most OPP. Thus, using 2-hydroxyquinoxaline (HQO), the leaving group of quinalphos, as the biomarker and meso-tetra (4-sulfonatophenyl) porphine (TPPS4) as an optical probe, quinalphos can be selectively detected. The molecular recognition between TPPS4 and HQO leads to a considerable sensitivity of the detection. The spectral responses of TPPS4 show a linear dependence on quinalphos concentration in the presence of plant-esterase within the 0.01-1 mg kg(-1) range. The detection limit is 0.01 mg kg(-1), well below the maximum residue limits (MRLs) defined by European Union (0.05 mg kg(-1)) and China (0.2 mg kg(-1)).
ESTHER : Yang_2015_Anal.Chem_87_5270
PubMedSearch : Yang_2015_Anal.Chem_87_5270
PubMedID: 25921798

Title : Occurrence and risk assessment of organophosphate esters in drinking water from Eastern China - Ding_2015_Sci.Total.Environ_538_959
Author(s) : Ding J , Shen X , Liu W , Covaci A , Yang F
Ref : Sci Total Environ , 538 :959 , 2015
Abstract : Organophosphate esters (OPEs) are ubiquitous in the environment and may pose potential health risks to humans. Drinking water is suspected as one possible exposure pathway of OPEs to humans. In this study, we investigated the residues of 9 OPEs in five types of drinking water in Eastern China. The median concentrations of Sigma9OPEs were determined to be 3.99, 4.50, 27.6, 59.2 and 192ng/L in the bottled, well, barreled, direct drinking and tap waters, respectively. Triethyl phosphate (TEP) was the most abundant OPE in the tap water and filtered drinking water with median concentrations of 50.2 and 30.2ng/L, respectively. The mixture of tri(chloropropyl) phosphate (TCPP) and tri(chloroisopropyl) phosphate (TCIPP), named here as TCPP, dominated in the barreled and well water with median concentrations of 8.04 and 2.49ng/L, respectively. The calculated average daily doses of OPEs ranged from 0.14 to 7.07ng/kgbw/day for people consuming the five different types of drinking water. Among the drinking water, the tap water exhibited the highest exposure doses of OPEs. The calculated non-cancer hazard quotients (10(-4)-10(-7)) from OPEs were much lower than the theoretical threshold of risk. The carcinogenic risks posed by TCEP were very low (<10(-7)) for all types of drinking water. The results revealed that there was currently low risk to human health from exposure to OPEs through drinking water in Eastern China.
ESTHER : Ding_2015_Sci.Total.Environ_538_959
PubMedSearch : Ding_2015_Sci.Total.Environ_538_959
PubMedID: 26363608

Title : Expanding the biotechnology potential of lactobacilli through comparative genomics of 213 strains and associated genera - Sun_2015_Nat.Commun_6_8322
Author(s) : Sun Z , Harris HM , McCann A , Guo C , Argimon S , Zhang W , Yang X , Jeffery IB , Cooney JC , Kagawa TF , Liu W , Song Y , Salvetti E , Wrobel A , Rasinkangas P , Parkhill J , Rea MC , O'Sullivan O , Ritari J , Douillard FP , Paul Ross R , Yang R , Briner AE , Felis GE , de Vos WM , Barrangou R , Klaenhammer TR , Caufield PW , Cui Y , Zhang H , O'Toole PW
Ref : Nat Commun , 6 :8322 , 2015
Abstract : Lactobacilli are a diverse group of species that occupy diverse nutrient-rich niches associated with humans, animals, plants and food. They are used widely in biotechnology and food preservation, and are being explored as therapeutics. Exploiting lactobacilli has been complicated by metabolic diversity, unclear species identity and uncertain relationships between them and other commercially important lactic acid bacteria. The capacity for biotransformations catalysed by lactobacilli is an untapped biotechnology resource. Here we report the genome sequences of 213 Lactobacillus strains and associated genera, and their encoded genetic catalogue for modifying carbohydrates and proteins. In addition, we describe broad and diverse presence of novel CRISPR-Cas immune systems in lactobacilli that may be exploited for genome editing. We rationalize the phylogenomic distribution of host interaction factors and bacteriocins that affect their natural and industrial environments, and mechanisms to withstand stress during technological processes. We present a robust phylogenomic framework of existing species and for classifying new species.
ESTHER : Sun_2015_Nat.Commun_6_8322
PubMedSearch : Sun_2015_Nat.Commun_6_8322
PubMedID: 26415554
Gene_locus related to this paper: 9laco-a0a0r1hz65 , 9laco-a0a0r1j1t4 , 9laco-a0a0r1j3p0 , 9laco-a0a0r1k3i0 , 9laco-a0a0r1k563 , 9laco-a0a0r1kgb3 , 9laco-a0a0r1kji2 , 9laco-a0a0r1kwq5 , 9laco-a0a0r1l700 , 9laco-a0a0r1p6l8 , 9laco-a0a0r1q939 , 9laco-a0a0r1qv39 , 9laco-a0a0r1wj75 , laccl-a0a0r2bne3 , 9laco-a0a0r2dnk9 , 9laco-a0a0r2ds70 , 9laco-a0a0r2k127 , 9laco-a0a0r2lee7 , 9laco-a0a0r2lqt2 , 9laco-a0a0r2m354 , 9laco-a0a0r2n9f2 , 9laco-a0a0r2nrk2 , lacze-a0a0r1ekw6 , 9laco-a0a0r1ju11 , 9laco-a0a0r1k516 , 9laco-a0a0r1leq9 , 9laco-a0a0r1lul8 , 9laco-a0a0r1lzg4 , 9laco-a0a0r1mhp8 , 9laco-a0a0r1mjt1 , 9laco-a0a0r1nv21 , 9laco-a0a0r1q1p6 , 9laco-a0a0r1qm41 , 9laco-a0a0r1qs58 , 9laco-a0a0r1rgu0 , 9laco-a0a0r1tg12 , 9laco-a0a0r1u777 , 9laco-a0a0r1ufv3 , 9laco-a0a0r1ul77 , 9laco-a0a0r1vad0 , 9laco-a0a0r1w3f4 , 9laco-a0a0r1w9r8 , 9laco-a0a0r1wpq2 , 9laco-a0a0r1x2g3 , 9laco-a0a0r2abe6 , 9laco-a0a0r2b6w1 , 9laco-a0a0r2b8g1 , 9laco-a0a0r2ch10 , 9laco-a0a0r2cld6 , 9laco-a0a0r2cv38 , 9laco-a0a0r2d3x3 , 9laco-a0a0r2dct2 , 9laco-a0a0r2flt3 , 9laco-a0a0r2frk5 , 9laco-a0a0r2guq4 , 9firm-a0a0r2h5m0 , weivi-a0a0r2h8r4 , 9lact-a0a0r2hnx4 , 9lact-a0a0r2jkt6 , 9lact-a0a0r2jmz1 , 9laco-a0a0r2jwg5 , 9laco-a0a0r2jxu0 , 9laco-a0a0r2jxw0 , lacam-a0a0r2kgt3 , 9laco-a0a0r2kx86 , 9laco-a0a0r2mxi6 , 9laco-a0a0r1vln2 , 9laco-a0a0r2ca25 , 9laco-a0a0r1zjs2 , weipa-c5rbw8

Title : The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1 - Liu_2015_Oncotarget_6_8851
Author(s) : Liu W , Yue F , Zheng M , Merlot A , Bae DH , Huang M , Lane D , Jansson P , Lui GY , Richardson V , Sahni S , Kalinowski D , Kovacevic Z , Richardson DR
Ref : Oncotarget , 6 :8851 , 2015
Abstract : N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.
ESTHER : Liu_2015_Oncotarget_6_8851
PubMedSearch : Liu_2015_Oncotarget_6_8851
PubMedID: 25860930

Title : Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt\/mTOR\/HIF-1alpha\/Stra13 pathway - Chen_2015_Xenobiotica_45_782
Author(s) : Chen R , Wang Y , Ning R , Hu J , Liu W , Xiong J , Wu L , Liu J , Hu G , Yang J
Ref : Xenobiotica , 45 :782 , 2015
Abstract : 1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1alpha/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1alpha or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1alpha/Stra13 (DEC1) pathway.
ESTHER : Chen_2015_Xenobiotica_45_782
PubMedSearch : Chen_2015_Xenobiotica_45_782
PubMedID: 25801056

Title : Genome sequence of cultivated Upland cotton (Gossypium hirsutum TM-1) provides insights into genome evolution - Li_2015_Nat.Biotechnol_33_524
Author(s) : Li F , Fan G , Lu C , Xiao G , Zou C , Kohel RJ , Ma Z , Shang H , Ma X , Wu J , Liang X , Huang G , Percy RG , Liu K , Yang W , Chen W , Du X , Shi C , Yuan Y , Ye W , Liu X , Zhang X , Liu W , Wei H , Wei S , Zhu S , Zhang H , Sun F , Wang X , Liang J , Wang J , He Q , Huang L , Cui J , Song G , Wang K , Xu X , Yu JZ , Zhu Y , Yu S
Ref : Nat Biotechnol , 33 :524 , 2015
Abstract : Gossypium hirsutum has proven difficult to sequence owing to its complex allotetraploid (AtDt) genome. Here we produce a draft genome using 181-fold paired-end sequences assisted by fivefold BAC-to-BAC sequences and a high-resolution genetic map. In our assembly 88.5% of the 2,173-Mb scaffolds, which cover 89.6% approximately 96.7% of the AtDt genome, are anchored and oriented to 26 pseudochromosomes. Comparison of this G. hirsutum AtDt genome with the already sequenced diploid Gossypium arboreum (AA) and Gossypium raimondii (DD) genomes revealed conserved gene order. Repeated sequences account for 67.2% of the AtDt genome, and transposable elements (TEs) originating from Dt seem more active than from At. Reduction in the AtDt genome size occurred after allopolyploidization. The A or At genome may have undergone positive selection for fiber traits. Concerted evolution of different regulatory mechanisms for Cellulose synthase (CesA) and 1-Aminocyclopropane-1-carboxylic acid oxidase1 and 3 (ACO1,3) may be important for enhanced fiber production in G. hirsutum.
ESTHER : Li_2015_Nat.Biotechnol_33_524
PubMedSearch : Li_2015_Nat.Biotechnol_33_524
PubMedID: 25893780
Gene_locus related to this paper: gosra-a0a0d2rxs2 , gosra-a0a0d2tng2 , gosra-a0a0d2twz7 , goshi-a0a1u8hr03 , gosra-a0a0d2vdc5 , goshi-a0a1u8ljh5 , gosra-a0a0d2vj24 , goshi-a0a1u8pxd3 , gosra-a0a0d2sr31 , goshi-a0a1u8knd1 , goshi-a0a1u8nhw9 , goshi-a0a1u8mt09 , goshi-a0a1u8kis4 , goshi-a0a1u8ibk3 , goshi-a0a1u8ieg2 , goshi-a0a1u8iki6 , goshi-a0a1u8jvp4 , goshi-a0a1u8jw35 , gosra-a0a0d2pzd7 , goshi-a0a1u8ied7

Title : Design, synthesis and preliminary structure-activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives - Liu_2015_J.Enzyme.Inhib.Med.Chem__1
Author(s) : Liu H , Fan H , Gao X , Huang X , Liu X , Liu L , Zhou C , Tang J , Wang Q , Liu W
Ref : J Enzyme Inhib Med Chem , :1 , 2015
Abstract : In order to study the structure-activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4 a-8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC50 value: 0.85 mumol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.
ESTHER : Liu_2015_J.Enzyme.Inhib.Med.Chem__1
PubMedSearch : Liu_2015_J.Enzyme.Inhib.Med.Chem__1
PubMedID: 26186269

Title : Paper-based chromatographic chemiluminescence chip for the detection of dichlorvos in vegetables - Liu_2014_Biosens.Bioelectron_52_76
Author(s) : Liu W , Kou J , Xing H , Li B
Ref : Biosensors & Bioelectronics , 52 :76 , 2014
Abstract : Paper chromatography was a big breakthrough in the early of 20th century but it is rarely used due to the long separation time and the diffusion on the sample spots. In this work, for the first time, a paper-based chemiluminescence (CL) analytical device combined with paper chromatography was developed for the determination of dichlorvos (DDV) in vegetables without complicated sample pretreatment. The paper chromatography separation procedure can be accomplished in 12 min on a paper support (0.8 x 7.0 cm(2)) by using 5 microL sample spotted on it. After sample developing, the detection area (0.8 x 1.0 cm(2)) was cut and inserted between two layers of water-impermeable single-sided adhesive tapes. The paper-based chip was made by attaching the middle layer of paper onto the bottom layer. Then it was covered by another tape layer, which was patterned by the cutting method to form a square hole (0.8 x 1.0 cm(2)) in it. 10 muL mixed solution of luminol and H2O2 was dropped on the detection area to produce CL. A linear relationship was obtained between the CL intensity and the concentrations of DDV in the range between 10.0 ng mL(-1) and 1.0 mug mL(-1)and the detection limit was 3.6 ng mL(-1). Water-soluble metal ions and vitamins can be developed at different spatial locations relative to DDV, eliminating interference with DDV during detection. The paper-based chromatographic chip can be successfully used for the determination of DDV without complicated sample preparation in vegetables. This study should, therefore, be suitable for rapid and sensitive detection of trace levels of organophosphate pesticides in environmental and food samples.
ESTHER : Liu_2014_Biosens.Bioelectron_52_76
PubMedSearch : Liu_2014_Biosens.Bioelectron_52_76
PubMedID: 24021659

Title : Rapid and sensitive detection of the inhibitive activities of acetyl- and butyryl-cholinesterases inhibitors by UPLC-ESI-MS\/MS - Liu_2014_J.Pharm.Biomed.Anal_94_215
Author(s) : Liu W , Yang Y , Cheng X , Gong C , Li S , He D , Yang L , Wang Z , Wang C
Ref : J Pharm Biomed Anal , 94 :215 , 2014
Abstract : Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are legitimate therapeutic targets for Alzheimer's disease. The classical approach for screening potential AChE/BChE inhibitors was developed by Ellman. However, the background color of compounds or plant extracts remained uncertain and frequently interfered with the detection of the secondary reaction, thereby easily yielding false positive or false negative results. Rapid, selective, and sensitive ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry method was developed and used for the detection of AChE and BChE inhibition by directly determining the common product, choline (Ch). Proper separation was achieved for choline and chlormequat (internal standard) within 1.2min via isocratic elution (0.1% fromic acid:methanol=98:2) on an HSS T3 column following a simple precipitation of proteins for sample treatment. The relative standard deviations of the intra- and inter-day precisions were below 7.34 and 9.09%, respectively, whereas the mean accuracy for the quality control samples was 100.31+/-10.93%. The method exhibited the advantages of small total reaction volume (100muL), short analysis time (1.2min), high sensitivity (LOQ of 0.036muM for Ch), and low cost (little consumption enzymes of 0.0035 and 0.008unitmL(-1) for AChE and BChE, and substrates of 5.505 and 7.152muM for ACh and BCh in individual inhibition, respectively), and without matrix effect (90.00-105.03%). The developed method was successfully applied for detecting the AChE and BChE inhibitive activities for model drugs, including galanthamine, tacrine, neostigmine methylsulfate, eserine, as well as beta-carboline and quinazoline alkaloids from Peganum harmala.
ESTHER : Liu_2014_J.Pharm.Biomed.Anal_94_215
PubMedSearch : Liu_2014_J.Pharm.Biomed.Anal_94_215
PubMedID: 24631841

Title : Potential mechanisms of neurobehavioral disturbances in mice caused by sub-chronic exposure to low-dose VOCs - Wang_2014_Inhal.Toxicol_26_250
Author(s) : Wang F , Li C , Liu W , Jin Y
Ref : Inhal Toxicol , 26 :250 , 2014
Abstract : Abstract To investigate effects of neurobehavioral disturbances in mice caused by sub-chronic exposure to low-dose volatile organic compounds (VOCs) and the possible mechanism for these effects, 60 male Kunming mice were exposed in 5 similar static chambers, 0 (control) and 4 different doses of VOCs mixture (G1-4) for consecutively 90 d at 2 h/d. The concentrations of VOCs mixture were as follows: formaldehyde, benzene, toluene, and xylene 0.05 + 0.05 + 0.10 + 0.10 mg/m(3), 0.10 + 0.11 + 0.20 + 0.20 mg/m(3), 0.50 + 0.55 + 1.00 + 1.00 mg/m(3), 1.00 +1.10 + 2.00 + 2.00 mg/m(3), respectively, which corresponded to 1/2, 1, 5, and 10 times of indoor air quality standard in China. Morris water maze (MWM) and Grip strength (GS) test were performed in the last 7 weeks. One day following VOCs exposure, oxidative stress markers, neurotransmitters, and cholinergic system enzymes in brain were examined. In addition, the expressions of N-methyl-d-aspartate (NMDA) receptor in hippocampus were determined. VOCs exposure induced behavioral impairment of mice in MWM and GS test. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and glutamic acid (Glu) were significantly increased, while the acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and acetylcholine (ACh) levels, and the expression of NMDA receptor were significantly decreased in VOCs exposed groups. Results showed that sub-chronic exposure to low-dose VOCs induced damage on physique and motor function, as well as impairment on learning and memory capacity of mice. Oxidative damage, abnormal metabolism of neurotransmitters and cholinergic system enzymes, and the alternation of NMDA receptor expression may be the possible mechanism for VOCs-induced neurotoxicity.
ESTHER : Wang_2014_Inhal.Toxicol_26_250
PubMedSearch : Wang_2014_Inhal.Toxicol_26_250
PubMedID: 24568580

Title : Dynamics of uptake and elimination of pyrethroid insecticides in zebrafish (Danio rerio) eleutheroembryos - Tu_2014_Ecotoxicol.Environ.Saf_107_186
Author(s) : Tu W , Lu B , Niu L , Xu C , Lin C , Liu W
Ref : Ecotoxicology & Environmental Safety , 107 :186 , 2014
Abstract : Synthetic pyrethroids (SPs) are among the most heavily used insecticides for residential and agricultural applications. Their residues have frequently been detected in aquatic ecosystems. Despite their high aquatic toxicity, their toxicokinetics are still unclear. In this study, the kinetics of uptake and depuration of three SPs, permethrin (PM), bifenthrin (BF) and lambda-cyhalothrin (lambda-CH), were determined for the first time using zebrafish eleutheroembryo assays. The diastereoisomer selectivity of PM in eleutheroembryos was further examined. The results indicated that three SPs were quickly taken up by eleutheroembryos. The bioaccumulation factors of the SPs ranged from 125.4 to 708.4. The depuration of SPs in zebrafish eleutheroembryos followed the first-order process. The elimination rate constants (k2) of SPs in eleutheroembryos ranged from 0.018 h(-1) to 0.0533 h(-1). The half-lives (t1/2) were in the range 13.0-38.5h. The diastereoisomer fraction (DF) values for PM in the eleutheroembryos estimated at different uptake and depuration times were all significantly greater than the original value (DF=0.43), indicating selective enrichment and elimination of cis-PM relative to trans-PM. These results reveal a high capacity for SP bioconcentration by zebrafish eleutheroembryos, suggesting that SPs possess a highly cumulative risk to fish.
ESTHER : Tu_2014_Ecotoxicol.Environ.Saf_107_186
PubMedSearch : Tu_2014_Ecotoxicol.Environ.Saf_107_186
PubMedID: 24952374

Title : Operon for biosynthesis of lipstatin, the Beta-lactone inhibitor of human pancreatic lipase - Bai_2014_Appl.Environ.Microbiol_80_7473
Author(s) : Bai T , Zhang D , Lin S , Long Q , Wang Y , Ou H , Kang Q , Deng Z , Liu W , Tao M
Ref : Applied Environmental Microbiology , 80 :7473 , 2014
Abstract : Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-beta-lactone structure with an N-formyl-l-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the alpha-branched 3,5-dihydroxy fatty acid beta-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two beta-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the alpha-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the alpha-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3beta-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the beta-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique beta-lactone ring.
ESTHER : Bai_2014_Appl.Environ.Microbiol_80_7473
PubMedSearch : Bai_2014_Appl.Environ.Microbiol_80_7473
PubMedID: 25239907

Title : Glucose dominates the regulation of carboxylesterases induced by lipopolysaccharide or interleukin-6 in primary mouse hepatocytes - Xiong_2014_Life.Sci_112_41
Author(s) : Xiong J , Shang W , Wu L , Chen R , Liu W , Ning R , Hu G , Yang J
Ref : Life Sciences , 112 :41 , 2014
Abstract : AIMS: Altered drug disposition has been associated with inflammation and diabetes, leading to the alteration of drug efficacy and toxicity. Carboxylesterases are major hydrolytic enzymes in the liver, catalyzing the hydrolytic biotransformation of numerous therapeutic agents. Therefore, how glucose affects the regulation of carboxylesterases by interleukin-6 (IL-6) and lipopolysaccharide (LPS) were investigated. MAIN
METHODS: Primary mouse hepatocytes were cultured. Protein levels were measured by Western blot or enzyme linked immunosorbent assay (ELISA), while confocal laser scanning microscope and flow cytometry were used to confirm the activation of pregnane X receptor (PXR). Carboxylesterase activity was evaluated by enzymatic and toxicological assays. KEY FINDINGS: Elevated glucose (11 or 25mM) significantly increased carboxylesterase expression compared to 5.6mM glucose. Carboxylesterase expression and activity were inhibited by LPS or IL-6 in 25mM glucose, but stimulated in 5.6mM glucose. The altered expression of carboxylesterases was not consistent with the activation of nuclear factor kappa B (NFkappaB) but repeatedly with the expression and activation of pregnane X receptor (PXR). The altered activation of PXR was further evidenced by the differential subcellular translocation and the expression of its target gene multidrug resistance 1 (MDR1). It implies that PXR, instead of inflammatory signaling, mediates the regulation of carboxylesterases by inflammatory mediators in different glucose concentrations. SIGNIFICANCE: The findings contribute to clarify the regulation of carboxylesterases by inflammatory mediators, and indicate that carboxylesterase-involved drug metabolism and drug-drug interactions in diabetes should be reevaluated according to the intensity of inflammatory reactions and hyperglycemia.
ESTHER : Xiong_2014_Life.Sci_112_41
PubMedSearch : Xiong_2014_Life.Sci_112_41
PubMedID: 25066929

Title : Importing, caring, breeding, genotyping, and phenotyping a genetic mouse in a chinese university - Kuo_2014_J.Mol.Neurosci_53_487
Author(s) : Kuo ST , Wu QH , Liu B , Xie ZL , Wu X , Shang SJ , Zhang XY , Kang XJ , Liu LN , Zhu FP , Wang YS , Hu MQ , Xu HD , Zhou L , Chai ZY , Zhang QF , Liu W , Teng SS , Wang CH , Guo N , Dou HQ , Zuo PL , Zheng LH , Zhang CX , Zhu DS , Wang L , Wang SR , Zhou Z
Ref : Journal of Molecular Neuroscience , 53 :487 , 2014
Abstract : The genetic manipulation of the laboratory mouse has been well developed and generated more and more mouse lines for biomedical research. To advance our science exploration, it is necessary to share genetically modified mouse lines with collaborators between institutions, even in different countries. The transfer process is complicated. Significant paperwork and coordination are required, concerning animal welfare, intellectual property rights, colony health status, and biohazard. Here, we provide a practical example of importing a transgenic mice line, Dynamin 1 knockout mice, from Yale University in the USA to Perking University in China for studying cell secretion. This example including the length of time that required for paper work, mice quarantine at the receiving institution, and expansion of the mouse line for experiments. The procedure described in this paper for delivery live transgenic mice from USA to China may serve a simple reference for transferring mouse lines between other countries too.
ESTHER : Kuo_2014_J.Mol.Neurosci_53_487
PubMedSearch : Kuo_2014_J.Mol.Neurosci_53_487
PubMedID: 24385195

Title : Effect of Cocaine on Ion Channels and Glutamatergic EPSCs in Noradrenergic Locus Coeruleus Neurons - Liu_2014_J.Mol.Neurosci_53_345
Author(s) : Liu LN , Zhu FP , Song MY , Kang XJ , Shang SJ , Zhang XY , Xu HD , Teng SS , Liu B , Kuo ST , Liu W , Li ML , Zhou L , Jiao RY , Wang CH , Wang SR , Yang H , Zhang B , Zhou Z , Xu ZQ
Ref : Journal of Molecular Neuroscience , 53 :345 , 2014
Abstract : The locus coeruleus (LC) is an important brainstem area involved in cocaine addiction. However, evidence to elucidate how cocaine modulates the activity of LC neurons remains incomplete. Here, we performed whole recordings in brain slices to evaluate the effects of cocaine on the sodium (Na(+)), potassium (K(+)), calcium (Ca(2+)) channels, and glutamatergic synaptic transmission in the locus coeruleus neurons. Local application of cocaine significantly and reversibly reduced the spontaneous firing rate but did not affect action potential amplitude, rising time, decay time, or half width of noradrenergic locus coeruleus neurons. Moreover, cocaine attenuated the sodium current but did not affect potassium and calcium currents. The N-methyl-D-aspartate receptor mediated excitatory postsynaptic currents were reduced by neuropeptide galanin but not cocaine. All those data demonstrate that cocaine has inhibitory effect on the spontaneous activities and sodium current in locus coeruleus neurons. Therefore, neuromodulation of sodium channel in locus coeruleus neurons may play an important role in drug addiction.
ESTHER : Liu_2014_J.Mol.Neurosci_53_345
PubMedSearch : Liu_2014_J.Mol.Neurosci_53_345
PubMedID: 24214104

Title : Enantioselective Interaction of Acid alpha-Naphthyl Acetate Esterase with Chiral Organophosphorus Insecticides - Zhang_2014_J.Agric.Food.Chem_62_1477
Author(s) : Zhang A , Sun J , Lin C , Hu X , Liu W
Ref : Journal of Agricultural and Food Chemistry , 62 :1477 , 2014
Abstract : Many previous works have demonstrated that acetylcholinesterase (AChE) was enantioselectively inhibited by chiral organophosphorus insecticides (OPs) and that a significant difference in reactivation existed for AChE inactivated by (1R)- versus (1S,3S)-stereoisomers of isomalathion. It had been known that alpha-naphthyl acetate esterase (ANAE), an enzyme which might play an essential role in the growth of plants and the defense of plants against environmental stress by regulating the concentration of hormones in plants, can be inhibited by OPs. However, it was unknown whether interaction of ANAE with chiral OPs was enantioselective. The present work investigated the inhibition kinetics and spontaneous reactivation of ANAE inactivated by enantiomers of malaoxon, isomalathion, and methamidophos. The order of inhibition potency is (R) > (S) for malaoxon, (1R,3R) > (1R,3S) > (1S,3R) > (1S,3S) for isomalathion, and (S) > (R) for methamidophos according to bimolecular rate constants of inhibition (ki), which is consistent with the order observed in the enantioselective inhibition of AChE by malaoxon, isomalathion, and methamidophos. The difference in spontaneous reactivation of AChE inactivated between (1R)- and (1S,3S)-isomers of isomalathion is conserved for ANAE. The observations indicated ANAE and AChE have similar selective inhibition kinetics and postinhibitory reactions in reaction with chiral OPs.
ESTHER : Zhang_2014_J.Agric.Food.Chem_62_1477
PubMedSearch : Zhang_2014_J.Agric.Food.Chem_62_1477
PubMedID: 24475784

Title : The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of beta-catenin through mechanisms involving FRAT1 and PAK4 - Jin_2014_J.Cell.Sci_127_3116
Author(s) : Jin R , Liu W , Menezes S , Yue F , Zheng M , Kovacevic Z , Richardson DR
Ref : Journal of Cell Science , 127 :3116 , 2014
Abstract : N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor beta (TGF-beta)-induced epithelial-to-mesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and beta-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of beta-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated beta-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting beta-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3beta-binding protein FRAT1, which prevents the association of GSK3beta with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of beta-catenin. Additionally, NDRG1 is shown to modulate the WNT-beta-catenin pathway by inhibiting the nuclear translocation of beta-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for beta-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of beta-catenin phosphorylation and distribution.
ESTHER : Jin_2014_J.Cell.Sci_127_3116
PubMedSearch : Jin_2014_J.Cell.Sci_127_3116
PubMedID: 24829151

Title : An acetylcholinesterase antibody-based quartz crystal microbalance for the rapid identification of spinal ventral and dorsal roots - Sui_2013_PLoS.One_8_e69049
Author(s) : Sui T , Ge Y , Liu W , Zhao ZK , Zhang N , Cao X
Ref : PLoS ONE , 8 :e69049 , 2013
Abstract : Differences in the levels of acetylcholinesterase (AChE) in ventral and dorsal spinal roots can be used to differentiate the spinal nerves. Although many methods are available to assay AChE, a rapid and sensitive method has not been previously developed. Here, we describe an antibody-based quartz crystal microbalance (QCM) assay and its application for the quantification of AChE in the solutions of ventral and dorsal spinal roots. The frequency variation of the QCM device corresponds to the level of AChE over a wide dynamic range (0.5-10 microg/ml), which is comparable to the response range of the ELISA method. The frequency shift caused by the ventral roots is 3-fold greater than that caused by the dorsal roots. The antibody-based QCM sensor was stable across many successive replicate samples, and the method required less than 10 min, including the AChE extraction and analysis steps. This method is a rapid and convenient means for the quantification of AChE in biological samples and may be applicable for distinguishing the ventral and dorsal roots during surgical operations.
ESTHER : Sui_2013_PLoS.One_8_e69049
PubMedSearch : Sui_2013_PLoS.One_8_e69049
PubMedID: 23935920

Title : Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors - Debenham_2013_Bioorg.Med.Chem.Lett_23_6228
Author(s) : Debenham JS , Graham TH , Verras A , Zhang Y , Clements MJ , Kuethe JT , Madsen-Duggan C , Liu W , Bhatt UR , Chen D , Chen Q , Garcia-Calvo M , Geissler WM , He H , Li X , Lisnock J , Shen Z , Tong X , Tung EC , Wiltsie J , Xu S , Hale JJ , Pinto S , Shen DM
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :6228 , 2013
Abstract : The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
ESTHER : Debenham_2013_Bioorg.Med.Chem.Lett_23_6228
PubMedSearch : Debenham_2013_Bioorg.Med.Chem.Lett_23_6228
PubMedID: 24157366

Title : Development and validation of a simple assay for the determination of cholinesterase activity in whole blood of laboratory animals - Naik_2013_J.Appl.Toxicol_33_290
Author(s) : Naik RS , Liu W , Saxena A
Ref : Journal of Applied Toxicology , 33 :290 , 2013
Abstract : Current methods for measuring acetylcholinesterase (AChE) activities in whole blood use butyrylcholinesterase (BChE)-selective inhibitors. However, the poor selectivity of these inhibitors results in the inhibition of AChE activity to some degree, leading to errors in reported values. The goal of this study was to develop and validate a simple assay for measuring AChE and BChE activities in whole blood from humans as well as experimental animals. Blood was fractionated into plasma and erythrocytes, and cholinesterase activities were titrated against ethopropazine and (-)-huperzine A to determine the lowest concentration of ethopropazine that inhibited BChE completely without affecting AChE activity and the lowest concentration of (-)-huperzine A that inhibited AChE completely without interfering with BChE activity. Results indicate that 20 microm ethopropazine can be successfully used for the accurate measurement of AChE activity in blood from humans as well as animals. Use of (-)-huperzine A is not required for measuring BChE activity in normal or 'exposed' blood samples. The method was validated for blood from several animal species, including mice, rats, guinea pigs, dogs, minipigs, and African green, cynomolgus and rhesus monkeys. This method is superior to all reported methods, does not require the separation of erythrocyte and plasma fractions, and is suitable for measuring cholinesterase activities in fresh or frozen blood from animals that were exposed to nerve agents or those that were administered high doses of BChE. The method is simple, direct, reproducible, and reliable and can easily be adapted for high-throughput screening of blood samples. Published 2012. This article is a US Government work and is in the public domain in the USA.
ESTHER : Naik_2013_J.Appl.Toxicol_33_290
PubMedSearch : Naik_2013_J.Appl.Toxicol_33_290
PubMedID: 22407886

Title : Lack of Association between NLGN3, NLGN4, SHANK2 and SHANK3 Gene Variants and Autism Spectrum Disorder in a Chinese Population - Liu_2013_PLoS.One_8_e56639
Author(s) : Liu Y , Du Y , Liu W , Yang C , Wang H , Gong X
Ref : PLoS ONE , 8 :e56639 , 2013
Abstract : Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, absence or delay in language development, and stereotyped or repetitive behaviors. Genetic studies show that neurexin-neuroligin (NRXN-NLGN) pathway genes contribute susceptibility to ASD, which include cell adhesion molecules , and scaffolding proteins and . Neuroligin proteins play an important role in synaptic function and trans-synaptic signaling by interacting with presynaptic neurexins. Shank proteins are scaffolding molecules of excitatory synapses, which function as central organizers of the postsynaptic density. Sequence level mutations and structural variations in these genes have been identified in ASD cases, while few studies were performed in Chinese population. In this study, we examined the copy numbers of four genes and in 285 ASD cases using multiplex fluorescence competitive polymerase chain reaction (PCR). We also screened the regulatory region including the promoter region and 5'/3' untranslated regions (UTR) and the entire coding region of in a cohort of 285 ASD patients and 384 controls by direct sequencing of genomic DNA using the Sanger method. DNA copy number calculation in four genes showed no deletion or duplication in our cases. No missense mutations in were identified in our cohort. Association analysis of 6 common SNPs in did not find significant difference between ASD cases and controls. These findings showed that these genes may not be major disease genes in Chinese ASD cases.
ESTHER : Liu_2013_PLoS.One_8_e56639
PubMedSearch : Liu_2013_PLoS.One_8_e56639
PubMedID: 23468870

Title : Hyperthermia-induced NDRG2 upregulation inhibits the invasion of human hepatocellular carcinoma via suppressing ERK1\/2 signaling pathway - Guo_2013_PLoS.One_8_e61079
Author(s) : Guo Y , Ma J , Wu L , Wang Q , Li X , Zhang Y , Zhang J , Yao L , Liu W
Ref : PLoS ONE , 8 :e61079 , 2013
Abstract : Hyperthermia (HT) has been proven to be able to alter the invasion capacity of cancer cells. However, the detailed mechanisms responsible for the anti-metastasis effects of HT have not been elucidated. N-myc downstream-regulated gene 2 (NDRG2), as a member of the NDRG family, has been suggested to be highly responsive to various stresses and is associated with tumor suppression. The present study aimed to investigate the biological role of NDRG2 in the invasion of human hepatocellular carcinoma (HCC) cells exposed to HT. We found that NDRG2 could be induced by HT at 45 degrees C. In addition, NDRG2 overexpression inhibited the expression of matrix metallo proteinases-2 (MMP-2) and MMP-9 as well as the invasion of HCC cells, whereas knockingdown NDRG2 reversed the anti-invasion effect of HT in vivo. Further investigation revealed that the phosphorylation level of ERK1/2, but not that of JNK and p38MAPK, was reduced in NDRG2 overexpressing cells. Moreover, the knockdown of NDRG2 expression resulted in increased cell invasion, which was rescued by treating the HepG2 cells with the ERK1/2 inhibitor PD98059, but not with the p38MAPK inhibitor SB203580 or the JNK inhibitor SP600125. Finally, the synergistic cooperation of HT at 43 degrees C and NDRG2 expression effectively reduced cytotoxicity and promoted the anti-invasion effect of HT at 45 degrees C. Taken together, these data suggest that NDRG2 can be induced by HT and that it mediates the HT-caused inhibition of invasion in HCC cells by suppressing the ERK1/2 signaling pathway. The combined application of constitutive NDRG2 expression with HT may yield an optimized therapeutic benefit.
ESTHER : Guo_2013_PLoS.One_8_e61079
PubMedSearch : Guo_2013_PLoS.One_8_e61079
PubMedID: 23630579

Title : Lipase-catalyzed synthesis and characterization of polymers by cyclodextrin as support architecture - Liu_2013_Carbohydr.Polym_92_633
Author(s) : Liu W , Wang F , Tan T , Chen B
Ref : Carbohydr Polym , 92 :633 , 2013
Abstract : Diesters and diols were successfully converted into aliphatic polyesters by enzymatic lipase Candida sp.99-125 catalysis, with beta-cyclodextrin acting as supporting architecture (in a similar way as chaperone proteins). No organic solvents were used. The polytransesterification was a much greener process, being solvent-free and without metal residues. Lipase Candida sp.99-125 showed a high catalytic activity for bulkpolymerization of diesters and diols with various numbers of methylene groups in their chains. beta-Cyclodextrin encircled the linear polymer chain and maintained the chain in a proper configuration to avoid its coagulation. Lipase initiated the polymerization and beta-cyclodextrin threaded onto the polymer chain to control the structure for producing high molecular weight polyesters. From a combination of diesters and diols, polyesters with a high molecular weight of 62,100Da were obtained at 70 degrees C. The corresponding polyesters showed an excellent thermal stability till 350 degrees C and had a strong ability to crystallize with up to 72% crystallinity, contributing to their high storage modulus.
ESTHER : Liu_2013_Carbohydr.Polym_92_633
PubMedSearch : Liu_2013_Carbohydr.Polym_92_633
PubMedID: 23218346

Title : Distinct molecular targets including SLO-1 and gap junctions are engaged across a continuum of ethanol concentrations in Caenorhabditis elegans - Dillon_2013_FASEB.J_27_4266
Author(s) : Dillon J , Andrianakis I , Mould R , Ient B , Liu W , James C , O'Connor V , Holden-Dye L
Ref : FASEB Journal , 27 :4266 , 2013
Abstract : Ethanol (alcohol) interacts with diverse molecular effectors across a range of concentrations in the brain, eliciting intoxication through to sedation. Invertebrate models including the nematode worm Caenorhabditis elegans have been deployed for molecular genetic studies to inform on key components of these alcohol signaling pathways. C. elegans studies have typically employed external dosing with high (>250 mM) ethanol concentrations: A careful analysis of responses to low concentrations is lacking. Using the C. elegans pharyngeal system as a paradigm, we report a previously uncharacterized continuum of cellular and behavioral responses to ethanol from low (10 mM) to high (300 mM) concentrations. The complexity of these responses indicates that the pleiotropic action of ethanol observed in mammalian brain is conserved in this invertebrate model. We investigated two candidate ethanol effectors, the calcium-activated K(+) channel SLO-1 and gap junctions, and show that they contribute to, but are not sole determinants of, the low- and high-concentration effects, respectively. Notably, this study shows cellular and whole organismal behavioral responses to ethanol in C. elegans that directly equate to intoxicating through to supralethal blood alcohol concentrations in humans and provides an important benchmark for interpretation of paradigms that seek to inform on human alcohol use disorders.
ESTHER : Dillon_2013_FASEB.J_27_4266
PubMedSearch : Dillon_2013_FASEB.J_27_4266
PubMedID: 23882127

Title : Preparation and in vitro and in vivo evaluation of HupA PLGA Microsphere - Ye_2013_Pak.J.Pharm.Sci_26_315
Author(s) : Ye L , Fu F , Liu W , Sun K , Li Y , He J , Yu X , Yu P , Tian J
Ref : Pak J Pharm Sci , 26 :315 , 2013
Abstract : Acetylcholinesterase inhibitors (AChEIs), including Huperzine A (HupA), have been the mainstay of treatment for Alzheimer's disease (AD). However, AChEIs can cause gastrointestinal side effects, which has been related to the high C and short tmax after oral administration. Clinical trials have verified that extended-release formulation with lower C and prolonged tmax, such as rivastigmine patch, could perform a similar efficacy with significantly improved tolerability compared with the oral formulations. In this study, we developed an extended-release microspheres formulation of HupA (called as HAM) with poly(lactide-co-glycolide) (PLGA) as drug carrier. HAM has showed the loading rate as 1.35% (w/w) and yielded 42% with mean particle size at 72.6 mum. In vitro and in vivo pharmacokinetics studies have showed that HAM produced a relatively smooth and continuous drug concentration in 14 days. Furthermore, in vivo pharmacokinetics data have demonstrated that the C was lower and the tmax was considerably later in single intramuscular administration of HAM (1,000 mug/kg) than the counterparts in single intragastric administration of HAT (75 mug/kg/d). Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in Abeta i.c.v. infused AD rat model for 14 days. The results have suggested that HAM has performed good extended-release properties and good prolonged pharmacological efficacy in vivo in the 2-week period, and could exert a similar efficacy with significantly lowered gastrointestinal side effects as compared with oral formulation.
ESTHER : Ye_2013_Pak.J.Pharm.Sci_26_315
PubMedSearch : Ye_2013_Pak.J.Pharm.Sci_26_315
PubMedID: 23455202

Title : Genome sequence of the date palm Phoenix dactylifera L - Al-Mssallem_2013_Nat.Commun_4_2274
Author(s) : Al-Mssallem IS , Hu S , Zhang X , Lin Q , Liu W , Tan J , Yu X , Liu J , Pan L , Zhang T , Yin Y , Xin C , Wu H , Zhang G , Ba Abdullah MM , Huang D , Fang Y , Alnakhli YO , Jia S , Yin A , Alhuzimi EM , Alsaihati BA , Al-Owayyed SA , Zhao D , Zhang S , Al-Otaibi NA , Sun G , Majrashi MA , Li F , Tala , Wang J , Yun Q , Alnassar NA , Wang L , Yang M , Al-Jelaify RF , Liu K , Gao S , Chen K , Alkhaldi SR , Liu G , Zhang M , Guo H , Yu J
Ref : Nat Commun , 4 :2274 , 2013
Abstract : Date palm (Phoenix dactylifera L.) is a cultivated woody plant species with agricultural and economic importance. Here we report a genome assembly for an elite variety (Khalas), which is 605.4 Mb in size and covers >90% of the genome (~671 Mb) and >96% of its genes (~41,660 genes). Genomic sequence analysis demonstrates that P. dactylifera experienced a clear genome-wide duplication after either ancient whole genome duplications or massive segmental duplications. Genetic diversity analysis indicates that its stress resistance and sugar metabolism-related genes tend to be enriched in the chromosomal regions where the density of single-nucleotide polymorphisms is relatively low. Using transcriptomic data, we also illustrate the date palm's unique sugar metabolism that underlies fruit development and ripening. Our large-scale genomic and transcriptomic data pave the way for further genomic studies not only on P. dactylifera but also other Arecaceae plants.
ESTHER : Al-Mssallem_2013_Nat.Commun_4_2274
PubMedSearch : Al-Mssallem_2013_Nat.Commun_4_2274
PubMedID: 23917264
Gene_locus related to this paper: phodc-a0a2h3y3d5 , phodc-a0a2h3z529 , phodc-a0a2h3y147 , phodc-a0a2h3xrz4 , phodc-a0a3q0ic37 , phodc-a0a2h3yxf0 , phodc-a0a2h3zh01 , phodc-a0a3q0hs32

Title : Quartromicin biosynthesis: two alternative polyketide chains produced by one polyketide synthase assembly line - He_2012_Chem.Biol_19_1313
Author(s) : He HY , Pan HX , Wu LF , Zhang BB , Chai HB , Liu W , Tang GL
Ref : Chemical Biology , 19 :1313 , 2012
Abstract : The antiviral compounds quartromicins represent unique members of a family of spirotetronate natural products. In this study, a biosynthetic gene cluster of quartromicins was identified by degenerate primer PCR amplification of specific genes involved in the biosynthesis of the tetronate moiety. The biochemical results confirmed that 1,3-bisphosphoglycerate was incorporated into the tetronate ring, and the intermediates of this ring were also reconstructed in vitro. The data also suggested a module skipping strategy for the production of two alternative polyketide chains by the same polyketide synthase assembly line. These findings set the stage for further investigations of the stereodivergent intermolecular cyclization mechanism, and highlight how nature has constructed this type of C2 symmetric molecule through intermolecular dimerization.
ESTHER : He_2012_Chem.Biol_19_1313
PubMedSearch : He_2012_Chem.Biol_19_1313
PubMedID: 23102224
Gene_locus related to this paper: strrg-k7qrj3

Title : Insights into pyrroindomycin biosynthesis reveal a uniform paradigm for tetramate\/tetronate formation - Wu_2012_J.Am.Chem.Soc_134_17342
Author(s) : Wu Q , Wu Z , Qu X , Liu W
Ref : Journal of the American Chemical Society , 134 :17342 , 2012
Abstract : The natural products pyrroindomycins (PYRs), active against various drug-resistant pathogens, possess a characteristic, cyclohexene ring spiro-linked tetramate moiety. In this study, investigation into PYR biosynthesis revealed two new proteins, both of which, phylogenetically distinct from but functionally substitutable to each other in vivo, individually catalyze a Dieckmann cyclization in vitro for converting an N-acetoacetyl-l-alanyl thioester into a tetramate. Their counterparts are commonly present in the biosynthetic pathways of spiro and polyether tetronates, supporting a uniform paradigm for tetronate/tetramate formation, which features an enzymatic way to generate the C-X (X = O or N) bond first and the C-C bond next in building of the 5-membered heterocycle.
ESTHER : Wu_2012_J.Am.Chem.Soc_134_17342
PubMedSearch : Wu_2012_J.Am.Chem.Soc_134_17342
PubMedID: 23062149
Gene_locus related to this paper: strrg-k7qrj3

Title : Complete genome sequence of Brucella melitensis biovar 3 strain NI, isolated from an aborted bovine fetus - Liu_2012_J.Bacteriol_194_6321
Author(s) : Liu W , Jing Z , Ou Q , Cui B , He Y , Wu Q
Ref : Journal of Bacteriology , 194 :6321 , 2012
Abstract : From an aborted bovine fetus in China, a bacterial strain named NI was isolated and identified as Brucella melitensis by a PCR assay. Strain NI was further characterized as B. melitensis biovar 3 using biochemical assays. Here we report the complete genome sequence of strain NI.
ESTHER : Liu_2012_J.Bacteriol_194_6321
PubMedSearch : Liu_2012_J.Bacteriol_194_6321
PubMedID: 23105063
Gene_locus related to this paper: brume-PCAD

Title : The discovery of non-benzimidazole and brain-penetrant prolylcarboxypeptidase inhibitors - Graham_2012_Bioorg.Med.Chem.Lett_22_658
Author(s) : Graham TH , Shen HC , Liu W , Xiong Y , Verras A , Bleasby K , Bhatt UR , Chabin RM , Chen D , Chen Q , Garcia-Calvo M , Geissler WM , He H , Lassman ME , Shen Z , Tong X , Tung EC , Xie D , Xu S , Colletti SL , Tata JR , Hale JJ , Pinto S , Shen DM
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :658 , 2012
Abstract : Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were also cell permeable and demonstrated in vivo brain exposure. The in vivo effect of compound (S)-6e on weight loss in an established diet-induced obesity (eDIO) mouse model was studied.
ESTHER : Graham_2012_Bioorg.Med.Chem.Lett_22_658
PubMedSearch : Graham_2012_Bioorg.Med.Chem.Lett_22_658
PubMedID: 22079761
Gene_locus related to this paper: human-PRCP

Title : Huperzine A ameliorates experimental autoimmune encephalomyelitis via the suppression of T cell-mediated neuronal inflammation in mice - Wang_2012_Exp.Neurol_236_79
Author(s) : Wang J , Chen F , Zheng P , Deng W , Yuan J , Peng B , Wang R , Liu W , Zhao H , Wang Y , Wu G
Ref : Experimental Neurology , 236 :79 , 2012
Abstract : Huperzine A (HupA), a sesquiterpene alkaloid and a potent and reversible inhibitor of acetylcholinesterase, possesses potential anti-inflammatory properties and is used for the treatment of certain neurodegenerative diseases such as Alzheimer's disease. However, it is still unknown whether this chemical is beneficial in the treatment of multiple sclerosis, a progressive inflammatory disease of the central nervous system. In this study, we examined the immunomodulatory properties of HupA in experimental autoimmune encephalomyelitis (EAE), a T-cell mediated murine model of multiple sclerosis. The following results were obtained: (1) intraperitoneal injections of HupA significantly attenuate the neurological severity of EAE in mice. (2) HupA decreases the accumulation of inflammatory cells, autoimmune-related demyelination and axonal injury in the spinal cords of EAE mice. (3) HupA down-regulates mRNA levels of the pro-inflammatory cytokines (IFN-gamma and IL-17) and chemokines (MCP-1, RANTES, and TWEAK) while enhancing levels of anti-inflammatory cytokines (IL-4 and IL-10) in the spinal cords of EAE mice. (4) HupA inhibits MOG(35-55) stimulation-induced T-cell proliferation and IFN-gamma and IL-17 secretion in cultured splenocytes. (5) HupA inhibition of T-cell proliferation is reversed by the nicotinic acetylcholinergic receptor antagonist mecamylamine. We conclude that HupA can ameliorate EAE by suppressing autoimmune responses, inflammatory reactions, subsequent demyelination and axonal injury in the spinal cord. Therefore, HupA may have a potential therapeutic value for the treatment of multiple sclerosis and as a neuroimmunomodulatory drug to control human CNS pathology.
ESTHER : Wang_2012_Exp.Neurol_236_79
PubMedSearch : Wang_2012_Exp.Neurol_236_79
PubMedID: 22524989

Title : Solvent-free enzymatic transesterification of ethyl ferulate and monostearin: optimized by response surface methodology - Sun_2012_J.Biotechnol_164_340
Author(s) : Sun S , Song F , Bi Y , Yang G , Liu W
Ref : J Biotechnol , 164 :340 , 2012
Abstract : In this study, enzymatic transesterification of ethyl ferulate (EF) and monostearin for feruloylated lipids production was investigated. Enzyme screening and the effect of feruloyl acceptors on the transesterification were also studied. Effects of reaction variables (reaction temperatures, enzyme load, and reaction time) on the transesterification were optimized using response surface methodology (RSM). The optimum conditions were as follows: reaction temperature 74 degrees C, reaction time 23h, and enzyme load 20% (w/w, relative to the weight of substrates). Under these conditions, EF conversion was 98.3+/-1.1%, and the transesterification product was consisted of 19.2+/-2.1% glyceryl ferulate (FG), 32.9+/-1.9% diferuloylated glycerols (DFG), 36.6+/-2.2% feruloylated monoacylglycerols (FMAG), 9.1+/-2.0% feruloylated diacylglycerols (FDAG), and 0.5% ferulic acid (FA). Analysis of variance (ANOVA) showed that the regression equation was adequate for predicting EF conversion. The activation energies for hydrolysis to form FG+DFG and transesterification to form FMAG+FDAG were calculated as 22.45 and 51.05kJ/mol, respectively, based on Arrhenius law.
ESTHER : Sun_2012_J.Biotechnol_164_340
PubMedSearch : Sun_2012_J.Biotechnol_164_340
PubMedID: 23376620

Title : Genome sequences of wild and domestic bactrian camels - Jirimutu_2012_Nat.Commun_3_1202
Author(s) : Jirimutu , Wang Z , Ding G , Chen G , Sun Y , Sun Z , Zhang H , Wang L , Hasi S , Zhang Y , Li J , Shi Y , Xu Z , He C , Yu S , Li S , Zhang W , Batmunkh M , Ts B , Narenbatu , Unierhu , Bat-Ireedui S , Gao H , Baysgalan B , Li Q , Jia Z , Turigenbayila , Subudenggerile , Narenmanduhu , Wang J , Pan L , Chen Y , Ganerdene Y , Dabxilt , Erdemt , Altansha , Altansukh , Liu T , Cao M , Aruuntsever , Bayart , Hosblig , He F , Zha-ti A , Zheng G , Qiu F , Zhao L , Zhao W , Liu B , Li C , Tang X , Guo C , Liu W , Ming L , Temuulen , Cui A , Li Y , Gao J , Wurentaodi , Niu S , Sun T , Zhai Z , Zhang M , Chen C , Baldan T , Bayaer T , Meng H
Ref : Nat Commun , 3 :1202 , 2012
Abstract : Bactrian camels serve as an important means of transportation in the cold desert regions of China and Mongolia. Here we present a 2.01 Gb draft genome sequence from both a wild and a domestic bactrian camel. We estimate the camel genome to be 2.38 Gb, containing 20,821 protein-coding genes. Our phylogenomics analysis reveals that camels shared common ancestors with other even-toed ungulates about 55-60 million years ago. Rapidly evolving genes in the camel lineage are significantly enriched in metabolic pathways, and these changes may underlie the insulin resistance typically observed in these animals. We estimate the genome-wide heterozygosity rates in both wild and domestic camels to be 1.0 x 10(-3). However, genomic regions with significantly lower heterozygosity are found in the domestic camel, and olfactory receptors are enriched in these regions. Our comparative genomics analyses may also shed light on the genetic basis of the camel's remarkable salt tolerance and unusual immune system.
ESTHER : Jirimutu_2012_Nat.Commun_3_1202
PubMedSearch : Jirimutu_2012_Nat.Commun_3_1202
PubMedID: 23149746
Gene_locus related to this paper: 9ceta-s9yik4 , 9ceta-s9yb99 , 9ceta-s9x0n3 , 9ceta-s9xqa3 , 9ceta-s9xi02 , camfr-s9wiw9 , camfr-s9x3r3 , camfr-s9xce1 , camfr-s9xcr2 , camfr-s9yuz0 , camfr-s9xlc8 , camfr-s9w5f6 , camfr-s9xmm4

Title : The yak genome and adaptation to life at high altitude - Qiu_2012_Nat.Genet_44_946
Author(s) : Qiu Q , Zhang G , Ma T , Qian W , Wang J , Ye Z , Cao C , Hu Q , Kim J , Larkin DM , Auvil L , Capitanu B , Ma J , Lewin HA , Qian X , Lang Y , Zhou R , Wang L , Wang K , Xia J , Liao S , Pan S , Lu X , Hou H , Wang Y , Zang X , Yin Y , Ma H , Zhang J , Wang Z , Zhang Y , Zhang D , Yonezawa T , Hasegawa M , Zhong Y , Liu W , Huang Z , Zhang S , Long R , Yang H , Lenstra JA , Cooper DN , Wu Y , Shi P , Liu J
Ref : Nat Genet , 44 :946 , 2012
Abstract : Domestic yaks (Bos grunniens) provide meat and other necessities for Tibetans living at high altitude on the Qinghai-Tibetan Plateau and in adjacent regions. Comparison between yak and the closely related low-altitude cattle (Bos taurus) is informative in studying animal adaptation to high altitude. Here, we present the draft genome sequence of a female domestic yak generated using Illumina-based technology at 65-fold coverage. Genomic comparisons between yak and cattle identify an expansion in yak of gene families related to sensory perception and energy metabolism, as well as an enrichment of protein domains involved in sensing the extracellular environment and hypoxic stress. Positively selected and rapidly evolving genes in the yak lineage are also found to be significantly enriched in functional categories and pathways related to hypoxia and nutrition metabolism. These findings may have important implications for understanding adaptation to high altitude in other animal species and for hypoxia-related diseases in humans.
ESTHER : Qiu_2012_Nat.Genet_44_946
PubMedSearch : Qiu_2012_Nat.Genet_44_946
PubMedID: 22751099
Gene_locus related to this paper: bosmu-l8ic43 , bovin-2neur , bovin-balip , bovin-BCHE , bovin-e1bbv2 , bovin-e1bn79 , bovin-est8 , bovin-f1mi11 , bovin-f1n385 , bovin-g3mxp5 , bovin-lipli , bovin-lipr2 , bovin-q2kj30 , bovin-q3sz79 , bovin-q3t0r6 , bovin-ABHDA , bovin-q08dw9 , bovin-ABHD16B , bovin-SPG21 , bovin-TEX30 , 9ceta-l8iwv2 , 9ceta-l8idy3 , 9ceta-l8hsi3 , bovin-e1bjq9 , bovin-f1mc21 , 9ceta-l8hyl8 , bovin-LIPG , bovin-a0a3q1nm09 , bovin-f1n2i5

Title : Effect of bis(7)-tacrine on cognition in rats with chronic cerebral ischemia - Shu_2012_Neurosci.Lett_512_103
Author(s) : Shu XJ , Liu W , Zhang L , Yang R , Yi HL , Li CL , Ye YJ , Ai YX
Ref : Neuroscience Letters , 512 :103 , 2012
Abstract : Bis(7)-tacrine (B7T), a novel dimeric acetyl cholinesterase (AChE) inhibitor, has multiple neuroprotective activities against neuronal damage. However, its therapeutic effects in chronic cerebral ischemia remain unknown. In the present study, adult male Sprague-Dawley rats were subjected with permanent ligation of the bilateral common carotid arteries to investigate the roles of B7T on cognitive function, neuronal apoptosis and neurogenesis in the hippocampus. Results from spatial navigation test showed that chronic cerebral ischemia impaired spatial learning, B7T treatment shorten escape latency of ischemia rats as compared with saline-treated rats. Probe trial test indicated that spatial memory deficit of chronic cerebral ischemic animals was reversed by B7T treatment. Immunohistochemical results showed that B7T reduced neuronal apoptosis in the hippocampal CA1 region as compared with ischemia rats, and B7T treatment increased neurogenesis in the hippocampus. These findings suggest that B7T may exert its neuroprotective effects by inhibiting apoptosis and promoting neurogenesis in 2VO rats.
ESTHER : Shu_2012_Neurosci.Lett_512_103
PubMedSearch : Shu_2012_Neurosci.Lett_512_103
PubMedID: 22330749

Title : Fluoxetine Induces Hepatic Lipid Accumulation Via Both Promotion of the SREBP1c-Related Lipogenesis and Reduction of Lipolysis in Primary Mouse Hepatocytes - Feng_2012_CNS.Neurosci.Ther_18_974
Author(s) : Feng XM , Xiong J , Qin H , Liu W , Chen RN , Shang W , Ning R , Hu G , Yang J
Ref : CNS Neurosci Ther , 18 :974 , 2012
Abstract : AIMS: In this study, we investigated the peripheral mechanisms underlying the metabolic side effects of fluoxetine (FLX) by focusing on hepatic lipid metabolism.
METHODS: Primary mouse hepatocytes were prepared from male mice by the two-step perfusion method. The lipid accumulation in primary mouse hepatocytes was analyzed via neutral oil staining. And the lipid metabolism enzymes were determined with RT-PCR and Western blot.
RESULTS: Fluoxetine significantly induced the lipid accumulation in primary mouse hepatocytes. Moreover, FLX increased the acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) expression, which are important enzymes in lipogenesis. Oppositely, Fluoxetine significantly decreased the carboxylesterase 3 (CES3) and carboxylesterase 1 (CES1) expression, which are related to lipolysis. Further study demonstrated FLX-activated SREBP1c, which is one of the most important transcription factors conducting coordinated transcriptional regulation of lipogenesis gene such as ACC1 and FAS. And the increase of lipogenesis gene (ACC1) was abolished by SB203580 but not by pyrrolidine dithiocarbamate (PDTC), suggesting through p38-MAPK pathway. CONCLUSION: Fluoxetine induces hepatic lipid accumulation via both promotion of the SREBP1c-related lipogenesis and reduction of lipolysis in primary mouse hepatocytes.
ESTHER : Feng_2012_CNS.Neurosci.Ther_18_974
PubMedSearch : Feng_2012_CNS.Neurosci.Ther_18_974
PubMedID: 23137031

Title : Complete genome sequences of Brucella melitensis strains M28 and M5-90, with different virulence backgrounds - Wang_2011_J.Bacteriol_193_2904
Author(s) : Wang F , Hu S , Gao Y , Qiao Z , Liu W , Bu Z
Ref : Journal of Bacteriology , 193 :2904 , 2011
Abstract : Brucella melitensis is a Gram-negative coccobacillus bacteria belonging to the Alphaproteobacteria subclass. It is an important zoonotic pathogen that causes brucellosis, a disease affecting sheep, cattle, and sometimes humans. The B. melitensis strain M5-90, a live attenuated vaccine cultured from the B. melitensis virulent strain M28, has been an effective tool to control brucellosis in goats and sheep in China. Here we report the complete genome sequences of B. melitensis M28 and M5-90, strains with different virulence backgrounds, which will serve as a valuable reference for future studies.
ESTHER : Wang_2011_J.Bacteriol_193_2904
PubMedSearch : Wang_2011_J.Bacteriol_193_2904
PubMedID: 21478357
Gene_locus related to this paper: brume-BMEI0552 , brume-BMEI1119 , brume-BMEI1365 , brume-BMEI1594 , brume-BMEI1608 , brume-BMEII0047 , brume-BMEII0681 , brume-BMEII0989 , brume-PCAD , brusu-BR1327

Title : Complete genome sequence of Mycoplasma hyopneumoniae strain 168 - Liu_2011_J.Bacteriol_193_1016
Author(s) : Liu W , Feng Z , Fang L , Zhou Z , Li Q , Li S , Luo R , Wang L , Chen H , Shao G , Xiao S
Ref : Journal of Bacteriology , 193 :1016 , 2011
Abstract : Mycoplasma hyopneumoniae strain 168, a pathogenic strain prevalent in China, was isolated in 1974. Although this strain has been widespread for a long time, the genome sequence had not been determined. Here, we announce the complete genome sequence of M. hyopneumoniae strain 168.
ESTHER : Liu_2011_J.Bacteriol_193_1016
PubMedSearch : Liu_2011_J.Bacteriol_193_1016
PubMedID: 21148737

Title : Genome sequence of a porcine extraintestinal pathogenic Escherichia coli strain - Tan_2011_J.Bacteriol_193_5038
Author(s) : Tan C , Xu Z , Zheng H , Liu W , Tang X , Shou J , Wu B , Wang S , Zhao GP , Chen H
Ref : Journal of Bacteriology , 193 :5038 , 2011
Abstract : Extraintestinal pathogenic Escherichia coli (ExPEC) is an important pathogen which can infect humans and animals and cause many diseases outside the intestine. Here, we report the first draft genome sequence of a porcine ExPEC strain, PCN033, isolated from a pig with meningitis.
ESTHER : Tan_2011_J.Bacteriol_193_5038
PubMedSearch : Tan_2011_J.Bacteriol_193_5038
PubMedID: 21742868
Gene_locus related to this paper: ecoli-IROD , ecoli-IROE , ecoli-ycfp , ecoli-YFBB , ecoli-ypt1 , ecoli-yqia

Title : Design, synthesis, and bioactivities screening of a diaryl ketone-inspired pesticide molecular library as derived from natural products - Zhang_2011_Chem.Biol.Drug.Des_78_94
Author(s) : Zhang H , Jin H , Ji LZ , Tao K , Liu W , Zhao HY , Hou TP
Ref : Chemical Biology Drug Des , 78 :94 , 2011
Abstract : Three natural products, 1,5-diphenylpentan-1-one, 1,5-diphenylpent-2-en-1-one, and 3-hydroxy-1,5-diphenylpentan-1-one, with good insecticidal activities were extracted from Stellera chamaejasme L. Based on their shared diaryl ketone moiety as 'pharmacophores', a series of diaryl ketones were synthesized and tested for insecticidal activity, acetylcholinesterase inhibitory activity, and antifungal activity. All synthesized compounds showed poor insecticidal and acetylcholinesterase inhibitory activities. Compound III with a furyl ring showed strong activities against plant pathogenic fungi. The IC(50) of compound (E)-1-(2,4-dichlorophenyl)-3-(furan-2-yl)- -prop-2-en-1-one (III(2) ) was 1.20 mg/L against Rhizoctonia solani, suggesting its strong potential as a novel antifungal drug.
ESTHER : Zhang_2011_Chem.Biol.Drug.Des_78_94
PubMedSearch : Zhang_2011_Chem.Biol.Drug.Des_78_94
PubMedID: 21457470

Title : Functionalized ionic liquid modified mesoporous silica SBA-15: a novel, designable and efficient carrier for porcine pancreas lipase - Zou_2011_Colloids.Surf.B.Biointerfaces_88_93
Author(s) : Zou B , Hu Y , Yu D , Jiang L , Liu W , Song P
Ref : Colloids Surf B Biointerfaces , 88 :93 , 2011
Abstract : A series of functionalized ionic liquid modified mesoporous silicas SBA-15 (FIL-SBA) were synthesized by modulating the loading and cation/anion ratio of the functionalized ionic liquid (FIL). The prepared materials FIL-SBA were used as a novel carrier system to immobilize porcine pancreas lipase (PPL). Enzymatic activity and reusability of the immobilized enzyme were investigated using the triacetin hydrolysis reaction. The combined advantages of the nano-sized pore diameter, large surface area and high pore volume of SBA-15, and the tunable properties of the FIL for enzymes immobilized in FIL-SBA gave a maximum improvement of 570% in relative activity, with 63% retention of initial activity after five cycles of use. Carriers and immobilized enzymes were characterized using nitrogen adsorption, small-angle X-ray diffraction (SXRD), Fourier transform infrared (FT-IR), elemental analysis, nuclear magnetic resonance (NMR), scanning and transmission electron microscopy (SEM and TEM). It was shown that the introduction of FIL influenced the catalytic behavior of PPL significantly by changing the structure and surface properties of the carriers.
ESTHER : Zou_2011_Colloids.Surf.B.Biointerfaces_88_93
PubMedSearch : Zou_2011_Colloids.Surf.B.Biointerfaces_88_93
PubMedID: 21872768

Title : Complete genome sequence of the pathogenic bacterium Riemerella anatipestifer strain RA-GD - Yuan_2011_J.Bacteriol_193_2896
Author(s) : Yuan J , Liu W , Sun M , Song S , Cai J , Hu S
Ref : Journal of Bacteriology , 193 :2896 , 2011
Abstract : Riemerella anatipestifer is a well-described pathogen of waterfowl and other avian species which can cause a great loss to the poultry industry. Here we obtained the complete genome sequence of R. anatipestifer strain RA-GD, which was isolated from an infected duck in Guangzhou, China, and was cultivated in our laboratory.
ESTHER : Yuan_2011_J.Bacteriol_193_2896
PubMedSearch : Yuan_2011_J.Bacteriol_193_2896
PubMedID: 21441509
Gene_locus related to this paper: riean-e6jh69 , riean-e6jim0

Title : Thiostrepton maturation involving a deesterification-amidation way to process the C-terminally methylated Peptide backbone - Liao_2011_J.Am.Chem.Soc_133_2852
Author(s) : Liao R , Liu W
Ref : J Am Chem Soc , 133 :2852 , 2011
Abstract : Thiopeptides are a class of clinically interesting and highly modified peptide antibiotics. Their biosyntheses share a common paradigm for characteristic core formation but differ in tailoring to afford individual members. Herein we report an unusual deesterification-amidation process in thiostrepton maturation to furnish the terminal amide moiety. TsrB, serving as a carboxylesterase, catalyzes the hydrolysis of the methyl ester intermediate to provide the carboxylate intermediate, which can be converted to the amide product by an amidotransferase, TsrC. These findings revealed a C-terminal methylation of the precursor peptide, which is cryptic in thiostrepton biosynthesis but potentially common in the formation of its homologous series of thiopeptides that vary in the C-terminal form as methyl ester, carboxylate, or amide.
ESTHER : Liao_2011_J.Am.Chem.Soc_133_2852
PubMedSearch : Liao_2011_J.Am.Chem.Soc_133_2852
PubMedID: 21323347

Title : [Analysis of prognostic risk factors in childhood hemophagocytic syndrome] - Li_2011_Zhonghua.Xue.Ye.Xue.Za.Zhi_32_836
Author(s) : Li YG , Mao YN , Liu W , Zhao R , Song LL , Gao HL , Li HX , Zhang HM
Ref : Zhonghua Xue Ye Xue Za Zhi , 32 :836 , 2011
Abstract : OBJECTIVE: To identify and explore the prognostic risk factors of the hemophagocytic syndrome (HPS). METHODS: A retrospective study was conducted on 50 childhood patients with HPS who were admitted to our hospital between 2007 and 2011. All their medical records were reviewed and analyzed. For each patient, demographic, laboratory data and outcome information were collected. The patients were divided into deceased or survived groups based on the follow-up results. Comparative analysis of the data was done by using independent-samples test and logistic multiple and univariate regression. RESULTS: Among the 50 HPS patients, 30 were male and 20 female, age ranged from 3 months to 10 years. Reduction of serum albumin, cholinesterase and natural killer (NK) cells was found in the forty-six patients. The laboratory features showed an elevation of serum ferritin with hypofibrinogenemia and hypertriglyceridemia in most of the patients. Forty of patients had hemophagocyte in bone marrow at diagnosis of HPS. The positive serum EBV-IgM was found in thirty-five patients.During the observation period, 25 of 37 patients (67.6%) died, while 13 of whom died within a month after hospitalization. The deceased patients were more likely to have lower albumin, cholinesterase, NK cells level and more prolonged active partial thromboplastin time than the survived patients (P < 0.05). Multivariate logistic regression analysis revealed that duration of illness > 1 month, albumin level < 25 g/L, cholinesterase level < 2000 U/L, NK cell level 0-3% and positive EBV-IgM were related with the prognosis significantly (P < 0.05 for all comparisons). CONCLUSION: This study revealed that duration of illness > 1 month, decreases in albumin, NK cell and cholinesterase, and positive EBV-IgM were the risk factors related to mortality in children.
ESTHER : Li_2011_Zhonghua.Xue.Ye.Xue.Za.Zhi_32_836
PubMedSearch : Li_2011_Zhonghua.Xue.Ye.Xue.Za.Zhi_32_836
PubMedID: 22339957

Title : Complete genome sequence of Mycoplasma hyorhinis strain HUB-1 - Liu_2010_J.Bacteriol_192_5844
Author(s) : Liu W , Fang L , Li S , Li Q , Zhou Z , Feng Z , Luo R , Shao G , Wang L , Chen H , Xiao S
Ref : Journal of Bacteriology , 192 :5844 , 2010
Abstract : Mycoplasma hyorhinis is generally considered a swine pathogen yet is most commonly found infecting laboratory cell lines. An increasing body of evidence suggests that chronic infections with M. hyorhinis may cause oncogenic transformation. Here, we announce the complete genome sequence of M. hyorhinis strain HUB-1.
ESTHER : Liu_2010_J.Bacteriol_192_5844
PubMedSearch : Liu_2010_J.Bacteriol_192_5844
PubMedID: 20802032

Title : Moving posttranslational modifications forward to biosynthesize the glycosylated thiopeptide nocathiacin I in Nocardia sp. ATCC202099 - Ding_2010_Mol.Biosyst_6_1180
Author(s) : Ding Y , Yu Y , Pan H , Guo H , Li Y , Liu W
Ref : Mol Biosyst , 6 :1180 , 2010
Abstract : Characterization of the biosynthetic gene cluster of glycosylated antibiotic nocathiacin I (NOC-I) here adds new insights to thiopeptide biosynthesis, showing the NOC-specific tailoring and unusual sugar formation. NOC-I biosynthesis shares the paradigm for forming a common thiopeptide core and the generality for converting to an e series member, as that of the parent compound nosiheptide (NOS). This may permit the production of NOC-I in the genetically amenable, NOS-producing strain by building NOC-specific genes for pathway engineering.
ESTHER : Ding_2010_Mol.Biosyst_6_1180
PubMedSearch : Ding_2010_Mol.Biosyst_6_1180
PubMedID: 20473441
Gene_locus related to this paper: 9noca-e5dui2

Title : Enantioselective cytotoxicity of isocarbophos is mediated by oxidative stress-induced JNK activation in human hepatocytes - Liu_2010_Toxicology_276_115
Author(s) : Liu H , Liu J , Xu L , Zhou S , Li L , Liu W
Ref : Toxicology , 276 :115 , 2010
Abstract : Recent studies have shown the enantioselectivity of chiral pesticides in environmental fate, aquatic toxicity, endocrine disruption and cytotoxicity. Thus it is of significance to investigate the molecular mechanisms of chiral pesticides enantioselectivity in cytotoxicity. In the present study, we used Hep G2 cells as in vitro model to assay cytotoxicity of enantiomers of isocarbophos (ICP), a widely used chiral organophosphorus pesticide. The results of cell viability assay and cytoflow assay indicated an obvious enantioselective hepatocyte toxicity of ICP: (-)-ICP was about two times more toxic than (+)-ICP in Hep G2 cells. We found that (-)-ICP, but not (+)-ICP, up-regulated Bax protein expression and down-regulated Bcl-2 expression levels, which resulted in an increase in Bax/Bcl-2 ratio with the apoptosis co-ordination. Although (-)-ICP enantioselectively activated both ERK and JNK, only the specific inhibitor for JNK could completely reverse (-)-ICP-induced apoptosis of Hep G2 cells. It suggests that (-)-ICP-induced hepatocyte toxicity was more dominantly through the sustained activation of JNK pathway, but only partially via ERK cascade. Furthermore, (-)-ICP induced ROS production, while (+)-ICP had no effect on ROS generation. The antioxidant MnTBAP attenuated (-)-ICP-induced activation of JNK and ERK, indicating that the outcome from challenge with (-)-ICP enantiomer depends on the oxidative stress-induced activation of a series of signaling cascades that promote hepatocyte apoptosis. In conclusion, (-)-ICP enantioselectively causes the change of Bax/Bcl-2 ratio, triggers the generation of intracellular ROS and sequentially induces sustainable activation of JNK, which in turn, results in a decrease in cell viability and an increase in cell apoptosis. Our observations provide further insight into enantiomers toxicity pathway which is able to differentiate between enantiomer activities at molecular level.
ESTHER : Liu_2010_Toxicology_276_115
PubMedSearch : Liu_2010_Toxicology_276_115
PubMedID: 20688129

Title : Surface display of active lipase in Saccharomyces cerevisiae using Cwp2 as an anchor protein - Liu_2010_Biotechnol.Lett_32_255
Author(s) : Liu W , Zhao H , Jia B , Xu L , Yan Y
Ref : Biotechnol Lett , 32 :255 , 2010
Abstract : Lipase Lip2 from Yarrowia lipolytica was displayed on the cell surface of Saccharomyces cerevisiae using Cwp2 as an anchor protein. Successful display of the lipase on the cell surface was confirmed by immunofluorescence microscopy and halo assay. The length of linker sequences was further examined to confirm that the correct conformation of Lip2 was maintained. The results showed that the displayed Lip2 exhibited the highest activity at 7.6 +/- 0.4 U/g (dry cell) when using (G(4)S)(3) sequence as the linker, with an optimal temperature and pH at 40 degrees C and pH 8.0. The displayed lipase did not lose any activity after being treated with 0.1% Triton X-100 and 0.1% Tween 80 for 30 min, and it retained 92% of its original activity after incubation in 10% DMSO for 30 min. It also exhibited better thermostability than free Lip2 as reported previously.
ESTHER : Liu_2010_Biotechnol.Lett_32_255
PubMedSearch : Liu_2010_Biotechnol.Lett_32_255
PubMedID: 19821073

Title : Enantioselective interaction with acetylcholinesterase of an organophosphate insecticide fenamiphos - Wang_2010_Chirality_22_612
Author(s) : Wang C , Zhang N , Li L , Zhang Q , Zhao M , Liu W
Ref : Chirality , 22 :612 , 2010
Abstract : Enantioselectivity in the environmental behavior and ecotoxicity of chiral pesticide is widely observed. However, the investigation of the enantioselective mechanisms remains limited. In this study, we used fenamiphos (FAP), an organophosphorus insecticide, to study enantioselectivity in toxicity to arthropods and the inhibition potential towards acetylcholinesterase (AChE) in the rat pheochromocytoma 12 (PC 12) cell line. Furthermore, we carried out molecular docking to help explain the mechanisms of enantioselective toxicity of FAP. The two enantiomers of FAP were successfully separated and identified as R-(+)-FAP and S-(-)-FAP. Toxicological assays revealed that R-(+)-FAP was 2.4-fold more toxic than S-(-)-FAP to Daphnia magna and approximately threefold more to PC12 cells. Based on molecular docking results, dynamic simulation shows that strong hydrophobic interactions and a key hydrogen bond can only exist between R-(+)-FAP and AChE, which helps explain the preference of R-(+) binding to AChE over that of the S-(-)-enantiomer, and supports our biological results. Our present study considers the impact of stereochemistry on ecotoxicological effects and, ultimately, on development of environmentally safe, insecticidally efficient pesticides.
ESTHER : Wang_2010_Chirality_22_612
PubMedSearch : Wang_2010_Chirality_22_612
PubMedID: 19899158

Title : Identification and characterization of HTD2: a novel gene negatively regulating tiller bud outgrowth in rice - Liu_2009_Planta_230_649
Author(s) : Liu W , Wu C , Fu Y , Hu G , Si H , Zhu L , Luan W , He Z , Sun Z
Ref : Planta , 230 :649 , 2009
Abstract : Tiller number is highly regulated by controlling the formation of tiller bud and its subsequent outgrowth in response to endogenous and environmental signals. Here, we identified a rice mutant htd2 from one of the 15,000 transgenic rice lines, which is characterized by a high tillering and dwarf phenotype. Phenotypic analysis of the mutant showed that the mutation did not affect formation of tiller bud, but promoted the subsequent outgrowth of tiller bud. To isolate the htd2 gene, a map-based cloning strategy was employed and 17 new insertions-deletions (InDels) markers were developed. A high-resolution physical map of the chromosomal region around the htd2 gene was made using the F(2) and F(3) population. Finally, the gene was mapped in 12.8 kb region between marker HT41 and marker HT52 within the BAC clone OSJNBa0009J13. Cloning and sequencing of the target region from the mutant showed that the T-DNA insertion caused a 463 bp deletion between the promoter and first exon of an esterase/lipase/thioesterase family gene in the 12.8 kb region. Furthermore, transgenic rice with reduced expression level of the gene exhibited an enhanced tillering and dwarf phenotype. Accordingly, the esterase/lipase/thioesterase family gene (TIGR locus Os03g10620) was identified as the HTD2 gene. HTD2 transcripts were expressed mainly in leaf. Loss of function of HTD2 resulted in a significantly increased expression of HTD1, D10 and D3, which were involved in the strigolactone biosynthetic pathway. The results suggest that the HTD2 gene could negatively regulate tiller bud outgrowth by the strigolactone pathway.
ESTHER : Liu_2009_Planta_230_649
PubMedSearch : Liu_2009_Planta_230_649
PubMedID: 19579033
Gene_locus related to this paper: orysj-Q10QA5

Title : Thiopeptide biosynthesis featuring ribosomally synthesized precursor peptides and conserved posttranslational modifications - Liao_2009_Chem.Biol_16_141
Author(s) : Liao R , Duan L , Lei C , Pan H , Ding Y , Zhang Q , Chen D , Shen B , Yu Y , Liu W
Ref : Chemical Biology , 16 :141 , 2009
Abstract : Thiopeptides, with potent activity against various drug-resistant pathogens, contain a characteristic macrocyclic core consisting of multiple thiazoles, dehydroamino acids, and a 6-membered nitrogen heterocycle. Their biosynthetic pathways remain elusive, in spite of great efforts by in vivo feeding experiments. Here, cloning, sequencing, and characterization of the thiostrepton and siomycin A gene clusters unveiled a biosynthetic paradigm for the thiopeptide specific core formation, featuring ribosomally synthesized precursor peptides and conserved posttranslational modifications. The paradigm generality for thiopeptide biosynthesis was supported by genome mining and ultimate confirmation of the thiocillin I production in Bacillus cereus ATCC 14579, a strain that was previously unknown as a thiopeptide producer. These findings set the stage to accelerate the discovery of thiopeptides by prediction at the genetic level and to generate structural diversity by applying combinatorial biosynthesis methods.
ESTHER : Liao_2009_Chem.Biol_16_141
PubMedSearch : Liao_2009_Chem.Biol_16_141
PubMedID: 19246004
Gene_locus related to this paper: 9acto-c0jrv0 , 9acto-c0jrv6 , strlu-c0jry1 , 9actn-c0jrw3 , strlu-c0l0l7

Title : [Immobilized lipase-catalyzed synthesis of biodiesel from crude cottonseed oil] - Liu_2009_Sheng.Wu.Gong.Cheng.Xue.Bao_25_1996
Author(s) : Liu W , Zhou L , Jiang Y , Gao J
Ref : Sheng Wu Gong Cheng Xue Bao , 25 :1996 , 2009
Abstract : We investigated the transesterification of crude cottonseed oil with methyl acetate to biodiesel, by using Lipozyme TL IM and Novozym 435 as catalysts. Results showed that the biodiesel yield significantly increased with the addition of methanol into the reaction system, and the highest biodiesel yield of 91.83% was achieved with the optimum conditions as follows: n-hexane as solvent, molar ratio of methyl acetate to oil 9:1, 3% methanol based on the oil mass to inhibit the creation of acetic acid, 10% Lipozyme TL IM and 5% Novozym 435 as catalyst based on the oil mass, reaction temperature 55 degrees C and reaction time 8 h. Additionally, we explored the kinetics of lipase-catalyzed crude cottonseed oil to biodiesel, and proposed a kinetic model.
ESTHER : Liu_2009_Sheng.Wu.Gong.Cheng.Xue.Bao_25_1996
PubMedSearch : Liu_2009_Sheng.Wu.Gong.Cheng.Xue.Bao_25_1996
PubMedID: 20352980

Title : Genetic and epigenetic inactivation of LPL gene in human prostate cancer - Kim_2009_Int.J.Cancer_124_734
Author(s) : Kim JW , Cheng Y , Liu W , Li T , Yegnasubramanian S , Zheng SL , Xu J , Isaacs WB , Chang BL
Ref : International Journal of Cancer , 124 :734 , 2009
Abstract : Lipoprotein lipase (LPL) is in chromosome 8p22, site of one of the most common somatic deletions in prostate tumors. Additionally, a CpG island (CGI) was identified in the LPL promoter region. To test the hypothesis that LPL is a tumor suppressor gene, which is inactivated by somatic deletion and hypermethylation in prostate cancer, we evaluated somatic DNA deletion and methylation status at LPL in 56 pairs of DNA samples isolated from prostate cancer tissues and matching normal controls and 11 prostate cell lines. We found that the DNA in 21 of 56 primary cancers (38%) was methylated in the LPL promoter CGI, whereas no methylation was detected in any normal samples. In addition, we found a hemizygous deletion at LPL in 38 of the 56 tumors (68%). When the results of deletion and methylation were considered together, we found LPL promoter CGI methylation occurred in 45% of LPL deleted tumors and in 22% of LPL retained tumors. Within several clinical characteristics tested, the preoperative PSA levels were found to be significantly higher in subjects with LPL promoter CGI methylation compared with subjects without LPL promoter methylation (p=0.0012). Additionally, demethylation of the LPL promoter CGI was accompanied by transcriptional reactivation of LPL in the prostate cancer cell lines DU145 and PC3. In summary, we report a novel finding that the LPL gene is commonly methylated in prostate tumors, and our results suggest that biallelic inactivation of LPL by chromosomal deletion and promoter hypermethylation may play a role in human prostate cancer.
ESTHER : Kim_2009_Int.J.Cancer_124_734
PubMedSearch : Kim_2009_Int.J.Cancer_124_734
PubMedID: 19004026

Title : Separation and toxicity of salithion enantiomers - Zhou_2009_Chirality_21_922
Author(s) : Zhou S , Lin K , Li L , Jin M , Ye J , Liu W
Ref : Chirality , 21 :922 , 2009
Abstract : Enantioseletive toxicities of chiral pesticides have become an environmental concern recently. In this study, we evaluated the enantiomeric separation of salithion on a suite of commercial chiral columns and assessed the toxicity of enantiomers toward butyrylcholinesterase and Daphnia magna. Satisfactory separations of salithion enantiomers could be achieved on all tested columns, that is, Chiralcel OD, Chiralcel OJ, and Chiralpak AD column. However, the Chiralpak AD column offered the best separation and was chosen to prepare micro-scale of pure salithion enantiomers for subsequent bioassays. The first and second enantiomers eluted on the Chiralpak AD column were further confirmed to be (-)-S-salithion and (+)-R-salithion, respectively. The half inhibition concentrations to butyrylcholinesterase of racemate, (+)-R-salithion, and (-)-S-salithion were 33.09, 2.92, and 15.60 mg/l, respectively, showing (+)-R-enantiomer being about 5.0 times more potent than its (-)-S-form. However, the median lethal concentrations (96 h) of racemate, (+)-R-salithion, and (-)-S-salithion toward D. magna were 3.54, 1.10, and 0.36 microg/l, respectively, suggesting that (-)-S-salithion was about 3.0 times more toxic than (+)-R-form. Racemic salithion was less toxic than either of the enantiomers in both bioassays, suggesting that antagonistic interactions might occur between the enantiomers during the toxication action. This work reveals that the toxicity of salithion toward butyrylcholinesterase and D. magna is enantioselective, and this factor should be taken into consideration in the environmental risk assessment of salithion.
ESTHER : Zhou_2009_Chirality_21_922
PubMedSearch : Zhou_2009_Chirality_21_922
PubMedID: 19161220

Title : Invasive mechanism and management strategy of Bemisia tabaci (Gennadius) biotype B: progress report of 973 Program on invasive alien species in China - Wan_2009_Sci.China.C.Life.Sci_52_88
Author(s) : Wan F , Zhang G , Liu S , Luo C , Chu D , Zhang Y , Zang L , Jiu M , Lu Z , Cui X , Zhang L , Zhang F , Zhang Q , Liu W , Liang P , Lei Z
Ref : Sci China C Life Sciences , 52 :88 , 2009
Abstract : Bemisia tabaci (Gennadius) biotype B, called a "superbug", is one of the most harmful biotypes of this species complex worldwide. In this report, the invasive mechanism and management of B. tabaci biotype B, based on our 5-year studies, are presented. Six B. tabaci biotypes, B, Q, ZHJ1, ZHJ2, ZHJ3 and FJ1, have been identified in China. Biotype B dominates the other biotypes in many regions of the country. Genetic diversity in biotype B might be induced by host plant, geographical conditions, and/or insecticidal application. The activities of CarE (carboxylesterase) and GSTs (glutathione-S-transferase) in biotype B reared on cucumber and squash were greater than on other host plants, which might have increased its resistance to insecticides. The higher activities of detoxification enzymes in biotype B might be induced by the secondary metabolites in host plants. Higher adaptive ability of biotype B adults to adverse conditions might be linked to the expression of heat shock protein genes. The indigenous B. tabaci biotypes were displaced by the biotype B within 225 d. The asymmetric mating interactions and mutualism between biotype B and begomoviruses via its host plants speed up widespread invasion and displacement of other biotypes. B. tabaci biotype B displaced Trialeurodes vaporariorum (Westwood) after 4-7 generations under glasshouse conditions. Greater adaptive ability of the biotype B to adverse conditions and its rapid population increase might be the reasons of its successful displacement of T. vaporariorum. Greater ability of the biotype B to switch to different host plants may enrich its host plants, which might enable it to better compete with T. vaporariorum. Native predatory natural enemies possess greater ability to suppress B. tabaci under field conditions. The kairomones in the 3rd and 4th instars of biotype B may provide an important stimulus in host searching and location by its parasitoids. The present results provide useful information in explaining the mechanisms of genetic diversity, evolution and molecular eco-adaptation of biotype B. Furthermore, it provides a base for sustainable management of B. tabaci using biological and ecological measures.
ESTHER : Wan_2009_Sci.China.C.Life.Sci_52_88
PubMedSearch : Wan_2009_Sci.China.C.Life.Sci_52_88
PubMedID: 19152088

Title : Mechanisms of composition change and toxic potentiation of chloramidophos emulsifiable concentrate during storage - Zhou_2009_J.Agric.Food.Chem_57_930
Author(s) : Zhou S , Zhang D , Yang H , Zhang Y , Liu W
Ref : Journal of Agricultural and Food Chemistry , 57 :930 , 2009
Abstract : Storage instability is one of the serious problems that greatly restrict pesticide use. Routine checks on the composition and toxicity of 30% emulsifiable concentrates (EC) of chloramidophos (CP) during storage indicated that 78.6% of the active ingredient had decreased, whereas the anti-acetylcholinesterase (AChE) activity of the formulation was potentiated by 3.5 times. To understand the mechanism for these changes, detailed knowledge of the products present and their effects on anti-AChE potential deserves attention. It was likely that the basis for these changes was methanol, the cosolvent of CP EC, because when the purified CP was stored in methanol at 50 degrees C for 2 weeks, CP drop and toxic potentiation similar to those observed in CP EC also appeared. The major products of the CP-methanol reaction mixture were isolated and identified by HPLC and GC-MS, respectively, and their inhibitory potentials against AChE and effectiveness as potentiators were assessed. Following redetermination of the main product (O,S-dimethyl-[(2,2,2)-trichloro-1-methoxyethyl]phosphoramidothioate (MCP)) and high anti-AChE material (methamidophos), which were preconfirmed in the reaction mixture in CP EC, it was successfully demonstrated that the majority of CP in the formulation had been transformed to a new stable compound, MCP. Meanwhile, formation of another product, methamidophos, resulted in toxic potentiation.
ESTHER : Zhou_2009_J.Agric.Food.Chem_57_930
PubMedSearch : Zhou_2009_J.Agric.Food.Chem_57_930
PubMedID: 19132886

Title : Lipase diversity in glacier soil based on analysis of metagenomic DNA fragments and cell culture - Yuhong_2009_J.Microbiol.Biotechnol_19_888
Author(s) : Yuhong Z , Shi P , Liu W , Meng K , Bai Y , Wang G , Zhan Z , Yao B
Ref : J Microbiol Biotechnol , 19 :888 , 2009
Abstract : Lipase diversity in glacier soil was assessed by culture independent metagenomic DNA fragment screening and confirmed by cell culture experiments. A set of degenerate PCR primers specific for lipases of the hormone-sensitive lipase family was designed based on conserved motifs and used to directly PCR amplify metagenomic DNA from glacier soil. These products were used to construct a lipase fragment clone library. Among the 300 clones sequenced for the analysis, 201 clones encoding partial lipases shared 51-82%identity to known lipases in GenBank. Based on a phylogenetic analysis, five divergent clusters were established, one of which may represent a previously unidentified lipase subfamily. In the culture study, 11 lipase-producing bacteria were selectively isolated and characterized by 16S rDNA sequences. Using the above mentioned degenerate primers, seven lipase gene fragments were cloned, but not all of them could be accounted for by the clones in the library. Two full-length lipase genes obtained by TAIL-PCR were expressed in Pichia pastoris and characterized. Both were authentic lipases with optimum temperatures of
ESTHER : Yuhong_2009_J.Microbiol.Biotechnol_19_888
PubMedSearch : Yuhong_2009_J.Microbiol.Biotechnol_19_888
PubMedID: 19809244

Title : Nosiheptide biosynthesis featuring a unique indole side ring formation on the characteristic thiopeptide framework - Yu_2009_ACS.Chem.Biol_4_855
Author(s) : Yu Y , Duan L , Zhang Q , Liao R , Ding Y , Pan H , Wendt-Pienkowski E , Tang G , Shen B , Liu W
Ref : ACS Chemical Biology , 4 :855 , 2009
Abstract : Nosiheptide (NOS), belonging to the e series of thiopeptide antibiotics that exhibit potent activity against various bacterial pathogens, bears a unique indole side ring system and regiospecific hydroxyl groups on the characteristic macrocyclic core. Here, cloning, sequencing, and characterization of the nos gene cluster from Streptomyces actuosus ATCC 25421 as a model for this series of thiopeptides has unveiled new insights into their biosynthesis. Bioinformatics-based sequence analysis and in vivo investigation into the gene functions show that NOS biosynthesis shares a common strategy with recently characterized b or c series thiopeptides for forming the characteristic macrocyclic core, which features a ribosomally synthesized precursor peptide with conserved posttranslational modifications. However, it apparently proceeds via a different route for tailoring the thiopeptide framework, allowing the final product to exhibit the distinct structural characteristics of e series thiopeptides, such as the indole side ring system. Chemical complementation supports the notion that the S-adenosylmethionine-dependent protein NosL may play a central role in converting tryptophan to the key 3-methylindole moiety by an unusual carbon side chain rearrangement, most likely via a radical-initiated mechanism. Characterization of the indole side ring-opened analogue of NOS from the nosN mutant strain is consistent with the proposed methyltransferase activity of its encoded protein, shedding light into the timing of the individual steps for indole side ring biosynthesis. These results also suggest the feasibility of engineering novel thiopeptides for drug discovery by manipulating the NOS biosynthetic machinery.
ESTHER : Yu_2009_ACS.Chem.Biol_4_855
PubMedSearch : Yu_2009_ACS.Chem.Biol_4_855
PubMedID: 19678698
Gene_locus related to this paper: stras-c6fx50

Title : Characterization of the saframycin A gene cluster from Streptomyces lavendulae NRRL 11002 revealing a nonribosomal peptide synthetase system for assembling the unusual tetrapeptidyl skeleton in an iterative manner - Li_2008_J.Bacteriol_190_251
Author(s) : Li L , Deng W , Song J , Ding W , Zhao QF , Peng C , Song WW , Tang GL , Liu W
Ref : Journal of Bacteriology , 190 :251 , 2008
Abstract : Saframycin A (SFM-A), produced by Streptomyces lavendulae NRRL 11002, belongs to the tetrahydroisoquinoline family of antibiotics, and its core is structurally similar to the core of ecteinascidin 743, which is a highly potent antitumor drug isolated from a marine tunicate. In this study, the biosynthetic gene cluster for SFM-A was cloned and localized to a 62-kb contiguous DNA region. Sequence analysis revealed 30 genes that constitute the SFM-A gene cluster, encoding an unusual nonribosomal peptide synthetase (NRPS) system and tailoring enzymes and regulatory and resistance proteins. The results of substrate prediction and in vitro characterization of the adenylation specificities of this NRPS system support the hypothesis that the last module acts in an iterative manner to form a tetrapeptidyl intermediate and that the colinearity rule does not apply. Although this mechanism is different from those proposed for the SFM-A analogs SFM-Mx1 and safracin B (SAC-B), based on the high similarity of these systems, it is likely they share a common mechanism of biosynthesis as we describe here. Construction of the biosynthetic pathway of SFM-Y3, an aminated SFM-A, was achieved in the SAC-B producer (Pseudomonas fluorescens). These findings not only shed new insight on tetrahydroisoquinoline biosynthesis but also demonstrate the feasibility of engineering microorganisms to generate structurally more complex and biologically more active analogs by combinatorial biosynthesis.
ESTHER : Li_2008_J.Bacteriol_190_251
PubMedSearch : Li_2008_J.Bacteriol_190_251
PubMedID: 17981978

Title : Single and joint acute toxicity of isocarbophos enantiomers to Daphnia magna - Lin_2008_J.Agric.Food.Chem_56_4273
Author(s) : Lin K , Liu W , Li L , Gan J
Ref : Journal of Agricultural and Food Chemistry , 56 :4273 , 2008
Abstract : Although enantioselectivity in the toxicity of chiral pesticides has received considerable attention over recent years, how coexisting enantiomers interact with each other during their toxic action remains unknown. In this study, we attempted to resolve the enantiomers of a chiral organophosphate insecticide, isocarbophos, and investigated the acute toxicity of individual enantiomers and various enantiomer mixtures. Baseline enantiomeric separation of isocarbophos was achieved on a Chiralcel OD column with the mobile phase of n-hexane/isopropanol (90/10, v/v) at a flow rate of 0.8 mL/min. The resolved enantiomers were differentiated by their responses on a circular dichroism detector. The median lethal concentrations (LC 50) of racemate, (+)-enantiomer, and (-)-enantiomer of isocarbophos toward Daphnia magna were 13.9, 7.08, and 353 microg/L, respectively, after 48 h of static exposure, displaying a 50-fold difference between the enantiomers. Toxic unit (TU) analysis was employed to evaluate the joint toxicity of isocarbophos enantiomer mixtures. The calculated TU mix for the acute toxicity (48 h test) of various binary mixtures ranged from 0.83 to 1.04, suggesting a mode of additive effect. Further evaluation of available literature data for chiral organophosphorus insecticides showed that the joint toxicity of enantiomers may be additive, synergistic, and antagonistic. Therefore, when significant enantioselectivity exists for a chiral pesticide, it is important to also evaluate the interaction of enantiomers in the joint toxicity effect when enantiomers are present in a mixture.
ESTHER : Lin_2008_J.Agric.Food.Chem_56_4273
PubMedSearch : Lin_2008_J.Agric.Food.Chem_56_4273
PubMedID: 18489111

Title : Preparation, stabilization, and bioefficacy of beta-cyclodextrin inclusion compounds of chloramidophos - Zhou_2008_J.Agric.Food.Chem_56_2708
Author(s) : Zhou S , Wang L , Zhang A , Lin K , Liu W
Ref : Journal of Agricultural and Food Chemistry , 56 :2708 , 2008
Abstract : Cyclodextrins are common compounds capable of forming inclusion complexes with a variety of pesticides to improve their solubility, bioavailability, and stability. In this study, chloramidophos (CP) was inclusion-complexed with beta-cyclodextrin (beta-CD) by a kneading method in an attempt to gain a more stable but equally effecacious formulation compared with CP alone. A 1:1 CP-beta-CD complex with an inclusion constant of 203.0 M(-1) was determined to exist by UV spectrophotometry. The structural identification, thermal stability, and biological assays of the CP-beta-CD complex were then carried out with a product with the maximum guest loading efficiency. The data measured by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR), and X-ray diffraction (XRD), where the endothermic peaks of beta-CD, the FT-IR bands, and the XRD peaks were generally changed, deduced the formation of complex. Results of the thermal stability assay showed that the degradation rate of CP in 14-day incubation was slowed by a factor of 3.6 when it was complexed with beta-CD. Then, activity and toxicity of CP influenced by the encapsulated process of beta-CD were evaluated by an in vitro acetylcholinesterase (AChE) inhibition assay and an acute aquatic toxicity assay, respectively. No significant differences were found in both the two biological assays by a t-test. This indicated that the encapsulation process greatly improved the thermal stability of the pesticide with no adverse effects on bioefficacy compared to that of CP. There is a promising outlook for CP-beta-CD to be produced as the active ingredient of various formulation additives of CP for its continued application.
ESTHER : Zhou_2008_J.Agric.Food.Chem_56_2708
PubMedSearch : Zhou_2008_J.Agric.Food.Chem_56_2708
PubMedID: 18370398

Title : Saponins (Ginsenosides) from stems and leaves of Panax quinquefolium prevented high-fat diet-induced obesity in mice - Liu_2008_Phytomedicine_15_1140
Author(s) : Liu W , Zheng Y , Han L , Wang H , Saito M , Ling M , Kimura Y , Feng Y
Ref : Phytomedicine , 15 :1140 , 2008
Abstract : The present study was performed to clarify whether the crude saponins from stems and leaves of Panax quinquefolium inhibited lipase activity in vitro, and prevented obesity induced in mice by feeding a high-fat diet for 8 weeks. For in vitro experiments, assay for the inhibitory effects of saponins from stems and leaves of Panax quinquefolium on pancreatic lipase activity was performed by measuring the rate of release of oleic acid from triolein. For in vivo experiments, female ICR mice were fed a high-fat diet with or without saponins from stems and leaves of Panax quinquefolium for 8 weeks. The crude saponins inhibited pancreatic lipase activity in vitro. Furthermore, crude saponins (lg/kg body weight) inhibited the elevations of plasma triacylglycerol in rats administered the oral lipid emulsion tolerance test. In addition, long-term administration of crude saponins, the parametrial adipose tissue weight was decreased by feeding a high-fat diet containing l% or 3% crude saponins compared to those of high-fat diet group. It is demonstrated that the anti-obesity effects of the crude saponins from stems and leaves of Panax quinquefolium in high-fat diet-treated mice may be due to the inhibition of intestinal absorption of dietary fat by ginsenosides Rc, Rb(1) and Rb(2).
ESTHER : Liu_2008_Phytomedicine_15_1140
PubMedSearch : Liu_2008_Phytomedicine_15_1140
PubMedID: 18768305

Title : Cloning and characterization of the tetrocarcin A gene cluster from Micromonospora chalcea NRRL 11289 reveals a highly conserved strategy for tetronate biosynthesis in spirotetronate antibiotics - Fang_2008_J.Bacteriol_190_6014
Author(s) : Fang J , Zhang Y , Huang L , Jia X , Zhang Q , Zhang X , Tang G , Liu W
Ref : Journal of Bacteriology , 190 :6014 , 2008
Abstract : Tetrocarcin A (TCA), produced by Micromonospora chalcea NRRL 11289, is a spirotetronate antibiotic with potent antitumor activity and versatile modes of action. In this study, the biosynthetic gene cluster of TCA was cloned and localized to a 108-kb contiguous DNA region. In silico sequence analysis revealed 36 putative genes that constitute this cluster (including 11 for unusual sugar biosynthesis, 13 for aglycone formation, and 4 for glycosylations) and allowed us to propose the biosynthetic pathway of TCA. The formation of D-tetronitrose, L-amicetose, and L-digitoxose may begin with D-glucose-1-phosphate, share early enzymatic steps, and branch into different pathways by competitive actions of specific enzymes. Tetronolide biosynthesis involves the incorporation of a 3-C unit with a polyketide intermediate to form the characteristic spirotetronate moiety and trans-decalin system. Further substitution of tetronolide with five deoxysugars (one being a deoxynitrosugar) was likely due to the activities of four glycosyltransferases. In vitro characterization of the first enzymatic step by utilization of 1,3-biphosphoglycerate as the substrate and in vivo cross-complementation of the bifunctional fused gene tcaD3 (with the functions of chlD3 and chlD4) to Delta chlD3 and Delta chlD4 in chlorothricin biosynthesis supported the highly conserved tetronate biosynthetic strategy in the spirotetronate family. Deletion of a large DNA fragment encoding polyketide synthases resulted in a non-TCA-producing strain, providing a clear background for the identification of novel analogs. These findings provide insights into spirotetronate biosynthesis and demonstrate that combinatorial-biosynthesis methods can be applied to the TCA biosynthetic machinery to generate structural diversity.
ESTHER : Fang_2008_J.Bacteriol_190_6014
PubMedSearch : Fang_2008_J.Bacteriol_190_6014
PubMedID: 18586939
Gene_locus related to this paper: micch-b5l6l6

Title : [Cell surface display of Yarrowia lipolytica lipase Lip2 in Saccharomyces cerevisiae with a-agglutinin as carrier protein] - Liu_2008_Wei.Sheng.Wu.Xue.Bao_48_1543
Author(s) : Liu W , Xu L , Zhao H , Yang J , Yan Y
Ref : Wei Sheng Wu Xue Bao , 48 :1543 , 2008
Abstract : OBJECTIVE: In order to display extracellular.lipase Lip2 from Yarrowia lipolytica on the surface of yeast Saccharomyces cerevisiae for whole cell catalysts. METHODS: The mature Lip2 encoding fragment was amplified from Yarrowia lipolytica total DNA, and was inserted into the 3'terminal of AGA2 to give the plasmid pCTLIP2 for surface display of Lip2. Olive oil, tributyrin and p-nitrophenyl palmitate (pNPP) were used as substrates to measure lipase activity. Moreover, the characterization of displayed lipase and its free form was analyzed. RESULTS: The surface displayed lipase was confirmed to be active towards olive oil, tributyrin and p-nitrophenyl palmitate (pNPP), and reached its highest expression level at 182 U/g dry cell after induced by galactose for 72h. The optimum temperature of cell surface displayed Lip2 was 40 degrees C After incubated at 50 degrees C for 4h, the surface displayed lipase retained 23.2% of its full activity, improved a little compared to free Lip2. The surface displayed lipase showed a preference to medium-chain and long-chain fatty acids p-nitrophenyl esters (C8-C16). CONCLUSION: The cell surface display system based on a-agglutinin is an effective system for displaying Lip2, and the whole cell EBY100-pCTLIP2 will be probably suited to a different range of applications.
ESTHER : Liu_2008_Wei.Sheng.Wu.Xue.Bao_48_1543
PubMedSearch : Liu_2008_Wei.Sheng.Wu.Xue.Bao_48_1543
PubMedID: 19149173

Title : Paradoxical DNA repair and peroxide resistance gene conservation in Bacillus pumilus SAFR-032 - Gioia_2007_PLoS.One_2_e928
Author(s) : Gioia J , Yerrapragada S , Qin X , Jiang H , Igboeli OC , Muzny D , Dugan-Rocha S , Ding Y , Hawes A , Liu W , Perez L , Kovar C , Dinh H , Lee S , Nazareth L , Blyth P , Holder M , Buhay C , Tirumalai MR , Liu Y , Dasgupta I ,