Fang J

References (26)

Title : Systems pharmacology-based mechanism exploration of Acanthopanax senticosusin for Alzheimer's disease using UPLC-Q-TOF-MS, network analysis, and experimental validation - Zhuo_2023_Eur.J.Pharmacol__175895
Author(s) : Zhuo Y , Fu X , Jiang Q , Lai Y , Gu Y , Fang S , Chen H , Liu C , Pan H , Wu Q , Fang J
Ref : European Journal of Pharmacology , :175895 , 2023
Abstract : BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive cognitive dysfunction and memory loss. However, the disease-modifying treatments for AD are still lacking. Traditional Chinese herbs, have shown their potentials as novel treatments for complex diseases, such as AD. PURPOSE: This study was aimed at investigating the mechanism of action (MOA) of Acanthopanax senticosusin (AS) for treatment of AD. METHODS: In this study, we firstly identified the chemical constituents in Acanthopanax senticosusin (AS) utilizing ultra-high performance liquid chromatography coupled with Q-TOF-mass spectrometry (UPLC-Q-TOF-MS), and next built the drug-target network of these compounds. We next performed the systems pharmacology-based analysis to preliminary explore the MOA of AS against AD. Moreover, we applied the network proximity approach to identify the potential anti-AD components in AS. Finally, experimental validations, including animal behavior test, ELISA and TUNEL staining, were conducted to verify our systems pharmacology-based analysis. RESULTS: 60 chemical constituents in AS were identified via the UPLC-Q-TOF-MS approach. The systems pharmacology-based analysis indicated that AS might exert its therapeutic effects on AD via acetylcholinesterase and apoptosis signaling pathway. To explore the material basis of AS against AD, we further identified 15 potential anti-AD components in AS. Consistently, in vivo experiments demonstrated that AS could protect cholinergic nervous system damage and decrease neuronal apoptosis caused by scopolamine. CONCLUSION: Overall, this study applied systems pharmacology approach, via UPLC-Q-TOF-MS, network analysis, and experimental validation to decipher the potential molecular mechanism of AS against AD.
ESTHER : Zhuo_2023_Eur.J.Pharmacol__175895
PubMedSearch : Zhuo_2023_Eur.J.Pharmacol__175895
PubMedID: 37422122

Title : Reusable carboxylesterase immobilized in ZIF for efficient degradation of chlorpyrifos in enviromental water - Wang_2023_Pestic.Biochem.Physiol_194_105519
Author(s) : Wang B , Chen J , Wu S , Fang J , Li Q , Wang G
Ref : Pestic Biochem Physiol , 194 :105519 , 2023
Abstract : The past few decades have witnessed biodegradation of pesticides as a significant method in remediation of the environment for its specificity, efficiency and biocompatibility. However, the tolerability and recyclability of the enzymes in pesticide degradation and the development of enzymes that biodegrad pesticides are still urgent problems to be solved so far. Herein, a novel hyper-thermostable and chlorpyrifos-hydrolyzing carboxylesterase EstC was immobilized by biomineralization using zeolitic imidazolate framework (ZIF), one of the metal-organic frameworks (MOFs) with highly diverse structure and porosity. Compared with free enzyme, EstC@ZIF with a cruciate flower-like morphology presented scarcely variation in catalytic efficiency and generally improved the tolerance to organic solvents or detergents. Furthermore, there was scarcely decrease in the catalytic efficiency of EstC@ZIF and it also showed good reusability with about 50% residual activity after 12 continuous uses. Notably, EstC@ZIF could be used in actual water environment with an excellent value of degradation rate of 90.27% in 120 min, and the degradation efficiency remained about 50% after 9 repetitions. The present strategy of immobilizing carboxylesterase to treat pesticide-contaminated water broadens the method of immobilized enzymes on MOFs, and envisions its recyclable applicability in globe environmental remediation.
ESTHER : Wang_2023_Pestic.Biochem.Physiol_194_105519
PubMedSearch : Wang_2023_Pestic.Biochem.Physiol_194_105519
PubMedID: 37532333
Gene_locus related to this paper: strco-estli

Title : Recent advances in the biodegradation of polyethylene terephthalate with cutinase-like enzymes - Sui_2023_Front.Microbiol_14_1265139
Author(s) : Sui B , Wang T , Fang J , Hou Z , Shu T , Lu Z , Liu F , Zhu Y
Ref : Front Microbiol , 14 :1265139 , 2023
Abstract : Polyethylene terephthalate (PET) is a synthetic polymer in the polyester family. It is widely found in objects used daily, including packaging materials (such as bottles and containers), textiles (such as fibers), and even in the automotive and electronics industries. PET is known for its excellent mechanical properties, chemical resistance, and transparency. However, these features (e.g., high hydrophobicity and high molecular weight) also make PET highly resistant to degradation by wild-type microorganisms or physicochemical methods in nature, contributing to the accumulation of plastic waste in the environment. Therefore, accelerated PET recycling is becoming increasingly urgent to address the global environmental problem caused by plastic wastes and prevent plastic pollution. In addition to traditional physical cycling (e.g., pyrolysis, gasification) and chemical cycling (e.g., chemical depolymerization), biodegradation can be used, which involves breaking down organic materials into simpler compounds by microorganisms or PET-degrading enzymes. Lipases and cutinases are the two classes of enzymes that have been studied extensively for this purpose. Biodegradation of PET is an attractive approach for managing PET waste, as it can help reduce environmental pollution and promote a circular economy. During the past few years, great advances have been accomplished in PET biodegradation. In this review, current knowledge on cutinase-like PET hydrolases (such as TfCut2, Cut190, HiC, and LCC) was described in detail, including the structures, ligand-protein interactions, and rational protein engineering for improved PET-degrading performance. In particular, applications of the engineered catalysts were highlighted, such as improving the PET hydrolytic activity by constructing fusion proteins. The review is expected to provide novel insights for the biodegradation of complex polymers.
ESTHER : Sui_2023_Front.Microbiol_14_1265139
PubMedSearch : Sui_2023_Front.Microbiol_14_1265139
PubMedID: 37849919

Title : Nanozyme-based dual-signal sensing system for colorimetric and photothermal detection of AChE activity in the blood of liver-injured mice - He_2023_Anal.Bioanal.Chem__
Author(s) : He C , Ke Z , Liu K , Peng J , Yang Q , Wang L , Feng G , Fang J
Ref : Anal Bioanal Chem , : , 2023
Abstract : Acetylcholinesterase (AChE), a crucial enzyme related to liver function, is involved in numerous physiological processes such as neurotransmission and muscular contraction. The currently reported techniques for detecting AChE mainly rely on a single signal output, limiting their high-accuracy quantification. The few reported dual-signal assays are challenging to implement in dual-signal point-of-care testing (POCT) because of the need for large instruments, costly modifications, and trained operators. Herein, we report a colorimetric and photothermal dual-signal POCT sensing platform based on CeO(2)-TMB (3,3',5,5'-tetramethylbenzidine) for the visualization of AChE activity in liver-injured mice. The method compensates for the false positives of a single signal and realizes the rapid, low-cost portable detection of AChE. More importantly, the CeO(2)-TMB sensing platform enables the diagnosis of liver injury and provides an effective tool for studying liver disease in basic medicine and clinical applications. Rapid colorimetric and photothermal biosensor for sensitive detection of acetylcholinesterase (I) and acetylcholinesterase levels in mouse serum (II).
ESTHER : He_2023_Anal.Bioanal.Chem__
PubMedSearch : He_2023_Anal.Bioanal.Chem__
PubMedID: 36995409

Title : Chemical profile, anti-hepatoma activity, anti-acetylcholinesterase and antioxidant activity of aerial part of Aconitum carmichaeli Debx - Yu_2022_Nat.Prod.Res__1
Author(s) : Yu J , Xia J , Xu J , Chen S , Zhang Y , Yin F , Fang J , Cai L , Zhang B , Zhan Y , Zhang X , Zeng Z , Liang Z
Ref : Nat Prod Res , :1 , 2022
Abstract : Five extracts of the aerial parts of Aconitum carmichaeli were obtained by different solvent extraction or macroporous adsorption resin purification: ethyl acetate layer extract (EAE), n-butanol layer extract (BuE), water layer extract (WE), extract eluted by 10% ethanol from macroporous resin (10%EE), extract eluted by 80% ethanol from macroporous resin (80%EE). Antioxidant activities of the five extracts were determined by ABTS, DPPH, FRAP assays, anti-AChE activities by modified Ellman's method, insvitro anti-hepatoma activities by CCK-8 assay, and chemical constituents of 80%EE were identified by UPLC-QE-Orbitrap-MS. The results demonstrated that the 80%EE showed the best insvitro anti-hepatoma activity on Huh-7 cell line with an IC(50) of 103.91 +/- 11.02 microg/mL. 10%EE and 80%EE gave the highest antioxidant activity. Furthermore, current findings demonstrated that the aerial part of Aconitum carmichaeli Debx. has high medicinal value and may be a good natural medicine.
ESTHER : Yu_2022_Nat.Prod.Res__1
PubMedSearch : Yu_2022_Nat.Prod.Res__1
PubMedID: 36503283

Title : Sucrose promotes D53 accumulation and tillering in rice - Patil_2022_New.Phytol_234_122
Author(s) : Patil SB , Barbier FF , Zhao J , Zafar SA , Uzair M , Sun Y , Fang J , Perez-Garcia MD , Bertheloot J , Sakr S , Fichtner F , Chabikwa TG , Yuan S , Beveridge CA , Li X
Ref : New Phytol , 234 :122 , 2022
Abstract : Shoot branching is regulated by multiple signals. Previous studies have indicated that sucrose may promote shoot branching through suppressing the inhibitory effect of the hormone strigolactone (SL). However, the molecular mechanisms underlying this effect are unknown. Here, we used molecular and genetic tools to identify the molecular targets underlying the antagonistic interaction between sucrose and SL. We showed that sucrose antagonizes the suppressive action of SL on tillering in rice and on the degradation of D53, a major target of SL signalling. Sucrose inhibits the gene expression of D3, the orthologue of the Arabidopsis F-box MAX2 required for SL signalling. Overexpression of D3 antagonizes sucrose inhibition of D53 degradation and enables the SL inhibition of tillering under high sucrose. Sucrose prevents SL-induced degradation of D14, the SL receptor involved in D53 degradation. In contrast to D3, D14 overexpression enhances D53 protein levels and sucrose-induced tillering, even in the presence of SL. Our results show that sucrose inhibits SL response by affecting key components of SL signalling and, together with previous studies reporting the inhibition of SL synthesis by nitrate and phosphate, demonstrate the central role played by SLs in the regulation of plant architecture by nutrients.
ESTHER : Patil_2022_New.Phytol_234_122
PubMedSearch : Patil_2022_New.Phytol_234_122
PubMedID: 34716593

Title : Transcriptome Analysis of Aedes albopictus (Diptera: Culicidae) Larvae Exposed With a Sublethal Dose of Haedoxan A - Hao_2021_J.Med.Entomol__
Author(s) : Hao H , Zuo Y , Fang J , Sun A , Aioub AAA , Hu Z
Ref : Journal of Medical Entomology , : , 2021
Abstract : Aedes albopictus is the vector of arbovirus diseases including yellow fever, dengue, Zika virus, and chikungunya fever, and it poses an enormous threat to human health worldwide. Previous studies have revealed that haedoxan A (HA), which is an insecticidal sesquilignan from Phryma leptostachya L., is a highly effective natural insecticide for managing mosquitoes and houseflies; however, the mechanisms underlying the response of Ae. albopictus after treatment with sublethal concentrations of HA is not clear. Here, high-throughput sequencing was used to analyze the gene expression changes in Ae. albopictus larvae after treatment with the LC30 of HA. In total, 416 differentially expressed genes (DEGs) were identified, including 328 upregulated genes and 88 downregulated genes. Identification and verification of related DEGs were performed by RT-qPCR. The results showed that two P450 unigenes (CYP4C21 and CYP304A1), one carboxylesterase, and one ABC transporter (ABCG1) were induced by HA, which indicated that these detoxifying enzyme genes might play a major role in the metabolic and detoxification processes of HA. Additionally, acetylcholine receptor subunit 2 (AChRalpha2), AChRalpha5, AChRalpha9, and the glutamate receptor ionotropic kainate 2 (GRIK2) were found to be upregulated in HA-treated larvae, suggesting that HA affected the conduction of action potentials and synaptic transmission by disrupting the function of neural receptors. These results provide a foundation for further elucidating the target of HA and the mechanism of detoxification metabolism in Ae. albopictus.
ESTHER : Hao_2021_J.Med.Entomol__
PubMedSearch : Hao_2021_J.Med.Entomol__
PubMedID: 33999150

Title : UHPLC With On-Line Coupled Biochemical Detection for High Throughput Screening of Acetylcholinesterase Inhibitors in Coptidis Rhizoma and Cortex Phellodendri - Tan_2021_J.Chromatogr.Sci__
Author(s) : Tan J , Zhang X , Fang J , Shen H , Ding X , Zheng G
Ref : Journal of Chromatography Sci , : , 2021
Abstract : We developed a new on-line method of ultra-performance liquid chromatography coupled with biochemical detection (UHPLC-BCD) to screen acetylcholinesterase (AChE) inhibitors in complex matrixes. Chromatography separation was performed using an Xtimate UHPLC C18 column (100 mm x 2.1 mm, 1.8 microm) and a gradient elution with methanol-0.1% formic acid at a flow rate of 0.08 mL/min. The BCD was based on a colorimetric method using Ellman's reagent, and the detection wavelength was at 405 nm. Galanthamine was used as a positive reference to validate the methodology. The detection and quantitation limits of the UHPLC-BCD method were 0.018 and 0.060 microg, respectively. A functional equation was generated in terms of the negative peak area (X) and galanthamine concentration (Y, microg/mL). The regression equation was Y = 0.0028X2 + 0.4574X + 50.7776, R2 = 0.9993. UHPLC-fourier-transform mass spectrometry detection results revealed that five alkaloids showed obvious AChE inhibitory activities including coptisin, epiberberine, jatrorrhizine, berberine and palmatine. The relative AChE inhibitory activities of jatrorrhizine, berberine and palmatine in the Coptidis Rhizoma sample were equal to that of 257.0, 2355 and 283.9 microg/mL of galanthamine, respectively. This work demonstrated that the UHPLC-BCD method was convenient and feasible, and could be widely used for the screening and activity evaluation of the bioactive components in the complex extracts.
ESTHER : Tan_2021_J.Chromatogr.Sci__
PubMedSearch : Tan_2021_J.Chromatogr.Sci__
PubMedID: 34664067

Title : Enantioselective bioaccumulation and detoxification mechanisms of earthworms (Eisenia fetida) exposed to mandipropamid - Fang_2021_Sci.Total.Environ_796_149051
Author(s) : Fang K , Han L , Liu Y , Fang J , Wang X , Liu T
Ref : Sci Total Environ , 796 :149051 , 2021
Abstract : As a novel chiral amide fungicide, the enantioselective behaviors of mandipropamid in the soil environment are unclear. Furthermore, there is a need to understand the stress response mechanisms of soil organisms exposed to mandipropamid isomers. Therefore, the selective bioaccumulation of mandipropamid isomers and detoxification mechanisms of earthworms (Eisenia fetida) were investigated in this study. Our results suggested that the enantioselective bioaccumulation of mandipropamid in earthworms occurred with the preferential enrichment of S-(+)-isomer. The activities of detoxification enzymes, such as cytochrome P450 (CYP450), glutathione-S-transferases (GST), and carboxylesterase (CarE), changed significantly upon exposure to S-(+)- and R-(-)-mandipropamid (particularly for CYP450 and GST). A transcriptome analysis revealed that more differentially expressed genes (DEGs) were observed under S-(+)-isomer exposure (15,798) than those under R-(-)-isomer exposure (12,222), as compared to the control group. These DEGs were mainly enriched in bile secretion and thyroid hormone signaling pathways, which were related to the detoxification process in earthworms. Moreover, the 20 DEGs, which exhibited the most profound changes (such as CYP2 and CYP3A4) in these pathways, were screened, clustered, and observed to be mainly involved in regulating the detoxification function of earthworm cells. These results indicated that detoxification systems played an essential role in the stress response to mandipropamid exposure. Additionally, earthworms were more sensitive to the stress induced by S-(+)-mandipropamid than that induced by R-(-)-mandipropamid. This is the first study to elucidate the mandipropamid detoxification mechanism of earthworms at the enantiomer level, which can be beneficial for remediating chiral pollutants.
ESTHER : Fang_2021_Sci.Total.Environ_796_149051
PubMedSearch : Fang_2021_Sci.Total.Environ_796_149051
PubMedID: 34280637

Title : Origin of resistance to pyrethroids in the redlegged earth mite (Halotydeus destructor) in Australia: repeated local evolution and migration - Yang_2020_Pest.Manag.Sci_76_509
Author(s) : Yang Q , Umina PA , Rasic G , Bell N , Fang J , Lord A , Hoffmann AA
Ref : Pest Manag Sci , 76 :509 , 2020
Abstract : BACKGROUND: Halotydeus destructor is a major pest of crops and pastures across southern parts of Australia. This invasive mite has been chemically controlled for over 50 years, but resistance to synthetic pyrethroids and organophosphates is developing. Understanding processes behind the emerging resistance is important for effective management efforts. We undertook a ddRAD pool-sequencing approach to analyse genome-wide single nucleotide polymorphism variation in H. destructor population samples at two scales: local resistance across a set of fields, and regional resistance across their Australian range, along with toxicology bioassays to screen for pyrethroid resistance. RESULTS: Spatial patterns of genomic variation and resistance at a local scale indicated that genetic similarity among samples was more closely correlated with distance along roads and fence-lines than with straight-line geographic distance. This pattern was particularly strong in resistant samples, which were also more related than susceptible samples, suggesting local spread of resistance within an area after it emerged. By contrast, regional data suggest resistance has emerged repeatedly within parts of Australia. Our de novo annotation of the H. destructor draft genome sequence and Bayesian analysis identified several candidate loci strongly associated with population-level resistance to pyrethroids, located in genomic regions that code for transmembrane transport and signalling proteins that have previously been linked to insecticide resistance in other arthropods. CONCLUSION: Our findings highlight multiple independent evolutionary events leading to resistance in H. destructor, and demonstrate the utility and cost-effectiveness of a cross-population, genome-wide association study to reveal processes underlying adaptive evolution in a non-model invasive species. 2019 Society of Chemical Industry.
ESTHER : Yang_2020_Pest.Manag.Sci_76_509
PubMedSearch : Yang_2020_Pest.Manag.Sci_76_509
PubMedID: 31259466

Title : Transcript-Level Analysis of Detoxification Gene Mutation-Mediated Chlorpyrifos Resistance in Laodelphax striatellus (Hemiptera: Delphacidae) - Zhang_2019_J.Econ.Entomol_112_1285
Author(s) : Zhang Y , Ma X , Han Y , Wang L , Liu Z , Guo H , Fang J
Ref : J Econ Entomol , 112 :1285 , 2019
Abstract : Enhanced detoxification and target mutations that weaken insecticide binding ability are major mechanisms of insecticide resistance. Among these, over-expression or site mutations of carboxylesterase (CarE), cytochrome P450s (CYP450), and glutathione-S-transferase (GST) were the main form responsible for insecticide detoxification; however, transcript-level analysis of the relationship of detoxification gene mutations with chlorpyrifos (an organophosphorus insecticide) resistance is scarce thus far. In this study, multiple sites exhibiting polymorphisms within three detoxification genes were firstly examined via sequencing among different chlorpyrifos-resistant and susceptible individuals of Laodelphax striatellus. For example, the mutation frequencies of A374V in LsCarE16 were 83, 33, and 3%, S277A in LsCarE24 were 88, 28, and 3%, E36K in LsCYP426A1 were 100, 65, and 0% for chlorpyrifos-resistant, resistant decay, and susceptible individuals, respectively. Analysis also found expression levels of GSTd1, GSTt1, GSTs2, CYP4DE1U1, and CYP425B1 are coordinated with chlorpyrifos resistance levels; moreover, we found the deficiencies of 43S and 44A as well as two point mutations of E60D and Q61H at N-terminal region of the OP potential target acetylcholinesterase (AChE) in high resistant but not in low-chlorpyrifos resistant individuals. The results above all demonstrated the dynamic evolutionary process of insecticide resistance and revealed some resistance factors that only played roles at certain resistance level; high insecticide resistance in this example is the result of synergistic impact from multiple resistance factors.
ESTHER : Zhang_2019_J.Econ.Entomol_112_1285
PubMedSearch : Zhang_2019_J.Econ.Entomol_112_1285
PubMedID: 30615131

Title : Biomarkers responses in Manila clam, Ruditapes philippinarum after single and combined exposure to mercury and benzo[a]pyrene - Jiang_2019_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_220_1
Author(s) : Jiang W , Fang J , Gao Y , Du M , Wang X , Li F , Lin F , Jiang Z
Ref : Comparative Biochemistry & Physiology C Toxicol Pharmacol , 220 :1 , 2019
Abstract : Physiological and biochemical responses in bivalves exposed to pollutants have proved a valuable tool to assess the health of organisms in aquatic ecosystems. The single and combined effects of mercury (Hg(2+), 2 and 10mug/L) and benzo[a]pyrene (BaP, 3mug/L) on physiological and biochemical biomarkers in Manila clam, Ruditapes philippinarum were evaluated. Results showed that significant higher oxygen consumption (OR) and ammonia-N excretion rates (NR) together with significant lower ingestion rates (IR) were observed for the 10mug/L Hg(2+) or 3mug/L BaP treatments compared to controls (P<0.05). However, clam NR decreased significantly in response to the binary mixtures of 10mug/L Hg(2+) and 3mug/L BaP (P<0.05). Moreover, the levels of superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferases (GSTs), glutathione (GSH), acetylcholinesterase (AChE) and malondialdehyde (MDA) in the hepatopancreas of clams were induced substantially, whereas glycogen (GLY) contents were suppressed dramatically after Hg(2+) and BaP exposure. Additionally, the integrated biomarker response (IBR) values measured showed significant increases in combination treatments and they were much higher than that in the Hg(2+) treatment. This study will provide further information on the defense mechanism in the Manila clam after exposure to marine pollutants and may help evaluate the quality of the aquatic environment.
ESTHER : Jiang_2019_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_220_1
PubMedSearch : Jiang_2019_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_220_1
PubMedID: 30802620

Title : DL0410 Ameliorates Memory and Cognitive Impairments Induced by Scopolamine via Increasing Cholinergic Neurotransmission in Mice - Lian_2017_Molecules_22_
Author(s) : Lian W , Fang J , Xu L , Zhou W , Kang , Xiong W , Jia H , Liu AL , Du GH
Ref : Molecules , 22 : , 2017
Abstract : Deficiency of the cholinergic system is thought to play a vital role in cognitive impairment of dementia. DL0410 was discovered as a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinestease (BuChE), with potent efficiency in in-vitro experiments, but its in vivo effect on the cholinergic model has not been evaluated, and its action mechanism has also not been illustrated. In the present study, the capability of DL0410 in ameliorating the amnesia induced by scopolamine was investigated, and its effect on the cholinergic system in the hippocampus and its binding mode in the active site of AChE was also explored. Mice were administrated DL0410 (3 mg/kg, 10 mg/kg, and 30 mg/kg), and mice treated with donepezil were used as a positive control. The Morris water maze, escape learning task, and passive avoidance task were used as behavioral tests. The test results indicated that DL0410 could significantly improve the learning and memory impairments induced by scopolamine, with 10 mg/kg performing best. Further, DL0410 inhibited the AChE activity and increased acetylcholine (ACh) levels in a dose-dependent manner, and interacted with the active site of AChE in a similar manner as donepezil. However, no difference in the activity of BuChE was found in this study. All of the evidence indicated that its AChE inhibition is an important mechanism in the anti-amnesia effect. In conclusion, DL0410 could be an effective therapeutic drug for the treatment of dementia, especially Alzheimer's disease.
ESTHER : Lian_2017_Molecules_22_
PubMedSearch : Lian_2017_Molecules_22_
PubMedID: 28272324

Title : Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure-Activity Relationships Models, Molecular Docking, and Molecular Dynamics Simulations - Fang_2016_Chem.Biol.Drug.Des_87_649
Author(s) : Fang J , Pang X , Wu P , Yan R , Gao L , Li C , Lian W , Wang Q , Liu AL , Du GH
Ref : Chemical Biology Drug Des , 87 :649 , 2016
Abstract : A dataset of 67 berberine derivatives for the inhibition of butyrylcholinesterase (BuChE) was studied based on the combination of quantitative structure-activity relationships models, molecular docking, and molecular dynamics methods. First, a series of berberine derivatives were reported, and their inhibitory activities toward butyrylcholinesterase (BuChE) were evaluated. By 2D- quantitative structure-activity relationships studies, the best model built by partial least-square had a conventional correlation coefficient of the training set (R(2) ) of 0.883, a cross-validation correlation coefficient (Qcv2) of 0.777, and a conventional correlation coefficient of the test set (Rpred2) of 0.775. The model was also confirmed by Y-randomization examination. In addition, the molecular docking and molecular dynamics simulation were performed to better elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. The predicted binding free energy results were consistent with the experimental data and showed that the van der Waals energy term (DeltaEvdw ) difference played the most important role in differentiating the activity among the three inhibitors (berberine, C2, and C55). The developed quantitative structure-activity relationships models provide details on the fine relationship linking structure and activity and offer clues for structural modifications, and the molecular simulation helps to understand the inhibitory mechanism of the three typical inhibitors. In conclusion, the results of this study provide useful clues for new drug design and discovery of BuChE inhibitors from berberine derivatives.
ESTHER : Fang_2016_Chem.Biol.Drug.Des_87_649
PubMedSearch : Fang_2016_Chem.Biol.Drug.Des_87_649
PubMedID: 26648584

Title : Discovery of Multitarget-Directed Ligands against Alzheimer's Disease through Systematic Prediction of Chemical-Protein Interactions - Fang_2015_J.Chem.Inf.Model_55_149
Author(s) : Fang J , Li Y , Liu R , Pang X , Li C , Yang R , He Y , Lian W , Liu AL , Du GH
Ref : J Chem Inf Model , 55 :149 , 2015
Abstract : To determine chemical-protein interactions (CPI) is costly, time-consuming, and labor-intensive. In silico prediction of CPI can facilitate the target identification and drug discovery. Although many in silico target prediction tools have been developed, few of them could predict active molecules against multitarget for a single disease. In this investigation, naive Bayesian (NB) and recursive partitioning (RP) algorithms were applied to construct classifiers for predicting the active molecules against 25 key targets toward Alzheimer's disease (AD) using the multitarget-quantitative structure-activity relationships (mt-QSAR) method. Each molecule was initially represented with two kinds of fingerprint descriptors (ECFP6 and MACCS). One hundred classifiers were constructed, and their performance was evaluated and verified with internally 5-fold cross-validation and external test set validation. The range of the area under the receiver operating characteristic curve (ROC) for the test sets was from 0.741 to 1.0, with an average of 0.965. In addition, the important fragments for multitarget against AD given by NB classifiers were also analyzed. Finally, the validated models were employed to systematically predict the potential targets for six approved anti-AD drugs and 19 known active compounds related to AD. The prediction results were confirmed by reported bioactivity data and our in vitro experimental validation, resulting in several multitarget-directed ligands (MTDLs) against AD, including seven acetylcholinesterase (AChE) inhibitors ranging from 0.442 to 72.26 muM and four histamine receptor 3 (H3R) antagonists ranging from 0.308 to 58.6 muM. To be exciting, the best MTDL DL0410 was identified as an dual cholinesterase inhibitor with IC50 values of 0.442 muM (AChE) and 3.57 muM (BCHE) as well as a H3R antagonist with an IC50 of 0.308 muM. This investigation is the first report using mt-QASR approach to predict chemical-protein interaction for a single disease and discovering highly potent MTDLs. This protocol may be useful for in silico multitarget prediction of other diseases.
ESTHER : Fang_2015_J.Chem.Inf.Model_55_149
PubMedSearch : Fang_2015_J.Chem.Inf.Model_55_149
PubMedID: 25531792

Title : Effect of different chemical bonds in pegylation of zinc protoporphyrin that affects drug release, intracellular uptake, and therapeutic effect in the tumor - Tsukigawa_2015_Eur.J.Pharm.Biopharm_89_259
Author(s) : Tsukigawa K , Nakamura H , Fang J , Otagiri M , Maeda H
Ref : Eur J Pharm Biopharm , 89 :259 , 2015
Abstract : Pegylated zinc protoporphyrin (PEG-ZnPP) is a water-soluble inhibitor of heme oxygenase-1. In this study, we prepared two types of PEG-ZnPP conjugates with different chemical bonds between PEG and ZnPP, i.e., ester bonds and ether bonds, where both conjugates also contain amide bonds. Cleavability of these bonds in vitro and in vivo, especially cancer tissue, and upon intracellular uptake, was investigated in parallel with biological activities of the conjugates. Each conjugate showed different cleavability by plasma esterases and tumor proteases, as revealed by HPLC analyses. PEG-ZnPP with ester bond (esPEG-ZnPP) was more sensitive than PEG-ZnPP with ether bond (etPEG-ZnPP) for cleavage of PEG chains. etPEG-ZnPP showed no cleavage of PEG chains and had lower intracellular uptake and antitumor activity than did esPEG-ZnPP. The degradation of esPEG-ZnPP appeared to be facilitated by both serine and cysteine proteases in tumor tissues, whereas it was significantly slower in normal organs except the liver. Depegylated products such as free ZnPP had higher intracellular uptake than did intact PEG-ZnPP. We also studied hydrolytic cleavage by blood plasma of different animal species; mouse plasma showed the fastest cleavage whereas human plasma showed the slowest. These results suggest that ester-linked conjugates manifest more efficient cleavage of PEG, and greater yield of the active principle from the conjugates in tumor tissues than in normal tissues. More efficient intracellular uptake and thus an improved therapeutic effect with ester-linked conjugates are thus anticipated with fain stability, particularly in human blood.
ESTHER : Tsukigawa_2015_Eur.J.Pharm.Biopharm_89_259
PubMedSearch : Tsukigawa_2015_Eur.J.Pharm.Biopharm_89_259
PubMedID: 25527214

Title : Cloning of Two Acetylcholinesterase Genes and Analysis of Point Mutations Putatively Associated with Triazophos Resistance in Chilo auricilius (Lepidoptera: Pyralidae) - Luo_2015_J.Econ.Entomol_108_1289
Author(s) : Luo G , Li X , Zhang Z , Liu B , Huang S , Fang J
Ref : J Econ Entomol , 108 :1289 , 2015
Abstract : Acetylcholinesterase (AChE) is the target of organophosphate (OP) and carbamate insecticides. Mutations in the AChE gene (ace) leading to decreased insecticide susceptibility is the main resistance mechanism in insects. In this study, two Chilo auricilius acetylcholinesterase genes, designated as Caace1 and Caace2, were cloned using RT-PCR and RACE. Caace1 cDNA is 2534 bp, with ORF of 2082 bp, and it encodes an acetylcholinesterase 1 (CaAChE1) protein comprising a calculated 693 amino acid (aa) residues. Caace2 cDNA contains 2280 bp, with a full-length ORF of 1917 bp, encoding acetylcholinesterase 2 (CaAChE2) comprising a calculated 638 aa residues. At the aa level, CaAChE1 displays the highest similarity (97%) with the Chilo suppressalis AChE1, and CaAChE2 shows the highest similarity with the C. suppressalis AChE2 (99%). From the restriction fragment length polymorphism (RFLP) PCR (RFLP-PCR) analysis, one mutation in Caace1, similar to the ace1 mutation associated with triazophos resistance in C. suppressalis, was detected. Detailed examination of field populations of C. auricilius indicated this resistance mutation in C. auricilius is still quite infrequent. Based on the assay of AChE activity and RFLP-PCR testing, an individual that contains resistance mutation has lower AChE activities, while the individual that does not contain the resistance mutation has higher AChE activities. This study provides a basis for future investigations into the mechanism of OP resistance in C. auricilius, as well as a guidance for C. auricilius control with reasonable choice of pesticides.
ESTHER : Luo_2015_J.Econ.Entomol_108_1289
PubMedSearch : Luo_2015_J.Econ.Entomol_108_1289
PubMedID: 26470257
Gene_locus related to this paper: 9neop-a0a076vew9 , 9neop-a0a076vj71

Title : Validating the importance of two acetylcholinesterases in insecticide sensitivities by RNAi in Pardosa pseudoannulata, an important predatory enemy against several insect pests - Meng_2015_Pestic.Biochem.Physiol_125_26
Author(s) : Meng X , Li C , Bao H , Fang J , Liu Z , Zhang Y
Ref : Pestic Biochem Physiol , 125 :26 , 2015
Abstract : The pond wolf spider (Pardosa pseudoannulata) is an important predatory enemy against several insect pests and showed relative different sensitivities to organophosphate and carbamate insecticides compared to insect pests. In our previous studies, two acetylcholinesterases were identified in P. pseudoannulata and played important roles in insecticide sensitivities. In order to understand the contributions of the two acetylcholinesterases to insecticide sensitivities, we firstly employed the RNAi technology in the spider. For a suitable microinjection RNAi method, the injection site, injection volume and interference time were optimized, which then demonstrated that the injection RNAi method was applicable in this spider. With the new RNAi method, it was revealed that both Pp-AChE1 and Pp-AChE2, encoded by genes Ppace1 and Ppace2, were the targets of organophosphate insecticides, but Pp-AChE1 would be more important. In contrast, the carbamate acted selectively on Pp-AChE1. The results showed that Pp-AChE1 was the major catalytic enzyme in P. pseudoannulata and the major target of organophosphate and carbamate insecticides. In a word, an RNAi method was established in the pond wolf spider, which further validated the importance of two acetylcholinesterases in insecticide sensitivities in this spider.
ESTHER : Meng_2015_Pestic.Biochem.Physiol_125_26
PubMedSearch : Meng_2015_Pestic.Biochem.Physiol_125_26
PubMedID: 26615147

Title : Inhibition of acetylcholinesterase by two genistein derivatives: kinetic analysis, molecular docking and molecular dynamics simulation - Fang_2014_Acta.Pharm.Sin.B_4_430
Author(s) : Fang J , Wu P , Yang R , Gao L , Li C , Wang D , Wu S , Liu AL , Du GH
Ref : Acta Pharm Sin B , 4 :430 , 2014
Abstract : In this study two genistein derivatives (G1 and G2) are reported as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and differences in the inhibition of AChE are described. Although they differ in structure by a single methyl group, the inhibitory effect of G1 (IC50=264 nmol/L) on AChE was 80 times stronger than that of G2 (IC50=21,210 nmol/L). Enzyme-kinetic analysis, molecular docking and molecular dynamics (MD) simulations were conducted to better understand the molecular basis for this difference. The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE. The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area (MM/GBSA) method were consistent with the experimental data. The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions (DeltaE ele+DeltaG GB) was responsible for the binding affinities of these two inhibitors. Additionally, analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124, Glu292, Val294 and Phe338 of AChE. In conclusion, the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.
ESTHER : Fang_2014_Acta.Pharm.Sin.B_4_430
PubMedSearch : Fang_2014_Acta.Pharm.Sin.B_4_430
PubMedID: 26579414

Title : Design, synthesis and biological evaluation of organophosphorous-homodimers as dual binding site acetylcholinesterase inhibitors - Xie_2013_Bioorg.Med.Chem_21_278
Author(s) : Xie R , Zhao Q , Zhang T , Fang J , Mei X , Ning J , Tang Y
Ref : Bioorganic & Medicinal Chemistry , 21 :278 , 2013
Abstract : The cluster effect is an effective strategy to explore new lead compounds, and has been successfully applied in rational drug design and screening. A series of novel organophosphorous-homodimers were designed and synthesized based on the dual-site structure characteristics of acetylcholinesterase (AChE). The compounds were evaluated in vitro for their inhibitory activity to AChE extracted from Drosophila melanogaster and Musca domestic. Compound 4H showed an excellent inhibitor activity to both Drosophila melanogaster and Musca domestic with the corresponding IC(50) values of 23 and 168nM, respectively. Meanwhile, its activities against Drosophila melanogaster and Musca domestic AChE were more than 10,00,000 and 100,000-fold higher compared with the parent compound (MH), and was up to 245 and 107-fold higher than those of the positive control omethoate. The molecular docking study revealed that 4H possessed an optimal spacer length and can perfectly fit into the central pocket, active gorge, and peripheral site of DmAChE, and consequently exhibited highly improved inhibitor potency to DmAChE. The bioassay tests showed that 4 series compounds showed prominent insecticidal activities against both Lipaphser erysimi and Tetranychus cinnbarinus at a concentration of 200mg/L. The insecticide activity of compound 4H was particularly significant that can cause 96% mortality to Tetranychus cinnbarinus after 24h of treatment.
ESTHER : Xie_2013_Bioorg.Med.Chem_21_278
PubMedSearch : Xie_2013_Bioorg.Med.Chem_21_278
PubMedID: 23200223

Title : Predictions of BCHE Inhibitors Using Support Vector Machine and Naive Bayesian Classification Techniques in Drug Discovery - Fang_2013_J.Chem.Inf.Model_53_3009
Author(s) : Fang J , Yang R , Gao L , Zhou D , Yang S , Liu AL , Du GH
Ref : J Chem Inf Model , 53 :3009 , 2013
Abstract : Butyrylcholinesterase (BCHE, EC is an important pharmacological target for Alzheimer's disease (AD) treatment. However, the currently available BCHE inhibitor screening assays are expensive, labor-intensive, and compound-dependent. It is necessary to develop robust in silico methods to predict the activities of BCHE inhibitors for the lead identification. In this investigation, support vector machine (SVM) models and naive Bayesian models were built to discriminate BCHE inhibitors (BCHEIs) from the noninhibitors. Each molecule was initially represented in 1870 structural descriptors (1235 from ADRIANA.Code, 334 from MOE, and 301 from Discovery studio). Correlation analysis and stepwise variable selection method were applied to figure out activity-related descriptors for prediction models. Additionally, structural fingerprint descriptors were added to improve the predictive ability of models, which were measured by cross-validation, a test set validation with 1001 compounds and an external test set validation with 317 diverse chemicals. The best two models gave Matthews correlation coefficient of 0.9551 and 0.9550 for the test set and 0.9132 and 0.9221 for the external test set. To demonstrate the practical applicability of the models in virtual screening, we screened an in-house data set with 3601 compounds, and 30 compounds were selected for further bioactivity assay. The assay results showed that 10 out of 30 compounds exerted significant BCHE inhibitory activities with IC50 values ranging from 0.32 to 22.22 muM, at which three new scaffolds as BCHE inhibitors were identified for the first time. To our best knowledge, this is the first report on BCHE inhibitors using machine learning approaches. The models generated from SVM and naive Bayesian approaches successfully predicted BCHE inhibitors. The study proved the feasibility of a new method for predicting bioactivities of ligands and discovering novel lead compounds.
ESTHER : Fang_2013_J.Chem.Inf.Model_53_3009
PubMedSearch : Fang_2013_J.Chem.Inf.Model_53_3009
PubMedID: 24144102

Title : Homo- and hetero-dimers of inactive organophosphorous group binding at dual sites of AChE - Zhao_2011_Bioorg.Med.Chem.Lett_21_6404
Author(s) : Zhao Q , Xie R , Zhang T , Fang J , Mei X , Ning J , Tang Y
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :6404 , 2011
Abstract : Homo- and hetero-dimers of inactive organophosphorous group(s) dramatically enhanced the acetylcholinesterase (AChE; EC inhibiting potency, with the highest potency observed at a tether length of 6 methylene groups (6d) for the homodimers, and 7 methylene groups (8e) for the heterodimers. The docking model of Drosophila melanogaster AChE suggested that 6d and 8e bound at the catalytic and peripheral sites of AChE, in which two organophosphorous groups of 6d individually oriented towards TRP83 of catalytic sites and TRP321 of peripheral sites, and phthalicimide group of 8e was appropriately arranged for a pi-pi interaction with the phenyl ring of TYR330, furthermore, the organophosphorous group introduced hydrophobic interaction with TRP83. The compounds prepared in this work demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnbarinus at the concentration 300mg/L.
ESTHER : Zhao_2011_Bioorg.Med.Chem.Lett_21_6404
PubMedSearch : Zhao_2011_Bioorg.Med.Chem.Lett_21_6404
PubMedID: 21940169

Title : Cross-resistance and possible mechanisms of chlorpyrifos resistance in Laodelphax striatellus (Fallen) - Wang_2010_Pest.Manag.Sci_66_1096
Author(s) : Wang L , Zhang Y , Han Z , Liu Y , Fang J
Ref : Pest Manag Sci , 66 :1096 , 2010
Abstract : BACKGROUND: Laodelphax striatellus (Fallen) is a major pest of cultivated rice and is commonly controlled in China with the organophosphate insecticides. To develop a better resistance management strategy, a chlorpyrifos-resistant strain of L. striatellus was selected in the laboratory, and its cross-resistance to other insecticides and possible mechanisms of the chlorpyrifos resistance were investigated. RESULTS: After 25 generations of selection with chlorpyrifos, the selected strain of L. striatellus developed 188-fold resistance to chlorpyrifos in comparison with the susceptible strain, and showed 14- and 1.6-fold cross-resistance to dichlorvos and thiamethoxam respectively. There was no apparent cross-resistance to abamectin. Chlorpyrifos was synergised by the inhibitor triphenyl phosphate; the carboxylesterase synergistic ratio was 3.8 for the selected strain, but only 0.92 for the susceptible strain. The carboxylesterase activity of the selected strain was approximately 4 times that of the susceptible strain, whereas there was no significant change in the activities of alkaline phosphatase, acid phosphatase, glutathione S-transferase and cytochrome P450 monooxygenase between the strains. The Michaelis constant of acetylcholinesterase, maximum velocity of acetylcholinesterase and median inhibitory concentration of chlorpyrifos-oxon on acetylcholinesterase were 1.7, 2.5 and 5 times higher respectively in the selected strain. CONCLUSION: The high cross-resistance to the organophosphate dichlorvos in the chlorpyrifos-resistant strain suggests that other non-organophosphate insecticides would be necessary to counter resistance, should it arise in the field. Enhanced activities of carboxylesterase and the acetylcholinesterase insensitivity appear to be important mechanisms for chlorpyrifos resistance in L. striatellus.
ESTHER : Wang_2010_Pest.Manag.Sci_66_1096
PubMedSearch : Wang_2010_Pest.Manag.Sci_66_1096
PubMedID: 20582994

Title : Mutation in acetylcholinesterase1 associated with triazophos resistance in rice stem borer, Chilo suppressalis (Lepidoptera: Pyralidae) - Jiang_2009_Biochem.Biophys.Res.Commun_378_269
Author(s) : Jiang X , Qu M , Denholm I , Fang J , Jiang W , Han Z
Ref : Biochemical & Biophysical Research Communications , 378 :269 , 2009
Abstract : Two full-length genes encoding different acetylcholinesterases (AChEs), designated as Ch-ace1 and Ch-ace2, were cloned from strains of the rice stem borer (Chilo suppressalis) susceptible and resistant to the organophosphate insecticide triazophos. Sequence analysis found an amino acid mutation A314S in Ch-ace1 (corresponding to A201 in Torpedo californica AChE) that was consistently associated with the occurrence of resistance. This mutation removed an MspA1 I restriction site from the wild type allele. An assay based on restriction fragment length polymorphism (RFLP) analysis was developed to diagnose A314S genotypes in field populations. Results showed a strong correlation between frequencies of the mutation and phenotypic levels of resistance to triazophos. The assay offers a prospect for rapid monitoring of resistance and assisting with the appropriate choice of insecticide for combating damage caused by C. suppressalis.
ESTHER : Jiang_2009_Biochem.Biophys.Res.Commun_378_269
PubMedSearch : Jiang_2009_Biochem.Biophys.Res.Commun_378_269
PubMedID: 19028456
Gene_locus related to this paper: 9neop-ACHE1 , 9neop-ACHE2

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 : 2-Cyano-4-fluoro-1-thiovalylpyrrolidine analogues as potent inhibitors of DPP-IV - Haffner_2005_Bioorg.Med.Chem.Lett_15_5257
Author(s) : Haffner CD , McDougald DL , Reister SM , Thompson BD , Conlee C , Fang J , Bass J , Lenhard JM , Croom D , Secosky-Chang MB , Tomaszek T , McConn D , Wells-Knecht K , Johnson PR
Ref : Bioorganic & Medicinal Chemistry Lett , 15 :5257 , 2005
Abstract : We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.
ESTHER : Haffner_2005_Bioorg.Med.Chem.Lett_15_5257
PubMedSearch : Haffner_2005_Bioorg.Med.Chem.Lett_15_5257
PubMedID: 16168640