Author Report for: Cheng XNo contact information in database for Cheng X
Gerlits O, Fajer M, Cheng X, Blumenthal DK, Radic Z, Kovalevsky A Ref: Structure, :, 2022 : PubMed ESTHER: Gerlits_2022_Structure__ PubMedSearch: Gerlits 2022 Structure PubMedID: 36265484 Abstract Organophosphorus (OP) compounds, including nerve agents and some pesticides, covalently bind to the catalytic serine of human acetylcholinesterase (hAChE), thereby inhibiting acetylcholine hydrolysis necessary for efficient neurotransmission. Oxime antidotes can reactivate the OP-conjugated hAChE, but reactivation efficiency can be low for pesticides, such as paraoxon (POX). Understanding structural and dynamic determinants of OP inhibition and reactivation can provide insights to design improved reactivators. Here, X-ray structures of hAChE with unaged POX, with POX and oximes MMB4 and RS170B, and with MMB4 are reported. A significant conformational distortion of the acyl loop was observed upon POX binding, being partially restored to the native conformation by oximes. Neutron vibrational spectroscopy combined with molecular dynamics simulations showed that picosecond vibrational dynamics of the acyl loop soften in the -20-50 cm(-1) frequency range. The acyl loop structural perturbations may be correlated with its picosecond vibrational dynamics to yield more comprehensive template for structure-based reactivator design. Title: Covalent inhibition of hAChE by organophosphates causes homodimer dissociation through long-range allosteric effects Blumenthal DK, Cheng X, Fajer M, Ho KY, Rohrer J, Gerlits O, Taylor P, Juneja P, Kovalevsky A, Radic Z Ref: Journal of Biological Chemistry, :101007, 2021 : PubMed ESTHER: Blumenthal_2021_J.Biol.Chem__ PubMedSearch: Blumenthal 2021 J.Biol.Chem PubMedID: 34324828 Gene_locus related to this paper: human-ACHE Inhibitor(s) related to this paper: Paraoxon, Sarin Abstract Acetylcholinesterase (EC 3.1.1.7; AChE), a key acetylcholine-hydrolyzing enzyme in cholinergic neurotransmission, is present in a variety of states in situ, including monomers, C-terminally disulfide-linked homodimers, homotetramers, and up to three tetramers covalently attached to structural subunits. Could oligomerization that ensures high local concentrations of catalytic sites necessary for efficient neurotransmission, be affected by environmental factors? Using small-angle X-ray scattering (SAXS) and cryo-EM, we demonstrate that homodimerization of recombinant monomeric human AChE (hAChE) in solution occurs through a C-terminal 4-helix bundle (4HB) at micromolar concentrations. We show that diethylphosphorylation of the active serine in the catalytic gorge or isopropylmethylphosphonylation by the R(P) enantiomer of sarin promotes a ten-fold increase in homodimer dissociation. We also demonstrate the dissociation of organophosphate (OP)-conjugated dimers is reversed by structurally diverse oximes 2PAM, HI6 or RS194B, as demonstrated by SAXS of diethylphosphoryl-hAChE. However, binding of oximes to the native ligand-free hAChE, binding of high-affinity reversible ligands, or formation of a S(P)-sarin-hAChE conjugate had no effect on homodimerization. Dissociation monitored by time-resolved SAXS (TR-SAXS) occurs in milliseconds, consistent with rates of hAChE covalent inhibition. OP-induced dissociation was not observed in the SAXS profiles of the double-mutant Y337A/F338A, where the active center gorge volume is larger than in wild-type hAChE. These observations suggest a key role of the tightly packed acyl pocket in allosterically triggered OP-induced dimer dissociation, with the potential for local reduction of acetylcholine-hydrolytic power in situ. Computational models predict allosteric correlated motions extending from the acyl pocket towards the 4HB dimerization interface 25 A away. Title: Dynamic changes in chemical compositions and anti-acetylcholinesterase activity associated with steaming process of stem-leaf saponins of Panax notoginseng Ma C, Guan H, Lin Q, Liu C, Ju Z, Xue Y, Cheng X, Wang C Ref: Biomedical Chromatography, :e5077, 2021 : PubMed ESTHER: Ma_2021_Biomed.Chromatogr__e5077 PubMedSearch: Ma 2021 Biomed.Chromatogr e5077 PubMedID: 33475178 Abstract Stem-leaf saponins (SLS), the total saponins from aerial part of P. notoginseng, are by-products of notoginseng, a famous tradition Chinese medicine. SLS have been used as a health functional food in China, but its mild effects limited clinical applications in diseases. Inspired by steaming of notoginseng to enhance pharmacological activity, a steaming protocol was developed to deal SLS. SLS were steamed at 100 degreesC, 120 degreesC, and 140 degreesC for 1, 2, 3, and 4 h, respectively. The UPLC-Q-TOF and UPLC-MS/MS were applied to analyze the dynamic changes in chemical compositions. Anti-acetylcholinesterase activity of steamed SLS were assessed in vitro by directly determining the metabolic product of acetylcholine, choline. The components of SLS were significantly changed by steaming. Total 117 saponins and aglycones were characterized, and 35 of them were newly generated. The anti-acetylcholinesterase activity of steamed SLS gradually increased with the extension of steamed time and the increase of steamed temperature and reached the maximum after 140 degreesC for 3 h. Furthermore, ginsenosides Rk1 and Rg5, the main components of steamed SLS, showed dose-dependent anti-acetylcholinesterase activities with IC(50) values of 26.88 +/- 0.53 microM and 22.41 +/- 1.31 microM that were only 1.8- and 1.5-fold higher than donepezil, respectively. Title: Combined effects of polyethylene and organic contaminant on zebrafish (Danio rerio): Accumulation of 9-Nitroanthracene, biomarkers and intestinal microbiota Zhang J, Meng H, Kong X, Cheng X, Ma T, He H, Du W, Yang S, Li S, Zhang L Ref: Environ Pollut, 277:116767, 2021 : PubMed ESTHER: Zhang_2021_Environ.Pollut_277_116767 PubMedSearch: Zhang 2021 Environ.Pollut 277 116767 PubMedID: 33640823 Abstract Microplastics, as emerging pollutant, are predicted to act as carriers for organic pollutants, but the carrier role and bio-toxic effects with other pollutants in environments are poorly acknowledged. In this study, both the single and combined effects of polyethylene (PE, 10 and 40 mg/L) with the particle size of 100-150 microm and 9-Nitroanthracene (9-NAnt, 5 and 500 microg/L) on zebrafish (Danio rerio) had been investigated. The results illustrated that PE could be as 9-NAnt carrier to enter into zebrafish body, but significantly reduced the bioaccumulation of 9-NAnt, due to the occurrence of adsorption interactions between the simultaneous presence of both PE and 9-NAnt. After 4 days, the enzymes activity of cytochrome P4501A, acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), lactate dehydrogenase (LDH), and the abundance of malondialdehyde (MDA), lipid peroxide (LPO) responded strongly to low-dose PE exposure (10 mg/L). After 7 days exposure to PE-9-NAnt (40 mg/L), the P4501A activity increased significantly, but the activities of AChE and LDH were inhibited clearly, causing certain neurotoxicity and disorders of energy metabolism to zebrafish. The analysis of integrated biomarker response index (IBR) suggested that PE had greater bio-toxicity to zebrafish in all exposure groups after short-term exposure, but the PE-9-NAnt complex showed greater bio-toxicity after 7 days, which indicated that complex exposure of PE-9-NAnt had a delayed effect on the bio-toxicity of zebrafish. Furthermore, analysis of the intestinal microbiota exhibited that under the conditions of the exposure group with 9-NAnt, the relative abundance of the five dominant bacterial phyla (Proteobacteria, Firmicutes, Fusobacteriota, Bacteroidota and Verrucomicrobiota) changed greatly. Overall, this study confirmed that PE could carry 9-NAnt into fish causing bioaccumulation, but in the case of coexisting exposures, PE reduced 9-NAnt bioaccumulation, suggesting that microplastics with other emerging pollutants in chronic toxicity are probably next objects in future works. Title: Potential of esterase DmtH in transforming plastic additive dimethyl terephthalate to less toxic mono-methyl terephthalate Cheng X, Dong S, Chen D, Rui Q, Guo J, Dayong W, Jiang J Ref: Ecotoxicology & Environmental Safety, 187:109848, 2020 : PubMed ESTHER: Cheng_2020_Ecotoxicol.Environ.Saf_187_109848 PubMedSearch: Cheng 2020 Ecotoxicol.Environ.Saf 187 109848 PubMedID: 31670182 Gene_locus related to this paper: 9sphn-a0a3s8nd90 Abstract Dimethyl terephthalate (DMT) is a primary ingredient widely used in the manufacture of polyesters and industrial plastics; its environmental fate is of concern due to its global use. Microorganisms play key roles in the dissipation of DMT from the environment; however, the enzymes responsible for the initial transformation of DMT and the possible altered toxicity due to this biotransformation have not been extensively studied. To reduce DMT toxicity, we identified the esterase gene dmtH involved in the initial transformation of DMT from the AOPP herbicide-transforming strain Sphingobium sp. C3. DmtH shows 24-41% identity with alpha/beta-hydrolases and belongs to subfamily V of bacterial esterases. The purified recombinant DmtH was capable of transforming DMT to mono-methyl terephthalate (MMT) and potentially transforming other p-phthalic acid esters, including diallyl terephthalate (DAT) and diethyl terephthalate (DET). Using C. elegans as an assay model, we observed the severe toxicity of DMT in inducing reactive oxygen species (ROS) production, decreasing locomotion behavior, reducing lifespan, altering molecular basis for oxidative stress, and inducing mitochondrial stress. In contrast, exposure to MMT did not cause obvious toxicity, induce oxidative stress, and activate mitochondrial stress in nematodes. Our study highlights the usefulness of Sphingobium sp. C3 and its esterase DmtH in transforming p-phthalic acid esters and reducing the toxicity of DMT to organisms. Title: Rational design, synthesis and evaluation of uncharged, smart bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase Gorecki L, Gerlits O, Kong X, Cheng X, Blumenthal DK, Taylor P, Ballatore C, Kovalevsky A, Radic Z Ref: Journal of Biological Chemistry, 295:4079, 2020 : PubMed ESTHER: Gorecki_2020_J.Biol.Chem_295_4079 PubMedSearch: Gorecki 2020 J.Biol.Chem 295 4079 PubMedID: 32019865 Gene_locus related to this paper: human-ACHE Inhibitor(s) related to this paper: VX Abstract Corrected : Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime-based therapies whose success rates are currently limited. The pyridinium cation hampers uptake into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are non-productive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)-inhibited human AChE (hAChE), here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-hAChE conjugates. Oxime group re-orientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, "smart" accelerated antidotes against OP toxicity. Title: No significant association between dipeptidyl peptidase-4 inhibitors and adverse outcomes of COVID-19 Zhou JH, Wu B, Wang WX, Lei F, Cheng X, Qin JJ, Cai JJ, Zhang XJ, Zhou F and Li HL <6 more author(s)> Zhou JH, Wu B, Wang WX, Lei F, Cheng X, Qin JJ, Cai JJ, Zhang XJ, Zhou F, Liu YM, Li HM, Zhu LH, She ZG, Zhang X, Yang J, Li HL (- 6) Ref: World J Clin Cases, 8:5576, 2020 : PubMed ESTHER: Zhou_2020_World.J.Clin.Cases_8_5576 PubMedSearch: Zhou 2020 World.J.Clin.Cases 8 5576 PubMedID: 33344548 Abstract BACKGROUND: Dipeptidyl peptidase-4 (DPP4) is commonly targeted to achieve glycemic control and has potent anti-inflammatory and immunoregulatory effects. Recent structural analyses indicated a potential tight interaction between DPP4 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raising a promising hypothesis that DPP4 inhibitor (DPP4i) drugs might be an optimal strategy for treating coronavirus disease 2019 (COVID-19) among patients with diabetes. However, there has been no direct clinical evidence illuminating the associations between DPP4i use and COVID-19 outcomes. AIM: To illuminate the associations between DPP4i usage and the adverse outcomes of COVID-19. METHODS: We conducted a multicenter, retrospective analysis including 2563 patients with type 2 diabetes who were hospitalized due to COVID-19 at 16 hospitals in Hubei Province, China. After excluding ineligible individuals, 142 patients who received DPP4i drugs and 1115 patients who received non-DPP4i oral anti-diabetic drugs were included in the subsequent analysis. We performed a strict propensity score matching (PSM) analysis where age, sex, comorbidities, number of oral hypoglycemic agents, heart rate, blood pressure, pulse oxygen saturation (SpO(2)) < 95%, CT diagnosed bilateral lung lesions, laboratory indicators, and proportion of insulin usage were matched. Finally, 111 participants treated with DPP4i drugs were successfully matched to 333 non-DPP4i users. Then, a linear logistic model and mixed-effect Cox model were applied to analyze the associations between in-hospital DPP4i use and adverse outcomes of COVID-19. RESULTS: After rigorous matching and further adjustments for imbalanced variables in the linear logistic model and Cox adjusted model, we found that there was no significant association between in-hospital DPP4i use (DPP4i group) and 28-d all-cause mortality (adjusted hazard ratio = 0.44, 95%CI: 0.09-2.11, P = 0.31). Likewise, the incidences and risks of secondary outcomes, including septic shock, acute respiratory distress syndrome, or acute organ (kidney, liver, and cardiac) injuries, were also comparable between the DPP4i and non-DPP4i groups. The performance of DPP4i agents in achieving glucose control (e.g., the median level of fasting blood glucose and random blood glucose) and inflammatory regulation was approximately equivalent in the DPP4i and non-DPP4i groups. Furthermore, we did not observe substantial side effects such as uncontrolled glycemia or acidosis due to DPP4i application relative to the use of non-DPP4i agents in the study cohort. CONCLUSION: Our findings demonstrated that DPP4i use is not significantly associated with poor outcomes of COVID-19 or other adverse effects of anti-diabetic treatment. The data support the continuation of DPP4i agents for diabetes management in the setting of COVID-19. Title: Development of chalcone-O-alkylamine derivatives as multifunctional agents against Alzheimer's disease Bai P, Wang K, Zhang P, Shi J, Cheng X, Zhang Q, Zheng C, Cheng Y, Yang J and Sang Z <1 more author(s)> Bai P, Wang K, Zhang P, Shi J, Cheng X, Zhang Q, Zheng C, Cheng Y, Yang J, Lu X, Sang Z (- 1) Ref: Eur Journal of Medicinal Chemistry, 183:111737, 2019 : PubMed ESTHER: Bai_2019_Eur.J.Med.Chem_183_111737 PubMedSearch: Bai 2019 Eur.J.Med.Chem 183 111737 PubMedID: 31581002 Abstract A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50=1.3+/-0.01muM) and butyrylcholinesterase (IC50=1.2+/-0.09muM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57+/-0.01muM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced Abeta1-42 aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu(2+)-induced Abeta1-42 aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro, and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, Abeta1-42 and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD. 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 G, Liu W, Ma C, Rong X, Zhang Y, Wang Y, Wu C, Cao N, Ding W and Wang C <2 more 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 (- 2) Ref: J Ethnopharmacol, 236:288, 2019 : PubMed ESTHER: Deng_2019_J.Ethnopharmacol_236_288 PubMedSearch: Deng 2019 J.Ethnopharmacol 236 288 PubMedID: 30872168 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. Title: Ameliorative effect of deoxyvasicine on scopolamine-induced cognitive dysfunction by restoration of cholinergic function in mice Deng G, Wu C, Rong X, Li S, Ju Z, Wang Y, Ma C, Ding W, Guan H and Wang C <2 more 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 (- 2) Ref: Phytomedicine, 63:153007, 2019 : PubMed ESTHER: Deng_2019_Phytomedicine_63_153007 PubMedSearch: Deng 2019 Phytomedicine 63 153007 PubMedID: 31301537 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. Title: A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies Gerlits O, Ho KY, Cheng X, Blumenthal D, Taylor P, Kovalevsky A, Radic Z Ref: Chemico-Biological Interactions, :, 2019 : PubMed ESTHER: Gerlits_2019_Chem.Biol.Interact_13ChEPon_ PubMedSearch: Gerlits 2019 Chem.Biol.Interact 13ChEPon PubMedID: 31176713 Gene_locus related to this paper: human-ACHE Abstract Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P31 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P31 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P31 space group structures appear similar to those previously obtained in the different P3121 unit cell. Successful solution of the new room temperature 3.2 A resolution structure of BW284c51*hAChE complex from large P31 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under closer-to-physiological temperature conditions. Title: Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase Gerlits O, Kong X, Cheng X, Wymore T, Blumenthal DK, Taylor P, Radic Z, Kovalevsky A Ref: Journal of Biological Chemistry, 294:10607, 2019 : PubMed ESTHER: Gerlits_2019_J.Biol.Chem_294_10607 PubMedSearch: Gerlits 2019 J.Biol.Chem 294 10607 PubMedID: 31138650 Gene_locus related to this paper: human-ACHE Abstract Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a "nonproductive" pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a "semi-productive" orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active-site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation antidotes. Title: Mechanism-based pharmacokinetics-pharmacodynamics studies of harmine and harmaline on neurotransmitters regulatory effects in healthy rats: Challenge on monoamine oxidase and acetylcholinesterase inhibition Jiang B, Meng L, Zou N, Wang H, Li S, Huang L, Cheng X, Wang Z, Chen W, Wang C Ref: Phytomedicine, 62:152967, 2019 : PubMed ESTHER: Jiang_2019_Phytomedicine_62_152967 PubMedSearch: Jiang 2019 Phytomedicine 62 152967 PubMedID: 31154274 Inhibitor(s) related to this paper: Harmine Abstract BACKGROUND: beta-Carboline alkaloid harmine (HAR) and harmaline (HAL) are monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors. However, whether HAR and HAL inhibit MAO or AChE selectively and competitively is unclear. PURPOSE: The purpose of this study was to investigate the potential competition inhibition of HAR and HAL on MAO and AChE in brain endothelial cells (RBE4) and in healthy rats to provide a basis for the application of the inhibitors in the treatment of patients with depression and with Parkinson's disease or Alzheimer's disease. STUDY DESIGN/METHODS: The transport properties of HAR and HAL by using blood-brain barrier models constructed with RBE4 were systematically investigated. Then, the modulation effects of HAR and HAL on CNS neurotransmitters (NTs) in healthy rat brains were determined by a microdialysis method coupled with LC-MS/MS. The competition inhibition of HAR and HAL on MAO and AChE was evaluated through real time-PCR, Western blot analysis, and molecular docking experiments. RESULTS: Results showed that HAL and HAR can be detected in the blood and striatum 300min after intravenous injection (1mg/kg). Choline (Ch), gamma-aminobutyric acid (GABA), glutamate (Glu), and phenylalanine (Phe) levels in the striatum decreased in a time-dependent manner after the HAL treatment, with average velocities of 1.41, 0.73, 3.86, and 1.10 (ng/ml)/min, respectively. The Ch and GABA levels in the striatum decreased after the HAR treatment, with average velocities of 1.16 and 0.22ng/ml/min, respectively. The results of the cocktail experiment using the human liver enzyme indicated that the IC50 value of HAL on MAO-A was 0.10 +/- 0.08microm and that of HAR was 0.38 +/- 0.21microm. Their IC50 values on AChE were not obtained. These findings indicated that HAL and HAR selectively acted on MAO in vitro. However, RT-PCR and Western blot analysis results showed that the AChE mRNA and protein expression decreased in a time-dependent manner in RBE4 cells after the HAR and HAL treatments. CONCLUSION: NT analysis results showed that HAL and HAR selectively affect AChE in vivo. HAL and HAR may be highly and suitably developed for the treatment of Alzheimer's disease. Title: Genome sequence of Isaria javanica and comparative genome analysis insights into family S53 peptidase evolution in fungal entomopathogens Lin R, Zhang X, Xin B, Zou M, Gao Y, Qin F, Hu Q, Xie B, Cheng X Ref: Applied Microbiology & Biotechnology, 103:7111, 2019 : PubMed ESTHER: Lin_2019_Appl.Microbiol.Biotechnol_103_7111 PubMedSearch: Lin 2019 Appl.Microbiol.Biotechnol 103 7111 PubMedID: 31273397 Gene_locus related to this paper: 9hypo-a0a545vqi9 Abstract The fungus Isaria javanica is an important entomopathogen that parasitizes various insects and is effective for pest control. In this study, we sequenced and assembled the genomes (IJ1G and IJ2G) of two I. javanica strains isolated from different insects. The genomes were approximately 35 Mb in size with 11,441 and 11,143 protein-coding genes, respectively. Using a phylogenomic approach, we evaluated genome evolution across five entomopathogenic fungi in Cordycipitaceae. By comparative genome analysis, it was found that family S53 serine peptidases were expanded in Cordycipitaceae entomopathogens, particularly in I. javanica. Gene duplication events were identified based on phylogenetic relationships inferred from 82 S53 peptidases within six entomopathogenic fungal genomes. Moreover, we found that carbohydrate-active enzymes and proteinases were the largest secretory protein groups encoded in the I. javanica genome, especially chitinases (GH18), serine and aspartic peptidases (S53, S08, S10, A01). Pathogenesis-related genes and genes for bacterial-like toxins and secondary metabolites were also identified. By comparative transcriptome analysis, differentially expressed genes in response to insect nutrients (in vitro) were identified. Moreover, most S53 peptidases were detected to be significantly upregulated during the initial fungal infection process in insects (in vivo) by RT-qPCR. Our results provide new clues about understanding evolution of pathogenic proteases and may suggest that abundant S53 peptidases in the I. javanica genome may contribute to its effective parasitism on various insects. Title: Potential Pharmacokinetic Drug(-)Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive N-Methyl-d-Aspartate Receptor Antagonist Zhang Y, Li S, Wang Y, Deng G, Cao N, Wu C, Ding W, Cheng X, Wang C Ref: Molecules, 24:, 2019 : PubMed ESTHER: Zhang_2019_Molecules_24_ PubMedSearch: Zhang 2019 Molecules 24 PubMedID: 30978991 Inhibitor(s) related to this paper: Harmine Abstract Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer's disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer's disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM. Title: Implications of Successful Symptomatic Treatment in Parkinson's Disease for Therapeutic Strategies of Alzheimer's Disease Zhao L, Cheng X, Zhong C Ref: ACS Chem Neurosci, 10:922, 2019 : PubMed ESTHER: Zhao_2019_ACS.Chem.Neurosci_10_922 PubMedSearch: Zhao 2019 ACS.Chem.Neurosci 10 922 PubMedID: 30474958 Abstract Alzheimer's disease (AD) has been a devastating neurodegenerative disorder and lacks effective treatment to improve the prognosis for patients. Symptomatic treatment for AD mainly includes two categories: Acetylcholinesterase inhibitors and the N-methyl-d-aspartate (NMDA) receptor antagonist (memantine). They cannot significantly improve the quality of life and extend survival time for AD patients. Worse, almost all clinical trials for disease-modifying drugs have failed, and the reduction of brain beta-amyloid (Abeta) deposition by multiple approaches, including inhibitors of beta- or gamma-secretase, vaccines, and antibodies against Abeta deposition, was found to have little effect on AD progression. A new therapeutic strategy for AD is urgently needed. Parkinson's disease also is a neurodegenerative disease having no effective treatment for modifying the disease. Nevertheless, successful symptomatic treatment using the combined therapies of l-DOPA supplement and modulators of l-DOPA metabolism greatly improves the prognosis for PD patients; the average survival time of the patient has been extended from 3-4 years to 10-15 years although dopaminergic neurons are still progressively decreasing. This provides useful implications for AD therapeutic strategies. AD patients manifest global cognitive decline, prominently represented by memory deficit, especially in the early stages of the disease. Further, the degree of decreased cognitive abilities correlates with cholinergic dysfunction and the hypometabolism of glucose, the dominant energy fuel for brain. Thus, the amelioration of brain cholinergic function and brain energy metabolism may be effective treatment to improve cognitive abilities of AD patients. Here, we highlighted the explorations of symptomatic therapeutics through modulating brain cholinergic function and energy metabolism in AD. Title: Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations Zhou Y, Lu X, Yang H, Chen Y, Wang F, Li J, Tang Z, Cheng X, Yang Y and Xia Q <1 more author(s)> Zhou Y, Lu X, Yang H, Chen Y, Wang F, Li J, Tang Z, Cheng X, Yang Y, Xu L, Xia Q (- 1) Ref: Molecules, 24:, 2019 : PubMed ESTHER: Zhou_2019_Molecules_24_ PubMedSearch: Zhou 2019 Molecules 24 PubMedID: 31757047 Abstract As there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer's disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to identify selective BChE inhibitors with new chemical scaffolds. In particular, a pharmacophore model served as a 3D search query to screen three compound collections containing 3.0 million compounds. Molecular docking and cluster analysis were performed to increase the efficiency and accuracy of virtual screening. Finally, 15 compounds were retained for biological investigation. Results revealed that compounds 8 and 18 could potently and highly selectively inhibit BChE activities (IC50 values < 10 muM on human BChE, selectivity index BChE > 30). These active compounds with novel scaffolds provided us with a good starting point to further design potent and selective BChE inhibitors, which may be beneficial for the treatment of AD. Title: Structural investigation of the enantioselectivity and thermostability mechanisms of esterase RhEst1 Chen Q, Yu HL, Cheng X, Xu JH Ref: J Mol Graph Model, 85:182, 2018 : PubMed ESTHER: Chen_2018_J.Mol.Graph.Model_85_182 PubMedSearch: Chen 2018 J.Mol.Graph.Model 85 182 PubMedID: 30227363 Gene_locus related to this paper: rhosp-AHY95170 Abstract The esterase RhEst1 can catalyze the asymmetric hydrolysis of ethyl (+/-)-2,2-dimethylcyclopropane carboxylate (DmCpCe), yielding a pharmaceutically relevant (S)-carboxylic acid. A triple mutant RhEst1A147I/V148F/G254A showed a 5-fold increase in the catalytic activity but a significant decrease in the enantioselectivity. Further optimization studies led to a new enzyme with an additional A143T mutation, which showed both increased catalytic activity and recovered enantioselectivity as well as improved thermostability. To reveal the detailed structural mechanisms for these improved properties, we performed all-atom molecular dynamics simulations on the wild type and two mutants A147I/V148F/G254A and A143T/A147I/V148F/G254A RhEst1, in complex with R-DmCpCe and S-DmCpCe substrates, respectively. The structural stability of the enzyme variants was investigated with the residue interaction network analysis. In RhEst1M2, S-DmCpCe was observed to adopt a more "activated" conformation than R-DmCpCe, with the active site residues better prearranged for the reaction, leading to the improved enantioselectivity towards S-DmCpCe. The mutations in the two mutants, especially A143T, could lead to different motion patterns in the cap domain, thus affecting the structure of the substrate entrance tunnel. The residue interaction networks analysis showed an increased number of interactions in RhEst1M1 and RhEst1M2 as compared to the wild type enzyme, especially the pi-pi stacking interactions between Phe148 and the nearby residues, providing an explanation for the increased thermostability of the two mutant enzymes observed experimentally. Our work provides essential molecular insights into the substrate binding, enantioselectivity and structural stability of esterase RhEst1, which will facilitate the development of more efficient RhEst1 variants for pharmaceutical applications. Title: The tomato MAX1 homolog, SlMAX1, is involved in the biosynthesis of tomato strigolactones from carlactone Zhang Y, Cheng X, Wang Y, Diez-Simon C, Flokova K, Bimbo A, Bouwmeester HJ, Ruyter-Spira C Ref: New Phytol, 219:297, 2018 : PubMed ESTHER: Zhang_2018_New.Phytol_219_297 PubMedSearch: Zhang 2018 New.Phytol 219 297 PubMedID: 29655242 Inhibitor(s) related to this paper: Solanacol, Carlactonoic-acid Abstract Strigolactones (SLs) are rhizosphere signalling molecules exuded by plants that induce seed germination of root parasitic weeds and hyphal branching of arbuscular mycorrhiza. They are also phytohormones regulating plant architecture. MORE AXILLARY GROWTH 1 (MAX1) and its homologs encode cytochrome P450 (CYP) enzymes that catalyse the conversion of the strigolactone precursor carlactone to canonical strigolactones in rice (Oryza sativa), and to an SL-like compound in Arabidopsis. Here, we characterized the tomato (Solanum lycopersicum) MAX1 homolog, SlMAX1. The targeting induced local lesions in genomes method was used to obtain Slmax1 mutants that exhibit strongly reduced production of orobanchol, solanacol and didehydro-orobanchol (DDH) isomers. This results in a severe strigolactone mutant phenotype in vegetative and reproductive development. Transient expression of SlMAX1 - together with SlD27, SlCCD7 and SlCCD8 - in Nicotiana benthamiana showed that SlMAX1 catalyses the formation of carlactonoic acid from carlactone. Plant feeding assays showed that carlactone, but not 4-deoxy-orobanchol, is the precursor of orobanchol, which in turn is the precursor of solanacol and two of the three DDH isomers. Inhibitor studies suggest that a 2-oxoglutarate-dependent dioxygenase is involved in orobanchol biosynthesis from carlactone and that the formation of solanacol and DDH isomers from orobanchol is catalysed by CYPs. Title: Stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic pharmacodynamics, and toxic properties of vasicine enantiomers in vitro and in vivo Zhu Y, Liu W, Qi S, Wang H, Wang Y, Deng G, Zhang Y, Li S, Ma C and Wang C <1 more author(s)> Zhu Y, Liu W, Qi S, Wang H, Wang Y, Deng G, Zhang Y, Li S, Ma C, Cheng X, Wang C (- 1) Ref: Eur J Pharm Sci, 123:459, 2018 : PubMed ESTHER: Zhu_2018_Eur.J.Pharm.Sci_123_459 PubMedSearch: Zhu 2018 Eur.J.Pharm.Sci 123 459 PubMedID: 30077712 Inhibitor(s) related to this paper: Peganine 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 (282.51mg.kg(-1)) was slight lower than l-VAS (319.75mg.kg(-1)). 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. Title: Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats Chen C, Zheng Y, Wu T, Wu C, Cheng X Ref: Behav Pharmacol, 28:207, 2017 : PubMed ESTHER: Chen_2017_Behav.Pharmacol_28_207 PubMedSearch: Chen 2017 Behav.Pharmacol 28 207 PubMedID: 27984208 Abstract Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer's disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments. Title: A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum Li S, Cheng X, Wang C Ref: J Ethnopharmacol, 203:127, 2017 : PubMed ESTHER: Li_2017_J.Ethnopharmacol_203_127 PubMedSearch: Li 2017 J.Ethnopharmacol 203 127 PubMedID: 28359849 Abstract ETHNOPHARMACOLOGICAL RELEVANCE: The plants of the genus Peganum have a long history as a Chinese traditional medicine for the treatment of cough, hypertension, diabetes, asthma, jaundice, colic, lumbago, and many other human ailments. Additionally, the plants can be used as an amulet against evil-eye, dye and so on, which have become increasingly popular in Asia, Iran, Northwest India, and North Africa. AIM OF THE REVIEW: The present paper reviewed the ethnopharmacology, phytochemistry, analytical methods, biological activities, metabolism, pharmacokinetics, toxicology, and drug interaction of the genus Peganum in order to assess the ethnopharmacological use and to explore therapeutic potentials and future opportunities for research. MATERIALS AND Title: Anti-amnesic effect of extract and alkaloid fraction from aerial parts of Peganum harmala on scopolamine-induced memory deficits in mice Liu W, Zhu Y, Wang Y, Qi S, Ma C, Li S, Jiang B, Cheng X, Wang Z and Wang C <1 more author(s)> Liu W, Zhu Y, Wang Y, Qi S, Ma C, Li S, Jiang B, Cheng X, Wang Z, Xuan Z, Wang C (- 1) Ref: J Ethnopharmacol, 204:95, 2017 : PubMed ESTHER: Liu_2017_J.Ethnopharmacol_204_95 PubMedSearch: Liu 2017 J.Ethnopharmacol 204 95 PubMedID: 28442406 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 Title: Rational Design of a Red-Emissive Fluorophore with AIE and ESIPT Characteristics and Its Application in Light-Up Sensing of Esterase Peng L, Xu S, Zheng X, Cheng X, Zhang R, Liu J, Liu B, Tong A Ref: Analytical Chemistry, 89:3162, 2017 : PubMed ESTHER: Peng_2017_Anal.Chem_89_3162 PubMedSearch: Peng 2017 Anal.Chem 89 3162 PubMedID: 28192960 Abstract The development of red fluorophores with efficient solid-state emission is still challenging. Herein, a red fluorophore 1 with aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) characteristics is rationally designed and facilely synthesized by attaching an electron-donor diethylamine and an electron-acceptor maleonitrile group to salicyladazine. In contrast to many red fluorophores which undergo serious aggregation-caused quenching (ACQ), compound 1 emits bright red fluorescence (lambdaem = 650 nm, PhiF = 24.3%) in the solid state with a large Stokes shift of 174 nm. Interestingly, control compounds 2 and 3, which have similar structures as 1, exhibit obvious aggregation-caused quenching (ACQ) characteristics. The difference in the crystal structures of 1, 2, and 3 reveals that the interplanar spacing among molecules plays a decisive role in realizing the AIE characteristics of 1. Moreover, when the hydroxyl group of 1 was substituted by an esterase reactive acetoxyl, a fluorescence light-up probe 4 was developed for sensing of esterase based on the selective reaction between 4 and esterase to generate the AIE and ESIPT active molecule 1. The linear range for in vitro quantification of esterase is 0.01-0.15 U/mL with a detection limit of 0.005 U/mL. Probe 4 was also successfully applied to image esterase in mitochondria of living cells. Title: Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning Kovalevsky A, Blumenthal DK, Cheng X, Taylor P, Radic Z Ref: Annals of the New York Academy of Sciences, 1378:41, 2016 : PubMed ESTHER: Kovalevsky_2016_Ann.N.Y.Acad.Sci_1378_41 PubMedSearch: Kovalevsky 2016 Ann.N.Y.Acad.Sci 1378 41 PubMedID: 27371941 Abstract Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and organophosphate (OP) pesticide intoxication. Catalytically inactive OP-AChE conjugates formed between the active-center serine and phosphorus of OPs can, in principle, be reactivated by nucleophilic oxime antidotes. Antidote efficacy is limited by the structural diversity of OP-AChE conjugates resulting from differences in the structure of the conjugated OP, the different active-center volumes they occupy when conjugated to the active-center serine of AChE, and the distinct chemical characteristics of both OPs and oximes documented in numerous X-ray structures of OP-conjugated AChEs. Efforts to improve oxime reactivation efficacy by AChE structure-based enhancement of oxime structure have yielded only limited success. We outline here the potential limitations of available AChE X-ray structures that preclude an accurate prediction of oxime structures, which are necessary for association in the OP-AChE gorge and nucleophilic attack of the OP-conjugated phosphorus. Title: Five new Lycopodium alkaloids from the aerial parts of Phlegmariurus henryi Liu YC, Su J, Wu XD, Zhang ZJ, Fan M, Zhu QF, He J, Li XN, Peng LY and Zhao QS <1 more author(s)> Liu YC, Su J, Wu XD, Zhang ZJ, Fan M, Zhu QF, He J, Li XN, Peng LY, Cheng X, Zhao QS (- 1) Ref: Fitoterapia, 115:148, 2016 : PubMed ESTHER: Liu_2016_Fitoterapia_115_148 PubMedSearch: Liu 2016 Fitoterapia 115 148 PubMedID: 27769820 Abstract A series of new Lycopodium alkaloids, namely 1-epi-malycorin A (1), 1-epi-17S-hydroxymalycorin A (2), 6alpha-hydroxyphlegmariurine A (3), 2S,4R-dihydroxyfawcettimine (4), and 16-hydroxylycodine (5), together with 24 known ones, have been isolated from the club moss Phlegmariurus henryi. The structures of the new compounds were determined by extensive spectroscopic analysis, including 1D and 2D NMR, as well as X-ray crystallographic analysis. Among them, the absolute configurations of 1, 2, and 4 and the structure of 3 were confirmed on the basis of the single-crystal X-ray diffraction analysis. 1-Epi-17S-hydroxymalycorin A (2) was a unique C19N-type Lycopodium alkaloid consisting of a serratinine skeleton with 1,2-propanediol unit. 2S,4R-dihydroxyfawcettimine (4) was a 2,4-dihydroxy derivative of fawcettimine. 16-Hydroxylycodine (5) was the oxidative product of lycodine with an unusual hydroxymethyl group at C-15. All new compounds were evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity and cytotoxicity against four human cancer cell lines. Title: Transcriptome differences between fiber-type and seed-type Cannabis sativa variety exposed to salinity Liu J, Qiao Q, Cheng X, Du G, Deng G, Zhao M, Liu F Ref: Physiol Mol Biol Plants, 22:429, 2016 : PubMed ESTHER: Liu_2016_Physiol.Mol.Biol.Plants_22_429 PubMedSearch: Liu 2016 Physiol.Mol.Biol.Plants 22 429 PubMedID: 27924117 Abstract The industrial hemp varieties 'Yunma 5' and 'Bamahuoma,' which demonstrate growth vigor and environmental adaptability, have been primarily cultivated in Yunnan and Guangxi, China, respectively, for fiber and seeds. The results of physiological measurements showed the phenotypic differences between the two varieties in response to salt stress. RNA-Seq analysis was first performed on leaves of both varieties sampled at four time intervals (0, 2, 4, 6 days) after treatment with salt (500 mM NaCl) We identified 220 co-up-regulated differentially expressed genes (DEGs) in the two varieties, while 26 up-regulated DEGs and 24 down-regulated DEGs were identified exclusively in the single varieties after 2 days of salt stress. Among the 220 DEGs, we identified 22 transcription factors, including key transcription factors involved in salt stress, such as MYB, NAC, GATA, and HSF. We applied gene expression profile analysis and found that 'Yunma 5' and 'Bamahuoma' have variety-specific pathways for resisting salt stress. The DEGs of 'Yunma 5' were enriched in spliceosome and amino acid metabolism genes, while the DEGs of 'Bamahuoma' were enriched in fatty acid metabolism, amino acid metabolism, and endoplasmic reticulum protein processing pathway. Although there were common DEGs, such as genes encoding cysteine protease and alpha/beta-hydrolase superfamily, the two varieties' responses to salt stress impacted different metabolic pathways. The DEGs that were co-expressed in both varieties under stress may provide useful insights into the tolerance of cultivated hemp and other bast fiber crops to saline soil conditions. These transcriptomes also represent reference sequences for industrial hemp. Title: Conifer flavonoid compounds inhibit detoxification enzymes and synergize insecticides Wang Z, Zhao Z, Cheng X, Liu S, Wei Q, Scott IM Ref: Pestic Biochem Physiol, 127:1, 2016 : PubMed ESTHER: Wang_2016_Pestic.Biochem.Physiol_127_1 PubMedSearch: Wang 2016 Pestic.Biochem.Physiol 127 1 PubMedID: 26821651 Abstract Detoxification by glutathione S-transferases (GSTs) and esterases are important mechanisms associated with insecticide resistance. Discovery of novel GST and esterase inhibitors from phytochemicals could provide potential new insecticide synergists. Conifer tree species contain flavonoids, such as taxifolin, that inhibit in vitro GST activity. The objectives were to test the relative effectiveness of taxifolin as an enzyme inhibitor and as an insecticide synergist in combination with the organophosphorous insecticide, Guthion (50% azinphos-methyl), and the botanical insecticide, pyrethrum, using an insecticide-resistant Colorado potato beetle (CPB) Leptinotarsa decemlineata (Say) strain. Both taxifolin and its isomer, quercetin, increased the mortality of 1(st) instar CPB larvae after 48h when combined with Guthion, but not pyrethrum. Taxifolin had greater in vitro esterase inhibition compared with the commonly used esterase inhibitor, S, S, S-tributyl phosphorotrithioate (DEF). An in vivo esterase and GST inhibition effect after ingestion of taxifolin was measured, however DEF caused a greater suppression of esterase activity. This study demonstrated that flavonoid compounds have both in vitro and in vivo esterase inhibition, which is likely responsible for the insecticide synergism observed in insecticide-resistant CPB. Title: Molecular dynamics investigation of the substrate binding mechanism in carboxylesterase Chen Q, Luan ZJ, Cheng X, Xu JH Ref: Biochemistry, 54:1841, 2015 : PubMed ESTHER: Chen_2015_Biochemistry_54_1841 PubMedSearch: Chen 2015 Biochemistry 54 1841 PubMedID: 25711934 Abstract A recombinant carboxylesterase, cloned from Pseudomonas putida and designated as rPPE, is capable of catalyzing the bioresolution of racemic 2-acetoxy-2-(2'-chlorophenyl)acetate (rac-AcO-CPA) with excellent (S)-enantioselectivity. Semirational design of the enzyme showed that the W187H variant could increase the activity by approximately 100-fold compared to the wild type (WT) enzyme. In this study, we performed all-atom molecular dynamics (MD) simulations of both apo-rPPE and rPPE in complex with (S)-AcO-CPA to gain insights into the origin of the increased catalysis in the W187H mutant. Our results show differential binding of (S)-AcO-CPA in the WT and W187H enzymes, especially the interactions of the substrate with the two active site residues Ser159 and His286. The replacement of Trp187 by His leads to considerable structural rearrangement in the active site of W187H. Unlike in the WT rPPE, the cap domain in the W187 mutant shows an open conformation in the simulations of both apo and substrate-bound enzymes. This open conformation exposes the catalytic triad to the solvent through a water accessible channel, which may facilitate the entry of the substrate and/or the exit of the product. Binding free energy calculations confirmed that the substrate binds more strongly in W187H than in WT. On the basis of these computational results, we further predicted that the mutations W187Y and D287G might also be able to increase the substrate binding and thus improve the enzyme's catalytic efficiency. Experimental binding and kinetic assays on W187Y and D287G show improved catalytic efficiency over WT, but not W187H. Contrary to our prediction, W187Y shows slightly decreased substrate binding coupled with a 100-fold increase in turnover rate, while in D287G the substrate binding is 8 times stronger but with a slightly reduced turnover rate. Our work provides important molecular-level insights into the binding of the (S)-AcO-CPA substrate to carboxylesterase rPPEs, which will help guide future development of more efficient rPPE variants. Title: Rational design of a carboxylic esterase RhEst1 based on computational analysis of substrate binding Chen Q, Luan ZJ, Yu HL, Cheng X, Xu JH Ref: J Mol Graph Model, 62:319, 2015 : PubMed ESTHER: Chen_2015_J.Mol.Graph.Model_62_319 PubMedSearch: Chen 2015 J.Mol.Graph.Model 62 319 PubMedID: 26556053 Abstract A new carboxylic esterase RhEst1 which catalyzes the hydrolysis of (S)-(+)-2,2-dimethylcyclopropanecarboxylate (S-DmCpCe), the key chiral building block of cilastatin, was identified and subsequently crystallized in our previous work. Mutant RhEst1A147I/V148F/G254A was found to show a 5-fold increase in the catalytic activity. In this work, molecular dynamic simulations were performed to elucidate the molecular determinant of the enzyme activity. Our simulations show that the substrate binds much more strongly in the A147I/V148F/G254A mutant than in wild type, with more hydrogen bonds formed between the substrate and the catalytic triad and the oxyanion hole. The OH group of the catalytic residue Ser101 in the mutant is better positioned to initiate the nucleophilic attack on S-DmCpCe. Interestingly, the "170-179" loop which is involved in shaping the catalytic sites and facilitating the product release shows remarkable dynamic differences in the two systems. Based on the simulation results, six residues were identified as potential "hot-spots" for further experimental testing. Consequently, the G126S and R133L mutants show higher catalytic efficiency as compared with the wild type. This work provides molecular-level insights into the substrate binding mechanism of carboxylic esterase RhEst1, facilitating future experimental efforts toward developing more efficient RhEst1 variants for industrial applications. Title: Geissoschizine methyl ether N-oxide, a new alkaloid with antiacetylcholinesterase activity from Uncaria rhynchophylla Jiang WW, Su J, Wu XD, He J, Peng LY, Cheng X, Zhao QS Ref: Nat Prod Res, 29:842, 2015 : PubMed ESTHER: Jiang_2015_Nat.Prod.Res_29_842 PubMedSearch: Jiang 2015 Nat.Prod.Res 29 842 PubMedID: 25496282 Abstract Geissoschizine methyl ether N-oxide, a new oxindole alkaloid, along with 14 known alkaloids, was isolated from the aerial part of Uncaria rhynchophylla. Their structures were identified by comprehensive spectral methods, including 2D NMR experiments, and confirmed by comparing with the literature data. In vitro acetylcholinesterase (AChE) inhibitory activity assay showed that the new compound exhibited anti-AChE activity with IC(5)(0) value of 23.4 muM. Title: Obscurumines H-P, new Lycopodium alkaloids from the club moss Lycopodium obscurum Jiang WW, Liu YC, Zhang ZJ, He J, Su J, Cheng X, Peng LY, Shao LD, Wu XD and Zhao QS <1 more author(s)> Jiang WW, Liu YC, Zhang ZJ, He J, Su J, Cheng X, Peng LY, Shao LD, Wu XD, Yang JH, Zhao QS (- 1) Ref: Fitoterapia, 109:155, 2015 : PubMed ESTHER: Jiang_2015_Fitoterapia_109_155 PubMedSearch: Jiang 2015 Fitoterapia 109 155 PubMedID: 26739385 Abstract Seven new fawcettimine-type (1-7) and two new lycopodine-type (8 and 9) Lycopodium alkaloids, as well as 10 known compounds, were isolated from the club moss, Lycopodium obscurum L. The structures of obscurumines H-P (1-9) were determined based on high-resolution MS and 1D and 2D NMR data. Compounds 1 and 2 include a new skeleton that is formed via the linkage of C-9-N-2', which is rarely present in Lycopodium alkaloids. The in vitro acetylcholinesterase (AChE) inhibitory activity assay showed that 5 exhibited weak anti-AChE activity with an IC50 value of 81.0muM. Compound 8 exhibited inhibition of the secretion of IL-2 in phytohemagglutinin (PHA) and phorbol myristate acetate (PMA) stimulated Jurkat cells, and the IC50 value was 17.2muM. Title: In vitro and in vivo metabolism and inhibitory activities of vasicine, a potent acetylcholinesterase and butyrylcholinesterase inhibitor Liu W, Shi X, Yang Y, Cheng X, Liu Q, Han H, Yang B, He C, Wang Y and Wang C <2 more 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 (- 2) Ref: PLoS ONE, 10:e0122366, 2015 : PubMed ESTHER: Liu_2015_PLoS.One_10_e0122366 PubMedSearch: Liu 2015 PLoS.One 10 e0122366 PubMedID: 25849329 Inhibitor(s) related to this paper: Peganine 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. Title: Four new fawcettimine-related alkaloids from Phlegmariurus squarrosus Liu YC, Fan M, Jiang WW, Liu F, Wu XD, He J, Cheng X, Peng LY, Su J and Zhao QS <1 more author(s)> Liu YC, Fan M, Jiang WW, Liu F, Wu XD, He J, Cheng X, Peng LY, Su J, Zhang ZJ, Zhao QS (- 1) Ref: J Asian Nat Prod Res, 17:967, 2015 : PubMed ESTHER: Liu_2015_J.Asian.Nat.Prod.Res_17_967 PubMedSearch: Liu 2015 J.Asian.Nat.Prod.Res 17 967 PubMedID: 26287979 Abstract Four new fawcettimine-related alkaloids (1-4), together with 17 known ones, were isolated from club moss Phlegmariurus squarrosus. Notably, compound 1 was the derivative of lycoflexine with an unprecedented additional methyl group at C-17. Their structures were determined by extensive spectroscopic analysis, including 1D and 2D NMR, and HR-MS, as well as by comparison with the literature data. All new compounds were tested for their beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) and acetylcholinesterase (AChE) inhibitory activities. Title: Potent AChE and BChE inhibitors isolated from seeds of Peganum harmala Linn by a bioassay-guided fractionation Yang Y, Cheng X, Liu W, Chou G, Wang Z, Wang C Ref: J Ethnopharmacol, 168:279, 2015 : PubMed ESTHER: Yang_2015_J.Ethnopharmacol_168_279 PubMedSearch: Yang 2015 J.Ethnopharmacol 168 279 PubMedID: 25862961 Inhibitor(s) related to this paper: Peganine 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 Title: Comparative genomics and metabolic profiling of the genus Lysobacter de Bruijn I, Cheng X, de Jager V, Exposito RG, Watrous J, Patel N, Postma J, Dorrestein PC, Kobayashi D, Raaijmakers JM Ref: BMC Genomics, 16:991, 2015 : PubMed ESTHER: de Bruijn_2015_BMC.Genomics_16_991 PubMedSearch: de Bruijn 2015 BMC.Genomics 16 991 PubMedID: 26597042 Gene_locus related to this paper: 9gamm-a0a021wfd8, 9gamm-a0a0s2fbf7, 9gamm-a0a0s2g0f6, 9gamm-a0a0s2g6c6, 9gamm-a0a0s2fcm5, 9gamm-a0a291a2f2, 9gamm-a0a0s2f7r5, 9gamm-a0a0s2g2h9 Abstract BACKGROUND: Lysobacter species are Gram-negative bacteria widely distributed in soil, plant and freshwater habitats. Lysobacter owes its name to the lytic effects on other microorganisms. To better understand their ecology and interactions with other (micro)organisms, five Lysobacter strains representing the four species L. enzymogenes, L. capsici, L. gummosus and L. antibioticus were subjected to genomics and metabolomics analyses. Title: Amino acid substitutions of acetylcholinesterase associated with carbofuran resistance in Chilo suppressalis Chang C, Cheng X, Huang XY, Dai SM Ref: Pest Manag Sci, 70:1930, 2014 : PubMed ESTHER: Chang_2014_Pest.Manag.Sci_70_1930 PubMedSearch: Chang 2014 Pest.Manag.Sci 70 1930 PubMedID: 24616070 Abstract BACKGROUND: Over 1000-fold carbofuran resistance has been observed in Chilo suppressalis (Walker) collected from the Changhua (CH) and Chiayi (CY) prefectures of Taiwan. An understanding of the pertinent mechanisms will benefit effective insecticide resistance management of C. suppressalis. Title: The role of synaptic activity in the regulation of amyloid beta levels in Alzheimer's disease Cheng X, Wu J, Geng M, Xiong J Ref: Neurobiology of Aging, 35:1217, 2014 : PubMed ESTHER: Cheng_2014_Neurobiol.Aging_35_1217 PubMedSearch: Cheng 2014 Neurobiol.Aging 35 1217 PubMedID: 24368087 Abstract Alzheimer's disease (AD) is the most common form of dementia. Accumulation of amyloid-beta (Abeta) peptides is regarded as the critical component associated with AD pathogenesis, which is derived from the amyloid precursor protein (APP) cleavage. Recent studies suggest that synaptic activity is one of the most important factors that regulate Abeta levels. It has been found that synaptic activity facilitates APP internalization and influences APP cleavage. Glutamatergic, cholinergic, serotonergic, leptin, adrenergic, orexin, and gamma-amino butyric acid receptors, as well as the activity-regulated cytoskeleton-associated protein (Arc) are all involved in these processes. The present review summarizes the evidence for synaptic activity-modulated Abeta levels and the mechanisms underlying this regulation. Interestingly, the immediate early gene product Arc may also be the downstream signaling molecule of several receptors in the synaptic activity-modulated Abeta levels. Elucidating how Abeta levels are regulated by synaptic activity may provide new insights in both the understanding of the pathogenesis of AD and in the development of therapies to slow down the progression of AD. Title: Molecular Cloning and Characterization of a Novel Cold-Adapted Family VIII Esterase from a Biogas Slurry Metagenomic Library Cheng X, Wang X, Qiu T, Yuan M, Sun J, Gao J Ref: J Microbiol Biotechnol, 24:1484, 2014 : PubMed ESTHER: Cheng_2014_J.Microbiol.Biotechnol_24_1484 PubMedSearch: Cheng 2014 J.Microbiol.Biotechnol 24 1484 PubMedID: 25394508 Abstract A novel esterase gene, est01, was successfully unearthed from a biogas digester microbiota metagenomic library. The 1,194 bp est01 gene encodes a protein of 44,804 Da (designated Est01). The amino acid sequence of Est01 shows only moderate (33%) identity to a lipase/ esterase. Phylogenetic analysis and biochemical characterization confirmed that Est01 is a new member of family VIII esterases. The purified Est01 from recombinant Escherichia coli BL21 (DE3) showed high hydrolytic activity against short-chain fatty acid esters, suggesting that it is a typical carboxylesterase rather than a lipase. Furthermore, the Est01 was even active at 10 degrees C (43% activity remained), with the optimal temperature at 20 degrees C, and had a broad pH range from 5.0 to 10.0, with the optimal pH of 8.0. These properties suggest that Est01 is a cold-adaptive esterase and could have good potential for low-temperature hydrolysis application. Title: Beyond autonomic neuromodulation: Acetylcholinesterase inhibitor against peripheral artery disease Hao CN, Shi YQ, Cheng ZE, Cheng X Ref: Int J Cardiol, 178C:253, 2014 : PubMed ESTHER: Hao_2014_Int.J.Cardiol_178C_253 PubMedSearch: Hao 2014 Int.J.Cardiol 178C 253 PubMedID: 25464264 Abstract The acetylcholinesterase inhibitor (AChEI)-based therapeutic strategies have been shown to have vasculoprotective properties in the animal model of hindlimb ischemia due to its activation of the endothelial cholinergic system. However, little is know about whether other cell types (myocytes, immunocytes) are involved in the AChEI-related therapeutic benefits in peripheral artery disease. Therefore, we review the multiple cell-targeted effects of AChEI on the animal model of hindlimb ischemia and explore its clinical application in angiomyogenesis. Title: Huperserines A-E, Lycopodium alkaloids from Huperzia serrata Jiang WW, Liu F, Gao X, He J, Cheng X, Peng LY, Wu XD, Zhao QS Ref: Fitoterapia, 99C:72, 2014 : PubMed ESTHER: Jiang_2014_Fitoterapia_99C_72 PubMedSearch: Jiang 2014 Fitoterapia 99C 72 PubMedID: 25218968 Abstract A phytochemical study on Huperzia serrata led to the isolation of four new 5-deoxyfawcettimine-related Lycopodium alkaloids, huperserines A-D (1-4), and one new lycodine-type alkaloid, huperserine E (5). Their structures were elucidated based on spectroscopic data, including 1D and 2D NMR techniques. 5-Carbonyl or 5-hydroxyl group is a typical characteristic of lycopodine- and fawcettimine-type alkaloids. This is the first report of the 5-deoxyfawcettimine type Lycopodium alkaloids. In vitro acetylcholinesterase (AChE) inhibitory activity assay showed that huperserine E exhibited moderate anti-AChE activity with an IC50 value of 6.71muM. Title: Rapid and sensitive detection of the inhibitive activities of acetyl- and butyryl-cholinesterases inhibitors by UPLC-ESI-MS/MS 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 : PubMed ESTHER: Liu_2014_J.Pharm.Biomed.Anal_94_215 PubMedSearch: Liu 2014 J.Pharm.Biomed.Anal 94 215 PubMedID: 24631841 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. Title: Carinatines A and B, Alkaloids from Liu F, Liu YC, Jiang WW, He J, Wu XD, Peng LY, Su J, Cheng X, Zhao QS Ref: Nat Prod Bioprospect, 4:221, 2014 : PubMed ESTHER: Liu_2014_Nat.Prod.Bioprospect_4_221 PubMedSearch: Liu 2014 Nat.Prod.Bioprospect 4 221 PubMedID: 25089240 Abstract Carinatine A (1), a C16N2-type Lycopodium alkaloid possessing a 5/6/6/6 ring system formed by a new C-4/C-12 bond, and carinatine B (2), the first derivative of lycojaponicumin C, along 16 known compounds, were isolated from the whole plant of Phlegmariurus carinatus. Their structures were elucidated based on the spectroscopic data. The two new isolates were no inhibitory activity for the acetylcholinesterase (AChE). Title: Targeting Lipid Esterases in Mycobacteria Grown Under Different Physiological Conditions Using Activity-based Profiling with Tetrahydrolipstatin (THL) Ravindran MS, Rao SP, Cheng X, Shukla A, Cazenave-Gassiot A, Yao SQ, Wenk MR Ref: Mol Cell Proteomics, 13:435, 2014 : PubMed ESTHER: Ravindran_2014_Mol.Cell.Proteomics_13_435 PubMedSearch: Ravindran 2014 Mol.Cell.Proteomics 13 435 PubMedID: 24345785 Gene_locus related to this paper: myctu-Rv2970c Inhibitor(s) related to this paper: Tetrahydrolipstatin-alkyne, Orlistat Abstract Tetrahydrolipstatin (THL) is bactericidal but its precise target spectrum is poorly characterized. Here, we used a THL analog and activity-based protein profiling to identify target proteins after enrichment from whole cell lysates of Mycobacterium bovis Bacillus Calmette-Guerin cultured under replicating and non-replicating conditions. THL targets alpha/beta-hydrolases, including many lipid esterases (LipD, G, H, I, M, N, O, V, W, and TesA). Target protein concentrations and total esterase activity correlated inversely with cellular triacylglycerol upon entry into and exit from non-replicating conditions. Cellular overexpression of lipH and tesA led to decreased THL susceptibility thus providing functional validation. Our results define the target spectrum of THL in a biological species with particularly diverse lipid metabolic pathways. We furthermore derive a conceptual approach that demonstrates the use of such THL probes for the characterization of substrate recognition by lipases and related enzymes. Title: Intramembrane proton binding site linked to activation of bacterial pentameric ion channel Wang HL, Cheng X, Sine SM Ref: Journal of Biological Chemistry, 287:6482, 2012 : PubMed ESTHER: Wang_2012_J.Biol.Chem_287_6482 PubMedSearch: Wang 2012 J.Biol.Chem 287 6482 PubMedID: 22084238 Abstract Prokaryotic orthologs of eukaryotic Cys-loop receptor channels recently emerged as structural and mechanistic surrogates to investigate this superfamily of intercellular signaling proteins. Here, we examine proton activation of the prokaryotic ortholog GLIC using patch clamp electrophysiology, mutagenesis, and molecular dynamics (MD) simulations. Whole-cell current recordings from human embryonic kidney (HEK) 293 cells expressing GLIC show half-maximal activation at pH 6, close to the pK(a) of histidine, implicating the three native His residues in proton sensing linked to activation. The mutation H235F abolishes proton activation, H277Y is without effect, and all nine mutations of His-127 prevent expression on the cell surface. In the GLIC crystal structure, His-235 on transmembrane (TM) alpha-helix 2, hydrogen bonds to the main chain carbonyl oxygen of Ile-259 on TM alpha-helix 3. MD simulations show that when His-235 is protonated, the hydrogen bond persists, and the channel remains in the open conformation, whereas when His-235 is deprotonated, the hydrogen bond dissociates, and the channel closes. Mutations of the proximal Tyr-263, which also links TM alpha-helices 2 and 3 via a hydrogen bond, alter proton sensitivity over a 1.5 pH unit range. MD simulations show that mutations of Tyr-263 alter the hydrogen bonding capacity of His-235. The overall findings show that His-235 in the TM region of GLIC is a novel proton binding site linked to channel activation. Title: Synthesis and acetylcholinesterase and butyrylcholinesterase inhibitory activities of 7-alkoxyl substituted indolizinoquinoline-5,12-dione derivatives Wu ZP, Wu XW, Shen T, Li YP, Cheng X, Gu LQ, Huang ZS, An LK Ref: Arch Pharm (Weinheim), 345:175, 2012 : PubMed ESTHER: Wu_2012_Arch.Pharm.(Weinheim)_345_175 PubMedSearch: Wu 2012 Arch.Pharm.(Weinheim) 345 175 PubMedID: 21989769 Abstract A series of novel 7-alkoxyl substituted indolizinoquinoline-5,12-dione derivatives were synthesized. The cholinesterase inhibition assays indicated that most synthesized compounds exhibited good activity for acetylcholinesterase (AChE) and high selectivity index of AChE over butyrylcholinesterase (BuChE). Compound 12b exhibited the most potent AChE inhibitory activity with an IC(50) value of 0.068 microM and the highest selectivity index of 144. Kinetic study of AChE indicated that a mixed type of inhibition pattern existed for these indolizinoquinoline-5,12-dione derivatives. Molecular docking study indicated that compound 12b could bind to both the catalytically active site and the peripheral anionic site of AChE. Title: Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice Zhang Y, Cheng X, Aleksunes L, Klaassen CD Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, 40:1191, 2012 : PubMed ESTHER: Zhang_2012_Drug.Metab.Dispos_40_1191 PubMedSearch: Zhang 2012 Drug.Metab.Dispos 40 1191 PubMedID: 22429928 Abstract The induction of drug-metabolizing enzymes by chemicals is one of the major reasons for drug-drug interactions. In the present study, the regulation of mRNA expression of one arylacetamide deacetylase (Aadac) and 11 carboxylesterases (Cess) by 15 microsomal enzyme inducers (MEIs) was examined in livers of male C57BL/6 mice. The data demonstrated that Aadac mRNA expression was suppressed by three aryl hydrocarbon receptor (AhR) ligands, two constitutive androstane receptor (CAR) activators, two pregnane X receptor (PXR) ligands, and one nuclear factor erythroid 2-related factor 2 (Nrf2) activator. Ces1 subfamily mRNA expression was not altered by most of the MEIs, whereas Ces2 subfamily mRNA was readily induced by the activators of CAR, PXR, and Nrf2 but not by peroxisome proliferator-activated receptor alpha activators. Studies using null mice demonstrated that 1) AhR was required for the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated suppression of Aadac and Ces3a; 2) CAR was involved in the 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene-mediated induction of Aadac, Ces2c, Ces2a, and Ces3a; 3) PXR was required for the pregnenolone-16alpha-carbonitrile-mediated induction of Aadac, Ces2c, and Ces2a; 4) Nrf2 was required for the oltipraz-mediated induction of Ces1g and Ces2c; and 5) PXR was not required for the DEX-mediated suppression of Cess in livers of mice. In conclusion, the present study systematically investigated the regulation of Cess by MEIs in livers of mice and demonstrated that MEIs modulated mRNA expression of mouse hepatic Cess through the activation of AhR, CAR, PXR, and/or Nrf2 transcriptional pathways. Title: Molecular-dynamics simulations of ELIC-a prokaryotic homologue of the nicotinic acetylcholine receptor Cheng X, Ivanov I, Wang H, Sine SM, McCammon JA Ref: Biophysical Journal, 96:4502, 2009 : PubMed ESTHER: Cheng_2009_Biophys.J_96_4502 PubMedSearch: Cheng 2009 Biophys.J 96 4502 PubMedID: 19486673 Abstract The ligand-gated ion channel from Erwinia chrysanthemi (ELIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor (nAChR) that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. ELIC is similar to the nAChR in its primary sequence and overall subunit organization, but despite their structural similarity, it is not clear whether these two ligand-gated ion channels operate in a similar manner. Further, it is not known to what extent mechanistic insights gleaned from the ELIC structure translate to eukaryotic counterparts such as the nAChR. Here we use molecular-dynamics simulations to probe the conformational dynamics and hydration of the transmembrane pore of ELIC. The results are compared with those from our previous simulation of the human alpha7 nAChR. Overall, ELIC displays increased stability compared to the nAChR, whereas the two proteins exhibit remarkable similarity in their global motion and flexibility patterns. The majority of the increased stability of ELIC does not stem from the deficiency of the models used in the simulations, and but rather seems to have a structural basis. Slightly altered dynamical correlation features are also observed among several loops within the membrane region. In sharp contrast to the nAChR, ELIC is completely dehydrated from the pore center to the extracellular end throughout the simulation. Finally, the simulation of an ELIC mutant substantiates the important role of F246 on the stability, hydration and possibly function of the ELIC channel. Title: Structural redesign of lipase B from Candida antarctica by circular permutation and incremental truncation Qian Z, Horton JR, Cheng X, Lutz S Ref: Journal of Molecular Biology, 393:191, 2009 : PubMed ESTHER: Qian_2009_J.Mol.Biol_393_191 PubMedSearch: Qian 2009 J.Mol.Biol 393 191 PubMedID: 19683009 Gene_locus related to this paper: canar-LipB Inhibitor(s) related to this paper: 4-methylumbelliferyl-hexylphosphonate Abstract Circular permutation of Candida antarctica lipase B yields several enzyme variants with substantially increased catalytic activity. To better understand the structural and functional consequences of protein termini reorganization, we have applied protein engineering and x-ray crystallography to cp283, one of the most active hydrolase variants. Our initial investigation has focused on the role of an extended surface loop, created by linking the native N- and C-termini, on protein integrity. Incremental truncation of the loop partially compensates for observed losses in secondary structure and the permutants' temperature of unfolding. Unexpectedly, the improvements are accompanied by quaternary-structure changes from monomer to dimer. The crystal structures of one truncated variant (cp283 Delta 7) in the apo-form determined at 1.49 A resolution and with a bound phosphonate inhibitor at 1.69 A resolution confirmed the formation of a homodimer by swapping of the enzyme's 35-residue N-terminal region. Separately, the new protein termini at amino acid positions 282/283 convert the narrow access tunnel to the catalytic triad into a broad crevice for accelerated substrate entry and product exit while preserving the native active-site topology for optimal catalytic turnover. Title: Control of cation permeation through the nicotinic receptor channel Wang HL, Cheng X, Taylor P, McCammon JA, Sine SM Ref: PLoS Comput Biol, 4:e41, 2008 : PubMed ESTHER: Wang_2008_PLoS.Comput.Biol_4_e41 PubMedSearch: Wang 2008 PLoS.Comput.Biol 4 e41 PubMedID: 18282090 Abstract We used molecular dynamics (MD) simulations to explore the transport of single cations through the channel of the muscle nicotinic acetylcholine receptor (nAChR). Four MD simulations of 16 ns were performed at physiological and hyperpolarized membrane potentials, with and without restraints of the structure, but all without bound agonist. With the structure unrestrained and a potential of -100 mV, one cation traversed the channel during a transient period of channel hydration; at -200 mV, the channel was continuously hydrated and two cations traversed the channel. With the structure restrained, however, cations did not traverse the channel at either membrane potential, even though the channel was continuously hydrated. The overall results show that cation selective transport through the nAChR channel is governed by electrostatic interactions to achieve charge selectivity, but ion translocation relies on channel hydration, facilitated by a trans-membrane field, coupled with dynamic fluctuations of the channel structure. Title: Nanosecond-timescale conformational dynamics of the human alpha7 nicotinic acetylcholine receptor Cheng X, Ivanov I, Wang H, Sine SM, McCammon JA Ref: Biophysical Journal, 93:2622, 2007 : PubMed ESTHER: Cheng_2007_Biophys.J_93_2622 PubMedSearch: Cheng 2007 Biophys.J 93 2622 PubMedID: 17573436 Abstract We explore the conformational dynamics of a homology model of the human alpha7 nicotinic acetylcholine receptor using molecular dynamics simulation and analyses of root mean-square fluctuations, block partitioning of segmental motion, and principal component analysis. The results reveal flexible regions and concerted global motions of the subunits encompassing extracellular and transmembrane domains of the subunits. The most relevant motions comprise a bending, hinged at the beta10-M1 region, accompanied by concerted tilting of the M2 helices that widens the intracellular end of the channel. Despite the nanosecond timescale, the observations suggest that tilting of the M2 helices may initiate opening of the pore. The results also reveal direct coupling between a twisting motion of the extracellular domain and dynamic changes of M2. Covariance analysis of interresidue motions shows that this coupling arises through a network of residues within the Cys and M2-M3 loops where Phe135 is stabilized within a hydrophobic pocket formed by Leu270 and Ile271. The resulting concerted motion causes a downward shift of the M2 helices that disrupts a hydrophobic girdle formed by 9' and 13' residues. Title: Estradiol replacement increases the low-density lipoprotein receptor related protein (LRP) in the mouse brain Cheng X, McAsey ME, Li M, Randall S, Cady C, Nathan BP, Struble RG Ref: Neuroscience Letters, 417:50, 2007 : PubMed ESTHER: Cheng_2007_Neurosci.Lett_417_50 PubMedSearch: Cheng 2007 Neurosci.Lett 417 50 PubMedID: 17346883 Abstract Numerous epidemiology studies have shown protective effects of hormone therapy (HT) on chronic neurological diseases. We have proposed that some of the neuroprotective effects of estrogen are mediated by apolipoprotein E (apoE). Polymorphisms of receptors for apoE modify the risk for dementia. To our knowledge, no reports exist showing CNS effects of estrogen replacement on members of the low-density lipoprotein receptor family. The current study focused on the effect of estradiol-17beta (E2) replacement on protein expression of two members of the receptor family, the low-density lipoprotein receptor (LDL-r) and low-density lipoprotein receptor related protein (LRP) in ovariectomized mice. Five days of E2 replacement significantly increased LRP expression in the hippocampus, olfactory bulb and neocortex but not in cerebellum. In contrast, E2 treatment decreased LDL-r protein expression in olfactory bulb. HT modification of both apoE and LRP could have wide-spread effects on cellular function given LRP's manifold signaling functions. Title: Acetylcholinesterase: mechanisms of covalent inhibition of wild-type and H447I mutant determined by computational analyses Cheng Y, Cheng X, Radic Z, McCammon JA Ref: Journal of the American Chemical Society, 129:6562, 2007 : PubMed ESTHER: Cheng_2007_J.Am.Chem.Soc_129_6562 PubMedSearch: Cheng 2007 J.Am.Chem.Soc 129 6562 PubMedID: 17461584 Abstract The reaction mechanisms of two inhibitors TFK+ and TFK0 binding to both the wild-type and H447I mutant mouse acetylcholinesterase (mAChE) have been investigated by using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach and classical molecular dynamics (MD) simulations. In the wild-type mAChE, the binding reactions of TFK+ and TFK0 are both spontaneous processes, which proceed through the nucleophilic addition of the Ser203-Ogamma to the carbonyl-C of TFK+ or TFK0, accompanied with a simultaneous proton transfer from Ser203 to His447. No barrier is found along the reaction paths, consistent with the experimental reaction rates approaching the diffusion-controlled limit. By contrast, TFK+ binding to the H447I mutant may proceed with a different reaction mechanism. A water molecule takes over the role of His447 and participates in the bond breaking and forming as a "charge relayer". Unlike in the wild-type mAChE case, Glu334, a conserved residue from the catalytic triad, acts as a catalytic base in the reaction. The calculated energy barrier for this reaction is about 8 kcal/mol. These predictions await experimental verification. In the case of the neutral ligand TFK0, however, multiple MD simulations on the TFK0/H447I complex reveal that none of the water molecules can be retained in the active site as a "catalytic" water. Furthermore, our alchemical free energy calculation also suggests that the binding of TFK0 to H447I is much weaker than that of TFK+. Taken together, our computational studies confirm that TFK0 is almost inactive in the H447I mutant and also provide detailed mechanistic insights into the experimental observations. Title: Barriers to ion translocation in cationic and anionic receptors from the Cys-loop family Ivanov I, Cheng X, Sine SM, McCammon JA Ref: J Am Chem Soc, 129:8217, 2007 : PubMed ESTHER: Ivanov_2007_J.Am.Chem.Soc_129_8217 PubMedSearch: Ivanov 2007 J.Am.Chem.Soc 129 8217 PubMedID: 17552523 Abstract Understanding the mechanisms of gating and ion permeation in biological channels and receptors has been a long-standing challenge in biophysics. Recent advances in structural biology have revealed the architecture of a number of transmembrane channels and allowed detailed, molecular-level insight into these systems. Herein, we have examined the barriers to ion conductance and origins of ion selectivity in models of the cationic human alpha7 nicotinic acetylcholine receptor (nAChR) and the anionic alpha1 glycine receptor (GlyR), based on the structure of Torpedo nAChR. Molecular dynamics simulations were used to determine water density profiles along the channel length, and they established that both receptor pores were fully hydrated. The very low water density in the middle of the nAChR pore indicated the existence of a hydrophobic constriction. By contrast, the pore of GlyR was lined with hydrophilic residues and remained well-hydrated throughout. Adaptive biasing force simulations allowed us to reconstruct potentials of mean force (PMFs) for chloride and sodium ions in the two receptors. For the nicotinic receptor we observed barriers to ion translocation associated with rings of hydrophobic residues-Val13' and Leu9'-in the middle of the transmembrane domain. This finding further substantiates the hydrophobic gating hypothesis for nAChR. The PMF revealed no significant hydrophobic barrier for chloride translocation in GlyR. For both receptors nonpermeant ions displayed considerable barriers. Thus, the overall electrostatics and the presence of rings of charged residues at the entrance and exit of the channels were sufficient to explain the experimentally observed anion and cation selectivity. Title: Estradiol regulation of astroglia and apolipoprotein E: an important role in neuronal regeneration Struble RG, Nathan BP, Cady C, Cheng X, McAsey M Ref: Experimental Gerontology, 42:54, 2007 : PubMed ESTHER: Struble_2007_Exp.Gerontol_42_54 PubMedSearch: Struble 2007 Exp.Gerontol 42 54 PubMedID: 16837159 Abstract The effects of ovarian hormone on neuronal growth and function are well known. However, equally important, but often neglected, are ovarian hormone effects on glia. Our in vivo and in vitro studies show that estradiol modifies both neuronal growth and glial activity and these effects are tightly linked. Estradiol stimulates neurite growth and the release of the glial apolipoprotein E (apoE) in culture studies. Estradiol-stimulated neurite growth in these cultures requires apoE. Estradiol replacement in ovariectomized mice transiently increases the expression of apoE, the low density lipoprotein receptor related protein (LRP) and synaptophysin throughout the brain. Continuous estradiol replacement over two months loses effect on apoE, LRP, and synaptophysin and suppresses reactive gliosis. Estrous cycle variation of glial activation (GFAP) and apoE are not identical. We propose that estradiol (and other ovarian hormones) functions as a zeitgeber to co-ordinate neuronal-glial interactions. Co-ordination assures temporally appropriate excitatory and inhibitory interactions between glia and neurons. With aging and the loss of ovarian cyclicity, some of this co-ordination must be diminished. These observations present significant clinical implications. Approaches to hormone therapy (HT), for diminishing the risk of chronic neurological diseases, need to consider the temporal nature of ovarian hormones in brain repair and plasticity. Moreover, approaches must consider apoE genotype. The neuroprotective effects of HT in numerous chronic age-related diseases may represent effective co-ordination of repair processes rather than direct disease-specific actions. Moreover, the role of glial-derived proteins in neuroprotection should not be ignored. Title: Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors Cheng X, Wang H, Grant B, Sine SM, McCammon JA Ref: PLoS Comput Biol, 2:e134, 2006 : PubMed ESTHER: Cheng_2006_PLoS.Comput.Biol_2_e134 PubMedSearch: Cheng 2006 PLoS.Comput.Biol 2 e134 PubMedID: 17009865 Abstract The initial coupling between ligand binding and channel gating in the human alpha7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced to move toward a ligand-bound conformation as captured in the crystallographic structure of acetylcholine binding protein (AChBP) in complex with carbamoylcholine. Comparison of apo- and ligand-bound AChBP structures shows only minor rearrangements distal from the ligand-binding site. In contrast, comparison of apo and TMD simulation structures of the nAChR reveals significant changes toward the bottom of the ligand-binding domain. These structural rearrangements are subsequently translated to the pore domain, leading to a partly open channel within 4 ns of TMD simulation. Furthermore, we confirmed that two highly conserved residue pairs, one located near the ligand-binding pocket (Lys145 and Tyr188), and the other located toward the bottom of the ligand-binding domain (Arg206 and Glu45), are likely to play important roles in coupling agonist binding to channel gating. Overall, our simulations suggest that gating movements of the alpha7 receptor may involve relatively small structural changes within the ligand-binding domain, implying that the gating transition is energy-efficient and can be easily modulated by agonist binding/unbinding. Title: Order N algorithm for computation of electrostatic interactions in biomolecular systems Lu B, Cheng X, Huang J, McCammon JA Ref: Proc Natl Acad Sci U S A, 103:19314, 2006 : PubMed ESTHER: Lu_2006_Proc.Natl.Acad.Sci.U.S.A_103_19314 PubMedSearch: Lu 2006 Proc.Natl.Acad.Sci.U.S.A 103 19314 PubMedID: 17148613 Abstract Poisson-Boltzmann electrostatics is a well established model in biophysics; however, its application to large-scale biomolecular processes such as protein-protein encounter is still limited by the efficiency and memory constraints of existing numerical techniques. In this article, we present an efficient and accurate scheme that incorporates recently developed numerical techniques to enhance our computational ability. In particular, a boundary integral equation approach is applied to discretize the linearized Poisson-Boltzmann equation; the resulting integral formulas are well conditioned and are extended to systems with arbitrary numbers of biomolecules. The solution process is accelerated by Krylov subspace methods and a new version of the fast multipole method. In addition to the electrostatic energy, fast calculations of the forces and torques are made possible by using an interpolation procedure. Numerical experiments show that the implemented algorithm is asymptotically optimal O(N) in both CPU time and required memory, and application to the acetylcholinesterase-fasciculin complex is illustrated. Title: The sorption behavior of complex pollution system composed of aldicarb and surfactant--SDBS Dai S, Liu G, Qian Y, Cheng X Ref: Water Res, 35:2286, 2001 : PubMed ESTHER: Dai_2001_Water.Res_35_2286 PubMedSearch: Dai 2001 Water.Res 35 2286 PubMedID: 11358309 Abstract The behavior of complex pollution system in soil composed of aldicarb, a carbamate pesticide, and sodium dodecylbenzenesulfonate (SDBS), an anionic surfactant, was studied by the experiment of shaking sorption balance. The range of concentration of aldicarb and SDBS was 0.4-5.0 and 1-1000 mg/kg of dried soil, respectively. Linear sorption isotherm was well fitted for these two chemicals. SDBS can decrease the sorption of aldicarb in soil remarkably. While the concentration of SDBS increased from 0 to 1000 mg/kg, the linear sorption coefficient can be decreased by 50%. But aldicarb showed no effect on the sorption of SDBS in experiment. In addition the mechanism of the effect of SDBS on sorption of aldicarb was discussed. | |||||||
|
