Chen K

References (45)

Title : Infiltration of porcine pancreatic lipase into magnetic hierarchical mesoporous UiO-66-NH(2) metal-organic frameworks for efficient detoxification of patulin from apple juice - Yan_2024_Food.Chem_431_137172
Author(s) : Yan X , Chen K , Jia H , Zhao Q , Du G , Guo Q , Chen H , Yuan Y , Yue T
Ref : Food Chem , 431 :137172 , 2024
Abstract : Patulin (PAT) is a mycotoxin known to globally contaminate fruits. The economic losses and health hazards caused by PAT desires a safe and efficient strategy for detoxifying PAT. Here, a magnetic core-shell hierarchical mesoporous metal-organic framework (Fe(3)O(4)@HMUiO-66-NH(2)) was synthesized via a salt-assisted nanoemulsion guided assembly method. This mesoporous structure (centered at 4.25 nm) allowed porcine pancreatic lipase (PPL) to infiltrate into the MOF shell at an immobilized amount of 255 mg/g, providing protection for PPL and enabling rapid separation and recovery. Compared with free PPL, PPL/Fe(3)O(4)@HMUiO-66-NH(2) at 70 degreesC possessed 4.7 folds improved thermal stability in terms of half-life. The detoxification rates of immobilized enzyme for PAT in neutral water, acidic water, and apple juice were 99.6%, 60.9%, and 52.6%, respectively. Moreover, the so designed PPL/Fe(3)O(4)@HMUiO-66-NH(2) showed extraordinary storage stability, reusability, and biocompatibility. Crucially, the quality of apple juice did not change significantly after PPL/Fe(3)O(4)@HMUiO-66-NH(2) treatment, which facilitated its application in apple juice. The magnetic core-shell mesoporous structure along with the revealed mechanism of immobilized enzyme detoxification of PAT provide tremendous opportunity for designing a safe and efficient PAT detoxification method.
ESTHER : Yan_2024_Food.Chem_431_137172
PubMedSearch : Yan_2024_Food.Chem_431_137172
PubMedID: 37603997

Title : Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers - Wang_2024_Clin.Pharmacol.Drug.Dev__
Author(s) : Wang X , Liu H , Cui C , Niu X , Li H , Niu S , Yan P , Wu N , Li F , Wu Q , Chen K , Hu B , Liu D
Ref : Clin Pharmacol Drug Dev , : , 2024
Abstract : Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (deltaQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (deltadeltaQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (C(max)) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.
ESTHER : Wang_2024_Clin.Pharmacol.Drug.Dev__
PubMedSearch : Wang_2024_Clin.Pharmacol.Drug.Dev__
PubMedID: 38757550

Title : Developing a Prognostic Model for Primary Biliary Cholangitis Based on a Random Survival Forest Model - Fu_2024_Int.J.Med.Sci_21_61
Author(s) : Fu XY , Song YQ , Lin JY , Wang Y , Wu WD , Peng JB , Ye LP , Chen K , Li SW
Ref : Int J Med Sci , 21 :61 , 2024
Abstract : Background: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease with few effective treatments and a poor prognosis, and its incidence is on the rise. There is an urgent need for more targeted treatment strategies to accurately identify high-risk patients. The use of stochastic survival forest models in machine learning is an innovative approach to constructing a prognostic model for PBC that can improve the prognosis by identifying high-risk patients for targeted treatment. Method: Based on the inclusion and exclusion criteria, the clinical data and follow-up data of patients diagnosed with PBC-associated cirrhosis between January 2011 and December 2021 at Taizhou Hospital of Zhejiang Province were retrospectively collected and analyzed. Data analyses and random survival forest model construction were based on the R language. Result: Through a Cox univariate regression analysis of 90 included samples and 46 variables, 17 variables with p-values <0.1 were selected for initial model construction. The out-of-bag (OOB) performance error was 0.2094, and K-fold cross-validation yielded an internal validation C-index of 0.8182. Through model selection, cholinesterase, bile acid, the white blood cell count, total bilirubin, and albumin were chosen for the final predictive model, with a final OOB performance error of 0.2002 and C-index of 0.7805. Using the final model, patients were stratified into high- and low-risk groups, which showed significant differences with a P value <0.0001. The area under the curve was used to evaluate the predictive ability for patients in the first, third, and fifth years, with respective results of 0.9595, 0.8898, and 0.9088. Conclusion: The present study constructed a prognostic model for PBC-associated cirrhosis patients using a random survival forest model, which accurately stratified patients into low- and high-risk groups. Treatment strategies can thus be more targeted, leading to improved outcomes for high-risk patients.
ESTHER : Fu_2024_Int.J.Med.Sci_21_61
PubMedSearch : Fu_2024_Int.J.Med.Sci_21_61
PubMedID: 38164345

Title : Computation-Based Design of Salt Bridges in PETase for Enhanced Thermostability and Performance for PET Degradation - Qu_2023_Chembiochem_24_e202300373
Author(s) : Qu Z , Chen K , Zhang L , Sun Y
Ref : Chembiochem , 24 :e202300373 , 2023
Abstract : Polyethylene terephthalate (PET) is one of the most widely used plastics, and the accumulation of PET poses a great threat to the environment. IsPETase can degrade PET rapidly at moderate temperatures, but its application is greatly limited by the low stability. Herein, molecular dynamics (MD) simulations combined with a sequence alignment strategy were adopted to introduce salt bridges into the flexible region of IsPETase to improve its thermal stability. In the designed variants, the T(m) values of IsPETase(I168R/S188D) and IsPETase(I168R/S188E) were 7.4 and 8.7 degreesC higher than that of the wild type, respectively. The release of products degraded by IsPETase(I168R/S188E) was 4.3times that of the wild type. Tertiary structure characterization demonstrated that the structure of the variants IsPETase(I168R/S188D) and IsPETase(I168R/S188E) became more compact. Extensive MD simulations verified that a stable salt bridge was formed between the residue R168 and D186 in IsPETase(I168R/S188D) , while in IsPETase(I168R/S188E) an R168-D186-E188 salt bridge network was observed. These results confirmed that the proposed computation-based salt bridge design strategy could efficiently generate variants with enhanced thermal stability for the long-term degradation of PET, which would be helpful for the design of enzymes with improved stability.
ESTHER : Qu_2023_Chembiochem_24_e202300373
PubMedSearch : Qu_2023_Chembiochem_24_e202300373
PubMedID: 37639367
Gene_locus related to this paper: idesa-peth

Title : The lipoprotein lipase that is shuttled into capillaries by GPIHBP1 enters the glycocalyx where it mediates lipoprotein processing - Song_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2313825120
Author(s) : Song W , Beigneux AP , Weston TA , Chen K , Yang Y , Nguyen LP , Guagliardo P , Jung H , Tran AP , Tu Y , Tran C , Birrane G , Miyashita K , Nakajima K , Murakami M , Tontonoz P , Jiang H , Ploug M , Fong LG , Young SG
Ref : Proc Natl Acad Sci U S A , 120 :e2313825120 , 2023
Abstract : Lipoprotein lipase (LPL), the enzyme that carries out the lipolytic processing of triglyceride-rich lipoproteins (TRLs), is synthesized by adipocytes and myocytes and secreted into the interstitial spaces. The LPL is then bound by GPIHBP1, a GPI-anchored protein of endothelial cells (ECs), and transported across ECs to the capillary lumen. The assumption has been that the LPL that is moved into capillaries remains attached to GPIHBP1 and that GPIHBP1 serves as a platform for TRL processing. In the current studies, we examined the validity of that assumption. We found that an LPL-specific monoclonal antibody (mAb), 88B8, which lacks the ability to detect GPIHBP1-bound LPL, binds avidly to LPL within capillaries. We further demonstrated, by confocal microscopy, immunogold electron microscopy, and nanoscale secondary ion mass spectrometry analyses, that the LPL detected by mAb 88B8 is located within the EC glycocalyx, distant from the GPIHBP1 on the EC plasma membrane. The LPL within the glycocalyx mediates the margination of TRLs along capillaries and is active in TRL processing, resulting in the delivery of lipoprotein-derived lipids to immediately adjacent parenchymal cells. Thus, the LPL that GPIHBP1 transports into capillaries can detach and move into the EC glycocalyx, where it functions in the intravascular processing of TRLs.
ESTHER : Song_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2313825120
PubMedSearch : Song_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2313825120
PubMedID: 37871217

Title : MAGL inhibition relieves synovial inflammation and pain via regulating NOX4-Nrf2 redox balance in osteoarthritis - Li_2023_Free.Radic.Biol.Med_208_13
Author(s) : Li X , Tao H , Zhou J , Zhang L , Shi Y , Zhang C , Sun W , Chu M , Chen K , Gu C , Yang X , Geng D , Hao Y
Ref : Free Radic Biol Med , 208 :13 , 2023
Abstract : Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage injury, hyperplasia of bone and inflammatory lesions of synovium. Monoacylglycerol lipase (MAGL), a member of the alpha/beta hydrolase superfamily, is involved in regulation of injury protection and immune-inflammation response. Autoinflammatory response of the synovium and the release of inflammatory mediators play critical roles in occurrence of early-stage OA. Fibroblast-like synoviocytes (FLSs) are resident mesenchymal cells of the synovial tissue. Considering that MAGL inhibition regulates the inflammatory signaling cascade, it is crucial to ascertain the biological effects and specific mechanisms of MAGL in alleviating inflammatory infiltration of OA FLSs. The aim of this study was to investigate the effect of MAGL on biological function in OA FLSs. Results from in vitro experiments showed that MAGL blockade not only effectively inhibited proliferation, invasion and migration of FLSs, but also downregulated expression of inflammatory-associated proteins. Sequencing results indicated that MAGL inhibition significantly suppressed NOX4-mediated oxidative stress, thus promoting Nrf2 nuclear accumulation and inhibiting generation of intracellular reactive oxygen species (ROS). Attenuation of NOX4 further alleviated redox dysplasia and ultimately improved tumor-like phenotypes, such as abnormal proliferation, migration and migration of FLSs. In vivo results corroborated this finding, with MAGL inhibition found to modulate pain and disease progression in an OA rat model. Collectively, these results indicate that MAGL administration is an ideal therapy treating OA.
ESTHER : Li_2023_Free.Radic.Biol.Med_208_13
PubMedSearch : Li_2023_Free.Radic.Biol.Med_208_13
PubMedID: 37516370
Gene_locus related to this paper: human-MGLL

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

Title : Sequentially co-immobilized PET and MHET hydrolases via Spy chemistry in calcium phosphate nanocrystals present high-performance PET degradation - Chen_2022_J.Hazard.Mater_438_129517
Author(s) : Chen K , Dong X , Sun Y
Ref : J Hazard Mater , 438 :129517 , 2022
Abstract : Accumulation of polyethylene terephthalate (PET) has brought an enormous threat to the ecosystem. The recently reported PET hydrolase (DuraPETase) and MHET hydrolase (MHETase) can synergistically catalyze the complete PET degradation. Hence, this work was designed to develop a bienzymatic cascade catalysis by co-immobilizing the two enzymes for PET biodegradation. DuraPETase and MHETase were sequentially co-immobilized in calcium phosphate nanocrystals (CaP) through SpyTag/SpyCatcher system. MHETase-SpyCatcher was first embedded inside the nanocrystals via biomimetic mineralization, and DuraPETase-SpyTag was then conjugated on the outlayer (~1.5 microm). The bienzyme compartmentalization facilitated DuraPETase interaction with the solid substrate, and the layered structures of the nanocrystals protected the enzymes, thus enhancing their stability. The high specific surface area of the nanocrystals and the proximity effects from the bienzymatic cascade were beneficial to the improved enzyme activity. Experimental data and molecular dynamics simulations revealed the activation effect of Ca(2+) on DuraPETase. Taken together, the final results indicate that the PET degradation efficiency of DuraPETase-MHETase@CaP increased by 6.1 and 1.5 times over the free bienzyme system within 10 d at 40 degreesC and 50 degreesC, with weight losses at 32.2% and 50.3%, respectively. The bienzymatic cascade with DuraPETase-MHETase@CaP can completely degrade PET, contributing to the recycling of PET.
ESTHER : Chen_2022_J.Hazard.Mater_438_129517
PubMedSearch : Chen_2022_J.Hazard.Mater_438_129517
PubMedID: 35809363

Title : Sweet potato extract alleviates high-fat-diet-induced obesity in C57BL\/6J mice, but not by inhibiting pancreatic lipases - Liu_2022_Front.Nutr_9_1016020
Author(s) : Liu T , Wu F , Chen K , Pan B , Yin X , You Y , Song Z , Li D , Huang D
Ref : Front Nutr , 9 :1016020 , 2022
Abstract : SCOPE AND AIM: Sweet potato is widely consumed as a healthy and nutritive vegetable containing bioactive constituents for health promotion. This study investigated the beneficial impact of white-fleshed sweet potato extract (SPE) on high fat diet (HFD)-induced obese mice. METHODS AND RESULTS: First, SPE, in which resin glycoside was found as the dominant constituent, was suggested as a potential anti-obesity agent, because 20-70% pancreatic lipase (PL) inhibition was measured with SPE by in vitro turbidity assay and pNPP assay. Hence, next, the effect of SPE on obese mice was detected by oral administration of HFD supplemented with 6% SPE on C57BL/6J mice for 9 weeks. Surprisingly, being the opposite of what was typically observed from a lipase inhibitor such as orlistat, the fecal fat content in SPE-fed obese mice was decreased (p < 0.01). Meanwhile, 6% SPE supplement indeed significantly ameliorated HFD-induced obesity in mice, including body weight gain, fat accumulation, adipocyte enlargement, insulin resistance, and hepatic steatosis (p < 0.05). The improved liver steatosis was found associated with a down-regulating action of SPE on nuclear factor kappa B activation in HFD-fed mice. The anti-obesity influence of SPE was also confirmed on the HepG2 cell model for non-alcoholic fatty liver disease (NAFLD). CONCLUSION: These results indicate that SPE, as a dietary supplement, has the great potential for weight control and treating hepatic steatosis, possibly through a different action mechanism from that of orlistat.
ESTHER : Liu_2022_Front.Nutr_9_1016020
PubMedSearch : Liu_2022_Front.Nutr_9_1016020
PubMedID: 36505243

Title : Pantao Pill Improves the Learning and Memory Abilities of APP\/PS1 Mice by Multiple Mechanisms - Xin_2022_Front.Pharmacol_13_729605
Author(s) : Xin Q , Shi W , Wang Y , Yuan R , Miao Y , Chen K , Cong W
Ref : Front Pharmacol , 13 :729605 , 2022
Abstract : Background: To explore the effect and mechanisms of Pantao Pill (PTP) on cognitive impairment. Methods: Network pharmacology was performed to analyze the mechanism of PTP treating cognitive impairment. The targets of PTP and cognitive impairment were predicted and used to construct protein-protein interaction (PPI) networks. The intersection network was selected, and the core network was obtained through topological analysis. Enrichment analysis was conducted to obtain the GOBP terms and KEGG pathways. We then performed experiments to validate the results of the network pharmacology by using an APP/PS1 transgenic mouse model. The APP/PS1 mice were divided into four groups: the model group, the high-dose PTP (3.6 g/kg.d) group, the low-dose PTP (1.8 g/kg.d) group, and the positive control group (donepezil hydrochloride, 2 mg/kg.d). Wild-type (WT) C57 mice served as a normal control group. PTP and donepezil were administered by gavage for 8 weeks. Results: Network pharmacology showed that PTP might improve cognitive impairment by regulating autophagy, apoptosis, and oxidative stress. For the Morris water maze test, a significant difference was shown in the total swimming distance among groups (p < 0.05) in the positioning navigation experiment, and with training time extension, the swimming speed increased (p < 0.01). In the space probe test, PTP administration significantly reduced the swimming path length and the escape latency of APP/PS1 mice (p < 0.05 or p < 0.01), whereas it had no effect on the swimming speed (p > 0.05). PTP (3.6 g/kg/d) rescued the reduction of norepinephrine and acetylcholine levels (p < 0.05), and increased the acetylcholinesterase concentration (p < 0.05) in the brain tissue. PTP (1.8 g/kg/d) increased the norepinephrine level (p < 0.01). PTP rescued the activity reduction of superoxide dismutase in the brain tissue (p < 0.01) and the neuron cell pyknosis in the hippocampal CA region (p < 0.05). PTP reduced ATG12 and PS1 expression (p < 0.05 or p < 0.01), and increased Bcl-2 expression in the brain tissue (p < 0.05). Conclusion: PTP can significantly improve the learning and memory abilities of APP/PS1 mice, and the mechanism may be related to the increase of neurotransmitter acetylcholine and norepinephrine levels, the reduction of the excessive autophagic activation, and the suppression of oxidative stress and excessive apoptotic activity.
ESTHER : Xin_2022_Front.Pharmacol_13_729605
PubMedSearch : Xin_2022_Front.Pharmacol_13_729605
PubMedID: 35281906

Title : Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 - Zhou_2021_Clin.Transl.Med_11_e449
Author(s) : Zhou L , Zhang C , Yang X , Liu L , Hu J , Hou Y , Tao H , Sugimura H , Chen Z , Wang L , Chen K
Ref : Clin Transl Med , 11 :e449 , 2021
Abstract : BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration-resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. METHODS: We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. RESULTS: We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta-analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1-knockout (Ces(-/-) ) mice verified the important role of endogenous Ces1 in PCa. CONCLUSIONS: Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa.
ESTHER : Zhou_2021_Clin.Transl.Med_11_e449
PubMedSearch : Zhou_2021_Clin.Transl.Med_11_e449
PubMedID: 34185414
Gene_locus related to this paper: human-CES1

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

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

Title : Impacts of chronic exposure to sublethal diazepam on behavioral traits of female and male zebrafish (Danio rerio) - Chen_2021_Ecotoxicol.Environ.Saf_208_111747
Author(s) : Chen K , Wu M , Chen C , Xu H , Wu X , Qiu X
Ref : Ecotoxicology & Environmental Safety , 208 :111747 , 2021
Abstract : Residues of the psychoactive drug diazepam (DZP) may pose potential risks to fish in aquatic environments, especially by disrupting their behavioral traits. In this study, female and male zebrafish were subjected to chronic exposure (21 days) to sublethal doses (120 and 12 microg/L) of DZP, aimed to compare the characteristics of their behavioral responses to DZP exposure, and to investigate the possible links between those behavioral responses and variations in their brain gamma-aminobutyric acid (GABA) and acetylcholinesterase (AChE) levels. Chronic exposure to DZP significantly decreased the swimming velocity and locomotor activity of both genders, indicating a typical sedative effect. Compared with males, whose locomotor activity was only significantly decreased by exposure to DZP for 21 days, females became hypoactive on day 14 (i.e., more sensitive), and they developed tolerance to the hypoactive effect induced by 120 microg/L DZP by day 21. Exposure to DZP significantly disturbed the behavioral traits related to social interactions in females but not in males. Those results indicate that DZP exhibits sex-dependent effects on the behaviors of fish. Moreover, exposure to DZP for 21 days significantly disturbed almost all of the tested behavioral traits associated with courtship when both genders were put together. Sex-dependent responses in brain GABA and AChE levels due to DZP exposure were also identified. Significant relationships between the brain GABA/AChE levels and some behavioral parameters related to locomotor activity were detected in females, but not in males.
ESTHER : Chen_2021_Ecotoxicol.Environ.Saf_208_111747
PubMedSearch : Chen_2021_Ecotoxicol.Environ.Saf_208_111747
PubMedID: 33396073

Title : Synthesis and Screening of alpha-Xylosides in Human Glioblastoma Cells - Kalita_2021_Mol.Pharm_18_451
Author(s) : Kalita M , Villanueva-Meyer J , Ohkawa Y , Kalyanaraman C , Chen K , Mohamed E , Parker MFL , Jacobson MP , Phillips JJ , Evans MJ , Wilson DM
Ref : Mol Pharm , 18 :451 , 2021
Abstract : Glycosaminoglycans (GAGs) such as heparan sulfate and chondroitin sulfate decorate all mammalian cell surfaces. These mucopolysaccharides act as coreceptors for extracellular ligands, regulating cell signaling, growth, proliferation, and adhesion. In glioblastoma, the most common type of primary malignant brain tumor, dysregulated GAG biosynthesis results in altered chain length, sulfation patterns, and the ratio of contributing monosaccharides. These events contribute to the loss of normal cellular function, initiating and sustaining malignant growth. Disruption of the aberrant cell surface GAGs with small molecule inhibitors of GAG biosynthetic enzymes is a potential therapeutic approach to blocking the rogue signaling and proliferation in glioma, including glioblastoma. Previously, 4-azido-xylose-alpha-UDP sugar inhibited both xylosyltransferase (XYLT-1) and beta-1,4-galactosyltransferase-7 (beta-GALT-7)-the first and second enzymes of GAG biosynthesis-when microinjected into a cell. In another study, 4-deoxy-4-fluoro-beta-xylosides inhibited beta-GALT-7 at 1 mM concentration in vitro. In this work, we seek to solve the enduring problem of drug delivery to human glioma cells at low concentrations. We developed a library of hydrophobic, presumed prodrugs 4-deoxy-4-fluoro-2,3-dibenzoyl-(alpha- or beta-) xylosides and their corresponding hydrophilic inhibitors of XYLT-1 and beta-GALT-7 enzymes. The prodrugs were designed to be activatable by carboxylesterase enzymes overexpressed in glioblastoma. Using a colorimetric MTT assay in human glioblastoma cell lines, we identified a prodrug-drug pair (4-nitrophenyl-alpha-xylosides) as lead drug candidates. The candidates arrest U251 cell growth at an IC(50) = 380 nM (prodrug), 122 microM (drug), and U87 cells at IC(50) = 10.57 microM (prodrug). Molecular docking studies were consistent with preferred binding of the alpha- versus beta-nitro xyloside conformer to XYLT-1 and beta-GALT-7 enzymes.
ESTHER : Kalita_2021_Mol.Pharm_18_451
PubMedSearch : Kalita_2021_Mol.Pharm_18_451
PubMedID: 33315406

Title : Inhibitory Potency of 4- Substituted Sampangine Derivatives toward Cu(2+) mediated aggregation of amyloid beta-peptide, Oxidative Stress, and Inflammation in Alzheimer's Disease - Su_2020_Neurochem.Int__104794
Author(s) : Su C , Chen Y , Chen K , Li W , Tang H
Ref : Neurochem Int , :104794 , 2020
Abstract : Cu(2+) plays a key role in the pathogenesis of Alzheimer's disease (AD). The dysregulation of Cu(2+) can cause neuronal damage and aggravate development of AD. Moreover, a series of 4-substituted sampangine derivatives have been investigated as inhibitors of acetylcholinesterase and beta-amyloid (Abeta) aggregation for the treatment of AD in our previous studies. In the present study, we reported that one of these derivatives SD-1 was able to modulate Cu(2+)-mediated multiple pathological elements in AD. The high selectivity of SD-1 for Cu(2+) over other biologically relevant metal ions was demonstrated by ITC. Western blotting analysis, light-scattering study, DCF-DA assay and paralysis experiment indicated that SD-1 suppressed the formation of Cu(2+)-Abeta species, alleviated the Cu(2+)-Abeta species induced neurotoxicity and inhibited the production of ROS catalyzed by Cu(2+)-Abeta species in SH-SY5Y cells over-expressing the Swedish mutant form of human APP (APPsw SH-SY5Y) and Abeta42 transgenic C elegans (CL2020). Furthermore, SD-1 inhibited the expressions of NO, iNOS, TNF-alpha, IL-1beta and IL-6 induced by Cu(2+) in BV2 microglial cells. Collectively, these findings provided valuable insights into the design and development of potent metal-chelating agents for AD treatment.
ESTHER : Su_2020_Neurochem.Int__104794
PubMedSearch : Su_2020_Neurochem.Int__104794
PubMedID: 32650027

Title : Artificial Nanometalloenzymes for Cooperative Tandem Catalysis - Li_2019_ACS.Appl.Mater.Interfaces_11_15718
Author(s) : Li H , Qiu C , Cao X , Lu Y , Li G , He X , Lu Q , Chen K , Ouyang P , Tan W
Ref : ACS Appl Mater Interfaces , 11 :15718 , 2019
Abstract : Artificial metalloenzymes that combine the advantages of natural enzymes and metal catalysts have been getting more attention in research. As a proof of concept, an artificial nanometalloenzyme (CALB-Shvo@MiMBN) was prepared by co-encapsulation of metallo-organic catalyst and enzyme in a soft nanocomposite consisting of 2-methylimidazole, metal ions, and biosurfactant in mild reaction conditions using a one-pot self-assembly method. The artificial nanometalloenzyme with lipase acted as the core, and the metallo-organic catalyst embedded in micropore exhibited a spherical structure of 30-50 nm in diameter. The artificial nanometalloenzyme showed high catalytic efficiency in the dynamic kinetic resolution of racemic primary amines or secondary alcohols compared to the one-pot catalytic reaction of immobilized lipase and free metallo-organic catalyst. This artificial nanometalloenzyme holds great promise for integrated enzymatic and heterogeneous catalysis.
ESTHER : Li_2019_ACS.Appl.Mater.Interfaces_11_15718
PubMedSearch : Li_2019_ACS.Appl.Mater.Interfaces_11_15718
PubMedID: 30986032

Title : Enhanced Diffusion and Oligomeric Enzyme Dissociation - Jee_2019_J.Am.Chem.Soc_141_20062
Author(s) : Jee AY , Chen K , Tlusty T , Zhao J , Granick S
Ref : Journal of the American Chemical Society , 141 :20062 , 2019
Abstract : The concept that catalytic enzymes can act as molecular machines transducing chemical activity into motion has conceptual and experimental support, but experimental support has involved oligomeric enzymes, often studied under conditions where the substrate concentration is higher than biologically relevant and accordingly exceeds kM, the Michaelis constant. Urease, a hexamer of subunits, has been considered to be the gold standard demonstrating enhanced diffusion. Here we show that urease and certain other oligomeric enzymes dissociate above kM into their subunits that diffuse more rapidly, thus providing a simple physical mechanism that contributes to enhanced diffusion in this regime of concentrations. Mindful that this conclusion may be controversial, our findings are supported by four independent analytical techniques: static light scattering, dynamic light scattering (DLS), size-exclusion chromatography (SEC), and fluorescence correlation spectroscopy (FCS). Data for urease are emphasized and the conclusion is validated for hexokinase, acetylcholinesterase, and aldolase. For hexokinase and aldolase no enhanced diffusion is observed except under conditions when these oligomeric enzymes dissociate. At substrate concentration regimes below kM at which acetylcholinesterase and urease do not dissociate, our finding showing up to 10% enhancement of the diffusion coefficient is consistent with various theoretical scenarios in the literature.
ESTHER : Jee_2019_J.Am.Chem.Soc_141_20062
PubMedSearch : Jee_2019_J.Am.Chem.Soc_141_20062
PubMedID: 31778607

Title : Peach Carboxylesterase PpCXE1 Is Associated with Catabolism of Volatile Esters - Cao_2019_J.Agric.Food.Chem_67_5189
Author(s) : Cao X , Xie K , Duan W , Zhu Y , Liu M , Chen K , Klee H , Zhang B
Ref : Journal of Agricultural and Food Chemistry , 67 :5189 , 2019
Abstract : Peach fruit volatile acetate esters impact consumer sensory preference and contribute to defense against biotic stresses. Previous studies showed that alcohol acyltransferase (AAT) family PpAAT1 is correlated with volatile ester formation in peach fruits. However, fruits also contain carboxylesterase (CXE) enzymes that hydrolyze esters. The functions of this family with regard to volatile ester content has not been explored. Here, we observed that content of acetate ester was negatively correlated with expression of PpCXE1. Recombinant PpCXE1 protein exhibited hydrolytic activity toward acetate esters present in peach fruit. Kinetic analysis showed that PpCXE1 showed the highest catalytic activity toward E-2-hexenyl acetate. Subcellular localization demonstrated that PpCXE1 is present in the cytoplasm. Transient expression in peach fruit and stable overexpression in tomato fruit resulted in significant reduction of volatile esters in vivo. Taken together, the results indicate that PpCXE1 expression is associated with catabolism of volatile acetate esters in peach fruit.
ESTHER : Cao_2019_J.Agric.Food.Chem_67_5189
PubMedSearch : Cao_2019_J.Agric.Food.Chem_67_5189
PubMedID: 30997798
Gene_locus related to this paper: prupe-m5w2v0 , prupe-m5vkk2 , prupe-m5vq13

Title : Genome-Wide Identification and Functional Analysis of Carboxylesterase and Methylesterase Gene Families in Peach (Prunus persica L. Batsch) - Cao_2019_Front.Plant.Sci_10_1511
Author(s) : Cao X , Duan W , Wei C , Chen K , Grierson D , Zhang B
Ref : Front Plant Sci , 10 :1511 , 2019
Abstract : Carboxylesterases (CXE) and methylesterases (MES) are hydrolytic enzymes that act on carboxylic esters and are involved in plant metabolic processes and defense responses. A few functions of plant CXE and MES genes have been identified but very little information is available about the role of most members. We made a comprehensive study of this gene family in a commercially important species, peach (Prunus persica L. Batsch). A total of 33 peach CXE genes and 18 MES genes were identified and shown to be distributed unevenly between the chromosomes. Based on phylogenetic analysis, CXEs and MESs clustered into two different branches. Comparison of the positions of intron and differences in motifs revealed the evolutionary relationships between CXE and MES genes. RNA-seq revealed differential expression patterns of CXE/MESs in peach flower, leaf, and ripening fruit and in response to methyl jasmonate (MeJA) and ultraviolet B treatment. Transcript levels of candidate genes were verified by real-time quantitative PCR. Heterologous expression in Escherichia coli identified three CXEs that were involved in the hydrolysis of volatile esters in vitro. Furthermore, two recombinant MES proteins were identified that could hydrolyze MeJA and methyl salicylate. Our results provide an important resource for the identification of functional CXE and MES genes involved in the catabolism of volatile esters, responses to biotic and abiotic stresses and activation of signaling molecules such as MeJA and methyl salicylate.
ESTHER : Cao_2019_Front.Plant.Sci_10_1511
PubMedSearch : Cao_2019_Front.Plant.Sci_10_1511
PubMedID: 31824538
Gene_locus related to this paper: prupe-m5w2v0 , prupe-m5vkk2 , prupe-m5vq13 , prupe-m5x0p5 , prupe-m5xkg4 , prupe-m5x0q4 , prupe-m5wiw5 , prupe-a0a0u2wu32 , prupe-a0a251mtk1 , prupe-m5vl29 , prupe-m5vn82 , prupe-m5vz47 , prupe-m5vq88 , prupe-m5y2s7 , prupe-m5wye7 , prupe-m5y9v4 , prupe-m5wxm4 , prupe-m5xqp6 , prupe-m5x4q4 , prupe-m5x4m1 , prupe-m5x6b3 , prupe-m5vlb6 , prupe-m5w4h3 , prupe-m5vlu4 , prupe-m5vln3 , prupe-a0a251myy7 , prupe-a0a251mws4 , prupe-m5vi18 , prupe-m5vh66 , prupe-m5xd54 , prupe-m5xqn2 , prupe-m5xr64 , prupe-m5vrm7 , prupe-m5vrk6 , prupe-m5vqp6 , prupe-a0a251nbb1 , prupe-a0a251nbd3 , prupe-a0a251nbb3 , prupe-a0a251nba0 , prupe-a0a251ndd4 , prupe-a0a251nbb6 , prupe-m5w315 , prupe-a0a251mwh1 , prupe-a0a251qn57 , prupe-m5vzh8 , prupe-m5xpz7 , prupe-m5xrp5 , prupe-m5wsr5

Title : Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk - Yang_2019_Cancer.Res_79_505
Author(s) : Yang Y , Wu L , Shu X , Lu Y , Shu XO , Cai Q , Beeghly-Fadiel A , Li B , Ye F , Berchuck A , Anton-Culver H , Banerjee S , Benitez J , Bjorge L , Brenton JD , Butzow R , Campbell IG , Chang-Claude J , Chen K , Cook LS , Cramer DW , deFazio A , Dennis J , Doherty JA , Dork T , Eccles DM , Edwards DV , Fasching PA , Fortner RT , Gayther SA , Giles GG , Glasspool RM , Goode EL , Goodman MT , Gronwald J , Harris HR , Heitz F , Hildebrandt MA , Hogdall E , Hogdall CK , Huntsman DG , Kar SP , Karlan BY , Kelemen LE , Kiemeney LA , Kjaer SK , Koushik A , Lambrechts D , Le ND , Levine DA , Massuger LF , Matsuo K , May T , McNeish IA , Menon U , Modugno F , Monteiro AN , Moorman PG , Moysich KB , Ness RB , Nevanlinna H , Olsson H , Onland-Moret NC , Park SK , Paul J , Pearce CL , Pejovic T , Phelan CM , Pike MC , Ramus SJ , Riboli E , Rodriguez-Antona C , Romieu I , Sandler DP , Schildkraut JM , Setiawan VW , Shan K , Siddiqui N , Sieh W , Stampfer MJ , Sutphen R , Swerdlow AJ , Szafron LM , Teo SH , Tworoger SS , Tyrer JP , Webb PM , Wentzensen N , White E , Willett WC , Wolk A , Woo YL , Wu AH , Yan L , Yannoukakos D , Chenevix-Trench G , Sellers TA , Pharoah PDP , Zheng W , Long J
Ref : Cancer Research , 79 :505 , 2019
Abstract : DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 x 10(-7). Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
ESTHER : Yang_2019_Cancer.Res_79_505
PubMedSearch : Yang_2019_Cancer.Res_79_505
PubMedID: 30559148

Title : Short-term and persistent impacts on behaviors related to locomotion, anxiety, and startle responses of Japanese medaka (Oryzias latipes) induced by acute, sublethal exposure to chlorpyrifos - Qiu_2017_Aquat.Toxicol_192_148
Author(s) : Qiu X , Nomichi S , Chen K , Honda M , Kang IJ , Shimasaki Y , Oshima Y
Ref : Aquat Toxicol , 192 :148 , 2017
Abstract : Although most exposures to chlorpyrifos (CPF) in natural flowing waters are brief and episodic, there have been a few reports of the persistence of abnormal fish behaviors caused by such acute exposure. The present study focused on the behavioral and biochemical responses of Japanese medaka (Oryzias latipes) to acute, sublethal exposure to CPF, as well as the persistence of the effects during a 3-week recovery test in CPF-free water. The medaka became hyperactive and exhibited an elevated anxiety state after a 4-day exposure to 0.024mg/L of CPF, but they recovered from these abnormal behavioral responses within 7days of recovery treatment. In contrast, persistent impacts on some startle responses to a sudden stimulation (induced by a ball drop) were observed in medaka exposed to CPF. The reaction latency did not change immediately after the 4-day exposure, but was significantly prolonged by as much as 21days after the termination of exposure. The post-stimulus swimming distance within 5s significantly decreased on the day immediately after the 4-day exposure, but it significantly increased after 7days of recovery treatment. The activity of acetylcholinesterase (AChE) in the brains of medaka was significantly inhibited on the day immediately after the 4-day exposure, but it returned to 80% and 110% of that in control fish on days 7 and 21 of the recovery period, respectively. However, AChE activities in the eyes of exposed medaka were persistently inhibited and declined to 33%, 71%, and 72% of that in control fish on days 0 (immediately after the 4-day exposure), 7, and 21 of recovery, respectively. Correlation analysis suggested that the changes of AChE activities in the brains of medaka may underlie some of the observed acute behavioral changes, and the changes of AChE activities in the eyes may contribute to the persistence of the abnormalities in the reaction latency of the startle response. Our findings suggest that medaka need a long time to recover from acute, sublethal exposure to CPF, and the persistence of the behavioral abnormalities might affect their fitness in natural habitats.
ESTHER : Qiu_2017_Aquat.Toxicol_192_148
PubMedSearch : Qiu_2017_Aquat.Toxicol_192_148
PubMedID: 28957716

Title : Synthesis of derivatives of cleistopholine and their anti-acetylcholinesterase and anti-beta-amyloid aggregation activity - Wu_2017_Bioorg.Chem_76_228
Author(s) : Wu Z , Liao W , Chen K , Qin J , Tang H
Ref : Bioorg Chem , 76 :228 , 2017
Abstract : A series of 6- and 9-substituted cleistopholine derivatives has been designed, synthesized and investigated to inhibit the aggregation of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-myloid (A beta). Results showed that these synthetic compounds had excellent AChE inhibitory activity and a significant in vitro inhibitory potency toward the self-induced A beta aggregation. When SH-SY5Y cells were treated with these substituted cleistopholine derivatives during they overexpressed the Swedish mutant form of human beta -amyloid precursor protein (APPsw), A beta 42 secretion levels were significantly reduced. According to a parallel artificial membrane permeation assay for BBB, seven out of these sixteen synthetic compounds probably could cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS).
ESTHER : Wu_2017_Bioorg.Chem_76_228
PubMedSearch : Wu_2017_Bioorg.Chem_76_228
PubMedID: 29195093

Title : Are we providing the best possible care for dementia patients? - Borisovskaya_2015_Neurodegener.Dis.Manag_5_217
Author(s) : Borisovskaya A , Chen K , Borson S
Ref : Neurodegener Dis Manag , 5 :217 , 2015
Abstract : SUMMARY Healthcare for patients with dementia is often reactive, poorly organized and fragmented. We discuss opportunities for improvements in the care of individuals living with dementia at home that can be implemented by physicians in their practices today. In particular, we argue that systematic identification and diagnosis of cognitive impairment and dementia in their early stages, coupled with a coherent, evidence-informed management framework, would benefit patients with dementia substantially and ease the burden of their caregivers. We emphasize that dementia influences all aspects of patient care, and each medical decision must be passed through the filter of knowledge that patients with dementia have special needs that can be identified and addressed.
ESTHER : Borisovskaya_2015_Neurodegener.Dis.Manag_5_217
PubMedSearch : Borisovskaya_2015_Neurodegener.Dis.Manag_5_217
PubMedID: 26107320

Title : Characterization of large structural genetic mosaicism in human autosomes - Machiela_2015_Am.J.Hum.Genet_96_487
Author(s) : Machiela MJ , Zhou W , Sampson JN , Dean MC , Jacobs KB , Black A , Brinton LA , Chang IS , Chen C , Chen K , Cook LS , Crous Bou M , De Vivo I , Doherty J , Friedenreich CM , Gaudet MM , Haiman CA , Hankinson SE , Hartge P , Henderson BE , Hong YC , Hosgood HD, 3rd , Hsiung CA , Hu W , Hunter DJ , Jessop L , Kim HN , Kim YH , Kim YT , Klein R , Kraft P , Lan Q , Lin D , Liu J , Le Marchand L , Liang X , Lissowska J , Lu L , Magliocco AM , Matsuo K , Olson SH , Orlow I , Park JY , Pooler L , Prescott J , Rastogi R , Risch HA , Schumacher F , Seow A , Setiawan VW , Shen H , Sheng X , Shin MH , Shu XO , VanDen Berg D , Wang JC , Wentzensen N , Wong MP , Wu C , Wu T , Wu YL , Xia L , Yang HP , Yang PC , Zheng W , Zhou B , Abnet CC , Albanes D , Aldrich MC , Amos C , Amundadottir LT , Berndt SI , Blot WJ , Bock CH , Bracci PM , Burdett L , Buring JE , Butler MA , Carreon T , Chatterjee N , Chung CC , Cook MB , Cullen M , Davis FG , Ding T , Duell EJ , Epstein CG , Fan JH , Figueroa JD , Fraumeni JF, Jr. , Freedman ND , Fuchs CS , Gao YT , Gapstur SM , Patino-Garcia A , Garcia-Closas M , Gaziano JM , Giles GG , Gillanders EM , Giovannucci EL , Goldin L , Goldstein AM , Greene MH , Hallmans G , Harris CC , Henriksson R , Holly EA , Hoover RN , Hu N , Hutchinson A , Jenab M , Johansen C , Khaw KT , Koh WP , Kolonel LN , Kooperberg C , Krogh V , Kurtz RC , Lacroix A , Landgren A , Landi MT , Li D , Liao LM , Malats N , McGlynn KA , McNeill LH , McWilliams RR , Melin BS , Mirabello L , Peplonska B , Peters U , Petersen GM , Prokunina-Olsson L , Purdue M , Qiao YL , Rabe KG , Rajaraman P , Real FX , Riboli E , Rodriguez-Santiago B , Rothman N , Ruder AM , Savage SA , Schwartz AG , Schwartz KL , Sesso HD , Severi G , Silverman DT , Spitz MR , Stevens VL , Stolzenberg-Solomon R , Stram D , Tang ZZ , Taylor PR , Teras LR , Tobias GS , Viswanathan K , Wacholder S , Wang Z , Weinstein SJ , Wheeler W , White E , Wiencke JK , Wolpin BM , Wu X , Wunder JS , Yu K , Zanetti KA , Zeleniuch-Jacquotte A , Ziegler RG , de Andrade M , Barnes KC , Beaty TH , Bierut LJ , Desch KC , Doheny KF , Feenstra B , Ginsburg D , Heit JA , Kang JH , Laurie CA , Li JZ , Lowe WL , Marazita ML , Melbye M , Mirel DB , Murray JC , Nelson SC , Pasquale LR , Rice K , Wiggs JL , Wise A , Tucker M , Perez-Jurado LA , Laurie CC , Caporaso NE , Yeager M , Chanock SJ
Ref : American Journal of Human Genetics , 96 :487 , 2015
Abstract : Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
ESTHER : Machiela_2015_Am.J.Hum.Genet_96_487
PubMedSearch : Machiela_2015_Am.J.Hum.Genet_96_487
PubMedID: 25748358

Title : Association of Lp-PLA2 Mass and Aysmptomatic Intracranial and Extracranial Arterial Stenosis in Hypertension Patients - Wang_2015_PLoS.One_10_e0130473
Author(s) : Wang Y , Zhang J , Qian Y , Tang X , Ling H , Chen K , Gao P , Zhu D
Ref : PLoS ONE , 10 :e0130473 , 2015
Abstract : BACKGROUND AND PURPOSE: Intracranial arterial stenosis (ICAS) is a common cause of ischemic stroke in Asians, whereas whites tend to have more extracranial lesions. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been associated with ischemic stroke by a large amount of work. However, there are few studies focusing on the relationship of Lp-PLA2 and asymptomatic ICAS or extracranial arterial stenosis (ECAS). Wehereby sought to explore the relationship of Lp-PLA2 and ICAS, ECAS and concurrent stenosis in stroke-free hypertensive patients in Chinese population.
METHODS: All the subjects were evaluated for the presence and severity of ICAS and ECAS through computerized tomographic angiography (CTA) covered the whole brain down to the level of aortic arch. Lp-PLA2 mass was measured by enzyme linked immunoassay. The association of Lp-PLA2 and vascular stenosis was analyzed through multivariate logistic regression.
RESULTS: Among 414 participants, 163 (39.4%) had no ICAS or ECAS, 63 (15.2%) had ECAS only, 111 (26.8%) had ICAS only and 77 (18.6%) had concurrent extraintracranial stenosis. Lp-PLA2 mass was significantly associated with isolated ICAS (OR: 2.3; 95% CI: 1.14-4.64), and concurrent stenosis (OR: 3.93; 95% CI: 1.62-9.51), but was not related to isolated ECAS (OR: 1.54; 95% CI: 0.68-3.48). Lp-PLA2 mass was also associated with moderate to severe ICAS no matter how was the ECAS. Moreover, patients with higher Lp-PLA2 mass showed more sever ICAS and had more intracranial arterial lesions. CONCLUSION: This study revealed the association of Lp-PLA2 mass with ICAS in stroke-free hypertensive patients in Chinese population. The further long-term cohort study was warranted to elucidate the concrete effect of Lp-PLA2 on the asymptomatic ICAS.
ESTHER : Wang_2015_PLoS.One_10_e0130473
PubMedSearch : Wang_2015_PLoS.One_10_e0130473
PubMedID: 26098634

Title : Surface display of the thermophilic lipase Tm1350 on the spore of Bacillus subtilis by the CotB anchor protein - Chen_2015_Extremophiles_19_799
Author(s) : Chen H , Tian R , Ni Z , Zhang Q , Zhang T , Chen Z , Chen K , Yang S
Ref : Extremophiles , 19 :799 , 2015
Abstract : Lipases expressed in microbial hosts have great commercial value, but their applications are restricted by the high costs of production and harsh conditions used in industrial processes, such as high temperature and alkaline environment. In this study, an Escherichia coli-Bacillus subtilis shuttle vector (pHS-cotB-Tm1350) was constructed for the spore surface display of the lipase Tm1350 from hyperthermophilic bacterium Thermotoga maritima MSB8. Successful display of the CotB-Tm1350 fusion protein on spore surface was confirmed by Western blot analysis and activity measurements. The optimal catalytic temperature and pH of the spore surface-displayed Tm1350 were 80 degreesC and 9, respectively, which were higher than non-immobilized Tm1350 (70 degreesC and pH 7.5). Analysis of thermal and pH stability showed that spore surface-displayed Tm1350 retained 81 or 70 % of its original activity after 8 h of incubation at pH 8 or pH 9 (70 degreesC), which were 18 % higher than the retained activity of the non-immobilized Tm1350 under the same conditions. Meanwhile, recycling experiments showed that the recombinant spores could be used for up to three reaction cycles without a significant decrease in the catalytic rate (84 %). These results suggested that enzyme display on the surface of the B. subtilis spore could serve as an effective approach for enzyme immobilization, which has potential applications in the harsh biochemical industry.
ESTHER : Chen_2015_Extremophiles_19_799
PubMedSearch : Chen_2015_Extremophiles_19_799
PubMedID: 26026992

Title : Expression and display of a novel thermostable esterase from Clostridium thermocellum on the surface of Bacillus subtilis using the CotB anchor protein - Chen_2015_J.Ind.Microbiol.Biotechnol_42_1439
Author(s) : Chen H , Zhang T , Jia J , Vastermark A , Tian R , Ni Z , Chen Z , Chen K , Yang S
Ref : J Ind Microbiol Biotechnol , 42 :1439 , 2015
Abstract : Esterases expressed in microbial hosts are commercially valuable, but their applications are limited due to high costs of production and harsh industrial processes involved. In this study, the esterase-DSM (from Clostridium thermocellum) was expressed and successfully displayed on the spore surface, and the spore-associated esterase was confirmed by western blot analysis and activity measurements. The optimal temperature and pH of spore surface-displayed DSM was 60 and 8.5 degrees C, respectively. It also demonstrates a broad temperature and pH optimum in the range of 50-70, 7-9.5 degrees C. The spore surface-displayed esterase-DSM retained 78, 68 % of its original activity after 5 h incubation at 60 and 70 degrees C, respectively, which was twofold greater activity than that of the purified DSM. The recombinant spores has high activity and stability in DMSO, which was 49 % higher than the retained activity of the purified DSM in DMSO (20 % v/v), and retained 65.2 % of activity after 7 h of incubation in DMSO (20 % v/v). However, the recombinant spores could retain 77 % activity after 3 rounds of recycling. These results suggest that enzyme displayed on the surface of the Bacillus subtilis spore could serve as an effective approach for enzyme immobilization.
ESTHER : Chen_2015_J.Ind.Microbiol.Biotechnol_42_1439
PubMedSearch : Chen_2015_J.Ind.Microbiol.Biotechnol_42_1439
PubMedID: 26318029

Title : Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor - Fang_2015_Chem.Biol_22_734
Author(s) : Fang P , Han H , Wang J , Chen K , Chen X , Guo M
Ref : Chemical Biology , 22 :734 , 2015
Abstract : Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits Plasmodium falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report three crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all three structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydropyran moiety of cladosporin are critical for the specificity of cladosporin against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure-driven drug development.
ESTHER : Fang_2015_Chem.Biol_22_734
PubMedSearch : Fang_2015_Chem.Biol_22_734
PubMedID: 26074468
Gene_locus related to this paper: clacd-cla3

Title : An Essential Esterase (BroH) for the Mineralization of Bromoxynil Octanoate by a Natural Consortium of Sphingopyxis sp. Strain OB-3 and Comamonas sp. Strain 7D-2 - Chen_2013_J.Agric.Food.Chem_61_11550
Author(s) : Chen K , Liu Y , Mao DM , Liu XM , Li SP , Jiang JD
Ref : Journal of Agricultural and Food Chemistry , 61 :11550 , 2013
Abstract : A natural consortium of two bacterial strains ( Sphingopyxis sp. OB-3 and Comamonas sp. 7D-2) was capable of utilizing bromoxynil octanoate as the sole source of carbon for its growth. Strain OB-3 was able to convert bromoxynil octanoate to bromoxynil but could not use the eight-carbon side chain as its sole carbon source. Strain 7D-2 could not degrade bromoxynil octanoate, although it was able to mineralize bromoxynil. An esterase (BroH) that is involved in the conversion of bromoxynil octanoate into bromoxynil and is essential for the mineralization of bromoxynil octanoate by the consortium was isolated from strain OB-3 and molecularly characterized. BroH encodes 304 amino acids and resembles alpha/beta-hydrolase fold proteins. Recombinant BroH was overexpressed in Escherichia coli BL21 (DE3) and purified by Ni-NTA affinity chromatography. BroH was able to transform p-nitrophenyl esters (C2-C14) and showed the highest activity toward p-nitrophenyl caproate (C6) on the basis of the catalytic efficiency value (Vmax/Km). Additionally, BroH activity decreased when the aliphatic chain length increased. The optimal temperature and pH for BroH activity was found to be 35 degrees C and 7.5, respectively. On the basis of a phylogenetic analysis, BroH belongs to subfamily V of bacterial lipolytic enzymes.
ESTHER : Chen_2013_J.Agric.Food.Chem_61_11550
PubMedSearch : Chen_2013_J.Agric.Food.Chem_61_11550
PubMedID: 24224769

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

Title : Drosophila Neuroligin 2 is Required Presynaptically and Postsynaptically for Proper Synaptic Differentiation and Synaptic Transmission - Chen_2012_J.Neurosci_32_16018
Author(s) : Chen YC , Lin YQ , Banerjee S , Venken K , Li J , Ismat A , Chen K , Duraine L , Bellen HJ , Bhat MA
Ref : Journal of Neuroscience , 32 :16018 , 2012
Abstract : Trans-synaptic adhesion between Neurexins (Nrxs) and Neuroligins (Nlgs) is thought to be required for proper synapse organization and modulation, and mutations in several human Nlgs have shown association with autism spectrum disorders. Here we report the generation and phenotypic characterization of Drosophila neuroligin 2 (dnlg2) mutants. Loss of dnlg2 results in reduced bouton numbers, aberrant presynaptic and postsynaptic development at neuromuscular junctions (NMJs), and impaired synaptic transmission. In dnlg2 mutants, the evoked responses are decreased in amplitude, whereas the total active zone (AZ) numbers at the NMJ are comparable to wild type, suggesting a decrease in the release probability. Ultrastructurally, the presynaptic AZ number per bouton area and the postsynaptic density area are both increased in dnlg2 mutants, whereas the subsynaptic reticulum is reduced in volume. We show that both presynaptic and postsynaptic expression of Dnlg2 is required to restore synaptic growth and function in dnlg2 mutants. Postsynaptic expression of Dnlg2 in dnlg2 mutants and wild type leads to reduced bouton growth whereas presynaptic and postsynaptic overexpression in wild-type animals results in synaptic overgrowth. Since Nlgs have been shown to bind to Nrxs, we created double mutants. These mutants are viable and display phenotypes that closely resemble those of dnlg2 and dnrx single mutants. Our results provide compelling evidence that Dnlg2 functions both presynaptically and postsynaptically together with Neurexin to determine the proper number of boutons as well as the number of AZs and size of synaptic densities during the development of NMJs.
ESTHER : Chen_2012_J.Neurosci_32_16018
PubMedSearch : Chen_2012_J.Neurosci_32_16018
PubMedID: 23136438
Gene_locus related to this paper: drome-CG13772

Title : No association of five candidate genetic variants with amyotrophic lateral sclerosis in a Chinese population - Chen_2012_Neurobiol.Aging_33_2721 e3
Author(s) : Chen Y , Zeng Y , Huang R , Yang Y , Chen K , Song W , Zhao B , Li J , Yuan L , Shang HF
Ref : Neurobiology of Aging , 33 :2721 e3 , 2012
Abstract : Recently, 5 single nucleotide polymorphisms (SNPs), rs2306677 in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2), rs1541160 in the kinesin-association protein 3 gene (KIFAP3), rs6690993 and rs6700125 in the FLJ10986 gene, and rs10260404 in the dipeptidyl-peptidase 6 gene (DPP6) have been reported to be associated with the risk of developing sporadic amyotrophic lateral sclerosis (SALS) in Caucasian populations. However, this association is not consistent among different studies and yet to be tested in Chinese SALS patients. We examined the above SNPs in a large cohort consisting of 395 SALS patients and 288 controls from Southwest China. Our results suggest that these SNPs are unlikely to be a common cause of SALS in Chinese populations.
ESTHER : Chen_2012_Neurobiol.Aging_33_2721 e3
PubMedSearch : Chen_2012_Neurobiol.Aging_33_2721 e3
PubMedID: 22795786

Title : Calibration and validation of a physiologically based model for soman intoxication in the rat, marmoset, guinea pig and pig - Chen_2012_J.Appl.Toxicol_32_673
Author(s) : Chen K , Seng KY
Ref : J Appl Toxicol , 32 :673 , 2012
Abstract : A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model has been developed for low, medium and high levels of soman intoxication in the rat, marmoset, guinea pig and pig. The primary objective of this model was to describe the pharmacokinetics of soman after intravenous, intramuscular and subcutaneous administration in the rat, marmoset, guinea pig, and pig as well as its subsequent pharmacodynamic effects on blood acetylcholinesterase (AChE) levels, relating dosimetry to physiological response. The reactions modelled in each physiologically realistic compartment are: (1) partitioning of C(+/-)P(+/-) soman from the blood into the tissue; (2) inhibition of AChE and carboxylesterase (CaE) by soman; (3) elimination of soman by enzymatic hydrolysis; (4) de novo synthesis and degradation of AChE and CaE; and (5) aging of AChE-soman and CaE-soman complexes. The model was first calibrated for the rat, then extrapolated for validation in the marmoset, guinea pig and pig. Adequate fits to experimental data on the time course of soman pharmacokinetics and AChE inhibition were achieved in the mammalian models. In conclusion, the present model adequately predicts the dose-response relationship resulting from soman intoxication and can potentially be applied to predict soman pharmacokinetics and pharmacodynamics in other species, including human.
ESTHER : Chen_2012_J.Appl.Toxicol_32_673
PubMedSearch : Chen_2012_J.Appl.Toxicol_32_673
PubMedID: 21433037

Title : An isofenphos-methyl hydrolase (Imh) capable of hydrolyzing the P-O-Z moiety of organophosphorus pesticides containing an aryl or heterocyclic group - Li_2012_Appl.Microbiol.Biotechnol_94_1553
Author(s) : Li R , Liu Y , Zhang J , Chen K , Li S , Jiang J
Ref : Applied Microbiology & Biotechnology , 94 :1553 , 2012
Abstract : Organophosphorus pesticide (OP) hydrolases play key roles in the degradation and decontamination of agricultural and household OPs and in the detoxification of chemical warfare agents. In this study, an isofenphos-methyl hydrolase gene (imh) was cloned from the isocarbophos-degrading strain of Arthrobacter sp. scl-2 using the polymerase chain reaction method. Isofenphos-methyl hydrolase (Imh) showed 98% sequence identity with the isofenphos hydrolase from Arthrobacter sp. strain B-5. Imh was highly expressed in Escherichia coli BL21 (DE3), and the His(6)-tagged Imh was purified (1.7 mg/ml) with a specific activity of 14.35 U/mg for the substrate isofenphos-methyl. The molecular mass of the denatured Imh is about 44 kDa, and the isoelectric point (pI) value was estimated to be 3.4. The optimal pH and temperature for hydrolysis of isofenphos-methyl were pH 8.0 and 35 degrees C, respectively. The secondary structure of Imh shows that Imh is a metallo-dependent hydrolase, and it was found that Imh was completely inhibited by the metalloprotease inhibitor 1,10-phenanthroline (0.5 mM), and the catalytic activity was restored by the subsequent addition of Zn(2+). Interestingly, Imh had a relatively broader substrate specificity and was capable of hydrolyzing 12 of the tested oxon and thion OPs with the P-O-Z moiety instead of the P-S(C)-Z moiety. Furthermore, it was found that the existence of an aryl or heterocyclic group in the leaving group (Z) is also important in determining the substrate specificity. Among all the substrates hydrolyzed by Imh, it was assumed that Imh preferred P-O-Z substrates still with a phosphamide bond (P-N), such as isofenphos-methyl, isofenphos, isocarbophos, and butamifos. The newly characterized Imh has a great potential for use in the decontamination and detoxification of agricultural and household OPs and is a good candidate for the study of the catalytic mechanism and substrate specificity of OP hydrolases.
ESTHER : Li_2012_Appl.Microbiol.Biotechnol_94_1553
PubMedSearch : Li_2012_Appl.Microbiol.Biotechnol_94_1553
PubMedID: 22120622

Title : Isolation of an isocarbophos-degrading strain of Arthrobacter sp. scl-2 and identification of the degradation pathway - Rong_2009_J.Microbiol.Biotechnol_19_1439
Author(s) : Rong L , Guo X , Chen K , Zhu J , Li S , Jiang J
Ref : J Microbiol Biotechnol , 19 :1439 , 2009
Abstract : Isocarbophos is a widely used organophosphorus insecticide that has caused environmental pollution in many areas. However, degradation of isocarbophos by pure cultures has not been extensively studied, and the degradation pathway has not been determined. In this paper, a highly effective isocarbophos-degrading strain, scl-2, was isolated from isocarbophos-polluted soil. Strain scl-2 was preliminarily identified as Arthrobacter sp. based on its morphological, physiological, and biochemical properties, as well as 16S rDNA analysis. Strain scl-2 could utilize isocarbophos as its sole source of carbon and phosphorus for growth. One hundred mg/l isocarbophos could be degraded to a nondetectable level in 18 h by scl-2 in cell culture, and isofenphos-methyl, profenofos, and phosmet could also be degraded. During the degradation of isocarbophos, the metabolites isopropyl salicylate, salicylate, and gentisate were detected and identified based on MS/MS analysis and their retention times in HPLC. Transformation of gentisate to pyruvate and fumarate via maleylpyruvate and fumarylpyruvate was detected by assaying for the activities of gentisate 1,2- dioxygenase (GDO) and maleylpyruvate isomerase. Therefore, we have identified the degradation pathway of isocarbophos in Arthrobacter sp. scl-2 for the first time. This study highlights an important potential use of the strain scl-2 for the cleanup of environmental contamination by isocarbophos and presents a mechanism of isocarbophos metabolism.
ESTHER : Rong_2009_J.Microbiol.Biotechnol_19_1439
PubMedSearch : Rong_2009_J.Microbiol.Biotechnol_19_1439
PubMedID: 19996699

Title : Novel anti-Alzheimer's dimer Bis(7)-cognitin: cellular and molecular mechanisms of neuroprotection through multiple targets - Li_2009_Neurotherapeutics_6_187
Author(s) : Li W , Mak M , Jiang H , Wang Q , Pang Y , Chen K , Han Y
Ref : Neurotherapeutics , 6 :187 , 2009
Abstract : Alzheimer's disease (AD) is a progressive and degenerative brain disorder that has emerged as one of the major public health problems in adults. Unfortunately, its molecular pathology and therapeutic strategies remain elusive. Because there are multiple factors closely indicated in the pathogenesis of AD, multiple drug therapy will be required to address the varied pathological aspects of this disease. Existing pharmacological approaches with one-molecule-one-target are limited in their ability to modify the pathology of AD. Novel therapeutics strategies comprise multifunctional compounds specifically designed to target concurrently on different sites at multifactorial etiopathogenesis of AD, thereby providing greater therapeutic efficacy. Over the past decade, our group has developed several series of dimeric acetylcholinesterase (AChE) inhibitors derived from tacrine and huperzine A, a unique anti-Alzheimer's drug originally discovered from a traditional Chinese medicinal plant. Bis(7)-Cognitin, one of our novel dimers, through inhibition of AChE, N-methyl-D-aspartate receptor, nitric oxide synthase, and amyloid precursor protein/beta-amyloid cascade concurrently, possesses remarkable neuroprotective activities. More importantly, the synergism between these targets might serve as one of the most effective therapeutic strategies to arrest/modify pathological process of AD in addition to improving the cognitive functions for AD.
ESTHER : Li_2009_Neurotherapeutics_6_187
PubMedSearch : Li_2009_Neurotherapeutics_6_187
PubMedID: 19110209

Title : Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophosphate-induced toxicity in mice and rats - Chen_2009_Toxicol.Mech.Methods_19_486
Author(s) : Chen K , Teo S , Seng KY
Ref : Toxicol Mech Methods , 19 :486 , 2009
Abstract : A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was recently developed to study the effect of diisopropylfluorophosphate (DFP) on acetylcholinesterase (AChE) activity in mouse and rat. That model takes into account relatively complex interactions involving many parameters, some of which may be uncertain and/or highly variable, especially those characterizing AChE activity after DFP intoxication. The primary objective of this study was to identify parameters that contribute most to the variability of AChE dynamics for model optimization against data. For this purpose, the influence of the variability of the rate constants for synthesis (K(syn)) and degradation (K(deg)) of AChE, and regeneration (K(reg)) and aging (K(age)) of inhibited AChE on the variability of AChE activity in mice and rat venous blood and brain was first calculated by a global sensitivity analysis. Next, the mouse PBPK/PD model was calibrated by optimizing the values of K(syn), K(deg), K(reg) and K(age). Thereafter, scale-up of the DFP-induced AChE activity was performed from mouse to rat. Validation of the rat model was performed by comparing the time course of venous blood and brain AChE activities from a Monte Carlo analysis to those obtained in vivo. Sensitivity analysis on the verified models showed that K(reg) and K(syn) were the most influential factors of AChE activity at shorter and longer durations, respectively, after DFP challenge. Scale-up of the AChE dynamics from mouse to rat was also successful, as evidenced by significant overlapping between the predicted 95(th) percentile confidence intervals and the experimental data.
ESTHER : Chen_2009_Toxicol.Mech.Methods_19_486
PubMedSearch : Chen_2009_Toxicol.Mech.Methods_19_486
PubMedID: 19788408

Title : Activation of brain regions vulnerable to Alzheimer's disease: the effect of mild cognitive impairment - Johnson_2006_Neurobiol.Aging_27_1604
Author(s) : Johnson SC , Schmitz TW , Moritz CH , Meyerand ME , Rowley HA , Alexander AL , Hansen KW , Gleason CE , Carlsson CM , Ries ML , Asthana S , Chen K , Reiman EM , Alexander GE
Ref : Neurobiology of Aging , 27 :1604 , 2006
Abstract : This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD.
ESTHER : Johnson_2006_Neurobiol.Aging_27_1604
PubMedSearch : Johnson_2006_Neurobiol.Aging_27_1604
PubMedID: 16226349

Title : Dynamic mechanism of E2020 binding to acetylcholinesterase: a steered molecular dynamics simulation - Niu_2005_J.Phys.Chem.B_109_23730
Author(s) : Niu C , Xu Y , Luo X , Duan W , Silman I , Sussman JL , Zhu W , Chen K , Shen J , Jiang H
Ref : J Phys Chem B , 109 :23730 , 2005
Abstract : The unbinding process of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine) leaving from the long active site gorge of Torpedo californica acetylcholinesterase (TcAChE) was studied by using steered molecular dynamics (SMD) simulations on a nanosecond scale with different velocities, and unbinding force profiles were obtained. Different from the unbinding of other AChE inhibitors, such as Huperzine A that undergoes the greatest barrier located at the bottleneck of the gorge, the major resistance preventing E2020 from leaving the gorge is from the peripheral anionic site where E2020 interacts intensively with several aromatic residues (e.g., Tyr70, Tyr121, and Trp279) through its benzene ring and forms a strong direct hydrogen bond and a water bridge with Ser286 via its O24. These interactions cause the largest rupture force, approximately 550 pN. It was found that the rotatable bonds of the piperidine ring to the benzene ring and dimethoxyindanone facilitate E2020 to pass the bottleneck through continuous conformation change by rotating those bonds to avoid serious conflict with Tyr121 and Phe330. The aromatic residues lining the gorge wall are the major components contributing to hydrophobic interactions between E2020 and TcAChE. Remarkably, these aromatic residues, acting in three groups as "sender" and "receiver", compose a "conveyer belt" for E2020 entering and leaving the TcAChE gorge.
ESTHER : Niu_2005_J.Phys.Chem.B_109_23730
PubMedSearch : Niu_2005_J.Phys.Chem.B_109_23730
PubMedID: 16375354

Title : How does huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations - Xu_2003_J.Am.Chem.Soc_125_11340
Author(s) : Xu Y , Shen J , Luo X , Silman I , Sussman JL , Chen K , Jiang H
Ref : Journal of the American Chemical Society , 125 :11340 , 2003
Abstract : The entering and leaving processes of Huperzine A (HupA) binding with the long active-site gorge of Torpedo californica acetylcholinesterase (TcAChE) have been investigated by using steered molecular dynamics simulations. The analysis of the force required along the pathway shows that it is easier for HupA to bind to the active site of AChE than to disassociate from it, which for the first time interprets at the atomic level the previous experimental result that unbinding process of HupA is much slower than its binding process to AChE. The direct hydrogen bonds, water bridges, and hydrophobic interactions were analyzed during two steered molecular dynamics (SMD) simulations. Break of the direct hydrogen bond needs a great pulling force. The steric hindrance of bottleneck might be the most important factor to produce the maximal rupture force for HupA to leave the binding site but it has a little effect on the binding process of HupA with AChE. Residue Asp72 forms a lot of water bridges with HupA leaving and entering the AChE binding gorge, acting as a clamp to take out HupA from or put HupA into the active site. The flip of the peptide bond between Gly117 and Gly118 has been detected during both the conventional MD and SMD simulations. The simulation results indicate that this flip phenomenon could be an intrinsic property of AChE and the Gly117-Gly118 peptide bond in both HupA bound and unbound AChE structures tends to adopt the native enzyme structure. At last, in a vacuum the rupture force is increased up to 1500 pN while in water solution the greatest rupture force is about 800 pN, which means water molecules in the binding gorge act as lubricant to facilitate HupA entering or leaving the binding gorge.
ESTHER : Xu_2003_J.Am.Chem.Soc_125_11340
PubMedSearch : Xu_2003_J.Am.Chem.Soc_125_11340
PubMedID: 16220957

Title : Metabolism of the dorsal cochlear nucleus in rat brain slices - Zheng_2000_Hear.Res_143_115
Author(s) : Zheng L , Godfrey DA , Waller HJ , Godfrey TG , Chen K , Kong W
Ref : Hearing Research , 143 :115 , 2000
Abstract : In vitro brain slices of the cochlear nucleus have been used for electrophysiological and pharmacological studies. More information is needed about the extent to which the slice resembles in vivo tissue, since this affects the interpretation of results obtained from slices. In this study, some chemical parameters of the dorsal cochlear nucleus (DCN) in rat brain slices were measured and compared to the in vivo state. The activities of malate dehydrogenase and lactate dehydrogenase were reduced in some DCN layers of incubated slices compared to in vivo brain tissue. The activities of choline acetyltransferase and acetylcholinesterase were increased or unchanged in DCN layers of slices. Adenosine triphosphate (ATP) concentrations for in vivo rat DCN were similar to those of cerebellar cortex. Compared with in vivo values, ATP concentrations were decreased in the DCN of brain slices, especially in the deep layer. Vibratome-cut slices had lower ATP levels than chopper-cut slices. Compared with the in vivo data, there were large losses of aspartate, glutamate, glutamine, gamma-aminobutyrate and taurine from incubated slices. These amino acid changes within the slices correlated with the patterns of release from the slices.
ESTHER : Zheng_2000_Hear.Res_143_115
PubMedSearch : Zheng_2000_Hear.Res_143_115
PubMedID: 10771189

Title : Synthesis and acetylcholinesterase inhibitory activity of huperzine A-E2020 combined compound - Zeng_1999_Bioorg.Med.Chem.Lett_9_3279
Author(s) : Zeng F , Jiang H , Zhai Y , Zhang H , Chen K , Ji R
Ref : Bioorganic & Medicinal Chemistry Lett , 9 :3279 , 1999
Abstract : The synthesis of huperzine-E2020 combined compound (3) has been accomplished and the activities of 3 and the intermediates 12 and 13 to inhibit the activity of acetylcholinesterase have been measured. Conformation analyses and molecular docking studies of E2020 and the eight isomers of 12 were carried out. The results indicated that binding energies of all isomers of 12 with AChE was much lower than E2020 except for isomer RRZ, which might be the reason that the activity of 12 was lower than that of E2020. Interaction pattern of RRZ in AChE was also studied. Both binding energy and interaction pattern shows that the biological activity of RRZ might be higher than that of E2020.
ESTHER : Zeng_1999_Bioorg.Med.Chem.Lett_9_3279
PubMedSearch : Zeng_1999_Bioorg.Med.Chem.Lett_9_3279
PubMedID: 10612585

Title : Effects of endogenous acetylcholine on spontaneous activity in rat dorsal cochlear nucleus slices - Chen_1998_Brain.Res_783_219
Author(s) : Chen K , Waller HJ , Godfrey DA
Ref : Brain Research , 783 :219 , 1998
Abstract : We have examined the contribution of endogenous acetylcholine (ACh) release to the spontaneous firing of both regular (probably fusiform cells) and bursting neurons (probably cartwheel cells) in the dorsal cochlear nucleus (DCN) in rat brainstem slices. The muscarinic antagonists atropine, scopolamine, and tropicamide (1-2 microM) caused substantial decreases of firing rates in a majority of the neurons. Reversible acetylcholinesterase (AChE) inhibitors typically caused large transient increases in firing that decayed more slowly than responses to carbachol. The irreversible AChE inhibitor diisopropyl fluorophosphate (DFP) usually caused a sustained increase, with an initial peak followed by a gradual change to a final level higher than before DFP. Tropicamide caused large decreases in firing after DFP, confirming sustained ACh release. Both neostigmine and DFP applied after AChE inhibition by DFP sometimes elicited a transient response. We conclude that the level of sustained response to DFP is determined by the rate of endogenous ACh release, and that DFP and reversible AChE inhibitors exert an initial transient agonist effect that overlaps the initial effect of acetylcholinesterase inhibition. The slice experiments provide a model for cholinergic mechanisms in vivo, confirm that the release of endogenous ACh increases the firing rates of regular and bursting neurons in superficial DCN, and support the hypothesis that spontaneous firing of DCN neurons is sustained in part by cholinergic inputs.
ESTHER : Chen_1998_Brain.Res_783_219
PubMedSearch : Chen_1998_Brain.Res_783_219
PubMedID: 9507142

Title : Synthesis and acetylcholinesterase inhibitory activity of (+\/-)-14- fluorohuperzine A - Zeng_1998_Bioorg.Med.Chem.Lett_8_1661
Author(s) : Zeng F , Jiang H , Tang X , Chen K , Ji R
Ref : Bioorganic & Medicinal Chemistry Lett , 8 :1661 , 1998
Abstract : The synthesis of (+/-)-14-Fluorohuperzine A has been accomplished and the ability of this agent to inhibit acetylcholinesterase has been measured. Taking into account its racemic form, this compound exhibits 62 times less potent activity than natural (-)-huperzine A.
ESTHER : Zeng_1998_Bioorg.Med.Chem.Lett_8_1661
PubMedSearch : Zeng_1998_Bioorg.Med.Chem.Lett_8_1661
PubMedID: 9873409