Ding J

References (59)

Title : Discovery of a novel lead characterized by a stilbene-extended scaffold against sepsis as soluble epoxide hydrolase inhibitors - Feng_2024_Eur.J.Med.Chem_266_116113
Author(s) : Feng ZQ , Ding J , Zhu MZ , Xie WS , Liu RC , Liu SS , Liu SM , Yu MJ , Zhu XH , Liang JH
Ref : Eur Journal of Medicinal Chemistry , 266 :116113 , 2024
Abstract : Recently, some inhibitors of soluble epoxide hydrolase (sEH) showed limited potential in treating sepsis by increasing survival time, but they have unfortunately failed to improve survival rates. In this study, we initially identified a new hit 11D, belonging to a natural skeleton known as stilbene and having an IC(50) of 644 nM on inhibiting murine sEH. Natural scaffold-based sEH inhibitors are paid less attention. A combination of structure-activity relationships (SARs)-guided structural optimization and computer-aided skeleton growth led to a highly effective lead compound 70P (IC(50): 4.0 nM). The dose-response study indicated that 70P (at doses of 0.5-5 mg/kg, ip.) significantly increased survival rates and survival time by reducing the levels of the inflammatory factors TNF-alpha and IL-6 in the liver. Interestingly, 70P exhibited much higher accumulation in the liver than in plasma (AUC ratio: 175). In addition, 70P exhibits equal IC50 value (1.5 nM) on inhibiting human sEH as EC5026 (1.7 nM). In conclusion, the natural scaffold-extended sEH inhibitor 70P has the potential to become a new promising lead for addressing the unmet medical need in sepsis treatment, which highlighted the importance of natural skeleton in developing sEH inhibitors.
ESTHER : Feng_2024_Eur.J.Med.Chem_266_116113
PubMedSearch : Feng_2024_Eur.J.Med.Chem_266_116113
PubMedID: 38215588

Title : DPPX antibody-mediated autoimmune encephalitisthe first case with breast cancer and review of the literature - Dai_2024_Heliyon_10_e27413
Author(s) : Dai Y , Zheng Y , Zhu J , Ding J , Qiu K , Tang B
Ref : Heliyon , 10 :e27413 , 2024
Abstract : Dipeptidyl-peptidase-like protein 6 (DPPX) antibody-mediated encephalitis is a rare type of autoimmune encephalitis (AE), which mainly manifests as diarrhea accompanied by weight loss, cognitive decline, epileptic seizures, and even psychiatric symptoms. Remarkably, it is also reported to be associated with tumors, predominantly B-cell lymphoma. Overall, the AE remains uncharacterized clinically and its long-term prognosis remains elusive. Herein, we report the first case of DPPX antibody-mediated AE secondary to breast cancer. Importantly, it substantially improves after aggressive immunotherapy. Our case highlights DPPX antibody-mediated AE as a paraneoplastic syndrome and discusses the pearls in its diagnosis and management.
ESTHER : Dai_2024_Heliyon_10_e27413
PubMedSearch : Dai_2024_Heliyon_10_e27413
PubMedID: 38449607

Title : Elucidating the toxicity mechanisms of organophosphate esters by adverse outcome pathway network - He_2024_Arch.Toxicol_98_233
Author(s) : He W , Ding J , Gao N , Zhu L , Feng J
Ref : Archives of Toxicology , 98 :233 , 2024
Abstract : With the widespread use of organophosphate esters (OPEs), the accumulation and toxicity effect of OPEs in biota are attracting more and more concern. In order to clarify the mechanism of toxicity of OPEs to organisms, this study reviewed the OPEs toxicity and systematically identified the mechanism of OPEs toxicity under the framework of adverse outcome pathway (AOP). OPEs were divided into three groups (alkyl-OPEs, aryl-OPEs, and halogenated-OPEs) and biota was divided into aquatic organism and mammals. The results showed that tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) mainly caused neurotoxicity, reproductive, and hepatotoxicity in different mechanisms. According to the constructed AOP network, the toxicity mechanism of OPEs on aquatic organisms and mammals is different, which is mainly attributed to the different biological metabolic systems of aquatic organisms and mammals. Interestingly, our results indicate that the toxicity effect of the three kinds of OPEs on aquatic organisms is different, while there was no obvious difference in the mechanism of toxicity of OPEs on mammals. This study provides a theoretical basis for OPEs risk assessment in the future.
ESTHER : He_2024_Arch.Toxicol_98_233
PubMedSearch : He_2024_Arch.Toxicol_98_233
PubMedID: 37864630

Title : Efgartigimod is a new option for the treatment of thymoma associated myasthenia gravis: A case report - Wang_2024_Int.J.Surg.Case.Rep_115_109241
Author(s) : Wang S , Wang Q , Jin L , Dong J , Ding J
Ref : Int J Surg Case Rep , 115 :109241 , 2024
Abstract : INTRODUCTION: The perioperative efficacy and safety of efgartigimod in patients with thymoma associated myasthenia gravis have not been reported. CASE PRESENTATION: We described the case of a 47-year-old woman who presented thymoma associated myasthenia gravis. Primarily, the patient was treated with acetylcholinesterase inhibitors, immunosuppressive medications, and intravenous immunoglobulin. Unfortunately, the control of symptoms was unsatisfactory. The patient was treated with recommended dosage of efgartigimod (10 mg/kg administered as a 1 h intravenous infusion once weekly for 2 weeks) combined with immunosuppressive therapy. Consequently, improved outcomes and rapid clinical remission were observed. Then, modified subxiphoid thoracoscopic thymectomy was performed smoothly and the patient was discharged from hospital after recovery in short time. DISCUSSION: Administration of efgartigimod could control symptoms significantly and rapidly. Efgartigimod provides the opportunity of thymectomy in short time. Importantly, there was no any perioperative complication or any adverse event related to efgartigimod. CONCLUSION: The improved outcomes of the patient with thymoma associated myasthenia gravis highlight the importance of efgartigimod. Large-scale clinical trials are needed to validate the safety and efficacy of efgartigimod during the perioperative period of thymectomy.
ESTHER : Wang_2024_Int.J.Surg.Case.Rep_115_109241
PubMedSearch : Wang_2024_Int.J.Surg.Case.Rep_115_109241
PubMedID: 38219512

Title : A multibiomarker approach to assess the ecotoxicological effects of diclofenac on Asian clam Corbicula fluminea (O. F. Muller, 1774) - Yuan_2023_Environ.Sci.Pollut.Res.Int__
Author(s) : Yuan N , Ding J , Wu J , Bao E , Chu Y , Hu F
Ref : Environ Sci Pollut Res Int , : , 2023
Abstract : Diclofenac (DCF), one of the most current and widely used nonsteroidal anti-inflammatory drugs (NSAIDs), has been frequently detected in aquatic environments worldwide. However, the ecotoxicological effects of DCF on freshwater invertebrates remain largely unknown. In the present study, Corbicula fluminea were exposed to environmentally relevant concentrations of DCF (0, 2, 20, and 200 microg/L) for 28 days, and the potential adverse effects of DCF on siphoning behavior, antioxidant responses, and apoptosis were investigated. Our results showed that the siphon efficiencies of clams were significantly suppressed under DCF stress. DCF exerted neurotoxicity via reducing the activity of acetylcholinesterase (AChE) in gills and digestive gland of C. fluminea. Exposure to DCF induced antioxidant stress and increased malondialdehyde (MDA) levels in both gills and digestive gland of C. fluminea. Transcriptional alterations of apoptosis-related genes indicated that DCF might induce apoptosis by triggering mitochondrial apoptotic pathway. These findings can improve our understanding of the ecological risk of DCF in freshwater ecosystems.
ESTHER : Yuan_2023_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Yuan_2023_Environ.Sci.Pollut.Res.Int__
PubMedID: 37438503

Title : Responses of gut microbiomes to commercial polyester polymer biodegradation in Tenebrio molitor Larvae - He_2023_J.Hazard.Mater_457_131759
Author(s) : He L , Yang SS , Ding J , He ZL , Pang JW , Xing DF , Zhao L , Zheng HS , Ren NQ , Wu WM
Ref : J Hazard Mater , 457 :131759 , 2023
Abstract : Polyethylene terephthalate (PET) is a mass-produced fossil-based plastic polymer that contributes to catastrophic levels of plastic pollution. Here we demonstrated that Tenebrio molitor (mealworms) was capable of rapidly biodegrading two commercial PET resins (microplastics) with respective weight-average molecular weight (M(w)) of 39.33 and 29.43 kDa and crystallinity of 22.8 +/- 3.06% and 18 +/- 2.25%, resulting in an average mass reduction of 71.03% and 73.28% after passage of their digestive tract, and respective decrease by 9.22% and 11.36% in M(w) of residual PET polymer in egested frass. Sequencing of 16 S rRNA gene amplicons of gut microbial communities showed that dominant bacterial genera were enriched and associated with PET degradation. Also, PICRUSt prediction exhibited that oxidases (monooxygenases and dioxygenases), hydrolases (cutinase, carboxylesterase and chitinase), and PET metabolic enzymes, and chemotaxis related functions were up-regulated in the PET-fed larvae. Additionally, metabolite analyses revealed that PET uptake caused alterations of stress response and plastic degradation related pathways, and lipid metabolism pathways in the T. molitor larvae could be reprogrammed when the larvae fed on PET. This study provides new insights into gut microbial community adaptation to PET diet under nutritional stress (especially nitrogen deficiency) and its contribution to PET degradation.
ESTHER : He_2023_J.Hazard.Mater_457_131759
PubMedSearch : He_2023_J.Hazard.Mater_457_131759
PubMedID: 37276692

Title : Neurodevelopmental toxicity of bisphenol AF in zebrafish larvae and the protective effects of curcumin - Yang_2023_J.Appl.Toxicol__
Author(s) : Yang Q , Liu J , Ding J
Ref : J Appl Toxicol , : , 2023
Abstract : Bisphenol AF (BPAF) is one of the most commonly used alternatives of bisphenol A in the plastics industry. The effects of BPAF on nervous development are unclear. Curcumin (CUR) has been determined to be an anti-inflammatory and antioxidant agent. In this study, the effects of BPAF on neurotoxicity of zebrafish embryos/larvae and whether CUR could reverse effects induced by BPAF were investigated. The results showed that BPAF treatment induced deficits in locomotor behavior, altered the larval brain development, caused aberrant expression of neurogenesis related genes (elavl3, zn5, alpha-tubulin, syn2a, and gap43), decreased acetylcholinesterase (AChE) activity, and induced oxidative stress, cell apoptosis, and neuroinflammation in zebrafish larvae. CUR addition could block the adverse effects of BPAF on nervous development by attenuated oxidative stress and cell apoptosis induced by BPAF in zebrafish, enhanced the activity of AChE, and increased the expression of genes involved in the pro-inflammatory cytokines (IL-6, IL-1beta, TNF-alpha, and IL-8). The results of this study indicate that BPAF could induce aberrant development on nervous system. However, CUR exerts neuroprotective effects on BPAF-induced neurotoxicity in zebrafish larvae.
ESTHER : Yang_2023_J.Appl.Toxicol__
PubMedSearch : Yang_2023_J.Appl.Toxicol__
PubMedID: 37423901

Title : Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial - Ji_2023_Diabetes.Obes.Metab_25_3671
Author(s) : Ji L , Lu J , Gao L , Ying C , Sun J , Han J , Zhao W , Gao Y , Wang K , Zheng X , Xie D , Ding J , Zhao J , Yu Q , Wang T
Ref : Diabetes Obes Metab , 25 :3671 , 2023
Abstract : AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.
ESTHER : Ji_2023_Diabetes.Obes.Metab_25_3671
PubMedSearch : Ji_2023_Diabetes.Obes.Metab_25_3671
PubMedID: 37661308

Title : A randomized, double-blind, placebo controlled, phase 3 trial to evaluate the efficacy and safety of cetagliptin added to ongoing metformin therapy in patients with uncontrolled type 2 diabetes with metformin monotherapy - Ji_2023_Diabetes.Obes.Metab_25_3788
Author(s) : Ji L , Lu J , Gao L , Yan X , Li J , Cheng Z , Zhang L , Tian J , Li P , Bai J , Xie D , Zhao J , Ding J , Yu Q , Wang T
Ref : Diabetes Obes Metab , 25 :3788 , 2023
Abstract : AIM: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. METHODS: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once-daily cetagliptin 100mg, cetagliptin 50mg and placebo in a 2:2:1 ratio for 24-week double-blind treatment. At week 24, patients initially randomized to cetagliptin 50mg and placebo were switched to cetagliptin 100mg for 28weeks open-label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all-patients-treated population using an analysis of co-variance. RESULTS: After 24weeks, both add-on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were -1.17+/-0.794%, -1.23+/-0.896% in cetagliptin 100mg and 50mg plus metformin group, respectively. No difference was observed between the cetagliptin 100mg and 50mg plus metformin group. Patients with higher baseline HbA1c levels (<=8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100mg (49.4%) and cetagliptin 50mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment beta-function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. CONCLUSIONS: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy.
ESTHER : Ji_2023_Diabetes.Obes.Metab_25_3788
PubMedSearch : Ji_2023_Diabetes.Obes.Metab_25_3788
PubMedID: 37724698

Title : A novel thermostable and salt-tolerant carboxylesterase involved in the initial aerobic degradation pathway for pyrethroids in Glycomyces salinus - Liu_2023_J.Hazard.Mater_451_131128
Author(s) : Liu Y , Tang S , Wang X , Tang X , Wu Q , Huang Z , Ding J
Ref : J Hazard Mater , 451 :131128 , 2023
Abstract : The long-term and excessive use of pyrethroid pesticides poses substantial health risks and ecosystem concerns. Several bacteria and fungi have been reported that could degrade pyrethroids. The ester-bond hydrolysis using hydrolases is the initial regulatory metabolic reaction of pyrethroids. However, the thoroughly biochemical characterization of hydrolases involved in this process is limited. Here, a novel carboxylesterase, designated as EstGS1 that could hydrolyze pyrethroid pesticides was characterized. EstGS1 showed low sequence identity (<27.03%) compared to other reported pyrethroid hydrolases and belonged to the hydroxynitrile lyase family that preferred short short-chain acyl esters (C2 to C8). EstGS1 displayed the maximal activity of 213.38 U/mg at 60 degreesC and pH 8.5 using pNPC2 as substrate, with K(m) and V(max) were 2.21 +/- 0.72 mM and 212.90 +/- 41.78 microM/min, respectively. EstGS1 is a halotolerant esterase and remains stable in 5.1 M NaCl. Based on molecular docking and mutational analysis, the catalytic triad of S(74)-D(181)-H(212) and three other substrate-binding residues I(108), S(159), and G(75) are critical for the enzymatic activity of EstGS1. Additionally, 61 and 40 mg/L of deltamethrin and lambda-cyhalothrin were hydrolyzed by 20 U of EstGS1 in 4 h. This work presents the first report on a pyrethroid pesticide hydrolase characterized from a halophilic actinobacteria.
ESTHER : Liu_2023_J.Hazard.Mater_451_131128
PubMedSearch : Liu_2023_J.Hazard.Mater_451_131128
PubMedID: 36893599
Gene_locus related to this paper: 9actn-EstGS1

Title : Display of a novel carboxylesterase CarCby on Escherichia coli cell surface for carbaryl pesticide bioremediation - Liu_2022_Microb.Cell.Fact_21_97
Author(s) : Liu Y , Wang X , Nong S , Bai Z , Han N , Wu Q , Huang Z , Ding J
Ref : Microb Cell Fact , 21 :97 , 2022
Abstract : BACKGROUND: Carbamate pesticides have been widely used in agricultural and forestry pest control. The large-scale use of carbamates has caused severe toxicity in various systems because of their toxic environmental residues. Carbaryl is a representative carbamate pesticide and hydrolase/carboxylesterase is the initial and critical enzyme for its degradation. Whole-cell biocatalysts have become a powerful tool for environmental bioremediation. Here, a whole cell biocatalyst was constructed by displaying a novel carboxylesterase/hydrolase on the surface of Escherichia coli cells for carbaryl bioremediation. RESULTS: The carCby gene, encoding a protein with carbaryl hydrolysis activity was cloned and characterized. Subsequently, CarCby was displayed on the outer membrane of E. coli BL21(DE3) cells using the N-terminus of ice nucleation protein as an anchor. The surface localization of CarCby was confirmed by SDS-PAGE and fluorescence microscopy. The optimal temperature and pH of the engineered E. coli cells were 30 degreesC and 7.5, respectively, using pNPC4 as a substrate. The whole cell biocatalyst exhibited better stability and maintained approximately 8-fold higher specific enzymatic activity than purified CarCby when incubated at 30 degreesC for 120 h. In addition, ~ 100% and 50% of the original activity was retained when incubated with the whole cell biocatalyst at 4 degC and 30 degreesC for 35 days, respectively. However, the purified CarCby lost almost 100% of its activity when incubated at 30 degreesC for 134 h or 37 degreesC for 96 h, respectively. Finally, approximately 30 mg/L of carbaryl was hydrolyzed by 200 U of the engineered E. coli cells in 12 h. CONCLUSIONS: Here, a carbaryl hydrolase-containing surface-displayed system was first constructed, and the whole cell biocatalyst displayed better stability and maintained its catalytic activity. This surface-displayed strategy provides a new solution for the cost-efficient bioremediation of carbaryl and could also have the potential to be used to treat other carbamates in environmental bioremediation.
ESTHER : Liu_2022_Microb.Cell.Fact_21_97
PubMedSearch : Liu_2022_Microb.Cell.Fact_21_97
PubMedID: 35643494
Gene_locus related to this paper: baca2-a7z924

Title : Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction - Liu_2022_Nat.Commun_13_3490
Author(s) : Liu Z , Yang N , Dong J , Tian W , Chang L , Ma J , Guo J , Tan J , Dong A , He K , Zhou J , Cinar R , Wu J , Salinas AG , Sun L , Kumar M , Sullivan BT , Oldham BB , Pitz V , Makarious MB , Ding J , Kung J , Xie C , Hawes SL , Wang L , Wang T , Chan P , Zhang Z , Le W , Chen S , Lovinger DM , Blauwendraat C , Singleton AB , Cui G , Li Y , Cai H , Tang B
Ref : Nat Commun , 13 :3490 , 2022
Abstract : Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase beta (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism.
ESTHER : Liu_2022_Nat.Commun_13_3490
PubMedSearch : Liu_2022_Nat.Commun_13_3490
PubMedID: 35715418
Gene_locus related to this paper: human-DAGLB , mouse-DGLB

Title : Soluble Epoxide Hydrolase Inhibition Protected against Diabetic Cardiomyopathy through Inducing Autophagy and Reducing Apoptosis Relying on Nrf2 Upregulation and Transcription Activation - Fang_2022_Oxid.Med.Cell.Longev_2022_3773415
Author(s) : Fang Q , Liu X , Ding J , Zhang Z , Chen G , Du T , Wang Y , Xu R
Ref : Oxid Med Cell Longev , 2022 :3773415 , 2022
Abstract : BACKGROUND: Many patients with diabetes die from diabetic cardiomyopathy (DCM); however, effective strategies for the prevention or treatment of DCM have not yet been clarified. METHODS: Leptin receptor-deficient (db/db) mice were treated with either the soluble epoxide hydrolase (sEH) inhibitor AUDA or vehicle alone. A virus carrying Nrf2 shRNA was used to manipulate Nrf2 expression in db/db mice. Cardiac structures and functions were analyzed using echocardiography and hemodynamic examinations. Primary cardiomyocytes cultured under high glucose and high fat (HGHF) conditions were used to conduct in vitro loss-of-function assays after culture in the presence or absence of AUDA (1 microM). Fluorescence microscopy-based detection of mCherry-GFP-LC3 was performed to assess autophagic flux. RESULTS: The sEH inhibitor AUDA significantly attenuated ventricular remodeling and ameliorated cardiac dysfunction in db/db mice. Interestingly, AUDA upregulated Nrf2 expression and promoted its nuclear translocation in db/db mice and the HGHF-treated cardiomyocytes. Additionally, AUDA increased autophagy and decreased apoptosis in db/db mice heart. Furthermore, the administration of AUDA promoted autophagic flux and elevated LC3-II protein level in the presence of bafilomycin A1. However, AUDA-induced autophagy was abolished, and the antiapoptotic effect was partially inhibited upon Nrf2 knockdown. CONCLUSION: Our findings suggest that the sEH inhibitor AUDA attenuates cardiac remodeling and dysfunction in DCM via increasing autophagy and reducing apoptosis, which is relevant to activate Nrf2 signaling pathway.
ESTHER : Fang_2022_Oxid.Med.Cell.Longev_2022_3773415
PubMedSearch : Fang_2022_Oxid.Med.Cell.Longev_2022_3773415
PubMedID: 35378826

Title : The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [(14)C] cetagliptin in healthy volunteers - Lu_2022_Xenobiotica_52_38
Author(s) : Lu J , Bian Y , Zhang H , Tang D , Tian X , Zhou X , Xu Z , Xiong Y , Gu Z , Yu Z , Wang T , Ding J , Yu Q
Ref : Xenobiotica , 52 :38 , 2022
Abstract : The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50microCi [(14)C] cetagliptin.The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [(14)C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulphate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and faeces at low levels, except that metabolite M640B was not detected in faeces. All metabolites were observed with <10% of parent compound systemic exposure after oral administration.
ESTHER : Lu_2022_Xenobiotica_52_38
PubMedSearch : Lu_2022_Xenobiotica_52_38
PubMedID: 34743655

Title : Disposition study of the novel dipeptidyl peptidase 4 inhibitor cetagliptin in rats - Lu_2022_Xenobiotica_52_468
Author(s) : Lu J , Hao Y , Zhang F , Pan H , Ding J , Yu Q , Wang T
Ref : Xenobiotica , 52 :468 , 2022
Abstract : Dipeptidyl peptidase-4 (DPP-4) inhibitor is a class of oral antihyperglycemic agents and therapeutic approach for type 2 diabetes. Cetagliptin is a novel oral and selective DPP-4 inhibitor and developed as a promising candidate for treatment of type 2 diabetes mellitus.This study aimed to evaluate the metabolism and excretion of cetagliptin in Sprague-Dawley (SD) rats, and to detect and identify metabolites of cetagliptin.The SD rats were administered with a single oral dose of 6mg/kg with approximately 100microCi of [(14)C] cetagliptin. The mean total recovery of radioactivity was 90.20% within 168h in SD rats excreta. Cetagliptin was the major radioactive component in SD rats plasma, urine and eliminated primarily by faecal excretion. The recovery of cetagliptin in urine and feces was 25.15% and 13.85% of the dose, respectively. Cetagliptin was well absorbed after oral administration in SD rats based on the total recovery of radioactivity in BDC SD rats bile and urine.Six major metabolites were observed and identified in SD rats, comprising 0.20 to 4.53% of total plasma AUC. These major metabolites were the hydroxylated, N-sulphate and N-carbamoyl glucuronic acid conjugates of the cetagliptin, two metabolites formed by glucuronide of a hydroxylated metabolite.
ESTHER : Lu_2022_Xenobiotica_52_468
PubMedSearch : Lu_2022_Xenobiotica_52_468
PubMedID: 35708192

Title : A double-blind, randomized, placebo and positive-controlled study in healthy volunteers to evaluate pharmacokinetic and pharmacodynamic properties of multiple oral doses of cetagliptin - Lu_2022_Br.J.Clin.Pharmacol_88_2946
Author(s) : Lu J , Wang L , Zhou S , Zhou C , Xie L , Chen J , Tang D , Tian X , Xie D , Ding J , Wang T , Yu Q , Shao F
Ref : British Journal of Clinical Pharmacology , 88 :2946 , 2022
Abstract : AIMS: This study investigated the pharmacokinetics and pharmacodynamics properties, safety and tolerability of cetagliptin. METHODS: Forty-eight healthy subjects were enrolled in this study. Three cohorts were investigated in sequential order: 50, 100 and 200mg cetagliptin. Positive control (sitagliptin 100mg) was designed as open label. Blood samples were collected and analysed for pharmacokinetic and pharmacodynamic properties. Safety and tolerability were assessed throughout the study. RESULTS: Following multiple oral doses, cetagliptin was rapidly absorbed and reached peak plasma concentrations after approximately 1.0-1.5 hours. Plasma cetagliptin concentrations increased at a rate greater than dose. Accumulation of cetagliptin was modest, and steady state was generally achieved at day 5. Doses <=50mg of cetagliptin administered once daily will result in sustained dipeptidyl peptidase-4 (DPP-4) inhibition (<=80%). The plasma concentration giving 50% of maximum drug effect of DPP-4 inhibition for cetagliptin (5.29ng/mL) was lower than that of sitagliptin (7.03ng/mL). Active glucagon-like-1 peptide (GLP-1) concentrations were significantly increased in the cetagliptin groups by 2.3- to 3.1-fold at day 1 and 3.1- to 3.6-fold at steady state compared with that of placebo, and active GLP-1 concentrations were increased with increasing dose. Compared with sitagliptin, doses <=100mg once daily of cetagliptin produced postprandial increases in active GLP-1 level and induced to long-lasting glucose-lowering efficacy. Cetagliptin was well tolerated across all doses studied. CONCLUSION: Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP-4, the increase in GLP-1 and insulin, the decrease in glucose, and might be more effective in DPP-4 inhibition than sitagliptin.
ESTHER : Lu_2022_Br.J.Clin.Pharmacol_88_2946
PubMedSearch : Lu_2022_Br.J.Clin.Pharmacol_88_2946
PubMedID: 34965609

Title : Development and validation of an ultrasensitive LC-MS\/MS method for the quantification of cetagliptin in human plasma and its application in a microdose clinical trial - Bai_2021_Biomed.Chromatogr_35_e4994
Author(s) : Bai H , Lu J , Cheng X , Liu L , Zhang W , Wei Y , Wang Y , Liu J , Ding J , Yu Q , Zhang Y , Chen G , Fan Y , Wang X
Ref : Biomedical Chromatography , 35 :e4994 , 2021
Abstract : This study established and validated an LC-MS/MS method for the ultrasensitive determination of cetagliptin in human plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and chromatographic separation was performed on an XB-C(18) analytical column (50x2.1mm, 5microm) with gradient elution (0.1% formic acid in acetonitrile and 0.1% formic acid) at a flow rate of 1.0mL/min. For mass spectrometric detection, multiple reaction monitoring was used, and the ion transitions monitored were m/z 421.2-86.0 for cetagliptin and m/z 424.2-88.0 for cetagliptin-d3. Method validation was performed according to the U.S. Food and Drug Administration Bioanalytical Method Validation Guidance, for which the calibration curve was linear in the range of 50.0-2000pg/mL. All of the other results, such as selectivity, lower limit of quantitation, precision, accuracy, matrix effect, recovery, and stability, met the acceptance criteria. The validated method was successfully applied in a microdose clinical trial to systematically investigate the pharmacokinetic profile of cetagliptin in healthy subjects. Both rapid absorption and prolonged duration demonstrate the potential value of cetagliptin for diabetes treatment.
ESTHER : Bai_2021_Biomed.Chromatogr_35_e4994
PubMedSearch : Bai_2021_Biomed.Chromatogr_35_e4994
PubMedID: 32986878

Title : Ensemble machine learning to evaluate the in vivo acute oral toxicity and in vitro human acetylcholinesterase inhibitory activity of organophosphates - Wang_2021_Arch.Toxicol__
Author(s) : Wang L , Ding J , Shi P , Fu L , Pan L , Tian J , Cao D , Jiang H , Ding X
Ref : Archives of Toxicology , : , 2021
Abstract : Organophosphates (OPs) are hazardous chemicals widely used in industry and agriculture. Distribution of their residues in nature causes serious risks to humans, animals, and plants. To reduce hazards from OPs, quantitative structure-activity relationship (QSAR) models for predicting their acute oral toxicity in rats and mice and inhibition constants concerning human acetylcholinesterase were developed according to the bioactivity data of 456 unique OPs. Based on robust, two-dimensional molecular descriptors and quantum chemical descriptors, which accurately reflect OP electronic structures and reactivities, the influences of eight machine-learning algorithms on the prediction performance of the QSAR models were explored, and consensus QSAR models were constructed. Several strict model validation indices and the results of applicability domain evaluations show that the established consensus QSAR models exhibit good robustness, practical prediction abilities, and wide application scopes. Poor correlation was observed between acute oral toxicity at the mammalian level and the inhibition constants at the molecular level, indicating that the acute toxicity of OPs cannot be evaluated only by the experimental data of enzyme inhibitory activity, their toxicokinetic characteristics must also be considered. The constructed QSAR models described herein provide rapid, theoretical assessment of the bioactivity of unstudied or unknown OPs, as well as guidance for making decisions regarding their regulation.
ESTHER : Wang_2021_Arch.Toxicol__
PubMedSearch : Wang_2021_Arch.Toxicol__
PubMedID: 33934188

Title : In vitro study of the drug-drug interaction potential of cetagliptin and clinical study of pharmacokinetic interaction of cetagliptin and metformin in healthy volunteers - Lu_2021_Xenobiotica_51_1122
Author(s) : Lu J , Tian X , Tang D , Zhou X , Xu Z , Ding J , Wang T , Yu Q
Ref : Xenobiotica , 51 :1122 , 2021
Abstract : Cetagliptin is an oral, potent, and newly developed selective inhibitor of dipeptidyl peptidase-4 (DPP-4). We evaluated the in vitro drug-drug interaction (DDI) potential of cetagliptin, as well as the pharmacokinetics of cetagliptin and metformin and the interaction between cetagliptin and metformin.Cetagliptin did not inhibit CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, only has a moderate inhibitory effect on CYP2D6, and did not induce CYP1A2, CYP2B6, and CYP3A4. Plasma protein binding of cetagliptin didn't have species differences or concentration dependence. Cetagliptin was a substrate for P-glycoprotein (P-gp).The 34 healthy subjects enrolled were randomly divided into two sequences (A and B) with 17 subjects in each sequence. Coadministration with metformin had no effect on cetagliptin AUC(0-120) (GMR, 99.25%; 90% CI, 95.96%-102.65%). There was a slightly increase in cetagliptin C(max) (GMR, 117.33%; 90% CI, 102.54%-134.25%). Coadministration with cetagliptin did not affect the metformin's AUC(0-24) (GMR, 108.54%; 90% CI, 101.41%-116.17%) or C(max) (GMR, 97.67%; 90% CI, 90.96%-104.89%).Based on in vitro study results, cetagliptin is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. Coadministration of cetagliptin and metformin had no clinically meaningful effect on the pharmacokinetics of each drug. There was no drug-drug interaction between cetagliptin and metformin. Both monotherapies and combination therapy were well tolerated. No serious AEs and hypoglycaemia was reported.
ESTHER : Lu_2021_Xenobiotica_51_1122
PubMedSearch : Lu_2021_Xenobiotica_51_1122
PubMedID: 34329567

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

Title : TPPU Pre-Treatment Rescues Dendritic Spine Loss and Alleviates Depressive Behaviours during the Latent Period in the Lithium Chloride-Pilocarpine-Induced Status Epilepticus Rat Model - Peng_2021_Brain.Sci_11_
Author(s) : Peng W , Shen Y , Wang Q , Ding J , Wang X
Ref : Brain Sci , 11 : , 2021
Abstract : Epileptogenesis may be responsible for both of recurrent seizures and comorbid depression in epilepsy. Disease-modifying treatments targeting the latent period before spontaneous recurrent seizures may contribute to the remission of seizures and comorbid depression. We hypothesized that pre-treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase (sEH) inhibitor, which has anti-inflammatory and neuroprotective effects might rescue status epilepticus (SE)-induced dendritic spine loss and alleviate depressive behaviours. Rats were either pre-treated with TPPU (0.1 mg/kg/d) intragastrically or with vehicle (40% polyethylene glycol 400) from 7 days before to 7 days after SE that was induced with lithium chloride and pilocarpine intraperitoneally. Rats in the Control group were given saline instead. The forced swim test (FST) was performed on the 8th day after SE to evaluate the depression-like behaviours in rats. The results showed that seizures severity during SE was significantly decreased, and the immobility time during FST was significantly increased through TPPU pre-treatment. Moreover, pre-treatment with TPPU attenuated inflammations including microglial gliosis and the level of proinflammatory cytokine IL-1beta in the hippocampus; in addition, neuronal and dendritic spine loss in the subfields of hippocampus was selectively rescued, and the expression of NR1 subunit of N-methyl-D-aspartate (NMDA) receptor, ERK1/2, CREB, and their phosphorylated forms involved in the dendritic spine development were all significantly increased. We concluded that pre-treatment with TPPU attenuated seizures severity during SE and depressive behaviours during the period of epileptogenesis probably by rescuing dendritic spine loss in the hippocampus.
ESTHER : Peng_2021_Brain.Sci_11_
PubMedSearch : Peng_2021_Brain.Sci_11_
PubMedID: 34827464

Title : Biodegradation of lambda-cyhalothrin through cell surface display of bacterial carboxylesterase - Ding_2021_Chemosphere_289_133130
Author(s) : Ding J , Liu Y , Gao Y , Zhang C , Wang Y , Xu B , Yang Y , Wu Q , Huang Z
Ref : Chemosphere , 289 :133130 , 2021
Abstract : Pyrethroids are the third widespread used insecticides globally which have been extensively applied in agricultural or household environments. Due to continuous applications, pyrethroids have been detected both in living cells and environments. The permanent exposure to pyrethroids have caused substantial health risks and ecosystem concerns. In this work, a lambda-cyhalothrin (one kind of pyrethroid insecticides) degrading bacterium Bacillus velezensis sd was isolated and a carboxylesterase gene, CarCB2 was characterized. A whole cell biocatalyst was developed for lambda-cyhalothrin biodegradation by displaying CarCB2 on the surface of Escherichia coli cells. CarCB2 was successfully displayed and functionally expressed on E. coli cells with optimal pH and temperature of 7.5 and 30 degreesC, using p-NPC(4) as substrate, respectively. The whole cell biocatalyst exhibited better stability than the purified CarCB2, and approximately 120%, 60% or 50% of its original activity at 4 degreesC, 30 degreesC or 37 degreesC over a period of 35 d was retained, respectively. No enzymatic activity was detected when incubated the purified CarCB2 at 30 degreesC for 120 h, or 37 degreesC for 72 h, respectively. Additionally, 30 mg/L of lambda-cyhalothrin was degraded in citrate-phosphate buffer by 10 U of the whole cell biocatalyst in 150 min. This work reveals that the whole cell biocatalyst affords a promising approach for efficient biodegradation of lambda-cyhalothrin, and might have the potential to be applied in further environmental bioremediation of other different kinds of pyrethroid insecticides.
ESTHER : Ding_2021_Chemosphere_289_133130
PubMedSearch : Ding_2021_Chemosphere_289_133130
PubMedID: 34863720
Gene_locus related to this paper: 9baci-MW588803

Title : Toxicological effects of nano- and micro-polystyrene plastics on red tilapia: Are larger plastic particles more harmless? - Ding_2020_J.Hazard.Mater_396_122693
Author(s) : Ding J , Huang Y , Liu S , Zhang S , Zou H , Wang Z , Zhu W , Geng J
Ref : J Hazard Mater , 396 :122693 , 2020
Abstract : Nanoplastics (NPs) and microplastics (MPs) are a heterogeneous class of pollutants with diverse sizes in aquatic environments. To evaluate the hazardous effects of N/MPs with different sizes, the accumulation, oxidative stress, cytochrome P450 (CYP) enzymes, neurotoxicity, and metabolomics changes were investigated in the red tilapia exposed to three sizes of polystyrene (PS) N/MPs (0.3, 5, and 70-90mum). After 14-d exposures, the largest particles (70-90mum) showed the highest accumulation levels in most cases. Exposures to PS-MPs (5 and 70-90mum) caused a more severe oxidative stress in red tilapia than PS-NPs. The activity of CYP3A-related enzyme was obviously inhibited by PS-NPs, whereas the CYP enzymes in the liver may not be sensitive to MP exposures. In the brain, only 5mumPS-MPs significantly inhibited the acetylcholinesterase activity. After exposures, the treatments with 0.3, 5, and 70-90mum N/MPs resulted in 31, 40, and 23 significantly differentially expressed metabolites, respectively, in which the pathway of tyrosine metabolism was significantly affected by all the three PS-N/MP exposures. Overall, the PS particles within the mum size posed more severe stress to red tilapia. Our results suggest that the toxicity of N/MPs may not show a simply monotonic negative correlation with their sizes.
ESTHER : Ding_2020_J.Hazard.Mater_396_122693
PubMedSearch : Ding_2020_J.Hazard.Mater_396_122693
PubMedID: 32353735

Title : Development of a whole-cell biocatalyst for diisobutyl phthalate degradation by functional display of a carboxylesterase on the surface of Escherichia coli - Ding_2020_Microb.Cell.Fact_19_114
Author(s) : Ding J , Zhou Y , Wang C , Peng Z , Mu Y , Tang X , Huang Z
Ref : Microb Cell Fact , 19 :114 , 2020
Abstract : BACKGROUND: Phthalic acid esters (PAEs) are widely used as plasticizers or additives during the industrial manufacturing of plastic products. PAEs have been detected in both aquatic and terrestrial environments due to their overuse. Exposure of PAEs results in human health concerns and environmental pollution. Diisobutyl phthalate is one of the main plasticizers in PAEs. Cell surface display of recombinant proteins has become a powerful tool for biotechnology applications. In this current study, a carboxylesterase was displayed on the surface of Escherichia coli cells, for use as whole-cell biocatalyst in diisobutyl phthalate biodegradation. RESULTS: A carboxylesterase-encoding gene (carEW) identified from Bacillus sp. K91, was fused to the N-terminal of ice nucleation protein (inpn) anchor from Pseudomonas syringae and gfp gene, and the fused protein was then cloned into pET-28a(+) vector and was expressed in Escherichia coli BL21(DE3) cells. The surface localization of INPN-CarEW/or INPN-CarEW-GFP fusion protein was confirmed by SDS-PAGE, western blot, proteinase accessibility assay, and green fluorescence measurement. The catalytic activity of the constructed E. coli surface-displayed cells was determined. The cell-surface-displayed CarEW displayed optimal temperature of 45 degrees C and optimal pH of 9.0, using p-NPC2 as substrate. In addition, the whole cell biocatalyst retained ~ 100% and ~ 200% of its original activity per OD600 over a period of 23 days at 45 degrees C and one month at 4 degrees C, exhibiting the better stability than free CarEW. Furthermore, approximately 1.5 mg/ml of DiBP was degraded by 10 U of surface-displayed CarEW cells in 120 min. CONCLUSIONS: This work provides a promising strategy of cost-efficient biodegradation of diisobutyl phthalate for environmental bioremediation by displaying CarEW on the surface of E. coli cells. This approach might also provide a reference in treatment of other different kinds of environmental pollutants by displaying the enzyme of interest on the cell surface of a harmless microorganism.
ESTHER : Ding_2020_Microb.Cell.Fact_19_114
PubMedSearch : Ding_2020_Microb.Cell.Fact_19_114
PubMedID: 32471417
Gene_locus related to this paper: bacsu-pnbae

Title : Characterization of EstZY: A new acetylesterase with 7-aminocephalosporanic acid deacetylase activity from Alicyclobacillus tengchongensis - Ding_2020_Int.J.Biol.Macromol_148_333
Author(s) : Ding J , Zhou Y , Zhu H , Deng M , Gao Y , Yang Y , Huang Z
Ref : Int J Biol Macromol , 148 :333 , 2020
Abstract : Deacetyl-7-aminocephalosporanic acid (D-7-ACA) is required for producing of many semisynthetic beta-lactam antibiotics; therefore, enzymes capable of converting 7-aminocephalosporanic acid (7-ACA) to D-7-ACA present a valuable resource to the pharmaceutical industry. In the present study, a putative acetylesterase, EstZY, was identified and characterized from a thermophilic bacterium Alicyclobacillus tengchongensis. Sequence alignment showed that EstZY was an acetylesterase which belonged to carbohydrate esterase family 7 (CE7), with substrate preference for short-chain acyl esters p-NPC(2) to p-NPC(8). Maximum enzyme activity was recorded at pH 9.0 and 50 degreesC, where K(m) and V(max) were calculated as 1.9 +/- 0.23 mM and 258 +/- 18.5 microM min(-)(1), respectively. The residues Ser185, Asp274, and His303 were identified as the putative catalytic triad by homology modelling, site-directed mutagenesis and molecular docking. Moreover, EstZY can remove the acetyl group at C3' position of 7-ACA to form D-7-ACA; this is the first report of a 7-ACA deacetylase from CE7 family in A. tengchongensis and may represent a new enzyme with industrial values.
ESTHER : Ding_2020_Int.J.Biol.Macromol_148_333
PubMedSearch : Ding_2020_Int.J.Biol.Macromol_148_333
PubMedID: 31954783
Gene_locus related to this paper: 9bacl-a0a6g6c491

Title : Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer's disease - Fu_2020_J.Enzyme.Inhib.Med.Chem_35_118
Author(s) : Fu J , Bao F , Gu M , Liu J , Zhang Z , Ding J , Xie SS
Ref : J Enzyme Inhib Med Chem , 35 :118 , 2020
Abstract : A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 muM for eeAChE; IC50 = 0.16 muM for hAChE), and it was also the best inhibitor to AChE-induced Abeta aggregation (29.02% at 100 muM) and an efficient inhibitor to self-induced Abeta aggregation (30.67% at 25 muM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).
ESTHER : Fu_2020_J.Enzyme.Inhib.Med.Chem_35_118
PubMedSearch : Fu_2020_J.Enzyme.Inhib.Med.Chem_35_118
PubMedID: 31694418

Title : Novel chromanone-dithiocarbamate hybrids as multifunctional AChE inhibitors with beta-amyloid anti-aggregation properties for the treatment of Alzheimer's disease - Jiang_2019_Bioorg.Chem_89_103027
Author(s) : Jiang N , Ding J , Liu J , Sun X , Zhang Z , Mo Z , Li X , Yin H , Tang W , Xie SS
Ref : Bioorg Chem , 89 :103027 , 2019
Abstract : By connecting chromanone with dithiocarbamate moieties through flexible linkers, a series of hybrids as novel multifunctional AChE inhibitors have been designed and synthesized. Most of these compounds displayed strong and excellently selective inhibition to eeAChE as well as potent inhibition to self- and AChE-induced Abeta aggregation. Among them, compound 6c showed the best activity to inhibit eeAChE (IC50=0.10muM) and AChE-induced Abeta aggregation (33.02% at 100muM), and could effectively inhibit self-induced Abeta aggregation (38.25% at 25muM). Kinetic analysis and docking study indicated that compound 6c could target both the CAS and PAS, suggesting that it was a dual binding site inhibitor for AChE. Besides, it exhibited good ability to penetrate the BBB and low neurotoxicity in SH-SY5Y cells. More importantly, compound 6c was well tolerated in mice (2500mg/kg, po) and could attenuate the memory impairment in a scopolamine-induced mouse model. Overall, these results highlight 6c as a promising multifunctional agent for treating AD and also demonstrate that the dithiocarbamate is a valid scaffold for design of multifunctional AChE inhibitors.
ESTHER : Jiang_2019_Bioorg.Chem_89_103027
PubMedSearch : Jiang_2019_Bioorg.Chem_89_103027
PubMedID: 31176237

Title : Identification and characterization of an acetyl esterase from Paenibacillus sp. XW-6-66 and its novel function in 7-aminocephalosporanic acid deacetylation - Ding_2019_Biotechnol.Lett_41_1059
Author(s) : Ding J , Zhou Y , Zhu H , Deng M , Long L , Yang Y , Wu Q , Huang Z
Ref : Biotechnol Lett , 41 :1059 , 2019
Abstract : OBJECTIVES: To obtain a new acetyl esterase from Paenibacillus sp. XW-6-66 and apply the enzyme to 7-aminocephalosporanic acid (7-ACA) deacetylation. RESULTS: The acetyl esterase AesZY was identified from Paenibacillus sp. XW-6-66, and its enzymatic properties were investigated. With the putative catalytic triad Ser114-Asp203-His235, AesZY belongs to the Acetyl esterase (Aes) family which is included in the alpha/beta hydrolase superfamily and contains the consensus Gly-X-Ser-X-Gly motif. The maximum activity of AesZY was detected at pH 8.0 and 40 degrees C. AesZY was stable at different pH values ranging from 5.0 to 12.0, and was tolerant to several metal ions. Furthermore, the deacetylation activity of AesZY toward 7-ACA was approximately 7.5 U/mg, and the Kcat/Km value was 2.04 s(-1) mM(-1). CONCLUSIONS: Our results demonstrate the characterization of a new acetyl esterase belonging to the Aes family with potential biotechnological applications.
ESTHER : Ding_2019_Biotechnol.Lett_41_1059
PubMedSearch : Ding_2019_Biotechnol.Lett_41_1059
PubMedID: 31302814
Gene_locus related to this paper: 9bacl-7ACAaes

Title : Anti-inflammatory treatment with a soluble epoxide hydrolase inhibitor attenuates seizures and epilepsy-associated depression in the LiCl-pilocarpine post-status epilepticus rat model - Shen_2019_Brain.Behav.Immun_81_535
Author(s) : Shen Y , Peng W , Chen Q , Hammock BD , Liu J , Li D , Yang J , Ding J , Wang X
Ref : Brain Behavior & Immunity , 81 :535 , 2019
Abstract : PURPOSE: This study aimed to investigate whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor with anti-inflammatory effects, could alleviate spontaneous recurrent seizures (SRS) and epilepsy-associated depressive behaviours in the lithium chloride (LiCl)-pilocarpine-induced post-status epilepticus (SE) rat model. METHODS: The rats were intraperitoneally (IP) injected with LiCl (127mg/kg) and pilocarpine (40mg/kg) to induce SE. A video surveillance system was used to monitor SRS in the post-SE model for 6weeks (from the onset of the 2nd week to the end of the 7th week after SE induction). TPPU (0.1mg/kg/d) was intragastrically given for 4weeks from the 21st day after SE induction in the SRS+0.1 TPPU group. The SRS+PEG 400 group was given the vehicle (40% polyethylene glycol 400) instead, and the control group was given LiCl and PEG 400 but not pilocarpine. The sucrose preference test (SPT) and forced swim test (FST) were conducted to evaluate the depression-like behaviours of rats. Immunofluorescent staining, enzyme-linked immunosorbent assay, and western blot analysis were performed to measure astrocytic and microglial gliosis, neuronal loss, and levels of soluble epoxide hydrolase (sEH), cytokines [tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6], and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB). RESULTS: The frequency of SRS was significantly decreased at 6weeks and 7weeks after SE induction in the 0.1TPP U group compared with the SRS+PEG 400 group. The immobility time (IMT) evaluated by FST was significantly decreased, whereas the climbing time (CMT) was increased, and the sucrose preference rate (SPR) evaluated by SPT was in an increasing trend. The levels of sEH, TNF-alpha, IL-1beta, and IL-6 in the hippocampus (Hip) and prefrontal cortex (PFC) were all significantly increased in the SRS+PEG 400 group compared with the control group; neuronal loss, astrogliosis, and microglial activation were also observed. The astrocytic and microglial activation and levels of the pro-inflammatory cytokines in the Hip and PFC were significantly attenuated in the TPPU group compared with the SRS+PEG 400 group; moreover, neuronal loss and the decreased CREB expression were significantly alleviated as well. CONCLUSION: TPPU treatment after SE attenuates SRS and epilepsy-associated depressive behaviours in the LiCl-pilocarpine induced post-SE rat model, and it also exerts anti-inflammatory effects in the brain. Our findings suggest a new therapeutic approach for epilepsy and its comorbidities, especially depression.
ESTHER : Shen_2019_Brain.Behav.Immun_81_535
PubMedSearch : Shen_2019_Brain.Behav.Immun_81_535
PubMedID: 31306773

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

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

Title : Accumulation, tissue distribution, and biochemical effects of polystyrene microplastics in the freshwater fish red tilapia (Oreochromis niloticus) - Ding_2018_Environ.Pollut_238_1
Author(s) : Ding J , Zhang S , Razanajatovo RM , Zou H , Zhu W
Ref : Environ Pollut , 238 :1 , 2018
Abstract : While the presence of microplastics (MPs) in marine environments has been detected worldwide, the importance of MPs pollution in freshwater environments has also been emphasized in recent years. However, the body of knowledge regarding the biological effects of MPs on freshwater organisms is still much more limited than on marine organisms. The aim of the present study was to evaluate the accumulation and tissue distribution of MPs in the freshwater fish red tilapia (Oreochromis niloticus), as well as the biochemical effects of MPs on O. niloticus. During 14 days of exposure to 0.1mum polystyrene-MPs at concentrations of 1, 10, and 100mugL(-1), the MPs concentrations in various tissues of O. niloticus generally increased over time following the order gut>gills>liver approximately brain. Moreover, the acetylcholinesterase (AChE) activity in the fish brain was inhibited by MPs exposure, with a maximum inhibition rate of 37.7%, suggesting the potential neurotoxicity of MPs to freshwater fish. The activities of cytochrome P450 (CYP) enzymes [7-ethoxyresorufin O-deethylase (EROD) and 7-benzyloxy-4-trifluoromethyl-coumarin O-dibenzyloxylase (BFCOD)] in the fish liver exhibited clear temporal variabilities, with significant decreases followed by elevations compared to the control. The alterations of the EROD and BFCOD activities indicate the potential involvement of CYP enzymes for the metabolism of MPs. The activity of antioxidative enzyme superoxide dismutase (SOD) in the liver was significantly induced throughout the exposure period, while the malondialdehyde (MDA) content did not vary with MPs exposure, suggesting that the antioxidative enzymatic system in O. niloticus could prevent oxidative damage. These results highlight the ingestion and accumulation of MPs in different tissues of freshwater fish, which lead to perturbations in fish biological systems and should be considered in environmental risk assessment.
ESTHER : Ding_2018_Environ.Pollut_238_1
PubMedSearch : Ding_2018_Environ.Pollut_238_1
PubMedID: 29529477

Title : Decreased vesicular acetylcholine transporter related to memory deficits in epilepsy: A [(18) F] VAT positron emission tomography brain imaging study - Wu_2018_Epilepsia_59_1655
Author(s) : Wu XQ , Zhao YN , Ding J , Si Z , Cheng DF , Shi HC , Wang X
Ref : Epilepsia , 59 :1655 , 2018
Abstract : OBJECTIVE: Vesicular acetylcholine transporter (VAChT) is a rate-limiting factor for synaptic acetylcholine transport. Our study focused on whether [(18) F] VAT, a novel positron emission tomography (PET) tracer, could be used in detecting cognitive deficits in epilepsy. METHODS: Morris water maze test was used to evaluate learning and memory deficits in pilocarpine-induced chronic epilepsy rats 12 weeks after status epilepticus. Interictal [(18) F] VAT PET was performed 13 weeks after status epilepticus to evaluate the level of VAChT in cholinergic pathways compared with [(18) F] fluorodeoxyglucose PET. The association between VAChT levels and memory measures was analyzed. Neuropathological tests were performed. RESULTS: Epileptic rats exhibited significant memory deficits in Morris water maze test. [(18) F] VAT uptake decreased in septum, hippocampus, thalamus, and basal forebrain, and correlated to memory function. Of note, the level of VAChT in basal forebrain significantly decreased, yet no glucose hypometabolism was detected. Immunofluorescence and Western blot demonstrated decreased expression of VAChT in hippocampus and basal forebrain in the epilepsy group, but no change of expression of acetyltransferase or activity of acetylcholinesterase was detected. SIGNIFICANCE: [(18) F] VAT PET is a promising method to test the level of VAChT as a valuable biomarker for memory deficits in pilocarpine-induced chronic epileptic rats.
ESTHER : Wu_2018_Epilepsia_59_1655
PubMedSearch : Wu_2018_Epilepsia_59_1655
PubMedID: 30126014

Title : Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation - He_2018_Bioorg.Chem_81_512
Author(s) : He Q , Liu J , Lan JS , Ding J , Sun Y , Fang Y , Jiang N , Yang Z , Sun L , Jin Y , Xie SS
Ref : Bioorg Chem , 81 :512 , 2018
Abstract : A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068muM and 0.0089muM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114microM for hAChE; 0.101microM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.
ESTHER : He_2018_Bioorg.Chem_81_512
PubMedSearch : He_2018_Bioorg.Chem_81_512
PubMedID: 30245233

Title : O-Linked N-acetylglucosamine transferase 1 regulates global histone H4 acetylation via stabilization of the nonspecific lethal protein NSL3 - Wu_2017_J.Biol.Chem_292_10014
Author(s) : Wu D , Zhao L , Feng Z , Yu C , Ding J , Wang L , Wang F , Liu D , Zhu H , Xing F , Conaway JW , Conaway RC , Cai Y , Jin J
Ref : Journal of Biological Chemistry , 292 :10014 , 2017
Abstract : The human males absent on the first (MOF)-containing histone acetyltransferase nonspecific lethal (NSL) complex comprises nine subunits including the O-linked N-acetylglucosamine (O-GlcNAc) transferase, isoform 1 (OGT1). However, whether the O-GlcNAc transferase activity of OGT1 controls histone acetyltransferase activity of the NSL complex and whether OGT1 physically interacts with the other NSL complex subunits remain unclear. Here, we demonstrate that OGT1 regulates the activity of the NSL complex by mainly acetylating histone H4 Lys-16, Lys-5, and Lys-8 via O-GlcNAcylation and stabilization of the NSL complex subunit NSL3. Knocking down or overexpressing OGT1 in human cells remarkably affected the global acetylation of histone H4 residues Lys-16, Lys-5, and Lys-8. Because OGT1 is a subunit of the NSL complex, we also investigated the function of OGT1 in this complex. Co-transfection/co-immunoprecipitation experiments combined with in vitro O-GlcNAc transferase assays confirmed that OGT1 specifically binds to and O-GlcNAcylates NSL3. In addition, wheat germ agglutinin affinity purification verified the occurrence of O-GlcNAc modification on NSL3 in cells. Moreover, O-GlcNAcylation of NSL3 by wild-type OGT1 (OGT1-WT) stabilized NSL3. This stabilization was lost after co-transfection of NSL3 with an OGT1 mutant, OGT1(C964A), that lacks O-GlcNAc transferase activity. Furthermore, stabilization of NSL3 by OGT1-WT significantly increased the global acetylation levels of H4 Lys-5, Lys-8, and Lys-16 in cells. These results suggest that OGT1 regulates the activity of the NSL complex by stabilizing NSL3.
ESTHER : Wu_2017_J.Biol.Chem_292_10014
PubMedSearch : Wu_2017_J.Biol.Chem_292_10014
PubMedID: 28450392
Gene_locus related to this paper: human-KANSL3

Title : Bioconcentration of the antidepressant fluoxetine and its effects on the physiological and biochemical status in Daphnia magna - Ding_2017_Ecotoxicol.Environ.Saf_142_102
Author(s) : Ding J , Zou H , Liu Q , Zhang S , Mamitiana Razanajatovo R
Ref : Ecotoxicology & Environmental Safety , 142 :102 , 2017
Abstract : The aim of this study was to evaluate the bioconcentration potential of fluoxetine and its biological effects in Daphnia magna. After 48h of waterborne exposure, the bioconcentration of fluoxetine in D. magna was determined to be 460.61 and 174.41Lkg-1 for nominal exposure concentrations of 0.5 and 5microgL-1, respectively. Moreover, various biological endpoints, including physiological responses (filtration and ingestion rates), enzymatic biomarkers related to neurotoxicity [acetylcholinesterase (AChE)] and antioxidant defense [superoxide dismutase (SOD)], and an oxidative stress damage marker [malondialdehyde (MDA)], were assessed. Fluoxetine exposure increased the filtration rate of daphnia, while the ingestion rate was not obviously modified. AChE activity was significantly inhibited, highlighting the neurotoxicity of fluoxetine on D. magna. However, with some alterations in the SOD activity and MDA content, no obvious oxidative damage was observed in D. magna exposed to fluoxetine at the tested concentrations. These results indicate that fluoxetine can be accumulated and consequently induce physiological and biochemical perturbations in D. magna.
ESTHER : Ding_2017_Ecotoxicol.Environ.Saf_142_102
PubMedSearch : Ding_2017_Ecotoxicol.Environ.Saf_142_102
PubMedID: 28395202

Title : Identification and Characterization of a New Alkaline SGNH Hydrolase from a Thermophilic Bacterium Bacillus sp. K91 - Yu_2016_J.Microbiol.Biotechnol_26_730
Author(s) : Yu T , Ding J , Zheng Q , Han N , Yu J , Yang Y , Li J , Mu Y , Wu Q , Huang Z
Ref : J Microbiol Biotechnol , 26 :730 , 2016
Abstract : est19 is a gene from Bacillus sp. K91 that encodes a new esterase. A comparison of the amino acid sequence showed that Est19 has typical Ser-Gly-Asn-His (SGNH) family motifs and could be grouped into the SGNH hydrolase family. The Est19 protein was functionally cloned, and expressed and purified from Escherichia coli BL21(DE3). The enzyme activity was optimal at 60 degrees C and pH 9.0, and displayed esterase activity towards esters with short-chain acyl esters (C(2)-C(6)). A structural model of Est19 was constructed using phospholipase A1 from Streptomyces albidoflavus NA297 as a template. The structure showed an alpha/beta-hydrolase fold and indicated the presence of the typical catalytic triad Ser49-Asp227-His230, which were further investigated by site-directed mutagenesis. To the best of our knowledge, Est19 is a new member of the SGNH hydrolase family identified from thermophiles, which may be applicable in the industrial production of semisynthetic beta-lactam antibiotics after modification.
ESTHER : Yu_2016_J.Microbiol.Biotechnol_26_730
PubMedSearch : Yu_2016_J.Microbiol.Biotechnol_26_730
PubMedID: 26699742

Title : A Three-Dimensional Origami Paper-Based Device for Potentiometric Biosensing - Ding_2016_Angew.Chem.Int.Ed.Engl_55_13033
Author(s) : Ding J , Li B , Chen L , Qin W
Ref : Angew Chem Int Ed Engl , 55 :13033 , 2016
Abstract : Current paper-based potentiometric ion-sensing platforms are planar devices used for clinically relevant ions. These devices, however, have not been designed for the potentiometric biosensing of proteins or small molecule analytes. A three-dimensional origami paper-based device, in which a solid-contact ion-selective electrode is integrated with an all-solid-state reference electrode, is described for the first time. The device is made by impregnation of paper with appropriate bioreceptors and reporting reagents on different zones. By folding and unfolding the paper structures, versatile potentiometric bioassays can be performed. A USB-controlled miniaturized electrochemical detector can be used for simple and in situ measurements. Using butyrylcholinesterase as a model enzyme, the device has been successfully applied to the detection of enzyme activities and organophosphate pesticides involved in the enzymatic system as inhibitors. The proposed 3D origami paper device allows the potentiometric biosensing of proteins and small molecules in a simple, portable, and cost-effective way.
ESTHER : Ding_2016_Angew.Chem.Int.Ed.Engl_55_13033
PubMedSearch : Ding_2016_Angew.Chem.Int.Ed.Engl_55_13033
PubMedID: 27634584

Title : Chromosome-level assembly of Arabidopsis thaliana Ler reveals the extent of translocation and inversion polymorphisms - Zapata_2016_Proc.Natl.Acad.Sci.U.S.A_113_E4052
Author(s) : Zapata L , Ding J , Willing EM , Hartwig B , Bezdan D , Jiao WB , Patel V , Velikkakam James G , Koornneef M , Ossowski S , Schneeberger K
Ref : Proc Natl Acad Sci U S A , 113 :E4052 , 2016
Abstract : Resequencing or reference-based assemblies reveal large parts of the small-scale sequence variation. However, they typically fail to separate such local variation into colinear and rearranged variation, because they usually do not recover the complement of large-scale rearrangements, including transpositions and inversions. Besides the availability of hundreds of genomes of diverse Arabidopsis thaliana accessions, there is so far only one full-length assembled genome: the reference sequence. We have assembled 117 Mb of the A. thaliana Landsberg erecta (Ler) genome into five chromosome-equivalent sequences using a combination of short Illumina reads, long PacBio reads, and linkage information. Whole-genome comparison against the reference sequence revealed 564 transpositions and 47 inversions comprising approximately 3.6 Mb, in addition to 4.1 Mb of nonreference sequence, mostly originating from duplications. Although rearranged regions are not different in local divergence from colinear regions, they are drastically depleted for meiotic recombination in heterozygotes. Using a 1.2-Mb inversion as an example, we show that such rearrangement-mediated reduction of meiotic recombination can lead to genetically isolated haplotypes in the worldwide population of A. thaliana Moreover, we found 105 single-copy genes, which were only present in the reference sequence or the Ler assembly, and 334 single-copy orthologs, which showed an additional copy in only one of the genomes. To our knowledge, this work gives first insights into the degree and type of variation, which will be revealed once complete assemblies will replace resequencing or other reference-dependent methods.
ESTHER : Zapata_2016_Proc.Natl.Acad.Sci.U.S.A_113_E4052
PubMedSearch : Zapata_2016_Proc.Natl.Acad.Sci.U.S.A_113_E4052
PubMedID: 27354520
Gene_locus related to this paper: arath-At1g73750 , arath-At1g15070 , arath-a0a1p8awg3

Title : Identification of new binding sites of human transferrin incubated with organophosphorus agents via Q Exactive LC-MS\/MS - Sun_2016_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1022_256
Author(s) : Sun F , Ding J , Yu H , Gao R , Wang H , Pei C
Ref : Journal of Chromatography B Analyt Technol Biomed Life Sciences , 1022 :256 , 2016
Abstract : Organophosphorus agents (OPs) like sarin, VX, or soman could inhibit acetylcholinesterase activity and cause poisoning. OPs could bind many proteins, such as butyrylcholinesterase and albumin, and the adducts formed could identify the exposure. In this paper, we studied human transferrin, which was one of the proteins that could be labeled by OPs. Pure human transferrin was incubated with an overdose of organophosphorus agents, including sarin, soman, VX, tabun, cyclosarin, ethyl tabun, and propyl tabun, and then additional OPs was removed through dialysis. Trypsin was used to cleave the OP-treated proteins and Q Exactive liquid chromatography tandem mass spectrometry (Q Exactive LC-MS/MS) was used to identify them. The present study set out to accomplish two goals. The first goal was to find a good method for identifying multiple binding sites on a given protein through Q Exactive LC-MS/MS. The second goal was to investigate the labeled peptides when transferrin was incubated with a numerous molar excess of OPs. Results showed that tyrosine, lysine, and serine formed covalent bonds with OPs. Twenty OP-labeled sites were found: ten tyrosine sites (including two reported sites), seven lysine sites, and three serine sites. Characteristic fragments for labeled-tyrosine and labeled-lysine adducts were summarized in detail. In conclusion, the method by Q Exactive LC-MS/MS using in this present work is a good way to diagnose exposure to OPs accurately when the binding sites of OPs are uncertain. Novel modified peptides and the characteristic ions found in this work could help investigators assess exposure to OPs.
ESTHER : Sun_2016_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1022_256
PubMedSearch : Sun_2016_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1022_256
PubMedID: 27128859

Title : Properties of a newly identified esterase from Bacillus sp. K91 and its novel function in diisobutyl phthalate degradation - Ding_2015_PLoS.One_10_e0119216
Author(s) : Ding J , Wang C , Xie Z , Li J , Yang Y , Mu Y , Tang X , Xu B , Zhou J , Huang Z
Ref : PLoS ONE , 10 :e0119216 , 2015
Abstract : The widely used plasticizer phthalate esters (PAEs) have become a public concern because of their effects on environmental contamination and toxicity on mammals. However, the biodegradation of PAEs, especially diisobutyl phthalate (DiBP), remains poorly understood. In particular, genes involved in the hydrolysis of these compounds were not conclusively identified. In this study, the CarEW gene, which encodes an enzyme that is capable of hydrolyzing ro-nitrophenyl esters of fatty acids, was cloned from a thermophilic bacterium Bacillus sp. K91 and heterologously expressed in Escherichia coli BL21 using the pEASY-E2 expression system. The enzyme showed a monomeric structure with a molecular mass of approximately 53.76 kDa and pI of 4.88. The enzyme exhibited maximal activity at pH 7.5 and 45 degreesC, with ro-NP butyrate as the best substrate. The enzyme was fairly stable within the pH range from 7.0 to 8.5. High-pressure liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS) were employed to detect the catabolic pathway of DiBP. Two intermediate products were identified, and a potential biodegradation pathway was proposed. Altogether, our findings present a novel DiBP degradation enzyme and indicate that the purified enzyme may be a promising candidate for DiBP detoxification and for environmental protection.
ESTHER : Ding_2015_PLoS.One_10_e0119216
PubMedSearch : Ding_2015_PLoS.One_10_e0119216
PubMedID: 25746227
Gene_locus related to this paper: bacsu-pnbae

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

Title : Conotoxin alphaD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors - Xu_2015_Sci.Rep_5_14261
Author(s) : Xu S , Zhang T , Kompella SN , Yan M , Lu A , Wang Y , Shao X , Chi C , Adams DJ , Ding J , Wang C
Ref : Sci Rep , 5 :14261 , 2015
Abstract : Nicotinic acetylcholine receptors (nAChRs) play essential roles in transmitting acetylcholine-mediated neural signals across synapses and neuromuscular junctions, and are also closely linked to various diseases and clinical conditions. Therefore, novel nAChR-specific compounds have great potential for both neuroscience research and clinical applications. Conotoxins, the peptide neurotoxins produced by cone snails, are a rich reservoir of novel ligands that target receptors, ion channels and transporters in the nervous system. From the venom of Conus generalis, we identified a novel dimeric nAChR-inhibiting alphaD-conotoxin GeXXA. By solving the crystal structure and performing structure-guided dissection of this toxin, we demonstrated that the monomeric C-terminal domain of alphaD-GeXXA, GeXXA-CTD, retains inhibitory activity against the alpha9alpha10 nAChR subtype. Furthermore, we identified that His7 of the rat alpha10 nAChR subunit determines the species preference of alphaD-GeXXA, and is probably part of the binding site of this toxin. These results together suggest that alphaD-GeXXA cooperatively binds to two inter-subunit interfaces on the top surface of nAChR, thus allosterically disturbing the opening of the receptor. The novel antagonistic mechanism of alphaD-GeXXA via a new binding site on nAChRs provides a valuable basis for the rational design of new nAChR-targeting compounds.
ESTHER : Xu_2015_Sci.Rep_5_14261
PubMedSearch : Xu_2015_Sci.Rep_5_14261
PubMedID: 26395518

Title : Bioconcentration, metabolism, and biomarker responses in freshwater fish Carassius auratus exposed to roxithromycin - Liu_2014_Chemosphere_99_102
Author(s) : Liu J , Lu G , Wang Y , Yan Z , Yang X , Ding J , Jiang Z
Ref : Chemosphere , 99 :102 , 2014
Abstract : To investigate the distribution, bioconcentration, metabolism, and biomarker responses of macrolide antibiotic roxithromycin (ROX) in fish, crucian carp (Carassius auratus) were exposed to various concentrations of ROX (4, 20, and 100mugL(-1)) for 20d. The ROX content in different tissues was quantified using UPLC/MS/MS. The liver exhibited the highest ROX concentration followed by the bile, gills, and muscle tissues. After 15d of exposure to different concentrations of ROX, the bioconcentration factors were 2.15-38.0 in the liver, 0.950-20.7 in the bile, 0.0506-19.7 in the gill, and 0.0439-13.8 in the muscle; these results were comparable to the estimated BCF values. The metabolites formed in the bile were identified based on metabolic identification in human bile. Additionally, the biomarkers, including acetylcholinesterase in the brain, as well as 7-ethoxyresorufin O-deethylase and superoxide dismutase in the liver changed significantly after 5, 10, 15, and 20d of exposure (P<0.05). Our results suggest that ROX can accumulate and be metabolized in fish; therefore, interactions between ROX or its metabolites and the biological systems may induce biochemical disturbances in fish.
ESTHER : Liu_2014_Chemosphere_99_102
PubMedSearch : Liu_2014_Chemosphere_99_102
PubMedID: 24210552

Title : Tissue distribution, bioconcentration, metabolism, and effects of erythromycin in crucian carp (Carassius auratus) - Liu_2014_Sci.Total.Environ_490C_914
Author(s) : Liu J , Lu G , Ding J , Zhang Z , Wang Y
Ref : Sci Total Environ , 490C :914 , 2014
Abstract : In this study, the tissue distribution, bioconcentration, metabolism and biological effects of the macrolide antibiotic erythromycin (ERY) were investigated in fish using crucian carp (Carassius auratus) as a model. Crucian carp were exposed to various concentrations of ERY (4, 20, and 100mug/L) for 28days. The UPLC/MS/MS analysis of both water and tissue provided the bioconcentration of ERY and its metabolites in the fish body. The results from tissue samples showed that a maximum tissue concentration occurred in the muscle and that the bioconcentration factor (BCF) of 72.2 was lower than the theoretical BCF of 90.4 calculated from the octanol-water coefficient of ERY. A significant portion of the absorbed ERY was metabolized via demethylation and dehydration and observed in the form of descladinose in fish. In addition, the relevant biomarkers, including acetylcholinesterase in the brain, as well as 7-ethoxyresorufin O-deethylase and superoxide dismutase in the liver, changed significantly during 28days of exposure (P<0.05). These results clearly indicated that ERY accumulated in fish and that similar metabolites as those observed in mammals were produced, resulting in the biochemical disturbance of biological systems.
ESTHER : Liu_2014_Sci.Total.Environ_490C_914
PubMedSearch : Liu_2014_Sci.Total.Environ_490C_914
PubMedID: 24911771

Title : Heterologous expression and characterization of a malathion-hydrolyzing carboxylesterase from a thermophilic bacterium, Alicyclobacillus tengchongensis - Xie_2013_Biotechnol.Lett_35_1283
Author(s) : Xie Z , Xu B , Ding J , Liu L , Zhang X , Li J , Huang Z
Ref : Biotechnol Lett , 35 :1283 , 2013
Abstract : A carboxylesterase gene from thermophilic bacterium, Alicyclobacillus tengchongensis, was cloned and expressed in Escherichia coli BL21 (DE3). The gene coded for a 513 amino acid protein with a calculated molecular mass of 57.82 kDa. The deduced amino acid sequence had structural features highly conserved among serine hydrolases, including Ser204, Glu325, and His415 as a catalytic triad, as well as type-B carboxylesterase serine active site (FGGDPENITIGGQSAG) and type-B carboxylesterase signature 2 (EDCLYLNIWTP). The purified enzyme exhibited optimum activity with beta-naphthyl acetate at 60 degrees C and pH 7 as well as stability at 25 degrees C and pH 7. One unit of the enzyme hydrolyzed 5 mg malathion l(-1) by 50 % within 25 min and 89 % within 100 min. The enzyme strongly degraded malathion and has a potential use for the detoxification of malathion residues.
ESTHER : Xie_2013_Biotechnol.Lett_35_1283
PubMedSearch : Xie_2013_Biotechnol.Lett_35_1283
PubMedID: 23801110
Gene_locus related to this paper: 9bacl-j9e7t9

Title : Poster: Novel strategy of blocking nAChR revealed by dissecting a dimeric conotoxin alphaD-GeXXA -
Author(s) : Kompella SN , Xu S , Zhang T , Yan M , Shao X , Chi C , Ding J , Wang C , Adams DJ
Ref : Biochemical Pharmacology , 86 :1229 , 2013

Title : Functional motor nerve regeneration without motor-sensory specificity following end-to-side neurorrhaphy: an experimental study - Yu_2011_J.Hand.Surg.Am_36_2010
Author(s) : Yu Q , Lin ZK , Ding J , Wang T , Chi YL , Gao WY
Ref : J Hand Surg Am , 36 :2010 , 2011
Abstract : PURPOSE: To evaluate the quality of regenerating myelinated axons and motor-sensory specificity in an end-to-side nerve repair model. METHODS: We divided 20 rats into 3 groups: (1) end-to-side neurorrhaphy using the ulnar nerve as donor nerve and the musculocutaneous nerve as recipient nerve; (2) normal control; and (3) transected nerve with the stumps buried. At 5 months, we monitored the grooming test, the electrophysiological response, and the histologic changes in nerve and muscle. RESULTS: Grooming recovered successfully, and electrophysiological investigations revealed that the target muscles had been reinnervated in the end-to-side group. The mean wet weight of the reinnervated biceps brachii muscle was 72% of the normal muscle, and the mean muscle fiber cross-sectional area of the reinnervated muscle was similar to the normal muscle. The implanted musculocutaneous nerve contained varying but satisfactory numbers of axons (end-to-side group: 596 +/- 348 vs normal group: 1,340 +/- 241). Acetylcholinesterase staining revealed a similar percentage of myelinated fibers in the musculocutaneous nerve (39%) and the biceps brachii branch of the musculocutaneous nerve (38%) in the end-to-side group. This was similar to the number of myelinated fibers in the donor ulnar nerve (37%). CONCLUSIONS: The present study confirms that limited but functional reinnervation can occur on the basis of collateral sprouting of intact axons from the ulnar nerve. The motor-sensory specificity is not important.
ESTHER : Yu_2011_J.Hand.Surg.Am_36_2010
PubMedSearch : Yu_2011_J.Hand.Surg.Am_36_2010
PubMedID: 22123048

Title : Biochemical responses and DNA damage in red sea bream from coastal Fujian Province, China - Gopalakrishnan_2011_Ecotoxicol.Environ.Saf_74_1526
Author(s) : Gopalakrishnan S , Nai Z , Thilagam H , Bei C , Ding J , Wang XH , Wang WX , Ke CH , Giesy JP , Zhang X , Wang KJ
Ref : Ecotoxicology & Environmental Safety , 74 :1526 , 2011
Abstract : Relationships between measures of oxidative stress and adaptive antioxidant defenses were studied in red sea bream (Pagrus major, RSB) caged at eight locations along the Fujian coast, China. Oxidative damage in tissues was investigated by measuring concentrations of protein carbonyl (CP) and reactive oxygen species (ROS), lipid peroxidation (LPO), acetyl cholinesterase activity (AChE), concentration of thiol groups and activities of enzymes associated with antioxidant defense. Magnitudes of antioxidant defense parameters were significantly, positively correlated with oxidative stress. Significantly greater ROS, LPO and CP content was observed in most tissues of RSB caged at three locations relative to those at the other locations. RSB caged at one location, Meizhou, exhibited significantly more DNA damage than did RSB caged at other locations. AChE activities in liver, kidney and muscle were statistically different among locations. Multivariate analyses were used to categorize the environmental quality of different locations. The battery of measures of oxidative stress proved to be a useful integrator of oxidative stresses that could be compared among locations.
ESTHER : Gopalakrishnan_2011_Ecotoxicol.Environ.Saf_74_1526
PubMedSearch : Gopalakrishnan_2011_Ecotoxicol.Environ.Saf_74_1526
PubMedID: 21621259

Title : Potentiometric sensing of butyrylcholinesterase based on in situ generation and detection of substrates - Ding_2009_Chem.Commun.(Camb)__971
Author(s) : Ding J , Qin W
Ref : Chem Commun (Camb) , :971 , 2009
Abstract : A novel reagentless biosensor has been developed in which the traditional ion selective electrode is used as a controlled-release system for in situ generation and detection of enzyme substrates.
ESTHER : Ding_2009_Chem.Commun.(Camb)__971
PubMedSearch : Ding_2009_Chem.Commun.(Camb)__971
PubMedID: 19214333

Title : Current-driven ion fluxes of polymeric membrane ion-selective electrode for potentiometric biosensing - Ding_2009_J.Am.Chem.Soc_131_14640
Author(s) : Ding J , Qin W
Ref : Journal of the American Chemical Society , 131 :14640 , 2009
Abstract : A polymeric membrane ion-selective electrode (ISE) for rapid potentiometric biosensing has been developed. Butyrylcholinesterase, as a target enzyme, is immobilized on the surface of the polymeric membrane. A macro-command-controlled procedure for switching between the potentiostatic and galvanostatic steps has been designed to provide a current-driven release of the butyrylcholine substrate for in situ biosensing of the enzyme and its inhibitors. This system has the flexibility of trapping substrate ions in the ISE inner filling solution and provides rapid, continuous, and reproducible measurements of enzymes and other bioanalytes involved in enzymatic systems.
ESTHER : Ding_2009_J.Am.Chem.Soc_131_14640
PubMedSearch : Ding_2009_J.Am.Chem.Soc_131_14640
PubMedID: 19785410

Title : In situ electrodeposited nanoparticles for facilitating electron transfer across self-assembled monolayers in biosensor design - Du_2008_Talanta_74_1337
Author(s) : Du D , Ding J , Cai J , Zhang J , Liu L
Ref : Talanta , 74 :1337 , 2008
Abstract : Gold nanoparticles (AuNPs) were synthesized in situ and electrodeposited onto Au substrate. The AuNPs modified interface facilitates electron transfer across self-assembled monolayers (SAMs) of 11-mercaptoundecanoic acid (MUA). After activation of surface carboxyl groups with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, the interface displayed good stability for immobilization of biomolecules. These modification processes were characterized by contact angle measurement, cyclic voltammetry and electrochemical impedance spectra. The immobilized acetylcholinesterase (AChE), as a model, showed excellent activity to its substrate, leading to a stable AChE biosensor. Under the optimal experimental conditions, the inhibition of malathion on AChE biosensor was proportional to its concentration in two ranges, from 0.001 to 0.1 microg mL(-1) and from 0.1 to 25 microg mL(-1), with detection limit of 0.001 microg mL(-1). The simple method showed good reproducibility and acceptable stability, which had potential application in biosensor design.
ESTHER : Du_2008_Talanta_74_1337
PubMedSearch : Du_2008_Talanta_74_1337
PubMedID: 18371787

Title : Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma - Yano_2008_Cancer.Sci_99_2309
Author(s) : Yano H , Kayukawa S , Iida S , Nakagawa C , Oguri T , Sanda T , Ding J , Mori F , Ito A , Ri M , Inagaki A , Kusumoto S , Ishida T , Komatsu H , Inagaki H , Suzuki A , Ueda R
Ref : Cancer Sci , 99 :2309 , 2008
Abstract : Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 microg/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted.
ESTHER : Yano_2008_Cancer.Sci_99_2309
PubMedSearch : Yano_2008_Cancer.Sci_99_2309
PubMedID: 18771527

Title : An amperometric acetylthiocholine sensor based on immobilization of acetylcholinesterase on a multiwall carbon nanotube-cross-linked chitosan composite - Du_2007_Anal.Bioanal.Chem_387_1059
Author(s) : Du D , Huang X , Cai J , Zhang A , Ding J , Chen S
Ref : Anal Bioanal Chem , 387 :1059 , 2007
Abstract : A simple method has been devised for immobilization of acetylcholinesterase (AChE)--covalent bonding to a multiwall carbon nanotube (MWNT)--cross-linked chitosan composite (CMC)-and a sensitive amperometric sensor for rapid detection of acetylthiocholine (ATCl) has been based on this. Fourier-transform infrared spectroscopy proved that the native structure of the immobilized enzyme was preserved on this chemically clean and homogeneous composite film, because of the excellent biocompatibility and non-toxicity of chitosan. Glutaraldehyde was used as cross-linker to covalently bond the AChE, and efficiently prevented leakage of the enzyme from the film. Because of the inherent conductive properties of the MWNT, the immobilized AChE had greater affinity for ATCl and excellent catalytic effect in the hydrolysis of ATCl, with a K(app)(m) value of 132 micromol L(-1), forming thiocholine, which was then oxidized to produce a detectable and rapid response. Under optimum conditions the amperometric current increased linearly with the increasing concentration of ATCl in the range 2.0-400 micromol L(-1), with a detection limit of 0.10 micromol L(-1). Fabrication reproducibility of the sensor was good and the stability was acceptable. The sensor is a promising new tool for characterization of enzyme inhibitors and for pesticide analysis. Abstract.
ESTHER : Du_2007_Anal.Bioanal.Chem_387_1059
PubMedSearch : Du_2007_Anal.Bioanal.Chem_387_1059
PubMedID: 17186224

Title : Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5-HT 2C, 5-HT6, and 5-HT7 serotonin receptors: implications for extrapyramidal side effects of serotonin reuptake inhibitors - Bonsi_2007_Neuropsychopharmacology_32_1840
Author(s) : Bonsi P , Cuomo D , Ding J , Sciamanna G , Ulrich S , Tscherter A , Bernardi G , Surmeier DJ , Pisani A
Ref : Neuropsychopharmacology , 32 :1840 , 2007
Abstract : The striatum is richly innervated by serotonergic afferents from the raphe nucleus. We explored the effects of this input on striatal cholinergic interneurons from rat brain slices, by means of both conventional intracellular and whole-cell patch-clamp recordings. Bath-applied serotonin (5-HT, 3-300 microM), induced a dose-dependent membrane depolarization and increased the rate of spiking. This effect was mimicked by the 5-HT reuptake blockers citalopram and fluvoxamine. In voltage-clamped neurons, 5-HT induced an inward current, whose reversal potential was close to the K(+) equilibrium potential. Accordingly, the involvement of K(+) channels was confirmed either by increasing extracellular K(+) concentration and by blockade of K(+) channels with barium. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) profiling demonstrated the presence of 5-HT2C, 5-HT6, and 5-HT7 receptor mRNAs in identified cholinergic interneurons. The depolarization/inward current induced by 5-HT was partially mimicked by the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine and antagonized by both ketanserin and the selective 5-HT2C antagonist RS102221, whereas the selective 5-HT3 and 5-HT4 receptor antagonists tropisetron and RS23597-190 had no effect. The depolarizing response to 5-HT was also reduced by the selective 5-HT6 and 5-HT7 receptor antagonists SB258585 and SB269970, respectively, and mimicked by the 5-HT7 agonist, 5-CT. Accordingly, activation of either 5-HT6 or 5-HT7 receptor induced an inward current. The 5-HT response was attenuated by U73122, blocker of phospholipase C, and by SQ22,536, an inhibitor of adenylyl cyclase. These results suggest that 5-HT released by serotonergic fibers originating in the raphe nuclei has a potent excitatory effect on striatal cholinergic interneurons.
ESTHER : Bonsi_2007_Neuropsychopharmacology_32_1840
PubMedSearch : Bonsi_2007_Neuropsychopharmacology_32_1840
PubMedID: 17203014

Title : Re-emergence of striatal cholinergic interneurons in movement disorders - Pisani_2007_Trends.Neurosci_30_545
Author(s) : Pisani A , Bernardi G , Ding J , Surmeier DJ
Ref : Trends in Neurosciences , 30 :545 , 2007
Abstract : Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders.
ESTHER : Pisani_2007_Trends.Neurosci_30_545
PubMedSearch : Pisani_2007_Trends.Neurosci_30_545
PubMedID: 17904652

Title : Determination of carbaryl pesticide using amperometric acetylcholinesterase sensor formed by electrochemically deposited chitosan - Du_2007_Colloids.Surf.B.Biointerfaces_58_145
Author(s) : Du D , Ding J , Cai J , Zhang A
Ref : Colloids Surf B Biointerfaces , 58 :145 , 2007
Abstract : A sensitive, fast and cheap sensor for quantitative determination of carbaryl pesticide using amperometric acetylcholinesterase (AChE) sensor based on electrochemically deposited chitosan was reported. From a mildly acidic chitosan solution, a chitosan film is electrochemically deposited on Au electrode surface via a negative voltage bias, leading to a stable AChE sensor. The characteristics of the deposited layer were observed to be dependent upon the deposition time, pH, and the chitosan concentration. Fourier-transform infrared spectra proved that the immobilized enzyme could preserve their native structure due to the excellent biocompatibility and non-toxicity of chitosan. Under the optimal experimental conditions, the carbaryl inhibition on AChE-CHIT/Au was proportional to its concentration in two ranges, from 0.005 to 0.1 microg/ml and 0.5 to 5 microg/ml, with the correlation coefficients of 0.9966 and 0.9982, respectively. The detection limit was 0.003 microg/ml taken as the concentration equivalent to a 10% decrease in signal. The determination of carbaryl in garlic samples obtained from export of farm base showed acceptable accuracy. The developed sensor exhibited good fabrication reproducibility and acceptable stability, which provided a new promising tool for pesticide analysis.
ESTHER : Du_2007_Colloids.Surf.B.Biointerfaces_58_145
PubMedSearch : Du_2007_Colloids.Surf.B.Biointerfaces_58_145
PubMedID: 17434296

Title : RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion - Ding_2006_Nat.Neurosci_9_832
Author(s) : Ding J , Guzman JN , Tkatch T , Chen S , Goldberg JA , Ebert PJ , Levitt P , Wilson CJ , Hamm HE , Surmeier DJ
Ref : Nat Neurosci , 9 :832 , 2006
Abstract : Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D(2) dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D(2) dopamine receptor modulation of calcium (Ca(2+)) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M(4) muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.
ESTHER : Ding_2006_Nat.Neurosci_9_832
PubMedSearch : Ding_2006_Nat.Neurosci_9_832
PubMedID: 16699510

Title : Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons - Wang_2006_Neuron_50_443
Author(s) : Wang Z , Kai L , Day M , Ronesi J , Yin HH , Ding J , Tkatch T , Lovinger DM , Surmeier DJ
Ref : Neuron , 50 :443 , 2006
Abstract : Long-term depression (LTD) of the synapse formed between cortical pyramidal neurons and striatal medium spiny neurons is central to many theories of motor plasticity and associative learning. The induction of LTD at this synapse is thought to depend upon D(2) dopamine receptors localized in the postsynaptic membrane. If this were true, LTD should be inducible in neurons from only one of the two projection systems of the striatum. Using transgenic mice in which neurons that contribute to these two systems are labeled, we show that this is not the case. Rather, in both cell types, the D(2) receptor dependence of LTD induction reflects the need to lower M(1) muscarinic receptor activity-a goal accomplished by D(2) receptors on cholinergic interneurons. In addition to reconciling discordant tracts of the striatal literature, these findings point to cholinergic interneurons as key mediators of dopamine-dependent striatal plasticity and learning.
ESTHER : Wang_2006_Neuron_50_443
PubMedSearch : Wang_2006_Neuron_50_443
PubMedID: 16675398