Wu C

References (65)

Title : Benzofuran Derivatives from Cortex Mori Radicis and Their Cholinesterase-Inhibitory Activity - Cui_2024_Molecules_29_
Author(s) : Cui X , Huang Z , Deng S , Zhang Y , Li G , Wang L , Deng Y , Wu C
Ref : Molecules , 29 : , 2024
Abstract : The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2-5) named albaphenol A-E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7-16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1-16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC(50) 45.5 and 61.0 microM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC(50) 2.5-32.8 microM) than the positive control galantamine (IC(50) 35.3 microM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 microM. The structure-activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor-enzyme complex.
ESTHER : Cui_2024_Molecules_29_
PubMedSearch : Cui_2024_Molecules_29_
PubMedID: 38257228

Title : Clinical Features of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome: a Retrospective Study - Wu_2024_Clin.Lab_70_
Author(s) : Wu C , Liu H , Chen J
Ref : Clin Lab , 70 : , 2024
Abstract : BACKGROUND: This study aims to improve the understanding of lymphoma-associated hemophagocytic syndrome, and find effective methods to identify and manage this fatal disease. METHODS: Patients diagnosed with non-Hodgkin lymphoma-associated hemophagocytic syndrome from January 2008 to December 2022 in our center were included. Univariate and multivariate analyses were also conducted using the Cox proportional hazards model. RESULTS: Among 26 patients, 22 patients were diagnosed with T/NK cell lymphoma, while 4 patients were diagnosed with diffuse large B cell lymphoma. A total of 16 patients died with a median follow-up of 71 (26, 236) days. Compared with B cell lymphoma-associated hemophagocytic syndrome patients, T/NK cell lymphoma patients are younger, have lower platelet count, fibrinogen concentration, and serum albumin, have higher blood beta2-mi-croglobulin levels and ferritin, are more likely to be infected with Epstein-Barr virus, are more inclined have a simultaneously occurrence of lymphoma and hemophagocytic syndrome. In multivariate analysis, fibrinogen, albumin, cholinesterase, uric acid, triglyceride, and ferritin are significantly associated with overall mortality. CONCLUSIONS: LAHS is a rare disease with poor prognosis. Early anti-inflammatory treatment combined with anti-lymphoma therapy can improve the overall survival time of patients. Prospective multi-center studies with larger sample sizes and longer follow-up periods are needed to further investigate optimal treatment and prognosis.
ESTHER : Wu_2024_Clin.Lab_70_
PubMedSearch : Wu_2024_Clin.Lab_70_
PubMedID: 38623661

Title : Integrating Enzymes with Supramolecular Polymers for Recyclable Photobiocatalytic Catalysis - Ouyang_2024_Angew.Chem.Int.Ed.Engl__e202400105
Author(s) : Ouyang J , Zhang Z , Li J , Wu C
Ref : Angew Chem Int Ed Engl , :e202400105 , 2024
Abstract : Chemical modifications of enzymes excel in the realm of enzyme engineering due to its directness, robustness, and efficiency; however, challenges persist in devising versatile and effective strategies. In this study, we introduce a supramolecular modification methodology that amalgamates a supramolecular polymer with Candida antarctica lipase B (CalB) to create supramolecular enzymes (SupEnzyme). This approach features the straightforward preparation of a supramolecular amphiphilic polymer (beta-CD@SMA), which was subsequently conjugated to the enzyme, resulting in a SupEnzyme capable of self-assembly into supramolecular nanoparticles. The resulting SupEnzyme nanoparticles can form micron-scale supramolecular aggregates via supramolecular and electrostatic interactions with guest entities, thus enhancing catalyst recycling. Remarkably, these aggregates maintain 80% activity after seven cycles, outperforming Novozym 435. Additionally, they can effectively initiate photobiocatalytic cascade reactions using guest photocatalysts. As a consequence, our SupEnzyme methodology exhibits noteworthy adaptability in enzyme modification, presenting a versatile platform for various polymer, enzyme, and biocompatible catalyst pairings, with potential applications in the fields of chemistry and biology.
ESTHER : Ouyang_2024_Angew.Chem.Int.Ed.Engl__e202400105
PubMedSearch : Ouyang_2024_Angew.Chem.Int.Ed.Engl__e202400105
PubMedID: 38386281

Title : Rivastigmine Nasal Spray for the Treatment of Alzheimer's Disease: Olfactory Deposition and Brain Delivery - Guo_2024_Int.J.Pharm__123809
Author(s) : Guo H , Wang G , Zhai Z , Huang J , Huang Z , Zhou Y , Xia X , Yao Z , Huang Y , Zhao Z , Wu C , Zhang X
Ref : Int J Pharm , :123809 , 2024
Abstract : Alzheimer's disease (AD) is characterized by a gradual decline in cognitive function and memory impairment, significantly impacting the daily lives of patients. Rivastigmine (RHT), a cholinesterase inhibitor, is used to treat mild to moderate AD via oral administration. However, oral administration is associated with slow absorption rate and severe systemic side effects. RHT nasal spray (RHT-ns), as a nose-to-brain delivery system, is more promising for AD management due to its efficient brain delivery and reduced peripheral exposure. This study constructed RHT-ns for enhancing AD treatment efficacy, and meanwhile the correlation between drug olfactory deposition and drug entering into the brain was explored. A 3D-printed nasal cast was employed to quantify the drug olfactory deposition. Brain delivery of RHT-ns was quantified using fluorescence tracking and Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) analysis, which showed a good correlation to the olfactory deposition. F(2) (containing 1% (w/v) viscosity modifier Avicel(a) RC-591) with high olfactory deposition and drug brain delivery was further investigated for pharmacodynamics study. F(2) exhibited superiority in AD treatment over the commercially available oral formulation. In summary, the present study showed the successful development of RHT-ns with improved olfactory deposition and enhanced brain delivery. It might provide new insight into the design and development of nose-to-brain systems for the treatment of AD.
ESTHER : Guo_2024_Int.J.Pharm__123809
PubMedSearch : Guo_2024_Int.J.Pharm__123809
PubMedID: 38224760

Title : Smartphone-assisted colorimetric biosensor for the determination of organophosphorus pesticides on the peel of fruits - Li_2024_Food.Chem_443_138459
Author(s) : Li D , Li J , Wu C , Liu H , Zhao M , Shi H , Zhang Y , Wang T
Ref : Food Chem , 443 :138459 , 2024
Abstract : Nowadays, the widespread use of organophosphorus pesticides (OPs) in agricultural production leads to varying degrees of residues in crops, which pose a potential threat to human health. Conventional methods used in national standard for the detection of OPs in fruits and vegetables require expensive instruments or cumbersome sample pretreatment steps for the analysis. To address these challenges, in this work, we took advantage of the peroxidase-like activity of PtCu(3) alloy nanocrystals (NCs) for a colorimetric and smartphone assisted sensitive detection of OPs. With the assist of a smartphone, the concentration of OPs on the peel of fruits could be obtained by comparing the B/RG value (the brightness value of blue divided by those of red and green) of a test strip with a calibration curve. This work not only provides a facile and cost-effective method to detect pesticides but also makes a positive contribution to food safety warning.
ESTHER : Li_2024_Food.Chem_443_138459
PubMedSearch : Li_2024_Food.Chem_443_138459
PubMedID: 38306911

Title : Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL - Ding_2024_Nat.Cell.Biol__
Author(s) : Ding L , Huwyler F , Long F , Yang W , Binz J , Wernle K , Pfister M , Klug M , Balaz M , Ukropcova B , Ukropec J , Wu C , Wang T , Gao M , Clavien PA , Dutkowski P , Tibbitt MW , Wolfrum C
Ref : Nat Cell Biol , : , 2024
Abstract : Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7(FBXW8) in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P-CUL7(FBXW8)-ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.
ESTHER : Ding_2024_Nat.Cell.Biol__
PubMedSearch : Ding_2024_Nat.Cell.Biol__
PubMedID: 38561547

Title : Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial - Xu_2023_BMC.Med_21_388
Author(s) : Xu M , Sun K , Xu W , Wang C , Yan D , Li S , Cong L , Pi Y , Song W , Sun Q , Xiao R , Peng W , Wang J , Peng H , Zhang Y , Duan P , Zhang M , Liu J , Huang Q , Li X , Bao Y , Zeng T , Wang K , Qin L , Wu C , Deng C , Huang C , Yan S , Zhang W , Li M , Sun L , Wang Y , Li H , Wang G , Pang S , Zheng X , Wang H , Wang F , Su X , Ma Y , Li Z , Xie Z , Xu N , Ni L , Zhang L , Deng X , Pan T , Dong Q , Wu X , Shen X , Zhang X , Zou Q , Jiang C , Xi J , Ma J , Sun J , Yan L
Ref : BMC Med , 21 :388 , 2023
Abstract : BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.
ESTHER : Xu_2023_BMC.Med_21_388
PubMedSearch : Xu_2023_BMC.Med_21_388
PubMedID: 37814306

Title : Elamipretide alleviates pyroptosis in traumatically injured spinal cord by inhibiting cPLA2-induced lysosomal membrane permeabilization - Zhang_2023_J.Neuroinflammation_20_6
Author(s) : Zhang H , Chen Y , Li F , Wu C , Cai W , Ye H , Su H , He M , Yang L , Wang X , Zhou K , Ni W
Ref : J Neuroinflammation , 20 :6 , 2023
Abstract : Spinal cord injury (SCI) is a devastating injury that may result in permanent motor impairment. The active ingredients of medications are unable to reach the affected area due to the blood-brain barrier. Elamipretide (SS-31) is a new and innovative aromatic cationic peptide. Because of its alternating aromatic and cationic groups, it freely crosses the blood-brain barrier. It is also believed to decrease inflammation and protect against a variety of neurological illnesses. This study explored the therapeutic value of SS-31 in functional recovery after SCI and its possible underlying mechanism. A spinal cord contusion injury model as well as the Basso Mouse Scale, footprint assessment, and inclined plane test were employed to assess how well individuals could function following SCI. The area of glial scarring, the number of dendrites, and the number of synapses after SCI were confirmed by HE, Masson, MAP2, and Syn staining. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were employed to examine the expression levels of pyroptosis-, autophagy-, lysosomal membrane permeabilization (LMP)- and MAPK signalling-related proteins. The outcomes showed that SS-31 inhibited pyroptosis, enhanced autophagy and attenuated LMP in SCI. Mechanistically, we applied AAV vectors to upregulate Pla2g4A in vivo and found that SS-31 enhanced autophagy and attenuated pyroptosis and LMP by inhibiting phosphorylation of cPLA2. Ultimately, we applied asiatic acid (a p38-MAPK agonist) to test whether SS-31 regulated cPLA2 partially through the MAPK-P38 signalling pathway. Our group is the first to suggest that SS-31 promotes functional recovery partially by inhibiting cPLA2-mediated autophagy impairment and preventing LMP and pyroptosis after SCI, which may have potential clinical application value.
ESTHER : Zhang_2023_J.Neuroinflammation_20_6
PubMedSearch : Zhang_2023_J.Neuroinflammation_20_6
PubMedID: 36609266

Title : Protocol for validating an algorithm to identify neurocognitive disorders in Canadian Longitudinal Study on Aging participants: an observational study - Mayhew_2023_BMJ.Open_13_e073027
Author(s) : Mayhew AJ , Hogan D , Raina P , Wolfson C , Costa AP , Jones A , Kirkland S , O'Connell M , Taler V , Smith EE , Liu-Ambrose T , Ma J , Thompson M , Wu C , Chertkow H , Griffith LE
Ref : BMJ Open , 13 :e073027 , 2023
Abstract : INTRODUCTION: In population-based research, disease ascertainment algorithms can be as accurate as, and less costly than, performing supplementary clinical examinations on selected participants to confirm a diagnosis of a neurocognitive disorder (NCD), but they require cohort-specific validation. To optimise the use of the Canadian Longitudinal Study on Aging (CLSA) to understand the epidemiology and burden of NCDs, the CLSA Memory Study will validate an NCD ascertainment algorithm to identify CLSA participants with these disorders using routinely acquired study data. METHODS AND ANALYSIS: Up to 600 CLSA participants with equal numbers of those likely to have no NCD, mild NCD or major NCD based on prior self-reported physician diagnosis of a memory problem or dementia, medication consumption (ie, cholinesterase inhibitors, memantine) and/or self-reported function will be recruited during the follow-up 3 CLSA evaluations (started August 2021). Participants will undergo an assessment by a study clinician who will also review an informant interview and make a preliminary determination of the presence or absence of an NCD. The clinical assessment and available CLSA data will be reviewed by a Central Review Panel who will make a final categorisation of participants as having (1) no NCD, (2) mild NCD or, (3) major NCD (according to fifth version of the Diagnostic and Statistical Manual of Mental Disorders criteria). These will be used as our gold standard diagnosis to determine if the NCD ascertainment algorithm accurately identifies CLSA participants with an NCD. Weighted Kappa statistics will be the primary measure of agreement. Sensitivity, specificity, the C-statistic and the phi coefficient will also be estimated. ETHICS AND DISSEMINATION: Ethics approval has been received from the institutional research ethics boards for each CLSA Data Collection Site (Universite de Sherbrooke, Hamilton Integrated Research Ethics Board, Dalhousie University, Nova Scotia Health Research Ethics Board, University of Manitoba, McGill University, McGill University Health Centre Research Institute, Memorial University of Newfoundland, University of Victoria, lisabeth Bruyere Research Institute of Ottawa, University of British Columbia, Island Health (Formerly the Vancouver Island Health Authority, Simon Fraser University, Calgary Conjoint Health Research Ethics Board).The results of this work will be disseminated to public health professionals, researchers, health professionals, administrators and policy-makers through journal publications, conference presentations, publicly available reports and presentations to stakeholder groups.
ESTHER : Mayhew_2023_BMJ.Open_13_e073027
PubMedSearch : Mayhew_2023_BMJ.Open_13_e073027
PubMedID: 37914306

Title : Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors - Tang_2023_J.Enzyme.Inhib.Med.Chem_38_2237213
Author(s) : Tang K , Li HH , Wu C , Zhang SL , Yang JG , Tang W , Qin HL
Ref : J Enzyme Inhib Med Chem , 38 :2237213 , 2023
Abstract : Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO(2)F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (K(i) = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Abeta(1 - 42)-induced cognitive impairment, significantly prevented the effects of Abeta(1 - 42) toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.
ESTHER : Tang_2023_J.Enzyme.Inhib.Med.Chem_38_2237213
PubMedSearch : Tang_2023_J.Enzyme.Inhib.Med.Chem_38_2237213
PubMedID: 37501629

Title : Enzymatic Characterization of a Novel HSL Family IV Esterase EstD04 from Pseudomonas sp. D01 in Mealworm Gut Microbiota - Kuan_2023_Molecules_28_
Author(s) : Kuan JE , Tsai CH , Chou CC , Wu C , Wu WF
Ref : Molecules , 28 : , 2023
Abstract : Pseudomonas sp. D01, capable of growing in tributyrin medium, was isolated from the gut microbiota of yellow mealworm. By using in silico analyses, we discovered a hypothesized esterase encoding gene in the D01 bacterium, and its encoded protein, EstD04, was classified as a bacterial hormone-sensitive lipase (bHSL) of the type IV lipase family. The study revealed that the recombinant EstD04-His(6x) protein exhibited esterase activity and broad substrate specificity, as it was capable of hydrolyzing p-nitrophenyl derivatives with different acyl chain lengths. By using the most favorable substrate p-nitrophenyl butyrate (C(4)), we defined the optimal temperature and pH value for EstD04 esterase activity as 40 degreesC and pH 8, respectively, with a catalytic efficiency (k(cat)/K(m)) of 6.17 x 10(3) mM(-1) s(-1) at 40 degreesC. EstD04 demonstrated high stability between pH 8 and 10, and thus, it might be capably used as an alkaline esterase in industrial applications. The addition of Mg(2+) and NH(4)(+), as well as DMSO, could stimulate EstD04 enzyme activity. Based on bioinformatic motif analyses and tertiary structural simulation, we determined EstD04 to be a typical bHSL protein with highly conserved motifs, including a triad catalytic center (Ser(160), Glu(253), and His(283)), two cap regions, hinge sites, and an oxyanion hole, which are important for the type IV enzyme activity. Moreover, the sequence analysis suggested that the two unique discrete cap regions of EstD04 may contribute to its alkali mesophilic nature, allowing EstD04 to exhibit extremely distinct physiological properties from its evolutionarily closest esterase.
ESTHER : Kuan_2023_Molecules_28_
PubMedSearch : Kuan_2023_Molecules_28_
PubMedID: 37513282
Gene_locus related to this paper: psent-EstD04

Title : Multi-biomarkers hazard assessment of microplastics with different polymers by acute embryo test and chronic larvae test with zebrafish (Danio rerio) - Chen_2023_Aquat.Toxicol_260_106595
Author(s) : Chen Y , Duan M , Xu X , Wu C
Ref : Aquat Toxicol , 260 :106595 , 2023
Abstract : Microplastics as emerging contaminants show various composition features in the environment. However, influence of polymer types on the toxicity of microplastics is still unclear, thus affecting evaluation of their toxicity and ecological risks. In this work, toxic effects of microplastics (fragment, 52-74 microm) with different polymer types including polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP) and polystyrene (PS) to zebrafish (Danio rerio) were studied using acute embryo test and chronic larvae test. Silicon dioxide (SiO(2)) was used as a control representing natural particles. Results showed microplastics with different polymers had no influence on embryonic development at environmental relevant concentration (10(2) particles/L), but could lead to accelerated heartbeat rate and increased embryonic death when exposed to SiO(2), PE and PS at higher concentrations (10(4) and 10(6) particles/L). Chronic exposure for zebrafish larvae indicated different polymers of microplastics did not affect zebrafish larvae' feeding and growth, nor induce oxidative stress. But larvae' locomotion level and AChE (acetylcholinesterase) activities could be inhibited by SiO(2) and microplastics at 10(4) particles/L. Our study demonstrated negligible toxicity of microplastics at environmental relevant concentration, while different polymers of microplastics have similar toxic effects as SiO(2) at high concentrations. We suggest that microplastic particles may have the same biological toxicity as natural particles.
ESTHER : Chen_2023_Aquat.Toxicol_260_106595
PubMedSearch : Chen_2023_Aquat.Toxicol_260_106595
PubMedID: 37269673

Title : Sulfur-fluoride exchange (SuFEx)-enabled lead discovery of AChE inhibitors by fragment linking strategies - Zhang_2023_Eur.J.Med.Chem_257_115502
Author(s) : Zhang Z , Zhang SL , Wu C , Li HH , Zha L , Shi J , Liu X , Qin HL , Tang W
Ref : Eur Journal of Medicinal Chemistry , 257 :115502 , 2023
Abstract : SuFEx click chemistry has been a method for the rapid synthesis of functional molecules with desirable properties. Here, we demonstrated a workflow that allows for in situ synthesis of sulfonamide inhibitors based on SuFEx reaction for high-throughput testing of their cholinesterase activity. According to fragment-based drug discovery (FBDD), sulfonyl fluorides [R-SO(2)F] with moderate activity were identified as fragment hits, rapidly diversified into 102 analogs in SuFEx reactions, and the sulfonamides were directly screened to yield drug-like inhibitors with 70-fold higher potency (IC(50) = 94 nM). Moreover, the improved molecule J8-A34 can ameliorate cognitive function in Abeta(1-42)-induced mouse model. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, this methodology can accelerate the development of robust biological probes and drug candidates.
ESTHER : Zhang_2023_Eur.J.Med.Chem_257_115502
PubMedSearch : Zhang_2023_Eur.J.Med.Chem_257_115502
PubMedID: 37224761

Title : Rhynchophylline relieves nonalcoholic fatty liver disease by activating lipase and increasing energy metabolism - Liu_2023_Int.Immunopharmacol_117_109948
Author(s) : Liu K , Liu S , Wu C , Wang Y , Zhang Y , Yu J , Li X , Qi X , Su S , Zhou L , Li Y
Ref : Int Immunopharmacol , 117 :109948 , 2023
Abstract : Hepatic fat metabolism may be altered in the context of overnutrition and obesity, often resulting in the accumulation of triglycerides in hepatocytes and leading to nonalcoholic fatty liver disease (NAFLD). Natural plant alkaloids have demonstrated great potential for the prevention and treatment of NAFLD. However, the role of rhynchophylline (RHY) in lipid metabolism is not clear. We explored the role of RHY in lipid metabolism in cells treated with oleic and palmitic acids to mimic high-fat diet (HFD) conditions. RHY attenuated oleic and palmitic acid-induced increases in triglyceride accumulation in HepG2, AML12, and LMH cells. RHY also increased energy metabolism and reduced oxidative stress. We further investigated the effect of RHY on hepatic lipid metabolism in mice fed an HFD including 40 mg/kg RHY. RHY alleviated hepatic steatosis, reduced fat deposition, promoted energy metabolism, and improved glucose metabolism. We investigated the mechanism responsible for this activity by docking with key proteins of lipid metabolism disorders using Discovery Studio software, which showed that RHY interacted well with lipases. Finally, we found that adding RHY promoted lipase activity and lipolysis. In conclusion, RHY ameliorated HFD-induced NAFLD and its complications by increasing lipase activity.
ESTHER : Liu_2023_Int.Immunopharmacol_117_109948
PubMedSearch : Liu_2023_Int.Immunopharmacol_117_109948
PubMedID: 37012893

Title : Durable recovery from amblyopia with donepezil - Wu_2023_Sci.Rep_13_10161
Author(s) : Wu C , Gaier ED , Nihalani BR , Whitecross S , Hensch TK , Hunter DG
Ref : Sci Rep , 13 :10161 , 2023
Abstract : An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI) can enable visual neuroplasticity and promote recovery from amblyopia in adult mice. Motivated by these promising findings, we sought to determine whether donepezil, a commercially available AChEI, can enable recovery in older children and adults with residual amblyopia. In this open-label pilot efficacy study, 16 participants (mean age 16 years; range 9-37 years) with residual anisometropic and/or strabismic amblyopia were treated with daily oral donepezil for 12 weeks. Donepezil dosage was started at 2.5 or 5.0 mg based on age and increased by 2.5 mg if the amblyopic eye visual acuity did not improve by 1 line from the visit 4 weeks prior for a maximum dosage of 7.5 or 10 mg. Participants < 18 years of age further patched the dominant eye. The primary outcome was visual acuity in the amblyopic eye at 22 weeks, 10 weeks after treatment was discontinued. Mean amblyopic eye visual acuity improved 1.2 lines (range 0.0-3.0), and 4/16 (25%) improved by <= 2 lines after 12 weeks of treatment. Gains were maintained 10 weeks after cessation of donepezil and were similar for children and adults. Adverse events were mild and self-limited. Residual amblyopia improves in older children and adults treated with donepezil, supporting the concept that the critical window of visual cortical plasticity can be pharmacologically manipulated to treat amblyopia. Placebo-controlled studies are needed.
ESTHER : Wu_2023_Sci.Rep_13_10161
PubMedSearch : Wu_2023_Sci.Rep_13_10161
PubMedID: 37349338

Title : Glutathione and Esterase Dual-Responsive Smart Nano-drug Delivery System Capable of Breaking the Redox Balance for Enhanced Tumor Therapy - Shen_2023_ACS.Appl.Mater.Interfaces__
Author(s) : Shen P , Zhang X , Ding N , Zhou Y , Wu C , Xing C , Zeng L , Du L , Yuan J , Kang Y
Ref : ACS Appl Mater Interfaces , : , 2023
Abstract : Conventional chemotherapy usually fails to achieve its intended effect because of the poor water solubility, poor tumor selectivity, and low tumor accumulation of chemotherapy drugs. The systemic toxicity of chemotherapy agents is also a problem that cannot be ignored. It is expected that smart nano-drug delivery systems that are able to respond to tumor microenvironments will provide better therapeutic outcomes with decreased side effects of chemotherapeutics. Nano-drug delivery systems capable of breaking the redox balance can also increase the sensitivity of tumor cells to chemotherapeutics. In this study, using polymer-containing disulfide bonds, ester bonds, and d-alpha-tocopherol polyethylene glycol succinate (TPGS), which can amplify reactive oxygen species (ROS) in tumor cells, we have successfully prepared a smart glutathione (GSH) and esterase dual-responsive nano-drug delivery system (DTX@PAMBE-SS-TPGS NPs) with the ability to deplete GSH as well as amplify ROS and effectively release an encapsulated chemotherapy drug (DTX) in tumor cells. The potential of DTX@PAMBE-SS-TPGS NPs for enhanced antitumor effects was thoroughly evaluated using in vitro as well as in vivo experiments. Our research offers a promising strategy for maximizing the efficacy of tumor therapy.
ESTHER : Shen_2023_ACS.Appl.Mater.Interfaces__
PubMedSearch : Shen_2023_ACS.Appl.Mater.Interfaces__
PubMedID: 37083309

Title : Exogenous methyl jasmonate induced cassava defense response and enhanced resistance to Tetranychus urticae - Zhang_2023_Exp.Appl.Acarol__
Author(s) : Zhang Y , Liu Y , Liang X , Wu C , Liu X , Wu M , Yao X , Qiao Y , Zhan X , Chen Q
Ref : Exp Appl Acarol , : , 2023
Abstract : Exogenous application of methyl jasmonate (MeJA) could activate plant defense response against the two-spotted spider mite (TSSM), Tetranychus urticae Koch,sin different plants. However, whether MeJA can also serve as an elicitor in cassava (Manihot esculenta Crantz) remains unknown. In this study, induced defense responses were investigated in TSSM-resistant cassava variety C1115 and TSSM-susceptible cassava variety KU50 when applied with MeJA. The performance of TSSM feeding on cassava plants that werespre-treated with various concentrations of MeJA was first evaluated. Subsequently, the activities of antioxidative enzymes (superoxide dismutase and catalase), detoxification enzymes (glutathione S-transferase, cytochrome P450 and carboxylesterase) and digestive enzymes (protease, amylase and invertase) in TSSM were analyzed at days 1, 2, 4 and 8 post-feeding. The results showed that MeJA treatment can induce cassava defense responses to TSSM in terms of reducing egg production and adult longevity as well as slowing development and prolonging thesegg stage. Noticeably, C1115 exhibited stronger inhibition of TSSM development and reproduction than KU50. In addition, the activities of all the tested enzymes were induced in both C1115 and KU50, the most in C1115. We conclude that exogenous methyl jasmonate can induce cassava defense responses and enhance resistance to TSSM.
ESTHER : Zhang_2023_Exp.Appl.Acarol__
PubMedSearch : Zhang_2023_Exp.Appl.Acarol__
PubMedID: 36635606

Title : Lipid droplets, the Holy Grail of hepatic stellate cells: In health and hepatic fibrosis - Mak_2022_Anat.Rec.(Hoboken)__
Author(s) : Mak KM , Wu C , Cheng CP
Ref : Anatomical Record (Hoboken) , : , 2022
Abstract : Morphological markers of hepatic stellate cells (HSCs). They are composed of a core of predominantly retinyl esters and triacylglycerols surrounded by a phospholipid layer; the latter harbors perilipins 2, 3, and 5, which help control LD lipolysis. Electron microscopy distinguishes between Types I and II LDs. Type I LDs are surrounded by acid phosphatase-positive lysosomes, which likely digest LDs. LD count and retinoid concentration are modulated by vitamin A intake. Alcohol consumption depletes hepatic retinoids and HSC LDs, with concomitant transformation of HSCs to fibrogenic myofibroblast-like cells. LD loss and accompanying HSC activation occur in HSC cell culture models. Loss of LDs is a consequence of and not a prerequisite for HSC activation. LDs are endowed with enzymes for synthesizing retinyl esters and triacylglycerols as well as neutral lipases and lysosomal acid lipase for breaking down LDs. HSCs have two distinct metabolic LD pools: an 'original' pool in quiescent HSCs and a 'new' pool emerging in HSC activation; this two-pool model provides a platform for analyzing LD dynamics in HSC activation. Besides lipolysis, LDs are degraded by lipophagy; however, the coordination between and relative contributions of these two pathways to LD removal are unclear. While induction of autophagy accelerates LD loss in quiescent HSCs and promotes HSC activation, blocking autophagy impairs LD degradation and inhibits HSC activation and fibrosis. This article is a critique of five decades of investigations into the morphology, molecular structure, synthesis, and degradation of LDs associated with HSC activation and fibrosis.
ESTHER : Mak_2022_Anat.Rec.(Hoboken)__
PubMedSearch : Mak_2022_Anat.Rec.(Hoboken)__
PubMedID: 36516055

Title : Fluorosulfate-containing pyrazole heterocycles as selective BuChE inhibitors: structure-activity relationship and biological evaluation for the treatment of Alzheimer's disease - Li_2022_J.Enzyme.Inhib.Med.Chem_37_2099
Author(s) : Li HH , Wu C , Zhang SL , Yang JG , Qin HL , Tang W
Ref : J Enzyme Inhib Med Chem , 37 :2099 , 2022
Abstract : Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC(50) = 0.79 microM and 6.59 microM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through Pi-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (K(i) = 0.77 microM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Abeta(1 - 42)-induced cognitive impairment, and significantly prevented the effects of Abeta(1 - 42) toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.
ESTHER : Li_2022_J.Enzyme.Inhib.Med.Chem_37_2099
PubMedSearch : Li_2022_J.Enzyme.Inhib.Med.Chem_37_2099
PubMedID: 35899776

Title : Butenolide derivatives from Aspergillus terreus selectively inhibit butyrylcholinesterase - Cui_2022_Front.Chem_10_1063284
Author(s) : Cui X , Deng S , Li G , Zhang Y , Wang L , Wu C , Deng Y
Ref : Front Chem , 10 :1063284 , 2022
Abstract : Two undescribed butenolide derivatives, asperteretal J (1) and K (2), together with 13 known ones (3-15) were isolated from an endophytic fungus Aspergillus terreus SGP-1, the fermentation product of which exhibited selective inhibitory activity toward butyrylcholinesterase. The structures of the new compounds were elucidated based on HRMS and NMR data, and the absolute configurations were determined by specific optical rotation comparison. All compounds were evaluated for cholinesterase inhibitory effects with galantamine as a positive control. Compounds 4-8 selectively inhibited butyrylcholinesterase with IC(50) values of 18.4-45.8smicroM in a competitive manner, with Ki values of 12.3-38.2smicroM. The structure-activity relationship was discussed. Molecular docking and dynamic simulation of the inhibitor-enzyme complex were performed to better understand the interactions.
ESTHER : Cui_2022_Front.Chem_10_1063284
PubMedSearch : Cui_2022_Front.Chem_10_1063284
PubMedID: 36618870

Title : Hesperidin methyl chalcone ameliorates lipid metabolic disorders by activating lipase activity and increasing energy metabolism - Liu_2022_Biochim.Biophys.Acta.Mol.Basis.Dis__166620
Author(s) : Liu S , Liu K , Wang Y , Wu C , Xiao Y , Yu J , Ma Z , Liang H , Li X , Li Y , Zhou L
Ref : Biochimica & Biophysica Acta Mol Basis Dis , :166620 , 2022
Abstract : Obesity has become an increasingly serious health issue with the continuous improvement in living standards. Its prevalence has become an economic burden on health care systems worldwide. Flavonoids have been shown to be beneficial in the prevention and treatment of obesity. Here, we evaluated the therapeutic potential of the flavonoid hesperidin methyl chalcone (HMC) on mice with high-fat diet (HFD)-induced hepatic steatosis in vivo and in vitro. Treatment with HMC reduced oleic and palmitic acid-induced increases in intracellular triglyceride accumulation in HepG2, AML12 and LMH cells. HMC also enhanced energy metabolism and lowered oxidative stress. We used Discovery studio to dock key proteins associated with lipid metabolism disorders to HMC, and found that HMC interacted with lipase. Furthermore, we demonstrated that HMC improved lipase activity and lipolysis. In addition, we found that HMC promoted glucose absorption, alleviated lipid metabolic disorders, improved HFD-induced liver injury, and regulated HFD-induced changes in energy metabolism. In conclusion, our study demonstrated that HMC ameliorated HFD-induced obesity and its complications by promoting lipase activity, and provides a novel approach for the prevention and treatment of obesity and related diseases.
ESTHER : Liu_2022_Biochim.Biophys.Acta.Mol.Basis.Dis__166620
PubMedSearch : Liu_2022_Biochim.Biophys.Acta.Mol.Basis.Dis__166620
PubMedID: 36494040

Title : Biological evaluation, molecular modeling and dynamics simulation of phenanthrenes isolated from Bletilla striata as butyrylcholinesterase inhibitors - Liu_2022_Sci.Rep_12_13649
Author(s) : Liu Y , Tu Y , Kang Y , Zhu C , Wu C , Chen G , Liu Z , Li Y
Ref : Sci Rep , 12 :13649 , 2022
Abstract : As part of our continuous studies on natural cholinesterase inhibitors from plant kingdom, the 95% ethanol extract from tubers of Bletilla striata showed promising butyrylcholinesterase (BChE) inhibition (IC(50) = 8.6 microg/mL). The extracts with different polarities (petroleum ether, ethyl acetate, n-butanol, and water) were prepared and evaluated for their inhibition of cholinesterases. The most active ethyl acetate extract was subjected to a bioassay-guided isolation and afforded twenty-two bibenzyls and phenanthrenes (1-22). All isolates were further evaluated for their BChE inhibition activity, and five phenanthrenes presented promising capacity (IC(50) < 10 microM). Further kinetic studies indicated their modes of inhibition. Compounds 6, 8, and 14 were found to be mixed-type inhibitors, while compounds 10 and 12 could be classified as non-competitive inhibitors. The potential interaction mechanism of them with BChE was demonstrated by molecular docking and molecular dynamics simulation, showing that they could interact with catalytic active site and peripheral anionic site of BChE. These natural phenanthrenes provide new scaffold for the further design and optimization, with the aim to discover new selective BChE inhibitors for the treatment of AD.
ESTHER : Liu_2022_Sci.Rep_12_13649
PubMedSearch : Liu_2022_Sci.Rep_12_13649
PubMedID: 35953511

Title : Methyl Jasmonate-Treated Pepper (Capsicum annuum L.) Depresses Performance and Alters Activities of Protective, Detoxification and Digestive Enzymes of Green Peach Aphid [Myzus persicae (Sulzer) (Hemiptera: Aphididae)] - Zhan_2022_J.Insect.Sci_22_
Author(s) : Zhan X , Liu Y , Liang X , Wu C , Liu X , Shui J , Zhang Y , Wang Y , Chen Q
Ref : J Insect Sci , 22 : , 2022
Abstract : Methyl jasmonate (MeJA) is a phytohormone that has been used to artificially induce plant resistance against multiple arthropod herbivores. However, it is still uncertain whether MeJA can trigger pepper plant resistance against Myzus persicae (Sulzer) (Hemiptera: Aphididae) (green peach aphid, GPA). In this study, we assessed the effects of different concentrations (0, 0.008, 0.04, 0.2, 1.0, and 5.0 mM) of MeJA-treated pepper on the development and reproduction performance of GPA to identify an appropriate concentration for vigorous resistance enhancement. MeJA dose was applied on the pepper to investigate the changes in activities of protective enzyme (superoxide dismutase, SOD; catalase, CAT; peroxidase, POD and polyphenol oxidase, PPO), detoxification enzymes (acetylcholinesterase, AchE; glutathione S-transferase, GSTs; cytocrome P450, CYP450, and carboxylesterase, CarE), and digestive enzymes (protease, PRO and amylase, AMY) in GPA. The results showed that all concentrations of MeJA-treated pepper significantly suppressed GPA performance, wherein 0.2 mM was the optimal concentration, as it presented the lowest intrinsic rate of increase (rm), finite rate of increase (lambda), and the highest population doubling time (Dt) values. Furthermore, the protective enzymes (SOD and CAT), detoxification enzymes (GSTs, CYP450, and CarE), and AMY activities increased significantly in MeJA-treated groups than the control group, while the POD and PPO activities were remarkly inhibited under 0.2 mM treatment. These findings indicate that exogenous spraying of 0.2 mM of MeJA significantly enhanced pepper resistance against GPA. The result of this study suggests MeJA application can be used as a promising strategy in integrative management of this insect pest.
ESTHER : Zhan_2022_J.Insect.Sci_22_
PubMedSearch : Zhan_2022_J.Insect.Sci_22_
PubMedID: 36545895

Title : Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease - Wu_2021_J.Enzyme.Inhib.Med.Chem_36_1860
Author(s) : Wu C , Zhang G , Zhang ZW , Jiang X , Zhang Z , Li H , Qin HL , Tang W
Ref : J Enzyme Inhib Med Chem , 36 :1860 , 2021
Abstract : To discover novel scaffolds as leads against dementia, a series of delta-aryl-1,3-dienesulfonyl fluorides with alpha-halo, alpha-aryl and alpha-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC(50) = 0.021 microM for eqBChE, 3.62 microM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH(3) > -CH(3) > -Cl (-Br) for delta-aryl; (ii) alpha-Br > alpha-Cl, alpha-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (K(i) = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Abeta(1-42)-induced cognitive dysfunction to the normal level, and the assessment of total amount of Abeta(1-42) confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.
ESTHER : Wu_2021_J.Enzyme.Inhib.Med.Chem_36_1860
PubMedSearch : Wu_2021_J.Enzyme.Inhib.Med.Chem_36_1860
PubMedID: 34425715

Title : Novel cannabidiol-carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease - Jiang_2021_Eur.J.Med.Chem_223_113735
Author(s) : Jiang X , Zhang Z , Zuo J , Wu C , Zha L , Xu Y , Wang S , Shi J , Liu XH , Zhang J , Tang W
Ref : Eur Journal of Medicinal Chemistry , 223 :113735 , 2021
Abstract : Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC(50) = 5.3 nM, SI > 4000), superior to CBD (IC(50) = 0.67 microM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (K(d) = 13 nM, k(2) = 0.26 min(-1)), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Abeta(1-42) (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.
ESTHER : Jiang_2021_Eur.J.Med.Chem_223_113735
PubMedSearch : Jiang_2021_Eur.J.Med.Chem_223_113735
PubMedID: 34371367

Title : A novel method to produce synthetic murine CXCL10 for efficient screening of functional variants - Decalf_2021_Bioorg.Chem_116_105376
Author(s) : Decalf J , Tom J , Mai E , Hernandez-Barry H , Noland CL , Vollmar BS , Li A , Li H , Xie D , Zhu L , Payandeh J , Wu C , Comps-Agrar L , Moussion C , Albert ML , Song A
Ref : Bioorg Chem , 116 :105376 , 2021
Abstract : Antitumor immune responses depend on the infiltration of solid tumors by effector T cells, a process guided by chemokines. In particular, the chemokine CXCL10 has been shown to play a critical role in mediating recruitment of CXCR3 + cytolytic T and NK cells in tumors, though its use as a therapeutic agent has not been widely explored. One of the limitations is due to the rapid inactivation of CXCL10 by dipeptidyl peptidase 4 (DPP4), a broadly expressed enzyme that is active in plasma and other bodily fluids. In the present study, we describe a novel method to produce synthetic CXCL10 that is resistant to DPP4 N-terminal truncation. Using a Fmoc solid-phase peptide synthesis approach, synthetic murine WT CXCL10 was produced, showing similar biochemical and biological properties to the recombinant protein. This synthesis method supported production of natural (amino acid substitution, insertion or deletion) and non-natural (chemical modifications) variants of CXCL10. In association with a functional screening cascade that assessed DPP4-mediated cleavage, CXCR3 signaling potency and chemotactic activity, we successfully generated 20 murine CXCL10 variants. Among those, two non-natural variants with N-methylated Leu3 (MeLeu3) and a reduced amide bond between Pro2 and Leu3 (rLeu3), respectively, showed resistance to DPP4 truncation but decreased CXCR3 signaling and chemotactic activity. Interestingly, MeLeu3 and rLeu3 CXCL10 behaved as DPP4 inhibitors, preventing the truncation of WT CXCL10. This study highlights the potential of using Fmoc solid-phase chemistry in association with biochemical and biological characterization to rapidly identify CXCL10 variants with desired properties. These novel methods unlock the opportunity to develop DPP4 resistant CXCL10 variants, as well as other chemokine substrates, while maintaining chemotactic properties.
ESTHER : Decalf_2021_Bioorg.Chem_116_105376
PubMedSearch : Decalf_2021_Bioorg.Chem_116_105376
PubMedID: 34560560

Title : Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease - Tang_2021_ChemMedChem__
Author(s) : Tang W , Zhang H , Wu C , Chen X , Zhang Z , Jiang X , Qin HL
Ref : ChemMedChem , : , 2021
Abstract : Novel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B > series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 microM), which was nicely fallen into Tc AChE via hydrogen interactions between delta-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive ( K i = 7.67 microM) AChE inhibition, nontoxicity and remarkable neuro-protective activity. In vivo studies confirmed that compound B4 significantly ameliorates performances of scopolamine-treated C57BL/6J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD.
ESTHER : Tang_2021_ChemMedChem__
PubMedSearch : Tang_2021_ChemMedChem__
PubMedID: 34036731

Title : Exposure of Helicoverpa armigera Larvae to Plant Volatile Organic Compounds Induces Cytochrome P450 Monooxygenases and Enhances Larval Tolerance to the Insecticide Methomyl - Wu_2021_Insects_12_
Author(s) : Wu C , Ding C , Chen S , Wu X , Zhang L , Song Y , Li W , Zeng R
Ref : Insects , 12 : , 2021
Abstract : Plants release an array of volatile chemicals into the air to communicate with other organisms in the environment. Insect attack triggers emission of herbivore-induced plant volatiles (HIPVs). How insect herbivores use these odors to plan their detoxification systems is vital for insect adaptation to environmental xenobiotics. Here we show that the larvae of Helicoverpa armigera (Hubner), a broadly polyphagous lepidopteran herbivore, have the capacity to use plant volatiles as cues to upregulate multiple detoxification systems, including cytochrome P450 monooxygenases (P450s), for detoxification of insecticides. Olfactory exposure of the fifth instars to two terpene volatiles limonene and nerolidol, and two green-leaf volatiles 2-heptanone and cis-3-hexenyl acetate significantly reduced larval susceptibility to the insecticide methomyl. However, larval pretreatment with piperonyl butoxide (PBO), a known P450 inhibitor, neutralized the effects of volatile exposure. Furthermore, larval exposure to the four plant volatiles enhanced activities of P450 enzymes in midguts and fatbodies, and upregulated expression of CYP6B2, CYP6B6 and CYP6B7, P450s involved in detoxification of the insecticide. Larval exposure to 2-heptanone and limonene volatiles also enhanced activities of glutathione-s-transferase and carboxylesterase. Our findings suggest that olfactory exposure to HIPVs enhances larval insecticide tolerance via induction of detoxification P450s.
ESTHER : Wu_2021_Insects_12_
PubMedSearch : Wu_2021_Insects_12_
PubMedID: 33808968

Title : Donepezil down-regulates propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion-induced vascular dementia rats - Wang_2020_Clin.Exp.Pharmacol.Physiol__
Author(s) : Wang H , Lu J , Gao WC , Ma X , Li N , Ding Z , Wu C , Zhu M , Qiao G , Xiao C , Zhang C , Chen C , Weng Z , Yang W , Zheng CB
Ref : Clinical & Experimental Pharmacology & Physiology , : , 2020
Abstract : Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris Water Maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Abeta1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Posttranslational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlightes the importance of PTMs in neurodegenerative diseases. In this study, we used Western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.
ESTHER : Wang_2020_Clin.Exp.Pharmacol.Physiol__
PubMedSearch : Wang_2020_Clin.Exp.Pharmacol.Physiol__
PubMedID: 32424975

Title : Tailoring Particle-Enzyme Nanoconjugates for Biocatalysis at the Organic-Organic Interface - Sun_2020_ChemSusChem_13_6523
Author(s) : Sun Z , Cai M , Hubner R , Ansorge-Schumacher MB , Wu C
Ref : ChemSusChem , 13 :6523 , 2020
Abstract : Nonaqueous Pickering emulsions (PEs) are a powerful platform for catalysis design, offering both a large interface contact and a preferable environment for water-sensitive synthesis. However, up to now, little progress has been made to incorporate insoluble enzymes into the nonaqueous system for biotransformation. Herein, we present biocatalytically active nonaqueous PEs, stabilized by particle-enzyme nanoconjugates, for the fast transesterification and esterification, and eventually for biodiesel synthesis. Our nanoconjugates are the hybrid biocatalysts tailor-made by loading hydrophilic Candida antarctica lipase B onto hydrophobic silica nanoparticles, resulting in not only catalytically active but highly amphiphilic particles for stabilization of a methanol-decane emulsion. The enzyme activity in these PEs is significantly enhanced, ca. 375-fold higher than in the nonaqueous biphasic control. Moreover, the PEs can be multiply reused without significant loss of enzyme performance. With this proof-of-concept, this system can be expanded for many advanced syntheses using different enzymes in the future.
ESTHER : Sun_2020_ChemSusChem_13_6523
PubMedSearch : Sun_2020_ChemSusChem_13_6523
PubMedID: 33078882

Title : Acupuncture of the Beishu acupoint participates in regulatory effects of ginsenoside Rg1 on T cell subsets of rats with chronic fatigue syndrome - He_2020_Ann.Palliat.Med_9_3436
Author(s) : He J , Yu Q , Wu C , Sun Z , Wu X , Liu R , Zhang H
Ref : Ann Palliat Med , 9 :3436 , 2020
Abstract : BACKGROUND: There are close relationships between the spleen and limb muscles and thoughts. The study aims to test the effects of ginsenoside Rg1 in combination with acupuncture of the Beishu acupoint on T cell subsets of rats with chronic fatigue syndrome (CFS). METHODS: The model was set up by combining forced cold-water swimming with chronic restraint. The rats were randomly divided into blank control, model, ginsenoside, acupuncture, and ginsenoside plus acupuncture groups (n=10). For the acupuncture group, the Beishu acupoint was acupunctured on the 2nd day after modeling. For the ginsenoside group, the ginsenoside Rg1 solution was injected into the tail vein on the 2nd day after modeling. For the combination group, both processes were conducted. These groups were compared regarding exhausted swimming time, number of struggles, resting time, serum levels of IgA, IgG, IgM, IFN-alpha, IFN-beta, and IFN-gamma, lymphocyte transformation rate, T cell subsets, and skeletal muscle activities of malondialdehyde (MDA), total antioxidative capacity (T-AOC) and acetylcholinesterase (Ache). RESULTS: The exhausted swimming time, number of struggles, and resting time of combination group surpassed those in the ginsenoside and acupuncture groups significantly (P<0.05). The serum levels of IgA, IgG, IgM, IFN-beta, IFN-gamma, T-AOC, and Ache, together with CD3+ and CD8+ T cell percentages of combination groups, were significantly higher than those of ginsenoside and acupuncture groups. However, the IFN-alpha level, MDA activity, and CD4+ T cell percentage were significantly lower (P<0.05). Compared with the model group, the CD4+/CD8+ T cell ratios of acupuncture, ginsenoside, and combination groups decreased significantly (P<0.05). Compared with the combination group, the ratio of the ginsenoside group increased significantly (P<0.05). CONCLUSIONS: Both acupuncture of the Beishu acupoint and intravenous injection of ginsenoside Rg1 have anti-fatigue effects, and their combination works synergistically. This study supplies an experimental basis for joint therapy using acupuncture and drugs to combat fatigue synergistically.
ESTHER : He_2020_Ann.Palliat.Med_9_3436
PubMedSearch : He_2020_Ann.Palliat.Med_9_3436
PubMedID: 33065794

Title : Observation of Acetylcholinesterase in Stress-Induced Depression Phenotypes by Two-Photon Fluorescence Imaging in the Mouse Brain - Wang_2019_J.Am.Chem.Soc_141_2061
Author(s) : Wang X , Li P , Ding Q , Wu C , Zhang W , Tang B
Ref : Journal of the American Chemical Society , 141 :2061 , 2019
Abstract : Oxidative stress in depression is a prime cause of neurotransmitter metabolism dysfunction in the brain. Acetylcholinesterase (AChE), a key hydrolase in the cholinergic system, directly determines the degradation of neurotransmitters. However, due to the complexity of the brain and lack of appropriate in situ imaging tools, the mechanism underlying the changes in AChE activity in depression remains unclear. Hence, we generated a two-photon fluorescence probe (MCYN) for real-time visualization of AChE with excellent sensitivity and selectivity. AChE can specifically recognize and cleave the carbamic acid ester bond in MCYN, and MCYN emits bright fluorescence at 560 nm by two-photon excitation at 800 nm. By utilizing MCYN to monitor AChE, we discovered a significant increase in AChE activity in the brains of mice with depression phenotypes. Notably, with the assistance of a two-photon fluorescence imaging probe of the superoxide anion radical (O2(*-)), in vivo visualization for the first time revealed the positive correlation between AChE and O2(*-) levels associated with depressive behaviors. This finding suggests that oxidative stress may induce AChE overactivation, leading to depression-related behaviors. This work provides a new and rewarding perspective to elucidate the role of oxidative stress regulating AChE in the pathology of depression.
ESTHER : Wang_2019_J.Am.Chem.Soc_141_2061
PubMedSearch : Wang_2019_J.Am.Chem.Soc_141_2061
PubMedID: 30638380

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

Title : Highly selective carbamate-based butyrylcholinesterase inhibitors derived from a naturally occurring pyranoisoflavone - Wu_2019_Bioorg.Chem_88_102949
Author(s) : Wu C , Tu YB , Li Z , Li YF
Ref : Bioorg Chem , 88 :102949 , 2019
Abstract : This current study described the design and synthesis of a series of derivatives based on a natural pyranoisaflavone, which was obtained from the seeds of Millettia pachycarpa and displayed attractive BChE inhibition and high selectivity in our previous study. The inhibitory potential of all derivatives against two cholinesterases was evaluated. Only a few compounds demonstrated AChE inhibitory activity at the tested concentrations, while 26 compounds showed significant inhibition on BChE (the IC50 values varied from 9.34muM to 0.093muM), most of them presented promising selectivity to ward BChE. Prediction of ADME properties for 7 most active compounds was performed. Among them, 9g (IC50=222nM) and 9h (IC50=93nM) were found to be the most potent BChE inhibitors with excellent selectivity over AChE (SI ratio=1339 and 836, respectively). The kinetic analysis demonstrated both of them acted as mixed-type BChE inhibitors, while the molecular docking results indicated that they interacted with both residues in the catalytic active site. A cytotoxicity test on PC12 cells showed that both 9g and 9h had a therapeutic safety range similar to tacrine. Overall, the results indicate that 9h could be a good candidate of BChE inhibitors.
ESTHER : Wu_2019_Bioorg.Chem_88_102949
PubMedSearch : Wu_2019_Bioorg.Chem_88_102949
PubMedID: 31054435

Title : Impact of the Chinese herbal medicines on dual antiplatelet therapy with clopidogrel and aspirin: Pharmacokinetics and pharmacodynamics outcomes and related mechanisms in rats - Xiao_2019_J.Ethnopharmacol_235_100
Author(s) : Xiao M , Qian C , Luo X , Yang M , Zhang Y , Wu C , Mok C , Lee P , Zuo Z
Ref : J Ethnopharmacol , 235 :100 , 2019
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Dual antiplatelet therapy (DAPT) with aspirin (ASA) and clopidogrel (CLP) has been consistently shown clinical effectiveness in patients with coronary artery disease. According to the literature, four traditional Chinese medicine (TCM) herbs effective for prevention cardiovascular diseases, namely Radix Salvia Miltiorrhiza (Red sage root, Danshen), Radix Pueraria Lobata (Kudzu root, Gegen), Radix Angelica Sinensis (Angelica root, Danggui), and Rhizoma Ligusticum chuanxiong (Szehuan lovage rhizome, Chuanxiong), are of high potential to be co-administered during DAPT. Since all these herbs are blood vitalizing medicines and can promote blood circulation and eliminate blood stasis, it was hypothesized that they may potentially alter the clinical outcomes of DAPT with clopidogrel and aspirin. AIM OF STUDY: The current study is proposed aiming to preliminarily evaluate the impact of these four commonly used Chinese medicinal herbs on the pharmacokinetics and pharmacodynamics of the combination therapy with clopidogrel and aspirin and its relevant outcomes and mechanisms. MATERIALS AND METHODS: In order to mimic the standard dosing regimen for DAPT in human, various Sprague-Dawley rats treatment groups were received a bolus oral dose of DAPT on day 1 followed by DAPT for consecutive 13 days in absence and presence of orally co-administered four TCM herbs (Danshen, Gegen, Danggui and Chuanxiong) at their low and high doses. On day 14, serial blood samples were collected after dosing to obtain the plasma concentrations of ASA, CLP and their corresponding metabolites by LC/MS/MS. At the end of last blood sampling point of each rat, about 4.5ml of whole blood were collected to estimate the prothrombin time from each treatment groups. After all the blood sampling, the rats were sacrificed followed by collecting their livers for evaluations of enzyme activities and expressions in the related liver microsome preparations and stomach tissues for evaluations of their potential ulcer index. In addition, gene expression and protein levels of related biomarkers (COX-1, COX-2, P2Y12) in rat livers were measured by RT-PCR and Western blot, respectively, and compared among different treatment groups. RESULTS: Co-administration of Gegen and Danggui significantly altered the pharmacokinetics of ASA and CLP in DAPT with increased systemic exposure of ASA and CLP respectively. Although minimal impact on aspirin esterase activity for all co-administered herbs, significant inhibition on rCyp2c11 and carboxylesterase activities were observed for DAPT with Danshen, Gegen and Danggui co-treatment. In addition, significantly longer PT were found in all DAPT treatment groups. However, a trend of decrease in PT of DAPT in presence of Gegen, Danggui and Chuanxiong was noticed. Nevertheless, all the treatments did not cause detectable changes in COX and P2Y12 mRNA and protein expressions. CONCLUSION: Among the four studied TCMs, it was demonstrated that co-administration of Gegen and Danggui could lead to altered pharmacokinetics of DAPT with significant inhibition on rCyp2c11 and carboxylesterase activities. Although Gegen, Danggui and Chuanxiong might potentially offset the anticoagulant activity of DAPT, the overall pharmacodynamics outcome was not considered to be harmful due to lack of risk in bleeding, which warrant further verification for its clinical impact.
ESTHER : Xiao_2019_J.Ethnopharmacol_235_100
PubMedSearch : Xiao_2019_J.Ethnopharmacol_235_100
PubMedID: 30710735

Title : Identifying the Potential Substrates of the Depalmitoylation Enzyme Acyl-protein Thioesterase 1 - Liu_2019_Curr.Mol.Med_19_364
Author(s) : Liu H , Yan P , Ren J , Wu C , Yuan W , Rao M , Zhang Z , Kong E
Ref : Curr Mol Med , 19 :364 , 2019
Abstract : BACKGROUND: The homeostasis of palmitoylation and depalmitoylation is involved in various cellular processes, the disruption of which induces severe physiological consequences. Acyl-protein thioesterase (APT) and palmitoyl-protein thioesterases (PPT) catalyze the depalmitoylation process. The natural mutation in human PPT1 caused neurodegenerative disease, yet the understanding of APT1 remains to be elucidated. While the deletion of APT1 in mice turned out to be potentially embryonically lethal, the decoding of its function strictly relied on the identification of its substrates. OBJECTIVE: To determine the potential substrates of APT1 by using the generated human APT1 knockout cell line. METHODS: The combined techniques of palmitoyl-protein enrichment and massspectrometry were used to analyze the different proteins. Palmitoyl-proteins both in HEK293T and APT1-KO cells were extracted by resin-assisted capture (RAC) and data independent acquisition (DIA) quantitative method of proteomics for data collection. RESULTS: In total, 382 proteins were identified. The gene ontology classification segregated these proteins into diverse biological pathways e.g. endoplasmic reticulum process and ubiquitin-mediated proteolysis. A few potential substrates were selected for verification; indeed, major proteins were palmitoylated. Importantly, their levels of palmitoylation were clearly changed in APT1-KO cells. Interestingly, the proliferation of APT1-KO cells escalated dramatically as compared to that of the WT cells, which could be rescued by APT1 overexpression. CONCLUSION: Our study provides a large scale of potential substrates of APT1, thus facilitating the understanding of its intervened molecular functions.
ESTHER : Liu_2019_Curr.Mol.Med_19_364
PubMedSearch : Liu_2019_Curr.Mol.Med_19_364
PubMedID: 30914023

Title : Heterogeneous Metal-Organic-Framework-Based Biohybrid Catalysts for Cascade Reactions in Organic Solvent - Wang_2019_Chemistry_25_1716
Author(s) : Wang Y , Zhang N , Zhang E , Han Y , Qi Z , Ansorge-Schumacher MB , Ge Y , Wu C
Ref : Chemistry , 25 :1716 , 2019
Abstract : In cooperative catalysis, the combination of chemo- and biocatalysts to perform one-pot reactions is a powerful tool for the improvement of chemical synthesis. Herein, UiO-66-NH2 was employed to stepwise immobilize Pd nanoparticles (NPs) and Candida antarctica lipase B (CalB) for the fabrication of biohybrid catalysts for cascade reactions. Distinct from traditional materials, UiO-66-NH2 has a robust but tunable structure that can be utilized with a ligand exchange approach to adjust its hydrophobicity, resulting in excellent catalyst dispersity in diverse reaction media. These attractive properties contribute to the formation of MOF-based biohybrid catalysts with high activity and selectivity in the synthesis of benzyl hexanoate from benzaldehyde and ethyl hexanoate. With this proof-of-concept, we reasonably expect that future tailor-made MOFs can combine other catalysts, ranging from chemical to biological catalysts for applications in industry.
ESTHER : Wang_2019_Chemistry_25_1716
PubMedSearch : Wang_2019_Chemistry_25_1716
PubMedID: 30475411

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

Title : Potential Pharmacokinetic Drug(-)Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive N-Methyl-d-Aspartate Receptor Antagonist - Zhang_2019_Molecules_24_
Author(s) : Zhang Y , Li S , Wang Y , Deng G , Cao N , Wu C , Ding W , Cheng X , Wang C
Ref : Molecules , 24 : , 2019
Abstract : Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer's disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer's disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM.
ESTHER : Zhang_2019_Molecules_24_
PubMedSearch : Zhang_2019_Molecules_24_
PubMedID: 30978991

Title : Hepatoprotective Potential of Partially Hydrolyzed Guar Gum against Acute Alcohol-Induced Liver Injury in Vitro and Vivo - Wu_2019_Nutrients_11_
Author(s) : Wu C , Liu J , Tang Y , Li Y , Yan Q , Jiang Z
Ref : Nutrients , 11 : , 2019
Abstract : Natural polysaccharides, particularly galactomannans, are potential candidates for treatment of alcoholic liver diseases (ALD). However, applications are restricted due to the physicochemical properties associated with the high molecular weight. In this work, guar gum galactomannans were partially hydrolyzed by beta-mannanase, and the molecular mechanisms of hepatoprotective effects were elucidated both in vitro and in vivo. Release of lactate dehydrogenase and cytochrome C were attenuated by partially hydrolyzed guar gum (PHGG) in HepG2 cells, due to protected cell and mitochondrial membrane integrity. PHGG co-administration decreased serum amino transaminases and cholinesterase levels of acute alcohol intoxicated mice, while hepatic pathologic morphology was depleted. Activity of superoxide dismutase, catalase, and glutathione peroxidase was recovered to 198.2, 34.5, 236.0 U/mg protein, respectively, while malondialdehyde level was decreased by 76.3% (PHGG, 1000 mg/kgday). Co-administration of PHGG induced a 4.4-fold increment of p-AMPK expression, and lipid metabolism was mediated. PHGG alleviated toll-like-receptor-4-mediated inflammation via the signaling cascade of MyD88 and IkappaBalpha, decreasing cytokine production. Moreover, mediated expression of Bcl-2 and Bax was responsible for inhibited acute alcohol-induced apoptosis with suppressed cleavage of caspase 3 and PARP. Findings gained suggest that PHGG can be used as functional food supplement for the treatment of acute alcohol-induced liver injury.
ESTHER : Wu_2019_Nutrients_11_
PubMedSearch : Wu_2019_Nutrients_11_
PubMedID: 31035540

Title : Bioactivity-guided identification of flavonoids with cholinesterase and beta-amyloid peptide aggregation inhibitory effects from the seeds of Millettia pachycarpa - Tu_2019_Bioorg.Med.Chem.Lett_29_1194
Author(s) : Tu Y , Wu C , Kang Y , Li Q , Zhu C , Li Y
Ref : Bioorganic & Medicinal Chemistry Lett , 29 :1194 , 2019
Abstract : Millettia pachycarpa Benth, a widely used anthelminthic drug in folk, is rich in flavonoids with various bioactivities. This study aimed to identify active flavonoids with anti-Alzheimer's disease (AD) effect from its seeds by a bioassay-guided isolation. A novel rotenoid with unusual oxidative ring-opening skeleton (10) and nine known flavonoids (1-9) were obtained, and their structures were elucidated by NMR and HR-ESIMS analysis. Among all isolates, 7 and 8 showed selective butyrylcholinesterase (BChE) inhibitory activities (IC50=2.34 and 11.49muM, respectively), while 3 was classified as a dual-action inhibitor against acetylcholinesterase (AChE) and BChE (IC50 AChE=17.14muM, IC50 BChE=5.68muM). Further kinetic study revealed that 3, 7, and 8 were mixed-type BChE inhibitors, but 3 was a competitive AChE inhibitor. Their strong binding affinities to BChE were confirmed by fluorescence quenching analysis. Additionally, 3 and 8 exhibited potent inhibitory effects against beta-amyloid peptide aggregation. These results revealed M. pachycarpa could be a valuable source for anti-AD leads development, and compounds 3, 7 and 8 were worthy of further study as multifunctional or specific agents for AD treatment.
ESTHER : Tu_2019_Bioorg.Med.Chem.Lett_29_1194
PubMedSearch : Tu_2019_Bioorg.Med.Chem.Lett_29_1194
PubMedID: 30910460

Title : Hydroxy-alpha-sanshool isolated from Zanthoxylum bungeanum attenuates learning and memory impairments in scopolamine-treated mice - Zhang_2019_Food.Funct_10_7315
Author(s) : Zhang M , Xie M , Wei D , Wang L , Hu M , Zhang Q , He Z , Peng W , Wu C
Ref : Food Funct , 10 :7315 , 2019
Abstract : Learning and memory impairments are common symptoms of dementia in neurodegenerative disorders. Occasionally, we found that Zanthoxylum bungeanum pericarps (ZBP) significantly activated the spontaneous activity of the hippocampus (HIPP) and paraHIPP (P < 0.001, uncorrected), implying the potential ability of ZBP to improve cognitive impairments. Thus, this study aimed to investigate the improving effect of hydroxy-alpha-sanshool (HAS), a characteristic ingredient of ZBP, against scopolamine (1 mg kg(-1), i.p.)-induced learning and memory deficits. HAS (5 mg kg(-1), p.o.) markedly reversed scopolamine-induced cognitive impairments, as indicated by its performance in the passive avoidance test and Morris water maze test (P < 0.01). Furthermore, HAS (2.5 and 5.0 mg kg(-1), p.o.) also dose-dependently prevented changes in hippocampal neuronal morphology and apoptosis, inhibited acetylcholinesterase (AChE) activity, increased the acetylcholine (ACh) content, and increased the protein and mRNA expression of brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding (p-CREB) compared with those in the model group (P < 0.05 & P < 0.01). These findings demonstrated that HAS attenuated scopolamine-induced cognitive impairments mainly by enhancing the activity of the cholinergic system and increasing the CREB/BDNF signalling pathway.
ESTHER : Zhang_2019_Food.Funct_10_7315
PubMedSearch : Zhang_2019_Food.Funct_10_7315
PubMedID: 31637395

Title : Psychosocial interventions for Alzheimer's disease cognitive symptoms: a Bayesian network meta-analysis - Duan_2018_BMC.Geriatr_18_175
Author(s) : Duan Y , Lu L , Chen J , Wu C , Liang J , Zheng Y , Wu J , Rong P , Tang C
Ref : BMC Geriatr , 18 :175 , 2018
Abstract : BACKGROUND: Alzheimer disease (AD) is the most common type of dementia with cognitive decline as one of the core symptoms in older adults. Numerous studies have suggested the value of psychosocial interventions to improve cognition in this population, but which one should be preferred are still matters of controversy. Consequently, we aim to compare and rank different psychosocial interventions in the management of mild to moderate AD with cognitive symptoms. METHODS: We did a network meta-analysis to identify both direct and indirect evidence in relevant studies. We searched MEDLINE, EMBASE, PsycINFO through the OVID database, CENTRAL through the Cochrane Library for clinical randomized controlled trials investigating psychosocial interventions of cognitive symptoms in patients with Alzheimer disease, published up to August 31, 2017. We included trials of home-based exercise(HE), group exercise(GE), walking program(WP), reminiscence therapy(RT), art therapy(AT) or the combination of psychosocial interventions and acetylcholinesterase inhibitor (ChEIs). We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool. The outcomes investigated were Mini-Mental State Examination (MMSE) and compliance. We did a pair-wise meta-analysis using the fixed-effects model and then did a random-effects network meta-analysis within a Bayesian framework. RESULTS: We deemed 10 trials eligible, including 682 patients and 11 treatments. The quality of included study was rated as low in most comparison with Cochrane tools. Treatment effects from the network meta-analysis showed WP was better than control (SMD 4.89, 95% CI -0.07 to 10.00) while cognitive training and acetylcholinesterase inhibitor (CT + ChEIs) was significantly better than the other treatments, when compared with simple ChEIs treatment, assessed by MMSE. In terms of compliance, the pair-wise meta-analysis indicated that WP and HE are better than GE and AT, while CT + ChEIs, CST + ChEIs are better than other combined interventions. CONCLUSION: Our study confirmed the effectiveness of psychosocial interventions for improving cognition or slowing down the progression of cognitive impairment in AD patients and recommended several interventions for clinical practice.
ESTHER : Duan_2018_BMC.Geriatr_18_175
PubMedSearch : Duan_2018_BMC.Geriatr_18_175
PubMedID: 30086714

Title : Studies on the interaction of BDE-47 and BDE-209 with acetylcholinesterase (AChE) based on the neurotoxicity through fluorescence, UV-vis spectra, and molecular docking - Wang_2018_Toxicol.Lett_287_42
Author(s) : Wang S , Wu C , Liu Z , You H
Ref : Toxicol Lett , 287 :42 , 2018
Abstract : The neurotoxicity of polybrominated diphenyl ethers (PBDEs) has been of concern. Acetylcholinesterase (AChE) is a critical enzyme in the central and peripheral nervous system related to neurotoxicity. The interaction between BDE-47, BDE-209, and AChE was investigated through fluorescence and UV-vis spectra combined with molecular docking. Both BDE-47 and BDE-209 bound with AChE and changed the microenvironment of some amino acid residues, resulting in a change of AChE conformation. Hydrophobic interaction is the main binding force between BDE-47, BDE-209, and AChE, and electrostatic interaction exists according to the thermodynamic parameters of the interaction between them. A hydrophobic interaction of BDE-47-AChE and BDE-209-AChE has been confirmed through molecular docking to dominate the binding force. The binding constants of BDE-47-AChE and BDE-209-AChE were 4.2x10(4) and 4.1x10(4)L/mol, respectively, and the lowest binding energies of BDE-47-AChE and BDE-209-AChE were -7.8 and -5.9kJ/mol, respectively. BDE-47 is more likely to bind with AChE than BED-209.
ESTHER : Wang_2018_Toxicol.Lett_287_42
PubMedSearch : Wang_2018_Toxicol.Lett_287_42
PubMedID: 29407791

Title : Xuebijing injection induces anti-inflammatory-like effects and downregulates the expression of TLR4 and NF-kappaB in lung injury caused by dichlorvos poisoning - He_2018_Biomed.Pharmacother_106_1404
Author(s) : He F , Wang J , Liu Y , Wang X , Cai N , Wu C , Gao Q
Ref : Biomed Pharmacother , 106 :1404 , 2018
Abstract : BACKGROUND: The mechanism in lung injury caused by acute organophosphate pesticide poisoning (AOPP) and an effective treatment remains unclear. We aim to clarify how the inflammatory lung injury caused by AOPP might be modulated by Xuebijing (XBJ) injection. METHODS: AOPP-induced lung injury model was induced by dichlorvos (DDVP) subcutaneous administration in rats and XBJ injection was administered by intraperitoneal injection after DDVP challenge. The effects of XBJ injection were assessed by lung histopathological analysis and lung injury scores, lung wet-to-dry weight ratios (WDR) and oxygenation, differential immune cell count in bronchoalveolar lavage fluid (BALF), IL-6 and TNF-alpha levels in blood, the levels of TLR4 and NF-kappaB proteins in lung tissue and blood acetylcholinesterase (AChE) activity. RESULTS: DDVP administration resulted in damage of lung histopathology and lower PaO2/FiO2 ratios (P < 0.05), which were notably attenuated by XBJ injection (P < 0.05). Total cell, macrophage, and neutrophils count in BALF and TNF-alpha and IL-6 levels in blood were significantly increased after DDVP exposure (P < 0.05), which were notably ameliorated by XBJ injection (P < 0.05). TLR4 and NF-kappaB protein in lung tissue expression after DDVP challenge were markedly increased (P < 0.05), and they were substantially downregulated by XBJ injection (P < 0.05). In addition, blood AChE activity was significantly decreased by DDVP administration (P < 0.05), however, there was no significant improvement after XBJ injection. CONCLUSION: XBJ injection prevents DDVP poisoning induced lung injury by attenuating the inflammatory response. The protective effect appears to be mediated through downregulation of the TLR4 and NF-kappaB expression.
ESTHER : He_2018_Biomed.Pharmacother_106_1404
PubMedSearch : He_2018_Biomed.Pharmacother_106_1404
PubMedID: 30119213

Title : Controllable Growth of Core-Shell Nanogels via Esterase-Induced Self-Assembly of Peptides for Drug Delivery - Wu_2018_J.Biomed.Nanotechnol_14_354
Author(s) : Wu C , Hu W , Wei Q , Qiao L , Gao Y , Lv Y , Liu M , Li C , Wang X , Wang Q
Ref : J Biomed Nanotechnol , 14 :354 , 2018
Abstract : In this work, we developed an unexplored enzyme-responsive core-shell nanogel via the assembly of hydrogelators at the surface of silicon nanoparticles. The immobilized carboxylesterase at the surface of silicon nanoparticles can catalyse precursors into hydrogelators, self-assembling around the surface of silicon nanoparticles owing to its surface confinement effect. These novel phenomena can be confirmed by observation of their morphology and increased diameters through scanning electron microscopy, transmission electron microscopy and dynamic light scattering. Moreover, these resulting core-shell nanogels can achieve controlled growth of the gel layer by means of changing the concentrations of precursors. Because of their good biocompatibility, these nanogels can realize applications in enzyme-specific drug delivery as nanocarriers.
ESTHER : Wu_2018_J.Biomed.Nanotechnol_14_354
PubMedSearch : Wu_2018_J.Biomed.Nanotechnol_14_354
PubMedID: 31352931

Title : The Associations between Paraoxonase 1 L55M\/Q192R Genetic Polymorphisms and the Susceptibilities of Diabetic Macroangiopathy and Diabetic Microangiopathy: A Meta-Analysis - Wu_2018_Diabetes.Ther_9_1669
Author(s) : Wu C , Wu D , Lin M , Zhong Y
Ref : Diabetes Ther , 9 :1669 , 2018
Abstract : INTRODUCTION: Plenty of studies have focused on the associations of paraoxonase 1 Q192R and L55M genetic polymorphisms with diabetic macroangiopathy and microangiopathy susceptibility, but these associations remain controversial. Therefore, this meta-analysis was conducted to demonstrate these relationships. METHODS: Relevant studies published in English or Chinese were identified in PubMed, Embase, Wanfang Database, and CNKI by applying specific inclusion and exclusion criteria. Statistical analyses were performed using the STATA 12.0 statistical software. RESULTS: 25 Case-control studies were included in the meta-analyses: six on the association between paraoxonase 1 L55M genetic polymorphism and diabetic macroangiopathy risk, nine on the association between L55M and diabetic microangiopathy risk, 12 on the association between Q192R and diabetic macroangiopathy risk, and 12 on the association between Q192R and diabetic microangiopathy risk. Paraoxonase 1 L55M genetic polymorphism was significantly associated with diabetic microangiopathy susceptibility in the dominant model [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.33-0.83, P = 0.006], the homozygous model (OR 0.37, 95% CI 0.16-0.86, P = 0.021), the allelic contrast model (OR 0.62, 95% CI 0.43-0.90, P = 0.011), the recessive model (OR 12.04, 95% CI 8.02-18.06, P = 0.000), and the heterozygous model (OR 0.57, 95% CI 0.38-0.85, P = 0.006), but L55M was not significantly associated with macroangiopathy susceptibility. Paraoxonase 1 Q192R genetic polymorphism was significantly associated with diabetic macroangiopathy susceptibility in the homozygous model (OR 1.88, 95% CI 1.06-3.32, P = 0.030), the allelic contrast model (OR 1.31, 95% CI 1.02-1.69, P = 0.038), and the recessive model (OR 1.55, 95% CI 1.11-2.16, P = 0.010), but not in the dominant and heterozygous models. Meanwhile, there was no significant association between paraoxonase 1 Q192R genetic polymorphism and diabetic microangiopathy susceptibility. CONCLUSION: Paraoxonase 1 L55M and Q192R genetic polymorphisms play important roles in diabetic macroangiopathy and microangiopathy susceptibility. Further well-designed studies based on large samples are needed to confirm these results.
ESTHER : Wu_2018_Diabetes.Ther_9_1669
PubMedSearch : Wu_2018_Diabetes.Ther_9_1669
PubMedID: 29987647

Title : Synaptic vesicles isolated from the electric organ of Torpedo californica and from the central nervous system of Mus musculus contain small ribonucleic acids (sRNAs) - Li_2017_Genom.Data_12_52
Author(s) : Li H , Wu C , Aramayo R , Sachs MS , Harlow ML
Ref : Genom Data , 12 :52 , 2017
Abstract : Synaptic vesicles (SVs) are presynaptic organelles that load and release small molecule neurotransmitters at chemical synapses. In addition to classic neurotransmitters, we have demonstrated that SVs isolated from the Peripheral Nervous Systems (PNS) of the electric organ of Torpedo californica, a model cholinergic synapse, and SVs isolated from the Central Nervous System (CNS) of Mus musculus (mouse) contain small ribonucleic acids (sRNAs; <= 50 nucleotides) (Scientific Reports, 5:1-14(14918) Li et al. (2015) [1]). Our previous publication provided the five most abundant sequences associated with the T. californica SVs, and the ten most abundant sequences associated with the mouse SVs, representing 59% and 39% of the total sRNA reads sequenced, respectively). We provide here a full repository of the SV sRNAs sequenced from T. californica and the mouse deposited in the NCBI as biosamples. Three data studies are included: SVs isolated from the electric organ of T. californica using standard techniques, SVs isolated from the electric organ of T. californica using standard techniques with an additional affinity purification step, and finally, SVs isolated from the CNS of mouse. The three biosamples are available at https://www.ncbi.nlm.nih.gov/biosample/ SRS1523467, SRS1523466, and SRS1523472 respectively.
ESTHER : Li_2017_Genom.Data_12_52
PubMedSearch : Li_2017_Genom.Data_12_52
PubMedID: 28367405

Title : Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats - Chen_2017_Behav.Pharmacol_28_207
Author(s) : Chen C , Zheng Y , Wu T , Wu C , Cheng X
Ref : Behav Pharmacol , 28 :207 , 2017
Abstract : Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer's disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments.
ESTHER : Chen_2017_Behav.Pharmacol_28_207
PubMedSearch : Chen_2017_Behav.Pharmacol_28_207
PubMedID: 27984208

Title : Medical Therapies of Amblyopia: Translational Research to Expand Our Treatment Armamentarium - Gore_2016_Semin.Ophthalmol_31_155
Author(s) : Gore C , Wu C
Ref : Semin Ophthalmol , 31 :155 , 2016
Abstract : Amblyopia is a developmental brain disorder in which vision is lost due to asymmetric or inadequate visual stimulation early in life. Although amblyopia is responsive to treatment if therapy is initiated early, treatment of older children and adults is usually unsuccessful due to closure of a window of cortical brain plasticity. Extensive basic research has been devoted to understanding modulators in shaping the visual cortex during the critical period of plasticity, and to providing potential clinical applications of neurotransmitters in the treatment of amblyopia. Current pharmacological treatments are reviewed from basic science research extending into clinical use, focusing on the acetylcholinesterase inhibitor donezepil, serotonin receptor inhibitor fluoxetine, dopamine precursors carbidopa-levodopa, and catecholamine modulator citicoline.
ESTHER : Gore_2016_Semin.Ophthalmol_31_155
PubMedSearch : Gore_2016_Semin.Ophthalmol_31_155
PubMedID: 26959141

Title : Donepezil Regulates 1-Methyl-4-phenylpyridinium-Induced Microglial Polarization in Parkinson's Disease - Chen_2015_ACS.Chem.Neurosci_6_1708
Author(s) : Chen T , Hou R , Xu S , Wu C
Ref : ACS Chem Neurosci , 6 :1708 , 2015
Abstract : 1-Methyl-4-phenylpyridinium (MPP+) induces microglial activation and degeneration of dopaminergic (DAergic) neurons. Donepezil is a well-known acetylcholinesterase inhibitor used clinically to treat cognitive dysfunction in Alzheimer's disease (AD). In the present study, we tested the hypothesis that MPP+ promotes microglial M1 polarization and suppresses M2 polarization and that this can be restored by donepezil. Results indicate that MPP+ treatment in microglial BV2 cells promotes microglial polarization toward the M1 state. However, pretreatment with donepezil inhibited MPP+-induced M1 polarization in microglia by suppressing the release of interleukin (IL)-6, IL-1beta, or tumor necrosis factor (TNF)-alpha. Importantly, we found that MPP+ inhibited microglial M2 polarization by suppressing expression of Arg-1, Fizz1, and Ym1, which was also rescued by pretreatment with donepezil. In addition, IL-4-mediated induction of anti-inflammatory marker genes IL-10, IL-13, and transforming growth factor-beta2 (TGF-beta2) were significantly attenuated by MPP+ in BV2 cells, which was restored by pretreatment with donepezil in a concentration-dependent manner. Mechanistically, we found that the addition of MPP+ reduced the intensity of phosphorylated signal transducer and activator of transcription 6 (STAT6) but not total STAT6 in IL-4-stimulated BV2 cells. Importantly, pretreatment of microglial BV2 cells with donepezil 3 h prior to administration of MPP+ rescued the reduction of STAT6 phosphorylation induced by MPP+.
ESTHER : Chen_2015_ACS.Chem.Neurosci_6_1708
PubMedSearch : Chen_2015_ACS.Chem.Neurosci_6_1708
PubMedID: 26114860

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

Title : Disease-modifying effects of RHC80267 and JZL184 in a pilocarpine mouse model of temporal lobe epilepsy - Ma_2014_CNS.Neurosci.Ther_20_905
Author(s) : Ma L , Wang L , Yang F , Meng XD , Wu C , Ma H , Jiang W
Ref : CNS Neurosci Ther , 20 :905 , 2014
Abstract : INTRODUCTION: Patients with temporal lobe epilepsy (TLE) often suffer from comorbid psychiatric diagnoses such as depression, anxiety, or impaired cognitive performance. Endocannabinoid (eCB) signaling is a key regulator of synaptic neurotransmission and has been implicated in the mechanisms of epilepsy as well as several mood disorders and cognitive impairments. AIMS: We employed a pilocarpine model of TLE in C57/BJ mice to investigate the role of eCB signaling in epileptogenesis and concomitant psychiatric comorbidities. METHODS AND
RESULTS: We sought to alter the neuronal levels of a known eCB receptor ligand, 2-arachidonylglycerol (2-AG), through the use of RHC80267 or JZL184. Pilocarpine-treated mice were treated with RHC80267 (1.3 mumol) or JZL184 (20 mg/kg) immediately after the termination of status epilepticus (SE), which was followed by daily treatment for the next 7 days. Our results indicated that RHC80267 treatment significantly reduced the percentage of mice suffering from spontaneous recurrent seizures (SRS) in addition to decreasing the duration of observed seizures when compared to vehicle treatment. Furthermore, RHC80267 attenuated depression and anxiety-related behaviors, improved previously impaired spatial learning and memory, and inhibited seizure-induced hippocampal neuronal loss during the chronic epileptic period. In contrast, JZL184 administration markedly increased the frequency and the duration of observed SRS, enhanced the previously impaired neuropsychological performance, and increased hippocampal damage following SE.
CONCLUSIONS: These findings suggest that RHC80267 treatment after the onset of SE could result in an amelioration of the effects found during the chronic epileptic period and yield an overall decrease in epileptic symptoms and comorbid conditions. Thus, alterations to endocannabinoid signaling may serve as a potential mechanism to prevent epileptogenesis and manipulation of this signaling pathway as a possible drug target.
ESTHER : Ma_2014_CNS.Neurosci.Ther_20_905
PubMedSearch : Ma_2014_CNS.Neurosci.Ther_20_905
PubMedID: 24989980

Title : Lipase-nanoporous gold biocomposite modified electrode for reliable detection of triglycerides - Wu_2014_Biosens.Bioelectron_53_26
Author(s) : Wu C , Liu X , Li Y , Du X , Wang X , Xu P
Ref : Biosensors & Bioelectronics , 53 :26 , 2014
Abstract : For triglycerides biosensor design, protein immobilization is necessary to create the interface between the enzyme and the electrode. In this study, a glassy carbon electrode (GCE) was modified with lipase-nanoporous gold (NPG) biocomposite (denoted as lipase/NPG/GCE). Due to highly conductive, porous, and biocompatible three-dimensional structure, NPG is suitable for enzyme immobilization. In cyclic voltammetry experiments, the lipase/NPG/GCE bioelectrode displayed surface-confined reaction in a phosphate buffer solution. Linear responses were obtained for tributyrin concentrations ranging from 50 to 250 mg dl(-1) and olive oil concentrations ranging from 10 to 200 mg dl(-1). The value of apparent Michaelis-Menten constant for tributyrin was 10.67 mg dl(-1) and the detection limit was 2.68 mg dl(-1). Further, the lipase/NPG/GCE bioelectrode had strong anti-interference ability against urea, glucose, cholesterol, and uric acid as well as a long shelf-life. For the detection of triglycerides in human serum, the values given by the lipase/NPG/GCE bioelectrode were in good agreement with those of an automatic biochemical analyzer. These properties along with a long self-life make the lipase/NPG/GCE bioelectrode an excellent choice for the construction of triglycerides biosensor.
ESTHER : Wu_2014_Biosens.Bioelectron_53_26
PubMedSearch : Wu_2014_Biosens.Bioelectron_53_26
PubMedID: 24121205

Title : Eliciting antibiotics active against the ESKAPE pathogens in a collection of actinomycetes isolated from mountain soils - Zhu_2014_Microbiology_160_1714
Author(s) : Zhu H , Swierstra J , Wu C , Girard G , Choi YH , van Wamel W , Sandiford SK , van Wezel GP
Ref : Microbiology , 160 :1714 , 2014
Abstract : The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a major threat for human health. In recent years, genome sequencing has unveiled many poorly expressed antibiotic clusters in actinomycetes. Here, we report a well-defined ecological collection of >800 actinomycetes obtained from sites in the Himalaya and Qinling mountains, and we used these in a concept study to see how efficiently antibiotics can be elicited against MDR pathogens isolated recently from the clinic. Using 40 different growth conditions, 96 actinomycetes were identified - predominantly Streptomyces - that produced antibiotics with efficacy against the MDR clinical isolates referred to as ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and/or Enterobacter cloacae. Antimicrobial activities that fluctuated strongly with growth conditions were correlated with specific compounds, including borrelidin, resistomycin, carbomethoxy-phenazine, and 6,7,8- and 5,6,8-trimethoxy-3-methylisocoumarin, of which the latter was not described previously. Our work provided insights into the potential of actinomycetes as producers of drugs with efficacy against clinical isolates that have emerged recently and also underlined the importance of targeting a specific pathogen.
ESTHER : Zhu_2014_Microbiology_160_1714
PubMedSearch : Zhu_2014_Microbiology_160_1714
PubMedID: 24794971
Gene_locus related to this paper: 9actn-a0a2s6pnd1

Title : Enzymatic synthesis of poly(sigma-caprolactone) in monocationic and dicationic ionic liquids - Wu_2013_Biotechnol.Lett_35_879
Author(s) : Wu C , Zhang Z , He F , Zhuo R
Ref : Biotechnol Lett , 35 :879 , 2013
Abstract : Enzymatic polymerization can offer metal-free routes to polymer materials that could be used in biomedical applications. To take advantage of the unique properties of ionic liquids (ILs) for enzyme stability, monocationic ionic liquid (MIL) and dicationic ionic liquid (DIL) were used to promote the ring-opening polymerization of sigma-caprolactone (sigma-CL) using Candida antarctica lipase B as catalyst. Considering the molecular weight (M n ) and reaction yield of the resulting polymer (PCL), high density and viscosity of ILs would be good, especially in the case of DIL. With the same total alkyl chain length, the density and viscosity of [C4(C6Im)2][PF6]2 were higher than that of [C12MIm][PF6]. Using a lipase/CL/ILs ratio of 1:20:20 (by wt) for 48 h at 90 degreesC, the highest M n and reaction yield of PCL were 26,200 g/mol and 62 % with [C4(C6Im)2][PF6]2, while the M n and reaction yield of PCL obtained in [C12MIm][PF6] were 11,700 g/mol and 37 %.
ESTHER : Wu_2013_Biotechnol.Lett_35_879
PubMedSearch : Wu_2013_Biotechnol.Lett_35_879
PubMedID: 23479410

Title : D14-SCFD3-dependent degradation of D53 regulates strigolactone signalling - Zhou_2013_Nature_504_406
Author(s) : Zhou F , Lin Q , Zhu L , Ren Y , Zhou K , Shabek N , Wu F , Mao H , Dong W , Gan L , Ma W , Gao H , Chen J , Yang C , Wang D , Tan J , Zhang X , Guo X , Wang J , Jiang L , Liu X , Chen W , Chu J , Yan C , Ueno K , Ito S , Asami T , Cheng Z , Lei C , Zhai H , Wu C , Wang H , Zheng N , Wan J
Ref : Nature , 504 :406 , 2013
Abstract : Strigolactones (SLs), a newly discovered class of carotenoid-derived phytohormones, are essential for developmental processes that shape plant architecture and interactions with parasitic weeds and symbiotic arbuscular mycorrhizal fungi. Despite the rapid progress in elucidating the SL biosynthetic pathway, the perception and signalling mechanisms of SL remain poorly understood. Here we show that DWARF 53 (D53) acts as a repressor of SL signalling and that SLs induce its degradation. We find that the rice (Oryza sativa) d53 mutant, which produces an exaggerated number of tillers compared to wild-type plants, is caused by a gain-of-function mutation and is insensitive to exogenous SL treatment. The D53 gene product shares predicted features with the class I Clp ATPase proteins and can form a complex with the alpha/beta hydrolase protein DWARF 14 (D14) and the F-box protein DWARF 3 (D3), two previously identified signalling components potentially responsible for SL perception. We demonstrate that, in a D14- and D3-dependent manner, SLs induce D53 degradation by the proteasome and abrogate its activity in promoting axillary bud outgrowth. Our combined genetic and biochemical data reveal that D53 acts as a repressor of the SL signalling pathway, whose hormone-induced degradation represents a key molecular link between SL perception and responses.
ESTHER : Zhou_2013_Nature_504_406
PubMedSearch : Zhou_2013_Nature_504_406
PubMedID: 24336215

Title : Synthesis of poly(sigma-caprolactone) by an immobilized lipase coated with ionic liquids in a solvent-free condition - Wu_2013_Biotechnol.Lett_35_1623
Author(s) : Wu C , Zhang Z , Chen C , He F , Zhuo R
Ref : Biotechnol Lett , 35 :1623 , 2013
Abstract : Polycaprolactone (PCL) was synthesized by ring-opening polymerization of sigma-caprolactone through two different enzymatic processes. The lipase from Candida antarctica B, immobilized on macroporous acrylic acid beads, was employed either untreated or coated with small amounts of ionic liquids (ILs). Monocationic ionic liquids, [C(n)MIm][NTf2] (n = 2, 6, 12), as well as a dicationic ionic liquid, ([C4(C6Im)2][NTf2]2), were used to coat the immobilized lipase and also as the reaction medium. In both methods, the polarity, anion of the ILs concentration and viscosity strongly influenced the reaction. Coating the immobilized enzyme with ILs improved catalytic activity and less ILs was required to produce PCL with a higher molecular weight and reaction yield. At 60 degreesC and ILs/Novozyme-435 coating ratio of 3:1 (w/w) for 48 h, the highest M(w) and reaction yield of PCL were 35,600 g/mol and 62% in the case of [C12MIm][NTf2], while the M(w) and reaction yield of PCL was 20,300 g/mol and 54 % with [C12MIm][NTf2] and catalyzed by untreated lipase.
ESTHER : Wu_2013_Biotechnol.Lett_35_1623
PubMedSearch : Wu_2013_Biotechnol.Lett_35_1623
PubMedID: 23708876

Title : Draft genome sequence of Gordonia neofelifaecis NRRL B-59395, a cholesterol-degrading actinomycete - Ge_2011_J.Bacteriol_193_5045
Author(s) : Ge F , Li W , Chen G , Liu Y , Zhang G , Yong B , Wang Q , Wang N , Huang Z , Wang J , Wu C , Xie Q , Liu G
Ref : Journal of Bacteriology , 193 :5045 , 2011
Abstract : We report a draft sequence of the genome of Gordonia neofelifaecis NRRL B-59395, a cholesterol-degrading actinomycete isolated from fresh feces of a clouded leopard (Neofelis nebulosa). As predicted, the reported genome contains several gene clusters for cholesterol degradation. This is the second available genome sequence of the family Gordoniaceae.
ESTHER : Ge_2011_J.Bacteriol_193_5045
PubMedSearch : Ge_2011_J.Bacteriol_193_5045
PubMedID: 21742880
Gene_locus related to this paper: 9acto-f1yem7 , 9acto-f1yf25 , 9acto-f1yf38 , 9acto-f1yie2 , 9acto-f1yih2 , 9acto-f1yj54 , 9acto-f1yj56 , 9acto-f1yjv0 , 9acto-f1yjw7 , 9acto-f1yk15 , 9acto-f1ykt6 , 9acto-f1ylb2 , 9acto-f1yld6 , 9acto-f1yme6 , 9acto-f1yma9 , 9acto-f1ymg7 , 9acto-f1ydt0 , 9acto-f1yfj9 , 9actn-f1yfi8

Title : Application of ultrasound-assisted surfactant-enhanced emulsification microextraction for the determination of some organophosphorus pesticides in water samples - Wu_2010_Anal.Chim.Acta_679_56
Author(s) : Wu C , Liu N , Wu Q , Wang C , Wang Z
Ref : Anal Chim Acta , 679 :56 , 2010
Abstract : An ultrasound-assisted surfactant-enhanced emulsification microextraction (UASEME) was developed as a new approach for the extraction of organophosphorus pesticides (OPs) in water samples prior to high-performance liquid chromatography with diode array detection (HPLC-DAD). The use of a surfactant as an emulsifier in the UASEME method could enhance the dispersion of water-immiscible extraction solvent into aqueous phase and is favorable for the mass-transfer of the analytes from aqueous phase to the organic phase. Several variables that affect the extraction efficiency, including the kind and volume of the extraction solvent, the type and concentration of the surfactant, salt addition, ultrasound emulsification time and temperature, were investigated and optimized. Under the optimum experimental conditions, the calibration curve was linear in the concentration range from 1 to 200 ng mL(-1) for the seven OPs (isocarbophos, phosmet, parathion, parathion-methyl, fenitrothion, fonofos and phoxim), with the correlation coefficients (r) varying from 0.9973 to 0.9998. High enrichment factors were achieved ranging from 210 to 242. The established UASEME-HPLC-DAD method has been successfully applied for the determination of the OPs in real water samples. The limits of detection were in the range between 0.1 and 0.3 ng mL(-1). The recoveries of the target analytes over the three spiked concentration levels of the compounds (10, 50, and 100 ng mL(-1), respectively) in rain, reservoir and well water samples were between 83% and 106% with the relative standard deviations varying from 3.3% to 5.6%.
ESTHER : Wu_2010_Anal.Chim.Acta_679_56
PubMedSearch : Wu_2010_Anal.Chim.Acta_679_56
PubMedID: 20951857

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

Title : Identification of novel esterase from metagenomic library of Yangtze river - Wu_2009_J.Microbiol.Biotechnol_19_187
Author(s) : Wu C , Sun B
Ref : J Microbiol Biotechnol , 19 :187 , 2009
Abstract : A metagenomic library of surface-water microbes from the Yangtze River in China was constructed, and a novel esterase, designated as EstY, was isolated and characterized. EstY had 423 amino acids with an estimated molecular mass of 44 kDa and pI of 7.28. It hydrolyzed various pnitrophenyl esters (acetate, butyrate, caprate, caprylate, laurate, myristate, and palmitate) and its best substrate was p-nitrophenyl caprate (C8). The optimum pH for EstY activity was 9.0 and the optimum temperature was 50 degrees . Metal ions, such as Mn2+, Co2+, Hg2+, Zn2+, and Fe3+, strongly inhibited the activity of EstY, whereas Mg2+ was required for maximal activity. Activity remained in the presence of 10% alcohol, acetone, isopropanol, and dimethyl sulfoxide, respectively. An analysis of the amino acid sequence deduced from estY revealed that it had 7 closely related lipolytic enzymes. Moreover, a sequence analysis showed that EstY, like its 7 relatives, did not belong to any known lipolytic enzyme family.
ESTHER : Wu_2009_J.Microbiol.Biotechnol_19_187
PubMedSearch : Wu_2009_J.Microbiol.Biotechnol_19_187
PubMedID: 19307769
Gene_locus related to this paper: 9bact-b0ln78

Title : Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome - Belichenko_2009_J.Comp.Neurol_512_453
Author(s) : Belichenko PV , Kleschevnikov AM , Masliah E , Wu C , Takimoto-Kimura R , Salehi A , Mobley WC
Ref : Journal of Comparative Neurology , 512 :453 , 2009
Abstract : Down syndrome (DS) is a neurological disorder causing impaired learning and memory. Partial trisomy 16 mice (Ts65Dn) are a genetic model for DS. Previously, we demonstrated widespread alterations of pre- and postsynaptic elements and physiological abnormalities in Ts65Dn mice. The average diameter of presynaptic boutons and spines in the neocortex and hippocampus was enlarged. Failed induction of long-term potentiation (LTP) due to excessive inhibition was observed. In this paper we investigate the morphological substrate for excessive inhibition in Ts65Dn. We used electron microscopy (EM) to characterize synapses, confocal microscopy to analyze colocalization of the general marker for synaptic vesicle protein with specific protein markers for inhibitory and excitatory synapses, and densitometry to characterize the distribution of the receptor and several proteins essential for synaptic clustering of neurotransmitter receptors. EM analysis of synapses in the Ts65Dn vs. 2N showed that synaptic opposition lengths were significantly greater for symmetric synapses (approximately 18%), but not for asymmetric ones. Overall, a significant increase in colocalization coefficients of glutamic acid decarboxylase (GAD)65/p38 immunoreactivity (IR) (approximately 27%) and vesicular GABA transporter (VGAT)/p38 IR (approximately 41%) was found, but not in vesicular glutamate transporter 1 (VGLUT1)/p38 IR. A significant overall decrease of IR in the hippocampus of Ts65Dn mice compared with 2N mice for glutamate receptor 2 (GluR2; approximately 13%) and anti-gamma-aminobutyric acid (GABA)(A) receptor beta2/3 subunit (approximately 20%) was also found. The study of proteins essential for synaptic clustering of receptors revealed a significant increase in puncta size for neuroligin 2 (approximately 13%) and GABA(A) receptor-associated protein (GABARAP; approximately 13%), but not for neuroligin 1 and gephyrin. The results demonstrate a significant alteration of inhibitory synapses in the fascia dentata of Ts65Dn mice.
ESTHER : Belichenko_2009_J.Comp.Neurol_512_453
PubMedSearch : Belichenko_2009_J.Comp.Neurol_512_453
PubMedID: 19034952

Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras - Tejada_2006_J.Med.Chem_49_7518
Author(s) : Tejada FR , Nagy PI , Xu M , Wu C , Katz T , Dorsey J , Rieman M , Lawlor E , Warrier M , Messer WS, Jr.
Ref : Journal of Medicinal Chemistry , 49 :7518 , 2006
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
ESTHER : Tejada_2006_J.Med.Chem_49_7518
PubMedSearch : Tejada_2006_J.Med.Chem_49_7518
PubMedID: 17149881

Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders - Cao_2003_J.Med.Chem_46_4273
Author(s) : Cao Y , Zhang M , Wu C , Lee S , Wroblewski ME , Whipple T , Nagy PI , Takacs-Novak K , Balazs A , Toros S , Messer WS, Jr.
Ref : Journal of Medicinal Chemistry , 46 :4273 , 2003
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
ESTHER : Cao_2003_J.Med.Chem_46_4273
PubMedSearch : Cao_2003_J.Med.Chem_46_4273
PubMedID: 13678406