Yang K

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Full name : Yang Kechun

First name : Kechun

Mail : University of Pennsylvania Philadelphia PA 19104

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Country : USA

Email : kechuny@mail.med.upenn.edu

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References (42)

Title : Perilipin1 deficiency prompts lipolysis in lipid droplets and aggravates the pathogenesis of persistent immune activation in Drosophila - Wang_2023_J.Innate.Immun__
Author(s) : Wang L , Lin J , Yang K , Wang W , Lv Y , Zeng X , Zhao Y , Yu J , Pan L
Ref : J Innate Immun , : , 2023
Abstract : Lipid droplets (LDs) are highly dynamic intracellular organelles, which are involved in lots of biological processes. However, the dynamic morphogenesis and functions of intracellular LDs during persistent innate immune responses remain obscure. In this study, we induce long-term systemic immune activation in Drosophila through genetic manipulation. Then, the dynamic pattern of LDs is traced in the Drosophila fat body. We find that deficiency of Plin1, a key regulator of LDs' reconfiguration, blocks LDs minimization at the initial stage of immune hyperactivation but enhances LDs breakdown at the later stage of sustained immune activation via recruiting the lipase Brummer (Bmm, homologous to human ATGL). The high wasting in LDs shortens the lifespan of flies with high-energy-cost immune hyperactivation. Therefore, these results suggest a critical function of LDs during long-term immune activation and provide a potential treatment for the resolution of persistent inflammation.
ESTHER : Wang_2023_J.Innate.Immun__
PubMedSearch : Wang_2023_J.Innate.Immun__
PubMedID: 37742619

Title : Variants within the LPL gene confer susceptility to diabetic kidney disease and rapid decline in kidney function in Chinese patients with type 2 diabetes - Wu_2023_Diabetes.Obes.Metab__
Author(s) : Wu Y , Cheng S , Gu H , Yang K , Xu Z , Meng X , Wang Y , Jiang Y , Li H , Zhou Y
Ref : Diabetes Obes Metab , : , 2023
Abstract : AIM: To examine the association between lipoprotein lipase (LPL) polymorphisms and susceptibility to diabetic kidney disease (DKD) and early renal function decline in Chinese patients with type 2 diabetes (T2D). METHODS: The association of eight LPL single nucleotide polymorphisms (SNPs) with DKD was analysed in 2793 patients with T2D from the third China National Stroke Registry. DKD was defined as either an urine albumin-to-creatinine ratio (UACR) of 30 mg/g or higher at baseline and 3 months, or an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m(2) at baseline and 3 months. Rapid decline in kidney function (RDKF) was defined as a reduction in the eGFR of 3 mL/min/1.73 m(2) or greater per year. Logistic regression models were used to evaluate the association of LPL SNP and DKD with an additive model. RESULTS: The SNPs rs285 C>T (OR = 1.40, P = .0154), rs328 C>G (OR = 2.24, P = .0104) and rs3208305 A>T (OR = 1.85, P = .0015) were identified to be significantly associated with DKD defined by eGFR. Among 1241 participants with follow-up data, 441 (35.5%) showed RDKF over a mean follow-up period of 1 year, and the rs285 C allele was associated with higher odds of RDKF (OR = 1.31, 95% CI 1.04-1.66; P = .025) after adjustment for multiple variables. CONCLUSIONS: These results suggest that LPL-related SNPs are new candidate factors for conferring susceptibility to DKD and may promote rapid loss of renal function in Chinese patients with T2D.
ESTHER : Wu_2023_Diabetes.Obes.Metab__
PubMedSearch : Wu_2023_Diabetes.Obes.Metab__
PubMedID: 37427758

Title : Attack Site Density of a Highly-efficient PET Hydrolases - Li_2023_Protein.Pept.Lett__
Author(s) : Li Q , Liu W , Jing N , Yang K , Yao J , Wang X
Ref : Protein Pept Lett , : , 2023
Abstract : INTRODUCTION: Poly (ethylene terephthalate) (PET) is one of the most abundant polyester materials used in daily life and it is also one of the main culprits of environmental pollution. ICCG (F243I/D238C/S283C/Y127G) is enzyme with four modifications of leaf-branch compost cutinase (LCC) that display outstanding performance in hydrolyzing PET and hold a great potential in further applications. METHOD: Here, we used ICCG to degrade PET particles of various sizes and use the density of attack sites (attack) and kinetic parameters to evaluate the effect of particle size on enzyme degradation efficiency. We are surprised to observe that there is a certain relationship between Km and attack. In order to further confirm the relationship, we obtained three different enzymes (Y95K, M166S and H218S) by site-directed mutagenesis on the basis of ICCG. RESULT: The results confirmed that there was a negative correlation between Km and attack. In addition, we also found that increasing the affinity between the enzyme and the substrate does not necessarily lead to the increase of degradation rate. CONCLUSION: These findings show that the granulation of PET and the selection of appropriate particle size are helpful to improve its industrial application value. At the same time, additional protein engineering to increase ICCG performance is realistic, but it can't be limited to enhance the affinity between enzyme and substrate.
ESTHER : Li_2023_Protein.Pept.Lett__
PubMedSearch : Li_2023_Protein.Pept.Lett__
PubMedID: 37165591
Gene_locus related to this paper: 9bact-g9by57

Title : Development of indole-2-carbonyl piperazine urea derivatives as selective FAAH inhibitors for efficient treatment of depression and pain - Shang_2022_Bioorg.Chem_128_106031
Author(s) : Shang Y , Wang M , Hao Q , Meng T , Li L , Shi J , Yang G , Zhang Z , Yang K , Wang J
Ref : Bioorg Chem , 128 :106031 , 2022
Abstract : Fatty acid amide hydrolase (FAAH), aserinehydrolase with significant role in thehydrolysis of endocannabinoids, is a promising therapeutic target for peripheral and central nervous system related disorders, including pain, neuroinflammation and depression. Employing a structure-based approach, a novel series of indole-2-carbonyl piperazine urea derivatives were designed and synthesized as FAAH inhibitors for the treatment of pain-depression comorbidity. Among them, compound 4i emerged as the most potent inhibitor (IC(50) = 0.12 microM) with fine selectivity versus CES2, ABHD6, MAGL and the cannabinoid receptor, which also displayed superior metabolic stability in human liver microsome and an adequate pharmacokinetic profile in rodents. Treatment of depressed rats with 4i demonstrated favorable antidepressant-like effects not only by increasing the level of BDNF in the hippocampus but also by restraining the apoptosis of hippocampal neurons. Also, 4i effectively suppressed the LPS-induced neuroinflammation in vitro. Moreover, 4i exhibited potent analgesic activity, which indicated its promising therapeutical application for pain and depression. These meaningful results shed light on FAAH inhibitors as promising pain-depression comorbidity therapeutics.
ESTHER : Shang_2022_Bioorg.Chem_128_106031
PubMedSearch : Shang_2022_Bioorg.Chem_128_106031
PubMedID: 36037600

Title : Human umbilical cord mesenchymal stem cells-derived exosomes for treating traumatic pancreatitis in rats - Han_2022_Stem.Cell.Res.Ther_13_221
Author(s) : Han L , Zhao Z , Chen X , Yang K , Tan Z , Huang Z , Zhou L , Dai R
Ref : Stem Cell Res Ther , 13 :221 , 2022
Abstract : BACKGROUND: The therapeutic and protective effects of human umbilical cord mesenchymal stem cells-exosomes (hucMSC-Exs) on traumatic pancreatitis (TP) remain unknown. Here, we established a rat model of TP and evaluated and compared the therapeutic effects of hUC-MSCs and hucMSC-Exs. METHODS: HucMSC-Exs were obtained by ultracentrifugation and identified using transmission electron microscopy and western blot analysis. TP rats were treated by tail vein injection of hUC-MSCs and hucMSC-Exs. Their homing in rats was observed by performing fluorescence microscopy. The degree of pancreatic tissue damage was assessed by HE staining, the expression levels of amylase, lipase, and inflammatory cytokines were detected by ELISA, apoptosis was detected by TUNEL assay, and the expression levels of various apoptosis-related proteins were detected by western-blot. The expression levels of apoptosis-related molecular markers were detected by RT-qPCR. RESULTS: The colonization of exosomes was observed in pancreatic tissue. Compared to TP group, the histopathological score of pancreas was significantly decreased in the TP + hUC-MSCs group and TP + hucMSC-Exs group (P < 0.05). Compared to TP group, the activity of serum amylase and lipase was significantly decreased (P < 0.05). The expression levels of IL-6 and TNF-alpha were significantly decreased, while those of IL-10 and TGF-beta were significantly increased (P < 0.05). The apoptosis index of the TP group was significantly increased (P < 0.05), whereas that of the TP + hUC-MSCs and TP + hucMSC-Exs groups was significantly decreased (P < 0.05). Compared to TP group, the expression levels of Bax, Bcl-2, and Caspase-3 were significantly decreased in the TP + hUC-MSCs group and TP + hucMSC-Exs group (P < 0.05). CONCLUSION: HucMSC-Exs can colonize injured pancreatic tissue, inhibit the apoptosis of acinar cells, and control the systemic inflammatory response to facilitate the repair of pancreatic tissue.
ESTHER : Han_2022_Stem.Cell.Res.Ther_13_221
PubMedSearch : Han_2022_Stem.Cell.Res.Ther_13_221
PubMedID: 35619158

Title : Integrating network pharmacology analysis and pharmacodynamic evaluation for exploring the active components and molecular mechanism of moutan seed coat extract to improve cognitive impairment - Wang_2022_Front.Pharmacol_13_952876
Author(s) : Wang Y , Wu X , Yang K , Liu Q , Jiang B , Yang R , Xiao P , He C
Ref : Front Pharmacol , 13 :952876 , 2022
Abstract : Paeonia suffruticosa (Moutan) is a traditional medicinal plant in China. Its seed coat is rich in resveratrol oligomer, especially suffruticosol B (SB). Previous studies had shown that the seed coat extracts of Paeonia suffruticosa (PSCE) had good cholinesterase inhibitory activity and neuroprotective effect, but the effective dose range was unknown, and the pharmacodynamic components and molecular mechanism of PSCE had not been discussed. The current study aimed to screen the pharmacodynamic components in PSCE and investigate the improvement effect of PSCE and the selected SB on scopolamine-induced cognitive dysfunction in mice and its mechanism. The results of high-throughput sequencing and bioinformatics analysis showed that suffruticosol B (SB) and trans-gnetin H (GH) might be the main active components of PSCE; PSCE might improve cognitive dysfunction through p53, HIF-1, MAPK, and PI3K-Akt signaling pathways, while SB and GH might improve cognitive dysfunction through HIF-1 signaling pathway. SB and GH had good molecular docking activity with the target of HIF-1 signaling pathway. The pharmacodynamic activities of PSCE and SB were further verified by behavioral experiments. PSCE and SB could improve the recognition ability of familiar and new objects and shorten the escape latency in the Morris Water Maze test (PSCE 120 mgkg-1, p < 0.05; SB 60 mgkg-1, p < 0.01); PSCE and SB could increase Ach and GSH levels, enhance the activities of ChAT, SOD and CAT, decrease the levels of IL-1beta, IL-6, and TNF-alpha, and decrease the activity of AChE. In conclusion, the results indicated that PSCE might exert pharmacodynamic activity through multiple components, targets, and pathways, and SB and GH might be the main active components of PSCE. PSCE and SB might improve cognitive dysfunction by regulating cholinergic, antioxidant, and anti-inflammatory effects. These results indicated that PSCE and SB might be potential anti-AD drug candidates, providing a scientific basis for the development and utilization of Moutan bark.
ESTHER : Wang_2022_Front.Pharmacol_13_952876
PubMedSearch : Wang_2022_Front.Pharmacol_13_952876
PubMedID: 36034803

Title : Discovering monoacylglycerol lipase inhibitors by a combination of fluorogenic substrate assay and activity-based protein profiling - Deng_2022_Front.Pharmacol_13_941522
Author(s) : Deng H , Zhang Q , Lei Q , Yang N , Yang K , Jiang J , Yu Z
Ref : Front Pharmacol , 13 :941522 , 2022
Abstract : The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment of diseases such as neurodegenerative disease and inflammation, pain, as well as cancer. Despite a number of MAGL inhibitors been reported, inhibitors with new chemotypes are still required. Here, we developed a substrate-based fluorescence assay by using a new fluorogenic probe AA-HNA and successfully screened a focused library containing 320 natural organic compounds. Furthermore, we applied activity-based protein profiling (ABPP) as an orthogonal method to confirm the inhibitory activity against MAGL in the primary substrate-based screening. Our investigations culminated in the identification of two major compound classes, including quinoid diterpene (23, cryptotanshinone) and beta-carbolines (82 and 93, cis- and trans-isomers), with significant potency towards MAGL and good selectivity over other 2-AG hydrolases (ABHD6 and ABHD12). Moreover, these compounds also showed antiproliferative activities against multiple cancer cells, including A431, H1975, B16-F10, OVCAR-3, and A549. Remarkably, 23 achieved complete inhibition towards endogenous MAGL in most cancer cells determined by ABPP. Our results demonstrate the potential utility of the substrate-based fluorescence assay in combination with ABPP for rapidly discovering MAGL inhibitors, as well as providing an effective approach to identify potential targets for compounds with significant biological activities.
ESTHER : Deng_2022_Front.Pharmacol_13_941522
PubMedSearch : Deng_2022_Front.Pharmacol_13_941522
PubMedID: 36105202

Title : Dual acting oximes designed for therapeutic decontamination of reactive organophosphates via catalytic inactivation and acetylcholinesterase reactivation - Cannon_2021_RSC.Med.Chem_12_1592
Author(s) : Cannon J , Tang S , Yang K , Harrison R , Choi SK
Ref : RSC Med Chem , 12 :1592 , 2021
Abstract : A conventional approach in the therapeutic decontamination of reactive organophosphate (OP) relies on chemical OP degradation by oxime compounds. However, their efficacy is limited due to their lack of activity in the reactivation of acetylcholinesterase (AChE), the primary target of OP. Here, we describe a set of alpha-nucleophile oxime derivatives which are newly identified for such dual modes of action. Thus, we prepared a 9-member oxime library, each composed of an OP-reactive oxime core linked to an amine-terminated scaffold, which varied through an N-alkyl functionalization. This library was screened by enzyme assays performed with human and electric eel subtypes of OP-inactivated AChE, which led to identifying three oxime leads that displayed significant enhancements in reactivation activity comparable to 2-PAM. They were able to reactivate both enzymes inactivated by three OP types including paraoxon, chlorpyrifos and malaoxon, suggesting their broad spectrum of OP susceptibility. All compounds in the library were able to retain catalytic reactivity in paraoxon inactivation by rates increased up to 5 or 8-fold relative to diacetylmonoxime (DAM) under controlled conditions at pH (8.0, 10.5) and temperature (17, 37 degreesC). Finally, selected lead compounds displayed superb efficacy in paraoxon decontamination on porcine skin in vitro. In summary, we addressed an unmet need in therapeutic OP decontamination by designing and validating a series of congeneric oximes that display dual modes of action.
ESTHER : Cannon_2021_RSC.Med.Chem_12_1592
PubMedSearch : Cannon_2021_RSC.Med.Chem_12_1592
PubMedID: 34671741

Title : Computational Design and Crystal Structure of a Highly Efficient Benzoylecgonine Hydrolase - Chen_2021_Angew.Chem.Int.Ed.Engl_60_21959
Author(s) : Chen X , Deng X , Zhang Y , Wu Y , Yang K , Li Q , Wang J , Yao W , Tong J , Xie T , Hou S , Yao J
Ref : Angew Chem Int Ed Engl , 60 :21959 , 2021
Abstract : Benzoylecgonine (BZE) is the major toxic metabolite of cocaine, and is responsible for the long-term cocaine-induced toxicity due to its long residence time in humans. BZE is also the main contaminant following cocaine consumption, representing a risk to our environment and non-target organisms. Here, we identified the bacterial cocaine esterase (CocE) as a BZE-metabolizing enzyme (BZEase), which can degrade BZE into biological inactive metabolites (ecgonine and benzoic acid). CocE was redesigned by a reactant-state-based enzyme design theory. An encouraging mutant denoted as BZEase2, presented a >400-fold improved catalytic efficiency against BZE compared with wild-type (WT) CocE. In vivo , a single dose of BZEase2 (1 mg/kg, IV) could eliminate nearly all BZE within only two minutes, suggesting the enzyme have the potential for cocaine overdose treatment and BZE elimination in the environment by accelerating BZE clearance. The crystal structure of a designed BZEase was determined, providing additional insights in support of our simulation results.
ESTHER : Chen_2021_Angew.Chem.Int.Ed.Engl_60_21959
PubMedSearch : Chen_2021_Angew.Chem.Int.Ed.Engl_60_21959
PubMedID: 34351032
Gene_locus related to this paper: rhosm-cocE

Title : Concurrent urinary organophosphate metabolites and acetylcholinesterase activity in Ecuadorian adolescents - Skomal_2021_Environ.Res__112163
Author(s) : Skomal AE , Zhang J , Yang K , Yen J , Tu X , Suarez-Torres J , Lopez-Paredes D , Calafat AM , Ospina M , Martinez D , Suarez-Lopez JR
Ref : Environ Research , :112163 , 2021
Abstract : BACKGROUND: Organophosphates are insecticides that inhibit the enzymatic activity of acetylcholinesterase (AChE). Because of this, AChE is considered a physiological marker of organophosphate exposure in agricultural settings. However, limited research exists on the associations between urinary organophosphate metabolites and AChE activity in children. METHODS: This study included 526 participants from 2 exams (April and July-October 2016) of ages 12-17 years living in agricultural communities in Ecuador. AChE activity was measured at both examinations, and organophosphate metabolites, including para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPy), and malathion dicarboxylic acid (MDA) were measured in urine collected in July-October. We used generalized estimating equation generalized linear model (GEEGLM), adjusting for hemoglobin, creatinine, and other demographic and anthropometric covariates, to estimate associations of urinary metabolite concentrations with AChE activity (July-October) and AChE % change between April and July-October. RESULTS: The mean (SD) of AChE and AChE % change (April vs July-October) were 3.67 U/mL (0.54) and -2.5 % (15.4 %), respectively. AChE activity was inversely associated with PNP concentration, whereas AChE % change was inversely associated with PNP and MDA. There was evidence of a threshold: difference was only significant above the 80th percentile of PNP concentration (AChE difference per SD increase of metabolite = -0.12 U/mL [95 %CI: 0.20, -0.04]). Likewise, associations with AChE % change were significant only above the 80th percentile of TCPy (AChE % change per SD increase of metabolite = -1.38 % [95 %CI: 2.43 %, -0.32 %]) and PNP -2.47 % [95 %CI: 4.45 %, -0.50 %]). PNP concentration at <=80th percentile was associated with elevated ORs for low AChE activity of 2.9 (95 % CI: 1.5, 5.7) and for AChE inhibition of >= -10 % of 3.7 (95 % CI: 1.4, 9.8). CONCLUSIONS: Urinary organophosphate metabolites, including PNP, TCPy and MDA, particularly at concentrations above the 80th percentile, were associated with lower AChE activity among adolescents. These findings bring attention to the value of using multiple constructs of pesticide exposure in epidemiologic studies.
ESTHER : Skomal_2021_Environ.Res__112163
PubMedSearch : Skomal_2021_Environ.Res__112163
PubMedID: 34627797

Title : Extradural Contralateral C7 Nerve Root Transfer in a Cervical Posterior Approach for Treating Spastic Limb Paralysis: A Cadaver Feasibility Study - Yang_2020_Spine.(Phila.Pa.1976)_45_E608
Author(s) : Yang K , Jiang F , Zhang S , Zhao H , Shi Z , Liu J , Cao X
Ref : Spine (Phila Pa 1976) , 45 :E608 , 2020
Abstract : STUDY DESIGN: Anatomic study in nine fresh-frozen cadavers. OBJECTIVE: To confirm the anatomical feasibility of transferring the extradural ventral roots (VRs) and dorsal roots (DRs) of contralateral C7 nerves to those of the ipsilateral C7 nerves respectively through a cervical posterior approach. SUMMARY OF BACKGROUND DATA: The contralateral C7 nerve root transfer technique makes breakthrough for treating spastic limb paralysis. However, its limitations include large surgical trauma and limited indications. METHODS: Nine fresh-frozen cadavers (four females and five males) were placed prone, and the feasibility of exposing the bilateral extradural C7 nerve roots, separation of the extradural C7 VR and DR, and transfer of the VR and DR of the contralateral C7 to those of the ipsilateral C7 on the dural mater were assessed. The pertinent distances and the myelography results of each specimen were analyzed. The acetylcholinesterase (AChE) and antineurofilament 200 (NF200) double immunofluorescent staining were preformed to determine the nerve fiber properties. RESULTS: A cervical posterior midline approach was made and the laminectomy was performed to expose the bilateral extradural C7 nerve roots. After the extradural C7 VR and DR are separated, the VR and DR of the contralateral C7 have sufficient lengths to be transferred to those of the ipsilateral C7 on the dural mater. The myelography results showed that the spinal cord is not compressed after the nerve anastomosis. The AChE and NF200 double immunofluorescent staining showed the distal ends of the contralateral C7 VRs were mostly motor nerve fibers, and the distal ends of the contralateral C7 DRs were mostly sensory nerve fibers. CONCLUSION: Extradural contralateral C7 nerve root transfer in a cervical posterior approach for treating spastic limb paralysis is anatomically feasible. LEVEL OF EVIDENCE: 5.
ESTHER : Yang_2020_Spine.(Phila.Pa.1976)_45_E608
PubMedSearch : Yang_2020_Spine.(Phila.Pa.1976)_45_E608
PubMedID: 31770316

Title : Per- and polyfluoroalkyl substances exert strong inhibition towards human carboxylesterases - Liu_2020_Environ.Pollut_263_114463
Author(s) : Liu YZ , Pan LH , Bai Y , Yang K , Dong PP , Fang ZZ
Ref : Environ Pollut , 263 :114463 , 2020
Abstract : PFASs are highly persistent in both natural and living environment, and pose a significant risk for wildlife and human beings. The present study was carried out to determine the inhibitory behaviours of fourteen PFASs on metabolic activity of two major isoforms of carboxylesterases (CES). The probe substrates 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) for CES1 and fluorescein diacetate (FD) for CES2 were utilized to determine the inhibitory potentials of PFASs on CES in vitro. The results demonstrated that perfluorododecanoic acid (PFDoA), perfluorotetradecanoic acid (PFTA) and perfluorooctadecanoic acid (PFOcDA) strongly inhibited CES1 and CES2. The half inhibition concentration (IC(50)) value of PFDoA, PFTA and PFOcDA for CES1 inhibition was 10.6 microM, 13.4 microM and 12.6 microM, respectively. The IC(50) for the inhibition of PFDoA, PFTA and PFOcDA towards CES2 were calculated to be 9.56 microM, 17.2 microM and 8.73 microM, respectively. PFDoA, PFTA and PFOcDA exhibited noncompetitive inhibition towards both CES1 and CES2. The inhibition kinetics parameters (K(i)) were 27.7 microM, 26.9 microM, 11.9 microM, 4.04 microM, 29.1 microM, 27.4 microM for PFDoA-CES1, PFTA-CES1, PFOcDA-CES1, PFDoA-CES2, PFTA-CES2, PFOcDA-CES2, respectively. In vitro-in vivo extrapolation (IVIVE) predicted that when the plasma concentrations of PFDoA, PFTA and PFOcDA were greater than 2.77 microM, 2.69 microM and 1.19 microM, respectively, it might interfere with the metabolic reaction catalyzed by CES1 in vivo; when the plasma concentrations of PFDoA, PFTA and PFOcDA were greater than 0.40 microM, 2.91 microM, 2.74 microM, it might interfere with the metabolic reaction catalyzed by CES2 in vivo. Molecular docking was used to explore the interactions between PFASs and CES. In conclusion, PFASs were found to cause inhibitory effects on CES in vitro, and this finding would provide an important experimental basis for further in vivo testing of PFASs focused on CES inhibition endpoints.
ESTHER : Liu_2020_Environ.Pollut_263_114463
PubMedSearch : Liu_2020_Environ.Pollut_263_114463
PubMedID: 32283456

Title : Detoxification enzymes associated with butene-fipronil resistance in Epacromius coerulipes - Jin_2020_Pest.Manag.Sci_76_227
Author(s) : Jin Y , Gao Y , Zhang H , Wang L , Yang K , Dong H
Ref : Pest Manag Sci , 76 :227 , 2020
Abstract : BACKGROUND: Epacromius coerulipes is a widely distributed locust pest species. Chemical control is the main method used to kill locusts; however, this can result in the selection of locusts with resistance to chemical pesticides. Therefore, the study of resistance is of great significance for the sustainable management of locusts. RESULTS: In this study, to investigate the relationship between detoxification enzymes and butene-fipronil resistance in E. coerulipes, resistant strains of the locust were compared with sensitive strains. The synergism of synergistic agents was significantly enhanced, and the activities of multifunctional oxidase, carboxylesterase, and glutathione sulfur transferase were significantly increased. Transcriptome sequencing revealed 226 detoxification enzyme genes and 23 upregulated genes. Neighbor-joining was used to construct a phylogenetic tree of related gene families, which included 59 P450 genes, 52 carboxylesterases (CarE) genes, and 25 glutathione S-transferase (GST) genes. Reverse transcription polymerase chain reaction (RT-PCR) analysis results of overexpressed genes in the resistant population combined with a phylogenetic tree showed that four P450 genes belonged to the CYP6, CYP4, CYP18 and CYP302 families, two CarE genes belonged to Clade A families, and one GST gene belonged to the Sigma family. These family members were annotated as detoxification enzyme genes of metabolic insecticide in the transcriptome databases. CONCLUSIONS: This study showed that P450, CarE and GST together resulted in moderate resistance to butene-fipronil in locusts. The analysis revealed several overexpressed detoxification enzyme genes that will be the focus of future studies on the mechanism of resistance to butene-fipronil. (c) 2019 Society of Chemical Industry.
ESTHER : Jin_2020_Pest.Manag.Sci_76_227
PubMedSearch : Jin_2020_Pest.Manag.Sci_76_227
PubMedID: 31150148

Title : Shielded alpha-Nucleophile Nanoreactor for Topical Decontamination of Reactive Organophosphate - Wong_2020_ACS.Appl.Mater.Interfaces_12_33500
Author(s) : Wong PT , Tang S , Cannon J , Yang K , Harrison R , Ruge M , O'Konek JJ , Choi SK
Ref : ACS Appl Mater Interfaces , 12 :33500 , 2020
Abstract : Here, we describe a nanoscale reactor strategy with a topical application in the therapeutic decontamination of reactive organophosphates (OPs) as chemical threat agents. It involves functionalization of poly(amidoamine) dendrimer through a combination of its partial PEG shielding and exhaustive conjugation with an OP-reactive alpha-nucleophile moiety at its peripheral branches. We prepared a 16-member library composed of two alpha-nucleophile classes (oxime, hydroxamic acid), each varying in its reactor valency (43-176 reactive units per nanoparticle), and linker framework for alpha-nucleophile tethering. Their mechanism for OP inactivation occurred via nucleophilic catalysis as verified against P-O and P-S bonded OPs including paraoxon-ethyl (POX), malaoxon, and omethoate by (1)H NMR spectroscopy. Screening their reactivity for POX inactivation was performed under pH- and temperature-controlled conditions, which resulted in identifying 13 conjugates, each showing shorter POX half-life up to 2 times as compared to a reference Dekon 139 at pH 10.5, 37 degreesC. Of these, 10 conjugates were further confirmed for greater efficacy in POX decontamination experiments performed in two skin models, porcine skin and an artificial human microtissue. Finally, a few lead conjugates were selected and demonstrated for their biocompatibility in vitro as evident with lack of skin absorption, no inhibition of acetylcholinesterase (AChE), and no cytotoxicity in human neuroblastoma cells. In summary, this study presents a novel nanoreactor library, its screening methods, and identification of potent lead conjugates with potential for therapeutic OP decontamination.
ESTHER : Wong_2020_ACS.Appl.Mater.Interfaces_12_33500
PubMedSearch : Wong_2020_ACS.Appl.Mater.Interfaces_12_33500
PubMedID: 32603588

Title : Design, synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors - Xu_2020_Bioorg.Med.Chem.Lett_30_126985
Author(s) : Xu Y , Jian MM , Han C , Yang K , Bai LG , Cao F , Ma ZY
Ref : Bioorganic & Medicinal Chemistry Lett , 30 :126985 , 2020
Abstract : A series of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized, Furthermore, their inhibitory activities against acetylcholinesterase in vitro were tested by Ellman spectrophotometry, and the results of inhibitory activity test showed that most of them had a certain acetylcholinesterase inhibitory activity in vitro. Moreover, the IC50 value of compound 4f was to 0.66 muM, which was higher than that of Rivastigmine and Huperzine-A as reference compounds, and it had a weak inhibitory effect on butyrylcholinesterase. The potential binding mode of compound 4f with AChE was investigated by the molecular docking, and the results showed that 4f was strongly bound up with AChE with the optimal conformation, in addition, their binding energy reached -11.27 Kcal*mol(-1). At last, in silico molecular property of the synthesized compounds were predicted by using Molinspiration online servers. It can be concluded that the lead AChEIs compound 4f presented satisfactory drug-like characteristics.
ESTHER : Xu_2020_Bioorg.Med.Chem.Lett_30_126985
PubMedSearch : Xu_2020_Bioorg.Med.Chem.Lett_30_126985
PubMedID: 32008906

Title : Bisphenol F-Induced Neurotoxicity toward Zebrafish Embryos - Yuan_2019_Environ.Sci.Technol_53_14638
Author(s) : Yuan L , Qian L , Qian Y , Liu J , Yang K , Huang Y , Wang C , Li Y , Mu X
Ref : Environ Sci Technol , 53 :14638 , 2019
Abstract : In this study, the influence of bisphenol F (BPF) toward central nervous system (CNS) was assessed using zebrafish embryos. We found that BPF could induce significant neurotoxicity toward zebrafish embryos, including inhibited locomotion, reduced moving distance, and CNS cell apoptosis at an effective concentration of 0.0005 mg/L. Immunofluorescence assay showed that both microglia and astrocyte in zebrafish brain were significantly activated by BPF, indicating the existence of neuroinflammatory response. Peripheral motor neuron development was significantly inhibited by BPF at 72 hpf. RNA-seq data indicated that neuronal developmental processes and cell apoptosis pathways were significantly affected by BPF exposure, which was consistent with the phenotypic results. Chip-seq assay implied that the transcriptional changes were not mediated by ERalpha. Additionally, no significant change was found in neurotransmitter levels (5-hydroxytryptamine, dopamine, and acetylcholine) or acetylcholinesterase (Ache) enzyme activity after BPF exposure, indicating that BPF may not affect neurotransmission. In conclusion, BPF could lead to abnormal neural outcomes during zebrafish early life stage through inducing neuroinflammation and CNS cell apoptosis even at environmentally relevant concentration.
ESTHER : Yuan_2019_Environ.Sci.Technol_53_14638
PubMedSearch : Yuan_2019_Environ.Sci.Technol_53_14638
PubMedID: 31702913

Title : Hydrophilic scaffolds of oxime as the potent catalytic inactivator of reactive organophosphate - Tang_2019_Chem.Biol.Interact_297_67
Author(s) : Tang S , Wong PT , Cannon J , Yang K , Bowden S , Bhattacharjee S , O'Konek JJ , Choi SK
Ref : Chemico-Biological Interactions , 297 :67 , 2019
Abstract : Despite its efficacy as a skin decontaminant of reactive organophosphates (OP), Dekon 139-a potassium salt of 2,3-butanedione monooxime (DAM)-is associated with adverse events related to percutaneous absorption largely due to its small size and lipophilicity. In order to address this physicochemical issue, we synthesized and evaluated the activity of a focused library of 14 hydrophilic oxime compounds, each designed with either a DAM or monoisonitrosoacetone (MINA) oxime tethered to a polar or charged scaffold in order to optimize the size, hydrophilicity, and oxime acidity. High-throughput colorimetric assays were performed with paraoxon (POX) as a model OP to determine the kinetics of POX inactivation by these compounds under various pH and temperature conditions. This primary screening led to the identification of 6 lead compounds, predominantly in the MINA series, which displayed superb catalytic activity by reducing the POX half-life (t1/2) by 2-3 fold relative to Dekon 139. Our mechanistic studies show that POX inactivation by the oxime compounds occurred faster at a higher temperature and in a pH-dependent manner in which the negatively charged oximate species is>/=10-fold more effective than the neutral oxime species. Lastly, using one of the lead compounds, we demonstrated its promising efficacy for POX decontamination in porcine skin ex vivo, and showed its potent ability to protect acetylcholine esterase (AChE) through POX inactivation. In summary, we report the rational design and chemical biological validation of novel hydrophilic oximes which address an unmet need in therapeutic OP decontamination.
ESTHER : Tang_2019_Chem.Biol.Interact_297_67
PubMedSearch : Tang_2019_Chem.Biol.Interact_297_67
PubMedID: 30393113

Title : A pH-responsive colorimetric strategy for DNA detection by acetylcholinesterase catalyzed hydrolysis and cascade amplification - Guo_2017_Biosens.Bioelectron_94_651
Author(s) : Guo Y , Yang K , Sun J , Wu J , Ju H
Ref : Biosensors & Bioelectronics , 94 :651 , 2017
Abstract : A pH-responsive colorimetric strategy was designed for sensitive and convenient biosensing by introducing acetylcholinesterase (AChE) catalyzed hydrolysis of acetylcholine to change solution pH and phenol red as an indicator. Using DNA as a target model, this technique was successfully employed for sensitive DNA analysis by labeling AChE to DNA. The sensitivity could be greatly improved by coupling a newly designed magnetic probe with target DNA-triggered nonenzymatic cascade amplification. In the presence of a help DNA (H) and the functional probe, the cascade assembly via toehold-mediated strand displacement released the AChE-conjugated sequence from magnetic beads, which could be simply separated from the reaction mixture to catalyze the hydrolysis of ACh in detection solution. The color change of detection solution from pink to orange-red, orange-yellow and ultimately yellow could be used for target DNA detection by naked eye and colorimetry with the absorbance ratio of detection solution at 558nm to 432nm as the signal. The nonenzymatically sensitized colorimetric strategy showed a linear range from 50pM to 50nM with a detection limit of 38pM, indicating a promising application in DNA analysis.
ESTHER : Guo_2017_Biosens.Bioelectron_94_651
PubMedSearch : Guo_2017_Biosens.Bioelectron_94_651
PubMedID: 28388529

Title : Enzymatic Hydrolytic Resolution of Racemic Ibuprofen Ethyl Ester Using an Ionic Liquid as Cosolvent - Wei_2016_Molecules_21_
Author(s) : Wei T , Yang K , Bai B , Zang J , Yu X , Mao D
Ref : Molecules , 21 : , 2016
Abstract : The aim of this study was to develop an ionic liquid (IL) system for the enzymatic resolution of racemic ibuprofen ethyl ester to produce (S)-ibuprofen. Nineteen ILs were selected for use in buffer systems to investigate the effects of ILs as cosolvents for the production of (S)-ibuprofen using thermostable esterase (EST10) from Thermotoga maritima. Analysis of the catalytic efficiency and conformation of EST10 showed that [OmPy][BF(4)] was the best medium for the EST10-catalyzed production of (S)-ibuprofen. The maximum degree of conversion degree (47.4%), enantiomeric excess of (S)-ibuprofen (96.6%) and enantiomeric ratio of EST10 (177.0) were achieved with an EST10 concentration of 15 mg/mL, racemic ibuprofen ethyl ester concentration of 150 mM, at 75 degrees C , with a reaction time of 10 h. The reaction time needed to achieve the highest yield of (S)-ibuprofen was decreased from 24 h to 10 h. These results are relevant to the proposed application of ILs as solvents for the EST10-catalyzed production of (S)-ibuprofen.
ESTHER : Wei_2016_Molecules_21_
PubMedSearch : Wei_2016_Molecules_21_
PubMedID: 27420042

Title : Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity - Jenson_2015_Neuropharmacol_90_23
Author(s) : Jenson D , Yang K , Acevedo-Rodriguez A , Levine A , Broussard JI , Tang J , Dani JA
Ref : Neuropharmacology , 90 :23 , 2015
Abstract : Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and beta-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors.
ESTHER : Jenson_2015_Neuropharmacol_90_23
PubMedSearch : Jenson_2015_Neuropharmacol_90_23
PubMedID: 25445492

Title : Identification of Alp1U and Lom6 as epoxy hydrolases and implications for kinamycin and lomaiviticin biosynthesis - Wang_2015_Nat.Commun_6_7674
Author(s) : Wang B , Guo F , Ren J , Ai G , Aigle B , Fan K , Yang K
Ref : Nat Commun , 6 :7674 , 2015
Abstract : The naturally occurring diazobenzofluorenes, kinamycins, fluostatins and lomaiviticins, possess highly oxygenated A-rings, via which the last forms a dimeric pharmacophore. However, neither the A-ring transformation nor the dimerization mechanisms have been explored thus far. Here we propose a unified biosynthetic logic for the three types of antibiotics and verify one key reaction via detailed genetic and enzymatic experiments. Alp1U and Lom6 from the kinamycin and lomaiviticin biosynthesis, respectively, are shown to catalyse epoxy hydrolysis on a substrate that is obtained by chemical deacetylation of a kinamycin-pathway-derived intermediate. Thus, our study provides the first evidence for the existence of an epoxy intermediate in lomaiviticin biosynthesis. Furthermore, our results suggest that the dimerization in the lomaiviticin biosynthesis proceeds after dehydration of a product generated by Lom6.
ESTHER : Wang_2015_Nat.Commun_6_7674
PubMedSearch : Wang_2015_Nat.Commun_6_7674
PubMedID: 26134788
Gene_locus related to this paper: 9actn-h1q5r8 , stram-q1rqu8

Title : Genome sequencing of adzuki bean (Vigna angularis) provides insight into high starch and low fat accumulation and domestication - Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_13213
Author(s) : Yang K , Tian Z , Chen C , Luo L , Zhao B , Wang Z , Yu L , Li Y , Sun Y , Li W , Chen Y , Zhang Y , Ai D , Zhao J , Shang C , Ma Y , Wu B , Wang M , Gao L , Sun D , Zhang P , Guo F , Wang W , Wang J , Varshney RK , Ling HQ , Wan P
Ref : Proc Natl Acad Sci U S A , 112 :13213 , 2015
Abstract : Adzuki bean (Vigna angularis), an important legume crop, is grown in more than 30 countries of the world. The seed of adzuki bean, as an important source of starch, digestible protein, mineral elements, and vitamins, is widely used foods for at least a billion people. Here, we generated a high-quality draft genome sequence of adzuki bean by whole-genome shotgun sequencing. The assembled contig sequences reached to 450 Mb (83% of the genome) with an N50 of 38 kb, and the total scaffold sequences were 466.7 Mb with an N50 of 1.29 Mb. Of them, 372.9 Mb of scaffold sequences were assigned to the 11 chromosomes of adzuki bean by using a single nucleotide polymorphism genetic map. A total of 34,183 protein-coding genes were predicted. Functional analysis revealed that significant differences in starch and fat content between adzuki bean and soybean were likely due to transcriptional abundance, rather than copy number variations, of the genes related to starch and oil synthesis. We detected strong selection signals in domestication by the population analysis of 50 accessions including 11 wild, 11 semiwild, 17 landraces, and 11 improved varieties. In addition, the semiwild accessions were illuminated to have a closer relationship to the cultigen accessions than the wild type, suggesting that the semiwild adzuki bean might be a preliminary landrace and play some roles in the adzuki bean domestication. The genome sequence of adzuki bean will facilitate the identification of agronomically important genes and accelerate the improvement of adzuki bean.
ESTHER : Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_13213
PubMedSearch : Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_13213
PubMedID: 26460024
Gene_locus related to this paper: phaan-a0a0l9ttq5 , phaan-a0a0l9vh69 , phaan-a0a0l9vh89 , phaan-a0a0s3tc53 , vigrr-a0a1s3v914 , phaan-a0a0s3s998 , phaan-a0a0s3siv8 , phaan-a0a0l9uys5 , phaan-a0a0s3rp07 , phaan-a0a0s3rbq0 , vigrr-a0a1s3tul4 , phaan-a0a0s3smk7 , phaan-a0a0s3slm9 , phaan-a0a0l9ujf5 , phaan-a0a0l9til9 , phaan-a0a0l9uqr2 , phaan-a0a0l9v1m8 , phaan-a0a0l9uc60 , phaan-a0a0l9ucr8

Title : An antenna-biased carboxylesterase is specifically active to plant volatiles in Spodoptera exigua - He_2015_Pestic.Biochem.Physiol_123_93
Author(s) : He P , Zhang YN , Yang K , Li ZQ , Dong SL
Ref : Pestic Biochem Physiol , 123 :93 , 2015
Abstract : Odorant-degrading enzymes (ODEs) in sensillar lymph are proposed to play important roles in the maintenance of the sensitivity of the olfactory sensilla, by timely degrading the odorants that have already fulfilled the activation of the odorant receptor (OR). Here we reported the cloning and characterization of an ODE gene (SexiCXE10) from the polyphagous insect pest Spodoptera exigua. SexiCXE10 is a carboxylesterase (CXE) gene, encoding a protein with 538 amino acid residues, and bearing typical characteristics of Carboxyl/cholinesterase (CCE, EC 3.1.1.1.) gene family. Tissue-temporal expression pattern by qPCR revealed that the SexiCXE10 mRNA was highly antenna biased, and maintained at high level throughout the adult stage. Further fluorescence in situ hybridization demonstrated that SexiCXE10 mRNA signal was detected under sensilla basiconica and short and long sensilla trichodea. Finally, enzymatic study using purified recombinant enzyme showed that SexiCXE10 had high activity specifically for ester plant volatiles with 7-10 carbon atoms, while no activity was found with S. exigua sex pheromone components and plant volatiles with more carbon atoms. In addition, SexiCXE10 displayed lower activity at acidic pH (pH 5.0), while higher activity was found at neutral and alkaline conditions (pH 6.5-9.0). Our results suggest that SexiCXE10 may play an important role in the degradation of the host plant volatiles, and thus contributes to the high sensitivity of the olfactory system in S. exigua. Meanwhile, the CXE would be a potential target for developing behavioral antagonists and pesticides against S. exigua.
ESTHER : He_2015_Pestic.Biochem.Physiol_123_93
PubMedSearch : He_2015_Pestic.Biochem.Physiol_123_93
PubMedID: 26267057
Gene_locus related to this paper: spoex-g1c2i6

Title : Plant-Generated Artificial Small RNAs Mediated Aphid Resistance - Guo_2014_PLoS.One_9_e97410
Author(s) : Guo H , Song X , Wang G , Yang K , Wang Y , Niu L , Chen X , Fang R
Ref : PLoS ONE , 9 :e97410 , 2014
Abstract : BACKGROUND: RNA silencing is an important mechanism for regulation of endogenous gene expression and defense against genomic intruders in plants. This natural defense system was adopted to generate virus-resistant plants even before the mechanism of RNA silencing was unveiled. With the clarification of that mechanism, transgenic antiviral plants were developed that expressed artificial virus-specific hairpin RNAs (hpRNAs) or microRNAs (amiRNAs) in host plants. Previous works also showed that plant-mediated RNA silencing technology could be a practical method for constructing insect-resistant plants by expressing hpRNAs targeting essential genes of insects. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we chose aphid Myzus persicae of order Hemiptera as a target insect. To screen for aphid genes vulnerable to attack by plant-mediated RNA silencing to establish plant aphid resistance, we selected nine genes of M. persicae as silencing targets, and constructed their hpRNA-expressing vectors. For the acetylcholinesterase 2 coding gene (MpAChE2), two amiRNA-expressing vectors were also constructed. The vectors were transformed into tobacco plants (Nicotiana tabacum cv. Xanti). Insect challenge assays showed that most of the transgenic plants gained aphid resistance, among which those expressing hpRNAs targeting V-type proton ATPase subunit E-like (V-ATPaseE) or tubulin folding cofactor D (TBCD) genes displayed stronger aphicidal activity. The transgenic plants expressing amiRNAs targeting two different sites in the MpAChE2 gene exhibited better aphid resistance than the plants expressing MpAChE2-specific hpRNA. CONCLUSIONS/SIGNIFICANCE: Our results indicated that plant-mediated insect-RNA silencing might be an effective way to develop plants resistant to insects with piercing-sucking mouthparts, and both the selection of vulnerable target genes and the biogenetic type of the small RNAs were crucial for the effectiveness of aphid control. The expression of insect-specific amiRNA is a promising and preferable approach to engineer plants resistant to aphids and, possibly, to other plant-infesting insects.
ESTHER : Guo_2014_PLoS.One_9_e97410
PubMedSearch : Guo_2014_PLoS.One_9_e97410
PubMedID: 24819752

Title : An antennae-enriched carboxylesterase from Spodoptera exigua displays degradation activity in both plant volatiles and female sex pheromones - He_2014_Insect.Mol.Biol_23_475
Author(s) : He P , Zhang YN , Li ZQ , Yang K , Zhu JY , Liu SJ , Dong SL
Ref : Insect Molecular Biology , 23 :475 , 2014
Abstract : Carboxyl/cholinesterase (CCE) is a large gene family of diverse functions, but in insects its function with respect to catabolism of sex pheromone components and plant volatiles is not well understood. In the present study, we cloned and functionally characterized one putative odorant-degrading enzyme (ODE) of the CCE family, SexiCXE14, from Spodoptera exigua. The tissue-temporal expression pattern revealed that the mRNA level of SexiCXE14 is antennae-enriched, sex equivalent and peaks at 3 days after moth eclosion. Functional study using the recombinant enzyme determined that SexiCXE14 has high degrading activity (Vmax ) to host plant volatiles, suggesting its role in degradation of these volatiles. In addition, SexiCXE14 may also play a role in the degradation of sex pheromone components, as the Vmax and affinity parameter (Km ) values with the sex pheromones are similar to those of reported pheromone degrading enzymes (PDEs). Further analysis of the relationship between substrate structure and enzymatic activity demonstrated that carbon chain length is a major influential factor, while the number of double bonds also affects the enzymatic activity. In addition, SexiCXE14 displays lower activity at acidic pH levels (pH 5.0) than in neutral conditions (pH 6.5). By characterizing this new ODE the present study provides insights in understanding of the high sensitivity of the moth olfactory system.
ESTHER : He_2014_Insect.Mol.Biol_23_475
PubMedSearch : He_2014_Insect.Mol.Biol_23_475
PubMedID: 24628907

Title : mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells - Yang_2014_BMC.Pulm.Med_14_53
Author(s) : Yang K , Song Y , Tang YB , Xu ZP , Zhou W , Hou LN , Zhu L , Yu ZH , Chen HZ , Cui YY
Ref : BMC Pulm Med , 14 :53 , 2014
Abstract : BACKGROUND: Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist.
METHODS: Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated usingwestern blot and immunofluorescence analyses.
RESULTS: Decreased E-cadherin expression and increased vimentin and alpha-SMA expression induced by TGF-beta1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-beta1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-beta1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP.
CONCLUSIONS: Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs.
ESTHER : Yang_2014_BMC.Pulm.Med_14_53
PubMedSearch : Yang_2014_BMC.Pulm.Med_14_53
PubMedID: 24678619

Title : Brain MRI of nasal MOG therapeutic effect in relapsing-progressive EAE - Levy_2014_Exp.Neurol_255_63
Author(s) : Levy Barazany H , Barazany D , Puckett L , Blanga-Kanfi S , Borenstein-Auerbach N , Yang K , Peron JP , Weiner HL , Frenkel D
Ref : Experimental Neurology , 255 :63 , 2014
Abstract : Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) considered to be a T cell-mediated autoimmune disease. Mucosally administered antigens induce regulatory T cells that secrete anti-inflammatory cytokines at the anatomic site where the mucosally administered Ag is located. We have previously reported in a mouse model of stroke that nasal treatment with MOG35-55 peptide reduces ischemic infarct size and improves behavior, by inducing IL-10-secreting T cells. We have also demonstrated that an experimental autoimmune encephalomyelitis (EAE) model in non-obese diabetic (NOD) mice leads to a relapsing progressive disease and that brain lesions can be visualized noninvasively by magnetic resonance imaging (MRI). Here, we investigated whether nasal treatment with 25mug of MOG35-55 after the first attack affects clinical progression and MRI outcome in the NOD model. We found that nasal MOG35-55 treatment administered three times after the first attack and then weekly reduced both the peak clinical disease score and clinical score during remission. Pathology revealed less infiltration of cells and reduction in white-matter damage as measured by Luxol blue staining in treated animals. This model is unique in that there are lesions in the corpus callosum, external capsule, fimbria, internal capsule and thalamus, which is analogous to what is observed in MS. MRI of individual animals using fractional anisotropy (FA) and T1-gadolinum (T1-Gd) imaging was able to identify lesions in all of these anatomic areas, and we found lower levels of brain pathology by MRI in treated mice with both methods. Our results indicate a beneficial effect of nasal MOG on relapsing-progressive EAE and demonstrate that non-invasive MRI imaging may be used to monitor treatment of ongoing disease in this model for testing new therapies for MS.
ESTHER : Levy_2014_Exp.Neurol_255_63
PubMedSearch : Levy_2014_Exp.Neurol_255_63
PubMedID: 24552689

Title : Functional characterization of an antennal esterase from the noctuid moth, Spodoptera exigua - He_2014_Arch.Insect.Biochem.Physiol_86_85
Author(s) : He P , Zhang J , Li ZQ , Zhang YN , Yang K , Dong SL
Ref : Archives of Insect Biochemistry & Physiology , 86 :85 , 2014
Abstract : Odorant-degrading esterases (ODEs) act in the fast deactivation of ester pheromone components and plant volatiles in insects. However, only few ODEs have been characterised to date. In this study, six full-length putative ODE genes (designated SexiCXE4, 5, 17, 18, 20, and 31) were cloned from the male antennae of Spodoptera exigua. The deduced amino acid sequences possessed typical characteristics of a carboxylesterase (CXE) and shared high identities with reported insect CXEs. The tissue and temporal expression patterns were investigated by quantitative real time PCR. Although all six SexiCXEs are expressed in antennae of both sexes, SexiCXE4, 17 and 20 are antennae-enriched; while SexiCXE5 and SexiCXE18 are dominantly expressed in wings, and SexiCXE31 is mainly expressed in proboscises, heads and legs. With the highly biased expression in antennae and proboscises, SexiCXE4 was selected for further functional assay. The recombinant SexiCXE4 were expressed in High-five cells and purified by a Ni(2+) affinity column. SexiCXE4 has much higher enzyme activity against plant volatiles (Z)-3-hexenyl acetate and hexyl acetate than to the sex pheromone components, suggesting that it may function mostly in the degradation of the plant volatiles.
ESTHER : He_2014_Arch.Insect.Biochem.Physiol_86_85
PubMedSearch : He_2014_Arch.Insect.Biochem.Physiol_86_85
PubMedID: 24753123

Title : Dopamine D1 and D5 receptors modulate spike timing-dependent plasticity at medial perforant path to dentate granule cell synapses - Yang_2014_J.Neurosci_34_15888
Author(s) : Yang K , Dani JA
Ref : Journal of Neuroscience , 34 :15888 , 2014
Abstract : Although evidence suggests that DA modulates hippocampal function, the mechanisms underlying that dopaminergic modulation are largely unknown. Using perforated-patch electrophysiological techniques to maintain the intracellular milieu, we investigated how the activation of D1-type DA receptors regulates spike timing-dependent plasticity (STDP) of the medial perforant path (mPP) synapse onto dentate granule cells. When D1-type receptors were inhibited, a relatively mild STDP protocol induced LTP only within a very narrow timing window between presynaptic stimulation and postsynaptic response. The stimulus protocol produced timing-dependent LTP (tLTP) only when the presynaptic stimulation was followed 30 ms later by depolarization-induced postsynaptic action potentials. That is, the time between presynaptic stimulation and postsynaptic response was 30 ms (Deltat = +30 ms). When D1-type receptors were activated, however, the same mild STDP protocol induced tLTP over a much broader timing window: tLTP was induced when -30 ms </= Deltat </= +30 ms. The result indicated that D1-type receptor activation enabled synaptic potentiation even when postsynaptic activity preceded presynaptic stimulation within this Deltat range. Results with null mice lacking the Kv4.2 potassium channel and with the potassium channel inhibitor, 4-aminopyridine, suggested that D1-type receptors enhanced tLTP induction by suppressing the transient IA-type K(+) current. Results obtained with antagonists and DA receptor knock-out mice indicated that endogenous activity of both D1 and D5 receptors modulated plasticity in the mPP. The DA D5 receptors appeared particularly important in regulating plasticity of the mPP onto the dentate granule cells.
ESTHER : Yang_2014_J.Neurosci_34_15888
PubMedSearch : Yang_2014_J.Neurosci_34_15888
PubMedID: 25429131

Title : Association of polymorphisms in prolylcarboxypeptidase and chymase genes with essential hypertension in the Chinese Han population - Wu_2013_J.Renin.Angiotensin.Aldosterone.Syst_14_263
Author(s) : Wu Y , Yang H , Yang B , Yang K , Xiao C
Ref : J Renin Angiotensin Aldosterone Syst , 14 :263 , 2013
Abstract : INTRODUCTION: The prolylcarboxypeptidase (PRCP) gene encodes a membrane protein that acts on angiotensin II (Ang II) and kallikrein to release vasoactive peptides. The chymase (CMA1) gene is important for Ang II generation. Therefore, the two genes might be involved in the pathogenesis of essential hypertension (EH). MATERIALS AND METHODS: Eleven tag single nucleotide polymorphisms (SNPs) in the PRCP gene and four tag SNPs and G-1903A (rs1800875) polymorphism in the CMA1 gene were genotyped in the Chinese Han population (n=1020) using a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: In the PRCP gene, single site analyses indicated that the rs7104980 G allele was a susceptible factor for EH (adjusted odds ratio (OR)=1.98, 95% confidence interval (CI) 1.62-2.43, p=0.3x10(-10)). The protective effect of Hap3 GAGCACTAACA was observed without carrying the susceptible rs7104908 G allele (OR=0.67, 95% CI 0.56-0.81, p=0.3x10(-4)) by haplotype analyses. In the case of the CMA1 gene, no associations with EH were found through single site analyses. However, haplotype analyses showed that Hap16 TTTA significantly increased the risk of EH with OR=3.15 (p=0.0002) which may be driven by interaction with a nearby SNP combination. CONCLUSIONS: The present results indicated PRCP rs7104980 can be considered as a marker for EH and Hap3 GAGCACTAACA (PRCP) and Hap16 TTTA (CMA1) might be associated with EH in Chinese Han population.
ESTHER : Wu_2013_J.Renin.Angiotensin.Aldosterone.Syst_14_263
PubMedSearch : Wu_2013_J.Renin.Angiotensin.Aldosterone.Syst_14_263
PubMedID: 22679278
Gene_locus related to this paper: human-PRCP

Title : TNF-alpha-induced CXCL8 production by A549 cells: Involvement of the non-neuronal cholinergic system - Xu_2012_Pharmacol.Res_68_16
Author(s) : Xu ZP , Devillier P , Xu GN , Qi H , Zhu L , Zhou W , Hou LN , Tang YB , Yang K , Yu ZH , Chen HZ , Cui YY
Ref : Pharmacol Res , 68 :16 , 2012
Abstract : It was recently suggested that the non-neuronal cholinergic system has a regulatory role in pulmonary inflammation. We investigated this system's involvement in the control of cytokine production by the A549 human alveolar epithelial cell line. CXCL8 and acetylcholine (ACh) concentrations were measured using ELISA and LC-MS/MS, respectively. The mRNA expression of muscarinic receptor (MR) subtypes was determined using RT-PCR. In A549 cells, TNF-alpha increased the release of CXCL8 and ACh and the expression of the subtype 3 MR (M3R). Furthermore, TNF-alpha-induced CXCL8 secretion was (i) inhibited by the MR antagonist tiotropium and the M3R antagonist 4-DAMP and (ii) enhanced by the M1/M3R agonist pilocarpine and the cholinesterase inhibitor physostigmine. Taken as a whole, these results suggest that ACh release by A549 cells enhances TNF-alpha-induced CXCL8 secretion through activation of the M3R. Western blot analysis revealed that pilocarpine and physostigmine enhanced the TNF-alpha-induced phosphorylation of ERK1/2 and p38 MAPK and the degradation of IkappaBalpha. Inhibition of these pathways with specific inhibitors abrogated the pilocarpine-induced CXCL8 release. Our results suggest that the TNF-alpha-induced secretion of CXCL8 in A549 cells is regulated by the release of ACh, the latter's binding to the M3R and the downstream activation of NF-kappaB and the ERK1/2 and p38 MAPK signaling pathways. Our findings suggest that MR antagonists may have anti-inflammatory effects by preventing pro-inflammatory events driven by endogenous, non-neuronal ACh.
ESTHER : Xu_2012_Pharmacol.Res_68_16
PubMedSearch : Xu_2012_Pharmacol.Res_68_16
PubMedID: 23142559

Title : Functional nicotinic acetylcholine receptors containing alpha6 subunits are on GABAergic neuronal boutons adherent to ventral tegmental area dopamine neurons - Yang_2011_J.Neurosci_31_2537
Author(s) : Yang K , Buhlman L , Khan GM , Nichols RA , Jin G , McIntosh JM , Whiteaker P , Lukas RJ , Wu J
Ref : Journal of Neuroscience , 31 :2537 , 2011
Abstract : Diverse nicotinic acetylcholine receptor (nAChR) subtypes containing different subunit combinations can be placed on nerve terminals or soma/dendrites in the ventral tegmental area (VTA). nAChR alpha6 subunit message is abundant in the VTA, but alpha6*-nAChR cellular localization, function, pharmacology, and roles in cholinergic modulation of dopaminergic (DA) neurons within the VTA are not well understood. Here, we report evidence for alpha6beta2*-nAChR expression on GABA neuronal boutons terminating on VTA DA neurons. alpha-Conotoxin (alpha-Ctx) MII labeling coupled with immunocytochemical staining localizes putative alpha6*-nAChRs to presynaptic GABAergic boutons on acutely dissociated, rat VTA DA neurons. Functionally, acetylcholine (ACh) induces increases in the frequency of bicuculline-, picrotoxin-, and 4-aminopyridine-sensitive miniature IPSCs (mIPSCs) mediated by GABA(A) receptors. These increases are abolished by alpha6*-nAChR-selective alpha-Ctx MII or alpha-Ctx PIA (1 nm) but not by alpha7 (10 nm methyllycaconitine) or alpha4* (1 mum dihydro-beta-erythroidine)-nAChR-selective antagonists. ACh also fails to increase mIPSC frequency in VTA DA neurons prepared from nAChR beta2 knock-out mice. Moreover, ACh induces an alpha-Ctx PIA-sensitive elevation in intraterminal Ca(2+) in synaptosomes prepared from the rat VTA. Subchronic exposure to 500 nm nicotine reduces ACh-induced GABA release onto the VTA DA neurons, as does 10 d of systemic nicotine exposure. Collectively, these results indicate that alpha6beta2*-nAChRs are located on presynaptic GABAergic boutons within the VTA and modulate GABA release onto DA neurons. These presynaptic alpha6beta2*-nAChRs likely play important roles in nicotinic modulation of DA neuronal activity.
ESTHER : Yang_2011_J.Neurosci_31_2537
PubMedSearch : Yang_2011_J.Neurosci_31_2537
PubMedID: 21325521

Title : Exposure of nicotine to ventral tegmental area slices induces glutamatergic synaptic plasticity on dopamine neurons - Jin_2011_Synapse_65_332
Author(s) : Jin Y , Yang K , Wang H , Wu J
Ref : Synapse , 65 :332 , 2011
Abstract : Nicotine promotes glutamatergic synaptic plasticity in dopaminergic (DA) neurons in the ventral tegmental area (VTA), which is thought to be an important mechanism underlying nicotine reward. However, it is unclear whether exposure of nicotine alone to VTA slice is sufficient to increase glutamatergic synaptic strength on DA neurons and which nicotinic acetylcholine receptor (nAChR) subtype mediates this effect. Here, we report that the incubation of rat VTA slices with 500 nM nicotine induces glutamatergic synaptic plasticity in DA neurons. We measure the ratio of AMPA and NMDA receptor-mediated currents (AMPA/NMDA) and compare these ratios between nicotine-treated and -untreated slices. Our results demonstrate that the incubation of VTA slices with 500 nM nicotine for 1 h (but not for 10 min) significantly increases the AMPA/NMDA ratio when compared with controls. Preincubation with 10 nM of the alpha7-nAChR antagonist, methyllycaconitine (MLA) but not 1 muM alpha4-containing nAChR antagonist, dihydro-beta-erythroidine (DHbetaE) prevents nicotinic effect, suggesting that alpha7-nAChRs are mainly mediated this nicotinic effect. This finding is further supported by the disappearance of this nicotinic effect in nAChR alpha7 knockout (KO) mice. Furthermore, nicotine reduced paired-pulse ratio (PPR) of evoked excitatory postsynaptic potential (eEPSP) in the VTA slices prepared from wild-type (WT) mice but not alpha7 KO mice. Collectively, these findings suggest that exposure of smoking-relevant concentrations of nicotine to VTA slices is sufficient to increase glutamatergic synaptic strength on DA neurons and that alpha7-nAChRs likely mediate this nicotinic effect through increasing presynaptic release of glutamate.
ESTHER : Jin_2011_Synapse_65_332
PubMedSearch : Jin_2011_Synapse_65_332
PubMedID: 20730803

Title : Potential antiosteoporosis effect of biodegradable magnesium implanted in STZ-induced diabetic rats - Yang_2011_J.Biomed.Mater.Res.A_99_386
Author(s) : Yang W , Zhang Y , Yang J , Tan L , Yang K
Ref : J Biomed Mater Res A , 99 :386 , 2011
Abstract : Pure magnesium (Mg) was implanted intramedullary into the femur of streptozotocin (STZ)-induced diabetic rats to investigate its effect on bone growth after 6 weeks degradation. The experimental results showed that the femoral BMD in diabetic rats was significantly lower than that in controls (p < 0.01) but restored notably by Mg implantation. The contents of calcium (Ca), phosphorus (P), Mg, zinc (Zn), potassium (K), strontium (Sr), and sulfur (S) in bone of diabetic group were significantly lower than those in controls but remarkably increased with implantation of Mg. The residual weight calculation showed that 29.41% of Mg was degraded in vivo. The energy dispersive X-ray spectroscopy (EDS) analysis showed that the reaction layer on the surface of the Mg implant mainly consisted of C, Ca, O, P, and Mg. Besides, serum Mg level was significantly decreased in diabetic group compared with the control group but increased by Mg treatment. Also, there were no significant differences in body weight and blood glucose, as well as blood glycosylated hemoglobin (HbAIc%), serum Ca, alanine aminitransperase (ALT), aspartate aminotransferase (AST), uric acid (UA), nonesterified fatty acid (NEFA), cholinesterase (CHE), and creatinine (CR) levels between diabetic and Mg-implanted rats. The study indicated that Mg implant had no obvious toxicity in STZ-induced diabetic rats and may act as a potential agent to treat osteoporosis.
ESTHER : Yang_2011_J.Biomed.Mater.Res.A_99_386
PubMedSearch : Yang_2011_J.Biomed.Mater.Res.A_99_386
PubMedID: 22021186

Title : CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance - Brown_2010_J.Lipid.Res_51_3306
Author(s) : Brown JM , Betters JL , Lord C , Ma Y , Han X , Yang K , Alger HM , Melchior J , Sawyer J , Shah R , Wilson MD , Liu X , Graham MJ , Lee R , Crooke R , Shulman GI , Xue B , Shi H , Yu L
Ref : J Lipid Res , 51 :3306 , 2010
Abstract : Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in approximately 80-95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels approximately 4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance.
ESTHER : Brown_2010_J.Lipid.Res_51_3306
PubMedSearch : Brown_2010_J.Lipid.Res_51_3306
PubMedID: 20802159
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Title : Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area - Gao_2010_J.Neurosci_30_13814
Author(s) : Gao M , Jin Y , Yang K , Zhang D , Lukas RJ , Wu J
Ref : Journal of Neuroscience , 30 :13814 , 2010
Abstract : Systemic exposure to nicotine induces glutamatergic synaptic plasticity on dopamine (DA) neurons in the ventral tegmental area (VTA), but mechanisms are largely unknown. Here, we report that single, systemic exposure in rats to nicotine (0.17 mg/kg free base) increases the ratio of DA neuronal currents mediated by AMPA relative to NMDA receptors (AMPA/NMDA ratio) assessed 24 h later, based on slice-patch recording. The AMPA/NMDA ratio increase is evident within 1 h and lasts for at least 72 h after nicotine exposure (and up to 8 d after repeated nicotine administration). This effect cannot be prevented by systemic injection of either alpha7-nAChR (nicotinic ACh receptor)-selective [methyllycaconitine (MLA)] or beta2*-nAChR-selective [mecamylamine (MEC)] antagonists but is prevented by coinjection of MLA and MEC. In either nAChR alpha7 or beta2 subunit knock-out mice, systemic exposure to nicotine still increases the AMPA/NMDA ratio. Preinjection in rats of a NMDA receptor antagonist MK-801((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), but neither DA receptor antagonists [SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) plus haloperidol] nor a calcineurin inhibitor (cyclosporine), prevents the nicotine-induced increase in AMPA/NMDA ratio. After systemic exposure to nicotine, glutamatergic (but not GABAergic) transmission onto rat VTA DA neuronal inputs is enhanced. Correspondingly, DA neuronal firing measured 24 h after nicotine exposure using extracellular single-unit recording in vivo is significantly faster, and there is conversion of silent to active DA neurons. Collectively, these findings demonstrate that systemic nicotine acting via either alpha7- or beta2*-nAChRs increases presynaptic and postsynaptic glutamatergic function, and consequently initiates glutamatergic synaptic plasticity, which may be an important, early neuronal adaptation in nicotine reward and reinforcement.
ESTHER : Gao_2010_J.Neurosci_30_13814
PubMedSearch : Gao_2010_J.Neurosci_30_13814
PubMedID: 20943922

Title : The anticonvulsive drug lamotrigine blocks neuronal {alpha}4{beta}2 nicotinic acetylcholine receptors - Zheng_2010_J.Pharmacol.Exp.Ther_335_401
Author(s) : Zheng C , Yang K , Liu Q , Wang MY , Shen J , Valles AS , Lukas RJ , Barrantes FJ , Wu J
Ref : Journal of Pharmacology & Experimental Therapeutics , 335 :401 , 2010
Abstract : Lamotrigine (LTG), an anticonvulsive drug, is often used for the treatment of a variety of epilepsies. In addition to block of sodium channels, LTG may act on other targets to exert its antiepileptic effect. In the present study, we evaluated the effects of LTG on neuronal nicotinic acetylcholine receptors (nAChRs) using the patch-clamp technique on human alpha4beta2-nAChRs heterologously expressed in the SH-EP1 cell line and on native alpha4beta2-nAChRs in dopaminergic (DA) neurons in rat ventral tegmental area (VTA). In SH-EP1 cells, LTG diminished the peak and steady-state components of the inward alpha4beta2-nAChR-mediated currents. This effect exhibited concentration-, voltage- and use-dependent behavior. Nicotine dose-response curves showed that in the presence of LTG, the nicotine-induced maximal current was reduced, suggesting a noncompetitive inhibition. These findings suggest that LTG inhibits human neuronal alpha4beta2-nAChR function through an open-channel blocking mechanism. LTG-induced inhibition in alpha4beta2-nAChRs was more profound when preceded by a 2-min pretreatment, after which the nicotine-induced current was reduced even without coapplication of LTG, suggesting that LTG is also able to inhibit alpha4beta2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited alpha4beta2-nAChR-mediated currents but did not affect glutamate- or GABA-induced currents, indicating that LTG selectively inhibits nAChR function. Collectively, our data suggest that the neuronal alpha4beta2-nAChR is likely an important target for mediating the anticonvulsive effect of LTG and the blockade of alpha4beta2-nAChR possibly underlying the mechanism through which LTG effectively controls some types of epilepsy, such as autosomal dominant nocturnal frontal lobe epilepsy or juvenile myoclonic epilepsy.
ESTHER : Zheng_2010_J.Pharmacol.Exp.Ther_335_401
PubMedSearch : Zheng_2010_J.Pharmacol.Exp.Ther_335_401
PubMedID: 20688974

Title : Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons - Yang_2009_J.Physiol_587_345
Author(s) : Yang K , Hu J , Lucero L , Liu Q , Zheng C , Zhen X , Jin G , Lukas RJ , Wu J
Ref : Journal of Physiology , 587 :345 , 2009
Abstract : Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch-clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole-cell current kinetics and pharmacology. Kinetic analysis demonstrated that comparing to ID, IID receptor-mediated current had faster activation and decay constant and IIID receptor-mediated current had larger current density. Pharmacologically, ID receptor-mediated current was sensitive to the alpha4beta2-nAChR agonist RJR-2403 and antagonist dihydro-beta-erythroidine (DHbetaE); IID receptor-mediated current was sensitive to the selective alpha7-nAChR agonist choline and antagonist methyllycaconitine (MLA); while IIID receptor-mediated current was sensitive to the beta4-containing nAChR agonist cytisine and antagonist mecamylamine (MEC). The agonist concentration-response relationships demonstrated that IID receptor-mediated current exhibited the highest EC(50) value compared to ID and IIID receptors, suggesting a relatively low agonist affinity of type IID receptors. These results suggest that the type ID, IID and IIID nAChR-mediated currents are predominately mediated by activation of alpha4beta2-nAChR, alpha7-nAChR and a novel nAChR subtype(s), respectively. Collectively, these findings indicate that the VTA DAergic neurons express diversity and multiplicity of functional nAChR subtypes. Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence.
ESTHER : Yang_2009_J.Physiol_587_345
PubMedSearch : Yang_2009_J.Physiol_587_345
PubMedID: 19047205

Title : Lysosomal phospholipase A2 and phospholipidosis - Hiraoka_2006_Mol.Cell.Biol_26_6139
Author(s) : Hiraoka M , Abe A , Lu Y , Yang K , Han X , Gross RW , Shayman JA
Ref : Molecular & Cellular Biology , 26 :6139 , 2006
Abstract : A lysosomal phospholipase A2, LPLA2, was recently characterized and shown to have substrate specificity for phosphatidylcholine and phosphatidylethanolamine. LPLA2 is ubiquitously expressed but is most highly expressed in alveolar macrophages. Double conditional gene targeting was employed to elucidate the function of LPLA2. LPLA2-deficient mice (Lpla2-/-) were generated by the systemic deletion of exon 5 of the Lpla2 gene, which encodes the lipase motif essential for the phospholipase A2 activity. The survival of the Lpla2-/- mice was normal. Lpla2-/- mouse mating pairs yielded normal litter sizes, indicating that the gene deficiency did not impair fertility or fecundity. Alveolar macrophages from wild-type but not Lpla2-/- mice readily degraded radiolabeled phosphatidylcholine. A marked accumulation of phospholipids, in particular phosphatidylethanolamine and phosphatidylcholine, was found in the alveolar macrophages, the peritoneal macrophages, and the spleens of Lpla2-/- mice. By 1 year of age, Lpla2-/- mice demonstrated marked splenomegaly and increased lung surfactant phospholipid levels. Ultrastructural examination of Lpla2-/- mouse alveolar and peritoneal macrophages revealed the appearance of foam cells with lamellar inclusion bodies, a hallmark of cellular phospholipidosis. Thus, a deficiency of lysosomal phospholipase A2 results in foam cell formation, surfactant lipid accumulation, splenomegaly, and phospholipidosis in mice.
ESTHER : Hiraoka_2006_Mol.Cell.Biol_26_6139
PubMedSearch : Hiraoka_2006_Mol.Cell.Biol_26_6139
PubMedID: 16880524

Title : [Synthesis of diacylglycerol using immoblized regiospecific lipase in continuously operated fixed bed reactors] - Meng_2005_Sheng.Wu.Gong.Cheng.Xue.Bao_21_425
Author(s) : Meng XH , Sun PL , Yang K , He RJ , Mao ZG
Ref : Sheng Wu Gong Cheng Xue Bao , 21 :425 , 2005
Abstract : Diacylglycerol, DAG, because of its multifunctional and nutritional properties, attracted considerable attention recently. Enzymatic synthesis of diacylglycerols from linoleic acid was investigated in a solvent-free reaction in a continuously operated fixed bed reactors containing Lipozyme RM IM. By appropriate manipulation of the fluid-residence time, the relative proportions of the various acylglycerols in the effluent stream can be controlled. In addition, the presence of excess glycerol is effective for the removal of water produced during the esterification reactions. Under the conditions of molar ratio of linoleic acid to glycerol of 0.5, the immoblized enzyme maintained high stability and allowed the reaction to continue for 10 days without significant deterioration in enzyme activity. It was determined that the conversion of fatty acid, content of 1,3-DAG and volume efficiency of reactor reached optima under the conditions: a packaged-bed reactor(with a ratio of packed length to inner diameter of 7.8), reacting temperature at 65 degrees C, molar ratio of linoleic acid to glycerol of 0.5, and feeding flow rate of 1.2 mL/min.
ESTHER : Meng_2005_Sheng.Wu.Gong.Cheng.Xue.Bao_21_425
PubMedSearch : Meng_2005_Sheng.Wu.Gong.Cheng.Xue.Bao_21_425
PubMedID: 16108368

Title : Characterization of the protocatechuic acid catabolic gene cluster from Streptomyces sp. strain 2065 - Iwagami_2000_Appl.Environ.Microbiol_66_1499
Author(s) : Iwagami SG , Yang K , Davies J
Ref : Applied Environmental Microbiology , 66 :1499 , 2000
Abstract : Protocatechuate 3,4-dioxygenase (EC 1.13.11.3) catalyzes the ring cleavage step in the catabolism of aromatic compounds through the protocatechuate branch of the beta-ketoadipate pathway. A protocatechuate 3,4-dioxygenase was purified from Streptomyces sp. strain 2065 grown in p-hydroxybenzoate, and the N-terminal sequences of the beta- and alpha-subunits were obtained. PCR amplification was used for the cloning of the corresponding genes, and DNA sequencing of the flanking regions showed that the pcaGH genes belonged to a 6. 5-kb protocatechuate catabolic gene cluster; at least seven genes in the order pcaIJFHGBL appear to be transcribed unidirectionally. Analysis of the cluster revealed the presence of a pcaL homologue which encodes a fused gamma-carboxymuconolactone decarboxylase/beta-ketoadipate enol-lactone hydrolase previously identified in the pca gene cluster from Rhodococcus opacus 1CP. The pcaIJ genes encoded proteins with a striking similarity to succinyl-coenzyme A (CoA):3-oxoacid CoA transferases of eukaryotes and contained an indel which is strikingly similar between high-G+C gram-positive bacteria and eukaryotes.
ESTHER : Iwagami_2000_Appl.Environ.Microbiol_66_1499
PubMedSearch : Iwagami_2000_Appl.Environ.Microbiol_66_1499
PubMedID: 10742233
Gene_locus related to this paper: strsp-PCAL

Title : Cloning, sequencing and disruption of a bromoperoxidase-catalase gene in Streptomyces venezuelae: evidence that it is not required for chlorination in chloramphenicol biosynthesis - Facey_1996_Microbiology_142_657
Author(s) : Facey SJ , Gross F , Vining LC , Yang K , van Pee KH
Ref : Microbiology , 142 :657 , 1996
Abstract : Genomic DNA libraries of Streptomyces venezuelae ISP5230 and of a mutant blocked at the chlorination step of chloramphenicol biosynthesis were probed by hybridization with a synthetic oligonucleotide corresponding to the N-terminal amino acid sequence of a bromoperoxidase-catalase purified from the wild-type strain. Hybridizing fragments obtained from the two strains were cloned and sequenced. Analysis of the nucleotide sequences demonstrated that the fragments contained the same 1449 bp open reading frame with no differences in nucleotide sequence. The deduced polypeptide encoded 483 amino acids with a calculated M(r) of 54,200; the N-terminal sequence was identical to that of the bromoperoxidase-catalase purified from wild-type S. venezuelae. Comparison of the amino acid sequence predicted for the cloned bromoperoxidase-catalase gene (bca) with database protein sequences showed a significant similarity to a group of prokaryotic and eukaryotic catalases, but none to other peroxidases or haloperoxidases. Replacement of the bca gene in the wild-type strain of S. venezuelae with a copy disrupted by insertion of a DNA fragment encoding apramycin resistance did not prevent chloramphenicol production. The results suggest that the role of the enzyme in S. venezuelae is related to its activity as a catalase rather than as a halogenating agent.
ESTHER : Facey_1996_Microbiology_142_657
PubMedSearch : Facey_1996_Microbiology_142_657
PubMedID: 8868441