Yang W

References (64)

Title : Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial - Wang_2024_Diabetes.Obes.Metab__
Author(s) : Wang W , Guo X , Zhang C , Ning T , Ma G , Huang Y , Jia R , Zhou D , Cao M , Zhang T , Yao L , Yuan J , Chen L , Wang Y , Jiang C , Dong X , Chen M , Gu Q , Zhang L , Fu Y , Pan T , Bi Y , Song W , Xu J , Lu W , Sun X , Ye Z , Zhang D , Peng L , Lin X , Dai W , Wang Q , Yang W
Ref : Diabetes Obes Metab , : , 2024
Abstract : AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.
ESTHER : Wang_2024_Diabetes.Obes.Metab__
PubMedSearch : Wang_2024_Diabetes.Obes.Metab__
PubMedID: 38221859 || 38618970

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 : Role of uranium toxicity and uranium-induced oxidative stress in advancing kidney injury and endothelial inflammation in rats - Yang_2024_BMC.Pharmacol.Toxicol_25_14
Author(s) : Yang Y , Dai C , Chen X , Zhang B , Li X , Yang W , Wang J , Feng J
Ref : BMC Pharmacol Toxicol , 25 :14 , 2024
Abstract : OBJECTIVE: Uranium exposure may cause serious pathological injury to the body, which is attributed to oxidative stress and inflammation. However, the pathogenesis of uranium toxicity has not been clarified. Here, we evaluated the level of oxidative stress to determine the relationship between uranium exposure, nephrotoxic oxidative stress, and endothelial inflammation. METHODS: Forty male Sprague-Dawley rats were divided into three experimental groups (U-24h, U-48h, and U-72h) and one control group. The three experimental groups were intraperitoneally injected with 2.0 mg/kg uranyl acetate, and tissue and serum samples were collected after 24, 48, and 72 h, respectively, whereas the control group was intraperitoneally injected with 1.0 ml/kg normal saline and samples were collected after 24 h. Then, we observed changes in the uranium levels and oxidative stress parameters, including the total oxidative state (TOS), total antioxidant state (TAS), and oxidative stress index (OSI) in kidney tissue and serum. We also detected the markers of kidney injury, namely urea (Ure), creatine (Cre), cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL). The endothelial inflammatory markers, namely C-reactive protein (CRP), lipoprotein phospholipase A2 (Lp-PLA2), and homocysteine (Hcy), were also quantified. Finally, we analyzed the relationship among these parameters. RESULTS: TOS (z = 3.949; P < 0.001), OSI (z = 5.576; P < 0.001), Ure (z = 3.559; P < 0.001), Cre (z = 3.476; P < 0.001), CysC (z = 4.052; P < 0.001), NGAL (z = 3.661; P < 0.001), and CRP (z = 5.286; P < 0.001) gradually increased after uranium exposure, whereas TAS (z = -3.823; P < 0.001), tissue U (z = -2.736; P = 0.001), Hcy (z = -2.794; P = 0.005), and Lp-PLA2 (z = -4.515; P < 0.001) gradually decreased. The serum U level showed a V-shape change (z = -1.655; P = 0.094). The uranium levels in the kidney tissue and serum were positively correlated with TOS (r = 0.440 and 0.424; P = 0.005 and 0.007) and OSI (r = 0.389 and 0.449; P = 0.013 and 0.004); however, serum U levels were negatively correlated with TAS (r = -0.349; P = 0.027). Partial correlation analysis revealed that NGAL was closely correlated to tissue U (r(partial) = 0.455; P = 0.003), CysC was closely correlated to serum U (r(partial) = 0.501; P = 0.001), and Lp-PLA2 was closely correlated to TOS (r(partial) = 0.391; P = 0.014), TAS (r(partial) = 0.569; P < 0.001), and OSI (r(partial) = -0.494; P = 0.001). Pearson correlation analysis indicated that the Hcy levels were negatively correlated with tissue U (r = -0.344; P = 0.030) and positively correlated with TAS (r = 0.396; P = 0.011). CONCLUSION: The uranium-induced oxidative injury may be mainly reflected in enhanced endothelial inflammation, and the direct chemical toxicity of uranium plays an important role in the process of kidney injury, especially in renal tubular injury. In addition, CysC may be a sensitive marker reflecting the nephrotoxicity of uranium; however, Hcy is not suitable for evaluating short-term endothelial inflammation involving oxidative stress.
ESTHER : Yang_2024_BMC.Pharmacol.Toxicol_25_14
PubMedSearch : Yang_2024_BMC.Pharmacol.Toxicol_25_14
PubMedID: 38308341

Title : Determination of Acetylcholinesterase Activity Based on Ratiometric Fluorescence Signal Sensing - Zhao_2024_J.Fluoresc__
Author(s) : Zhao F , Guo H , Yang W , Guo L , Li J , Chen H
Ref : J Fluoresc , : , 2024
Abstract : Acetylcholinesterase (AChE) plays an important role in the treatment of human diseases, environmental security and global food supply. In this study, the simple fluorescent indicators and MnO(2) nanosheets were developed and integrated to establish a ratiometric fluorescence sensing system for the detection of AChE activity. Two fluorescence signals could be recorded independently at the same excitation wavelength, which extended the detection range and enhanced the visibility of results. Fluorescence of F-PDA was quenched by MnO(2) nanosheets on account of inner filtering effect. Meanwhile, the nonfluorescent OPD was catalytically oxidized to 2,3-diaminophenazine by MnO(2) nanosheets. The acetylcholine (ATCh) was catalytically hydrolyzed by AChE to enzymatic thiocholine, which decomposed MnO(2) to Mn(2+), recovered the fluorescence of F-PDA and reduced the emission of ox-OPD. Utilizing the fluorescence intensity ratio F(468)/F(558) as the signal readout, the ratiometric fluorescence method was established to detect AChE activity. Under the excitation wavelength of 410 nm, the ratio F(460)/F(558) against the AChE concentration demonstrated two linear relationships in the range 0.05 -1.0 and 1.0-50 U.L(- 1) with a limit of detection (LOD) of 0.073 U.L(- 1). The method was applied to the detection of AChE activity and the analysis of the inhibitor Huperzine-A. Due to the advantages of high sensitivity and favorable selectivity, the method possesses an application prospect in the activity deteceion of AChE and the screening of inhibitors.
ESTHER : Zhao_2024_J.Fluoresc__
PubMedSearch : Zhao_2024_J.Fluoresc__
PubMedID: 38613708

Title : Current advances in the structural biology and molecular engineering of PETase - Liu_2023_Front.Bioeng.Biotechnol_11_1263996
Author(s) : Liu F , Wang T , Yang W , Zhang Y , Gong Y , Fan X , Wang G , Lu Z , Wang J
Ref : Front Bioeng Biotechnol , 11 :1263996 , 2023
Abstract : Poly(ethylene terephthalate) (PET) is a highly useful synthetic polyester plastic that is widely used in daily life. However, the increase in postconsumer PET as plastic waste that is recalcitrant to biodegradation in landfills and the natural environment has raised worldwide concern. Currently, traditional PET recycling processes with thermomechanical or chemical methods also result in the deterioration of the mechanical properties of PET. Therefore, it is urgent to develop more efficient and green strategies to address this problem. Recently, a novel mesophilic PET-degrading enzyme (IsPETase) from Ideonella sakaiensis was found to streamline PET biodegradation at 30 degreesC, albeit with a lower PET-degrading activity than chitinase or chitinase-like PET-degrading enzymes. Consequently, the molecular engineering of more efficient PETases is still required for further industrial applications. This review details current knowledge on IsPETase, MHETase, and IsPETase-like hydrolases, including the structures, ligandprotein interactions, and rational protein engineering for improved PET-degrading performance. In particular, applications of the engineered catalysts are highlighted, including metabolic engineering of the cell factories, enzyme immobilization or cell surface display. The information is expected to provide novel insights for the biodegradation of complex polymers.
ESTHER : Liu_2023_Front.Bioeng.Biotechnol_11_1263996
PubMedSearch : Liu_2023_Front.Bioeng.Biotechnol_11_1263996
PubMedID: 37795175

Title : Ent-Pimaranes isolated from Flickingeria fimbriata and their acetylcholinesterase inhibitory activities - Zhang_2023_Fitoterapia__105687
Author(s) : Zhang X , Zheng R , Hu S , Cao W , Tan J , Yang W , Chen J
Ref : Fitoterapia , :105687 , 2023
Abstract : Two new and six known ent-pimaranes were isolated from Flickingeria fimbriata. One of them possesses a rare carbon skeleton. It is the first time such a compound with this specific carbon skeleton has been isolated from a natural source. The structure and absolute configuration were determined by NMR, MS, and X-ray diffraction analysis. The biosynthetic pathway of the rare skeleton was proposed and suggested a new pathway for these nor-ent-pimarane analogues. All isolated compounds were screened for inhibitory activity against acetylcholinesterase (AChE). The compound 4 exhibits potent inhibitory effect on AChE with the 50% inhibitory concentration (IC(50)) being 5.8 microM, which is close to that of the positive control (Huperzine A). This is the first report about inhibitory activity on AChE of ent-pimaranes.
ESTHER : Zhang_2023_Fitoterapia__105687
PubMedSearch : Zhang_2023_Fitoterapia__105687
PubMedID: 37769998

Title : Quinolinones Alkaloids with AChE inhibitory Activity from Mangrove Endophytic Fungus Penicillium citrinum YX-002 - Zhang_2023_Chem.Biodivers__e202300735
Author(s) : Zhang Y , Liu Y , Xue X , Zhou L , Yang W , She Z , Liao Q , Feng Y , Chen X
Ref : Chem Biodivers , :e202300735 , 2023
Abstract : Acetylcholinesterase (AChE) inhibitory activity-guided studies on the mangrove-derived endophytic fungus Penicillium citrinum YX-002 led to the isolation of nine secondary metabolites, including one new quinolinone derivative, quinolactone A (1), a pair of epimers quinolactacin C1 (2) and 3-epi-quinolactacin C1 (3), together with six known analogues (4-9) . Their structures were elucidated based on extensive mass spectrometry (MS) and 1D/2D nuclear magnetic resonance (NMR) spectroscopic analyses, and compared with data in the literature. The absolute configurations of compounds 1-3 was determined by combination of electronic circular dichroism (ECD) calculations and X-Ray single crystal diffraction technique using Cu Kalpha radiation. In bioassays, compounds 1, 4 and 7 showed moderate AChE inhibitory activities with IC50 values of 27.6, 19.4 and 11.2 micromol/L, respectively. The structure-activity relationships (SARs) analysis suggested that the existence of carbonyl group on C-3 and the oxygen atom on the five-membered ring were beneficial to the activity. Molecular docking results showed that compound 7 had a lower affinity interaction energy (-9.3 kcal/mol) with stronger interactions with different sites in AChE activities, which explained its higher activities.
ESTHER : Zhang_2023_Chem.Biodivers__e202300735
PubMedSearch : Zhang_2023_Chem.Biodivers__e202300735
PubMedID: 37423890

Title : Human Butyrylcholinesterase Mutants for (-)-Cocaine Hydrolysis: A Correlation Relationship between Catalytic Efficiency and Total Hydrogen Bonding Energy with an Oxyanion Hole - Zheng_2023_J.Phys.Chem.B__
Author(s) : Zheng F , Hou S , Xue L , Yang W , Zhan CG
Ref : J Phys Chem B , : , 2023
Abstract : A combined computational and experimental study has been carried out to explore and test a quantitative correlation relationship between the relative catalytic efficiency (RCE) of human butyrylcholinesrase (BChE) mutant-catalyzed hydrolysis of substrate (-)-cocaine and the total hydrogen bonding energy (tHBE) of the carbonyl oxygen of the substrate with the oxyanion hole of the enzyme in the modeled transition-state structure (TS1), demonstrating a satisfactory linear correlation relationship between ln(RCE) and tHBE. The satisfactory correlation relationship has led us to computationally predict and experimentally confirm new human BChE mutants that have a further improved catalytic activity against (-)-cocaine, including the most active one (the A199S/F227S/S287G/A328W/Y332G mutant) with a 2790-fold improved catalytic efficiency (k(cat)/K(M) = 2.5 x 10(9) min(-1) M(-1)) compared to the wild-type human BChE. Compared to the reference mutant (the A199S/S287G/A328W/Y332G mutant) tested in the reported clinical development of an enzyme therapy for cocaine dependence treatment, this new mutant (with a newly predicted additional F227S mutation) has an improved catalytic efficiency against (-)-cocaine by -2.6-fold. The good agreement between the computational and experimental ln(RCE) values suggests that the obtained correlation relationship is robust for computational prediction. A similar correlation relationship could also be explored in studying BChE or other serine hydrolases/esterases with an oxyanion hole stabilizing the carbonyl oxygen in the rate-determining reaction step of the enzymatic hydrolysis of other substrates.
ESTHER : Zheng_2023_J.Phys.Chem.B__
PubMedSearch : Zheng_2023_J.Phys.Chem.B__
PubMedID: 38063500

Title : Spatial distribution differences of cholinesterase in healthy Chinese under the influence of geographical environmental factors - Yang_2023_Environ.Sci.Pollut.Res.Int__
Author(s) : Yang W , Ge M , Wang Z , Li T
Ref : Environ Sci Pollut Res Int , : , 2023
Abstract : The main targets of this were to screen the factors that may influence the distribution of cholinesterase (CHE) reference value in healthy people, and further explored the geographical distribution differences of CHE reference value in China. In this study, we collected the CHE data of 17,601 healthy people from 173 cities in China to analyse the correlation between CHE and 22 geography secondary indexes through spearman regression analysis. Six indexes with significant correlation were extracted, and a ridge regression model was built, and the country's urban CHE reference value of healthy Chinese was predicted. By using the disjunctive kriging method, we obtained the geographical distribution of CHE reference values for healthy people in China. The reference value of CHE for healthy Chinese was significantly correlated with the 6 secondary indexes, namely, latitude ( degrees), altitude (m), annual average temperature ( degreesC), annual average relative humidity (%) and annual precipitation (mm), and topsoil sand gravel percentage (% wt). The geographical distribution of CHE values of healthy Chinese showed a trend of being higher in southeast China and lower in northwest. This study lays a foundation for further research on the mechanism of different influencing factors on the reference value of CHE index. A ridge regression model composed of significant influencing factors has been established to provide the basis for formulating reference criteria for the treatment factors of the liver damage diseases and liver cancer using CHE reference values in different regions.
ESTHER : Yang_2023_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Yang_2023_Environ.Sci.Pollut.Res.Int__
PubMedID: 36800095

Title : Tanshinone IIA regulates glycogen synthase kinase-3beta-related signaling pathway and ameliorates memory impairment in APP\/PS1 transgenic mice - Peng_2022_Eur.J.Pharmacol__174772
Author(s) : Peng X , Chen L , Wang Z , He Y , Ruganzu JB , Guo H , Zhang X , Ji S , Zheng L , Yang W
Ref : European Journal of Pharmacology , :174772 , 2022
Abstract : Our previous findings indicated that tanshinone IIA (tan IIA), a natural component extracted from the root and rhizome of danshen, significantly attenuated beta-amyloid accumulation, neuroinflammation, and endoplasmic reticulum stress, as well as improved learning and memory deficits in APP/PS1 transgenic mouse model of Alzheimer's disease (AD). However, whether tan IIA can ameliorate tau pathology and the underlying mechanism in APP/PS1 mice remains unclear. In the current study, tan IIA (15 mg/kg and 30 mg/kg) or saline was intraperitoneally administered to the 5-month-old APP/PS1 mice once daily for 4 weeks. The open-field test, novel object recognition test, Y-maze test, and Morris water maze test were performed to assess the cognitive function. Nissl staining, immunohistochemistry, TUNEL, and western blotting were conducted to explore tau hyperphosphorylation, neuronal injury, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway. The activity of GSK-3beta, acetylcholinesterase (AChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) were measured using commercial kits. Our results revealed that tan IIA treatment significantly ameliorated behavioral deficits and improved spatial learning and memory ability of APP/PS1 mice. Additionally, tan IIA markedly attenuated tau hyperphosphorylation and prevented neuronal loss and apoptosis in the parietal cortex and hippocampus. Simultaneously, tan IIA reversed cholinergic dysfunction and reduced oxidative stress. Furthermore, tan IIA activated the PI3K/Akt signaling pathway and suppressed GSK-3beta. Taken together, the above findings suggested that tan IIA improves cognitive decline and tau pathology may through modulation of PI3K/Akt/GSK-3beta signaling pathway.
ESTHER : Peng_2022_Eur.J.Pharmacol__174772
PubMedSearch : Peng_2022_Eur.J.Pharmacol__174772
PubMedID: 35090935

Title : Paeoniflorin Can Improve Acute Lung Injury Caused by Severe Acute Pancreatitis through Nrf2\/ARE Pathway - Hu_2022_Comput.Math.Methods.Med_2022_5712219
Author(s) : Hu Y , Yang W
Ref : Comput Math Methods Med , 2022 :5712219 , 2022
Abstract : OBJECTIVE: To evaluate the potential therapeutic effect of paeoniflorin on acute lung injury induced by severe acute pancreatitis (SAP) and to initially explore the possible protective mechanisms of paeoniflorin. METHOD: The SAP lung injury rat model was established by retrograde injection of 5% sodium taurocholate to the cholangiopancreatic duct. H&E staining was used to detect pathological changes in rat lung tissue. W/D ratio method, serum amylase (AMY), and lipase activity were used to assess the degree of lung injury in rats. Oxidation indicators such as LDH, MDA, and SOD in lung tissue were measured. Levels of inflammatory factors TNF-alpha, IL-6, and IL-10 were measured in bronchoalveolar lavage fluid (BALF). At the same time, Western blot was used to detect the expression of related proteins in the Nrf2/ARE signaling pathway. RESULTS: In SAP rats, paeoniflorin treatment could significantly alleviate lung injury conditions such as pulmonary edema and inflammatory cell infiltration in lung tissue and reduce serum amylase and lipase activities. Paeoniflorin can reduce the content of LDH and MDA in lung tissue and increase the content of SOD. In addition, ELISA results showed that paeoniflorin could inhibit the levels of TNF-alpha and IL-6 in BALF and upregulate the levels of IL-10. Paeoniflorin could upregulate the expression of Nrf2/ARE signaling pathway proteins Cyt-Nrf2, HO-1, and NQO1 in lung tissue of SAP rats. CONCLUSION: Paeoniflorin may improve acute lung injury in rats with severe pancreatitis by inhibiting inflammation and oxidative stress response. These effects may be related to activating the Nrf2/ARE signaling pathway.
ESTHER : Hu_2022_Comput.Math.Methods.Med_2022_5712219
PubMedSearch : Hu_2022_Comput.Math.Methods.Med_2022_5712219
PubMedID: 35586665

Title : Propofol protects rats against intra-cerebroventricular Streptozotocin-induced cognitive dysfunction and neuronal damage - Sun_2022_Folia.Morphol.(Warsz)__
Author(s) : Sun L , Dou X , Yang W
Ref : Folia Morphologica (Warsz) , : , 2022
Abstract : BACKGROUND: Cognitive dysfunction is a severe issue of Alzheimer's disease. Thus, the present study was conducted to enumerate the protective effect of Propofol (PPL) in rats against intra-cerebroventricular Streptozotocin-induced cognitive dysfunction and neuronal damage. METHODS: The effect of PPL was investigated to evaluate behavioral changes in Streptozotocin (STZ)-induced cognitive dysfunction in Wistar rats using Object recognition task (ORT) for nonspatial, Morris water maze (MWM) for spatial and locomotor activity. The effect of PPL was also investigated on acetylcholinesterase (AChE) activity and oxidative stress markers, e.g., nitrite, malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). The level of pro-inflammatory cytokines, e.g., tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, was also studied in the PPL-treated group. The effect of PPL on the level of neurotransmitters, e.g., dopamine (DA), Serotonin (5-HT), and norepinephrine (NE) and their metabolites 3,4-Dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and Homovanillic acid (HVA) levels were also estimated in frozen hippocampal tissues by HPLC. Histopathology analysis of neurons in the hippocampus of rats was performed using Hematoxylin and eosin (H&E) staining. RESULTS: PPL showed significant improvement in the spatial and nonspatial memory deficit of rats in the Morris Water Maze test and ORT in rats. It also causes improvement in locomotor activity of rats by preserving Ach via inhibition of AChE. It also potentiates the expression of DA, 5-HT, and NE with a simultaneous reduction in the level of metabolites (DOPAC, HVA, and 5-HIAA). PPL showed a reduction of oxidative stress in rats by restoring the level of nitrite, SOD, MDA, and GSH near to normal. In the PPL-treated group, the level of TNF-alpha, IL-1beta, and IL-6 was found reduced in a dose-dependent manner. In histopathology analysis of neurons in the hippocampus of the STZ rats, PPL causes dose-dependent reduction of pyknosis in the nucleus, which confirmed the protective effect of PPL. CONCLUSIONS: The present study demonstrated that PPL could significantly attenuate cognitive dysfunction and neuronal damage in STZ-induced rats.
ESTHER : Sun_2022_Folia.Morphol.(Warsz)__
PubMedSearch : Sun_2022_Folia.Morphol.(Warsz)__
PubMedID: 35347698

Title : Structure-guided rational design of the Geobacillus thermoglucosidasius feruloyl esterase GthFAE to improve its thermostability - Yang_2022_Biochem.Biophys.Res.Commun_600_117
Author(s) : Yang W , Sun L , Dong P , Chen Y , Zhang H , Huang X , Wu L , Chen L , Jing D , Wu Y
Ref : Biochemical & Biophysical Research Communications , 600 :117 , 2022
Abstract : Feruloyl esterases are indispensable biocatalysts catalyzing the cleavage of ester bonds between polysaccharides and their hydroxycinnamoyl cross-links. GthFAE from Geobacillus thermoglucosidasius was identified as a thermophilic alkaline feruloyl esterase with potential applications in paper manufacturing. To improve the enzymatic properties rationally and efficiently, the structure of GthFAE was solved at 1.9 A, revealing a core domain of classical alpha/beta hydrolase fold and an inserted alpha/beta cap domain. In silico analysis based on it helped us to investigate whether the residues at the active center have positive effects on the stability, and how. Several site-directed mutations were conducted, of which substitutions at residues T41 and T150 apparently improved the thermostability. The combination mutant T41N/T150R exhibited an optimal temperature of 65 degreesC, a 6.4 degreesC higher T(m) compared to wild type by 80 degreesC, and a 35-fold longer in half-life (201 min) at 70 degreesC. Molecular dynamics simulations further illustrated that the structure of T41N/T150R was more stable than the wild type and T150R stabilized the cap domain by introducing salt bridges to the region with E154 and D164. This study not only highlighted residues within the active center on their thermostability improving effects, but also contributed to the prospective industrial application of GthFAE.
ESTHER : Yang_2022_Biochem.Biophys.Res.Commun_600_117
PubMedSearch : Yang_2022_Biochem.Biophys.Res.Commun_600_117
PubMedID: 35219099
Gene_locus related to this paper: partm-GthFAE

Title : Natural products as sources of acetylcholinesterase inhibitors: Synthesis, biological activities, and molecular docking studies of osthole-based ester derivatives - Yu_2022_Front.Plant.Sci_13_1054650
Author(s) : Yu X , Zhang Y , Zhang M , Chen Y , Yang W
Ref : Front Plant Sci , 13 :1054650 , 2022
Abstract : Osthole is a natural coumarin compound which isolated from Cnidium monnieri (L.) Cusson, has extensive pharmacological activities and could be used as a leading compound for drug research and development. In a continuous effort to develop new acetylcholinesterase inhibitors from natural products, eighteen osthole esters were designed, synthesized, and confirmed by (1)H NMR, (13)C NMR and HRMS. The anti-AChE activity of These derivatives was measured at a concentration of 1.0 mol/mL in vitro by Ellman's method, and the result showed that 4m and 4o had moderate inhibitory activities with 68.8% and 62.6%, respectively. Molecular docking study results further revealed AChE interacted optimally with docking poses 4m and 4o. Network pharmacology also predicted that compound 4m could be involved in Ras signaling pathway, which made it a potential therapeutic target of AD.
ESTHER : Yu_2022_Front.Plant.Sci_13_1054650
PubMedSearch : Yu_2022_Front.Plant.Sci_13_1054650
PubMedID: 36466282

Title : Inhibition of Dipeptidyl Peptidase-4 by Flavonoids: Structure-Activity Relationship, Kinetics and Interaction Mechanism - Pan_2022_Front.Nutr_9_892426
Author(s) : Pan J , Zhang Q , Zhang C , Yang W , Liu H , Lv Z , Liu J , Jiao Z
Ref : Front Nutr , 9 :892426 , 2022
Abstract : With the aim to establish a structure-inhibitory activity relationship of flavonoids against dipeptidyl peptidase-4 (DPP-4) and elucidate the interaction mechanisms between them, a pannel of 70 structurally diverse flavonoids was used to evaluate their inhibitory activities against DPP-4, among which myricetin, hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin showed higher inhibitory activities in a concentration-dependent manner. Structure-activity relationship analysis revealed that introducing hydroxyl groups to C3', C4', and C6 of the flavonoid structure was beneficial to improving the inhibitory efficacy against DPP-4, whereas the hydroxylation at position 3 of ring C in the flavonoid structure was unfavorable for the inhibition. Besides, the methylation of the hydroxyl groups at C3', C4', and C7 of the flavonoid structure tended to lower the inhibitory activity against DPP-4, and the 2,3-double bond and 4-carbonyl group on ring C of the flavonoid structure was essential for the inhibition. Glycosylation affected the inhibitory activity diversely, depending on the structure of flavonoid aglycone, type of glycoside, as well as the position of substitution. Inhibition kinetic analysis suggested that myricetin reversibly inhibited DPP-4 in a non-competitive mode, whereas hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin all reversibly inhibited DPP-4 in a mixed type. Moreover, the fluorescence quenching analysis indicated that all the five flavonoid compounds could effectively quench the intrinsic fluorescence of DPP-4 by spontaneously binding with it to form an unstable complex. Hydrogen bonds and van der Waals were the predominant forces to maintain the complex of myricetin with DPP-4, and electrostatic forces might play an important role in stabilizing the complexes of the remaining four flavonoids with DPP-4. The binding of the tested flavonoids to DPP-4 could also induce the conformation change of DPP-4 and thus led to inhibition on the enzyme. Molecular docking simulation further ascertained the binding interactions between DPP-4 and the selected five flavonoids, among which hyperoside, narcissoside, cyaniding 3-O-glucoside, and isoliquiritigenin inserted into the active site cavity of DPP-4 and interacted with the key amino acid residues of the active site, whereas the binding site of myricetin was located in a minor cavity close to the active pockets of DPP-4.
ESTHER : Pan_2022_Front.Nutr_9_892426
PubMedSearch : Pan_2022_Front.Nutr_9_892426
PubMedID: 35634373

Title : Adsorption mechanism of two pesticides on polyethylene and polypropylene microplastics: DFT calculations and particle size effects - Mo_2021_Environ.Pollut_291_118120
Author(s) : Mo Q , Yang X , Wang J , Xu H , Li W , Fan Q , Gao S , Yang W , Gao C , Liao D , Li Y , Zhang Y
Ref : Environ Pollut , 291 :118120 , 2021
Abstract : Polyethylene (PE) and polypropylene (PP) microplastics (MPs), as carriers, can bind with pesticides, which propose harmful impacts to aqueous ecosystems. Meanwhile, carbofuran and carbendazim (CBD), two widely used carbamate pesticides, are toxic to humans because of the inhibition of acetylcholinesterase activity. The interaction between two MPs and two pesticides could start in farmland and be maintained during transportation to the ocean. Herein, the adsorption behavior and mechanism of carbofuran and carbendazim (CBD) by PE and PP MPs were investigated via characterization and density functional theory (DFT) simulation. The adsorption kinetic and thermodynamic data were best described by pseudo-second-order kinetics and the Freundlich models. The adsorption behaviors of individual carbofuran/CBD on both MPs were very similar. The CBD adsorption rate and capacity of PE and PP MPs were higher than those of carbofuran. This phenomenon explained the lower negative effects of DOM (oxalic acid, glycine (Gly)) on CBD adsorption relative to those of carbofuran. The presence of oxalic acid and Gly decreased the PE adsorption by 20.40-48.02% and the PP adsorption by 19.27-42.11%, respectively. It indicated the significance of DOM in carbofuran cycling. The adsorption capacities were negatively correlated with MPs size, indicating the importance of specific surficial area. Fourier transformation infrared spectroscopy before and after adsorption suggested that the adsorption process did not produce any new covalent bond. Instead, intermolecular van der Waals forces were one of the primary adsorption mechanisms of carbofuran and CBD by MPs, as evidenced by DFT calculations. Based on the zeta potential, the electrostatic interaction explained the higher adsorption CBD by MPs than carbofuran.
ESTHER : Mo_2021_Environ.Pollut_291_118120
PubMedSearch : Mo_2021_Environ.Pollut_291_118120
PubMedID: 34520951

Title : A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling - Du_2021_Circ.Res__
Author(s) : Du WW , Xu J , Yang W , Wu N , Li F , Zhou L , Wang S , Li X , He AT , Du KY , Zeng K , Ma J , Lyu J , Zhang C , Zhou C , Maksimovic K , Yang BB
Ref : Circulation Research , : , 2021
Abstract : Rationale: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrythmia and progressive heart failure. The underlying mechanisms remain unclear.Objective: We performed high-throughput RNA sequencing to analyze circular RNA (circRNA) profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA-derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 and C8orf44-SGK3 promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared to wild type mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload-induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.
ESTHER : Du_2021_Circ.Res__
PubMedSearch : Du_2021_Circ.Res__
PubMedID: 34261347

Title : AOAH remodels arachidonic acid-containing phospholipid pools in a model of interstitial cystitis pain: A MAPP Network study - Yang_2020_PLoS.One_15_e0235384
Author(s) : Yang W , Yaggie RE , Schaeffer AJ , Klumpp DJ
Ref : PLoS ONE , 15 :e0235384 , 2020
Abstract : Interstitial cystitis/bladder pain syndrome (IC) is a debilitating condition of chronic pelvic pain with unknown etiology. Recently, we used a genetic approach in a murine model of IC to identify the lipase acyloxyacyl hydrolase (AOAH) as a modulator of pelvic pain. We found that AOAH-deficient mice have elevated pelvic pain responses, and AOAH immunoreactivity was detected along the bladder-brain axis. Lipidomic analyses identified arachidonic acid (AA) and its metabolite PGE2 as significantly elevated in the sacral spinal cord of AOAH-deficient mice, suggesting AA is a substrate for AOAH. Here, we quantified the effects of AOAH on phospholipids containing AA. Spinal cord lipidomics revealed increased AA-containing phosphatidylcholine in AOAH-deficient mice and concomitantly decreased AA-phosphatidylethanolamine, consistent with decreased CoA-independent transferase activity (CoIT). Overexpression of AOAH in cell cultures similarly altered distribution of AA in phospholipid pools, promoted AA incorporation, and resulted in decreased membrane fluidity. Finally, administration of a PGE2 receptor antagonist reduced pelvic pain in AOAH-deficient mice. Together, these findings suggest that AOAH represents a potential CoA-independent AA transferase that modulates CNS pain pathways at the level of phospholipid metabolism.
ESTHER : Yang_2020_PLoS.One_15_e0235384
PubMedSearch : Yang_2020_PLoS.One_15_e0235384
PubMedID: 32925915

Title : Double-enzymes-mediated fluorescent assay for sensitive determination of organophosphorus pesticides based on the quenching of upconversion nanoparticles by Fe(3) - Lin_2020_Food.Chem_345_128809
Author(s) : Lin X , Yu Q , Yang W , He C , Zhou Y , Duan N , Wu S
Ref : Food Chem , 345 :128809 , 2020
Abstract : Herein, a new double-enzymes-modulated fluorescent assay based on the quenching of upconversion nanoparticles (UCNPs) by Fe(3+) was constructed for sensitive determination of OPs. OPs can inhibit the activity of acetylcholinesterase to reduce the production of choline and further lead to the lack of H(2)O(2) in the presence of choline oxidase. Therefore, Fe(2+) cannot be converted into Fe(3+), resulting in "turn-on" fluorescence of UCNPs. Under optimal conditions, an excellent linear correlation between the inhibition efficiency and the logarithm of the chlorpyrifos concentration was achieved with a detection limit (LOD) of 6.7 ng/mL in the range of 20-2000 ng/mL. The recovery for chlorpyrifos in apples and cucumbers was 89.5-97.1%. The results were consistent with those obtained by GC-MS. Overall, the integration of UCNPs into the double-enzymes-mediated Fe(3+)/Fe(2+) conversion endows this method with desirable rapidity, sensitivity, selectivity, stability, operational simplicity, and strong anti-interference capability, holding great potential in the application of food safety.
ESTHER : Lin_2020_Food.Chem_345_128809
PubMedSearch : Lin_2020_Food.Chem_345_128809
PubMedID: 33338834

Title : Transcription Factors ZEB1 and CREB Promote the Transcription of Bovine ABHD5 Gene - Wang_2021_DNA.Cell.Biol_40_219
Author(s) : Wang X , Li A , Raza SHA , Liang C , Zhang S , Mei C , Yang W , Zan L
Ref : DNA & Cell Biology , 40 :219 , 2020
Abstract : Alpha/beta hydrolase domain 5 (ABHD5) plays a significant role in intracellular lipid metabolism, which is regulated by a complex network of transcription factors. The transcriptional regulation of the ABHD5 gene in cattle and other livestock, however, has not been previously investigated. Investigations in humans and animal models indicate that the transcription factors zinc finger E-box binding homeobox 1 (ZEB1) and cAMP-response element binding protein (CREB) may play important roles in the transcriptional regulation of ABHD5 in cattle. Our comparison of the sequence similarities in the transcription factor binding sites in Bos taurus, Bos indicus, Bos mutus, and Homo sapiens revealed high homology. Based on the data collected by the Cistrome Data Browser and its visualization window, we found that ZEB1 and CREB have significant ChIP-seq enrichments in the 5'-untranslated region (5' UTR) of the human ABHD5 gene. In bovine adipocytes, we detected ZEB1 and CREB binding sites in the ABHD5 gene. Mutations in the ZEB1 and CREB binding sites significantly reduced the promoter activity (p < 0.05 and p < 0.01, respectively). Moreover, electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP) assays demonstrated the binding of the transcription factors in vivo and in vitro, respectively. And overexpression or silencing the expression of the ZEB1 and CREB, respectively, resulted in significant changes to the ABHD5 promoter activity. Collectively, these results indicate that ZEB1 and CREB are important transcription factors that regulate ABHD5 gene expression in bovine adipocytes. They further our understanding of the transcriptional regulation and biological functions of the bovine ABHD5 gene.
ESTHER : Wang_2021_DNA.Cell.Biol_40_219
PubMedSearch : Wang_2021_DNA.Cell.Biol_40_219
PubMedID: 33332227
Gene_locus related to this paper: bovin-q0vcc8 , human-ABHD5

Title : Sequencing of Transcriptome and Small RNA Revealed the Xenobiotic Metabolism-Related Genes and Potential Regulatory miRNA in Asian Tramp Snail - Yang_2020_Front.Genet_11_595166
Author(s) : Yang Q , Yang W , Shang F , Ding B , Niu J , Wang J
Ref : Front Genet , 11 :595166 , 2020
Abstract : The Asian tramp snail, Bradybaena similaris (Ferusssac), is an invasive land snail species and has been a rising agricultural pest in south of China. As a pest, it also plays a role in transmission of Angiostrongylus cantonensis. However, present studies on this species are rare and the molecular information is limited. For this purpose, we sequenced the transcriptome and small RNA of B. similaris collected from citrus orchards. In total, 89,747 unigenes with an N50 size of 1287 bp and an average length of 817 bp were generated from -8.9 Gb transcriptome and 31 Mb clean reads were generated from -36 Mb small RNA library. To demonstrate the usefulness of these two datasets, we analyzed a series of genes associated with xenobiotic metabolism and core RNAi machinery. Analysis of the transcripts resulted in annotation of 126 putative genes encoding cytochrome P450 monooxygenases (CYP, 45), carboxyl/cholinesterases (CCE, 13), glutathione-S-transferases (GST, 24), and ATP-binding cassette transporters (ABC, 44). Analysis of the small RNA detected 42 miRNAs. In addition, four genes involved in small RNA pathways (miRNA, piRNA, and siRNA) were identified, and a total of 430 genes that can be targeted by miRNAs were predicted. Moreover, we found that a few miRNAs could target certain genes involved in xenobiotic metabolism. Therefore, we believe that these two datasets and the characterization of the identified/predicted genes will facilitate the molecular study of this species as well as other land snails with agricultural importance.
ESTHER : Yang_2020_Front.Genet_11_595166
PubMedSearch : Yang_2020_Front.Genet_11_595166
PubMedID: 33519897

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 : AChR myasthenia gravis switching to MuSK or double antibody positive myasthenia gravis in two children and literature review - Lu_2020_Neuromuscul.Disord__
Author(s) : Lu Y , Ran H , Yang W , Ma Q , Qiu L , Ou C , Chen P , Lin Z , Liu W
Ref : Neuromuscular Disorders , : , 2020
Abstract : Muscle-specific tyrosine kinase antibody (MuSK-Ab) and acetylcholine receptor antibody (AChR-Ab) coexistence in myasthenia gravis (MG) is very rare. In this report, two children with AChR-Ab switching to double antibody positive MG (DP-MG) or MuSK-Ab positive MG (MuSK-MG) are described. Six similar cases were found in the literature via online database search. Therefore, this study describes eight patients in total, six female and two male. The average age of onset was 7.25 +/- 5.95 years. Four AChR-MG patients switched to DP-MG with no known precipitating factor and four switched after thymectomy (two to MuSK-MG and two to DP-MG). After the serological switch, the patients transitioned to the phenotype of MuSK-MG and responded poorly to cholinesterase inhibitors and well to corticosteroids and plasma exchange.
ESTHER : Lu_2020_Neuromuscul.Disord__
PubMedSearch : Lu_2020_Neuromuscul.Disord__
PubMedID: 32387283

Title : ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield - Ou_2019_Nat.Commun_10_1078
Author(s) : Ou J , Peng Y , Yang W , Zhang Y , Hao J , Li F , Chen Y , Zhao Y , Xie X , Wu S , Zha L , Luo X , Xie G , Wang L , Sun W , Zhou Q , Li J , Liang H
Ref : Nat Commun , 10 :1078 , 2019
Abstract : The efficacy of Fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance. Autophagy has been implicated in chemoresistance, but the role of selective autophagic degradation in regulating chemoresistance remains unknown. In this study, we revealed a critical role of ABHD5 in charging CRC sensitivity to FU via regulating autophagic uracil yield. We demonstrated that ABHD5 localizes to lysosome and interacts with PDIA5 to prevent PDIA5 from interacting with RNASET2 and inactivating RNASET2. ABHD5 deficiency releases PDIA5 to directly interact with RNASET2 and leave RNASET2 in an inactivate state, which impairs RNASET2-mediated autophagic uracil yield and promotes CRC cells to uptake FU as an exogenous uracil, thus increasing their sensitivity to FU. Our findings for the first time reveal a novel role of ABHD5 in regulating lysosome function, highlighting the significance of ABHD5 as a compelling biomarker predicting the sensitivity of CRCs to FU-based chemotherapy.
ESTHER : Ou_2019_Nat.Commun_10_1078
PubMedSearch : Ou_2019_Nat.Commun_10_1078
PubMedID: 30842415
Gene_locus related to this paper: human-ABHD5

Title : Pyrrole 2-carbaldehyde derived alkaloids from the roots of Angelica dahurica - Qi_2019_J.Nat.Med_73_769
Author(s) : Qi B , Yang W , Ding N , Luo Y , Jia F , Liu X , Wang J , Wang X , Tu P , Shi S
Ref : J Nat Med , 73 :769 , 2019
Abstract : Six new pyrrole 2-carbaldehyde derived alkaloids, dahurines A-F (1-6), along with five known ones (7-11) and butyl 2-pyrrolidone-5-carboxylate (12) were isolated from the roots of Angelica dahurica. Their structures were determined by extensive spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism (ECD) methods. Although compounds 7 and 8 have been chemically synthesized, they were obtained from natural materials for the first time. Compounds 2, 3, 4, 10, and 11 exhibited acetylcholinesterase inhibitory activity with IC50 values in the range of 47.5-52.5 muM. Pyrrole 2-carbaldehyde derived alkaloids from the roots of Angelica dahurica.
ESTHER : Qi_2019_J.Nat.Med_73_769
PubMedSearch : Qi_2019_J.Nat.Med_73_769
PubMedID: 31209724

Title : Molecular characterization of ABHD5 gene promoter in intramuscular preadipocytes of Qinchuan cattle: Roles of Evi1 and C\/EBPalpha - Wang_2019_Gene_690_38
Author(s) : Wang X , Khan R , Raza SHA , Li A , Zhang Y , Liang C , Yang W , Wu S , Zan L
Ref : Gene , 690 :38 , 2019
Abstract : The genetic regulation of lipolytic enzyme is closely related to carcass quality traits through deposition of intramuscular fat (marbling) in beef cattle breeds. The alpha/beta hydrolase domain containing 5 (ABHD5) is an accelerating factor of adipose triglyceride lipase (ATGL), which plays a key role in triglyceride metabolism. In this study, we determined that bovine ABHD5 gene was highly expressed in adult bovine adipose tissue. To elucidate the molecular mechanisms involved in bovine ABHD5 regulation, we cloned and characterized the promoter region of ABHD5. Applying 5'-rapid amplification of cDNA end analysis (RACE), we identified transcriptional start site (TSS) found in the predicted CpG island within promoter region of ABHD5 gene. Using the recombinant dual fluorescent reporter vectors, the fragment of -109/+307 was identified as proximal minimum core promoter region of ABHD5 in bovine intramuscular adipocytes. Site directed mutagenesis and electrophoretic mobility shift assay (EMSA) confirmed the role of two transcription factors, namely Ectopic viral integration site-1 (Evi1) and CCAAT/enhancer binding protein alpha (C/EBPalpha), in the regulation of ABHD5 gene. Taken together these findings we can conclude that ABHD5 gene regulated by Evi1 and C/EBPalpha could be used as potential marker in marker assisted selection for the improvement of Qinchuan cattle breed for carcass quality traits.
ESTHER : Wang_2019_Gene_690_38
PubMedSearch : Wang_2019_Gene_690_38
PubMedID: 30583026
Gene_locus related to this paper: bovin-q0vcc8

Title : Trace determination of carbamate pesticides in medicinal plants by a fluorescent technique - Wei_2018_Food.Chem.Toxicol_119_430
Author(s) : Wei JC , Wei B , Yang W , He CW , Su HX , Wan JB , Li P , Wang YT
Ref : Food & Chemical Toxicology , 119 :430 , 2018
Abstract : The safety issue of using carbamate pesticides in medicinal plants (MPs) has been a global concern and hence attracted attention of many researchers to develop analytical tools for trace pesticides detection. Derived from the fluorescence-based techniques, a rapid, convenient and efficient method for the detection of three carbamate pesticides, including carbofuran, aldicarb and methomyl has been developed by using core-shell QDs. By optimizing experimental parameters, the system demonstrated high detection sensitivities for the investigated carbamates, with the lowest detectable concentrations less than 0.05muM. The molecular docking study indicated that the selected carbamate pesticides bound to the catalytic active site of acetylcholinesterase via pi-pi or H-pi interactions, which also revealed the potential mechanism of the differences in inhibition strength among the three pesticides on AChE. Moreover, in order to investigate the applicability and reliability of the proposed method for the pesticide analysis in real sample with complex matrix, the matrix effects of eight common MPs have been systematically explored. These findings suggested that this technique was a simple, sensitive and reliable method for rapid determination of carbamate pesticides in real samples, especially those with complex matrices like MPs, vegetables, fruits, and other agricultural crops.
ESTHER : Wei_2018_Food.Chem.Toxicol_119_430
PubMedSearch : Wei_2018_Food.Chem.Toxicol_119_430
PubMedID: 29269059

Title : Evidence for multiple-insecticide resistance in urban Aedes albopictus populations in southern China - Li_2018_Parasit.Vectors_11_4
Author(s) : Li Y , Xu J , Zhong D , Zhang H , Yang W , Zhou G , Su X , Wu Y , Wu K , Cai S , Yan G , Chen XG
Ref : Parasit Vectors , 11 :4 , 2018
Abstract : BACKGROUND: Aedes albopictus (Skuse) is an invasive mosquito that has become an important vector of chikungunya, dengue and Zika viruses. In the absence of specific antiviral therapy or a vaccine, vector management is the sole method available for reducing Aedes-induced disease morbidity. Determining the resistance status of Ae. albopictus to insecticides and exploring the resistance mechanisms is essential for future vector control planning. METHODS: Aedes albopictus larvae and pupae were sampled from six sites (two sites each from urban, suburban and rural) in Guangzhou. The resistance bioassays were conducted against Bacillus thuringiensis israelensis (Bti): deltamethrin, propoxur and malathion for larvae; and deltamethrin, DDT, propoxur and malathion for adults. P450 monooxygenase (P450s), glutathione S-transferase (GSTs) and carboxylesterase (COEs) activities of adult mosquitoes were measured. Mutations at the knockdown resistance (kdr) gene were analyzed, and the association between kdr mutations and phenotypic resistance was tested. RESULTS: Adult bioassays revealed varied susceptibility against DDT, deltamethrin and propoxur in the six Ae. albopictus populations. Significantly lower mortality rates were found in urban populations than suburban and rural populations. Urban mosquito populations showed resistance against DDT, deltamethrin and propoxur, while one rural population was resistant to DDT. All populations tested were susceptible to malathion. Larval bioassays results indicated that all populations of Ae. albopictus were sensitive to the larvicide Bti and malathion. Resistance to deltamethrin and propoxur was common in larval populations. The F1534S and F1534 L mutations were found to be significantly associated with deltamethrin resistance. Biochemical assays indicated elevated detoxification enzyme activities in the field mosquito populations. CONCLUSIONS: Aedes albopictus populations in Guangzhou, especially in urban areas, have developed resistance to the commonly used insecticides, primarily DDT and deltamethrin. This finding calls for resistance management and developing counter measures to mitigate the spread of resistance.
ESTHER : Li_2018_Parasit.Vectors_11_4
PubMedSearch : Li_2018_Parasit.Vectors_11_4
PubMedID: 29298700

Title : Chronic brain toxicity response of juvenile Chinese rare minnows (Gobiocypris rarus) to the neonicotinoid insecticides imidacloprid and nitenpyram - Tian_2018_Chemosphere_210_1006
Author(s) : Tian X , Yang W , Wang D , Zhao Y , Yao R , Ma L , Ge C , Li X , Huang Z , He L , Jiao W , Lin A
Ref : Chemosphere , 210 :1006 , 2018
Abstract : Imidacloprid and nitenpyram are widely used neonicotinoid pesticides worldwide and were observed to adversely affect non-target aquatic organisms. In this study, the toxic effect of imidacloprid and nitenpyram on the brain of juvenile Chinese rare minnows (Gobiocypris rarus) was investigated by determining the oxidative stress, 8-hydroxy-2-deoxyguanosine (8-OHdG) content and acetylcholinesterase (AChE) activity. The superoxide dismutase (SOD) activities did not significantly change after long-term exposure to imidacloprid and nitenpyram. A noticeable increase of catalase (CAT) activities was observed on the brain tissues under 0.1mg/L imidacloprid and under all nitenpyram treatments (p<0.05). The malondialdehyde (MDA) content increased markedly under 2.0mg/L imidacloprid and 0.1mg/L nitenpyram treatments (p<0.05). The glutathione (GSH) content in the brain significantly increased under 0.5 and 2.0mg/L imidacloprid (p<0.05). A significant decrease was observed in the mRNA levels of Cu/Zn-sod under 2.0mg/L imidacloprid and those of cat under 0.1 and 0.5mg/L nitenpyram (p<0.05). The mRNA levels of gpx1 clearly decreased under 2.0mg/L imidacloprid and under 0.1mg/L nitenpyram (p<0.05). The treatments of 0.1 and 0.5mg/L nitenpyram decreased cat expression levels markedly (p<0.05). 2.0mg/L imidacloprid raised the 8-OHdG content. The AChE activities increased markedly under 0.5 and 2.0mg/L imidacloprid while clearly decreasing under 2.0mg/L nitenpyram (p<0.05). Therefore, our results indicate that imidacloprid and nitenpyram might cause adverse effects on juvenile Chinese rare minnows brain. Notably, imidacloprid had greater impacts on juvenile rare minnows compared to nitenpyram.
ESTHER : Tian_2018_Chemosphere_210_1006
PubMedSearch : Tian_2018_Chemosphere_210_1006
PubMedID: 30208524

Title : Complete Genome Sequence of Fish Pathogen Aeromonas hydrophila JBN2301 - Yang_2016_Genome.Announc_4_
Author(s) : Yang W , Li N , Li M , Zhang D , An G
Ref : Genome Announc , 4 : , 2016
Abstract : Aeromonas hydrophila is one of the most important fish pathogens in China. Here, we report complete genome sequence of a virulent strain, A. hydrophila JBN2301, which was isolated from diseased crucian carp.
ESTHER : Yang_2016_Genome.Announc_4_
PubMedSearch : Yang_2016_Genome.Announc_4_
PubMedID: 26823580
Gene_locus related to this paper: aerhy-a0a0s3bhm4

Title : Treatment effects of tanshinone IIA against intracerebroventricular streptozotocin induced memory deficits in mice - Liu_2016_Brain.Res_1631_137
Author(s) : Liu C , Wu Y , Zha S , Liu M , Wang Y , Yang G , Ma K , Fei Y , Zhang Y , Hu X , Yang W , Qian Y
Ref : Brain Research , 1631 :137 , 2016
Abstract : Our previous studies demonstrated that tanshinone IIA (tan IIA) has significant protective effects against the neurotoxicity induced by beta-amyloid protein (Abeta) in cultured cortical neurons and PC12 cells. This study was designed to investigate the protective effects of tan IIA against memory deficits induced by streptozotocin (STZ) in a model of sporadic Alzheimer's disease (AD). STZ was injected twice intracerebroventrically (3mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with tan IIA (20, 40, and 80mg/kg, i.g.) starting from the first dose of STZ for 28 days showed a dose dependent improvement in STZ induced memory deficits as assessed by Morris water maze (MWM) test. Nissl staining results confirmed the protective effects of tan IIA on cerebral cortical and hippocampal neurons damage induced by STZ. In addition, tan IIA markedly reduced STZ induced elevation in acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level, and significantly inhibited STZ induced reduction in superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities in the parietal cortex and hippocampus. Moreover, tan IIA attenuated p38 mitogen activated protein kinase (MAPK) phosphorylation in the parietal cortex and hippocampus. These findings demonstrate that tan IIA prevents STZ induced memory deficits may be attributed to ameliorating neuronal damage, restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. Based on our previous studies, the present study provides further support for the potential use of tan IIA in the treatment of AD.
ESTHER : Liu_2016_Brain.Res_1631_137
PubMedSearch : Liu_2016_Brain.Res_1631_137
PubMedID: 26656068

Title : ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2 - Peng_2016_Autophagy_12_2167
Author(s) : Peng Y , Miao H , Wu S , Yang W , Zhang Y , Xie G , Xie X , Li J , Shi C , Ye L , Sun W , Wang L , Liang H , Ou J
Ref : Autophagy , 12 :2167 , 2016
Abstract : Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene BECN1 (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.
ESTHER : Peng_2016_Autophagy_12_2167
PubMedSearch : Peng_2016_Autophagy_12_2167
PubMedID: 27559856
Gene_locus related to this paper: human-ABHD5

Title : A direct assay of butyrylcholinesterase activity using a fluorescent substrate - Kang_2016_Org.Biomol.Chem_14_8815
Author(s) : Kang S , Lee S , Yang W , Seo J , Han MS
Ref : Org Biomol Chem , 14 :8815 , 2016
Abstract : In this study, we report a direct fluorometric assay for butyrylcholinesterase (BChE) activity and screening of its inhibitor, using a fluorescent substrate. 2-(2-(5,6-Dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)-N,N,N-trimethylethan-1-ammo nium iodide (1) was hydrolyzed by BChE, and its fluorescence was quenched by an intramolecular photoinduced electron transfer process. The resulting change in fluorescence provided a facile method for real-time BChE activity testing. Remarkably, 1 was selectively hydrolyzed by BChE, even in the presence of excess acetylcholinesterase, thereby facilitating the specific monitoring of BChE activity. This assay method is also useful for screening potential BChE inhibitors. Given its simplicity, selectivity, and higher assay speed, this method may be extended to high-throughput screening of BChE inhibitors and relevant drug discovery.
ESTHER : Kang_2016_Org.Biomol.Chem_14_8815
PubMedSearch : Kang_2016_Org.Biomol.Chem_14_8815
PubMedID: 27714157

Title : A novel eurythermic and thermostale lipase LipM from Pseudomonas moraviensis M9 and its application in the partial hydrolysis of algal oil - Yang_2015_BMC.Biotechnol_15_94
Author(s) : Yang W , Cao H , Xu L , Zhang H , Yan Y
Ref : BMC Biotechnol , 15 :94 , 2015
Abstract : BACKGROUND: Lipases are regularly used in biotechnology to catalyse the hydrolysis of triglycerides and the synthesis of esters. Microbial lipases in particular have been widely used in a variety of industrial applications. However, the current commercial microbial lipases cannot meet industrial demand due to rapid inactivation under harsh conditions. Therefore, in order to identify more stable enzymes, we isolated novel eurythermic and thermostable lipase(s) from Pseudomonas moraviensis M9. METHODS: Cloning of lipM was based on Touchdown PCR and genome walking, and then recombinant LipM was purified by guanidine hydrochloride and the nickel-nitrilotriacetic acid resins affinity chromatography. Finally, the hydrolysis of algal oil by LipM was analyzed by gas chromatograph-mass spectrometer, thin layer chromatography and gas chromatograph. RESULTS: The lipM gene was first cloned from Pseudomonas moraviensis M9 via Touchdown PCR and genome walking. Sequence analysis reveals that LipM is a member of subfamily I.3 of lipases, and the predicted amino acid sequences of LipM has 82 % identity to lipase LipT from Pseudomonas mandelii JR-1, and 54 % identity to lipase PML from Pseudomonas sp. MIS38 and lipase Lip I.3 from Pseudomonas sp. CR-611. LipM was expressed in Escherichia coli, purified from inclusion bodies, and further biochemically characterized. Purified LipM differed significantly from previously reported subfamily I.3 lipases, and was eurythermic between 10 degreesC-95 degreesC. LipM activity was enhanced by Ca(2+), Sr(2+), Mn(2+), and Ba(2+), but sharply inhibited by Cu(2+), Zn(2+), Co(2+), Ni(2+), and EDTA. Compared with other lipases, LipM exhibited medium tolerance to methanol, ethanol, and isopropanol. When applied for hydrolysis of algal oil, LipM could enrich 65.88 % polyunsaturated fatty acids, which include 1.25 % eicosapentaenoic acid, 17.61 % docosapentaenoic acid, and 47.02 % docosahexaenoic acid with derivative glycerides containing 32.46 % diacylglycerols. CONCLUSIONS: A novel eurythermic I.3 subfamily lipase with high tolerance and stability was identified from Pseudomonas moraviensis and biochemically characterized. It will not only improve our understanding of subfamily I.3 lipases, but also provides an ideal biocatalyst for the enrichment of polyunsaturated fatty acids. Pseudomonas moraviensis have been investigated as a potential resource of lipases.
ESTHER : Yang_2015_BMC.Biotechnol_15_94
PubMedSearch : Yang_2015_BMC.Biotechnol_15_94
PubMedID: 26463643

Title : Genome sequence of cultivated Upland cotton (Gossypium hirsutum TM-1) provides insights into genome evolution - Li_2015_Nat.Biotechnol_33_524
Author(s) : Li F , Fan G , Lu C , Xiao G , Zou C , Kohel RJ , Ma Z , Shang H , Ma X , Wu J , Liang X , Huang G , Percy RG , Liu K , Yang W , Chen W , Du X , Shi C , Yuan Y , Ye W , Liu X , Zhang X , Liu W , Wei H , Wei S , Zhu S , Zhang H , Sun F , Wang X , Liang J , Wang J , He Q , Huang L , Cui J , Song G , Wang K , Xu X , Yu JZ , Zhu Y , Yu S
Ref : Nat Biotechnol , 33 :524 , 2015
Abstract : Gossypium hirsutum has proven difficult to sequence owing to its complex allotetraploid (AtDt) genome. Here we produce a draft genome using 181-fold paired-end sequences assisted by fivefold BAC-to-BAC sequences and a high-resolution genetic map. In our assembly 88.5% of the 2,173-Mb scaffolds, which cover 89.6% approximately 96.7% of the AtDt genome, are anchored and oriented to 26 pseudochromosomes. Comparison of this G. hirsutum AtDt genome with the already sequenced diploid Gossypium arboreum (AA) and Gossypium raimondii (DD) genomes revealed conserved gene order. Repeated sequences account for 67.2% of the AtDt genome, and transposable elements (TEs) originating from Dt seem more active than from At. Reduction in the AtDt genome size occurred after allopolyploidization. The A or At genome may have undergone positive selection for fiber traits. Concerted evolution of different regulatory mechanisms for Cellulose synthase (CesA) and 1-Aminocyclopropane-1-carboxylic acid oxidase1 and 3 (ACO1,3) may be important for enhanced fiber production in G. hirsutum.
ESTHER : Li_2015_Nat.Biotechnol_33_524
PubMedSearch : Li_2015_Nat.Biotechnol_33_524
PubMedID: 25893780
Gene_locus related to this paper: gosra-a0a0d2rxs2 , gosra-a0a0d2tng2 , gosra-a0a0d2twz7 , goshi-a0a1u8hr03 , gosra-a0a0d2vdc5 , goshi-a0a1u8ljh5 , gosra-a0a0d2vj24 , goshi-a0a1u8pxd3 , gosra-a0a0d2sr31 , goshi-a0a1u8knd1 , goshi-a0a1u8nhw9 , goshi-a0a1u8mt09 , goshi-a0a1u8kis4 , goshi-a0a1u8ibk3 , goshi-a0a1u8ieg2 , goshi-a0a1u8iki6 , goshi-a0a1u8jvp4 , goshi-a0a1u8jw35 , gosra-a0a0d2pzd7 , goshi-a0a1u8ied7

Title : Characterizing LipR from Pseudomonas sp. R0-14 and Applying in Enrichment of Polyunsaturated Fatty Acids from Algal Oil - Yang_2015_J.Microbiol.Biotechnol_25_1880
Author(s) : Yang W , Xu L , Zhang H , Yan Y
Ref : J Microbiol Biotechnol , 25 :1880 , 2015
Abstract : In this study, Pseudomonas R0-14, which was isolated from Arctic soil samples, showed a clear halo when grown on M9 medium agarose plates containing olive oil-rhodamine B as substrate, suggesting that it expressed putative lipase(s). A putative lipase gene, lipR, was cloned from R0-14 by genome walking and Touchdown PCR. lipR encodes a 562-amino-acid polypeptide showing a typical alpha/beta hydrolase structure with a catalytic triad consisting of Ser153-Asp202-His260 and one alpha-helical lid (residues 103-113). A phylogenetic analysis revealed that LipR belongs to the lipase subfamily I.3. LipR was successfully expressed in Escherichia coli, purified, and biochemically characterized. Recombinant LipR exhibited its maximum activity towards p-nitrophenyl butyrate at pH 8.5 and 60 degrees C with a Km of 0.37 mM and a kcat of 6.42 s(-1). It retained over 90% of its original activity after incubation at 50 degrees C for 12 h. In addition, LipR was activated by Ca(2+), Mg(2+), Ba(2+), and Sr(2+), while strongly inhibited by Cu(2+), Zn(2+), Mn(2+), and ethylenediaminetetraacetic acid. Moreover, it showed a certain tolerance to organic solvents, including acetonitrile, isopropanol, acetone, methanol, and tert-butanol. When algal oil was hydrolyzed by LipR for 24 h, there was an enrichment of n-3 long-chain polyunsaturated fatty acids, including eicosapentaenoic acid (1.22%, 1.65-fold), docosapentaenoic acid (21.24%, 2.04-fold), and docosahexaenoic acid (36.98%, 1.33-fold), and even a certain amount of diacylglycerols was also produced. As a result, LipR has great prospect in industrial applications, especially in food and/or cosmetics applications.
ESTHER : Yang_2015_J.Microbiol.Biotechnol_25_1880
PubMedSearch : Yang_2015_J.Microbiol.Biotechnol_25_1880
PubMedID: 26215266

Title : Quantitative Proteomics Analysis of the Hepatitis C Virus Replicon High-Permissive and Low-Permissive Cell Lines - Ye_2015_PLoS.One_10_e0142082
Author(s) : Ye F , Xin Z , Han W , Fan J , Yin B , Wu S , Yang W , Yuan J , Qiang B , Sun W , Peng X
Ref : PLoS ONE , 10 :e0142082 , 2015
Abstract : Chronic hepatitis C virus (HCV) infection is one of the leading causes of severe hepatitis. The molecular mechanisms underlying HCV replication and pathogenesis remain unclear. The development of the subgenome replicon model system significantly enhanced study of HCV. However, the permissiveness of the HCV subgenome replicon greatly differs among different hepatoma cell lines. Proteomic analysis of different permissive cell lines might provide new clues in understanding HCV replication. In this study, to detect potential candidates that might account for the differences in HCV replication. Label-free and iTRAQ labeling were used to analyze the differentially expressed protein profiles between Huh7.5.1 wt and HepG2 cells. A total of 4919 proteins were quantified in which 114 proteins were commonly identified as differentially expressed by both quantitative methods. A total of 37 differential proteins were validated by qRT-PCR. The differential expression of Glutathione S-transferase P (GSTP1), Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), carboxylesterase 1 (CES1), vimentin, Proteasome activator complex subunit1 (PSME1), and Cathepsin B (CTSB) were verified by western blot. And over-expression of CTSB or knock-down of vimentin induced significant changes to HCV RNA levels. Additionally, we demonstrated that CTSB was able to inhibit HCV replication and viral protein translation. These results highlight the potential role of CTSB and vimentin in virus replication.
ESTHER : Ye_2015_PLoS.One_10_e0142082
PubMedSearch : Ye_2015_PLoS.One_10_e0142082
PubMedID: 26544179

Title : Molecular traces of alternative social organization in a termite genome - Terrapon_2014_Nat.Commun_5_3636
Author(s) : Terrapon N , Li C , Robertson HM , Ji L , Meng X , Booth W , Chen Z , Childers CP , Glastad KM , Gokhale K , Gowin J , Gronenberg W , Hermansen RA , Hu H , Hunt BG , Huylmans AK , Khalil SM , Mitchell RD , Munoz-Torres MC , Mustard JA , Pan H , Reese JT , Scharf ME , Sun F , Vogel H , Xiao J , Yang W , Yang Z , Zhou J , Zhu J , Brent CS , Elsik CG , Goodisman MA , Liberles DA , Roe RM , Vargo EL , Vilcinskas A , Wang J , Bornberg-Bauer E , Korb J , Zhang G , Liebig J
Ref : Nat Commun , 5 :3636 , 2014
Abstract : Although eusociality evolved independently within several orders of insects, research into the molecular underpinnings of the transition towards social complexity has been confined primarily to Hymenoptera (for example, ants and bees). Here we sequence the genome and stage-specific transcriptomes of the dampwood termite Zootermopsis nevadensis (Blattodea) and compare them with similar data for eusocial Hymenoptera, to better identify commonalities and differences in achieving this significant transition. We show an expansion of genes related to male fertility, with upregulated gene expression in male reproductive individuals reflecting the profound differences in mating biology relative to the Hymenoptera. For several chemoreceptor families, we show divergent numbers of genes, which may correspond to the more claustral lifestyle of these termites. We also show similarities in the number and expression of genes related to caste determination mechanisms. Finally, patterns of DNA methylation and alternative splicing support a hypothesized epigenetic regulation of caste differentiation.
ESTHER : Terrapon_2014_Nat.Commun_5_3636
PubMedSearch : Terrapon_2014_Nat.Commun_5_3636
PubMedID: 24845553
Gene_locus related to this paper: zoone-a0a067r283 , zoone-a0a067qst6 , zoone-a0a067rbc7 , zoone-a0a067qz43 , zoone-a0a067qn94 , zoone-a0a067rbw9 , zoone-a0a067qx93 , zoone-a0a067rcf4 , zoone-a0a067r8q8 , zoone-a0a067rh81 , zoone-a0a067r506 , zoone-a0a067qxd4 , zoone-a0a067qy86 , zoone-a0a067qsw2 , zoone-a0a067qfp9 , zoone-a0a067ru91 , zoone-a0a067rwu7 , zoone-a0a067rmu8 , zoone-a0a067r773 , zoone-a0a067qlt8 , zoone-a0a067qhm6 , zoone-a0a067qjz2 , zoone-a0a067qs20 , zoone-a0a067rmu4 , zoone-a0a067qty7 , zoone-a0a067rk35 , zoone-a0a067rk64 , zoone-a0a067rj74 , zoone-a0a067rp97 , zoone-a0a067rjm1

Title : Complete genome sequencing and comparative analysis of the linezolid-resistant Enterococcus faecalis strain DENG1 - Yu_2014_Arch.Microbiol_196_513
Author(s) : Yu Z , Chen Z , Cheng H , Zheng J , Li D , Deng X , Pan W , Yang W , Deng Q
Ref : Arch Microbiol , 196 :513 , 2014
Abstract : Genome level analysis of bacterial strains provides information on genetic composition and resistance mechanisms to clinically relevant antibiotics. To date, whole genome characterization of linezolid-resistant Enterococcus faecalis isolated in the clinic is lacking. In this study, we report the entire genome sequence, genomic characteristics and virulence factors of a pathogenic E. faecalis strain, DENG1. Our results showed considerable differences in genomic characteristics and virulence factors compared with other E. faecalis strains (V583 and OG1RF). The genome of this LZD-resistant E. faecalis strain can be used as a reference to study the mechanism of LZD resistance and the phylogenetic relationship of E. faecalis strains worldwide.
ESTHER : Yu_2014_Arch.Microbiol_196_513
PubMedSearch : Yu_2014_Arch.Microbiol_196_513
PubMedID: 24800692

Title : Inhibition of flavonoids on acetylcholine esterase: binding and structure-activity relationship - Xie_2014_Food.Funct_5_2582
Author(s) : Xie Y , Yang W , Chen X , Xiao J
Ref : Food Funct , 5 :2582 , 2014
Abstract : The inhibitory effects of flavonoids on acetylcholinesterase (AChE) have attracted great interest among researchers. However, few reports have focused on the structure-activity relationship for AChE inhibition of flavonoids. This work mainly concerns the structural aspects of inhibitory activities and binding affinities of flavonoids as AChE inhibitors. The results show that hydroxyl groups in the A ring of flavonoids are favorable for inhibiting AChE, and the hydroxylation increases the affinities for AChE. However, methoxylation may decrease or increase the activities depending on the class of flavonoids. The glycosylation decreases the AChE inhibitory activities of flavonoids and lowers the affinities for AChE by 1 to 5 times depending on the conjunction site and the type of sugar moiety. The hydrogenation of the C2-C3 double bond of apigenin decreases both the affinity for AChE and AChE inhibition. The molecular property-affinity relationship reveals that the hydrogen bond force plays an important role in binding flavonoids to AChE. The AChE inhibitions generally increase with the increasing affinities of flavonoids within the class, especially for flavones and flavonols.
ESTHER : Xie_2014_Food.Funct_5_2582
PubMedSearch : Xie_2014_Food.Funct_5_2582
PubMedID: 25143139

Title : Protective effects of perindopril on d-galactose and aluminum trichloride induced neurotoxicity via the apoptosis of mitochondria-mediated intrinsic pathway in the hippocampus of mice - Yang_2014_Brain.Res.Bull_109_46
Author(s) : Yang W , Shi L , Chen L , Zhang B , Ma K , Liu Y , Qian Y
Ref : Brain Research Bulletin , 109 :46 , 2014
Abstract : Perindopril, an angiotensin converting enzyme inhibitor, has been reported to improve learning and memory in a mouse or rat model of Alzheimer's disease (AD) induced by injection of beta-amyloid protein. However, the exact mechanism of perindopril on the cognitive deficits is not fully understood. Our previous data have indicated that perindopril improves learning and memory in a mouse model of AD induced by d-galactose (d-gal) and aluminum trichloride (AlCl3) via inhibition of acetylcholinesterase activity and oxidative stress. Whether perindopril also inhibit apoptosis to prevent cognitive decline remains unknown in mice. Therefore, the present study explored the protective effects of perindopril in the hippocampus of mice further. Perindopril (0.5mg/kg/day) was administered intragastrically for 60 days after the mice were given a d-gal (150mg/kg/day) and AlCl3 (10mg/kg/day) intraperitoneally for 90 days. Then the expression of Bcl-2, Bax, Fas, FasL, caspase-3, caspase-8 and caspase-9 were analyzed by RT-PCR and western blotting in the hippocampus. Perindopril significantly decreased caspase-3 and caspase-9 activities, and elevated Bcl-2/Bax ratio in the hippocampus. However, the expression of Fas, FasL and caspase-8 did not change in the hippocampus whether treatment with d-gal and AlCl3 or perindopril. Taken together, the above findings indicated that perindopril inhibited apoptosis in the hippocampus may be another mechanism by which perindopril improves learning and memory functions in d-gal and AlCl3 treated mice.
ESTHER : Yang_2014_Brain.Res.Bull_109_46
PubMedSearch : Yang_2014_Brain.Res.Bull_109_46
PubMedID: 25290208

Title : A highly efficient cocaine-detoxifying enzyme obtained by computational design - Zheng_2014_Nat.Commun_5_3457
Author(s) : Zheng F , Xue L , Hou S , Liu J , Zhan M , Yang W , Zhan CG
Ref : Nat Commun , 5 :3457 , 2014
Abstract : Compared with naturally occurring enzymes, computationally designed enzymes are usually much less efficient, with their catalytic activities being more than six orders of magnitude below the diffusion limit. Here we use a two-step computational design approach, combined with experimental work, to design a highly efficient cocaine hydrolysing enzyme. We engineer E30-6 from human butyrylcholinesterase (BChE), which is specific for cocaine hydrolysis, and obtain a much higher catalytic efficiency for cocaine conversion than for conversion of the natural BChE substrate, acetylcholine (ACh). The catalytic efficiency of E30-6 for cocaine hydrolysis is comparable to that of the most efficient known naturally occurring hydrolytic enzyme, acetylcholinesterase, the catalytic activity of which approaches the diffusion limit. We further show that E30-6 can protect mice from a subsequently administered lethal dose of cocaine, suggesting the enzyme may have therapeutic potential in the setting of cocaine detoxification or cocaine abuse.
ESTHER : Zheng_2014_Nat.Commun_5_3457
PubMedSearch : Zheng_2014_Nat.Commun_5_3457
PubMedID: 24643289
Gene_locus related to this paper: human-BCHE

Title : Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update - Wu_2014_Arch.Toxicol_88_1309
Author(s) : Wu QH , Wang X , Yang W , Nussler AK , Xiong LY , Kuca K , Dohnal V , Zhang XJ , Yuan ZH
Ref : Archives of Toxicology , 88 :1309 , 2014
Abstract : Trichothecenes are a large family of structurally related toxins mainly produced by Fusarium genus. Among the trichothecenes, T-2 toxin and deoxynivalenol (DON) cause the most concern due to their wide distribution and highly toxic nature. Trichothecenes are known for their inhibitory effect on eukaryotic protein synthesis, and oxidative stress is one of their most important underlying toxic mechanisms. They are able to generate free radicals, including reactive oxygen species, which induce lipid peroxidation leading to changes in membrane integrity, cellular redox signaling, and in the antioxidant status of the cells. The mitogen-activated protein kinases signaling pathway is induced by oxidative stress, which also induces caspase-mediated cellular apoptosis pathways. Several new metabolites and novel metabolic pathways of T-2 toxin have been discovered very recently. In human cell lines, HT-2 and neosolaniol (NEO) are the major metabolites of T-2 toxin. Hydroxylation on C-7 and C-9 are two novel metabolic pathways of T-2 toxin in rats. The metabolizing enzymes CYP3A22, CYP3A29, and CYP3A46 in pigs, as well as the enzymes CYP1A5 and CYP3A37 in chickens, are able to catalyze T-2 toxin and HT-2 toxin to form the C-3'-OH metabolites. Similarly to carboxylesterase, CYP3A29 possesses the hydrolytic ability in pigs to convert T-2 toxin to NEO. T-2 toxin is able to down- or upregulate cytochrome P-450 enzymes in different species. The metabolism of DON in humans is region-dependent. Free DON and DON-glucuronide are considered to be the biomarkers for humans. The masked mycotoxin DON-3-beta-D-glucoside can be hydrolyzed to free DON in the body. This review will provide useful information on the progress of oxidative stress as well as on the metabolism and the metabolizing enzymes of T-2 toxin and DON. Moreover, the literature will throw light on the blind spots of metabolism and toxicological studies in trichothecenes that have to be explored in the future.
ESTHER : Wu_2014_Arch.Toxicol_88_1309
PubMedSearch : Wu_2014_Arch.Toxicol_88_1309
PubMedID: 24894432

Title : Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (-)-cocaine - Xue_2013_Chem.Biol.Interact_203_57
Author(s) : Xue L , Hou S , Yang W , Fang L , Zheng F , Zhan CG
Ref : Chemico-Biological Interactions , 203 :57 , 2013
Abstract : It can be argued that an ideal anti-cocaine medication would be one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma. However, wild-type BChE has a low catalytic efficiency against naturally occurring (-)-cocaine. Interestingly, wild-type BChE has a much higher catalytic activity against unnatural (+)-cocaine. According to available positron emission tomography (PET) imaging analysis using [(11)C](-)-cocaine and [(11)C](+)-cocaine tracers in human subjects, only [(11)C](-)-cocaine was observed in the brain, whereas no significant [(11)C](+)-cocaine signal was observed in the brain. The available PET data imply that an effective therapeutic enzyme for treatment of cocaine abuse could be an exogenous cocaine-metabolizing enzyme with a catalytic activity against (-)-cocaine comparable to that of wild-type BChE against (+)-cocaine. Our recently designed A199S/F227A/S287G/A328 W/Y332G mutant of human BChE has a considerably improved catalytic efficiency against (-)-cocaine and has been proven active in vivo. In the present study, we have characterized the catalytic activities of wild-type BChE and the A199S/F227A/S287G/A328 W/Y332G mutant against both (+)- and (-)-cocaine at the same time under the same experimental conditions. Based on the obtained kinetic data, the A199S/F227A/S287G/A328 W/Y332G mutant has a similarly high catalytic efficiency (kcat/KM) against (+)- and (-)-cocaine, and indeed has a catalytic efficiency (kcat/KM=1.84x10(9)M(-1)min(-1)) against (-)-cocaine comparable to that (kcat/KM=1.37x10(9)M(-1)min(-1)) of wild-type BChE against (+)-cocaine. Thus, the mutant may be used to effectively prevent (-)-cocaine from entering brain and producing physiological effects in the enzyme-based treatment of cocaine abuse.
ESTHER : Xue_2013_Chem.Biol.Interact_203_57
PubMedSearch : Xue_2013_Chem.Biol.Interact_203_57
PubMedID: 22917637

Title : Draft genome of the wheat A-genome progenitor Triticum urartu - Ling_2013_Nature_496_87
Author(s) : Ling HQ , Zhao S , Liu D , Wang J , Sun H , Zhang C , Fan H , Li D , Dong L , Tao Y , Gao C , Wu H , Li Y , Cui Y , Guo X , Zheng S , Wang B , Yu K , Liang Q , Yang W , Lou X , Chen J , Feng M , Jian J , Zhang X , Luo G , Jiang Y , Liu J , Wang Z , Sha Y , Zhang B , Tang D , Shen Q , Xue P , Zou S , Wang X , Liu X , Wang F , Yang Y , An X , Dong Z , Zhang K , Luo MC , Dvorak J , Tong Y , Yang H , Li Z , Wang D , Zhang A
Ref : Nature , 496 :87 , 2013
Abstract : Bread wheat (Triticum aestivum, AABBDD) is one of the most widely cultivated and consumed food crops in the world. However, the complex polyploid nature of its genome makes genetic and functional analyses extremely challenging. The A genome, as a basic genome of bread wheat and other polyploid wheats, for example, T. turgidum (AABB), T. timopheevii (AAGG) and T. zhukovskyi (AAGGA(m)A(m)), is central to wheat evolution, domestication and genetic improvement. The progenitor species of the A genome is the diploid wild einkorn wheat T. urartu, which resembles cultivated wheat more extensively than do Aegilops speltoides (the ancestor of the B genome) and Ae. tauschii (the donor of the D genome), especially in the morphology and development of spike and seed. Here we present the generation, assembly and analysis of a whole-genome shotgun draft sequence of the T. urartu genome. We identified protein-coding gene models, performed genome structure analyses and assessed its utility for analysing agronomically important genes and for developing molecular markers. Our T. urartu genome assembly provides a diploid reference for analysis of polyploid wheat genomes and is a valuable resource for the genetic improvement of wheat.
ESTHER : Ling_2013_Nature_496_87
PubMedSearch : Ling_2013_Nature_496_87
PubMedID: 23535596
Gene_locus related to this paper: triua-m8a764 , triua-m8ag96 , triua-m7zp69 , wheat-w5d1z6 , wheat-w5d232 , wheat-w5bnf5 , triua-t1nm05 , wheat-w5cae4 , triua-m7ytf7 , wheat-w5f1j8 , triua-m8ad49 , wheat-a0a077s1q2 , wheat-a0a3b6c2m6 , triua-m7zi26 , wheat-a0a3b6at77 , wheat-a0a3b6atp7

Title : Two new acridone alkaloids from the branch of Atalantia buxifolia and their biological activity - Yang_2013_J.Asian.Nat.Prod.Res_15_899
Author(s) : Yang YY , Yang W , Zuo WJ , Zeng YB , Liu SB , Mei WL , Dai HF
Ref : J Asian Nat Prod Res , 15 :899 , 2013
Abstract : Two new acridone alkaloids, 3-methoxy-1,4,5-trihydroxy-10-methylacridone (1) and 2,3-dimethoxy-1,4,5-trihydroxy-10-methylacridone (2), were isolated from the ethanol extract of the branch of Atalantia buxifolia. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR. Compounds 1 and 2 exhibited significant antibacterial activity against Staphylococcus aureus and weak inhibitory effect on acetylcholinesterase.
ESTHER : Yang_2013_J.Asian.Nat.Prod.Res_15_899
PubMedSearch : Yang_2013_J.Asian.Nat.Prod.Res_15_899
PubMedID: 23796077

Title : Substrate selectivity of high-activity mutants of human butyrylcholinesterase - Hou_2013_Org.Biomol.Chem_11_7477
Author(s) : Hou S , Xue L , Yang W , Fang L , Zheng F , Zhan CG
Ref : Org Biomol Chem , 11 :7477 , 2013
Abstract : Cocaine is one of the most addictive drugs, and there is still no FDA (Food and Drug Administration)-approved medication specific for cocaine abuse. A promising therapeutic strategy is to accelerate cocaine metabolism, producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e. cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma. However, the native BChE has a low catalytic efficiency against the abused cocaine, i.e. (-)-cocaine. Our recently designed and discovered A199S/F227A/S287G/A328W/Y332G mutant and other mutants of human BChE have a considerably improved catalytic efficiency against (-)-cocaine. In the present study, we carried out both computational modeling and experimental kinetic analysis on the catalytic activities of these promising new BChE mutants against other known substrates, including neurotransmitter acetylcholine (ACh), acetylthiocholine (ATC), butyrylthiocholine (BTC), and (+)-cocaine, in comparison with the corresponding catalytic activity against (-)-cocaine. Both the computational modeling and kinetic analysis have consistently revealed that all the examined amino acid mutations only considerably improve the catalytic efficiency of human BChE against (-)-cocaine, without significantly improving the catalytic efficiency of the enzyme against any of the other substrates examined. In particular, all the examined BChE mutants have a slightly lower catalytic efficiency against neurotransmitter ACh compared to the wild-type BChE. This observation gives us confidence in developing an anti-cocaine enzyme therapy by using one of these BChE mutants, particularly the A199S/F227A/S287G/A328W/Y332G mutant.
ESTHER : Hou_2013_Org.Biomol.Chem_11_7477
PubMedSearch : Hou_2013_Org.Biomol.Chem_11_7477
PubMedID: 24077614

Title : High level expression, purification and activation of human dipeptidyl peptidase I from mammalian cells - Yang_2011_Protein.Expr.Purif_76_59
Author(s) : Yang W , Xia W , Mao J , Xu D , Chen J , Feng S , Wang J , Li H , Theisen CF , Petersen JM , Thorolfsson M , Rasmussen HB , Junker F , Boel E , Su J
Ref : Protein Expr Purif , 76 :59 , 2011
Abstract : Dipeptidyl peptidase I (DPPI) plays a crucial role in maturation of many regulatory peptides and has been suggested as a pharmaceutical target in several inflammatory diseases. It is also a useful processing enzyme for the generation of authentic protein products by catalyzing the removal of N-terminal fusion peptides. We used a robust transient transfection system in human embryonic kidney 293 cells to exploit expression and activation of DPPI from chicken, rat and man for the development of an industrial production process. The expression of human and rat DPPI was significantly higher in the human HEK293 cell line than that obtained with avian DPPI. A CHO K1SV stable cell line was selected as the optimal stable host system for production of human DPPI yielding expression levels higher than 1.5 g/L. The secreted pro-DPPI underwent auto-maturation during defined buffer conditions during the purification steps. Active human DPPI was purified with a three-step purification strategy employing: Butyl Sepharose 4 Fast Flow, Sephadex G-25 Medium and Q Sepharose Fast Flow chromatography. The final yield of active enzyme was approximately 1 g/L cell culture. The enzyme exhibited exopeptidase activity against both a dipeptide-p-nitroanilide substrate and N-terminally extended MEAE-hGH (Met-Glu-Ala-Glu-human growth hormone). In conclusion, an efficient production process for recombinant human DPPI has been developed including a highly efficient and stable CHO cell system and an efficient purification procedure, which is simple and easy to scale for industrial purposes. The present data facilitates not only industrial applications of DPPI as a processing enzyme, but also provides active enzyme useful in the identification of small molecule inhibitors.
ESTHER : Yang_2011_Protein.Expr.Purif_76_59
PubMedSearch : Yang_2011_Protein.Expr.Purif_76_59
PubMedID: 20828618

Title : Z-ligustilide isolated from Radix Angelicae sinensis ameliorates the memory impairment induced by scopolamine in mice - Cheng_2011_Fitoterapia_82_1128
Author(s) : Cheng LL , Chen XN , Wang Y , Yu L , Kuang X , Wang LL , Yang W , Du JR
Ref : Fitoterapia , 82 :1128 , 2011
Abstract : We investigated the effect of Z-ligustilide (LIG) on scopolamine-induced memory impairment in ICR mice. LIG (2.5-40 mg/kg) or tacrine (10 mg/kg) was orally administrated for 26 days. Behavior was examined in the Morris water maze and Y-maze after scopolamine administration (2 mg/kg, i.p.). The central acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities were assessed spectrophotometrically. LIG significantly improved spatial long-term memory and short-term memory impairment, inhibited AChE activity and increased ChAT activity. Moreover, LIG and tacrine showed the comparable efficacy in both neurobehavioral and cholinergic evaluation. These data suggest that LIG may alleviate memory deficits probably via enhancing cholinergic function.
ESTHER : Cheng_2011_Fitoterapia_82_1128
PubMedSearch : Cheng_2011_Fitoterapia_82_1128
PubMedID: 21807074

Title : Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (-)-cocaine: unexpected common rate-determining step - Liu_2011_J.Phys.Chem.B_115_5017
Author(s) : Liu J , Zhao X , Yang W , Zhan CG
Ref : J Phys Chem B , 115 :5017 , 2011
Abstract : First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to examine the catalytic mechanism for cocaine esterase (CocE)-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. It has been shown that the acylation of (+)-cocaine consists of nucleophilic attack of the hydroxyl group of Ser117 on the carbonyl carbon of (+)-cocaine benzoyl ester and the dissociation of (+)-cocaine benzoyl ester. The first reaction step of deacylation of (+)-cocaine, which is identical to that of (-)-cocaine, is rate-determining, indicating that CocE-catalyzed hydrolyses of (+)- and (-)-cocaine have a common rate-determining step. The computational results predict that the catalytic rate constant of CocE against (+)-cocaine should be the same as that of CocE against (-)-cocaine, in contrast with the remarkable difference between human butyrylcholinesterase-catalyzed hydrolyses of (+)- and (-)-cocaine. The prediction has been confirmed by experimental kinetic analysis on CocE-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. The determined common rate-determining step indicates that rational design of a high-activity mutant of CocE should be focused on the first reaction step of the deacylation. Furthermore, the obtained mechanistic insights into the detailed differences in the acylation between the (+)- and (-)-cocaine hydrolyses provide indirect clues for rational design of amino acid mutations that could more favorably stabilize the rate-determining transition state in the deacylation and, thus, improve the catalytic activity of CocE. This study provides a valuable mechanistic base for rational design of an improved esterase for therapeutic treatment of cocaine abuse.
ESTHER : Liu_2011_J.Phys.Chem.B_115_5017
PubMedSearch : Liu_2011_J.Phys.Chem.B_115_5017
PubMedID: 21486046

Title : Design, preparation, and characterization of high-activity mutants of human butyrylcholinesterase specific for detoxification of cocaine - Xue_2011_Mol.Pharmacol_79_290
Author(s) : Xue L , Ko MC , Tong M , Yang W , Hou S , Fang L , Liu J , Zheng F , Woods JH , Tai HH , Zhan CG
Ref : Molecular Pharmacology , 79 :290 , 2011
Abstract : Cocaine is a widely abused drug without a U.S. Food and Drug Administration-approved medication. There is a recognized, promising anticocaine medication to accelerate cocaine metabolism, producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway [i.e., cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma]. An ideal, therapeutically valuable mutant of human BChE should have not only a significantly improved catalytic activity against (-)-cocaine but also certain selectivity for (-)-cocaine over neurotransmitter acetylcholine (ACh), such that one would not expect systemic administration of the BChE mutant to interrupt cholinergic transmission. The present study accounting for the mutation-caused changes of the catalytic activities of BChE against both (-)-cocaine and ACh by means of molecular modeling and site-directed mutagenesis has led to identification of three BChE mutants that have not only a considerably improved catalytic efficiency against (-)-cocaine but also the desirable selectivity for (-)-cocaine over ACh. Two representative BChE mutants have been confirmed to be potent in actual protection of mice from acute toxicity (convulsion and lethality) of a lethal dose of cocaine (180 mg/kg). Pretreatment with the BChE mutant (i.e., 1 min before cocaine administration) dose-dependently protected mice against cocaine-induced convulsions and lethality. In particular, all mice pretreated with the mutant (e.g., 0.02 mg or more of A199S/F227A/S287G/A328W/E441D BChE) survived. The in vivo data reveal the primary factor (i.e., the relative catalytic efficiency), determining the efficacy in practical protection of mice from the acute cocaine toxicity and future direction for further improving the efficacy of the enzyme in the cocaine overdose treatment.
ESTHER : Xue_2011_Mol.Pharmacol_79_290
PubMedSearch : Xue_2011_Mol.Pharmacol_79_290
PubMedID: 20971807

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 : Free energy perturbation simulation on transition states and high-activity mutants of human butyrylcholinesterase for (-)-cocaine hydrolysis - Yang_2010_J.Phys.Chem.B_114_10889
Author(s) : Yang W , Pan Y , Fang L , Gao D , Zheng F , Zhan CG
Ref : J Phys Chem B , 114 :10889 , 2010
Abstract : A unified computational approach based on free energy perturbation (FEP) simulations of transition states has been employed to calculate the mutation-caused shifts of the free energy change from the free enzyme to the rate-determining transition state for (-)-cocaine hydrolysis catalyzed by the currently most promising series of mutants of human butyrylcholinesterase (BChE) that contain the A199S/A328W/Y332G mutations. The FEP simulations were followed by Michaelis-Menten kinetics analysis determining the individual k(cat) and K(M) values missing for the A199S/F227A/A328W/Y332G mutant in this series. The calculated mutation-caused shifts of the free energy change from the free enzyme to the rate-determining transition state are in good agreement with the experimental kinetic data, demonstrating that the unified computational approach based on the FEP simulations of the transition states may be valuable for future computational design of new BChE mutants with a further improved catalytic efficiency against (-)-cocaine.
ESTHER : Yang_2010_J.Phys.Chem.B_114_10889
PubMedSearch : Yang_2010_J.Phys.Chem.B_114_10889
PubMedID: 20677742

Title : Design of high-activity mutants of human butyrylcholinesterase against (-)-cocaine: structural and energetic factors affecting the catalytic efficiency - Zheng_2010_Biochemistry_49_9113
Author(s) : Zheng F , Yang W , Xue L , Hou S , Liu J , Zhan CG
Ref : Biochemistry , 49 :9113 , 2010
Abstract : The present study was aimed to explore the correlation between the protein structure and catalytic efficiency of butyrylcholinesterase (BChE) mutants against (-)-cocaine by modeling the rate-determining transition state (TS1), i.e., the transition state for the first step of chemical reaction process, of (-)-cocaine hydrolysis catalyzed by various mutants of human BChE in comparison with the wild type. Molecular modeling of the TS1 structures revealed that mutations on certain nonactive site residues can indirectly affect the catalytic efficiency of the enzyme against (-)-cocaine through enhancing or weakening the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of the enzyme. Computational insights and predictions were supported by the catalytic activity data obtained from wet experimental tests on the mutants of human BChE, including five new mutants reported for the first time. The BChE mutants with at least approximately 1000-fold improved catalytic efficiency against (-)-cocaine compared to the wild-type BChE are all associated with the TS1 structures having stronger overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of the enzyme. The combined computational and experimental data demonstrate a reasonable correlation relationship between the hydrogen-bonding distances in the TS1 structure and the catalytic efficiency of the enzyme against (-)-cocaine.
ESTHER : Zheng_2010_Biochemistry_49_9113
PubMedSearch : Zheng_2010_Biochemistry_49_9113
PubMedID: 20886866

Title : Characterization of a high-activity mutant of human butyrylcholinesterase against (-)-cocaine - Yang_2010_Chem.Biol.Interact_187_148
Author(s) : Yang W , Xue L , Fang L , Chen X , Zhan CG
Ref : Chemico-Biological Interactions , 187 :148 , 2010
Abstract : Cocaine addiction and overdose are a well-known public health problem. There is no approved medication available for cocaine abuse treatment. Our recently designed and discovered high-activity mutant (A199S/S287G/A328W/Y332G) of human butyrylcholinesterase (BChE) has been recognized to be worth exploring for clinical application in humans as a potential anti-cocaine medication. The catalytic rate constant (k(cat)) and Michaelis-Menten constant (K(M)) for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W/Y332G BChE (without fusion with any other peptide) have been determined to be 3,060 min(-1) and 3.1 microM, respectively, in the present study. The determined kinetic parameters reveal that the un-fused A199S/S287G/A328W/Y332G mutant has a approximately 1,080-fold improved catalytic efficiency (k(cat)/K(M)) against (-)-cocaine compared to the wild-type BChE. The approximately 1,080-fold improvement in the catalytic efficiency of the un-fused A199S/S287G/A328W/Y332G mutant is very close to the previously reported the approximately 1,000-fold improvement in the catalytic efficiency of the A199S/S287G/A328W/Y332G mutant fused with human serum albumin. These results suggest that the albumin fusion did not significantly change the catalytic efficiency of the BChE mutant while extending the plasma half-life. In addition, we have also examined the catalytic activities of the A199S/S287G/A328W/Y332G mutant against two other substrates, acetylthiocholine (ATC) and butyrylthiocholine (BTC). It has been shown that the A199S/S287G/A328W/Y332G mutations actually decreased the catalytic efficiencies of BChE against ATC and BTC, while considerably improving the catalytic efficiency of BChE against (-)-cocaine.
ESTHER : Yang_2010_Chem.Biol.Interact_187_148
PubMedSearch : Yang_2010_Chem.Biol.Interact_187_148
PubMedID: 20060817

Title : Free-energy perturbation simulation on transition states and redesign of butyrylcholinesterase - Yang_2009_Biophys.J_96_1931
Author(s) : Yang W , Pan Y , Zheng F , Cho H , Tai HH , Zhan CG
Ref : Biophysical Journal , 96 :1931 , 2009
Abstract : It is recognized that an ideal anti-cocaine treatment is to accelerate cocaine metabolism by producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., butyrylcholinesterase (BChE)-catalyzed hydrolysis of cocaine. BChE mutants with a higher catalytic activity against (-)-cocaine are highly desired for use as an exogenous enzyme in humans. To develop a rational design for high-activity mutants, we carried out free-energy perturbation (FEP) simulations on various mutations of the transition-state structures in addition to the corresponding free-enzyme structures by using an extended FEP procedure. The FEP simulations on the mutations of both the free-enzyme and transition-state structures allowed us to calculate the mutation-caused shift of the free-energy change from the free enzyme (BChE) to the transition state, and thus to theoretically predict the mutation-caused shift of the catalytic efficiency (k(cat)/K(M)). The computational predictions are supported by the kinetic data obtained from the wet experiments, demonstrating that the FEP-based computational design approach is promising for rational design of high-activity mutants of an enzyme. One of the BChE mutants designed and discovered in this study has an approximately 1800-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE. The high-activity mutant may be therapeutically valuable.
ESTHER : Yang_2009_Biophys.J_96_1931
PubMedSearch : Yang_2009_Biophys.J_96_1931
PubMedID: 19254552

Title : Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24-week, double-blind, randomized trial - Pan_2008_Diabet.Med_25_435
Author(s) : Pan C , Yang W , Barona JP , Wang Y , Niggli M , Mohideen P , Foley JE
Ref : Diabet Med , 25 :435 , 2008
Abstract : AIMS: To compare the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, vildagliptin, with the alpha glucosidase inhibitor, acarbose, in drug-naive patients with Type 2 diabetes. METHODS: This multi-centre, randomized, double-blind, parallel-arm study compared the efficacy and tolerability of vildagliptin (100 mg daily, given as 50 mg twice daily, n = 441) and acarbose (up to 300 mg daily, given as three equally divided doses, n = 220) during 24-week treatment in drug-naive patients with Type 2 diabetes. RESULTS: Monotherapy with vildagliptin or acarbose decreased glycated haemoglobin (HbA(1c)) (baseline approximately 8.6%) to a similar extent during 24-week treatment. The adjusted mean change from baseline to end-point (AMDelta) in HbA(1c) was -1.4 +/- 0.1% and -1.3 +/- 0.1% in patients receiving vildagliptin and acarbose, respectively, meeting the statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment difference < or = 0.4%). The decrease in fasting plasma glucose was similar with acarbose (-1.5 +/- 0.2 mmol/l) and vildagliptin (-1.2 +/- 0.1 mmol/l). Body weight did not change in vildagliptin-treated patients (-0.4 +/- 0.1 kg) but decreased in acarbose-treated patients (-1.7 +/- 0.2 kg, P < 0.001 vs. vildagliptin). The proportion of patients experiencing any adverse event (AE) was 35% vs. 51% in patients receiving vildagliptin or acarbose, respectively; gastrointestinal AEs were significantly more frequent with acarbose (25.5%) than vildagliptin (12.3%, P < 0.001). No hypoglycaemia was reported for either group. CONCLUSIONS: Vildagliptin is effective and well tolerated in patients with Type 2 diabetes, demonstrating similar glycaemic reductions to acarbose, but with better tolerability.
ESTHER : Pan_2008_Diabet.Med_25_435
PubMedSearch : Pan_2008_Diabet.Med_25_435
PubMedID: 18341596

Title : Most efficient cocaine hydrolase designed by virtual screening of transition states - Zheng_2008_J.Am.Chem.Soc_130_12148
Author(s) : Zheng F , Yang W , Ko MC , Liu J , Cho H , Gao D , Tong M , Tai HH , Woods JH , Zhan CG
Ref : Journal of the American Chemical Society , 130 :12148 , 2008
Abstract : Cocaine is recognized as the most reinforcing of all drugs of abuse. There is no anticocaine medication available. The disastrous medical and social consequences of cocaine addiction have made the development of an anticocaine medication a high priority. It has been recognized that an ideal anticocaine medication is one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., cocaine hydrolysis catalyzed by plasma enzyme butyrylcholinesterase (BChE). However, wild-type BChE has a low catalytic efficiency against the abused cocaine. Design of a high-activity enzyme mutant is extremely challenging, particularly when the chemical reaction process is rate-determining for the enzymatic reaction. Here we report the design and discovery of a high-activity mutant of human BChE by using a novel, systematic computational design approach based on transition-state simulations and activation energy calculations. The novel computational design approach has led to discovery of the most efficient cocaine hydrolase, i.e., a human BChE mutant with an approximately 2000-fold improved catalytic efficiency, promising for therapeutic treatment of cocaine overdose and addiction as an exogenous enzyme in human. The encouraging discovery resulted from the computational design not only provides a promising anticocaine medication but also demonstrates that the novel, generally applicable computational design approach is promising for rational enzyme redesign and drug discovery.
ESTHER : Zheng_2008_J.Am.Chem.Soc_130_12148
PubMedSearch : Zheng_2008_J.Am.Chem.Soc_130_12148
PubMedID: 18710224

Title : Free energy perturbation (FEP) simulation on the transition states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants - Pan_2007_J.Am.Chem.Soc_129_13537
Author(s) : Pan Y , Gao D , Yang W , Cho H , Zhan CG
Ref : Journal of the American Chemical Society , 129 :13537 , 2007
Abstract : A novel computational protocol based on free energy perturbation (FEP) simulations on both the free enzyme and transition state structures has been developed and tested to predict the mutation-caused shift of the free energy change from the free enzyme to the rate-determining transition state for human butyrylcholinesterase (BChE)-catalyzed hydrolysis of (-)-cocaine. The calculated shift, denoted by DeltaDeltaG(1 --> 2), of such kind of free energy change determines the catalytic efficiency (kcat/KM) change caused by the simulated mutation transforming enzyme 1 to enzyme 2. By using the FEP-based computational protocol, the DeltaDeltaG(1 --> 2) values for the mutations A328W/Y332A --> A328W/Y332G and A328W/Y332G --> A328W/Y332G/A199S were calculated to be -0.22 and -1.94 kcal/mol, respectively. The calculated DeltaDeltaG(1 --> 2) values predict that the change from the A328W/Y332A mutant to the A328W/Y332G mutant should slightly improve the catalytic efficiency and that the change from the A328W/Y332G mutant to the A328W/Y332G/A199S mutant should significantly improve the catalytic efficiency of the enzyme for the (-)-cocaine hydrolysis. The predicted catalytic efficiency increases are supported by the experimental data showing that kcat/KM = 8.5 x 10(6), 1.4 x 10(7), and 7.2 x 10(7) min(-1) M(-1) for the A328W/Y332A, A328W/Y332G, and A328W/Y332G/A199S mutants, respectively. The qualitative agreement between the computational and experimental data suggests that the FEP simulations may provide a promising protocol for rational design of high-activity mutants of an enzyme. The general computational strategy of the FEP simulation on a transition state can be used to study the effects of a mutation on the activation free energy for any enzymatic reaction.
ESTHER : Pan_2007_J.Am.Chem.Soc_129_13537
PubMedSearch : Pan_2007_J.Am.Chem.Soc_129_13537
PubMedID: 17927177

Title : One-step purification of a fusion protein of glucagon-like peptide-1 and human serum albumin expressed in pichia pastoris by an immunomagnetic separation technique - Chen_2007_Biosci.Biotechnol.Biochem_71_2655
Author(s) : Chen J , Bai G , Cao Y , Gao Z , Zhang Q , Zhu Y , Yang W
Ref : Biosci Biotechnol Biochem , 71 :2655 , 2007
Abstract : Glucagon-like peptide-1 (GLP-1) has great therapeutic potential to treat diabetes type 2, mainly due to its unique glucose-dependent stimulation of insulin secretion profiles, but its clinical application is limited by its short half-life in vivo, which resultes from degradation by dipeptidyl peptidase IV and/or renal clearance. Developing long-acting GLP-1 analogs is therefore an important step toward using them therapeutically. In this study, the GLP-1/human serum albumin (HSA) fusion protein gene was cloned into the secretor type expression vector pPIC9K and subsequently expressed in Pichia pastoris. The expression quantity reached 58.5 mg/l in small-scale incubation. After optimization and characterization, the GLP-1/HSA fusion protein was successfully purified from the supernatant of the broth using immunomagnetic cellulose microspheres. HPLC showed that the purified GLP-1/HSA had an overall purity of 93.9%, and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) confirmed the fusion protein exhibited the expected molecular mass of 70 kDa. Furthermore, that analysis of in vivo activity indicated that GLP-1/HSA reduced the blood glucose level after intraperitoneal administration to Chinese Kunming mice in a dose-dependent manner, and the effects held significantly 4 h after administration. Overall, this study illustrates the development of a long-acting GLP-1/HSA fusion protein expressed in Pichia pastoris.
ESTHER : Chen_2007_Biosci.Biotechnol.Biochem_71_2655
PubMedSearch : Chen_2007_Biosci.Biotechnol.Biochem_71_2655
PubMedID: 17986790

Title : Computational design of a human butyrylcholinesterase mutant for accelerating cocaine hydrolysis based on the transition-state simulation -
Author(s) : Gao D , Cho H , Yang W , Pan Y , Yang G , Tai HH , Zhan CG
Ref : Angew Chem Int Ed Engl , 45 :653 , 2006
PubMedID: 16355430

Title : Computational redesign of human butyrylcholinesterase for anticocaine medication - Pan_2005_Proc.Natl.Acad.Sci.U.S.A_102_16656
Author(s) : Pan Y , Gao D , Yang W , Cho H , Yang G , Tai HH , Zhan CG
Ref : Proc Natl Acad Sci U S A , 102 :16656 , 2005
Abstract : Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of BChE in the TS1 structure for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W/Y332G BChE should be significantly stronger than that in the TS1 structure for (-)-cocaine hydrolysis catalyzed by the WT BChE and other simulated BChE mutants. Thus, the transition-state simulations predict that A199S/S287G/A328W/Y332G mutant of BChE should have a significantly lower energy barrier for the reaction process and, therefore, a significantly higher catalytic efficiency for (-)-cocaine hydrolysis. The theoretical prediction has been confirmed by wet experimental tests showing an approximately (456 +/- 41)-fold improved catalytic efficiency of A199S/S287G/A328W/Y332G BChE against (-)-cocaine. This is a unique study to design an enzyme mutant based on transitionstate simulation. The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery.
ESTHER : Pan_2005_Proc.Natl.Acad.Sci.U.S.A_102_16656
PubMedSearch : Pan_2005_Proc.Natl.Acad.Sci.U.S.A_102_16656
PubMedID: 16275916

Title : Lipoprotein lipase gene is in linkage with blood pressure phenotypes in Chinese pedigrees - Yang_2004_Hum.Genet_115_8
Author(s) : Yang W , Huang J , Ge D , Yao C , Duan X , Shen Y , Qiang B , Gu D
Ref : Hum Genet , 115 :8 , 2004
Abstract : To elucidate the mechanism of lipid metabolism in the genesis of essential hypertension (EH), we linked blood pressure (BP) phenotypes with the lipoprotein lipase (LPL) gene. Variance component and sib-pair linkage models were used to test the relationship of the polymorphisms in the LPL gene region and EH in 148 Chinese hypertensive families. Linkage evidence with systolic BP (SBP) and diastolic BP (DBP) was observed in a total population of 148 pedigrees with seven flanking microsatellite markers of the LPL gene, with a maximum two-point LOD score of 2.68 and a maximum multipoint LOD score (MLS) of 2.37 for SBP and a maximum MLS of 1.54 for DBP. Suggestive linkage results around this region were also obtained in northern and southern subsets by geographic distribution. In addition, quantitative-transmission/disequilibrium-test analyses showed that there was linkage between DBP and two single nucleotide polymorphisms in the LPL gene. This is the first report of linkage between LPL gene and DBP in the Chinese population. The LPL gene itself might explain our results or the LPL gene region might harbor some genes to explain the observed results to some degree and might contribute to the variation of BP in the Chinese population.
ESTHER : Yang_2004_Hum.Genet_115_8
PubMedSearch : Yang_2004_Hum.Genet_115_8
PubMedID: 15127290

Title : Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase - Gu_2003_J.Biol.Chem_278_25895
Author(s) : Gu J , Weng Y , Zhang QY , Cui H , Behr M , Wu L , Yang W , Zhang L , Ding X
Ref : Journal of Biological Chemistry , 278 :25895 , 2003
Abstract : A mouse model with liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene (designated Alb-Cre/Cprlox mice) was generated and characterized in this study. Hepatic microsomal CPR expression was significantly reduced at 3 weeks and was barely detectable at 2 months of age in the Alb-Cre+/-/Cprlox+/+ (homozygous) mice, with corresponding decreases in liver microsomal cytochrome P450 (CYP) and heme oxygenase (HO) activities, in pentobarbital clearance, and in total plasma cholesterol level. Nevertheless, the homozygous mice are fertile and are normal in gross appearance and growth rate. However, at 2 months, although not at 3 weeks, the homozygotes had significant increases in liver weight, accompanied by hepatic lipidosis and other pathologic changes. Intriguingly, total microsomal CYP content was increased in the homozygotes about 2-fold at 3 weeks and about 3-fold at 2 months of age; at 2 months, there were varying degrees of induction in protein (1-5-fold) and mRNA expression (0-67-fold) for all CYPs examined. There was also an induction of HO-1 protein (nearly 9-fold) but no induction of HO-2. These data indicate the absence of significant alternative redox partners for liver microsomal CYP and HO, provide in vivo evidence for the significance of hepatic CPR-dependent enzymes in cholesterol homeostasis and systemic drug clearance, and reveal novel regulatory pathways of CYP expression associated with altered cellular homeostasis. The Alb-Cre/Cprlox mouse represents a unique model for studying the in vivo function of hepatic HO and microsomal CYP-dependent pathways in the biotransformation of endogenous and xenobiotic compounds.
ESTHER : Gu_2003_J.Biol.Chem_278_25895
PubMedSearch : Gu_2003_J.Biol.Chem_278_25895
PubMedID: 12697746