Wang K

References (108)

Title : Donepezil promotes skin flap survival through activation of the HIF-1alpha\/VEGF signalling pathway - Lin_2024_Wound.Repair.Regen__
Author(s) : Lin H , Wang K , Yang J , Wang A , Deng J , Lin D
Ref : Wound Repair Regen , : , 2024
Abstract : Flaps are mainly used to repair wounds in the clinical setting but can sometimes experience ischaemic necrosis postoperatively. This study investigated whether donepezil, an acetylcholinesterase inhibitor, can enhance the survival rate of flaps. We randomly allocated 36 rats into control, low-dose (3 mg/kg/day), and high-dose (5 mg/kg/day) groups. On Postoperative day 7, we assessed flap viability and calculated the mean area of viable flap. After euthanizing the rats, we employed immunological and molecular biology techniques to examine the changes in flap tissue vascularization, apoptosis, autophagy, and inflammation. Donepezil enhanced the expression of hypoxia-inducible factor and vascular endothelial growth factor to facilitate angiogenesis. In addition, it elevated the expression of LC3B, p62, and beclin to stimulate autophagy. Furthermore, it increased the expression of Bcl-2 while reducing the expression of Bax, thus inhibiting apoptosis. Finally, it had anti-inflammatory effects by reducing the levels of IL-1beta, IL-6, and TNF-alpha. The results suggest that donepezil can enhance the viability of randomly generated skin flaps by upregulating HIF-1alpha/VEGF signalling pathway, facilitating vascularization, inducing autophagy, suppressing cell apoptosis, and mitigating inflammation within the flap tissue.
ESTHER : Lin_2024_Wound.Repair.Regen__
PubMedSearch : Lin_2024_Wound.Repair.Regen__
PubMedID: 38551210

Title : Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression - Hao_2024_Eur.J.Med.Chem_268_116285
Author(s) : Hao Q , Shi J , Zhang Z , Yang G , Zhi Y , Wang K , Ma D , Fu S , Dong H , Zhi Z , Zhang W , Li T , Wang J
Ref : Eur Journal of Medicinal Chemistry , 268 :116285 , 2024
Abstract : Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol lipase (MAGL), an essential enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), is a novel target for developing antidepressants. A decrease of 2-AG levels in the hippocampus of the brain has been observed in depressive-like models induced by chronic stress. Herein, employing a structure-based approach, we designed and synthesized a new class of (piperazine-1-carbonyl) quinolin-2(1H)-one derivatives as potent, reversible and selective MAGL inhibitors. And detailed structure-activity relationships (SAR) studies were discussed. Compound 27 (IC(50) = 10.3 nM) exhibited high bioavailability (92.7%) and 2-AG elevation effect in vivo. Additionally, compound 27 exerted rapid antidepressant effects caused by chronic restraint stress (CRS) and didn't show signs of addictive properties in the conditioned place preference (CPP) assays. Our study is the first to report that reversible MAGL inhibitors can treat chronic stress-induced depression effectively, which may provide a new potential therapeutic strategy for the discovery of an original class of safe, rapid antidepressant drugs.
ESTHER : Hao_2024_Eur.J.Med.Chem_268_116285
PubMedSearch : Hao_2024_Eur.J.Med.Chem_268_116285
PubMedID: 38428273

Title : Rational Design of a Highly Sensitive Carboxylesterase Probe and Its Application in High-Throughput Screening for Uncovering Carboxylesterase Inhibitors - Wang_2024_J.Org.Chem__
Author(s) : Wang K , Wang R , Yan Z , Li Y , Shi Y , Ge JY , Bai Y , Chen Z , Zhang L
Ref : J Org Chem , : , 2024
Abstract : Tracking carboxylesterases (CESs) through noninvasive and dynamic imaging is of great significance for diagnosing and treating CES-related metabolic diseases. Herein, three BODIPY-based fluorescent probes with a pyridine unit quaternarized via an acetoxybenzyl group were designed and synthesized to detect CESs based on the photoinduced electron transfer process. Notably, among these probes, BDPN2-CES exhibited a remarkable 182-fold fluorescence enhancement for CESs within 10 min. Moreover, BDPN2-CES successfully enabled real-time imaging of endogenous CES variations in living cells. Using BDPN2-CES, a visual high-throughput screening method for CES inhibitors was established, culminating in the discovery of an efficient inhibitor, WZU-13, sourced from a chemical library. These findings suggest that BDPN2-CES could provide a new avenue for diagnosing CES-related diseases, and WZU-13 emerges as a promising therapeutic candidate for CES-overexpression pathological processes.
ESTHER : Wang_2024_J.Org.Chem__
PubMedSearch : Wang_2024_J.Org.Chem__
PubMedID: 38720168

Title : GehB Inactivates Lipoproteins to Delay the Healing of Acute Wounds Infected with Staphylococcus aureus - Wang_2023_Curr.Microbiol_81_36
Author(s) : Wang K , Cai X , Rao Y , Liu L , Hu Z , Peng H , Wang Y , Yang Y , Rao X , Nie K , Shang W
Ref : Curr Microbiol , 81 :36 , 2023
Abstract : Staphylococcus aureus is one of the most prevalent bacteria found in acute wounds. S. aureus produces many virulence factors and extracellular enzymes that contribute to bacterial survival, dissemination, and pathogenicity. Lipase GehB is a glycerol ester hydrolase that hydrolyzes triglycerides to facilitate the evasion of S. aureus from host immune recognition. However, the role and mechanism of lipase GehB in skin acute wound healing after S. aureus infection remain unclear. In this study, we found that the gehB gene deletion mutant (USA300deltagehB) stimulated significantly higher levels of pro-inflammatory cytokines in RAW264.7 and Toll-like receptor 2 (TLR2)-transfected HEK293 cells than the wild-type USA300 strain did. Recombinant GehB-His treated lipoprotein (Lpp) reduced stimulation of TLR2-dependent TNF-alpha production by RAW264.7 macrophages. GehB delayed the skin acute wound healing in BALB/c mice infected with S. aureus, while wound healing was similar in C57BL/6 TLR2(-/-) mice infected with either wild-type USA300 or USA300deltagehB. In BALB/c mice, we also observed more bacterial survival, less leukocyte recruitment, lower IL-8 production, and adipocyte differentiation in USA300-infected skin acute wound tissues than those in USA300deltagehB-challenged ones. Our data indicated that GehB inactivates lipoproteins to shield S. aureus from innate immune killing, resulting in delayed the healing of skin acute wounds infected with S. aureus.
ESTHER : Wang_2023_Curr.Microbiol_81_36
PubMedSearch : Wang_2023_Curr.Microbiol_81_36
PubMedID: 38063939

Title : Sublethal Effects of Neonicotinoid Insecticides on the Development, Body Weight and Economic Characteristics of Silkworm - Chen_2023_Toxics_11_
Author(s) : Chen Q , Sun S , Yang X , Yan H , Wang K , Ba X , Wang H
Ref : Toxics , 11 : , 2023
Abstract : Silkworm Bombyx mori (L.) (Lepidoptera: Bombycidae) is a critical insect for silk producers, but the inappropriate application of insecticides negatively affects the physiology and behavior of silkworms. This study found that the effects of neonicotinoid insecticides applied using two spraying methods on the growth and development of silkworms were different: the median lethal concentration (LC(50)) values of two pesticides applied using the leaf-dipping method were 0.33 and 0.83 mg L(-1) and those of two pesticides applied using the quantitative spraying method were 0.91 and 1.23 mg kg(-1). The concentration of pesticides on the mulberry leaves did not decrease after their application using the quantitative spraying method, and a uniform spraying density was observed after the mulberry leaves were air-dried (no liquid) under realistic conditions. We then treated silkworms with the quantitative spraying method and leaf-dipping method. The treatment of silkworm larvae with imidacloprid and thiamethoxam at sublethal concentrations significantly prolonged the development time and significantly decreased the weight and pupation rate, as well as economic indicators of enamel layers and sputum production. Thiamethoxam treatment significantly increased the activities of carboxylesterase (CarE) and glutathione-S-transferase (GST). The activity of CarE and GST increased, decreased, and then increased, and the highest activity was detected on the 10th and 12th days. Thiamethoxam exposure significantly elevated the transcription levels of CarE-11, GSTe3 and GSTz2 and induced DNA damage in hemocytes. This study confirmed that the quantitative spray method is more stable than the leaf-dipping method. Moreover, imidacloprid and thiamethoxam treatment affected the economy and indexes of silkworms and induced changes in detoxification enzymes and DNA damage in silkworms. These results provide a basis for understanding the mechanism of the sublethal effects of insecticides on silkworms.
ESTHER : Chen_2023_Toxics_11_
PubMedSearch : Chen_2023_Toxics_11_
PubMedID: 37235217

Title : Hyperoside inhibits pancreatic lipase activity in vitro and reduces fat accumulation in vivo - Zhang_2023_Food.Funct_14_4763
Author(s) : Zhang X , Li D , Wang K , Xie J , Liu Y , Wang T , Liu S , Huang Q , Guo Q , Wang H
Ref : Food Funct , 14 :4763 , 2023
Abstract : Hyperoside, the main component of many anti-obesity plants, might exhibit a lipase inhibition effect to reduce fat accumulation. The anti-obesity effect of hyperoside was investigated by studying its inhibitory effect and mechanism on pancreatic lipase in vitro and evaluating its ability to reduce lipid accumulation in vivo. Hyperoside is a mixed-type inhibitor of lipase with an IC(50) of 0.67 +/- 0.02 mmol L(-)in vitro. Hyperoside changed the secondary conformation of lipase, increased the alpha-helix content, and changed the microenvironment of lipase through static quenching. The interaction between hyperoside and lipase results from a strong binding spontaneous exothermic reaction, mainly through hydrogen bonding, van der Waals force and electrostatic force. Hyperoside protected hepatic lipid accumulation and adipose tissue hypertrophy and reduced the expression of inflammatory factors in high-fat diet-induced rats. Moreover, hyperoside had a good inhibitory effect on lipase activity in serum and increased fecal fat excretion, thereby reducing lipid absorption in vivo. This study provides theoretical support for the research and development of hyperoside in fat-reducing functional foods.
ESTHER : Zhang_2023_Food.Funct_14_4763
PubMedSearch : Zhang_2023_Food.Funct_14_4763
PubMedID: 37128768

Title : Lipase-catalyzed ring-opening polymerization of natural compound-based cyclic monomers - Wang_2023_Chem.Commun.(Camb)__
Author(s) : Wang K , Li C , Man L , Zhang M , Jia YG , Zhu XX
Ref : Chem Commun (Camb) , : , 2023
Abstract : The need for sustainable and environment-friendly materials has led to growing interest in the development of biodegradable polymers based on natural compounds. However, metal-based catalysts used in the polymerization process may cause concerns about the toxicity of the resultant polymers. Therefore, polymers derived from natural compounds and synthesized through the use of green catalysts are highly desirable. Lipase-catalyzed ring-opening polymerization (ROP) of biocompound-based cyclic monomers has emerged as a promising and green strategy for the design and synthesis of such polymers. In this review, we summarize reports on the use of ROP catalyzed by lipase for cyclic monomers derived from natural compounds, including bile acid- and porphyrin-based macrocycles, carbonate-based macrocycles, lactones, and cyclic anhydrides, with an emphasis on ring-closure reactions for the synthesis of cyclic monomers, the types of lipases for the ROP and the choice of reaction conditions (temperature, solvent, reaction time, etc.). Moreover, the current challenges and perspectives for the choice and reusability of lipases, ring-closure versus ring-opening reactions, monomer design, and potential applications are discussed.
ESTHER : Wang_2023_Chem.Commun.(Camb)__
PubMedSearch : Wang_2023_Chem.Commun.(Camb)__
PubMedID: 37431654

Title : Small molecular fluorescent probes for Alzheimer's disease associated active species - Tang_2023_Chemistry__e202300592
Author(s) : Tang F , Wang K , Liu X , Zhang X , Zhou W , Mu Z , Zhang T , Shu W , Liu Y , Xiao H
Ref : Chemistry , :e202300592 , 2023
Abstract : Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the main cause of dementia worldwide. As the pathogenesis of AD is quite complicated, there is continuous attention to AD-associated active species, such as amyloid-beta plaques, neurofibrillary tangles, metal ions, reactive oxygen/nitrogen/sulphurspecies, cholinesterase, viscosity, formaldehyde and so on. To this end, a series of small molecular fluorescent probes for these active species have been explored for early diagnosis and even remedy of AD. Herein, we systematacially summarize the versatile fluorescent probes mainly in recent three years, including the relationship between the structure and properties as well as the targeted diagnosis and imaging application of all these fluorescent probes. Moreover, the challenges and perspectives of the AD-related fluorescent probes are briefly explicated. We firmly expect this review may provide guidance for constructing new AD-relevant fluorescent probes and promote the clinical study of AD.
ESTHER : Tang_2023_Chemistry__e202300592
PubMedSearch : Tang_2023_Chemistry__e202300592
PubMedID: 37078523

Title : The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling - Shi_2023_Cell.Death.Dis_14_560
Author(s) : Shi J , Miao D , Lv Q , Wang K , Wang Q , Liang H , Yang H , Xiong Z , Zhang X
Ref : Cell Death Dis , 14 :560 , 2023
Abstract : Metabolic reprogramming is a hallmark of cancer, and the impact of lipid metabolism as a crucial aspect of metabolic reprogramming on clear cell renal cell carcinoma (ccRCC) progression has been established. However, the regulatory mechanisms underlying the relationship between metabolic abnormalities and ccRCC progression remain unclear. Therefore, this study aimed to identify key regulatory factors of metabolic reprogramming in ccRCC and provide potential therapeutic targets for ccRCC patients. Potential metabolic regulatory factors in ccRCC were screened using bioinformatics analysis. Public databases and patient samples were used to investigate the aberrant expression of Oxoglutarate dehydrogenase-like (OGDHL) in ccRCC. The function of OGDHL in ccRCC growth and metastasis was evaluated through in vitro and in vivo functional experiments. Mechanistic insights were obtained through luciferase reporter assays, chromatin immunoprecipitation, RNA methylation immunoprecipitation, and mutagenesis studies. OGDHL mRNA and protein levels were significantly downregulated in ccRCC tissues. Upregulation of OGDHL expression effectively inhibited ccRCC growth and metastasis both in vitro and in vivo. Furthermore, FTO-mediated OGDHL m6A demethylation suppressed its expression in ccRCC. Mechanistically, low levels of OGDHL promoted TFAP2A expression by inhibiting ubiquitination levels, which then bound to the FASN promoter region and transcriptionally activated FASN expression, thereby promoting lipid accumulation and ERK pathway activation. Our findings demonstrate the impact of OGDHL on ccRCC progression and highlight the role of the FTO/OGDHL/TFAP2A/FASN axis in regulating ccRCC lipid metabolism and progression, providing new targets for ccRCC therapy.
ESTHER : Shi_2023_Cell.Death.Dis_14_560
PubMedSearch : Shi_2023_Cell.Death.Dis_14_560
PubMedID: 37626050

Title : Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target - Wang_2023_Science_381_eadd5787
Author(s) : Wang K , Zhang Z , Hang J , Liu J , Guo F , Ding Y , Li M , Nie Q , Lin J , Zhuo Y , Sun L , Luo X , Zhong Q , Ye C , Yun C , Zhang Y , Wang J , Bao R , Pang Y , Wang G , Gonzalez FJ , Lei X , Qiao J , Jiang C
Ref : Science , 381 :eadd5787 , 2023
Abstract : A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.
ESTHER : Wang_2023_Science_381_eadd5787
PubMedSearch : Wang_2023_Science_381_eadd5787
PubMedID: 37535747
Gene_locus related to this paper: bactn-BT4193

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

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

Title : Responses and detoxification mechanisms of earthworm Amynthas hupeiensis to metal contaminated soils of North China - Liu_2023_Environ.Pollut__121584
Author(s) : Liu Y , Chen M , Mu X , Wang X , Zhang M , Yin Y , Wang K
Ref : Environ Pollut , :121584 , 2023
Abstract : Metal contamination is widespread, but only a few studies have evaluated the toxicological risks of metals (Cd, Cu, and Pb) in earthworms from farmlands in North China (Hebei province). Amynthas hupeiensis, the dominant species in the study area, was used to determine the responses and detoxification mechanisms of uncontaminated (CK), and low (LM)-, and high (HM)-metal-contaminated soils following 7-, 14-, and 28-days exposure. Metal toxicity in LM and HM soils inhibited the biomass of A. hupeiensis. The concentrations of Cd in A. hupeiensis bodies indicated accumulated Cd appeared to remain steady with prolonged exposure, while Cu/Pb increased significantly with soil levels. Bioaccumulation occurred in the order Cd > Pb > Cu in LM soil, and in the order Cd > Cu = Pb in HM soil, which was attributed to differences in available fractions between LM and HM soils. Physiological levels of biomarkers in A. hupeiensis were determined, including total protein (TP), glutathione (GSH), glutathione peroxidase (GPx), acetylcholinesterase (AChE), and malondialdehyde (MDA). Deviations in GSH, GPx, and AChE were considered to denote sensitive biomarkers using the IBRv2 index. Metabolomics data ((1)H nuclear magnetic resonance-based) revealed changes in metabolites following 28-days exposure to LM and HM soils. Differences in metabolism in A. hupeiensis following exposure to LM and HM were related to energy metabolism, amino acid biosynthesis, glycerophospholipid metabolism, inositol phosphate metabolism, and glutathione metabolism. Metal stress from LM and HM soils disturbed osmoregulation, resulting in oxidative stress, destruction of cell membranes and inflammation, and altered levels of amino acids required for energy by A. hupeiensis. These findings provide biochemical insights into the physiological and metabolic mechanisms underlying the ability of A. hupeiensis to resist metal stress, and for assessing the environmental risks of metal-contaminated soils in farmland in North China.
ESTHER : Liu_2023_Environ.Pollut__121584
PubMedSearch : Liu_2023_Environ.Pollut__121584
PubMedID: 37037277

Title : Effects of Lipid Metabolism-Related Genes PTGIS and HRASLS on Phenotype, Prognosis, and Tumor Immunity in Lung Squamous Cell Carcinoma - Lei_2023_Oxid.Med.Cell.Longev_2023_6811625
Author(s) : Lei K , Liang R , Tan B , Li L , Lyu Y , Wang K , Wang W , Hu X , Wu D , Lin H , Wang M
Ref : Oxid Med Cell Longev , 2023 :6811625 , 2023
Abstract : BACKGROUND: Lipid metabolism reprogramming played an important role in cancer occurrence, development, and immune regulation. The aim of this study was to identify and validate lipid metabolism-related genes (LMRGs) associated with the phenotype, prognosis, and immunological characteristics of lung squamous cell carcinoma (LUSC). METHODS: In the TCGA cohort, bioinformatics and survival analysis were used to identify lipid metabolism-related differentially expressed genes (DEGs) associated with the prognosis of LUSC. PTGIS/HRASLS knockdown and overexpression effects on the LUSC phenotype were analyzed in vitro experiments. Based on the expression distribution of PTGIS/HRASLS, LUSC patients were divided into two clusters by consensus clustering. Clinical information, prognosis, immune infiltration, expression of immune checkpoints, and tumor mutation burden (TMB) level were compared between the TCGA and GSE4573 cohorts. The genes related to clustering and tumor immunity were screened by weighted gene coexpression network analysis (WGCNA), and the target module genes were analyzed by functional enrichment analysis, protein-protein interaction (PPI) analysis, and immune correlation analysis. RESULTS: 191 lipid metabolism-related DEGs were identified, of which 5 genes were independent prognostic genes of LUSC. PTGIS/HRASLS were most closely related to LUSC prognosis and immunity. RT-qPCR, western blot (WB) analysis, and immunohistochemistry (IHC) showed that the expression of PTGIS was low in LUSC, while HRASLS was high. Functionally, PTGIS promoted LUSC proliferation, migration, and invasion, while HRASLS inhibited LUSC proliferation, migration, and invasion. The two clusters' expression and distribution of PTGIS/HRASLS had the opposite trend. Cluster 1 was associated with lower pathological staging (pT, pN, and pTNM stages), better prognosis, stronger immune infiltration, higher expression of immune checkpoints, and higher TMB level than cluster 2. WGCNA found that 28 genes including CD4 and IL10RA were related to the expression of PTGIS/HRASLS and tumor immune infiltration. PTGIS/HRASLS in the GSE4573 cohort had the same effect on LUSC prognosis and tumor immunity as the TCGA cohort. CONCLUSIONS: PTGIS and HRASLS can be used as new therapeutic targets for LUSC as well as biomarkers for prognosis and tumor immunity, which has positive significance for guiding the immunotherapy of LUSC.
ESTHER : Lei_2023_Oxid.Med.Cell.Longev_2023_6811625
PubMedSearch : Lei_2023_Oxid.Med.Cell.Longev_2023_6811625
PubMedID: 36703911

Title : New insights into the role of dipeptidyl peptidase 8 and dipeptidyl peptidase 9 and their inhibitors - Cui_2022_Front.Pharmacol_13_1002871
Author(s) : Cui C , Tian X , Wei L , Wang Y , Wang K , Fu R
Ref : Front Pharmacol , 13 :1002871 , 2022
Abstract : Dipeptidyl peptidase 8 (DPP8) and 9 (DPP9) are widely expressed in mammals including humans, mainly locate in the cytoplasm. The DPP8 and DPP9 (DPP8/9) belong to serine proteolytic enzymes, they can recognize and cleave N-terminal dipeptides of specific substrates if proline is at the penultimate position. Because the localization of DPP8/9 is different from that of DPP4 and the substrates for DPP8/9 are not yet completely clear, their physiological and pathological roles are still being further explored. In this article, we will review the recent research advances focusing on the expression, regulation, and functions of DPP8/9 in physiology and pathology status. Emerging research results have shown that DPP8/9 is involved in various biological processes such as cell behavior, energy metabolism, and immune regulation, which plays an essential role in maintaining normal development and physiological functions of the body. DPP8/9 is also involved in pathological processes such as tumorigenesis, inflammation, and organ fibrosis. In recent years, related research on immune cell pyroptosis has made DPP8/9 a new potential target for the treatment of hematological diseases. In addition, DPP8/9 inhibitors also have great potential in the treatment of tumors and chronic kidney disease.
ESTHER : Cui_2022_Front.Pharmacol_13_1002871
PubMedSearch : Cui_2022_Front.Pharmacol_13_1002871
PubMedID: 36172198
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies - Sang_2022_Bioorg.Chem_127_106007
Author(s) : Sang Z , Bai P , Ban Y , Wang K , Wu A , Mi J , Hu J , Xu R , Zhu G , Wang J , Zhang J , Wang C , Tan Z , Tang L
Ref : Bioorg Chem , 127 :106007 , 2022
Abstract : Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC(50) = 0.87 microM) and huBuChE (IC(50) = 3.3 microM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-alpha production, and significantly inhibited self-mediated Abeta(1-42) aggregation (60.6%) and huAChE-mediated induced Abeta(1-40) aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Abeta(1-42)-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [(11)C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations.
ESTHER : Sang_2022_Bioorg.Chem_127_106007
PubMedSearch : Sang_2022_Bioorg.Chem_127_106007
PubMedID: 35849893

Title : Sensitive detection of organophosphorus pesticides based on the localized surface plasmon resonance and fluorescence dual-signal readout - Wang_2022_Anal.Chim.Acta_1235_340536
Author(s) : Wang K , Li Q , Wang Y , Wu Y , Liu Z , Liu S
Ref : Anal Chim Acta , 1235 :340536 , 2022
Abstract : In this work, a dual-signal visual biosensor was designed for organophosphorus pesticides (OPs) detection using DNA functionalized Ag/Au bimetallic nanoparticles (Ag/Au NPs) as multifunctional nanoprobe. The dual-signal detection strategy was based on the inhibition of enzyme-induced H(2)O(2) generation by OPs in the detection solution containing acetylcholinesterase (AChE), choline oxidase (CHO), acetylcholine (ACh) and nanoprobe. H(2)O(2) produced by enzyme-catalyzed reaction could trigger the etching of Ag and dissociation of carboxyfluorescein (FAM)-labeled aptamer from the nanoprobe, resulting in significant localized surface plasmon resonance (LPRR) and fluorescence (FL) signal responses. In the presence of OPs, AChE activity was inhibited to disrupt the enzymatic generation of H(2)O(2), which allowed to simultaneous quantitative measure OPs through the LSPR peak shifts and FL intensity variations of the nanoprobe. The LSPR/FL dual-signal biosensor showed great selectivity and sensitivity for OPs detection. In addition, two distinct colour changes were visually observed to match the LSPR/FL spectra signal responses, which was a feasible means for visual analysis of OPs. Consequently, the work provided a dual-signal visual biosensor via the combination of multifunctional nanoprobe, and had significant potential to monitor pesticide residue with high anti-interference capability and detection accuracy.
ESTHER : Wang_2022_Anal.Chim.Acta_1235_340536
PubMedSearch : Wang_2022_Anal.Chim.Acta_1235_340536
PubMedID: 36368824

Title : Effects of urea application on the reproduction of Pardosa pseudoannulata: Field and laboratory studies - Yang_2022_Chemosphere_301_134697
Author(s) : Yang Z , Wang Y , Wang K , Zhang Y , Yu N , Liu Z
Ref : Chemosphere , 301 :134697 , 2022
Abstract : As an important chemical fertilizer, urea can greatly increase crop yields, but it also has negative effects on beneficial arthropods in the agricultural field, such as spiders. Here, we reported that urea application reduced the reproductive performance in Pardosa pseudoannulata, a dominant species of spider in rice fields, which preys on a range of insect pests, based on both field and laboratory studies. In a field test, urea application significantly reduced the egg production of adult and subadult females collected from the urea-treated fields. A laboratory test was set up to further evaluate the impact of urea application on P. pseudoannulata reproduction. In consistent with field test results, the spiders treated by urea for 14 d and 28 d had lower reproduction ability than their control counterparts, with regard to the mating rate, egg production, and egg hatchability. The transcriptomic sequencing of individuals treated by urea for 28 d showed that urea application caused a number of differentially expressed transcripts with several downregulated unigenes related to basic enzymes and several upregulated unigenes involved in stress resistance. The knockdown of a metalloproteinase gene caused a significant decrease in egg production, and the silencing of a carboxylesterase gene significantly reduced both the egg production and egg hatchability. Taken together, the present study found that urea application reduced P. pseudoannulata reproduction ability and the negative impact partially resulted from the downregulation of certain basic enzyme genes. The study provided a fresh view of fertilizers on beneficial arthropods with great potential in the protection of P. pseudoannulata in fields.
ESTHER : Yang_2022_Chemosphere_301_134697
PubMedSearch : Yang_2022_Chemosphere_301_134697
PubMedID: 35513078

Title : In situ identification of cellular drug targets in mammalian tissue - Pang_2022_Cell_185_1793
Author(s) : Pang Z , Schafroth MA , Ogasawara D , Wang Y , Nudell V , Lal NK , Yang D , Wang K , Herbst DM , Ha J , Guijas C , Blankman JL , Cravatt BF , Ye L
Ref : Cell , 185 :1793 , 2022
Abstract : The lack of tools to observe drug-target interactions at cellular resolution in intact tissue has been a major barrier to understanding in vivo drug actions. Here, we develop clearing-assisted tissue click chemistry (CATCH) to optically image covalent drug targets in intact mammalian tissues. CATCH permits specific and robust in situ fluorescence imaging of target-bound drug molecules at subcellular resolution and enables the identification of target cell types. Using well-established inhibitors of endocannabinoid hydrolases and monoamine oxidases, direct or competitive CATCH not only reveals distinct anatomical distributions and predominant cell targets of different drug compounds in the mouse brain but also uncovers unexpected differences in drug engagement across and within brain regions, reflecting rare cell types, as well as dose-dependent target shifts across tissue, cellular, and subcellular compartments that are not accessible by conventional methods. CATCH represents a valuable platform for visualizing in vivo interactions of small molecules in tissue.
ESTHER : Pang_2022_Cell_185_1793
PubMedSearch : Pang_2022_Cell_185_1793
PubMedID: 35483372

Title : Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease - Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
Author(s) : Zhu G , Bai P , Wang K , Mi J , Yang J , Hu J , Ban Y , Xu R , Chen R , Wang C , Tang L , Sang Z
Ref : J Enzyme Inhib Med Chem , 37 :1375 , 2022
Abstract : Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC(50) = 0.32, 0.56, 0.54, 0.73, and 0.86 microM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Abeta(1-42) aggregation, and potent neuroprotective effect on Abeta(1-42)-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood-brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [(11)C]5f demonstrated that [(11)C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.
ESTHER : Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
PubMedSearch : Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
PubMedID: 35549612

Title : Molecular and Biochemical Analyses of a Novel Trifunctional Endoxylanase\/Endoglucanase\/Feruloyl Esterase from the Human Colonic Bacterium Bacteroides intestinalis DSM 17393 - Zhang_2022_J.Agric.Food.Chem__
Author(s) : Zhang R , Lin D , Zhang L , Zhan R , Wang S , Wang K
Ref : Journal of Agricultural and Food Chemistry , : , 2022
Abstract : A novel enzyme Bi76 comprising GH10, E_set_Esterase_N, and CE1 modules was identified, with the highest homology (62.9%) with a bifunctional endoxylanase/feruloyl esterase among characterized enzymes. Interestingly, Bi76 hydrolyzed glucan substrates besides xylans and feruloylated substrates, suggesting that it is the first characterized trifunctional endoxylanase/endoglucanase/feruloyl esterase. Analyses of truncation variants revealed that GH10 and E_set_Esterase_N + CE1 modules encoded endoxylanase/endoglucanase and feruloyl esterase activities, respectively. Synergism analyses indicated that endoxylanase, alpha-l-arabinofuranosidase, and feruloyl esterase acted cooperatively in releasing ferulic acid (FA) and xylooligosaccharides from feruloylated arabinoxylan. The interdomain synergism of Bi76 overmatched the intermolecular synergism of TM1 and TM2. Importantly, Bi76 exhibited good capacity in producing FA, releasing 5.20, 4.38, 2.12, 1.35, 0.46, and 0.19 mg/g from corn bran, corn cob, wheat bran, corn stover, rice husk, and rice bran, respectively. This study expands the trifunctional endoxylanase/endoglucanase/feruloyl esterase repertoire and demonstrates the great potential of Bi76 in agricultural residue utilization.
ESTHER : Zhang_2022_J.Agric.Food.Chem__
PubMedSearch : Zhang_2022_J.Agric.Food.Chem__
PubMedID: 35316064
Gene_locus related to this paper: 9bace-b3c594

Title : Enteral Nutrition Combined with Improved-Sijunzi Decoction Shows Positive Effect in Precachexia Cancer Patients: A Retrospective Analysis - Li_2021_Evid.Based.Complement.Alternat.Med_2021_7357521
Author(s) : Li Y , Chen Y , Zeng Y , Dong J , Li C , Jia Y , Zhao Y , Wang K
Ref : Evid Based Complement Alternat Med , 2021 :7357521 , 2021
Abstract : BACKGROUND: Cancer has been considered as the leading cause of death in the world. In patients with cancer, up to 80% display a cachectic period after diagnosis. Cachexia is known to have a negative impact on function, treatment tolerance, higher rates of hospitalizations, and mortality. Anorexia is often used as a warning sign of precachexia. Long-term anorexia may lead to malnutrition and, then, accelerate the occurrence of cachexia. A safe and effective treatment, which can both improve appetite and assist nutritional support for precachexia cancer patients shows its particular important role. METHODS: A retrospective analysis comparing the different therapeutic effects on precachexia cancer patients with anorexia-malnutrition. We recorded 46 patients with the improved-Sijunzi decoction combined with enteral nutrition emulsion (ISJZ group) and 35 patients with single enteral nutrition emulsion (SEN group). The different therapeutic effects of the two groups were observed by recording indicators before and 2 weeks after treatment, including patient-generated subjective global assessment score, quality of life score, Karnofsky performance status scale, Eastern cooperative oncology group scale standard and traditional Chinese medicine syndrome, daily total dietary intake, red blood cells, hemoglobin, prealbumin, albumin, total protein cholinesterase, C-reactive protein, leukocytes, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea nitrogen, and creatinine. RESULTS: ISJZ group exhibited prominent improvement of traditional Chinese medicine syndrome (TCMS), nutritional condition, and quality of life compared with the SEN group (QOL: p=0.0001, PG-SGA: p=0.019, dietary intake: p=0.0001, TCMS: p=0.0001). The levels of HGB (p=0.006), PAlb (p=0.001), Alb (p=0.0001), TP (p=0.008), and ChE (p=0.0001) in the ISJZ group were higher than the SEN group after treatment. Moreover, the ratios of CRP/ALB (p=0.028) and CRP/PALB (p=0.005) in the two groups have obvious differences; they were lower for the ISJZ group than the SEN group. CONCLUSIONS: Enteral nutrition combined with ISJZ decoction is an effective treatment in precachexia cancer patients for the prevention of cachexia. This treatment therapy can alleviate the inflammatory response, improve malnutrition state, and promote the performance status. Tianjin Medical University Cancer Institute and Hospital approved this study (Trial No. 1913).
ESTHER : Li_2021_Evid.Based.Complement.Alternat.Med_2021_7357521
PubMedSearch : Li_2021_Evid.Based.Complement.Alternat.Med_2021_7357521
PubMedID: 34603476

Title : Genome-Wide Identification of Tannase Genes and Their Function of Wound Response and Astringent Substances Accumulation in Juglandaceae - Wang_2021_Front.Plant.Sci_12_664470
Author(s) : Wang J , Wang K , Lyu S , Huang J , Huang C , Xing Y , Wang Y , Xu Y , Li P , Hong J , Xi J , Si X , Ye H , Li Y
Ref : Front Plant Sci , 12 :664470 , 2021
Abstract : Tannins are important polyphenol compounds with different component proportions in different plant species. The plants in the Juglandaceae are rich in tannins, including condensed tannins and hydrolyzable tannins. In this study, we identified seven tannase genes (TAs) responsible for the tannin metabolism from walnut, pecan, and Chinese hickory, and three nut tree species in the Juglandaceae, which were divided into two groups. The phylogenetic and sequence analysis showed that TA genes and neighboring clade genes (TA-like genes) had similar sequences compared with other carboxylesterase genes, which may be the origin of TA genes produced by tandem repeat. TA genes also indicated higher expressions in leaf than other tissues and were quickly up-regulated at 3 h after leaf injury. During the development of the seed coat, the expression of the synthesis-related gene GGTs and the hydrolase gene TAs was continuously decreased, resulting in the decrease of tannin content in the dry sample of the seed coat of Chinese hickory. However, due to the reduction in water content during the ripening process, the tannin content in fresh sample increased, so the astringent taste was obvious at the mature stage. In addition, the CcGGTs' expression was higher than CiGGTs in the initiation of development, but CcTAs continued to be down-regulated while CiTA2a and CiTA2b were up-regulated, which may bring about the significant differences in tannin content and astringent taste between Chinese hickory and pecan. These results suggested the crucial role of TAs in wound stress of leaves and astringent ingredient accumulation in seed coats of two nut tree species in the Juglandaceae.
ESTHER : Wang_2021_Front.Plant.Sci_12_664470
PubMedSearch : Wang_2021_Front.Plant.Sci_12_664470
PubMedID: 34079571
Gene_locus related to this paper: camsi-CsTA

Title : Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway - Wang_2021_Planta.Med__
Author(s) : Wang D , Ren Y , Sun W , Gong J , Zou X , Dong H , Xu L , Wang K , Lu F
Ref : Planta Med , : , 2021
Abstract : Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1beta and TNF-alpha in the serum and downregulated nuclear factor kappaB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.
ESTHER : Wang_2021_Planta.Med__
PubMedSearch : Wang_2021_Planta.Med__
PubMedID: 33682914

Title : Metabolic degradation of lentinan in liver mediated by CYP450 enzymes and epoxide hydrolase - Zheng_2021_Carbohydr.Polym_253_117255
Author(s) : Zheng Z , Zhang Y , Liu Y , Wang J , Cui Z , Pan X , Tang W , Wang K
Ref : Carbohydr Polym , 253 :117255 , 2021
Abstract : Lentinan (LNT), a typical triple helix beta-glucan, has been widely used as drug and biomaterial. However, its pharmacokinetics in vivo is rarely reported, which severely limits its further development and application. The aim of this study is to establish a sensitive method for detecting LNT in biosamples and to evaluate the plasma level, tissue distribution and metabolic degradation of LNT in rats. 5-([4,6-Dichlorotriazin-2-yl] amino) fluorescein (DTAF) was labelled to LNT. After purification and identification, FLNT was intravenously administered to rats at dose of 32 mg/kg. LNT was predominantly incorporated into the liver and liver microsomes were used to study the degradation mechanism of LNT in the liver. The results showed that two cytochrome P450 (CYP450) enzymes subtypes (CYP2D6 and CYP2C9), as well as epoxide hydrolase, were involved in the metabolic degradation of LNT. These findings provide a pharmacokinetic reference for further study and application of LNT and other beta-glucans.
ESTHER : Zheng_2021_Carbohydr.Polym_253_117255
PubMedSearch : Zheng_2021_Carbohydr.Polym_253_117255
PubMedID: 33279005

Title : Tracing the genetic footprints of vertebrate landing in non-teleost ray-finned fishes - Bi_2021_Cell_184_1377
Author(s) : Bi X , Wang K , Yang L , Pan H , Jiang H , Wei Q , Fang M , Yu H , Zhu C , Cai Y , He Y , Gan X , Zeng H , Yu D , Zhu Y , Qiu Q , Yang H , Zhang YE , Wang W , Zhu M , He S , Zhang G
Ref : Cell , 184 :1377 , 2021
Abstract : Rich fossil evidence suggests that many traits and functions related to terrestrial evolution were present long before the ancestor of lobe- and ray-finned fishes. Here, we present genome sequences of the bichir, paddlefish, bowfin, and alligator gar, covering all major early divergent lineages of ray-finned fishes. Our analyses show that these species exhibit many mosaic genomic features of lobe- and ray-finned fishes. In particular, many regulatory elements for limb development are present in these fishes, supporting the hypothesis that the relevant ancestral regulation networks emerged before the origin of tetrapods. Transcriptome analyses confirm the homology between the lung and swim bladder and reveal the presence of functional lung-related genes in early ray-finned fishes. Furthermore, we functionally validate the essential role of a jawed vertebrate highly conserved element for cardiovascular development. Our results imply the ancestors of jawed vertebrates already had the potential gene networks for cardio-respiratory systems supporting air breathing.
ESTHER : Bi_2021_Cell_184_1377
PubMedSearch : Bi_2021_Cell_184_1377
PubMedID: 33545088
Gene_locus related to this paper: atrsp-a0a8j7tiu5

Title : Resistance of Bemisia tabaci Mediterranean (Q-biotype) to pymetrozine: resistance risk assessment, cross-resistance to six other insecticides and detoxification enzyme assay - Wang_2021_Pest.Manag.Sci_77_2114
Author(s) : Wang F , Liu J , Shuai S , Miao C , Chi B , Chen P , Wang K , Li H , Liu Y
Ref : Pest Manag Sci , 77 :2114 , 2021
Abstract : BACKGROUND: The whitefly Bemisia tabaci (Gennadius) is a severe pest that affects many field and glasshouse crops worldwide and has developed resistance to insecticides in most chemical classes. Pymetrozine, a neuroactive pyridine azomethine, is selective towards piercing-sucking pests in Hemiptera. The aim of this study was to assess the resistance of B. tabaci Mediterranean (MED) to pymetrozine in the laboratory. RESULTS: After successive selection of 18 generations of MED in the presence of using pymetrozine, there was an 11.28-fold increase in the median lethal concentration (LC(50) ). When the realized heritability (h(2) ) of B. tabaci to pymetrozine in the field was assumed to be the value estimated in the laboratory (h(2) = 0.1360) and the mortality was 70-90%, only 7.2-15.9 generations were estimated to be needed to obtain a ten-fold increase in resistance to pymetrozine. Compared with the susceptible populations (G(0) ), the Pyme-SEL strain (G(18) ) showed a low level of cross-resistance to neonicotinoids (nitenpyram, imidacloprid, acetamiprid, and thiamethoxam) and no cross-resistance to chlorpyrifos or abamectin. With the G(0) and the Pyme-SEL strains (G(11) and G(18) ) as test strains, the activity of multifunctional oxidase exhibited the greatest increase during selection, while the activities of carboxylesterase and glutathione-S-transferase did not change significantly. CONCLUSION: This study show that a potential risk of development of resistance to pymetrozine exists in B. tabaci after continuous application. During the application of pymetrozine to control B. tabaci in the field, the frequency of its use in combination with neonicotinoids should be used with caution. 2020 Society of Chemical Industry.
ESTHER : Wang_2021_Pest.Manag.Sci_77_2114
PubMedSearch : Wang_2021_Pest.Manag.Sci_77_2114
PubMedID: 33332688

Title : Protein liposomes-mediated targeted acetylcholinesterase gene delivery for effective liver cancer therapy - Wang_2021_J.Nanobiotechnology_19_31
Author(s) : Wang K , Shang F , Chen D , Cao T , Wang X , Jiao J , He S , Liang X
Ref : J Nanobiotechnology , 19 :31 , 2021
Abstract : BACKGROUND: Effective methods to deliver therapeutic genes to solid tumors and improve their bioavailability are the main challenges of current medical research on gene therapy. The development of efficient non-viral gene vector with tumor-targeting has very important application value in the field of cancer therapy. Proteolipid integrated with tumor-targeting potential of functional protein and excellent gene delivery performance has shown potential for targeted gene therapy. RESULTS: Herein, we prepared transferrin-modified liposomes (Tf-PL) for the targeted delivery of acetylcholinesterase (AChE) therapeutic gene to liver cancer. We found that the derived Tf-PL/AChE liposomes exhibited much higher transfection efficiency than the commercial product Lipo 2000 and shown premium targeting efficacy to liver cancer SMMC-7721 cells in vitro. In vivo, the Tf-PL/AChE could effectively target liver cancer, and significantly inhibit the growth of liver cancer xenografts grafted in nude mice by subcutaneous administration. CONCLUSIONS: This study proposed a transferrin-modified proteolipid-mediated gene delivery strategy for targeted liver cancer treatment, which has a promising potential for precise personalized cancer therapy.
ESTHER : Wang_2021_J.Nanobiotechnology_19_31
PubMedSearch : Wang_2021_J.Nanobiotechnology_19_31
PubMedID: 33482834

Title : Biochemical and Structural Characterization of a Novel Bacterial Tannase From Lachnospiraceae bacterium in Ruminant Gastrointestinal Tract - Guan_2021_Front.Bioeng.Biotechnol_9_806788
Author(s) : Guan L , Wang K , Gao Y , Li J , Yan S , Ji N , Ren C , Wang J , Zhou Y , Li B , Lu S
Ref : Front Bioeng Biotechnol , 9 :806788 , 2021
Abstract : Tannases are a family of esterases that catalyze the hydrolysis of ester and depside bonds present in hydrolyzable tannins to release gallic acid. Here, a novel tannase from Lachnospiraceae bacterium (TanA(Lb)) was characterized. The recombinant TanA(Lb) exhibited maximal activity at pH 7.0 and 50 degreesC, and it maintained more than 70% relative activity from 30 degreesC to 55 degreesC. The activity of TanA(Lb) was enhanced by Mg(2+) and Ca(2+), and was dramatically reduced by Cu(2+) and Mn(2+). TanA(Lb) is capable of degrading esters of phenolic acids with long-chain alcohols, such as lauryl gallate as well as tannic acid. The Km value and catalytic efficiency (k (cat) /Km) of TanA(Lb) toward five substrates showed that tannic acid (TA) was the favorite substrate. Homology modeling and structural analysis indicated that TanA(Lb) contains an insertion loop (residues 341-450). Based on the moleculer docking and molecular dynamics (MD) simulation, this loop was observed as a flap-like lid to interact with bulk substrates such as tannic acid. TanA(Lb) is a novel bacterial tannase, and the characteristics of this enzyme make it potentially interesting for industrial use.
ESTHER : Guan_2021_Front.Bioeng.Biotechnol_9_806788
PubMedSearch : Guan_2021_Front.Bioeng.Biotechnol_9_806788
PubMedID: 34976993
Gene_locus related to this paper: 9firm-TanALb

Title : The Effects of Benoxacor on the Liver and Gut Microbiome of C57BL\/6 Mice - Simonsen_2021_Toxicol.Sci__
Author(s) : Simonsen D , Cady N , Zhang C , Shrode RL , McCormick ML , Spitz DR , Chimenti MS , Wang K , Mangalam A , Lehmler HJ
Ref : Toxicol Sci , : , 2021
Abstract : The toxicity of many "inert" ingredients of pesticide formulations, such as safeners, is poorly characterized, despite evidence that humans may be exposed to these chemicals. Analysis of ToxCast data for dichloroacetamide safeners with the ToxPi tool identified benoxacor as the safener with the highest potential for toxicity, especially liver toxicity. Benoxacor was subsequently administered to mice via oral gavage for three days at concentrations of 0, 0.5, 5, and 50 mg/kg bodyweight (b.w.). Bodyweight-adjusted liver and testes weights were significantly increased in the 50 mg/kg b.w. group. There were no overt pathologies in either the liver or the intestine. 16S rRNA analysis of the cecal microbiome revealed no effects of benoxacor on alpha- or beta-diversity; however, changes were observed in the abundance of certain bacteria. RNAseq analysis identified 163 hepatic genes affected by benoxacor exposure. Benoxacor exposure expressed a gene regulation profile similar to dichloroacetic acid and the fungicide sedaxane. Metabolomic analysis identified nine serum and fifteen liver metabolites that were affected by benoxacor exposure, changes that were not significant after correcting for multiple comparisons. The activity of antioxidant enzymes was not altered by benoxacor exposure. In vitro metabolism studies with liver microsomes and cytosol from male mice demonstrated that benoxacor is enantioselectively metabolized by cytochrome P450 enzymes (CYPs), carboxylesterases (CESs), and glutathione S-transferases (GSTs). These findings suggest that the minor toxic effects of benoxacor may be due to its rapid metabolism to toxic metabolites, such as dichloroacetic acid. This result challenges the assumption that inert ingredients of pesticide formulations are safe.
ESTHER : Simonsen_2021_Toxicol.Sci__
PubMedSearch : Simonsen_2021_Toxicol.Sci__
PubMedID: 34850242

Title : Detoxification II Prescription Suppresses the Th-17\/IL-17 Inflammatory Axis to Improve the Liver Function of ACLF-Rats via Inactivating the P38MAPK Pathway - Shi_2021_J.Healthc.Eng_2021_7563383
Author(s) : Shi Q , Bai W , Mao D , Chen Y , Wang K , Qiu H , Wu J
Ref : J Healthc Eng , 2021 :7563383 , 2021
Abstract : Hepatitis is a metabolic system disease which is a serious challenge to the medical and healthcare system of the world. This study attempted to investigate the therapeutic effect and illustrate the regulation pharmacological mechanism of Detoxification II Prescription on ACLF. In this study, the rats were injected with D-galactosamine to establish ACLF-rat models, and the levels of cholinesterase (CHE), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBiL) were measured with the related kits to reflect the liver functions of the rats. The levels of IL-17, IL-6, and IFN-gamma in the serums of the rats were detected by qRT-PCR, and the percentages of Th-17 cells in CD4(+) cells of the rats were measured by flow cytometry assay. In the results, the increased ALT, AST, TBiL, IL-6, IL-17, IFN-gamma, and percentage of Th-17 cells in CD4(+) and decreased ALB and CHE were found in the serums of the ACLF-rats, while Detoxification II Prescription could partly reverse those indexes of the ACLF-rats. Moreover, it was also found that Detoxification II Prescription could inhibit the expression of P38MAPK, and P38MAPK downregulation obviously improved the liver function indexes of the ACLF-rats including the levels of ALT, AST, TBiL, IL-6, IL-17, IFN-gamma, and percentage of Th-17 cells in CD4(+) cells. In conclusion, this study suggested that Detoxification II Prescription could suppress the Th-17/IL-17 inflammatory axis to improve the liver function of ACLF-rats via inhibiting the activity of the P38MAPK pathway.
ESTHER : Shi_2021_J.Healthc.Eng_2021_7563383
PubMedSearch : Shi_2021_J.Healthc.Eng_2021_7563383
PubMedID: 34900202

Title : Genome-wide analysis of the serine carboxypeptidase-like protein family in Triticum aestivum reveals TaSCPL184-6D is involved in abiotic stress response - Xu_2021_BMC.Genomics_22_350
Author(s) : Xu X , Zhang L , Zhao W , Fu L , Han Y , Wang K , Yan L , Li Y , Zhang XH , Min DH
Ref : BMC Genomics , 22 :350 , 2021
Abstract : BACKGROUND: The serine carboxypeptidase-like protein (SCPL) family plays a vital role in stress response, growth, development and pathogen defense. However, the identification and functional analysis of SCPL gene family members have not yet been performed in wheat. RESULTS: In this study, we identified a total of 210 candidate genes encoding SCPL proteins in wheat. According to their structural characteristics, it is possible to divide these members into three subfamilies: CPI, CPII and CPIII. We uncovered a total of 209 TaSCPL genes unevenly distributed across 21 wheat chromosomes, of which 65.7% are present in triads. Gene duplication analysis showed that ~ 10.5% and ~ 64.8% of the TaSCPL genes are derived from tandem and segmental duplication events, respectively. Moreover, the Ka/Ks ratios between duplicated TaSCPL gene pairs were lower than 0.6, which suggests the action of strong purifying selection. Gene structure analysis showed that most of the TaSCPL genes contain multiple introns and that the motifs present in each subfamily are relatively conserved. Our analysis on cis-acting elements showed that the promoter sequences of TaSCPL genes are enriched in drought-, ABA- and MeJA-responsive elements. In addition, we studied the expression profiles of TaSCPL genes in different tissues at different developmental stages. We then evaluated the expression levels of four TaSCPL genes by qRT-PCR, and selected TaSCPL184-6D for further downstream analysis. The results showed an enhanced drought and salt tolerance among TaSCPL184-6D transgenic Arabidopsis plants, and that the overexpression of the gene increased proline and decreased malondialdehyde levels, which might help plants adapting to adverse environments. Our results provide comprehensive analyses of wheat SCPL genes that might work as a reference for future studies aimed at improving drought and salt tolerance in wheat. CONCLUSIONS: We conducte a comprehensive bioinformatic analysis of the TaSCPL gene family in wheat, which revealing the potential roles of TaSCPL genes in abiotic stress. Our analysis also provides useful resources for improving the resistance of wheat.
ESTHER : Xu_2021_BMC.Genomics_22_350
PubMedSearch : Xu_2021_BMC.Genomics_22_350
PubMedID: 33992092

Title : Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease - Sang_2020_Eur.J.Med.Chem_194_112265
Author(s) : Sang Z , Wang K , Bai P , Wu A , Shi J , Liu W , Zhu G , Wang Y , Lan Y , Chen Z , Zhao Y , Qiao Z , Wang C , Tan Z
Ref : Eur Journal of Medicinal Chemistry , 194 :112265 , 2020
Abstract : A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 muM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 muM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Abeta aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl3-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Abeta1-40. PET-CT imaging demonstrated that [(11)C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease.
ESTHER : Sang_2020_Eur.J.Med.Chem_194_112265
PubMedSearch : Sang_2020_Eur.J.Med.Chem_194_112265
PubMedID: 32240904

Title : Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach - Huang_2020_J.Med.Chem_63_7052
Author(s) : Huang F , Hu H , Wang K , Peng C , Xu W , Zhang Y , Gao J , Liu Y , Zhou H , Huang R , Li M , Shen J , Xu Y
Ref : Journal of Medicinal Chemistry , 63 :7052 , 2020
Abstract : Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.
ESTHER : Huang_2020_J.Med.Chem_63_7052
PubMedSearch : Huang_2020_J.Med.Chem_63_7052
PubMedID: 32459096
Gene_locus related to this paper: human-PLA2G7

Title : Directed Evolution of Pseudomonas fluorescens Lipase Variants With Improved Thermostability Using Error-Prone PCR - Guan_2020_Front.Bioeng.Biotechnol_8_1034
Author(s) : Guan L , Gao Y , Li J , Wang K , Zhang Z , Yan S , Ji N , Zhou Y , Lu S
Ref : Front Bioeng Biotechnol , 8 :1034 , 2020
Abstract : Lipases catalyze the hydrolysis of fats and oils, and have been widely used in various industrial fields. However, bacterial lipases have a lower thermostability in industrial processes, which was a limiting factor in their industrial application. In this study, we obtained an improve variant of Pseudomonas fluorescens lipase (PFL) with enhanced thermostability using classical error-prone PCR. Wild-type PFL showed an optimal temperature and pH of 50degC and pH 7.5, respectively. Due to the low thermostability of PFL, a library containing over 3000 individual mutants as constructed using error-prone PCR. Screening for thermotolerance yielded the mutants L218P and P184C/M243C with T (m) values of 62.5 and 66.0degC, which was 2.5 and 6degC higher than that of the WT, respectively. The combination of the two mutants (P184C/M243C/L218P) resulted in an approximately additive effect with a T (m) value of 68.0degC. Although the increase of T (m) was not substantial, the mutant also had dramatically increased methanol tolerance. Structural analysis revealed that the introduction of a disulfide bond between P184C and M243C and the substitution of Pro to reduce the flexibility of a loop increased the thermostability of PFL, which provides a theoretical foundation for improving the thermostability and methanol tolerance of lipase family I.1 to resist the harsh conditions of industrial processes.
ESTHER : Guan_2020_Front.Bioeng.Biotechnol_8_1034
PubMedSearch : Guan_2020_Front.Bioeng.Biotechnol_8_1034
PubMedID: 32984290
Gene_locus related to this paper: psefl-lipa

Title : Lipoprotein-associated phospholipase A2: The story continues - Huang_2020_Med.Res.Rev_40_79
Author(s) : Huang F , Wang K , Shen J
Ref : Med Res Rev , 40 :79 , 2020
Abstract : Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation-related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp-PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp-PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp-PLA2 have been reported recently, while novel inhibitors were identified through a fragment-based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp-PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp-PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp-PLA2, identify more potent and selective Lp-PLA2 inhibitors, and discover the potential indications of Lp-PLA2 inhibitors.
ESTHER : Huang_2020_Med.Res.Rev_40_79
PubMedSearch : Huang_2020_Med.Res.Rev_40_79
PubMedID: 31140638
Gene_locus related to this paper: human-PLA2G7

Title : The seasonal development dynamics of the yak hair cycle transcriptome - Bao_2020_BMC.Genomics_21_355
Author(s) : Bao P , Luo J , Liu Y , Chu M , Ren Q , Guo X , Tang B , Ding X , Qiu Q , Pan H , Wang K , Yan P
Ref : BMC Genomics , 21 :355 , 2020
Abstract : BACKGROUND: Mammalian hair play an important role in mammals' ability to adapt to changing climatic environments. The seasonal circulation of yak hair helps them adapt to high altitude but the regulation mechanisms of the proliferation and differentiation of hair follicles (HFs) cells during development are still unknown. Here, using time series data for transcriptome and hormone contents, we systematically analyzed the mechanism regulating the periodic expression of hair development in the yak and reviewed how different combinations of genetic pathways regulate HFs development and cycling. RESULTS: This study used high-throughput RNA sequencing to provide a detailed description of global gene expression in 15 samples from five developmental time points during the yak hair cycle. According to clustering analysis, we found that these 15 samples could be significantly grouped into three phases, which represent different developmental periods in the hair cycle. A total of 2316 genes were identified in these three consecutive developmental periods and their expression patterns could be divided into 9 clusters. In the anagen, genes involved in activating hair follicle growth are highly expressed, such as the WNT pathway, FGF pathway, and some genes related to hair follicle differentiation. In the catagen, genes that inhibit differentiation and promote hair follicle cell apoptosis are highly expressed, such as BMP4, and Wise. In the telogen, genes that inhibit hair follicle activity are highly expressed, such as DKK1 and BMP1. Through co-expression analysis, we revealed a number of modular hub genes highly associated with hormones, such as SLF2, BOP1 and DPP8. They may play unique roles in hormonal regulation of events associated with the hair cycle. CONCLUSIONS: Our results revealed the expression pattern and molecular mechanisms of the seasonal hair cycle in the yak. The findings will be valuable in further understanding the alpine adaptation mechanism in the yak, which is important in order to make full use of yak hair resources and promote the economic development of pastoral plateau areas.
ESTHER : Bao_2020_BMC.Genomics_21_355
PubMedSearch : Bao_2020_BMC.Genomics_21_355
PubMedID: 32393236

Title : Genome sequencing of the Australian wild diploid species Gossypium australe highlights disease resistance and delayed gland morphogenesis - Cai_2020_Plant.Biotechnol.J_18_814
Author(s) : Cai Y , Cai X , Wang Q , Wang P , Zhang Y , Cai C , Xu Y , Wang K , Zhou Z , Wang C , Geng S , Li B , Dong Q , Hou Y , Wang H , Ai P , Liu Z , Yi F , Sun M , An G , Cheng J , Shi Q , Xie Y , Shi X , Chang Y , Huang F , Chen Y , Hong S , Mi L , Sun Q , Zhang L , Zhou B , Peng R , Zhang X , Liu F
Ref : Plant Biotechnol J , 18 :814 , 2020
Abstract : The diploid wild cotton species Gossypium australe possesses excellent traits including resistance to disease and delayed gland morphogenesis, and has been successfully used for distant breeding programmes to incorporate disease resistance traits into domesticated cotton. Here, we sequenced the G. australe genome by integrating PacBio, Illumina short read, BioNano (DLS) and Hi-C technologies, and acquired a high-quality reference genome with a contig N50 of 1.83 Mb and a scaffold N50 of 143.60 Mb. We found that 73.5% of the G. australe genome is composed of various repeat sequences, differing from those of G. arboreum (85.39%), G. hirsutum (69.86%) and G. barbadense (69.83%). The G. australe genome showed closer collinear relationships with the genome of G. arboreum than G. raimondii and has undergone less extensive genome reorganization than the G. arboreum genome. Selection signature and transcriptomics analyses implicated multiple genes in disease resistance responses, including GauCCD7 and GauCBP1, and experiments revealed induction of both genes by Verticillium dahliae and by the plant hormones strigolactone (GR24), salicylic acid (SA) and methyl jasmonate (MeJA). Experiments using a Verticillium-resistant domesticated G. barbadense cultivar confirmed that knockdown of the homologues of these genes caused a significant reduction in resistance against Verticillium dahliae. Moreover, knockdown of a newly identified gland-associated gene GauGRAS1 caused a glandless phenotype in partial tissues using G. australe. The G. australe genome represents a valuable resource for cotton research and distant relative breeding as well as for understanding the evolutionary history of crop genomes.
ESTHER : Cai_2020_Plant.Biotechnol.J_18_814
PubMedSearch : Cai_2020_Plant.Biotechnol.J_18_814
PubMedID: 31479566
Gene_locus related to this paper: gosra-a0a0d2pzd7

Title : Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation - Pfitzinger_2020_J.Exp.Clin.Cancer.Res_39_289
Author(s) : Pfitzinger PL , Fangmann L , Wang K , Demir E , Gurlevik E , Fleischmann-Mundt B , Brooks J , D'Haese JG , Teller S , Hecker A , Jesinghaus M , Jger C , Ren L , Istvanffy R , Kuhnel F , Friess H , Ceyhan GO , Demir IE
Ref : J Exp Clin Cancer Research , 39 :289 , 2020
Abstract : BACKGROUND: Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. METHODS: We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. RESULTS: We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. CONCLUSION: For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.
ESTHER : Pfitzinger_2020_J.Exp.Clin.Cancer.Res_39_289
PubMedSearch : Pfitzinger_2020_J.Exp.Clin.Cancer.Res_39_289
PubMedID: 33357230

Title : Bemisia tabaci (Hemiptera: Aleyrodidae) Insecticide Resistance in Shandong Province, China - Wang_2020_J.Econ.Entomol_113_911
Author(s) : Wang F , Liu J , Chen P , Li HY , Ma JJ , Liu YJ , Wang K
Ref : J Econ Entomol , 113 :911 , 2020
Abstract : The Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) complex comprises important pests and virus vectors in agricultural crops worldwide. In China, B. tabaci has spread to more than 20 provinces and caused severe losses of vegetables, fruits, and ornamental plants. However, B. tabaci has developed resistance to many insecticidal classes in Shandong Province, eastern China. In this study, we investigated the cryptic species, insecticide resistance and detoxifying enzymes of B. tabaci from six representative locations exhibiting severe damage in Shandong. At four of the six locations, B. tabaci Mediterranean (MED) comprised 100% of the samples collected. In a further two locations, species composition was predominantly (>94%) MED with B. tabaci Middle East-Asia Minor 1 (MEAM1), comprising a low proportion (<6%) of the samples collected. For all field populations, avermectin was the most effective insecticide against adult B. tabaci, pyriproxyfen had a significant effect on B. tabaci eggs and field populations were susceptible to pymetrozine. Six field populations of B. tabaci have developed low-to-moderate resistance to neonicotinoids. The detoxifying enzyme activity of carboxylesterase, glutathione S-transferase, and multifunctional oxidase were quantified. Multifunctional oxidase and glutathione S-transferase activity were positively correlated with insecticide resistance in several B. tabaci populations.
ESTHER : Wang_2020_J.Econ.Entomol_113_911
PubMedSearch : Wang_2020_J.Econ.Entomol_113_911
PubMedID: 31800055

Title : Berberine Ameliorates Spatial Learning Memory Impairment and Modulates Cholinergic Anti-Inflammatory Pathway in Diabetic Rats - Wang_2019_Front.Pharmacol_10_1003
Author(s) : Wang K , Chen Q , Wu N , Li Y , Zhang R , Wang J , Gong D , Zou X , Liu C , Chen J
Ref : Front Pharmacol , 10 :1003 , 2019
Abstract : Background: Cognitive impairment caused by diabetes has been recognized. Berberine is well known for its resistance to peripheral lesions, but it is rarely used for the treatment of spatial learning and memory caused by diabetes. This study explored the mechanism of berberine to alleviate cognitive impairment via the cholinergic anti-inflammatory and insulin signaling pathways. Methods: Morris water maze was used to appraise spatial learning and memory. Positron-emission tomography (PET) imaging was adopted to detect the transport of glucose, and blood/cerebrospinal fluid (CSF) glucose was checked using commercial blood glucose meter. Insulin level was measured by ELISA kit and beta-Amyloid (Abeta) formation was observed by Congo red staining. Western-blot was performed to appraise protein expression. Results: We found that berberine rectified some aberrant changes in signal molecules concerning inflammation, and cholinergic and insulin signaling pathways in the hippocampus. Furthermore, CSF/blood glucose, inflammatory response or acetyl cholinesterase enzyme (AChE) activity were reduced by berberine. Additionally, acetylcholine levels were enhanced after berberine treatment in diabetic rats. Finally, Abeta formation in diabetic hippocampus was inhibited and spatial learning memory was ameliorated by berberine. Discussion: In conclusion, berberine clears Abeta deposit and consequently ameliorates spatial learning memory impairment via the activation of the cholinergic anti-inflammatory and insulin signaling pathways in diabetic rats.
ESTHER : Wang_2019_Front.Pharmacol_10_1003
PubMedSearch : Wang_2019_Front.Pharmacol_10_1003
PubMedID: 31551793

Title : Development of chalcone-O-alkylamine derivatives as multifunctional agents against Alzheimer's disease - Bai_2019_Eur.J.Med.Chem_183_111737
Author(s) : Bai P , Wang K , Zhang P , Shi J , Cheng X , Zhang Q , Zheng C , Cheng Y , Yang J , Lu X , Sang Z
Ref : Eur Journal of Medicinal Chemistry , 183 :111737 , 2019
Abstract : A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50=1.3+/-0.01muM) and butyrylcholinesterase (IC50=1.2+/-0.09muM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57+/-0.01muM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced Abeta1-42 aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu(2+)-induced Abeta1-42 aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro, and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, Abeta1-42 and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD.
ESTHER : Bai_2019_Eur.J.Med.Chem_183_111737
PubMedSearch : Bai_2019_Eur.J.Med.Chem_183_111737
PubMedID: 31581002

Title : Ultrasensitive and visible light-responsive photoelectrochemical aptasensor for edifenphos based on Zinc phthalocyanine sensitized MoS2 nanosheets - Ding_2019_Biosens.Bioelectron__111867
Author(s) : Ding L , Jiang D , Wen Z , Xu Y , Guo Y , Ding C , Wang K
Ref : Biosensors & Bioelectronics , :111867 , 2019
Abstract : Developing a simple, rapid detection method for the analysis of edifenphos (EDI) is crucial due to its residue is harmful to acetylcholinesterase on the human cellular system, and cause a lot of complications. Herein, we synthesized visible light-responsive MoS2 nanosheets decorated with Zinc phthalocyanine (ZnPc) nanoparticles (ZnPc/n-MoS2). Due to the sensitization of ZnPc nanoparticles, the resulting ZnPc/n-MoS2 exhibited narrower energy bandgap and efficient charge transfer. Especially, the carrier lifetime of ZnPc/n-MoS2 is 2 more times longer than n-MoS2, and the photocurrent intensity of ZnPc/n-MoS2 is 24 times of n-MoS2 and 22 times of ZnPc nanoparticles under visible light irradiation. Further, a visible light-responsive ultrasensitive photoelectrochemical (PEC) aptasensor for selectivity recognition of EDI was triumphantly established by using EDI aptamer as a biorecognition element, which exhibited a wide linear ranking from 5ngL(-1) to 10mugL(-1) (R(2)=0.996) and a low detection limit of 1.667ngL(-1) (S/N=3). The splendid performance of the ZnPc/n-MoS2 nanosheet ultrasensitive sensing platform can be applied to detect the concentration of EDI in food, biomedical and environmental analysis.
ESTHER : Ding_2019_Biosens.Bioelectron__111867
PubMedSearch : Ding_2019_Biosens.Bioelectron__111867
PubMedID: 31748191

Title : Occupational pesticide exposure and symptoms of attention deficit hyperactivity disorder in adolescent pesticide applicators in Egypt - Rohlman_2019_Neurotoxicol_74_1
Author(s) : Rohlman DS , Ismail A , Bonner MR , Abdel Rasoul G , Hendy O , Ortega Dickey L , Wang K , Olson JR
Ref : Neurotoxicology , 74 :1 , 2019
Abstract : BACKGROUND: Exposure to environmental chemicals, including organophosphorus pesticides, is associated with behavioral disorders such as attention deficit hyperactivity disorder (ADHD). However, the impact of occupational pesticide exposure on ADHD development in adolescents has not been examined. OBJECTIVE: We examined the association between exposure to chlorpyrifos and ADHD symptoms among adolescents in Egypt. METHODS: Adolescent pesticide applicators and non-applicators, 12-21 years old, participated in a 10-month longitudinal study examining health effects from pesticide exposure. Repeated urine and blood samples were collected at various time points during the 10-months to assess biomarkers of chlorpyrifos exposure (urinary trichloro-2-pyridinol or TCPy) and effect (blood acetyl cholinesterase activity and butyryl cholinesterase activity). Parents from a subset of the cohort (N = 64) completed the Short Form of Conners' Parent Rating Scale - Revised. Poisson regressions were used to examine the associations between the number of ADHD symptoms and occupation and biomarkers. RESULTS: Pesticide applicators had significantly more symptoms of ADHD than participants in the non-applicator group. Urinary TCPy levels were associated with increased symptoms, demonstrating a dose-response effect. Applicators with ADHD reported applying pesticides for more hours during the application season and had greater cumulative TCPy levels than participants without ADHD. One fourth of all applicators met the criteria for an ADHD diagnosis (having 6 or more reported symptoms). CONCLUSIONS: This study provides preliminary evidence of an association between occupational exposure to chlorpyrifos and ADHD symptoms among adolescent pesticide applicators in spite of its limited small sample size. There is a critical need to investigate the susceptibility of children and adolescents to repeated occupational and environmental exposures to pesticides because the developing brain may be uniquely sensitive to the neurotoxic effects of these agents.
ESTHER : Rohlman_2019_Neurotoxicol_74_1
PubMedSearch : Rohlman_2019_Neurotoxicol_74_1
PubMedID: 31077682

Title : Molecular and functional properties of two Spodoptera exigua acetylcholinesterase genes - Zhao_2019_Arch.Insect.Biochem.Physiol__e21554
Author(s) : Zhao J , Hao D , Xiao L , Tan Y , Jiang Y , Bai L , Wang K
Ref : Archives of Insect Biochemistry & Physiology , :e21554 , 2019
Abstract : Acetylcholinesterase (AChE) is a vital enzyme that hydrolyzes acetylcholine. Here, full-length complementary DNAs (cDNAs) of two acetylcholinesterase genes (SeAce1 and SeAce2) were obtained from Spodoptera exigua, a widespread phytophagous pest in agriculture. The complete SeAce1 cDNA comprised 5447 nucleotides including an open reading frame (ORF) encoding 694 amino acids, while SeAce2 cDNA encompassed a 1917-bp ORF which would likely yield 638 amino acids. Both SeAce1 and SeAce2 contained specific characteristics of functional AChE. A phylogenetic tree of all lepidopteran insect Aces showed S. exigua clustered with S. litura, Helicoverpa assulta, and H. armigera, all of which are Noctuidae. In S. exigua, SeAce1 gene expression levels (reverse transcription polymerase chain reaction [RT-PCR] and quantitative RT-PCR) were markedly increased compared with SeAce2 in all developmental phases and tissue types. Both genes were down regulated by inserting the corresponding dsRNAs in 5th instar larvae, which resulted in 56.7% (SeAce1) and 24.6% (SeAce2) death. Downregulation of both SeAce1 and SeAce2 significantly reduced fecundity and vitellogenin gene expression in S. exigua. These results revealed the biological functions of the two Ace genes (SeAce1 and SeAce2), providing novel insights into the development of strategies for controlling insect pests.
ESTHER : Zhao_2019_Arch.Insect.Biochem.Physiol__e21554
PubMedSearch : Zhao_2019_Arch.Insect.Biochem.Physiol__e21554
PubMedID: 31033012
Gene_locus related to this paper: spolt-ACHE2 , spolt-ACHE1

Title : Design, Synthesis, and Evaluation of Novel Ferulic Acid Derivatives as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease - Sang_2019_ACS.Chem.Neurosci_10_1008
Author(s) : Sang Z , Wang K , Han X , Cao M , Tan Z , Liu W
Ref : ACS Chem Neurosci , 10 :1008 , 2019
Abstract : A novel series of ferulic acid derivatives was designed and synthesized on the basis of the multi-target-directed ligands strategy for the treatment of Alzheimer's disease (AD). In vitro results revealed that all the target compounds were highly effective and selective butyrylcholinesterase (BuChE) inhibitors. In particular, compound TM-10 showed the best BuChE inhibitory activity, with IC(50) = 8.9 nM, and remarkable monoamine oxidase A and B inhibitory potency, with IC(50) = 6.3 and 8.6 microM, respectively. TM-10 could inhibit (53.9%) and disaggregate (43.8%) self-induced amyloid-beta peptide (Abeta) aggregation. In addition, TM-10 exhibited potent antioxidant activity (ORAC = 0.52 equiv) and neuroprotective effect against Abeta(1-42)-mediated SH-SY5Y neurotoxicity, and it acted as an autophagic activator. TM-10 also showed good blood-brain barrier penetration. Furthermore, TM-10 exhibited a favorable dyskinesia recovery rate and response efficiency on an AlCl(3)-induced zebrafish AD model and a potent neuroprotective effect on Abeta(1-40)-induced zebrafish vascular injury. Further, in vivo assays demonstrated that TM-10 showed low acute toxicity, and the step-down passive avoidance test indicated that this compound could improve scopolamine-induced memory deficit in mice. Therefore, the present study displays evidence that TM-10 is a potent, multi-functional agent against AD and could be a promising lead candidate for anti-Alzheimer's disease drug development.
ESTHER : Sang_2019_ACS.Chem.Neurosci_10_1008
PubMedSearch : Sang_2019_ACS.Chem.Neurosci_10_1008
PubMedID: 30537804

Title : ATGL promotes the proliferation of hepatocellular carcinoma cells via the p-AKT signaling pathway - Liu_2019_J.Biochem.Mol.Toxicol__e22391
Author(s) : Liu M , Yu X , Lin L , Deng J , Wang K , Xia Y , Tang X , Hong H
Ref : J Biochem Mol Toxicol , :e22391 , 2019
Abstract : Abnormal metabolism, including abnormal lipid metabolism, is a hallmark of cancer cells. Some studies have demonstrated that the lipogenic pathway might promote the development of hepatocellular carcinoma (HCC). However, the role of adipose triglyceride lipase (ATGL) in hepatocellular carcinoma cells has not been elucidated. We evaluated the function of ATGL in hepatocellular carcinoma using methyl azazolyl blue and migration assay through overexpression of ATGL in HepG2 cells. Quantitative reverse-transcription polymerase chain reaction and Western blot analyses were used to assess the mechanisms of ATGL in hepatocellular carcinoma. In the current study, we first constructed and transiently transfected ATGL into hepatocellular carcinoma cells. Secondly, we found that ATGL promoted the proliferation of hepatoma cell lines via upregulating the phosphorylation of AKT, but did not affect the metastatic ability of HCC cells. Moreover, the p-AKT inhibitor significantly eliminated the effect of ATGL on the proliferation of hepatoma carcinoma cells. Taken together, our results indicated that ATGL promotes hepatocellular carcinoma cells proliferation through upregulation of the AKT signaling pathway.
ESTHER : Liu_2019_J.Biochem.Mol.Toxicol__e22391
PubMedSearch : Liu_2019_J.Biochem.Mol.Toxicol__e22391
PubMedID: 31476254

Title : The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease - Zhu_2019_Bioorg.Med.Chem.Lett_29_126625
Author(s) : Zhu G , Wang K , Shi J , Zhang P , Yang D , Fan X , Zhang Z , Liu W , Sang Z
Ref : Bioorganic & Medicinal Chemistry Lett , 29 :126625 , 2019
Abstract : A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC(50) value of 2.9 microM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu(2+) complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC(50) = 6.8 microM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease.
ESTHER : Zhu_2019_Bioorg.Med.Chem.Lett_29_126625
PubMedSearch : Zhu_2019_Bioorg.Med.Chem.Lett_29_126625
PubMedID: 31444085

Title : A new prognostic factor of breast cancer: High carboxyl ester lipase expression related to poor survival - Cui_2019_Cancer.Genet_239_54
Author(s) : Cui Y , Jiao Y , Wang K , He M , Yang Z
Ref : Cancer Genet , 239 :54 , 2019
Abstract : OBJECTIVE: The enzyme carboxyl ester lipase (CEL), known as bile salt-dependent lipase (BSDL) or bile salt-stimulated lipase (BSSL), is mainly expressed in pancreatic acinar cells and lactating mammary glands. To investigate the link between CEL expression of breast cancer (BC) tissues and the survival of BC patients by analyzing The Cancer Genome Atlas Breast Carcinoma (TCGA-BRCA) level 3 data. METHODS: The clinical information and RNA-sequencing (RNA-Seq) expression data were downloaded from TCGA. Patients were divided into a high CEL expression group and a low CEL expression group using the optimal cutoff value (5.611) identified from the ROC curve. Chi-square test and Fisher exact test were used to find the correlation between the expression of CEL and clinicopathologic features. To assess the diagnostic capability, the receiver operating characteristic (ROC) curve of CEL was drawn. The survival differences between high and low CEL expression groups were compared by Cox regression analysis. Log-rank test was applied to the calculation of p values and the comparison of the Kaplan-Meier curves. Furthermore, Gene Expression Omnibus (GEO) datasets were used for external data validation. RESULTS: Analysis of 1104 cases of tumor data showed that CEL was over-expressed in breast cancer. There were relationships between high CEL expression and clinicopathologic features. The high CEL expression group had a lower survival. By analyzing the area under the ROC curve (AUC) of CEL, it was found to have a limited diagnostic capability. CEL expression may be an independent prognostic factor for breast cancer survival through the multivariate analysis. The validation in GEO datasets also showed that CEL expression was higher in breast tumor tissues than in normal breast tissues. High CEL expression was associated with the poor overall survival of breast cancer. CONCLUSIONS: High CEL expression may be an independent prognostic factor for the poor survival of breast cancer.
ESTHER : Cui_2019_Cancer.Genet_239_54
PubMedSearch : Cui_2019_Cancer.Genet_239_54
PubMedID: 31561066

Title : Electro-acupuncture regulates the cholinergic anti-inflammatory pathway in a rat model of chronic obstructive pulmonary disease - Zhang_2018_J.Integr.Med_16_418
Author(s) : Zhang XF , Xiang SY , Geng WY , Cong WJ , Lu J , Jiang CW , Wang K , Liu ZB
Ref : J Integr Med , 16 :418 , 2018
Abstract : OBJECTIVE: Acupuncture has a definite therapeutic effect on chronic obstructive pulmonary disease (COPD), and the cholinergic anti-inflammatory pathway (CAP) has been shown to be involved in regulation of inflammation. In this study, we investigated whether electro-acupuncture (EA) affects the CAP in COPD. METHODS: Sprague-Dawley rats were induced into COPD through exposure to cigarette smoke combined with lipopolysaccharide. EA treatment was applied at Zusanli (ST36) and Feishu (BL13) points for 30min/d for 7d. Seventy-two rats were randomly divided into six study groups, including normal, normal+EA, normal+alpha-bungarotoxin (alpha-BGT) (the antagonist of the nicotinic acetylcholine receptor alpha7 subunit (alpha7nAChR))+EA, COPD, COPD+EA, and COPD+alpha-BGT+EA. Lung function, pathology and vagus nerve discharge were tested. The levels of acetylcholine (ACh), acetylcholinesterase (AChE), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid (BALF) and lung tissue were measured by enzyme-linked immunosorbent assay. The mRNA and protein expression and immunoreactivity of alpha7nAChR and its postreceptor inflammation signal pathway, including janus kinase 2 (JAK2), signal transducers and activators of transcription 3 (STAT3), nuclear factor-kappaB (NF-kappaB), were observed by quantitative reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. RESULTS: Compared with normal rats, there were a significant decline in lung function and discharge of the vagus nerve (P<0.01), a marked sign of lung inflammation and an increase of ACh, AChE, IL-6 and TNF-alpha level in BALF or lung tissue (P<0.05, P<0.01) and higher expression of alpha7nAChR, JAK2, STAT3 and NF-kappaB (P<0.05, P<0.01) in the COPD rats. In rats receiving EA, the lung function and vagal discharge were enhanced (P<0.01), lung inflammation was improved and the levels of ACh, AChE, IL-6 and TNF-alpha were decreased (P<0.01). Further, the expression of alpha7nAChR, JAK2, STAT3 and NF-kappaB was downregulated (P<0.05, P<0.01). However, the above effects of EA were blocked in rats injected with alpha-BGT (P<0.01). CONCLUSION: EA treatment can reduce the lung inflammatory response and improve lung function in COPD, which may be related to its involvement in the regulation of CAP.
ESTHER : Zhang_2018_J.Integr.Med_16_418
PubMedSearch : Zhang_2018_J.Integr.Med_16_418
PubMedID: 30341024

Title : Two Abscisic Acid-Responsive Plastid Lipase Genes Involved in Jasmonic Acid Biosynthesis in Arabidopsis thaliana - Wang_2018_Plant.Cell_30_1006
Author(s) : Wang K , Guo Q , Froehlich JE , Hersh HL , Zienkiewicz A , Howe GA , Benning C
Ref : Plant Cell , 30 :1006 , 2018
Abstract : Chloroplast membranes with their unique lipid composition are crucial for photosynthesis. Maintenance of the chloroplast membranes requires finely tuned lipid anabolic and catabolic reactions. Despite the presence of a large number of predicted lipid-degrading enzymes in the chloroplasts, their biological functions remain largely unknown. Recently, we described PLASTID LIPASE1 (PLIP1), a plastid phospholipase A1 that contributes to seed oil biosynthesis. The Arabidopsis thaliana genome encodes two putative PLIP1 paralogs, which we designated PLIP2 and PLIP3. PLIP2 and PLIP3 are also present in the chloroplasts, but likely with different subplastid locations. In vitro analysis indicated that both are glycerolipid A1 lipases. In vivo, PLIP2 prefers monogalactosyldiacylglycerol as substrate and PLIP3 phosphatidylglycerol. Overexpression of PLIP2 or PLIP3 severely reduced plant growth and led to accumulation of the bioactive form of jasmonate and related oxylipins. Genetically blocking jasmonate perception restored the growth of the PLIP2/3-overexpressing plants. The expression of PLIP2 and PLIP3, but not PLIP1, was induced by abscisic acid (ABA), and plip1 plip2 plip3 triple mutants exhibited compromised oxylipin biosynthesis in response to ABA. The plip triple mutants also showed hypersensitivity to ABA. We propose that PLIP2 and PLIP3 provide a mechanistic link between ABA-mediated abiotic stress responses and oxylipin signaling.
ESTHER : Wang_2018_Plant.Cell_30_1006
PubMedSearch : Wang_2018_Plant.Cell_30_1006
PubMedID: 29666162
Gene_locus related to this paper: arath-AT3g62590 , arath-T14P4.6

Title : Protective effects of tetrahydropalmatine against ketamine-induced learning and memory injury via antioxidative, anti-inflammatory and anti-apoptotic mechanisms in mice - Zhang_2018_Mol.Med.Rep_17_6873
Author(s) : Zhang Y , Sha R , Wang K , Li H , Yan B , Zhou N
Ref : Mol Med Rep , 17 :6873 , 2018
Abstract : Tetrahydropalmatine exerts numerous pharmacological activities, including analgesic and narcotic effects; anti-arrhythmic, blood pressure lowering and cardioprotective effects; protective effects against cerebral ischemia-reperfusion injury; inhibition of platelet aggregation; prevention of ulcerative diseases and inhibition of gastric acid secretion; antitumor effects; and beneficial effects on the withdrawal symptoms associated with drug addiction. The present study aimed to investigate the protective effects of tetrahydropalmatine against ketamineinduced learning and memory impairment in mice. The Morris water maze test and open field test were used to analyzed learning and memory impairment in mice. ELISA kits and western blotting were used to analyze oxidative stress, inflammation factors, caspease3 and caspase9, iNOS, glial fibrillary acidic protein (GFAP), glial cellderived neurotrophic factor (GDNF), cytochrome c and phospholipase C (PLC)gamma1 protein expression. The results demonstrated that tetrahydropalmatine treatment significantly decreased escape latency in the learning phase and increased the number of platform site crossings in ketamineinduced mice. In addition, tetrahydropalmatine significantly inhibited oxidative stress, inflammation and acetylcholinesterase activity, and decreased acetylcholine levels in ketamineinduced mice. Tetrahydropalmatine also suppressed iNOS protein expression, weakened caspase3 and caspase9 activation, inhibited nuclear factorkappaB, glial fibrillary acidic protein, cytochrome c and phospholipase Cgamma1 protein expression, and induced glial cellderived neurotrophic factor protein expression in ketamineinduced mice. Taken together, these results indicated that tetrahydropalmatine may protect against ketamineinduced learning and memory impairment in mice via antioxidative, antiinflammatory and antiapoptotic mechanisms. The present study provided an experimental basis for the clinical application of tetrahydropalmatine to reduce the severe side effects associated with ketamine therapy in future studies.
ESTHER : Zhang_2018_Mol.Med.Rep_17_6873
PubMedSearch : Zhang_2018_Mol.Med.Rep_17_6873
PubMedID: 29512789

Title : Functional Analysis of a Carboxylesterase Gene Associated With Isoprocarb and Cyhalothrin Resistance in Rhopalosiphum padi (L.) - Wang_2018_Front.Physiol_9_992
Author(s) : Wang K , Huang Y , Li X , Chen M
Ref : Front Physiol , 9 :992 , 2018
Abstract : Carboxylesterase (CarE) is an important class of detoxification enzymes involved in insecticide resistance. However, the molecular mechanism of CarE-mediated insecticide resistance in Rhopalosiphum padi, a problematic agricultural pest, remains largely unknown. In the present study, an isoprocarb-resistant (IS-R) strain and a cyhalothrin-resistant (CY-R) strain were successively selected from a susceptible (SS) strain of R. padi. The enzyme activity indicated that enhanced carboxylesterase activity contributes to isoprocarb and cyhalothrin resistance. The expression levels of putative CarE genes were examined and compared among IS-R, CY-R, and SS strains, and only the R. padi carboxylesterase gene (RpCarE) was significantly over expressed in both the IS-R and CY-R strains compared to the SS strain. The coding region of the RpCarE gene was cloned and expressed in Escherichia coli. The purified RpCarE protein was able to catalyze the model substrate, alpha-naphtyl acetate (Kcat = 5.50 s(-1); Km = 42.98 muM). HPLC assay showed that the recombinant protein had hydrolase activity against isoprocarb and cyhalothrin. The modeling and docking analyses consistently indicated these two insecticide molecules fit snugly into the catalytic pocket of RpCarE. Taken together, these findings suggest that RpCarE plays an important role in metabolic resistance to carbamates and pyrethroids in R. padi.
ESTHER : Wang_2018_Front.Physiol_9_992
PubMedSearch : Wang_2018_Front.Physiol_9_992
PubMedID: 30090072

Title : The impact of repeated organophosphorus pesticide exposure on biomarkers and neurobehavioral outcomes among adolescent pesticide applicators - Ismail_2017_J.Toxicol.Environ.Health.A__1
Author(s) : Ismail AA , Wang K , Olson JR , Bonner MR , Hendy O , Rasoul GA , Rohlman DS
Ref : J Toxicol Environ Health A , :1 , 2017
Abstract : Egyptian adolescents are hired as seasonal workers to apply pesticides to the cotton crop and may perform this occupation for several years. However, few studies examined the effects of repeated pesticide exposure on health outcomes The goal of this study was to determine the impact of repeated pesticide exposure on neurobehavioral (NB) performance and biomarkers of exposure (urinary metabolite) and effect (cholinesterase activity). Eighty-four adolescents from two field stations in Menoufia, Egypt, were examined four times: before and during pesticide application season in 2010 and again before and during application season in 2011. At each of the four time points, participants completed a questionnaire, performed an NB test battery, and were assessed for urinary levels of the chlorpyrifos metabolite TCPy (3,5,6-trichloro-2-pyridinol) and blood cholinesterase activity. Following the study cohort over two consecutive pesticide application seasons revealed that TCPy levels significantly increased following exposure, and returned to baseline levels following the end of the application season. Blood butyryl cholinesterase activity exhibited a similar pattern. Although NB outcomes displayed learning and practice effects over time, deficits in performance were significantly associated with increased TCPy levels with reduction in the number of NB measures showing improvement over time. Biomarkers of exposure and effect demonstrated changes associated with pesticide application and recovery after application ended. Deficits in NB performance were correlated with elevated pesticide exposure. Data demonstrated that repeated pesticide exposure may exert a long-term adverse impact on human health.
ESTHER : Ismail_2017_J.Toxicol.Environ.Health.A__1
PubMedSearch : Ismail_2017_J.Toxicol.Environ.Health.A__1
PubMedID: 28880741

Title : A Plastid Phosphatidylglycerol Lipase Contributes to the Export of Acyl Groups from Plastids for Seed Oil Biosynthesis - Wang_2017_Plant.Cell_29_1678
Author(s) : Wang K , Froehlich JE , Zienkiewicz A , Hersh HL , Benning C
Ref : Plant Cell , 29 :1678 , 2017
Abstract : The lipid composition of thylakoid membranes inside chloroplasts is conserved from leaves to developing embryos. A finely tuned lipid assembly machinery is required to build these membranes during Arabidopsis thaliana development. Contrary to thylakoid lipid biosynthetic enzymes, the functions of most predicted chloroplast lipid-degrading enzymes remain to be elucidated. Here, we explore the biochemistry and physiological function of an Arabidopsis thylakoid membrane-associated lipase, PLASTID LIPASE1 (PLIP1). PLIP1 is a phospholipase A1 In vivo, PLIP1 hydrolyzes polyunsaturated acyl groups from a unique chloroplast-specific phosphatidylglycerol that contains 16:1 (Delta3trans) as its second acyl group. Thus far, a specific function of this 16:1 (Delta3trans) -containing phosphatidylglycerol in chloroplasts has remained elusive. The PLIP1 gene is highly expressed in seeds, and plip1 mutant seeds contain less oil and exhibit delayed germination compared with the wild type. Acyl groups released by PLIP1 are exported from the chloroplast, reincorporated into phosphatidylcholine, and ultimately enter seed triacylglycerol. Thus, 16:1 (Delta3trans) uniquely labels a small but biochemically active plastid phosphatidylglycerol pool in developing Arabidopsis embryos, which is subject to PLIP1 activity, thereby contributing a small fraction of the polyunsaturated fatty acids present in seed oil. We propose that acyl exchange involving thylakoid lipids functions in acyl export from plastids and seed oil biosynthesis.
ESTHER : Wang_2017_Plant.Cell_29_1678
PubMedSearch : Wang_2017_Plant.Cell_29_1678
PubMedID: 28687655
Gene_locus related to this paper: arath-At3g61680

Title : The Aegilops tauschii genome reveals multiple impacts of transposons - Zhao_2017_Nat.Plants_3_946
Author(s) : Zhao G , Zou C , Li K , Wang K , Li T , Gao L , Zhang X , Wang H , Yang Z , Liu X , Jiang W , Mao L , Kong X , Jiao Y , Jia J
Ref : Nat Plants , 3 :946 , 2017
Abstract : Wheat is an important global crop with an extremely large and complex genome that contains more transposable elements (TEs) than any other known crop species. Here, we generated a chromosome-scale, high-quality reference genome of Aegilops tauschii, the donor of the wheat D genome, in which 92.5% sequences have been anchored to chromosomes. Using this assembly, we accurately characterized genic loci, gene expression, pseudogenes, methylation, recombination ratios, microRNAs and especially TEs on chromosomes. In addition to the discovery of a wave of very recent gene duplications, we detected that TEs occurred in about half of the genes, and found that such genes are expressed at lower levels than those without TEs, presumably because of their elevated methylation levels. We mapped all wheat molecular markers and constructed a high-resolution integrated genetic map corresponding to genome sequences, thereby placing previously detected agronomically important genes/quantitative trait loci (QTLs) on the Ae. tauschii genome for the first time.
ESTHER : Zhao_2017_Nat.Plants_3_946
PubMedSearch : Zhao_2017_Nat.Plants_3_946
PubMedID: 29158546
Gene_locus related to this paper: horvv-m0utz9 , wheat-a0a3b6c2m6 , wheat-a0a3b5zwb6 , wheat-a0a3b6bzs8 , wheat-a0a1d5zte7 , wheat-a0a1d5uwn5

Title : Metabolic profiles of corydaline in rats by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry - Chai_2017_Xenobiotica__1
Author(s) : Chai L , Donkor PO , Wang K , Sun Y , Oppong MB , Ding L , Qiu F
Ref : Xenobiotica , :1 , 2017
Abstract : Corydaline, an isoquinoline alkaloid obtained from the rhizomes of Corydalis yanhusuo, exhibits anti-acetylcholinesterase, anti-angiogenic, anti-allergic and gastric emptying activities. In this study, a rapid and reliable ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) method was developed and employed for the comprehensive study of the metabolites of corydaline in rats. Altogether, 43 metabolites were identified in the plasma (11), bile (9), urine (34) and feces (21) of rats after oral administration of corydaline at a dose of 4.5mg/kg. It was demonstrated that demethylation, hydroxylation, sulfation and glucuronidation were the major metabolic transformation pathways. Among these, two metabolites were identified as tetrahydropalmatine and isocorybulbine, and thirty-three (33) phase I and phase II products were inferred to be new metabolites arising from the in vivo metabolism of corydaline. Importantly, this research provides scientific and reliable support for full understanding of the metabolic profiles of corydaline and the results could help to elucidate its safety and efficacy.
ESTHER : Chai_2017_Xenobiotica__1
PubMedSearch : Chai_2017_Xenobiotica__1
PubMedID: 29235899

Title : Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase\/monoamine oxidase inhibitors for the treatment of Alzheimer's disease - Sang_2017_Bioorg.Med.Chem_25_3006
Author(s) : Sang Z , Pan W , Wang K , Ma Q , Yu L , Liu W
Ref : Bioorganic & Medicinal Chemistry , 25 :3006 , 2017
Abstract : A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC50 values of 0.56muM, 2.3muM, 0.3muM and 1.4muM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM-33 could cross the blood-brain barrier (BBB) in vitro, and abided by Lipinski's rule of five. The results suggest that compound TM-33, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
ESTHER : Sang_2017_Bioorg.Med.Chem_25_3006
PubMedSearch : Sang_2017_Bioorg.Med.Chem_25_3006
PubMedID: 28487125

Title : The Protective Effect of Lavender Essential Oil and Its Main Component Linalool against the Cognitive Deficits Induced by D-Galactose and Aluminum Trichloride in Mice - Xu_2017_Evid.Based.Complement.Alternat.Med_2017_7426538
Author(s) : Xu P , Wang K , Lu C , Dong L , Gao L , Yan M , Aibai S , Yang Y , Liu X
Ref : Evid Based Complement Alternat Med , 2017 :7426538 , 2017
Abstract : Lavender essential oil (LO) is a traditional medicine used for the treatment of Alzheimer's disease (AD). It was extracted from Lavandula angustifolia Mill. This study was designed to investigate the effects of lavender essential oil (LO) and its active component, linalool (LI), against cognitive impairment induced by D-galactose (D-gal) and AlCl3 in mice and to explore the related mechanisms. Our results revealed that LO (100 mg/kg) or LI (100 mg/kg) significantly protected the cognitive impairments as assessed by the Morris water maze test and step-though test. The mechanisms study demonstrated that LO and LI significantly protected the decreased activity of superoxide dismutase (SOD), glutathione peroxidase (GPX), and protected the increased activity of acetylcholinesterase (AChE) and content of malondialdehyde (MDA). Besides, they protected the suppressed nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression significantly. Moreover, the decreased expression of synapse plasticity-related proteins, calcium-calmodulin-dependent protein kinase II (CaMKII), p-CaMKII, brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus were increased with drug treatment. In conclusion, LO and its active component LI have protected the oxidative stress, activity of cholinergic function and expression of proteins of Nrf2/HO-1 pathway, and synaptic plasticity. It suggest that LO, especially LI, could be a potential agent for improving cognitive impairment in AD.
ESTHER : Xu_2017_Evid.Based.Complement.Alternat.Med_2017_7426538
PubMedSearch : Xu_2017_Evid.Based.Complement.Alternat.Med_2017_7426538
PubMedID: 28529531

Title : Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2 - Liu_2017_J.Med.Chem_60_10231
Author(s) : Liu Q , Huang F , Yuan X , Wang K , Zou Y , Shen J , Xu Y
Ref : Journal of Medicinal Chemistry , 60 :10231 , 2017
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
ESTHER : Liu_2017_J.Med.Chem_60_10231
PubMedSearch : Liu_2017_J.Med.Chem_60_10231
PubMedID: 29193967
Gene_locus related to this paper: human-PLA2G7

Title : Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease - Sang_2017_Bioorg.Med.Chem.Lett_27_5053
Author(s) : Sang Z , Wang K , Wang H , Yu L , Ma Q , Ye M , Han X , Liu W
Ref : Bioorganic & Medicinal Chemistry Lett , 27 :5053 , 2017
Abstract : A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2muM, 3.8muM and 2.6muM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
ESTHER : Sang_2017_Bioorg.Med.Chem.Lett_27_5053
PubMedSearch : Sang_2017_Bioorg.Med.Chem.Lett_27_5053
PubMedID: 29033232

Title : Hypermethylation of the N-Myc Downstream-Regulated Gene 2 Promoter in Peripheral Blood Mononuclear Cells is Associated with Liver Fibrosis in Chronic Hepatitis B - Liu_2017_Tohoku.J.Exp.Med_241_155
Author(s) : Liu XY , Fan YC , Gao S , Zhao J , Li F , Zhang J , Wang K
Ref : Tohoku J Exp Med , 241 :155 , 2017
Abstract : DNA methylation is a fundamental epigenetic modification to regulate gene expression. N-Myc downstream-regulated gene (NDRG) 2 is a cytoplasmic protein and participates in the pathogenesis of liver fibrosis. In this study, the mRNA expression and methylation status of NDRG2 was evaluated in patients with chronic hepatitis B (CHB). The study included 143 CHB patients and 65 normal controls (NC). The mRNA expression of NDRG2 in peripheral blood mononuclear cells (PBMCs) was detected by quantitative real-time polymerase chain reaction. The methylation status of the NDRG2 promoter in PBMCs was detected by methylation-specific polymerase chain reaction. The NDRG2 mRNA level was lower in the CHB group than in the NC group (p < 0.001). Methylation frequency of the NDRG2 promoter was significantly higher in CHB patients than in the NC group (52.44% vs. 26.15%, p < 0.001). Importantly, the relative expression levels of NDRG2 mRNA were significantly lower in the methylated group than in the unmethylated group in both CHB patients and NC (p < 0.001). Furthermore, a lower mRNA level and hypermethylation of NDRG2 were associated with liver fibrosis and inflammation grade in CHB. The aspartate aminotransferase-to-platelet ratio index (APRI) score is widely used to predict liver fibrosis. The mRNA expression levels and methylation status of NDRG2 showed a better score compared to APRI for discriminating the severity of liver fibrosis. In conclusion, hypermethylation of NDRG2 in PBMCs was correlated with decreased mRNA expression and with liver fibrosis. The methylation status of the NDRG2 promoter in PBMCs is a potential noninvasive biomarker to predict the severity of liver fibrosis.
ESTHER : Liu_2017_Tohoku.J.Exp.Med_241_155
PubMedSearch : Liu_2017_Tohoku.J.Exp.Med_241_155
PubMedID: 28202850

Title : Association of Lp-PLA2 G994T gene polymorphism with risk of ischemic stroke in Chinese population - Ni_2017_J.Biochem.Mol.Toxicol_31_
Author(s) : Ni J , Gu H , Hu W , Zhou F , Zhu X , Wang K
Ref : J Biochem Mol Toxicol , 31 : , 2017
Abstract : The association between lipoprotein-associated phospholipase A2 (Lp-PLA2) G994T gene polymorphism and the risk of ischemic stroke is unclear. The aim of this study is to investigate the influence of Lp-PLA2 G994T genetic variant on the pathogenesis of ischemic stroke in Chinese population. A total of 348 patients with a clinical diagnosis of ischemic stroke and 260 gender-matched control subjects under physical examination were recruited from hospitals and genotyped for G994T gene polymorphism. The results showed that there was a significant difference in the genotype distribution between the two groups and people with GT or TT genotype were associated with the higher risk of ischemic stroke even after adjusting the effects of potential confounding factors. In addition, both ischemic stroke patients and control subjects carrying T allele showed relatively lower Lp-PLA2 activity and higher oxLDL level. Therefore, Lp-PLA2 G994T gene polymorphism may be an independent risk factor of ischemic stroke in Chinese population.
ESTHER : Ni_2017_J.Biochem.Mol.Toxicol_31_
PubMedSearch : Ni_2017_J.Biochem.Mol.Toxicol_31_
PubMedID: 28960681
Gene_locus related to this paper: human-PLA2G7

Title : N-myc downstream regulated gene 1(NDRG1) promotes the stem-like properties of lung cancer cells through stabilized c-Myc - Wang_2017_Cancer.Lett_401_53
Author(s) : Wang Y , Zhou Y , Tao F , Chai S , Xu X , Yang Y , Xu H , Wang K
Ref : Cancer Letters , 401 :53 , 2017
Abstract : Tumor-initiating cells (TICs) play an important role in tumorigenesis and development for many various tissue origin cancers including non-small cell lung cancer (NSCLC). However, the mechanism to maintain TICs in NSCLC is still largely unknown. Here, we evaluated differences of mRNA expression between parental and oncosphere cells that enriched TICs. We found that N-myc downstream regulated gene 1(NDRG1) was upregulated in oncosphere cells derived from human NSCLC cell lines and primary NSCLC cells. NDRG1 promoted stem-like properties of LTICs in NSCLC including iPSC (induced pluripotent stem cell) factors (OCT4, SOX2, KLF4, and C-MYC), the spheres-forming ability and the tumorigenicity of NSCLC. NDRG1 prevented the degradation of c-Myc through Skp2-mediated ubiquitination. NDRG1 directly interacted with Skp2, and decreased phosphorylation of Skp2 through inactivation of CDK2. Finally, we confirmed that NDRG1 was negatively correlated with survival and prognosis. Thus, our findings indicate that NDRG1 is a potential target for eradicating TICs in NSCLC.
ESTHER : Wang_2017_Cancer.Lett_401_53
PubMedSearch : Wang_2017_Cancer.Lett_401_53
PubMedID: 28456659
Gene_locus related to this paper: human-NDRG1

Title : Design, synthesis and evaluation of novel ferulic acid-O-alkylamine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease - Sang_2017_Eur.J.Med.Chem_130_379
Author(s) : Sang Z , Pan W , Wang K , Ma Q , Yu L , Yang Y , Bai P , Leng C , Xu Q , Li X , Tan Z , Liu W
Ref : Eur Journal of Medicinal Chemistry , 130 :379 , 2017
Abstract : A series of novel ferulic acid-O-alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced beta-amyloid (Abeta) aggregation and acted as potential antioxidants. Particularly, compound 7f, one of the most potent BuChE inhibitor (IC50 value of 0.021 muM for equine serum BuChE, 8.63 muM for ratBuChE and 0.07 muM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC50 = 2.13 muM for electric eel AChE, 1.8 muM for ratAChE and 3.82 muM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced Abeta1-42 aggregation (50.8 +/- 0.82%) and was found to disaggregate self-induced Abeta1-42 aggregation (38.7 +/- 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H2O2-induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro. Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of AD.
ESTHER : Sang_2017_Eur.J.Med.Chem_130_379
PubMedSearch : Sang_2017_Eur.J.Med.Chem_130_379
PubMedID: 28279845

Title : Biochemical and Structural Analyses of Two Cryptic Esterases in Bacteroides intestinalis and their Synergistic Activities with Cognate Xylanases - Wefers_2017_J.Mol.Biol_429_2509
Author(s) : Wefers D , Cavalcante JJV , Schendel RR , Deveryshetty J , Wang K , Wawrzak Z , Mackie RI , Koropatkin NM , Cann I
Ref : Journal of Molecular Biology , 429 :2509 , 2017
Abstract : Arabinoxylans are constituents of the human diet. Although not utilizable by the human host, they can be fermented by colonic bacteria. The arabinoxylan backbone is decorated with arabinose side chains that may be substituted with ferulic acid, thus limiting depolymerization to fermentable sugars. We investigated the polypeptides encoded by two genes upregulated during growth of the colonic bacterium Bacteroides intestinalis on wheat arabinoxylan. The recombinant proteins, designated BiFae1A and BiFae1B, were functionally assigned esterase activities. Both enzymes were active on acetylated substrates, although each showed a higher ferulic acid esterase activity on methyl-ferulate. BiFae1A showed a catalytic efficiency of 12mM s(-1) on para-nitrophenyl-acetate, and on methyl-ferulate, the value was 27 times higher. BiFae1B showed low catalytic efficiencies for both substrates. Furthermore, the two enzymes released ferulic acid from various structural elements, and NMR spectroscopy indicated complete de-esterification of arabinoxylan oligosaccharides from wheat bran. BiFae1A is a tetramer based on the crystal structure, whereas BiFae1B is a dimer in solution based on size exclusion chromatography. The structure of BiFae1A was solved to 1.98A resolution, and two tetramers were observed in the asymmetric unit. A flexible loop that may act as a hinge over the active site and likely coordinates critical interactions with the substrate was prominent in BiFae1A. Sequence alignments of the esterase domains in BiFae1B with the feruloyl esterase from Clostridium thermocellum suggest that both domains lack the flexible hinge in BiFae1A, an observation that may partly provide a molecular basis for the differences in activities in the two esterases.
ESTHER : Wefers_2017_J.Mol.Biol_429_2509
PubMedSearch : Wefers_2017_J.Mol.Biol_429_2509
PubMedID: 28669823
Gene_locus related to this paper: 9bace-b3c9d0.2 , 9bace-b3cet1

Title : Comparison of neurological health outcomes between two adolescent cohorts exposed to pesticides in Egypt - Ismail_2017_PLoS.One_12_e0172696
Author(s) : Ismail AA , Bonner MR , Hendy O , Abdel Rasoul G , Wang K , Olson JR , Rohlman DS
Ref : PLoS ONE , 12 :e0172696 , 2017
Abstract : Pesticide-exposed adolescents may have a higher risk of neurotoxic effects because of their developing brains and bodies. However, only a limited number of studies have addressed this risk among adolescents. The aim of this study was to compare neurological outcomes from two cohorts of Egyptian adolescents working as pesticide applicators. In 2005 and 2009, two cohorts of male adolescents working as pesticide applicators for the cotton crop were recruited from Menoufia Governorate, Egypt. The same application schedule and pesticides were used at both times, including both organophosphorus, and pyrethroid compounds. Participants in both cohorts completed three neurobehavioral tests, health and exposure questionnaires, and medical and neurological screening examinations. In addition, blood samples were collected to measure butyryl cholinesterase (BChE) activity. Pesticide applicators in both cohorts reported more neurological symptoms and signs than non-applicators, particularly among participants in the 2005 cohort (OR ranged from 1.18 to 15.3). Except for one test (Trail Making B), there were no significant differences between either applicators or non-applicators of both cohorts on the neurobehavioral outcome measures (p > 0.05). The 2005 cohort showed greater inhibition of serum BChE activity than the 2009 cohort (p < 0.05). In addition, participants with depressed BChE activity showed more symptoms and signs than others without BChE depression (p < 0.05). Our study is the first to examine the consistency of health outcomes associated with pesticide exposure across two cohorts tested at different times from the same geographical region in rural Egypt. This similar pattern of findings across the two cohorts provides strong evidence of the health impact of exposure of adolescents to pesticides.
ESTHER : Ismail_2017_PLoS.One_12_e0172696
PubMedSearch : Ismail_2017_PLoS.One_12_e0172696
PubMedID: 28231336

Title : Protective effect of lavender oil on scopolamine induced cognitive deficits in mice and H2O2 induced cytotoxicity in PC12 cells - Xu_2016_J.Ethnopharmacol_193_408
Author(s) : Xu P , Wang K , Lu C , Dong L , Gao L , Yan M , Aibai S , Liu X
Ref : J Ethnopharmacol , 193 :408 , 2016
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Lavender essential oil (LO), an aromatic liquid extracted from Lavandula angustifolia Mill., has been traditionally used in the treatments of many nervous system diseases, and recently LO also reported to be effective for the Alzheimer's disease (AD). AIM OF THE STUDY: The improvement effect of lavender oil (LO) on the scopolamine-induced cognitive deficits in mice and H2O2 induced cytotoxicity in PC12 cells have been evaluated. The relevant mechanism was also researched from the perspective of antioxidant effect and cholinergic system modulation. MATERIALS AND
METHODS: Cognitive deficits were induced in C57BL/6J mice treated with scopolamine (1mg/kg, i.p.) and were assessed by Morris water maze (MWM) and step-through passive avoidance tests. Then their hippocampus were removed for biochemical assays (acetylcholinesterase (AChE), superoxide dismutase (SOD), glutathione peroxidase (GPX) and malondialdehyde (MDA)). In vitro, the cytotoxicity were induced by 4h exposure to H2O2 in PC12 and evaluated by cell viability (MTT), lactate dehydrogenase (LDH) level, nitric oxide (NO) release, reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP).
RESULTS: The results demonstrated that LO (100mg/kg) could improve the cognitive performance of scopolamine induced mice in behavioral tests. Meanwhile, it significantly decreased the AChE activity, MDA level, and increase SOD and GPX activities of the model. Moreover, LO (12mug/mL) protected PC12 cells from H2O2 induced cytotoxicity by reducing LDH, NO release, intracellular ROS accumulation and MMP loss.
CONCLUSIONS: It was suggested that LO could show neuroprotective effect in AD model in vivo (scopolamine-treated mice) and in vitro (H2O2 induced PC12 cells) via modulating oxidative stress and AChE activity.
ESTHER : Xu_2016_J.Ethnopharmacol_193_408
PubMedSearch : Xu_2016_J.Ethnopharmacol_193_408
PubMedID: 27558947

Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema - Chen_2016_J.Med.Chem_59_2674
Author(s) : Chen X , Wang K , Xu W , Ma Q , Chen M , Du L , Mo M , Wang Y , Shen J
Ref : Journal of Medicinal Chemistry , 59 :2674 , 2016
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
ESTHER : Chen_2016_J.Med.Chem_59_2674
PubMedSearch : Chen_2016_J.Med.Chem_59_2674
PubMedID: 26927682
Gene_locus related to this paper: human-PLA2G7

Title : Development of self-assembling peptide nanovesicle with bilayers for enhanced EGFR-targeted drug and gene delivery - Liang_2015_Biomaterials_82_194
Author(s) : Liang X , Shi B , Wang K , Fan M , Jiao D , Ao J , Song N , Wang C , Gu J , Li Z
Ref : Biomaterials , 82 :194 , 2015
Abstract : Development of rational vectors for efficient drug and gene delivery is crucial for cancer treatment. In this study, epidermal growth factor receptor (EGFR)-binding peptide amphiphile (PA) were used as the primary bilayer skeleton material to construct ultra-stable self-assembling peptide nanovesicle (SPV). The resulted EGFR-targeted SPV (ESPV) could efficiently encapsulate therapeutic cargos (drugs or small interfering RNAs [siRNAs]) or labelled fluorescent cargo (quantum dots [QDs]) and exhibited excellent affinity for EGFR-positive cancer cells. Moreover, ESPV could deliver more drug or plasmid DNA to tumour sites and promote gene expression (a three-fold ratio of ESPVs vs cationic liposomes). Notably, the individual delivery or co-delivery of doxorubicin (DOX) and the acetylcholinesterase (AChE) gene via the ESPVs resulted in excellent drug/gene delivery both in vitro and in vivo and exerted a significant growth-suppressing effect on a liver cancer xenograft. This nanoscale, targeted cargo-packaging technology may provide a new strategy for the design of highly targeted cancer therapy vectors.
ESTHER : Liang_2015_Biomaterials_82_194
PubMedSearch : Liang_2015_Biomaterials_82_194
PubMedID: 26763734

Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors - Chen_2015_J.Med.Chem_58_8529
Author(s) : Chen X , Xu W , Wang K , Mo M , Zhang W , Du L , Yuan X , Xu Y , Wang Y , Shen J
Ref : Journal of Medicinal Chemistry , 58 :8529 , 2015
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
ESTHER : Chen_2015_J.Med.Chem_58_8529
PubMedSearch : Chen_2015_J.Med.Chem_58_8529
PubMedID: 26479945
Gene_locus related to this paper: human-PLA2G7

Title : Vagal modulation of high mobility group box-1 protein mediates electroacupuncture-induced cardioprotection in ischemia-reperfusion injury - Zhang_2015_Sci.Rep_5_15503
Author(s) : Zhang J , Yong Y , Li X , Hu Y , Wang J , Wang YQ , Song W , Chen WT , Xie J , Chen XM , Lv X , Hou LL , Wang K , Zhou J , Wang XR , Song JG
Ref : Sci Rep , 5 :15503 , 2015
Abstract : Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a alpha7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion.
ESTHER : Zhang_2015_Sci.Rep_5_15503
PubMedSearch : Zhang_2015_Sci.Rep_5_15503
PubMedID: 26499847

Title : Novel link between prostaglandin E2 (PGE2) and cholinergic signaling in lung cancer: The role of c-Jun in PGE2-induced alpha7 nicotinic acetylcholine receptor expression and tumor cell proliferation - Zhong_2015_Thorac.Cancer_6_488
Author(s) : Zhong X , Fan Y , Ritzenthaler JD , Zhang W , Wang K , Zhou Q , Roman J
Ref : Thorac Cancer , 6 :488 , 2015
Abstract : BACKGROUND: Cyclooxygenase-2-derived prostaglandin E2 (PGE2) stimulates tumor cell growth and progression. alpha7 nicotinic acetylcholine receptor (nAChR) is a major mediator of cholinergic signaling in tumor cells. In the present study, we investigated the mechanisms by which PGE2 increases non-small cell lung cancer (NSCLC) proliferation via alpha7 nAChR induction.
METHODS: The effects of PGE2 on alpha7 nAChR expression, promoter activity, and cell signaling pathways were detected by Western blot analysis, real time reverse transcriptase polymerase chain reaction, and transient transfection assay. The effect of PGE2 on cell growth was determined by cell viability assay.
RESULTS: We found that PGE2 induced alpha7 nAChR expression and its promoter activity in NSCLC cells. The stimulatory role of PGE2 on cell proliferation was attenuated by alpha7 nAChR small interfering ribonucleic acids (siRNA) or acetylcholinesterase. PGE2-induced alpha7 nAChR expression was blocked by an antagonist of the PGE2 receptor subtype EP4 and by EP4 siRNA. Furthermore, PGE2 enhanced alpha7 nAChR expression via activation of c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3-K), and protein kinase A (PKA) pathways followed by increased c-Jun expression, a critical transcription factor. Blockade of c-Jun diminished the effects of PGE2 on alpha7 nAChR promoter activity and protein expression, and cell growth. CONCLUSION: Our results demonstrate that PGE2 promotes NSCLC cell growth through increased alpha7 nAChR expression. This effect is dependent on EP4-mediated activation of JNK, PI3K, and PKA signals that induce c-Jun protein expression and alpha7 nAChR gene promoter activity. Our findings unveil a novel link between prostanoids and cholinergic signaling.
ESTHER : Zhong_2015_Thorac.Cancer_6_488
PubMedSearch : Zhong_2015_Thorac.Cancer_6_488
PubMedID: 26273406

Title : Evaluation of the Toxicity, AChE Activity and DNA Damage Caused by Imidacloprid on Earthworms, Eisenia fetida - Wang_2015_Bull.Environ.Contam.Toxicol_95_475
Author(s) : Wang K , Qi S , Mu X , Chai T , Yang Y , Wang D , Li D , Che W , Wang C
Ref : Bulletin of Environmental Contamination & Toxicology , 95 :475 , 2015
Abstract : Imidacloprid is a well-known pesticide and it is timely to evaluate its toxicity to earthworms (Eisenia fetida). In the present study, the effect of imidacloprid on reproduction, growth, acetylcholinesterase (AChE) and DNA damage in earthworms was assessed using an artificial soil medium. The median lethal concentration (LC50) and the median number of hatched cocoons (EC50) of imidacloprid to earthworms was 3.05 and 0.92 mg/kg respectively, the lowest observed effect concentration of imidacloprid about hatchability, growth, AChE activity and DNA damage was 0.02, 0.5, 0.1 and 0.5 mg/kg, respectively.
ESTHER : Wang_2015_Bull.Environ.Contam.Toxicol_95_475
PubMedSearch : Wang_2015_Bull.Environ.Contam.Toxicol_95_475
PubMedID: 26293707

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 : Toxicity of a neonicotinoid insecticide, guadipyr, in earthworm (Eisenia fetida) - Wang_2015_Ecotoxicol.Environ.Saf_114C_17
Author(s) : Wang K , Mu X , Qi S , Chai T , Pang S , Yang Y , Wang C , Jiang J
Ref : Ecotoxicology & Environmental Safety , 114C :17 , 2015
Abstract : Neonicotinoid insecticides are new class of pesticides and it is very meaningful to evaluate the toxicity of guadipyr to earthworm (Eisenia fetida). In the present study, effects of guadipyr on reproduction, growth, catalase(CAT), superoxide dismutase (SOD), acetylcholinesterase (AChE) and DNA damage in earthworm were assessed using an artificial soil medium. Guadipyr showed low toxicity to earthworms and did not elicit an effect on earthworm reproduction or growth in artificial soils at concentrations <100mg/kg. However, after exposure to guadipyr, the activity of SOD and CAT in earthworm increased and then decreased to control level. AChE activity decreased at day 3 at 50 and 100mg/kg and then increased to control level. Our data indicate that guadipyr did not induce DNA damage in earthworms at concentration of <100mg/kg.
ESTHER : Wang_2015_Ecotoxicol.Environ.Saf_114C_17
PubMedSearch : Wang_2015_Ecotoxicol.Environ.Saf_114C_17
PubMedID: 25594687

Title : A visible light photoelectrochemical biosensor coupling enzyme-inhibition for organophosphates monitoring based on a dual-functional Cd(0.5)Zn(0.5)S-reduced graphene oxide nanocomposite - Liu_2014_Analyst_139_1121
Author(s) : Liu Q , Cai J , Huan J , Dong X , Wang C , Qiu B , Wang K
Ref : Analyst , 139 :1121 , 2014
Abstract : A novel visible light photoelectrochemical (PEC) platform coupled with enzyme-inhibition for rapid and sensitive determination of organophosphates (OPs) was constructed based on a dual-functional Cd0.5Zn0.5S-reduced graphene oxide (Cd0.5Zn0.5S-rGO) nanocomposite. Due to the inherent biocompatibility of the Cd0.5Zn0.5S-rGO nanocomposite, acetylcholinesterase (AChE) immobilized on the Cd0.5Zn0.5S-rGO modified electrode can hydrolyze acetylthiocholine chloride into thiocholine, which could increase the photocurrent of the enzyme electrode, and the further inhibition of OPs on the enzyme electrode could decrease the photocurrent response. Based on the notable change in the PEC response of the AChE-Cd0.5Zn0.5S-rGO modified electrode and using Dursban as a model, a simple and effective way for PEC monitoring of OPs is proposed, which showed a wide linear range of 0.001-1 mug mL(-1) with a low detection limit of 0.3 ng mL(-1) (S/N = 3). Moreover, the biosensor was successfully challenged with water samples, demonstrating a new method for rapid and sensitive screening/evaluating exposure to organophosphorus pesticides and other hazardous substances.
ESTHER : Liu_2014_Analyst_139_1121
PubMedSearch : Liu_2014_Analyst_139_1121
PubMedID: 24416761

Title : Enhanced production of lipstatin from Streptomyces toxytricini by optimizing fermentation conditions and medium - Zhu_2014_J.Gen.Appl.Microbiol_60_106
Author(s) : Zhu T , Wang L , Wang W , Hu Z , Yu M , Wang K , Cui Z
Ref : J Gen Appl Microbiol , 60 :106 , 2014
Abstract : This paper is concerned with optimization of fermentation conditions for lipstatin production with Streptomyces toxytricini zjut011 by the single factor and orthogonal tests. Five single factors of important effects on lipstatin production were explored. L-Leucine was identified to be the most suitable precursor for lipstatin biosynthesis and for the first time the divalent cations Mg(2+), Co(2+) and Zn(2+) were found to have significant effect on enhancing lipstatin fermentation titer. The effects of the additives on the lipstatin production were in the order of L-leucine Mg(2+) Co(2+) Zn(2+) octanoic acid. The optimized conditions for lipstatin production were determined as 45.72 mmol/L of L-leucine (added on the 4 th day), 31.1985 mmol/L of octanoic acid (added on the 6th day), 12 mmol/L of Mg(2+), 1 mmol/L of Co(2+) and 0.25 mmol/L of Zn(2+). Under these conditions, a maximum lipstatin of 4.208 g/ml was achieved in verification experiments in 500 ml shake flasks.
ESTHER : Zhu_2014_J.Gen.Appl.Microbiol_60_106
PubMedSearch : Zhu_2014_J.Gen.Appl.Microbiol_60_106
PubMedID: 25008166

Title : Whole-Genome Sequence of Streptococcus suis Serotype 4 Reference Strain 6407 - Wang_2014_Genome.Announc_2_e00770
Author(s) : Wang K , Chen J , Yao H , Lu C
Ref : Genome Announc , 2 : , 2014
Abstract : We report here the second complete genome sequence of Streptococcus suis serotype 4 (strain 6407). The genome is 2,292,360 bp in length, covering 2,239 coding sequences, 58 tRNAs, and 4 rRNA loci.
ESTHER : Wang_2014_Genome.Announc_2_e00770
PubMedSearch : Wang_2014_Genome.Announc_2_e00770
PubMedID: 25125641
Gene_locus related to this paper: strsu-b9wvz1

Title : Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11) - Chen_2013_Proc.Natl.Acad.Sci.U.S.A_110_19143
Author(s) : Chen S , Yueh MF , Bigo C , Barbier O , Wang K , Karin M , Nguyen N , Tukey RH
Ref : Proc Natl Acad Sci U S A , 110 :19143 , 2013
Abstract : Camptothecin (CPT)-11 (irinotecan) has been used widely for cancer treatment, particularly metastatic colorectal cancer. However, up to 40% of treated patients suffer from severe late diarrhea, which prevents CPT-11 dose intensification and efficacy. CPT-11 is a prodrug that is hydrolyzed by hepatic and intestinal carboxylesterase to form SN-38, which in turn is detoxified primarily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation. To better understand the mechanism associated with toxicity, we generated tissue-specific Ugt1 locus conditional knockout mouse models and examined the role of glucuronidation in protecting against irinotecan-induced toxicity. We targeted the deletion of the Ugt1 locus and the Ugt1a1 gene specifically in the liver (Ugt1(DeltaHep)) and the intestine (Ugt1(DeltaGI)). Control (Ugt1(F/F)), Ugt1(DeltaHep), and Ugt1(DeltaGI) adult male mice were treated with different concentrations of CPT-11 daily for four consecutive days. Toxicities were evaluated with regard to tissue glucuronidation potential. CPT-11-treated Ugt1(DeltaHep) mice showed a similar lethality rate to the CPT-11-treated Ugt1(F/F) mice. However, Ugt1(DeltaGI) mice were highly susceptible to CPT-11-induced diarrhea, developing severe and lethal mucositis at much lower CPT-11 doses, a result of the proliferative cell loss and inflammation in the intestinal tract. Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissue are dramatically different, providing for the opportunity to improve therapy by differential gene regulation. Intestinal expression of the UGT1A proteins is critical toward the detoxification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the efficacy associated with CPT-11 treatment.
ESTHER : Chen_2013_Proc.Natl.Acad.Sci.U.S.A_110_19143
PubMedSearch : Chen_2013_Proc.Natl.Acad.Sci.U.S.A_110_19143
PubMedID: 24191041

Title : Expression of neurexin and neuroligin in the enteric nervous system and their down-regulated expression levels in Hirschsprung disease - Zhang_2013_Mol.Biol.Rep_40_2969
Author(s) : Zhang Q , Wang J , Li A , Liu H , Zhang W , Cui X , Wang K
Ref : Mol Biol Rep , 40 :2969 , 2013
Abstract : To investigate the expression levels of neurexins and neuroligins in the enteric nervous system (ENS) in Hirschsprung Disease (HSCR). Longitudinal muscles with adherent mesenteric plexus were obtained by dissection of the fresh gut wall of mice, guinea pigs, and humans. Double labeling of neurexin I and Hu (a neuron marker), neuroligin 1 and Hu, neurexin I and synaptophysin (a presynaptic marker), and neuroligin 1 and PSD95 (a postsynaptic marker) was performed by immunofluorescence staining. Images were merged to determine the relative localizations of the proteins. Expression levels of neurexin and neuroligin in different segments of the ENS in HSCR were investigated by immunohistochemistry. Neurexin and neuroligin were detected in the mesenteric plexus of mice, guinea pigs, and humans with HSCR. Neurexin was located in the presynapse, whereas neuroligin was located in the postsynapse. Expression levels of neurexin and neuroligin were significant in the ganglionic colonic segment of HSCR, moderate in the transitional segment, and negative in the aganglionic colonic segment. The expressions of neurexin and neuroligin in the transitional segments were significantly down-regulated compared with the levels in the normal segments (P < 0.05). Expression levels of neurexin and neuroligin in ENS are significantly down-regulated in HSCR, which may be involved in the pathogenesis of HSCR.
ESTHER : Zhang_2013_Mol.Biol.Rep_40_2969
PubMedSearch : Zhang_2013_Mol.Biol.Rep_40_2969
PubMedID: 23264101

Title : The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells - Shi_2013_Hum.Mol.Genet_22_3749
Author(s) : Shi L , Chang X , Zhang P , Coba MP , Lu W , Wang K
Ref : Hum Mol Genet , 22 :3749 , 2013
Abstract : Genetic mutations in NLGN4X (neuroligin 4), including point mutations and copy number variants (CNVs), have been associated with susceptibility to autism spectrum disorders (ASDs). However, it is unclear how mutations in NLGN4X result in neurodevelopmental defects. Here, we used neural stem cells (NSCs) as in vitro models to explore the impacts of NLGN4X knockdown on neurodevelopment. Using two shRNAmir-based vectors targeting NLGN4X and one control shRNAmir vector, we modulated NLGN4X expression and differentiated these NSCs into mature neurons. We monitored the neurodevelopmental process at Weeks 0, 0.5, 1, 2, 4 and 6, based on morphological analysis and whole-genome gene expression profiling. At the cellular level, in NSCs with NLGN4X knockdown, we observed increasingly delayed neuronal development and compromised neurite formation, starting from Week 2 through Week 6 post differentiation. At the molecular level, we identified multiple pathways, such as neurogenesis, neuron differentiation and muscle development, which are increasingly disturbed in cells with NLGN4X knockdown. Notably, several postsynaptic genes, including DLG4, NLGN1 and NLGN3, also have decreased expression. Based on in vitro models, NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. Our functional genomics study highlights the utility of NSCs models in understanding the functional roles of CNVs in affecting neurodevelopment and conferring susceptibility to neurodevelopmental diseases.
ESTHER : Shi_2013_Hum.Mol.Genet_22_3749
PubMedSearch : Shi_2013_Hum.Mol.Genet_22_3749
PubMedID: 23710042

Title : Complete Genome Sequence of Streptococcus suis Serotype 16 Strain TL13 - Wang_2013_Genome.Announc_1_e00394
Author(s) : Wang K , Yao H , Lu C , Chen J
Ref : Genome Announc , 1 : , 2013
Abstract : We report here the first complete genome sequence of Streptococcus suis serotype 16, which has been identified to be zoonotic. The sequenced strain TL13 was isolated from a pig in China. The genome is 2,038,146 bp in length, covering 1,950 coding sequences, 53 tRNAs, and 4 rRNA loci.
ESTHER : Wang_2013_Genome.Announc_1_e00394
PubMedSearch : Wang_2013_Genome.Announc_1_e00394
PubMedID: 23814033
Gene_locus related to this paper: strsu-b9wvz1

Title : Whole-Genome Sequence of Streptococcus suis Serotype 3 Strain YB51 - Wang_2013_Genome.Announc_1_e00884
Author(s) : Wang K , Chen J , Yao H , Lu C
Ref : Genome Announc , 1 : , 2013
Abstract : We report here the second complete genome sequence of Streptococcus suis serotype 3 (strain YB51). The genome is 2,043,655 bp in length, which is 14,840 bp longer than the first reported genome of the same serotype, and it covers 2,012 coding sequences, 56 tRNAs, and 4 rRNA loci.
ESTHER : Wang_2013_Genome.Announc_1_e00884
PubMedSearch : Wang_2013_Genome.Announc_1_e00884
PubMedID: 24179118
Gene_locus related to this paper: strsu-b9wvz1

Title : Highly sensitive visible light activated photoelectrochemical biosensing of organophosphate pesticide using biofunctional crossed bismuth oxyiodide flake arrays - Gong_2012_Biosens.Bioelectron_38_43
Author(s) : Gong J , Wang X , Li X , Wang K
Ref : Biosensors & Bioelectronics , 38 :43 , 2012
Abstract : A new, highly sensitive and selective biosensor for the photoelectrochemical (PEC) detection of organophosphate pesticides (OPs) has been developed, whereby newly synthesized crossed bismuth oxyiodide (BiOI) nanoflake arrays (BiOINFs) are fabricated as a photoactive electrode via a successive ionic layer adsorption and reaction (SILAR) approach. The smart integration of BiOINFs with biomolecules acetylcholinesterase (AChE) yields a novel AChE-BiOINFs hybrid, constructing a three-dimensional (3D) porous network biosensing platform. The composition and surface structure of the sensor were carefully characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and various electrochemical techniques. Such interlaced network architectures, providing better mass transport and allowing more AChE loading per unit area, as well as the intrinsically strong visible light-harvesting effect from BiOI, greatly facilitate the PEC responses. On the basis of the effect of OPs on the photocurrent of AChE-BiOINFs/ITO, a highly sensitive visible light-activated photoelectrochemical biosensor was developed for biosensing OPs. The conditions for OPs detection were optimized by using methyl parathion (MP) as a model OP compound. Under the optimized experimental conditions, our results show that such a newly designed AChE-BiOINFs/ITO photoactive electrode provides remarkably improved sensitivity and selectivity for the biosensing of OPs. The detection limit was found to be as low as about 0.04 ng mL(-1) (S/N=3). Toward the goal for practical applications, the resulting sensor was further evaluated by monitoring MP in spiked vegetable samples, showing fine applicability for the detection of MP in real samples.
ESTHER : Gong_2012_Biosens.Bioelectron_38_43
PubMedSearch : Gong_2012_Biosens.Bioelectron_38_43
PubMedID: 22647535

Title : Residues and dissipation dynamics of fosthiazate in tomato and soil - Wu_2012_Bull.Environ.Contam.Toxicol_89_664
Author(s) : Wu J , Wang K , Zhang H
Ref : Bulletin of Environmental Contamination & Toxicology , 89 :664 , 2012
Abstract : Residue dynamics of fosthiazate in tomato and soil was studied in this paper utilizing liquid chromatography with tandem mass spectrometry (LC-MS/MS). The field trial was conducted in three sites: Beijing, Liaoning, Hubei in China. Fosthiazate dissipated with the half-life 0.75-2.6 days in tomato or tomato plants and 2.5-11.6 days in soil. In the terminal residue experiment, no higher residue than 0.023 mg kg(-1) in tomato and 0.27 mg kg(-1) in soil was detected. Residues of fosthiazte in tomato were far below Japan maximum residue levels (0.2 mg kg(-1)).
ESTHER : Wu_2012_Bull.Environ.Contam.Toxicol_89_664
PubMedSearch : Wu_2012_Bull.Environ.Contam.Toxicol_89_664
PubMedID: 22801926

Title : Classification of acetylcholinesterase inhibitors and decoys by a support vector machine - Wang_2012_Comb.Chem.High.Throughput.Screen_15_492
Author(s) : Wang K , Hu X , Wang Z , Yan A
Ref : Comb Chem High Throughput Screen , 15 :492 , 2012
Abstract : Acetylcholinesterase has long been considered as a target for Alzheimer disease therapy. In this work, several classification models were built for the purpose of distinguishing acetylcholinesterase inhibitors (AChEIs) and decoys. Each molecule was initially represented by 211 ADRIANA.Code and 334 MOE descriptors. Correlation analysis, F-score and attribute selection methods in Weka were used to find the best reduced set of descriptors, respectively. Additionally, models were built using a Support Vector Machine and evaluated by 5-, 10-fold and leave-one-out cross-validation. The best model gave a Matthews Correlation Coefficient (MCC) of 0.99 and a prediction accuracy (Q) of 99.66% for the test set. The best model also gave good result on an external test set of 86 compounds (Q=96.51%, MCC=0.93). The descriptors selected by our models suggest that H-bond and hydrophobicity interactions are important for the classification of AChEIs and decoys.
ESTHER : Wang_2012_Comb.Chem.High.Throughput.Screen_15_492
PubMedSearch : Wang_2012_Comb.Chem.High.Throughput.Screen_15_492
PubMedID: 22263859

Title : Cholinesterase-responsive supramolecular vesicle - Guo_2012_J.Am.Chem.Soc_134_10244
Author(s) : Guo DS , Wang K , Wang YX , Liu Y
Ref : Journal of the American Chemical Society , 134 :10244 , 2012
Abstract : Enzyme-responsive, amphiphilic self-assembly represents one of the increasingly significant topics in biomaterials research and finds feasible applications to the controlled release of therapeutic agents at specific sites where the target enzyme is located. The supramolecular approach, using "superamphiphiles", provides a smart way to fabricate drug delivery systems responsive to enzymatic catalysis. In this work based on the concept of supramolecular chemistry, we report an enzyme-responsive vesicle using p-sulfonatocalix[4]arene as the macrocyclic host and natural enzyme-cleavable myristoylcholine as the guest molecule. The complexation of p-sulfonatocalix[4]arene with myristoylcholine directs the formation of a supramolecular binary vesicle, which is dissipated by cholinesterase with high specificity and efficiency. Cholinesterase is a key protein overexpressed in Alzheimer's disease, and therefore, the present system may have potential for the delivery of Alzheimer's disease drugs.
ESTHER : Guo_2012_J.Am.Chem.Soc_134_10244
PubMedSearch : Guo_2012_J.Am.Chem.Soc_134_10244
PubMedID: 22686862

Title : Exploration of two-enzyme coupled catalysis system using scanning electrochemical microscopy - Wu_2012_Anal.Chem_84_10586
Author(s) : Wu ZQ , Jia WZ , Wang K , Xu JJ , Chen HY , Xia XH
Ref : Analytical Chemistry , 84 :10586 , 2012
Abstract : In biological metabolism, a given metabolic process usually occurs via a group of enzymes working together in sequential pathways. To explore the metabolism mechanism requires the understanding of the multienzyme coupled catalysis systems. In this paper, an approach has been proposed to study the kinetics of a two-enzyme coupled reaction using SECM combining numerical simulations. Acetylcholine esterase and choline oxidase are immobilized on cysteamine self-assembled monolayers on tip and substrate gold electrodes of SECM via electrostatic interactions, respectively. The reaction kinetics of this two-enzyme coupled system upon various separation distance precisely regulated by SECM are measured. An overall apparent Michaelis-Menten constant of this enzyme cascade is thus measured as 2.97 mM at an optimal tip-substrate gap distance of 18 mum. Then, a kinetic model of this enzyme cascade is established for evaluating the kinetic parameters of individual enzyme by using the finite element method. The simulated results demonstrate the choline oxidase catalytic reaction is the rate determining step of this enzyme cascade. The Michaelis-Menten constant of acetylcholine esterase is evaluated as 1.8 mM. This study offers a promising approach to exploring mechanism of other two-enzyme coupled reactions in biological system and would promote the development of biosensors and enzyme-based logic systems.
ESTHER : Wu_2012_Anal.Chem_84_10586
PubMedSearch : Wu_2012_Anal.Chem_84_10586
PubMedID: 23181438

Title : The yak genome and adaptation to life at high altitude - Qiu_2012_Nat.Genet_44_946
Author(s) : Qiu Q , Zhang G , Ma T , Qian W , Wang J , Ye Z , Cao C , Hu Q , Kim J , Larkin DM , Auvil L , Capitanu B , Ma J , Lewin HA , Qian X , Lang Y , Zhou R , Wang L , Wang K , Xia J , Liao S , Pan S , Lu X , Hou H , Wang Y , Zang X , Yin Y , Ma H , Zhang J , Wang Z , Zhang Y , Zhang D , Yonezawa T , Hasegawa M , Zhong Y , Liu W , Huang Z , Zhang S , Long R , Yang H , Lenstra JA , Cooper DN , Wu Y , Shi P , Liu J
Ref : Nat Genet , 44 :946 , 2012
Abstract : Domestic yaks (Bos grunniens) provide meat and other necessities for Tibetans living at high altitude on the Qinghai-Tibetan Plateau and in adjacent regions. Comparison between yak and the closely related low-altitude cattle (Bos taurus) is informative in studying animal adaptation to high altitude. Here, we present the draft genome sequence of a female domestic yak generated using Illumina-based technology at 65-fold coverage. Genomic comparisons between yak and cattle identify an expansion in yak of gene families related to sensory perception and energy metabolism, as well as an enrichment of protein domains involved in sensing the extracellular environment and hypoxic stress. Positively selected and rapidly evolving genes in the yak lineage are also found to be significantly enriched in functional categories and pathways related to hypoxia and nutrition metabolism. These findings may have important implications for understanding adaptation to high altitude in other animal species and for hypoxia-related diseases in humans.
ESTHER : Qiu_2012_Nat.Genet_44_946
PubMedSearch : Qiu_2012_Nat.Genet_44_946
PubMedID: 22751099
Gene_locus related to this paper: bosmu-l8ic43 , bovin-2neur , bovin-balip , bovin-BCHE , bovin-e1bbv2 , bovin-e1bn79 , bovin-est8 , bovin-f1mi11 , bovin-f1n385 , bovin-g3mxp5 , bovin-lipli , bovin-lipr2 , bovin-q2kj30 , bovin-q3sz79 , bovin-q3t0r6 , bovin-ABHDA , bovin-q08dw9 , bovin-ABHD16B , bovin-SPG21 , bovin-TEX30 , 9ceta-l8iwv2 , 9ceta-l8idy3 , 9ceta-l8hsi3 , bovin-e1bjq9 , bovin-f1mc21 , 9ceta-l8hyl8 , bovin-LIPG , bovin-a0a3q1nm09 , bovin-f1n2i5

Title : Quantitative structure and bioactivity relationship study on human acetylcholinesterase inhibitors - Yan_2012_Bioorg.Med.Chem.Lett_22_3336
Author(s) : Yan A , Wang K
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :3336 , 2012
Abstract : Several QSAR (Quantitative Structure-Activity Relationships) models for predicting the inhibitory activity of 404 Acetylcholinesterase inhibitors were developed. The whole dataset was split into a training set and a test set randomly or using a Kohonen's self-organizing map. Then the inhibitory activity of 404 Acetylcholinesterase inhibitors was predicted using Multilinear Regression (MLR) analysis and Support Vector Machine (SVM) methods, respectively. For the test sets, correlation coefficients of all our models over 0.90 were achieved. Y-randomization test was employed to ensure the robustness of our models and a docking simulation was used to confirm the descriptors we used.
ESTHER : Yan_2012_Bioorg.Med.Chem.Lett_22_3336
PubMedSearch : Yan_2012_Bioorg.Med.Chem.Lett_22_3336
PubMedID: 22460031

Title : TiO2-decorated graphene nanohybrids for fabricating an amperometric acetylcholinesterase biosensor - Wang_2011_Analyst_136_3349
Author(s) : Wang K , Li HN , Wu J , Ju C , Yan JJ , Liu Q , Qiu B
Ref : Analyst , 136 :3349 , 2011
Abstract : This work describes a highly sensitive and rapid amperometric biosensor for organophosphate compounds (OPs) based on immobilization of acetylcholinesterase (AChE) on a novel TiO(2)-decorated graphene (TiO(2)-G) nanohybrid, which was constructed by in situ growth of TiO(2) nanoparticles (NPs) on the graphene sheet. The well-dispersed TiO(2) NPs eliminated the restacking of TiO(2)-G nanohybrids. Due to the integrating of TiO(2)-G nanohybrids, the as-prepared biosensor showed high affinity to acetylthiocholine (ATCl) with a Michaelis-Menten constant (K(m)) value of 0.22 mM, and rapid inhibition time (3 min). Further, based on the inhibition of OPs on the enzymatic activity of the immobilized AChE, and using carbaryl as a model compound, the inhibition of carbaryl was proportional to its concentration ranging from 0.001 to 0.015 and 0.015 to 2 mug mL(-1) with a detection limit of 0.3 ng mL(-1) (S/N = 3). The developed biosensor exhibited a good performance for organophosphate pesticide detection, including good reproducibility and acceptable stability, which provided a new and promising tool for the analysis of enzyme inhibitors.
ESTHER : Wang_2011_Analyst_136_3349
PubMedSearch : Wang_2011_Analyst_136_3349
PubMedID: 21738917

Title : The Medicago genome provides insight into the evolution of rhizobial symbioses - Young_2011_Nature_480_520
Author(s) : Young ND , Debelle F , Oldroyd GE , Geurts R , Cannon SB , Udvardi MK , Benedito VA , Mayer KF , Gouzy J , Schoof H , Van de Peer Y , Proost S , Cook DR , Meyers BC , Spannagl M , Cheung F , De Mita S , Krishnakumar V , Gundlach H , Zhou S , Mudge J , Bharti AK , Murray JD , Naoumkina MA , Rosen B , Silverstein KA , Tang H , Rombauts S , Zhao PX , Zhou P , Barbe V , Bardou P , Bechner M , Bellec A , Berger A , Berges H , Bidwell S , Bisseling T , Choisne N , Couloux A , Denny R , Deshpande S , Dai X , Doyle JJ , Dudez AM , Farmer AD , Fouteau S , Franken C , Gibelin C , Gish J , Goldstein S , Gonzalez AJ , Green PJ , Hallab A , Hartog M , Hua A , Humphray SJ , Jeong DH , Jing Y , Jocker A , Kenton SM , Kim DJ , Klee K , Lai H , Lang C , Lin S , Macmil SL , Magdelenat G , Matthews L , McCorrison J , Monaghan EL , Mun JH , Najar FZ , Nicholson C , Noirot C , O'Bleness M , Paule CR , Poulain J , Prion F , Qin B , Qu C , Retzel EF , Riddle C , Sallet E , Samain S , Samson N , Sanders I , Saurat O , Scarpelli C , Schiex T , Segurens B , Severin AJ , Sherrier DJ , Shi R , Sims S , Singer SR , Sinharoy S , Sterck L , Viollet A , Wang BB , Wang K , Wang M , Wang X , Warfsmann J , Weissenbach J , White DD , White JD , Wiley GB , Wincker P , Xing Y , Yang L , Yao Z , Ying F , Zhai J , Zhou L , Zuber A , Denarie J , Dixon RA , May GD , Schwartz DC , Rogers J , Quetier F , Town CD , Roe BA
Ref : Nature , 480 :520 , 2011
Abstract : Legumes (Fabaceae or Leguminosae) are unique among cultivated plants for their ability to carry out endosymbiotic nitrogen fixation with rhizobial bacteria, a process that takes place in a specialized structure known as the nodule. Legumes belong to one of the two main groups of eurosids, the Fabidae, which includes most species capable of endosymbiotic nitrogen fixation. Legumes comprise several evolutionary lineages derived from a common ancestor 60 million years ago (Myr ago). Papilionoids are the largest clade, dating nearly to the origin of legumes and containing most cultivated species. Medicago truncatula is a long-established model for the study of legume biology. Here we describe the draft sequence of the M. truncatula euchromatin based on a recently completed BAC assembly supplemented with Illumina shotgun sequence, together capturing approximately 94% of all M. truncatula genes. A whole-genome duplication (WGD) approximately 58 Myr ago had a major role in shaping the M. truncatula genome and thereby contributed to the evolution of endosymbiotic nitrogen fixation. Subsequent to the WGD, the M. truncatula genome experienced higher levels of rearrangement than two other sequenced legumes, Glycine max and Lotus japonicus. M. truncatula is a close relative of alfalfa (Medicago sativa), a widely cultivated crop with limited genomics tools and complex autotetraploid genetics. As such, the M. truncatula genome sequence provides significant opportunities to expand alfalfa's genomic toolbox.
ESTHER : Young_2011_Nature_480_520
PubMedSearch : Young_2011_Nature_480_520
PubMedID: 22089132
Gene_locus related to this paper: medtr-b7fki4 , medtr-b7fmi1 , medtr-g7itl1 , medtr-g7iu67 , medtr-g7izm0 , medtr-g7j641 , medtr-g7jtf8 , medtr-g7jtg2 , medtr-g7jtg4 , medtr-g7kem3 , medtr-g7kml3 , medtr-g7ksx5 , medtr-g7leb3 , medtr-q1s5d8 , medtr-q1s9m3 , medtr-q1t171 , medtr-g7k9e1 , medtr-g7k9e3 , medtr-g7k9e5 , medtr-g7k9e8 , medtr-g7k9e9 , medtr-g7lbp2 , medtr-g7lch3 , medtr-g7ib94 , medtr-g7ljk8 , medtr-g7i6w5 , medtr-g7kvg4 , medtr-g7iam1 , medtr-g7iam3 , medtr-g7l754 , medtr-g7jr41 , medtr-g7l4f5 , medtr-g7l755 , medtr-a0a072vyl4 , medtr-g7jwk8 , medtr-a0a072vhg0 , medtr-a0a072vrv9 , medtr-g7kmk5 , medtr-a0a072uuf6 , medtr-a0a072urp3 , medtr-g7zzc3 , medtr-g7ie19 , medtr-g7kst7 , medtr-a0a072u5k5 , medtr-a0a072v056 , medtr-scp1 , medtr-g7kyn0 , medtr-g7inw6 , medtr-g7j3q3

Title : A highly sensitive and rapid organophosphate biosensor based on enhancement of CdS-decorated graphene nanocomposite - Wang_2011_Anal.Chim.Acta_695_84
Author(s) : Wang K , Liu Q , Dai L , Yan J , Ju C , Qiu B , Wu X
Ref : Anal Chim Acta , 695 :84 , 2011
Abstract : This work reports a rapid and sensitive organophosphates (OPs) amperometric biosensor based on acetylcholinesterase (AChE) immobilized on CdS-decorated graphene (CdS-G) nanocomposite. The as-prepared biosensor shows high affinity to acetylthiocholine (ATCl) with a Michaelis-Menten constant (K(m)) value of 0.24 mM. A rapid inhibition time (2 min) is obtained due to the integration of the CdS-G nanocomposite. Based on the inhibition of OPs on the enzymatic activity of the immobilized AChE, and used carbaryl as the model compound, the resulting biosensor exhibits excellent performance for OPs detection including good reproducibility, acceptable stability, and a reliable linear relationship between the inhibition and log[carbaryl] from 2 ng mL(-)(1) up to 2 mug mL(-)(1) with a detection limit of 0.7 ng mL(-)(1),which provides a new promising tool for analysis of enzyme inhibitors.
ESTHER : Wang_2011_Anal.Chim.Acta_695_84
PubMedSearch : Wang_2011_Anal.Chim.Acta_695_84
PubMedID: 21601034

Title : A sensitive enzymatic method for paraoxon detection based on enzyme inhibition and fluorescence quenching - Wang_2011_Talanta_84_400
Author(s) : Wang K , Wang L , Jiang W , Hu J
Ref : Talanta , 84 :400 , 2011
Abstract : A sensitive and selective method for the paraoxon detection based on enzyme inhibition and fluorescence quenching was presented in this study. Under the catalytic effect of acetylcholinesterase (AChE), acetylthiocholine (ATCh) hydrolysis released thiocholine (TCh) which could react with N-(7-dimethylamino-4-methylcoumarin-3-yl) maleimide (DACM) to produce a blue fluorescence compound. Subsequently, AChE catalytic activity was inhibited with the addition of paraoxon, which caused TCh decreased, leading to a significant decrease of the blue fluorescent compound. Meanwhile, p-nitrophenol, the hydrolysis product of paraoxon, would lead to a quenching of the fluorescence. Therefore, fluorescence intensity of the system would decrease dramatically by a combined effect of enzyme inhibition and fluorescence quenching. Under optimal experimental conditions, an excellent linear relationship between the decrease of fluorescence intensity and paraoxon concentration over the range from 5.5 x 10(-12) to 1.8 x 10(-10) mol L(-1) was obtained. Fluorescence background caused by nonenzymatic hydrolysis of ATCh or other matters was relatively low, the proposed approach offered adequate sensitivity for the detection of paraoxon at 3.5 x 10(-12) mol L(-1).
ESTHER : Wang_2011_Talanta_84_400
PubMedSearch : Wang_2011_Talanta_84_400
PubMedID: 21376964

Title : Inhibition of lipoprotein-associated phospholipase A2 ameliorates inflammation and decreases atherosclerotic plaque formation in ApoE-deficient mice - Wang_2011_PLoS.One_6_e23425
Author(s) : Wang WY , Zhang J , Wu WY , Li J , Ma YL , Chen WH , Yan H , Wang K , Xu WW , Shen JH , Wang YP
Ref : PLoS ONE , 6 :e23425 , 2011
Abstract : BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-alpha in the darapladib group. CONCLUSIONS/SIGNIFICANCE: Inhibition of lp-PLA2 by darapladib leads to attenuation of in vivo inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis.
ESTHER : Wang_2011_PLoS.One_6_e23425
PubMedSearch : Wang_2011_PLoS.One_6_e23425
PubMedID: 21909350

Title : Decoding state transitions in hippocampal oscillatory activity in mice - Dragomir_2010_Conf.Proc.IEEE.Eng.Med.Biol.Soc_2010_2822
Author(s) : Dragomir A , Akay YM , Wang K , Wu J , Akay M
Ref : Conf Proc IEEE Eng Med Biol Soc , 2010 :2822 , 2010
Abstract : Understanding the intricate dynamics of the hippocampal neural network, from which several types of neural oscillation rhythms arise, is an important step in uncovering the role of the hippocampus in the formation of memory. The different oscillation types commonly recorded in the hippocampus are thought to correspond to several states of neural network synchronization. Therefore, accurate segmentation and decoding of these underlying states provide useful insight on the rhythms' generation. In this study we use a framework based on Hidden Markov Models, coupled with a nonlinear dynamics method based on the Lempel-Ziv estimator. The method allows us to decode and model the neural state transitions. Network synchronization was induced by acute exposure to cholinergic agonist carbachol and oscillations were recorded from the Cornu Ammonis (CA1) region of the mouse hippocampus. Our results prove that deficits in cholinergic neuro-transmission found in triple transgenic mice (3xTG, as Alzheimer's disease animal model) lead to increased instability in the hippocampal neural network synchronization.
ESTHER : Dragomir_2010_Conf.Proc.IEEE.Eng.Med.Biol.Soc_2010_2822
PubMedSearch : Dragomir_2010_Conf.Proc.IEEE.Eng.Med.Biol.Soc_2010_2822
PubMedID: 21096221

Title : Identifying unexpected therapeutic targets via chemical-protein interactome - Yang_2010_PLoS.One_5_e9568
Author(s) : Yang L , Chen J , Shi L , Hudock MP , Wang K , He L
Ref : PLoS ONE , 5 :e9568 , 2010
Abstract : Drug medications inevitably affect not only their intended protein targets but also other proteins as well. In this study we examined the hypothesis that drugs that share the same therapeutic effect also share a common therapeutic mechanism by targeting not only known drug targets, but also by interacting unexpectedly on the same cryptic targets. By constructing and mining an Alzheimer's disease (AD) drug-oriented chemical-protein interactome (CPI) using a matrix of 10 drug molecules known to treat AD towards 401 human protein pockets, we found that such cryptic targets exist. We recovered from CPI the only validated therapeutic target of AD, acetylcholinesterase (ACHE), and highlighted several other putative targets. For example, we discovered that estrogen receptor (ER) and histone deacetylase (HDAC), which have recently been identified as two new therapeutic targets of AD, might already have been targeted by the marketed AD drugs. We further established that the CPI profile of a drug can reflect its interacting character towards multi-protein sets, and that drugs with the same therapeutic attribute will share a similar interacting profile. These findings indicate that the CPI could represent the landscape of chemical-protein interactions and uncover "behind-the-scenes" aspects of the therapeutic mechanisms of existing drugs, providing testable hypotheses of the key nodes for network pharmacology or brand new drug targets for one-target pharmacology paradigm.
ESTHER : Yang_2010_PLoS.One_5_e9568
PubMedSearch : Yang_2010_PLoS.One_5_e9568
PubMedID: 20221449

Title : Resistance selection and biochemical characterization of spinosad resistance in Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) - Wang_2009_Pestic.Biochem.Physiol_95_90
Author(s) : Wang D , Qiu X , Ren X , Niu F , Wang K
Ref : Pesticide Biochemistry and Physiology , 95 :90 , 2009
Abstract : A Helicoverpa armigera population was collected from Shandong province, China. After 15 generations of selection in the laboratory, the H. armigera strain developed more than 20-fold resistance to spinosad. At LD50 level, no significant cross-resistance was found between spinosad and chlorpyrifos, methomyl, avermectin and chlorfenapyr except for fenvalerate with a low cross-resistance of 2.4-fold. However, LD99 values of fenvalerate against the parental and resistant strains were not different significantly. After inhibitors were used, spinosad resistance could be partially suppressed by piperonylbutoxide (PBO) and triphenylphosphate (TPP), but not by diethylmaleate (DEM). Activities of p-nitroanisole O-demethylase (ODM) developed to 8.26-fold compared with the parental strain, but no obvious changes were found in activities of carboxyl esterase (CarE) and glutathione-S-transferase (GST). The results indicated that resistance to spinosad in the cotton bollworm might be associated with an increase in cytochrome P450 monooxygenase.
ESTHER : Wang_2009_Pestic.Biochem.Physiol_95_90
PubMedSearch : Wang_2009_Pestic.Biochem.Physiol_95_90

Title : Effects of spinosad on Helicoverpa armigera (Lepidoptera: Noctuidae) from China: tolerance status, synergism and enzymatic responses - Wang_2009_Pest.Manag.Sci_65_1040
Author(s) : Wang D , Qiu X , Ren X , Zhang W , Wang K
Ref : Pest Manag Sci , 65 :1040 , 2009
Abstract : BACKGROUND: Spinosad is increasingly used in pest management programmes, and resistance to it has been detected in recent years. However, there is no report on the susceptibilities of field populations of Helicoverpa armigera (Hbner) from China. Furthermore, the impact of spinosad on metabolic enzymes in this pest remains unknown. RESULTS: Four populations of H. armigera from different locations in China displayed less than 6.5-fold difference in LC(50) to spinosad, the highest being in the Xinjiang population, followed by Xiajin, Taian and Hubei populations, while there was no significant difference at LC(99) level among the four populations. The toxicity of spinosad could be synergised by piperonyl butoxide (PBO) and triphenylphosphate (TPP), but not by diethyl maleate (DEM). Spinosad exposure for 48 h significantly increased the activities of p-nitroanisole O-demethylase (ODM), while no significant changes in glutathione-S-transferase (GST) and carboxyl esterase (CarE) were observed. CONCLUSION: Field populations of H. armigera from China displayed marginally different susceptibilities to spinosad and had a relatively low LC(50). Cytochrome P450 monooxygenase might be involved in the metabolism of, and hence resistance to, spinosad in this pest in China.
ESTHER : Wang_2009_Pest.Manag.Sci_65_1040
PubMedSearch : Wang_2009_Pest.Manag.Sci_65_1040
PubMedID: 19533589

Title : Isolation and Characterization of a Methomyl-Degrading Paracoccus sp. mdw-1 - Xu_2009_Pedosphere_19_238
Author(s) : Xu JL , Wu J , Wang ZC , Wang K , Li MY , Jiang JD , He J , Li SP
Ref : Pedosphere , 19 :238 , 2009
Abstract : Methomyl, an extremely toxic pesticide, is widely used in agriculture. A strain named mdw-1 capable of degrading methomyl rapidly was successfully isolated from activated sludge in this study. It could utilize methomyl as the sole carbon or nitrogen source. The optimal temperature and medium pH for its growth and methomyl biodegradation were 30 C and 7.0, respectively. It was identified as a Paracoccus sp. according to its morphological features, physiological and biochemical characteristics, and phylogenetic analysis based on the sequence of 16S rDNA. Gas chromatography-mass spectrometry (GC-MS) analysis showed that methomyl could be completely transformed to S-methyl-N-hydroxythioacetamidate in 10 h of incubation with the isolate mdw-1.
ESTHER : Xu_2009_Pedosphere_19_238
PubMedSearch : Xu_2009_Pedosphere_19_238

Title : Nonlinear dynamical analysis of carbachol induced hippocampal oscillations in mice - Akay_2009_Acta.Pharmacol.Sin_30_859
Author(s) : Akay M , Wang K , Akay YM , Dragomir A , Wu J
Ref : Acta Pharmacol Sin , 30 :859 , 2009
Abstract : AIM: Hippocampal neuronal network and synaptic impairment underlie learning and memory deficit in Alzheimer's disease (AD) patients and animal models. In this paper, we analyzed the dynamics and complexity of hippocampal neuronal network synchronization induced by acute exposure to carbachol, a nicotinic and muscarinic receptor co-agonist, using the nonlinear dynamical model based on the Lempel-Ziv estimator. We compared the dynamics of hippocampal oscillations between wild-type (WT) and triple-transgenic (3xTg) mice, as an AD animal model. We also compared these dynamic alterations between different age groups (5 and 10 months). We hypothesize that there is an impairment of complexity of CCh-induced hippocampal oscillations in 3xTg AD mice compared to WT mice, and that this impairment is age-dependent.
METHODS: To test this hypothesis, we used electrophysiological recordings (field potential) in hippocampal slices.
RESULTS: Acute exposure to 100 micromol/L CCh induced field potential oscillations in hippocampal CA1 region, which exhibited three distinct patterns: (1) continuous neural firing, (2) repeated burst neural firing and (3) the mixed (continuous and burst) pattern in both WT and 3xTg AD mice. Based on Lempel-Ziv estimator, pattern (2) was significantly lower than patterns (1) and (3) in 3xTg AD mice compared to WT mice (P<0.001), and also in 10-month old WT mice compared to those in 5-month old WT mice (P<0.01). CONCLUSION: These results suggest that the burst pattern (theta oscillation) of hippocampal network is selectively impaired in 3xTg AD mouse model, which may reflect a learning and memory deficit in the AD patients.
ESTHER : Akay_2009_Acta.Pharmacol.Sin_30_859
PubMedSearch : Akay_2009_Acta.Pharmacol.Sin_30_859
PubMedID: 19498425

Title : Molecular cloning and characterization of a novel pyrethroid-hydrolyzing esterase originating from the Metagenome - Li_2008_Microb.Cell.Fact_7_38
Author(s) : Li G , Wang K , Liu YH
Ref : Microb Cell Fact , 7 :38 , 2008
Abstract : BACKGROUND: Pyrethroids and pyrethrins are widely used insecticides. Extensive applications not only result in pest resistance to these insecticides, but also may lead to environmental issues and human exposure. Numerous studies have shown that very high exposure to pyrethroids might cause potential problems to man and aquatic organisms. Therefore, it is important to develop a rapid and efficient disposal process to eliminate or minimize contamination of surface water, groundwater and agricultural products by pyrethroid insecticides. Bioremediation is considered to be a reliable and cost-effective technique for pesticides abatement and a major factor determining the fate of pyrethroid pesticides in the environment, and suitable esterase is expected to be useful for potential application for detoxification of pyrethroid residues. Soil is a complex environment considered as one of the main reservoirs of microbial diversity on the planet. However, most of the microorganisms in nature are inaccessible as they are uncultivable in the laboratory. Metagenomic approaches provide a powerful tool for accessing novel valuable genetic resources (novel enzymes) and developing various biotechnological applications.
RESULTS: The pyrethroid pesticides residues on foods and the environmental contamination are a public safety concern. Pretreatment with pyrethroid-hydrolyzing esterase has the potential to alleviate the conditions. To this end, a pyrethroid-hydrolyzing esterase gene was successfully cloned using metagenomic DNA combined with activity-based functional screening from soil, sequence analysis of the DNA responsible for the pye3 gene revealed an open reading frame of 819 bp encoding for a protein of 272 amino acid residues. Extensive multiple sequence alignments of the deduced amino acid of Pye3 with the most homologous carboxylesterases revealed moderate identity (45-49%). The recombinant Pye3 was heterologously expressed in E. coli BL21(DE3), purified and characterized. The molecular mass of the native enzyme was approximately 31 kDa as determined by gel filtration. The results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the deduced amino acid sequence of the Pye3 indicated molecular mass of 31 kDa and 31.5 kDa, respectively, suggesting that the Pye3 is a monomer. The purified Pye3 not only degraded all pyrethroid pesticides tested, but also hydrolyzed rho-nitrophenyl esters of medium-short chain fatty acids, indicating that the Pye3 is an esterase with broader specificity. The Km values for trans-Permethrin and cis-permethrin are 0.10 muM and 0.18 muM, respectively, and these catalytic properties were superior to carboxylesterases from resistant insects and mammals. The catalytic activity of the Pye3 was strongly inhibited by Hg2+, Ag+, rho-chloromercuribenzoate, whereas less pronounced effect was observed in the presence of divalent cations, the chelating agent EDTA and phenanthroline. CONCLUSION: A novel pyrethroid-hydrolyzing esterase gene was successfully cloned using metagenomic DNA combined with activity-based functional screening from soil, the broader substrate specificities and higher activity of the pyrethroid-hydrolyzing esterase (Pye3) make it an ideal candidate for in situ for detoxification of pyrethroids where they cause environmental contamination problems. Consequently, metagenomic DNA clone library offers possibilities to discover novel bio-molecules through the expression of genes from uncultivated bacteria.
ESTHER : Li_2008_Microb.Cell.Fact_7_38
PubMedSearch : Li_2008_Microb.Cell.Fact_7_38
PubMedID: 19116015
Gene_locus related to this paper: 9zzzz-b6vg94

Title : Genome biology of Actinobacillus pleuropneumoniae JL03, an isolate of serotype 3 prevalent in China - Xu_2008_PLoS.One_3_e1450
Author(s) : Xu Z , Zhou Y , Li L , Zhou R , Xiao S , Wan Y , Zhang S , Wang K , Li W , Jin H , Kang M , Dalai B , Li T , Liu L , Cheng Y , Zhang L , Xu T , Zheng H , Pu S , Wang B , Gu W , Zhang XL , Zhu GF , Wang S , Zhao GP , Chen H
Ref : PLoS ONE , 3 :e1450 , 2008
Abstract : Actinobacillus pleuropneumoniae is the etiologic agent of porcine contagious pleuropneumonia, a cause of considerable world wide economic losses in the swine industry. We sequenced the complete genome of A. pleuropneumoniae, JL03, an isolate of serotype 3 prevalent in China. Its genome is a single chromosome of 2,242,062 base pairs containing 2,097 predicted protein-coding sequences, six ribosomal rRNA operons, and 63 tRNA genes. Preliminary analysis of the genomic sequence and the functions of the encoded proteins not only confirmed the present physiological and pathological knowledge but also offered new insights into the metabolic and virulence characteristics of this important pathogen. We identified a full spectrum of genes related to its characteristic chemoheterotrophic catabolism of fermentation and respiration with an incomplete TCA system for anabolism. In addition to confirming the lack of ApxI toxin, identification of a nonsense mutation in apxIVA and a 5'-proximal truncation of the flp operon deleting both its promoter and the flp1flp2tadV genes have provided convincing scenarios for the low virulence property of JL03. Comparative genomic analysis using the available sequences of other serotypes, probable strain (serotype)-specific genomic islands related to capsular polysaccharides and lipopolysaccharide O-antigen biosyntheses were identified in JL03, which provides a foundation for future research into the mechanisms of serotypic diversity of A. pleuropneumoniae.
ESTHER : Xu_2008_PLoS.One_3_e1450
PubMedSearch : Xu_2008_PLoS.One_3_e1450
PubMedID: 18197260
Gene_locus related to this paper: actp2-a3n347 , actp7-b3h2v1 , actp7-b3h2x2 , actpj-b0bpm3 , actpj-b0bqd8 , actpj-b0brq2

Title : Characterization of chlorpyrifos-induced apoptosis in placental cells - Saulsbury_2008_Toxicology_244_98
Author(s) : Saulsbury MD , Heyliger SO , Wang K , Round D
Ref : Toxicology , 244 :98 , 2008
Abstract : The mechanism by which chlorpyrifos exerts its toxicity in fetal and perinatal animals has yet to be elucidated. Since the placenta is responsible for transport of nutrients and is a major supplier hormone to the fetus, exposure to xenobiotics that alter the function or viability of placenta cells could ostensibly alter the development of the fetus. In this study, JAR cells were used to determine if CPF and the metabolites 3,5,6-trichloro-2-pyridinol (TCP) and chlorpyrifos-oxon (CPO) are toxic to the placenta. Our results indicate that chlorpyrifos (CPF), and its metabolite chlorpyrifos-oxon (CPO) caused a dose-dependent reduction in cellular viability with CPF being more toxic than its metabolites. Chlorpyrifos-induced toxicity was characterized by the loss of mitochondrial potential, the appearance of nuclear condensation and fragmentation, down-regulation of Bcl-2 as well as up-regulation of TNFalpha and FAS mRNA. Pharmacological inhibition of FAS, nicotinic and TNF-alpha receptors did not attenuate CPF-induced toxicity. Atropine exhibited minimal ability to reverse toxicity. Furthermore, signal transduction inhibitors PD98059, SP600125, LY294002 and U0126 failed to attenuate toxicity; however, SB202190 (inhibitor of p38alpha and p38beta MAPK) sensitized cells to CPF-induced toxicity. Pan-caspase inhibitor Q-VD-OPh produced a slight but significant reversal of CPF-induced toxicity indicating that the major caspase pathways are not integral to CPF-induced toxicity. Taken collectively, these results suggest that chlorpyrifos induces apoptosis in placental cells through pathways not dependent on FAS/TNF signaling, activation of caspases or inhibition of cholinesterase. In addition, our data further indicates that activation of p38 MAPK is integral to the protection cells against CPF-induced injury.
ESTHER : Saulsbury_2008_Toxicology_244_98
PubMedSearch : Saulsbury_2008_Toxicology_244_98
PubMedID: 18155347

Title : Regulation of the neuronal nicotinic acetylcholine receptor by SRC family tyrosine kinases - Wang_2004_J.Biol.Chem_279_8779
Author(s) : Wang K , Hackett JT , Cox ME , Van Hoek M , Lindstrom JM , Parsons SJ
Ref : Journal of Biological Chemistry , 279 :8779 , 2004
Abstract : Src family kinases (SFKs) are abundant in chromaffin cells that reside in the adrenal medulla and respond to cholinergic stimulation by secreting catecholamines. Our previous work indicated that SFKs regulate acetylcholine- or nicotine-induced secretion, but the site of modulatory action was unclear. Using whole cell recordings, we found that inhibition of SFK tyrosine kinase activity by PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine) treatment or expression of a kinase-defective c-Src reduced the peak amplitude of nicotine-induced currents in chromaffin cells or in human embryonic kidney cells ectopically expressing functional neuronal alpha3beta4alpha5 acetylcholine receptors (AChRs). Conversely, the phosphotyrosine phosphatase inhibitor, sodium vanadate, or expression of mutationally activated c-Src resulted in enhanced current amplitudes. These results suggest that SFKs and putative phosphotyrosine phosphatases regulate the activity of AChRs by opposing actions. This proposed model was supported further by the findings that SFKs physically associate with the receptor and that the AChR is tyrosine-phosphorylated.
ESTHER : Wang_2004_J.Biol.Chem_279_8779
PubMedSearch : Wang_2004_J.Biol.Chem_279_8779
PubMedID: 14679211

Title : Novel function of lecithin-cholesterol acyltransferase. Hydrolysis of oxidized polar phospholipids generated during lipoprotein oxidation - Goyal_1997_J.Biol.Chem_272_16231
Author(s) : Goyal J , Wang K , Liu M , Subbaiah PV
Ref : Journal of Biological Chemistry , 272 :16231 , 1997
Abstract : Although the major function of lecithin-cholesterol acyltransferase (LCAT) is cholesterol esterification, our previous studies showed that it can also hydrolyze platelet-activating factor (PAF). Because of the structural similarities between PAF and the truncated phosphatidylcholines (polar PCs) generated during lipoprotein oxidation, we investigated the possibility that LCAT may also hydrolyze polar PCs to lyso-PC during the oxidation of plasma. PAF acetylhydrolase (PAF-AH), which is known to hydrolyze polar PCs in human plasma, was completely inhibited by 0.2 mM p-aminoethyl benzenesulfonyl fluoride (Pefabloc), a new serine esterase inhibitor, which had no effect on LCAT at this concentration. On the other hand, 1 mM diisopropylfluorophosphate (DFP) completely inhibited LCAT but had no effect on PAF-AH. Polar PC accumulation during the oxidation of plasma increased by 44% in the presence of 0.2 mM Pefabloc and by 30% in the presence of 1 mM DFP. The formation of lyso-PC was concomitantly inhibited by both of the inhibitors. The combination of the two inhibitors resulted in the maximum accumulation of polar PCs, suggesting that both PAF-AH and LCAT are involved in their breakdown. Oxidation of chicken plasma, which has no PAF-AH activity, also resulted in the formation of lyso-PC from the hydrolysis of polar PC, which was inhibited by DFP. Polar PCs, either isolated from oxidized plasma or by oxidation of labeled synthetic PCs, were hydrolyzed by purified LCAT, which had no detectable PAF-AH activity. These results demonstrate a novel function for LCAT in the detoxification of polar PCs generated during lipoprotein oxidation, especially when the PAF-AH is absent or inactivated.
ESTHER : Goyal_1997_J.Biol.Chem_272_16231
PubMedSearch : Goyal_1997_J.Biol.Chem_272_16231
PubMedID: 9195924

Title : Chimeras of hepatic lipase and lipoprotein lipase. Domain localization of enzyme-specific properties - Davis_1992_J.Biol.Chem_267_21499
Author(s) : Davis RC , Wong H , Nikazy J , Wang K , Han Q , Schotz MC
Ref : Journal of Biological Chemistry , 267 :21499 , 1992
Abstract : Chimeric molecules between human lipoprotein lipase (LPL) and rat hepatic lipase (HL) were used to identify structural elements responsible for functional differences. Based on the close sequence homology with pancreatic lipase, both LPL and HL are believed to have a two-domain structure composed of an amino-terminal (NH2-terminal) domain containing the catalytic Ser-His-Asp triad and a smaller carboxyl-terminal (COOH-terminal) domain. Experiments with chimeric lipases containing the HL NH2-terminal domain and the LPL COOH-terminal domain (HL/LPL) or the reverse chimera (LPL/HL) showed that the NH2-terminal domain is responsible for the catalytic efficiency (Vmax/Km) of these enzymes. Furthermore, it was demonstrated that the stimulation of LPL activity by apolipoprotein C-II and the inhibition of activity by 1 M NaCl originate in structural features within the NH2-terminal domain. HL and LPL bind to vascular endothelium, presumably by interaction with cell surface heparan sulfate proteoglycans. However, the two enzymes differ significantly in their heparin affinity. Experiments with the chimeric lipases indicated that heparin binding avidity was primarily associated with the COOH-terminal domain. Specifically, both HL and the LPL/HL chimera were eluted from immobilized heparin by 0.75 M NaCl, whereas 1.1 M NaCl was required to elute LPL and the HL/LPL chimera. Finally, HL is more active than LPL in the hydrolysis of phospholipid substrates. However, the ratio of phospholipase to neutral lipase activity in both chimeric lipases was enhanced by the presence of the heterologous COOH-terminal domain, demonstrating that this domain strongly influences substrate specificity. The NH2-terminal domain thus controls the kinetic parameters of these lipases, whereas the COOH-terminal domain modulates substrate specificity and heparin binding.
ESTHER : Davis_1992_J.Biol.Chem_267_21499
PubMedSearch : Davis_1992_J.Biol.Chem_267_21499
PubMedID: 1400461