Zhou G

References (31)

Title : Attenuation of Polycyclic Aromatic Hydrocarbon (PAH)-Induced Carcinogenesis and Tumorigenesis by Omega-3 Fatty Acids in Mice In Vivo - Xia_2024_Int.J.Mol.Sci_25_
Author(s) : Xia G , Zhou G , Jiang W , Chu C , Wang L , Moorthy B
Ref : Int J Mol Sci , 25 : , 2024
Abstract : Lung cancer is the leading cause of cancer death worldwide. Polycyclic aromatic hydrocarbons (PAHs) are metabolized by the cytochrome P450 (CYP)1A and 1B1 to DNA-reactive metabolites, which could lead to mutations in critical genes, eventually resulting in cancer. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial against cancers. In this investigation, we elucidated the mechanisms by which omega-3 fatty acids EPA and DHA will attenuate PAH-DNA adducts and lung carcinogenesis and tumorigenesis mediated by the PAHs BP and MC. Adult wild-type (WT) (A/J) mice, Cyp1a1-null, Cyp1a2-null, or Cyp1b1-null mice were exposed to PAHs benzo[a]pyrene (BP) or 3-methylcholanthrene (MC), and the effects of omega-3 fatty acid on PAH-mediated lung carcinogenesis and tumorigenesis were studied. The major findings were as follows: (i) omega-3 fatty acids significantly decreased PAH-DNA adducts in the lungs of each of the genotypes studied; (ii) decreases in PAH-DNA adduct levels by EPA/DHA was in part due to inhibition of CYP1B1; (iii) inhibition of soluble epoxide hydrolase (sEH) enhanced the EPA/DHA-mediated prevention of pulmonary carcinogenesis; and (iv) EPA/DHA attenuated PAH-mediated carcinogenesis in part by epigenetic mechanisms. Taken together, our results suggest that omega-3 fatty acids have the potential to be developed as cancer chemo-preventive agents in people.
ESTHER : Xia_2024_Int.J.Mol.Sci_25_
PubMedSearch : Xia_2024_Int.J.Mol.Sci_25_
PubMedID: 38612589

Title : Gelsemine relieves the neuropathic pain by down-regulating DPP4 level in rats - Yang_2022_Neurosci.Lett_792_136961
Author(s) : Yang L , Zhou G , Chen J , Zhang S
Ref : Neuroscience Letters , 792 :136961 , 2022
Abstract : BACKGROUND: Based on the previous findings on the relieving role of gelsemine in neuropathic pain, this research aims to further investigate the relevant regulatory mechanism. METHODS: Targets of gelsemine were predicted using SwissTargetPrediction. The peripheral neuropathic pain rat model was established by ligating spinal nerves, and then gelsemine (10 g for one day) or dipeptidyl peptidase 4 (DPP4) oligonucleotides (5 g/day, for 7 days) was injected into intrathecal bolus of rats. The mechanical threshold (0, 1, 2, 4 h after the last injection) was examined to evaluate the mechanical allodynia of rats. After the mechanical threshold measurement, the rats were anesthetized with isoflurane and then sacrificed by cervical dislocation. IBA1- and DPP4-positive cells in the spinal dorsal horn of rats were determined using immunohistochemistry and immunofluorescence assays. The expressions of DPP4, IL-1 and TNF-alpha in the spinal dorsal horn of rats were measured by Western blot and quantitative real-time PCR. RESULTS: DPP4 was one of the targets of gelsemine. Gelsemine could elevate the down-regulated mechanical threshold, and lessen the up-regulated IBA1- and DPP4-positive cells and expressions of DPP4, IL-1 and TNF-alpha in the spinal dorsal horn of rats with neuropathic pain. DPP4 overexpression reversed the role of gelsemine in neuropathic pain. CONCLUSION: Gelsemine relieves neuropathic pain by down-regulating DPP4 level in rats, providing a novel drug candidate and biomarker for neuropathic pain treatment.
ESTHER : Yang_2022_Neurosci.Lett_792_136961
PubMedSearch : Yang_2022_Neurosci.Lett_792_136961
PubMedID: 36370955

Title : Emerging Mosquito Resistance to Piperonyl Butoxide-Synergized Pyrethroid Insecticide and Its Mechanism - Zhou_2022_J.Med.Entomol__
Author(s) : Zhou G , Li Y , Jeang B , Wang X , Cummings RF , Zhong D , Yan G
Ref : Journal of Medical Entomology , : , 2022
Abstract : Piperonyl butoxide (PBO)-synergized pyrethroid products are widely available for the control of pyrethroid-resistant mosquitoes. To date, no study has examined mosquito resistance after pre-exposure to PBO and subsequent enzymatic activity when exposed to PBO-synergized insecticides. We used Culex quinquefasciatus Say (Diptera: Culicidae), an important vector of arboviruses and lymphatic filariasis, as a model to examine the insecticide resistance mechanisms of mosquitoes to PBO-synergized pyrethroid using modified World Health Organization tube bioassays and biochemical analysis of metabolic enzyme expressions pre- and post-PBO exposure. Mosquito eggs and larvae were collected from three cities in Orange County in July 2020 and reared in insectary, and F0 adults were used in this study. A JHB susceptible strain was used as a control. Mosquito mortalities and metabolic enzyme expressions were examined in mosquitoes with/without pre-exposure to different PBO concentrations and exposure durations. Except for malathion, wild strain Cx quinquefasciatus mosquitoes were resistant to all insecticides tested, including PBO-synergized pyrethroids (mortality range 3.7 +/- 4.7% to 66.7 +/- 7.7%). Wild strain mosquitoes had elevated levels of carboxylesterase (COE, 3.8-fold) and monooxygenase (P450, 2.1-fold) but not glutathione S-transferase (GST) compared to susceptible mosquitoes. When wild strain mosquitoes were pre-exposed to 4% PBO, the 50% lethal concentration of deltamethrin was reduced from 0.22% to 0.10%, compared to 0.02% for a susceptible strain. The knockdown resistance gene mutation (L1014F) rate was 62% in wild strain mosquitoes. PBO pre-exposure suppressed P450 enzyme expression levels by 25~34% and GST by 11%, but had no impact on COE enzyme expression. Even with an optimal PBO concentration (7%) and exposure duration (3h), wild strain mosquitoes had significantly higher P450 enzyme expression levels after PBO exposure compared to the susceptible laboratory strain. These results further demonstrate other studies that PBO alone may not be enough to control highly pyrethroid-resistant mosquitoes due to multiple resistance mechanisms. Mosquito resistance to PBO-synergized insecticide should be closely monitored through a routine resistance management program for effective control of mosquitoes and the pathogens they transmit.
ESTHER : Zhou_2022_J.Med.Entomol__
PubMedSearch : Zhou_2022_J.Med.Entomol__
PubMedID: 35050361

Title : Insecticide resistance status of Anopheles arabiensis in irrigated and non-irrigated areas in western Kenya - Orondo_2021_Parasit.Vectors_14_335
Author(s) : Orondo PW , Nyanjom SG , Atieli H , Githure J , Ondeto BM , Ochwedo KO , Omondi CJ , Kazura JW , Lee MC , Zhou G , Zhong D , Githeko AK , Yan G
Ref : Parasit Vectors , 14 :335 , 2021
Abstract : BACKGROUND: Malaria control in Kenya is based on case management and vector control using long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS). However, the development of insecticide resistance compromises the effectiveness of insecticide-based vector control programs. The use of pesticides for agricultural purposes has been implicated as one of the sources driving the selection of resistance. The current study was undertaken to assess the status and mechanism of insecticide resistance in malaria vectors in irrigated and non-irrigated areas with varying agrochemical use in western Kenya. METHODS: The study was carried out in 2018-2019 in Homa Bay County, western Kenya. The bioassay was performed on adults reared from larvae collected from irrigated and non-irrigated fields in order to assess the susceptibility of malaria vectors to different classes of insecticides following the standard WHO guidelines. Characterization of knockdown resistance (kdr) and acetylcholinesterase-inhibiting enzyme/angiotensin-converting enzyme (Ace-1) mutations within Anopheles gambiae s.l. species was performed using the polymerase chain reaction (PCR) method. To determine the agricultural and public health insecticide usage pattern, a questionnaire was administered to farmers, households, and veterinary officers in the study area. RESULTS: Anopheles arabiensis was the predominant species in the irrigated (100%, n = 154) area and the dominant species in the non-irrigated areas (97.5%, n = 162), the rest being An. gambiae sensu stricto. In 2018, Anopheles arabiensis in the irrigated region were susceptible to all insecticides tested, while in the non-irrigated region reduced mortality was observed (84%) against deltamethrin. In 2019, phenotypic mortality was decreased (97.8-84% to 83.3-78.2%). In contrast, high mortality from malathion (100%), DDT (98.98%), and piperonyl butoxide (PBO)-deltamethrin (100%) was observed. Molecular analysis of the vectors from the irrigated and non-irrigated areas revealed low levels of leucine-serine/phenylalanine substitution at position 1014 (L1014S/L1014F), with mutation frequencies of 1-16%, and low-frequency mutation in the Ace-1R gene (0.7%). In addition to very high coverage of LLINs impregnated with pyrethroids and IRS with organophosphate insecticides, pyrethroids were the predominant chemical class of pesticides used for crop and animal protection. CONCLUSION: Anopheles arabiensis from irrigated areas showed increased phenotypic resistance, and the intensive use of pesticides for crop protection in this region may have contributed to the selection of resistance genes observed. The susceptibility of these malaria vectors to organophosphates and PBO synergists in pyrethroids offers a promising future for IRS and insecticide-treated net-based vector control interventions. These findings emphasize the need for integrated vector control strategies, with particular attention to agricultural practices to mitigate mosquito resistance to insecticides.
ESTHER : Orondo_2021_Parasit.Vectors_14_335
PubMedSearch : Orondo_2021_Parasit.Vectors_14_335
PubMedID: 34174946

Title : The cholinergic system, intelligence, and dental fluorosis in school-aged children with low-to-moderate fluoride exposure - Wang_2021_Ecotoxicol.Environ.Saf_228_112959
Author(s) : Wang S , Zhao Q , Li G , Wang M , Liu H , Yu X , Chen J , Li P , Dong L , Zhou G , Cui Y , Liu L , Wang A
Ref : Ecotoxicology & Environmental Safety , 228 :112959 , 2021
Abstract : Disruption of cholinergic neurotransmission can affect cognition, but little is known about whether low-to-moderate fluoride exposure affects cholinergic system and its effect on the prevalence of dental fluorosis (DF) and intelligence quotient (IQ). A cross-sectional study was conducted to explore the associations of moderate fluoride exposure and cholinergic system in relation to children's DF and IQ. We recruited 709 resident children in Tianjin, China. Ion selective electrode method was used to detect fluoride concentrations in water and urine. Cholinergic system was assessed by the detection of choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and acetylcholine (ACh) levels in serum. Compared with children in the first quartile, those in fourth quartile the risk of either developing DF or IQ < 120 increased by 19% and 20% for water and urinary fluoride. The risk of having both increased by 58% and 62% in third and fourth quartile for water fluoride, 52% and 65% for urinary fluoride. Water fluoride concentrations were positively associated with AChE and negatively associated with ChAT and ACh, trends were same for urinary fluoride except for ACh. The risk of either developing DF or having non-high intelligence rose by 22% (95%CI: 1.07%, 1.38%) for the fourth quartile than those in the first quartile of AChE, for having the both, the risk was 1.27 (95%CI: 1.07, 1.50), 1.37 (95%CI: 1.17, 1.62) and 1.44 (95%CI: 1.23, 1.68) in second, third and fourth quartiles. The mediation proportion by AChE between water fluoride and either developing DF or IQ < 120 was 15.7%. For both to exist, the proportion was 6.7% and 7.2% for water and urinary fluoride. Our findings suggest low-to-moderate fluoride exposure was associated with dysfunction of cholinergic system for children. AChE may partly mediate the prevalence of DF and lower probability of having superior and above intelligence.
ESTHER : Wang_2021_Ecotoxicol.Environ.Saf_228_112959
PubMedSearch : Wang_2021_Ecotoxicol.Environ.Saf_228_112959
PubMedID: 34808511

Title : ABHD5 suppresses cancer cell anabolism through lipolysis-dependent activation of the AMPK\/mTORC1 pathway - Chen_2020_J.Biol.Chem_296_100104
Author(s) : Chen G , Zhou G , Lotvola A , Granneman JG , Wang J
Ref : Journal of Biological Chemistry , 296 :100104 , 2020
Abstract : ABHD5 is an essential coactivator of ATGL, the rate-limiting triglyceride (TG) lipase in many cell types. Importantly, ABHD5 also functions as a tumor suppressor, and ABHD5 mRNA expression levels correlate with patient survival for several cancers. Nevertheless, the mechanisms involved in ABHD5-dependent tumor suppression are not known. We found that overexpression of ABHD5 induces cell-cycle arrest at the G1 phase and causes growth retardation in a panel of prostate cancer cells. Transcriptomic profiling and biochemical analysis revealed that genetic or pharmacological activation of lipolysis by ABHD5 potently inhibits mTORC1 signaling, leading to a significant downregulation of protein synthesis. Mechanistically, we found that ABHD5 elevates intracellular AMP content, which activates AMPK, leading to inhibition of mTORC1. Interestingly, ABHD5-dependent suppression of mTORC1 was abrogated by pharmacological inhibition of DGAT1 or DGAT2, isoenzymes that re-esterify fatty acids in a process that consumes ATP. Collectively, this study maps out a novel molecular pathway crucial for limiting cancer cell proliferation, in which ABHD5-mediated lipolysis creates an energy-consuming futile cycle between TG hydrolysis and resynthesis, leading to inhibition of mTORC1 and cancer cell growth arrest.
ESTHER : Chen_2020_J.Biol.Chem_296_100104
PubMedSearch : Chen_2020_J.Biol.Chem_296_100104
PubMedID: 33219129
Gene_locus related to this paper: human-ABHD5

Title : Phenotypic, genotypic and biochemical changes during pyrethroid resistance selection in Anopheles gambiae mosquitoes - Machani_2020_Sci.Rep_10_19063
Author(s) : Machani MG , Ochomo E , Zhong D , Zhou G , Wang X , Githeko AK , Yan G , Afrane YA
Ref : Sci Rep , 10 :19063 , 2020
Abstract : The directional selection for insecticide resistance due to indiscriminate use of insecticides in public health and agricultural system favors an increase in the frequency of insecticide-resistant alleles in the natural populations. Similarly, removal of selection pressure generally leads to decay in resistance. Past investigations on the emergence of insecticide resistance in mosquitoes mostly relied on field survey of resistance in vector populations that typically had a complex history of exposure to various public health and agricultural pest control insecticides in nature, and thus the effect of specific insecticides on rate of resistance emergency or resistance decay rate is not known. This study examined the phenotypic, genotypic, and biochemical changes that had occurred during the process of selection for pyrethroid resistance in Anopheles gambiae, the most important malaria vector in Africa. In parallel, we also examined these changes in resistant populations when there is no selection pressure applied. Through repeated deltamethrin selection in adult mosquitoes from a field population collected in western Kenya for 12 generations, we obtained three independent and highly pyrethroid-resistant An. gambiae populations. Three susceptible populations from the same parental population were generated by removing selection pressure. These two lines of mosquito populations differed significantly in monooxygenase and beta-esterase activities, but not in Vgsc gene mutation frequency, suggesting metabolic detoxification mechanism plays a major role in generating moderate-intensity resistance or high-intensity resistance. Pre-exposure to the synergist piperonyl butoxide restored the susceptibility to insecticide among the highly resistant mosquitoes, confirming the role of monooxygenases in pyrethroid resistance. The rate of resistance decay to become fully susceptible from moderate-intensity resistance took 15 generations, supporting at least 2-years interval is needed when the rotational use of insecticides with different modes of action is considered for resistance management.
ESTHER : Machani_2020_Sci.Rep_10_19063
PubMedSearch : Machani_2020_Sci.Rep_10_19063
PubMedID: 33149227

Title : Acetylcholinesterase-catalyzed silver deposition for ultrasensitive electrochemical biosensing of organophosphorus pesticides - Liu_2020_Analyst__
Author(s) : Liu Z , Xia X , Zhou G , Ge L , Li F
Ref : Analyst , : , 2020
Abstract : Herein, an electrochemical biosensing platform with acetylcholinesterase (AChE)-catalyzed silver deposition was developed for the ultrasensitive detection of organophosphorus pesticides (OPs). The biosensing mechanism is based on the fact that AChE can catalyze the rapid hydrolysis of indoxyl acetate to form hydroxyindole, which in turn reduces silver ions to metallic silver, resulting in the deposition of silver on the gold electrode. Upon sweeping positive voltages on the gold electrode using linear sweep voltammetry (LSV), the deposited silver on the gold electrode surface undergoes a rapid electrochemical oxidation reaction. Due to its lower oxidation potential under facile conditions with a relatively sharp peak, a small amount of deposited silver generated from AChE-catalysis could result in a significant change in the LSV response. In the presence of OPs, the AChE-catalyzed hydrolysis of indoxyl acetate is blocked, and then the silver deposition on the gold electrode declines, leading to a remarkable decrease in the LSV response and, thus producing a large signal output for the ultrasensitive detection of chlorpyrifos, a proof-of-concept OP in this work. The change in the LSV peak current intensity is linearly correlated with the logarithmic value of the chlorpyrifos concentration ranging from 10 pM to 10 nM with a low detection limit of 4.0 pM. To the best of our knowledge, this is the first example of a biosensing platform for ultrasensitive OP assay using AChE-controlled silver deposition to enhance the output of electronic signals.
ESTHER : Liu_2020_Analyst__
PubMedSearch : Liu_2020_Analyst__
PubMedID: 32031197

Title : Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I \/ II) - Ye_2020_Trials_21_520
Author(s) : Ye Q , Wang H , Xia X , Zhou C , Liu Z , Xia ZE , Zhang Z , Zhao Y , Yehenala J , Wang S , Zhou G , Hu K , Wu B , Wu CT , He Y
Ref : Trials , 21 :520 , 2020
Abstract : OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. INCLUSION CRITERIA: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: 1)Adults aged 18-65 years;2)Voluntarily participate in this clinical trial and sign the "informed consent form" or have consent from a legal representative.3)Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg).4)COVID-19 featured lung lesions in chest X-ray image. EXCLUSION CRITERIA: Patients will be excluded from the study if they meet any of the following criteria. 1.Patients have received other experimental treatment for COVID-19 within the last 30 days;2.Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit);3.Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m(2)) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis;4.Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses;5.Female patients who have no sexual protection in the last 30 days prior to the screening assessment;6.Pregnant or lactating women or women using estrogen contraception;7.Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period;8.Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: GradeDescriptionGrade 1:Discharged of patient;Grade 2:Hospitalized without oxygen supplement;Grade 3:Hospitalized, oxygen supplement is required, but NIV / HFNC is not required;Grade 4:Hospitalized in intensive care unit, and NIV / HFNC treatment is required;Grade 5:Hospitalized in intensive care unit, requiring ECMO and/or IMV;Grade 6:Death. ABBREVIATIONS: NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h +/- 30min, 24h +/- 30min after the injection) and follow-up period D90 +/- 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h +/- 30min, 24h +/- 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 +/- 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 +/- 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 beta, IL-2, TNF-a, ITN-gamma), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood beta-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 +/- 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h +/- 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient's randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16(th) April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
ESTHER : Ye_2020_Trials_21_520
PubMedSearch : Ye_2020_Trials_21_520
PubMedID: 32532356

Title : Widespread Multiple Insecticide Resistance in the Major Dengue Vector Aedes albopictus in Hainan Province, China - Li_2020_Pest.Manag.Sci_77_1945
Author(s) : Li Y , Zhou G , Zhong D , Wang X , Hemming-Schroeder E , David RE , Lee MC , Zhong S , Yi G , Liu Z , Cui G , Yan G
Ref : Pest Manag Sci , 77 :1945 , 2020
Abstract : BACKGROUND: Aedes albopictus is a highly invasive mosquito and has become a potential vector of dengue, chikungunya and Zika viruses. Insecticide-based mosquito interventions are the main tools for vector-borne disease control. However, mosquito resistance to insecticides is a major threat to effective prevention and control. Five Ae. albopictus populations across Hainan Province, China were investigated for susceptibility to multiple insecticides and resistance mechanisms. RESULTS: Larval bioassays indicated that resistance to pyrethroids was common in all larval populations. Adult bioassays revealed all populations were either resistant or highly resistant to at least 4 of the 6 synthetic insecticides (deltamethrin, permethrin, cyfluthrin, propoxur, malathion, and DDT) tested. Pre-exposure of mosquitoes to the synergistic agent piperonyl butoxide (PBO) increased mosquito mortality by 2.4-43.3% in bioassays to DDT, malathion, and permethrin and rendered mosquito sensitive to deltamethrin, cyfluthrin, and propoxur. The frequency of knockdown resistance (kdr) mutations (F1534S and F1534C) ranged from 69.8% to 89.3% and from 38.1% to 87.0% in field resistant and sensitive populations, respectively. F1534S mutation was significantly associated with pyrethroid resistance. No mutation was detected in acetylcholinesterase (ace-1) gene in the two examined populations. CONCLUSION: This study provides evidence of widespread resistance to multiple insecticides in Ae. albopictus in Hainan Province, China. Both kdr mutations and metabolic detoxification were the potential causes of insecticide resistance for Ae. albopictus. Our findings highlight the need for insecticide resistance management and mosquito control measures that do not entirely depend on synthetic insecticides.
ESTHER : Li_2020_Pest.Manag.Sci_77_1945
PubMedSearch : Li_2020_Pest.Manag.Sci_77_1945
PubMedID: 33301644

Title : Circulating lncRNA ABHD11-AS1 serves as a biomarker for early pancreatic cancer diagnosis - Liu_2019_J.Cancer_10_3746
Author(s) : Liu Y , Feng W , Liu W , Kong X , Li L , He J , Wang D , Zhang M , Zhou G , Xu W , Chen W , Gong A , Xu M
Ref : J Cancer , 10 :3746 , 2019
Abstract : Background: Recent studies have shown that circulating long noncoding RNAs (lncRNAs) could be stably detectable in the blood of cancer patients and play important roles in the diagnosis of many different cancers. However, the value of lncRNAs in the diagnosis of pancreatic cancer (PC) has not been fully explored. Methods: Eleven PC-related lncRNAs were selected by analyzing bioinformatics databases. The expression levels of the lncRNAs were further analyzed in a small set of plasma samples from a training group including 30 noncancer samples (15 healthy and 15 chronic pancreatitis (CP) subjects) and 15 PC samples. Then, the candidate lncRNAs were validated with data from 46 healthy controls, 97 CP patients and 114 PC patients. Receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic performance of the identified lncRNAs. Results: After selection and validation, three characteristic plasma candidate lncRNAs, ABHD11-AS1, LINC00176 and SNHG11, were identified, and their levels were significantly higher in PC patients than in normal controls. We found that among the three candidate lncRNAs, ABHD11-AS1 showed the best diagnostic performance for the detection of PC. Furthermore, ABHD11-AS1 had a higher area under the ROC curve (AUC) than CEA, CA199 and CA125 for early PC diagnosis, while the combination of ABHD11-AS1 and CA199 was more effective than ABHD11-AS1 alone. Conclusions: Plasma ABHD11-AS1 could serve as a potential biomarker for detecting PC, and the combination of ABHD11-AS1 and CA199 was more efficient for the diagnosis of PC than ABHD11-AS1 alone, particularly for early tumor screening.
ESTHER : Liu_2019_J.Cancer_10_3746
PubMedSearch : Liu_2019_J.Cancer_10_3746
PubMedID: 31333792
Gene_locus related to this paper: human-ABHD11

Title : Anti-cholinesterase activities of constituents isolated from Lycopodiastrum casuarinoides - Liu_2019_Fitoterapia__104366
Author(s) : Liu Y , Li J , Li D , Li XM , Zhou G , Xu KP , Kang FH , Zou ZX , Xu PS , Tan GS
Ref : Fitoterapia , :104366 , 2019
Abstract : Phytochemical investigation of the ethyl acetate extract of Lycopodiastrum casuarinoides (Spring) Holub (Lycopodiaceae) led to the isolation of nine compounds, including two new serratene triterpenoids, serrat-14-en-3alpha,21alpha-diol (1), 26-nor-8-oxo-21-one-alpha-onocerin (6), one new abietane diterpenoid, lycocasuarinone A (7), one new sesquiterpene acid, 7, 9-diene-1,4-epoxy-2-hydroxy-10-carboxylic acid (8) and one new chromone derivative, 5,7-dihydroxy-2-methyl esterchromone (9), together with four known serratene triterpenoids (2-5). Abietane diterpenoid (7) and sesquiterpene acid (8) from Lycopodiastrum casuarinoides are reported for the first time. Their structures and stereochemistry were unambiguously elucidated by spectroscopic analysis and comparison with known ones. All the compounds were tested for acetylcholinesterase (AChE) and butyrocholinesterase (BuChE) inhibitory activities. Bioactivity assays revealed that compound 6 exhibited the most potent AChE inhibitory effect.
ESTHER : Liu_2019_Fitoterapia__104366
PubMedSearch : Liu_2019_Fitoterapia__104366
PubMedID: 31629868

Title : Fast emerging insecticide resistance in Aedes albopictus in Guangzhou, China: Alarm to the dengue epidemic - Su_2019_PLoS.Negl.Trop.Dis_13_e0007665
Author(s) : Su X , Guo Y , Deng J , Xu J , Zhou G , Zhou T , Li Y , Zhong D , Kong L , Wang X , Liu M , Wu K , Yan G , Chen XG
Ref : PLoS Negl Trop Dis , 13 :e0007665 , 2019
Abstract : Dengue is one of the most serious mosquito-borne infectious diseases in the world. Aedes albopictus is the most invasive mosquito and one of the primary vectors of dengue. Vector control using insecticides is the only viable strategy to prevent dengue virus transmission. In Guangzhou, after the 2014 pandemic, massive insecticides have been implemented. Massive insecticide use may lead to the development of resistance, but few reports are available on the status of insecticide resistance in Guangzhou after 2014. In this study, Ae. albopictus were collected from four districts with varied dengue virus transmission intensity in Guangzhou from 2015 to 2017. Adult Ae. albopictus insecticide susceptibility to deltamethrin (0.03%), permethrin(0.25%), DDT(4%), malathion (0.8%) and bendiocarb (0.1%) was determined by the standard WHO tube test, and larval resistance bioassays were conducted using temephos, Bacillus thuringiensis israelensis (Bti), pyriproxyfen (PPF) and hexaflumuron. Mutations at the voltage-gated sodium channel (VGSC) gene and acetylcholinesterase (AChE) gene were analyzed. The effect of cytochrome P450s on the resistance of Ae. albopictus to deltamethrin was tested using the synergistic agent piperonyl butoxide (PBO). The results showed that Ae. albopictus populations have rapidly developed very high resistances to multiple commonly used insecticides at all study areas except malathion, Bti and hexaflumuron. We found 1534 codon mutations in the VGSC gene that were significantly correlated with the resistance to pyrethroids and DDT, and 11 synonymous mutations were also found in the gene. The resistance to deltamethrin can be significantly reduced by PBO but may generated cross-resistance to PPF. Fast emerging resistance in Ae. albopictus may affect mosquito management and threaten the prevention and control of dengue, similar to the resistance in Anopheles mosquitoes has prevented the elimination of malaria and call for timely and guided insecticide management.
ESTHER : Su_2019_PLoS.Negl.Trop.Dis_13_e0007665
PubMedSearch : Su_2019_PLoS.Negl.Trop.Dis_13_e0007665
PubMedID: 31525199

Title : Lycodine-type alkaloids from Lycopodiastrum casuarinoides and their cholinesterase inhibitory activities - Liu_2018_Fitoterapia_130_203
Author(s) : Liu Y , Xu PS , Ren Q , Chen X , Zhou G , Li D , Li XM , Xu KP , Yu X , Tan GS
Ref : Fitoterapia , 130 :203 , 2018
Abstract : Four new trace alkaloids with lycodine-related structures, Lycocasuarinines A-D (1-4), together with seven known analogues (5-11), were isolated from the chloroform extract of Lycopodiastrum casuarinoides. The structures and stereochemistry of 1-4 were elucidated by spectroscopic analysis (IR, UV, MS, NMR, HRESIMS and CD) and comparison with known ones. The acetylcholinesterase (AChE) and butyrocholinesterase (BuChE) inhibitory activities of nine isolates were evaluated. Lycocasuarinine D (4) showed the most potent AChE inhibitory effect. In addition, a plausible biogenetic pathway of compound 4 was proposed.
ESTHER : Liu_2018_Fitoterapia_130_203
PubMedSearch : Liu_2018_Fitoterapia_130_203
PubMedID: 30213757

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

Title : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan: In vitro and in vivo insights from quantitative ultra-performance liquid chromatography-mass spectrometry analysis - Qin_2018_Biomed.Chromatogr__e4320
Author(s) : Qin Y , Kang A , Zhou G , Wang H , Wei W , Cao Y , Chen Y , Wang J , Shi Y , Tang Y , Jiang J
Ref : Biomedical Chromatography , :e4320 , 2018
Abstract : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan (CPT-11) has long been proposed to be responsible for its anti-tumor activity and toxicity, like delayed-onset diarrhea. However, recent studies failed to gain more comprehensive in vivo and in vitro pharmacokinetic profiles of irinotecan. Herein, we choose rat plasma, human liver microsomes and immortalized HepG2 cell as experimental subjects to describes an sensitive and versatile UHPLC-MS/MS method for simultaneously quantify CPT-11 and its metabolites, including SN-38 and SN-38G. Meanwhile, we have adopted the method to investigate the pharmacokinetic or metabolism behavior of CPT-11 in the above biological samples. Calibration curves for all bio-matrices showed desirable linearity (r(2) >0.99). The intra-day and inter-day precision (RSD, %) were within 15 % and the excellent accuracy (RE, %) was between 2.96% and 14.12%. In addition, the specificity, matrix effect and extraction recovery were all meet the requirements of biological sample analysis. We have successfully applied this method to investigating pharmacokinetic of irinotecan in different biological samples, which mediated by carboxylesterase and UDP-glucuronosyltransferases. And this method could be emplyed in monitoring the metabolic status and clinical efficacy of irinotecan in the future.
ESTHER : Qin_2018_Biomed.Chromatogr__e4320
PubMedSearch : Qin_2018_Biomed.Chromatogr__e4320
PubMedID: 29920713

Title : Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients - Xiao_2017_Sci.Rep_7_7244
Author(s) : Xiao FY , Luo JQ , Liu M , Chen BL , Cao S , Liu ZQ , Zhou HH , Zhou G , Zhang W
Ref : Sci Rep , 7 :7244 , 2017
Abstract : Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. The effects of CES1 S75N (rs2307240,C>T) on clopidogrel response among 851 acute coronary syndrome patients who came from the north, central and south of China were studied. The occurrence ratios of each endpoint in the CC group were significantly higher than in the CT + TT group for cerebrovascular events (14% vs 4.8%, p < 0.001, OR = 0.31), acute myocardial infarction (15.1% vs 6.1%, p < 0.001, OR = 0.37) and unstable angina (62.8% vs 37.7%, p < 0.001, OR = 0.36). The results showed that there was a significant association between CES1 S75N (rs2307240) and the outcome of clopidogrel therapy. Moreover, the frequency of the T allele of rs2307240 in acute coronary syndrome patients (MAF = 0.22) was more than four times higher than that in the general public (MAF = 0.05).
ESTHER : Xiao_2017_Sci.Rep_7_7244
PubMedSearch : Xiao_2017_Sci.Rep_7_7244
PubMedID: 28775293
Gene_locus related to this paper: human-CES1

Title : Loss of ABHD5 promotes the aggressiveness of prostate cancer cells - Chen_2017_Sci.Rep_7_13021
Author(s) : Chen G , Zhou G , Aras S , He Z , Lucas S , Podgorski I , Skar W , Granneman JG , Wang J
Ref : Sci Rep , 7 :13021 , 2017
Abstract : The accumulation of neutral lipids in intracellular lipid droplets has been associated with the formation and progression of many cancers, including prostate cancer (PCa). Alpha-beta Hydrolase Domain Containing 5 (ABHD5) is a key regulator of intracellular neutral lipids that has been recently identified as a tumor suppressor in colorectal cancer, yet its potential role in PCa has not been investigated. Through mining publicly accessible PCa gene expression datasets, we found that ABHD5 gene expression is markedly decreased in metastatic castration-resistant PCa (mCRPC) samples. We further demonstrated that RNAi-mediated ABHD5 silencing promotes, whereas ectopic ABHD5 overexpression inhibits, the invasion and proliferation of PCa cells. Mechanistically, we found that ABHD5 knockdown induces epithelial to mesenchymal transition, increasing aerobic glycolysis by upregulating the glycolytic enzymes hexokinase 2 and phosphofrucokinase, while decreasing mitochondrial respiration by downregulating respiratory chain complexes I and III. Interestingly, knockdown of ATGL, the best-known molecular target of ABHD5, impeded the proliferation and invasion, suggesting an ATGL-independent role of ABHD5 in modulating PCa aggressiveness. Collectively, these results provide evidence that ABHD5 acts as a metabolic tumor suppressor in PCa that prevents EMT and the Warburg effect, and indicates that ABHD5 is a potential therapeutic target against mCRPC, the deadly aggressive PCa.
ESTHER : Chen_2017_Sci.Rep_7_13021
PubMedSearch : Chen_2017_Sci.Rep_7_13021
PubMedID: 29026202
Gene_locus related to this paper: human-ABHD5

Title : Improvement of the activation of lipase from Candida rugosa following physical and chemical immobilization on modified mesoporous silica - Wang_2014_Mater.Sci.Eng.C.Mater.Biol.Appl_45_261
Author(s) : Wang C , Li Y , Zhou G , Jiang X , Xu Y , Bu Z
Ref : Mater Sci Eng C Mater Biol Appl , 45 :261 , 2014
Abstract : Lipase from Candida rugosa (CRL) was chemically and physically immobilized onto four types of rod-shaped mesoporous silica (RSMS). RSMS prepared using surfactant P123 and poly(ethylene glycol) as co-templates was functionalized with (3-aminopropyl)triethoxysilane (APTES) to obtain P-RSMS by post-synthesis grafting. Tetraethoxysilane was hydrothermally co-condensed with APTES to obtain C-RSMS. A two-step process using APTES and glutaraldehyde was also performed to obtain G-RSMS. The effects of modification methods (including post-synthesis grafting and co-condensation) and glutaraldehyde on the mesoscopic order, interplanar spacing d100, cell parameter a0, mesoporous structure, and wall thickness of RSMS were studied in detail. Results showed that all samples were mesoporous materials with 2D mesostructures (p6mm). Pore size and d100 decreased, whereas the wall thickness increased after different modifications. CRL was used as a model enzyme to determine the effect of physical and chemical adsorption on loading amount and enzymatic activity. The possible mechanism of CRL immobilization on G-RSMS by chemical adsorption was systematically investigated. The chemical immobilization of CRL on G-RSMS increased the loading amount, hydrolytic activity, thermal stability, and reusability. Moreover, immobilized CRL was employed to catalyze the resolution of 2-octanol by esterification with caprylic acid. The enantiomeric excess of 2-octanol was 45.8% when the reaction was catalyzed by G-RSMS-CRL and decreased to about 38%-39% using the physically immobilized CRL, after 48h of reaction in hexane.
ESTHER : Wang_2014_Mater.Sci.Eng.C.Mater.Biol.Appl_45_261
PubMedSearch : Wang_2014_Mater.Sci.Eng.C.Mater.Biol.Appl_45_261
PubMedID: 25491828

Title : Multiple resistances and complex mechanisms of Anopheles sinensis mosquito: a major obstacle to mosquito-borne diseases control and elimination in China - Chang_2014_PLoS.Negl.Trop.Dis_8_e2889
Author(s) : Chang X , Zhong D , Fang Q , Hartsel J , Zhou G , Shi L , Fang F , Zhu C , Yan G
Ref : PLoS Negl Trop Dis , 8 :e2889 , 2014
Abstract : Malaria, dengue fever, and filariasis are three of the most common mosquito-borne diseases worldwide. Malaria and lymphatic filariasis can occur as concomitant human infections while also sharing common mosquito vectors. The overall prevalence and health significance of malaria and filariasis have made them top priorities for global elimination and control programmes. Pyrethroid resistance in anopheline mosquito vectors represents a highly significant problem to malaria control worldwide. Several methods have been proposed to mitigate insecticide resistance, including rotational use of insecticides with different modes of action. Anopheles sinensis, an important malaria and filariasis vector in Southeast Asia, represents an interesting mosquito species for examining the consequences of long-term insecticide rotation use on resistance. We examined insecticide resistance in two An. Sinensis populations from central and southern China against pyrethroids, organochlorines, organophosphates, and carbamates, which are the major classes of insecticides recommended for indoor residual spray. We found that the mosquito populations were highly resistant to the four classes of insecticides. High frequency of kdr mutation was revealed in the central population, whereas no kdr mutation was detected in the southern population. The frequency of G119S mutation in the ace-1 gene was moderate in both populations. The classification and regression trees (CART) statistical analysis found that metabolic detoxification was the most important resistance mechanism, whereas target site insensitivity of L1014 kdr mutation played a less important role. Our results indicate that metabolic detoxification was the dominant mechanism of resistance compared to target site insensitivity, and suggests that long-term rotational use of various insecticides has led An. sinensis to evolve a high insecticide resistance. This study highlights the complex network of mechanisms conferring multiple resistances to chemical insecticides in mosquito vectors and it has important implication for designing and implementing vector resistance management strategies.
ESTHER : Chang_2014_PLoS.Negl.Trop.Dis_8_e2889
PubMedSearch : Chang_2014_PLoS.Negl.Trop.Dis_8_e2889
PubMedID: 24852174

Title : Colorimetric and fluorometric assays for acetylcholinesterase and its inhibitors screening based on a fluorescein derivate - Wang_2014_Bioorg.Med.Chem.Lett_24_552
Author(s) : Wang B , Wang H , Wang F , Zhou G , Wang Y , Kambam S , Chen X
Ref : Bioorganic & Medicinal Chemistry Lett , 24 :552 , 2014
Abstract : A fluorescein-based sensor was developed for the AChE activity assay and the inhibitor screening. The sensor provided the dual assay methods for the screening of AChE activity in the presence or absence of inhibitor. The colorimetric and fluorometric assays were based on the following processes: (1) owing to the hydrolysis of acetylthiocholine in the presence of AChE, the fluorescein-based probe can rapidly induce 1,4-addition of the hydrolysis product thiocholine to alpha,beta-unsaturated ketone in the compound 1, resulting in strong fluorescence and absorption changes; (2) in the presence of the corresponding inhibitor, the fluorescence enhancement or the absorption change would be inhibited in that the formation of thiocholine was hindered.
ESTHER : Wang_2014_Bioorg.Med.Chem.Lett_24_552
PubMedSearch : Wang_2014_Bioorg.Med.Chem.Lett_24_552
PubMedID: 24360998

Title : Aspirin Hydrolysis in Plasma Is a Variable Function of Butyrylcholinesterase and Platelet-activating Factor Acetylhydrolase 1b2 (PAFAH1b2) - Zhou_2013_J.Biol.Chem_288_11940
Author(s) : Zhou G , Marathe GK , Hartiala J , Hazen SL , Allayee H , Tang WH , McIntyre TM
Ref : Journal of Biological Chemistry , 288 :11940 , 2013
Abstract : Aspirin is rapidly hydrolyzed within erythrocytes by a heterodimer of PAFAH1b2/PAFAH1b3 but also in plasma by an unidentified activity. Hydrolysis in both compartments was variable, with a 12-fold variation in plasma among 2226 Cleveland Clinic GeneBank patients. Platelet inhibition by aspirin was suppressed in plasma that rapidly hydrolyzed aspirin. Plasma aspirin hydrolysis was significantly higher in patients with coronary artery disease compared with control subjects (16.5 +/- 4.4 versus 15.1 +/- 3.7 nmol/ml/min; p = 3.4 x 10(-8)). A genome-wide association study of 2054 GeneBank subjects identified a single locus immediately adjacent to the BCHE (butyrylcholinesterase) gene associated with plasma aspirin hydrolytic activity (lead SNP, rs6445035; p = 9.1 x 10(-17)). However, its penetrance was low, and plasma from an individual with an inactivating mutation in BCHE still effectively hydrolyzed aspirin. A second aspirin hydrolase was identified in plasma, the purification of which showed it to be homomeric PAFAH1b2. This is distinct from the erythrocyte PAFAH1b2/PAFAH1b3 heterodimer. Inhibitors showed that both butyrylcholinesterase (BChE) and PAFAH1b2 contribute to aspirin hydrolysis in plasma, with variation primarily reflecting non-genetic variation of BChE activity. Therefore, aspirin is hydrolyzed in plasma by two enzymes, BChE and a new extracellular form of platelet-activating factor acetylhydrolase, PAFAH1b2. Hydrolytic effectiveness varies widely primarily from non-genetic variation of BChE activity that affects aspirin bioavailability in blood and the ability of aspirin to inhibit platelet aggregation.
ESTHER : Zhou_2013_J.Biol.Chem_288_11940
PubMedSearch : Zhou_2013_J.Biol.Chem_288_11940
PubMedID: 23508960

Title : Genome sequencing and comparative transcriptomics of the model entomopathogenic fungi Metarhizium anisopliae and M. acridum - Gao_2011_PLoS.Genet_7_e1001264
Author(s) : Gao Q , Jin K , Ying SH , Zhang Y , Xiao G , Shang Y , Duan Z , Hu X , Xie XQ , Zhou G , Peng G , Luo Z , Huang W , Wang B , Fang W , Wang S , Zhong Y , Ma LJ , St Leger RJ , Zhao GP , Pei Y , Feng MG , Xia Y , Wang C
Ref : PLoS Genet , 7 :e1001264 , 2011
Abstract : Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ~30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ~16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogeneous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties.
ESTHER : Gao_2011_PLoS.Genet_7_e1001264
PubMedSearch : Gao_2011_PLoS.Genet_7_e1001264
PubMedID: 21253567
Gene_locus related to this paper: metaq-dapb , metaq-e9dr02 , metaq-e9dr46 , metaq-e9dx32 , metaq-e9dy00 , metaq-e9e6i5 , metaq-e9e332 , metaq-e9e873 , metaq-e9eaq4 , metaq-e9ebs3 , metaq-e9ebt3 , metaq-e9edi2 , metaq-e9edr0 , metaq-e9ee29 , metaq-e9eej3 , metaq-e9ef60 , metaq-e9ef98 , metaq-e9efc1 , metaq-e9eg97 , metaq-e9egz7 , metaq-kex1 , metar-dapb , metar-e9ej81 , metar-e9ejw6 , metar-e9ek06 , metar-e9eka7 , metar-e9eku9 , metar-e9em68 , metar-e9emd0 , metar-e9enf9 , metar-e9eny8 , metar-e9ep20 , metar-e9ep60 , metar-e9eqh0 , metar-e9etb2 , metar-e9etp6 , metar-e9euh9 , metar-e9ey62 , metar-e9eyx6 , metar-e9ezk2 , metar-e9f3f2 , metar-e9f3j3 , metar-e9f3l3 , metar-e9f3z5 , metar-e9f6q5 , metar-e9f6t6 , metar-e9f7y7 , metar-e9f9h2 , metar-e9f029 , metar-e9f205 , metar-e9f721 , metar-e9fa63 , metar-e9fab1 , metar-e9fas3 , metar-e9fbn5 , metar-e9fbt1 , metar-e9fd34 , metaq-e9eej8 , metaq-e9dx35 , metar-e9f3e9 , metar-e9f0w8 , metan-a0a086npb7 , 9hypo-a0a014p983 , metan-a0a086nhe0 , 9hypo-a0a0a1v7e9 , metaq-e9e0y0 , metan-a0a0d9pev7 , metaq-e9edt7 , metra-e9ewg3 , metra-pks2 , metaf-pks1 , metaq-pks2 , metaq-e9e9z0

Title : Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement - Shen_2009_J.Med.Chem_52_5009
Author(s) : Shen HC , Ding FX , Wang S , Deng Q , Zhang X , Chen Y , Zhou G , Xu S , Chen HS , Tong X , Tong V , Mitra K , Kumar S , Tsai C , Stevenson AS , Pai LY , Alonso-Galicia M , Chen X , Soisson SM , Roy S , Zhang B , Tata JR , Berger JP , Colletti SL
Ref : Journal of Medicinal Chemistry , 52 :5009 , 2009
Abstract : 4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.
ESTHER : Shen_2009_J.Med.Chem_52_5009
PubMedSearch : Shen_2009_J.Med.Chem_52_5009
PubMedID: 19645482

Title : Muscarinic M2 antagonists: anthranilamide derivatives with exceptional selectivity and in vivo activity - Clader_2004_Bioorg.Med.Chem_12_319
Author(s) : Clader JW , Billard W , Binch H, 3rd , Chen LY , Crosby G, Jr. , Duffy RA , Ford J , Kozlowski JA , Lachowicz JE , Li S , Liu C , McCombie SW , Vice S , Zhou G , Greenlee WJ
Ref : Bioorganic & Medicinal Chemistry , 12 :319 , 2004
Abstract : Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.
ESTHER : Clader_2004_Bioorg.Med.Chem_12_319
PubMedSearch : Clader_2004_Bioorg.Med.Chem_12_319
PubMedID: 14723952

Title : Substituted 2-(R)-methyl piperazines as muscarinic M(2) selective ligands - Kozlowski_2002_Bioorg.Med.Chem.Lett_12_791
Author(s) : Kozlowski JA , Zhou G , Tagat JR , Lin SI , McCombie SW , Ruperto VB , Duffy RA , McQuade RA , Crosby G , Taylor LA , Billard W , Binch H , Lachowicz JE
Ref : Bioorganic & Medicinal Chemistry Lett , 12 :791 , 2002
Abstract : A novel series of 2-(R)-methyl-substituted piperazines (e.g., 2) is described. They are potent M(2) selective ligands that have >100-fold selectivity versus the M(1) receptor. In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration.
ESTHER : Kozlowski_2002_Bioorg.Med.Chem.Lett_12_791
PubMedSearch : Kozlowski_2002_Bioorg.Med.Chem.Lett_12_791
PubMedID: 11859004

Title : Synthesis and structure-activity relationships of M(2)-selective muscarinic receptor ligands in the 1-[4-(4-arylsulfonyl)-phenylmethyl]-4-(4-piperidinyl)-piperazine family - McCombie_2002_Bioorg.Med.Chem.Lett_12_795
Author(s) : McCombie SW , Lin SI , Tagat JR , Nazareno D , Vice S , Ford J , Asberom T , Leone D , Kozlowski JA , Zhou G , Ruperto VB , Duffy RA , Lachowicz JE
Ref : Bioorganic & Medicinal Chemistry Lett , 12 :795 , 2002
Abstract : The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
ESTHER : McCombie_2002_Bioorg.Med.Chem.Lett_12_795
PubMedSearch : McCombie_2002_Bioorg.Med.Chem.Lett_12_795
PubMedID: 11859005

Title : Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution - Boyle_2001_Bioorg.Med.Chem.Lett_11_2311
Author(s) : Boyle CD , Chackalamannil S , Clader JW , Greenlee WJ , Josien HB , Kaminski JJ , Kozlowski JA , McCombie SW , Nazareno DV , Tagat JR , Wang Y , Zhou G , Billard W , Binch H , Crosby G , Cohen-Williams M , Coffin VL , Cox KA , Grotz DE , Duffy RA , Ruperto V , Lachowicz JE
Ref : Bioorganic & Medicinal Chemistry Lett , 11 :2311 , 2001
Abstract : The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
ESTHER : Boyle_2001_Bioorg.Med.Chem.Lett_11_2311
PubMedSearch : Boyle_2001_Bioorg.Med.Chem.Lett_11_2311
PubMedID: 11527721

Title : Muscarinic agonists and antagonists in the treatment of Alzheimer's disease - Greenlee_2001_Farmaco_56_247
Author(s) : Greenlee W , Clader J , Asberom T , McCombie S , Ford J , Guzik H , Kozlowski J , Li S , Liu C , Lowe D , Vice S , Zhao H , Zhou G , Billard W , Binch H , Crosby R , Duffy R , Lachowicz J , Coffin V , Watkins R , Ruperto V , Strader C , Taylor L , Cox K
Ref : Farmaco , 56 :247 , 2001
Abstract : Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.
ESTHER : Greenlee_2001_Farmaco_56_247
PubMedSearch : Greenlee_2001_Farmaco_56_247
PubMedID: 11421251

Title : Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788 - Lachowicz_2001_Life.Sci_68(22-23)_2585
Author(s) : Lachowicz JE , Duffy RA , Ruperto V , Kozlowski J , Zhou G , Clader J , Billard W , Binch H, 3rd , Crosby G , Cohen-Williams M , Strader CD , Coffin V
Ref : Life Sciences , 68 :2585 , 2001
Abstract : Current treatment of Alzheimer's Disease (AD) requires acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft. Another mechanism by which ACh levels can be increased is blockade of presynaptic M2 muscarinic autoreceptors that regulate ACh release. An antagonist designed for this purpose must be highly selective for M2 receptors to avoid blocking postsynaptic M1 receptors, which mediate the cognitive effects of ACh. Structure-activity studies of substituted methylpiperadines led to the synthesis of 4-[4-[1(S)-[4-[(1,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-1-piperaz inyl]-4-methyl-1-(propylsulfonyl)piperidine. This compound, SCH 72788, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 0.5 nM, and its affinity at M1 receptors is 84-fold lower. SCH 72788 is a functional M2 antagonist that competitively inhibits the ability of the agonist oxotremorine-M to inhibit adenylyl cyclase activity. In an in vivo microdialysis paradigm, SCH 72788 increases ACh release from the striatum of conscious rats. The compound is also active in a rodent model of cognition, the young rat passive avoidance response paradigm. The effects of SCH 72788 suggest that M2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias.
ESTHER : Lachowicz_2001_Life.Sci_68(22-23)_2585
PubMedSearch : Lachowicz_2001_Life.Sci_68(22-23)_2585
PubMedID: 11392630

Title : Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor - Kozlowski_2000_Bioorg.Med.Chem.Lett_10_2255
Author(s) : Kozlowski JA , Lowe DB , Guzik HS , Zhou G , Ruperto VB , Duffy RA , McQuade R , Crosby G , Taylor LA , Billard W , Binch H , Lachowicz JE
Ref : Bioorganic & Medicinal Chemistry Lett , 10 :2255 , 2000
Abstract : Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.
ESTHER : Kozlowski_2000_Bioorg.Med.Chem.Lett_10_2255
PubMedSearch : Kozlowski_2000_Bioorg.Med.Chem.Lett_10_2255
PubMedID: 11055332