Qian Y

References (43)

Title : Adverse effects of Microcystis aeruginosa exudates on the filtration, digestion, and reproduction organs of benthic bivalve Corbicula fluminea - Hong_2024_Sci.Rep_14_10934
Author(s) : Hong Z , Chen X , Hu J , Chang X , Qian Y
Ref : Sci Rep , 14 :10934 , 2024
Abstract : Cyanobacteria bloom and the secondary metabolites released by the microorganism are extremely harmful to aquatic animals, yet study on their adverse effects in zoobenthos is rare. Corbicula fluminea widely distributed in freshwater environment with algal blooms. It is a typical filter feeding zoobenthos that may be affected by the secondary metabolites of cyanobacteria due to its high filtering rate. In this study, C. fluminea was exposed to Microcystis aeruginosa exudates (MaE) for 96 h, which was obtained from 5x10(5) cells/mL and 2.5x10(6) cells/mL exponential stage M. aeruginosa culture solution that represented cyanobacteria cell density needs environmental risk precaution control and emergent control, respectively. The responses of C. fluminea critical organs to MaE were analyzed and evaluated based on histopathological sections, antitoxicity biomarkers, and organ function biomarkers. The results showed that all the organs underwent structural disorders, cell vacuolization, apoptosis, and necrosis, and the damage levels increased as MaE concentration increased. The detoxification and antioxidant defense systems biomarkers in each organ response to MaE exposure differently and the level of reaction improved when MaE concentration increased. The siphon rate and acetylcholinesterase activity showed that the filtration function decreased significantly as the MaE concentration increased. Increased activity of glutathione S-transferase and amylase in the digestive gland indicate that it is the major detoxification organ of C. fluminea. Increased vitellogenin concentration and enlarged oocytes in the gonad indicate that MaE may have an estrogenic effect on C. fluminea. This study demonstrates that cyanobacteria threat benthic bivalves by inducing oxidative stress, inhibiting filtering feeding system, and disturbing digestion system and reproduction potential of C. fluminea.
ESTHER : Hong_2024_Sci.Rep_14_10934
PubMedSearch : Hong_2024_Sci.Rep_14_10934
PubMedID: 38740841

Title : Screening of Active Substances Regulating Alzheimer's Disease in Ginger and Visualization of the Effectiveness on 6-Gingerol Pathway Targets - Pan_2024_Foods_13_
Author(s) : Pan Y , Li Z , Zhao X , Du Y , Zhang L , Lu Y , Yang L , Cao Y , Qiu J , Qian Y
Ref : Foods , 13 : , 2024
Abstract : Ginger has been reported to potentially treat Alzheimer's disease (AD), but the specific compounds responsible for this biological function and their mechanisms are still unknown. In this study, a combination of network pharmacology, molecular docking, and dynamic simulation technology was used to screen active substances that regulate AD and explore their mechanisms. The TCMSP, GeneCards, OMIM, and DisGeNET databases were utilized to obtain 95 cross-targets related to ginger's active ingredients and AD as key targets. A functional enrichment analysis revealed that the pathways in which ginger's active substances may be involved in regulating AD include response to exogenous stimuli, response to oxidative stress, response to toxic substances, and lipid metabolism, among others. Furthermore, a drug-active ingredient-key target interaction network diagram was constructed, highlighting that 6-Gingerol is associated with 16 key targets. Additionally, a protein-protein interaction (PPI) network was mapped for the key targets, and HUB genes (ALB, ACTB, GAPDH, CASP3, and CAT) were identified. Based on the results of network pharmacology and cell experiments, 6-Gingerol was selected as the active ingredient for further investigation. Molecular docking was performed between 6-Gingerol and its 16 key targets, and the top three proteins with the strongest binding affinities (ACHE, MMP2, and PTGS2) were chosen for molecular dynamics analysis together with the CASP3 protein as the HUB gene. The findings indicate that 6-Gingerol exhibits strong binding ability to these disease targets, suggesting its potential role in regulating AD at the molecular level, as well as in abnormal cholinesterase metabolism and cell apoptosis, among other related regulatory pathways. These results provide a solid theoretical foundation for future in vitro experiments using actual cells and animal experiments to further investigate the application of 6-Gingerol.
ESTHER : Pan_2024_Foods_13_
PubMedSearch : Pan_2024_Foods_13_
PubMedID: 38397589

Title : Adipose triglyceride lipase suppresses noncanonical inflammasome by hydrolyzing LPS - Li_2024_Nat.Chem.Biol__
Author(s) : Li W , Liu Q , Qian Y , Wang C , Kong C , Sun L , Liu H , Zhang Y , Jiang D , Jiang C , Wang S , Xia P
Ref : Nat Chemical Biology , : , 2024
Abstract : Intracellular recognition of lipopolysaccharide (LPS) by mouse caspase-11 or human caspase-4 is a vital event for the activation of the noncanonical inflammasome. Whether negative regulators are involved in intracellular LPS sensing is still elusive. Here we show that adipose triglyceride lipase (ATGL) is a negative regulator of the noncanonical inflammasome. Through screening for genes participating in the noncanonical inflammasome, ATGL is identified as a negative player for intracellular LPS signaling. ATGL binds LPS and catalyzes the removal of the acylated side chains that contain ester bonds. LPS with under-acylated side chains no longer activates the inflammatory caspases. Cells with ATGL deficiency exhibit enhanced immune responses when encountering intracellular LPS, including an elevated secretion of interleukin-1beta, decreased cell viability and increased cell cytotoxicity. Moreover, ATGL-deficient mice show exacerbated responses to endotoxin challenges. Our results uncover that ATGL degrades cytosolic LPS to suppress noncanonical inflammasome activation.
ESTHER : Li_2024_Nat.Chem.Biol__
PubMedSearch : Li_2024_Nat.Chem.Biol__
PubMedID: 38413746

Title : Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3\/8 activity - Chen_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2322332121
Author(s) : Chen YQ , Yang Y , Zhen EY , Beyer TP , Li H , Wen Y , Ehsani M , Jackson N , Xie K , Jung H , Scheithauer JL , Kumari A , Birrane G , Russell AM , Balasubramaniam D , Liao Z , Siegel RW , Qian Y , Ploug M , Young SG , Konrad RJ
Ref : Proc Natl Acad Sci U S A , 121 :e2322332121 , 2024
Abstract : Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5delta35"). We found that wild-type (WT) human APOA5, but not APOA5delta35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5delta40"). Mouse WT-APOA5, but not APOA5delta40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5delta40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5(-/-) mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5delta40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.
ESTHER : Chen_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2322332121
PubMedSearch : Chen_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2322332121
PubMedID: 38625948
Gene_locus related to this paper: human-LPL

Title : Angiopoietin-like protein 4\/8 complex-mediated plasmin generation leads to cleavage of the complex and restoration of LPL activity - Zhen_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2214081120
Author(s) : Zhen EY , Chen YQ , Russell AM , Ehsani M , Siegel RW , Qian Y , Konrad RJ
Ref : Proc Natl Acad Sci U S A , 120 :e2214081120 , 2023
Abstract : Triglyceride (TG) metabolism is highly regulated by angiopoietin-like protein (ANGPTL) family members [Y. Q. Chen et al., J. Lipid Res. 61, 1203-1220 (2020)]. During feeding, ANGPTL8 forms complexes with the fibrinogen-like domain-containing protein ANGPTL4 in adipose tissue to decrease ANGPTL3/8- and ANGPTL4-mediated lipoprotein lipase (LPL)-inhibitory activity and promote TG hydrolysis and fatty acid (FA) uptake. The ANGPTL4/8 complex, however, tightly binds LPL and partially inhibits it in vitro. To try to reconcile the in vivo and in vitro data on ANGPTL4/8, we aimed to find novel binding partners of ANGPTL4/8. To that end, we performed pulldown experiments and found that ANGPTL4/8 bound both tissue plasminogen activator (tPA) and plasminogen, the precursor of the fibrinolytic enzyme plasmin. Remarkably, ANGPTL4/8 enhanced tPA activation of plasminogen to generate plasmin in a manner like that observed with fibrin, while minimal plasmin generation was observed with ANGPTL4 alone. The addition of tPA and plasminogen to LPL-bound ANGPTL4/8 caused rapid, complete ANGPTL4/8 cleavage and increased LPL activity. Restoration of LPL activity in the presence of ANGPTL4/8 was also achieved with plasmin but was blocked when catalytically inactive plasminogen (S760A) was added to tPA or when plasminogen activator inhibitor-1 was added to tPA + plasminogen, indicating that conversion of plasminogen to plasmin was essential. Together, these results suggest that LPL-bound ANGPTL4/8 mimics fibrin to recruit tPA and plasminogen to generate plasmin, which then cleaves ANGPTL4/8, enabling LPL activity to be increased. Our observations thus reveal a unique link between the ANGPTL4/8 complex and plasmin generation.
ESTHER : Zhen_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2214081120
PubMedSearch : Zhen_2023_Proc.Natl.Acad.Sci.U.S.A_120_e2214081120
PubMedID: 36763533

Title : Decoding the role of angiopoietin-like protein 4\/8 complex-mediated plasmin generation in the regulation of LPL activity - Chen_2023_J.Lipid.Res__100441
Author(s) : Chen YQ , Zhen EY , Russell AM , Ehsani M , Siegel RW , Qian Y , Konrad RJ
Ref : J Lipid Res , :100441 , 2023
Abstract : After feeding, adipose tissue lipoprotein lipase (LPL) activity should be maximized, therefore the potent LPL-inhibitory activity of angiopoietin-like protein 4 (ANGPTL4) must be blocked by ANGPTL8 through formation of ANGPTL4/8 complexes. ANGPTL4/8 tightly binds and protects LPL but also partially inhibits its activity. Recently, we demonstrated ANGPTL4/8 also binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin that cleaves ANGPTL4/8 to restore LPL activity [Zhen, E. Y. et al., (2023) Proc. Natl. Acad. Sci. U. S. A. 120, e2214081120]. Although fully active LPL in the fat postprandially is desirable, ANGPTL4/8 removal could subject LPL to profound inhibition by ANGPTL3/8 (the most potent circulating LPL inhibitor), inhibition by other LPL inhibitors like ANGPTL4, ANGPTL3, and apolipoprotein C3 (ApoC3), or interfere with ApoC2-mediated LPL activation. To understand better these potential paradoxes, we examined LPL inhibition by ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 and LPL stimulation by ApoC2 in the presence of ANGPTL4/8 + tPA + plasminogen. Remarkably, ANGPTL3/8-mediated LPL inhibition was almost completely blocked, with the mechanism being cleavage of fibrinogen-like domain-containing ANGPTL3 present in the ANGPTL3/8 complex. The LPL-inhibitory effects of ANGPTL4, ANGPTL3, and ApoC3 were also largely reduced in the presence of ANGPTL4/8 + tPA + plasminogen. In contrast, the ability of ApoC2 to stimulate LPL activity was unaffected by ANGPTL4/8-mediated plasmin generation. Together, these results explain how plasmin generated by increased postprandial ANGPTL4/8 levels in adipose tissue enables maximal LPL activity by preventing ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 from inhibiting LPL, while permitting ApoC2-mediated LPL activation to occur.
ESTHER : Chen_2023_J.Lipid.Res__100441
PubMedSearch : Chen_2023_J.Lipid.Res__100441
PubMedID: 37666362

Title : Prediction of Carboxylesterase 1 (CES1)-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models - Qian_2022_Drug.Metab.Dispos__
Author(s) : Qian Y , Markowitz JS
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , : , 2022
Abstract : The use of cannabis products has increased substantially. Cannabis products have been perceived and investigated as potential treatments for attention-deficit/hyperactivity disorder (ADHD). Accordingly, co-administration of cannabis products and methylphenidate (MPH), a first-line medication for ADHD, is possible. Oral MPH undergoes extensive pre-systemic metabolism by carboxylesterase 1 (CES1), a hepatic enzyme which can be inhibited by two prominent cannabinoids, delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). This prompts further investigation into the likelihood of clinical interactions between MPH and these two cannabinoids through CES1 inhibition. In the present study, inhibition parameters were obtained from a human liver S9 system and then incorporated into static and physiologically-based pharmacokinetic (PBPK) models for prediction of potential clinical significance. The inhibition of MPH hydrolysis by THC and CBD was reversible, with estimated unbound inhibition constants (K(i,u)) of 0.031 and 0.091 microM, respectively. The static model predicted a mild increase in MPH exposure by concurrent THC (34%) and CBD (94%) from smoking a cannabis cigarette and ingestion of prescriptive CBD, respectively. PBPK models suggested no significant interactions between single doses of MPH and CBD (2.5 - 10 mg/kg) when administered simultaneously, while a mild interaction (AUC increased by up to 55% and C(max) by up to 45%) is likely if multiple doses of CBD (10 mg/kg twice daily) are administered. In conclusion, the pharmacokinetic disposition of MPH can be potentially influenced by THC and CBD under certain clinical scenarios. Whether the magnitude of predicted interactions translates into clinically relevant outcomes requires verification in an appropriately designed clinical study. Significance Statement This work demonstrated a potential mechanism of drug-drug interactions between methylphenidate (MPH) and two major cannabinoids (delta(9)-tetrahydrocannabinol [THC] and cannabidiol [CBD]) not previously reported. We predicted a mild interaction between MPH and THC when the cannabinoid exposure occurred via cannabis smoking. Mild interactions between MPH and CBD were predicted with multiple oral administrations of CBD.
ESTHER : Qian_2022_Drug.Metab.Dispos__
PubMedSearch : Qian_2022_Drug.Metab.Dispos__
PubMedID: 35512806

Title : Insights into acylation mechanisms: co-expression of serine carboxypeptidase-like acyltransferases and their non-catalytic companion paralogs - Yao_2022_Plant.J_111_117
Author(s) : Yao S , Liu Y , Zhuang J , Zhao Y , Dai X , Jiang C , Wang Z , Jiang X , Zhang S , Qian Y , Tai Y , Wang Y , Wang H , Xie DY , Gao L , Xia T
Ref : Plant J , 111 :117 , 2022
Abstract : Serine carboxypeptidase-like acyltransferases (SCPL-ATs) play a vital role in the diversification of plant metabolites. Galloylated flavan-3-ols highly accumulate in tea (Camellia sinensis), grape (Vitis vinifera), and persimmon (Diospyros kaki). To date, the biosynthetic mechanism of these compounds remains unknown. Herein, we report that two SCPL-AT paralogs are involved in galloylation of flavan-3-ols: CsSCPL4, which contains the conserved catalytic triad S-D-H, and CsSCPL5, which has the alternative triad T-D-Y. Integrated data from transgenic plants, recombinant enzymes, and gene mutations showed that CsSCPL4 is a catalytic acyltransferase, while CsSCPL5 is a non-catalytic companion paralog (NCCP). Co-expression of CsSCPL4 and CsSCPL5 is likely responsible for the galloylation. Furthermore, pull-down and co-immunoprecipitation assays showed that CsSCPL4 and CsSCPL5 interact, increasing protein stability and promoting post-translational processing. Moreover, phylogenetic analyses revealed that their homologs co-exist in galloylated flavan-3-ol- or hydrolyzable tannin-rich plant species. Enzymatic assays further revealed the necessity of co-expression of those homologs for acyltransferase activity. Evolution analysis revealed that the mutations of the CsSCPL5 catalytic residues may have taken place about 10 million years ago. These findings show that the co-expression of SCPL-ATs and their NCCPs contributes to the acylation of flavan-3-ols in the plant kingdom.
ESTHER : Yao_2022_Plant.J_111_117
PubMedSearch : Yao_2022_Plant.J_111_117
PubMedID: 35437852
Gene_locus related to this paper: dioka-dkSCPL1 , camsi-SCPL5 , camsi-SCPL4

Title : Involvement of esterases in the pulmonary metabolism of beclomethasone dipropionate and the potential influence of cannabis use - Qian_2022_Chem.Biol.Interact__110228
Author(s) : Qian Y , Melchert PW , Markowitz JS
Ref : Chemico-Biological Interactions , :110228 , 2022
Abstract : Beclomethasone dipropionate (BDP) is an inhaled glucocorticoid used for maintenance treatment of asthma in adults and children. BDP is a prodrug activated in lung when hydrolyzed to its major active metabolite beclomethasone-17-monopropionate (17-BMP), which can be further deactivated to beclomethasone (BOH). The specific hydrolases contributing to these processes have not been identified which warrants an investigation to enable a better assessment of the drug-drug interaction (DDI) liability and a better management of drug efficacy and systemic toxicity. In the present study, the pulmonary metabolism of BDP was investigated using both human lung S9 (HLuS9) and recombinant carboxylesterase 1 (CES1) S9. By employing the relative activity approach, we tested the hypothesis of CES1 being the major enzyme involved. Assessment of other hydrolases were conducted in an assay with selective esterase inhibitors. In addition, the DDI potentials between BDP and delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) were evaluated due to the increasing use of inhaled cannabis both recreationally and medically. The mechanism of DDI was conducted in an in vitro time-dependent inhibition assay, and further interpreted utilizing a proposed model. In HLuS9, BDP was efficiently metabolized almost completely to 17-BMP, which was then converted to BOH at a much lower rate. CES1 was found as a minor contributor accounting for only 1.4% of BDP metabolism in HLuS9, while arylacetamide deacetylase might be the main enzyme involved. Both THC and CBD inhibited the HLuS9 mediated BDP hydrolysis in a reversible manner, with reported IC(50) values estimated as 8.98 and 36.8 microM, respectively. Our proposed model suggested a moderately decreased 17-BMP exposure in lung by concomitant THC from a cannabis cigarette, while the effects from orally taken CBD was expected to be of no clinical relevance.
ESTHER : Qian_2022_Chem.Biol.Interact__110228
PubMedSearch : Qian_2022_Chem.Biol.Interact__110228
PubMedID: 36283465

Title : In vitro inhibition of carboxylesterase 1 by Kava (Piper methysticum) Kavalactones - Melchert_2022_Chem.Biol.Interact__109883
Author(s) : Melchert PW , Qian Y , Zhang Q , Klee BO , Xing C , Markowitz JS
Ref : Chemico-Biological Interactions , :109883 , 2022
Abstract : Kava refers to the extracts from the rhizome of the plant Piper methysticum which is of particular significance to various indigenous cultures in the South Pacific region. Kavalactones are the active constituents of kava products and are associated with sedative and anxiolytic effects. Kavalactones have been evaluated in vitro for their potential to alter the activity of various CYP450 enzymes but have undergone little systematic investigation as to their potential influence on esterases. This study investigated the inhibition effects of kava and its kavalactones on carboxylesterase 1 (CES1) in an in vitro system and established associated kinetic parameters. Kava and its kavalactones were found to produce reversible inhibition of CES1 to varying degrees. Kavain, dihydrokavain, and desmethoxyyangonin displayed competitive type inhibition, while methysticin, dihydromethysticin, and yangonin displayed a mixed competitive-noncompetitive type inhibition. The inhibition constants (K(i)) values for each of the kavalactones were as follows: methysticin (35.2 microM), dihydromethysticin (68.2 microM), kavain (81.6 microM), dihydrokavain (105.3 microM), yangonin (24.9 microM), and desmethoxyyangonin (25.2 microM). With consideration to the in vitro K(i) for each evaluated kavalactone as well as available clinical kavalactone concentrations in blood circulation, co-administration of CES1 substrate medications and kava products at the recommended daily dose is generally free of drug interaction concerns. However, uncertainty around kavalactone exposure in humans has been noted and a clinically relevant CES1 inhibition by kavain, dihydrokavain, and dihydromethysticin is indeed possible if the kavalactone consumption is higher than 1000 mg in the context of over-the-counter usage. Further clinical studies would be required to assess the possibility of clinically significant kava drug-drug interactions with CES1 substrate medications.
ESTHER : Melchert_2022_Chem.Biol.Interact__109883
PubMedSearch : Melchert_2022_Chem.Biol.Interact__109883
PubMedID: 35278473

Title : The Influence of Cannabidiol on the Pharmacokinetics of Methylphenidate in Healthy Subjects - Markowitz_2022_Med.Cannabis.Cannabinoids_5_199
Author(s) : Markowitz JS , De Faria L , Zhang Q , Melchert PW , Frye RF , Klee BO , Qian Y
Ref : Med Cannabis Cannabinoids , 5 :199 , 2022
Abstract : INTRODUCTION: Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as an over-the-counter supplement, a component of medical cannabis, and a prescriptive treatment of childhood epilepsies. In vitro studies suggest CBD may inhibit a number of drug-metabolizing enzymes, including carboxylesterase 1 (CES1). The aim of this study was to evaluate effect of CBD on the disposition of the CES1 substrate methylphenidate (MPH). METHODS: In a randomized, placebo-controlled, crossover study, 12 subjects ingested 750 mg of CBD solution, or alternatively, a placebo solution twice daily for a 3-day run-in period followed by an additional CBD dose (or placebo) and a single 10 mg dose of MPH and completed serial blood sampling for pharmacokinetic analysis. MPH and CBD concentrations were measured by liquid chromatography with tandem mass spectrometry. RESULTS: The C(max) (mean +/- CV) for the CBD group and placebo group was 13.5 +/- 43.7% ng/mL and 12.2 +/- 36.4% ng/mL, respectively. AUC(inf) (ng/mL*h) for the CBD group and placebo group was 70.7 +/- 32.5% and 63.6 +/- 25.4%, respectively. The CBD AUC(0-8h) (mean +/- CV) was 1,542.2 +/- 32% ng/mL*h, and C(max) was 389.2 +/- 39% ng/mL. When compared to MPH only, the geometric mean ratio (CBD/control, 90% CI) for AUC(inf) and C(max) with CBD co-administration was 1.09 (0.89, 1.32) and 1.08 (0.85, 1.37), respectively. DISCUSSION/CONCLUSION: Although the upper bound of bioequivalence was not met, the mean estimates of AUC and C(max) ratios were generally small and unlikely to be of clinical significance.
ESTHER : Markowitz_2022_Med.Cannabis.Cannabinoids_5_199
PubMedSearch : Markowitz_2022_Med.Cannabis.Cannabinoids_5_199
PubMedID: 36467779

Title : The Angiopoietin-Like Protein 3 and 8 Complex Interacts with Lipoprotein Lipase and Induces LPL Cleavage - Jin_2021_ACS.Chem.Biol__
Author(s) : Jin N , Matter WF , Michael LF , Qian Y , Gheyi T , Cano L , Perez C , Lafuente C , Broughton HB , Espada A
Ref : ACS Chemical Biology , : , 2021
Abstract : Lipoprotein lipase (LPL) is the key enzyme that hydrolyzes triglycerides from triglyceride-rich lipoproteins. Angiopoietin-like proteins (ANGPTL) 3, 4, and 8 are well-characterized protein inhibitors of LPL. ANGPTL8 forms a complex with ANGPTL3, and the complex is a potent endogenous inhibitor of LPL. However, the nature of the structural interaction between ANGPTL3/8 and LPL is unknown. To probe the conformational changes in LPL induced by ANGPTL3/8, we found that HDX-MS detected significantly altered deuteration in the lid region, ApoC2 binding site, and furin cleavage region of LPL in the presence of ANGPTL3/8. Supporting this HDX structural evidence, we found that ANGPTL3/8 inhibits LPL enzymatic activities and increases LPL cleavage. ANGPTL3/8-induced effects on LPL activity and LPL cleavage are much stronger than those of ANGPTL3 or ANGPTL8 alone. ANGPTL3/8-mediated LPL cleavage is blocked by both an ANGPTL3 antibody and a furin inhibitor. Knock-down of furin expression by siRNA significantly reduced ANGPT3/8-induced cleavage of LPL. Our data suggest ANGPTL3/8 promotes furin-mediated LPL cleavage.
ESTHER : Jin_2021_ACS.Chem.Biol__
PubMedSearch : Jin_2021_ACS.Chem.Biol__
PubMedID: 33656326

Title : Natural Products as Modulators of CES1 Activity - Qian_2020_Drug.Metab.Dispos_48_993
Author(s) : Qian Y , Markowitz JS
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 48 :993 , 2020
Abstract : Carboxylesterase (CES) 1 is the predominant esterase expressed in the human liver and is capable of catalyzing the hydrolysis of a wide range of therapeutic agents, toxins, and endogenous compounds. Accumulating studies have demonstrated associations between the expression and activity of CES1 and the pharmacokinetics and/or pharmacodynamics of CES1 substrate medications (e.g., methylphenidate, clopidogrel, oseltamivir). Therefore, any perturbation of CES1 by coingested xenobiotics could potentially compromise treatment. Natural products are known to alter drug disposition by modulating cytochrome P450 and UDP-glucuronosyltransferase enzymes, but this issue is less thoroughly explored with CES1. We report the results of a systematic literature search and discuss natural products as potential modulators of CES1 activity. The majority of research reports reviewed were in vitro investigations that require further confirmation through clinical study. Cannabis products (delta (9)-tetrahydrocannabinol, cannabidiol, cannabinol); supplements from various plant sources containing naringenin, quercetin, luteolin, oleanolic acid, and asiatic acid; and certain traditional medicines (danshen and zhizhuwan) appear to pose the highest inhibition potential. In addition, ursolic acid, gambogic acid, and glycyrrhetic acid, if delivered intravenously, may attain high enough systemic concentrations to significantly inhibit CES1. The provision of a translational interpretation of in vitro assessments of natural product actions and interactions is limited by the dearth of basic pharmacokinetic data of the natural compounds exhibiting potent in vitro influences on CES1 activity. This is a major impediment to assigning even potential clinical significance. The modulatory effects on CES1 expression after chronic exposure to natural products warrants further investigation. SIGNIFICANCE STATEMENT: Modulation of CES1 activity by natural products may alter the course of treatment and clinical outcome. In this review, we have summarized the natural products that can potentially interact with CES1 substrate medications. We have also noted the limitations of existing reports and outlined challenges and future directions in this field.
ESTHER : Qian_2020_Drug.Metab.Dispos_48_993
PubMedSearch : Qian_2020_Drug.Metab.Dispos_48_993
PubMedID: 32591414

Title : A novel diterpene agent isolated from Microbispora hainanensis strain CSR-4 and its in vitro and in silico inhibition effects on acetylcholine esterase enzyme - Thawai_2020_Sci.Rep_10_11058
Author(s) : Thawai C , Bunbamrung N , Pittayakhajonwut P , Chongruchiroj S , Pratuangdejkul J , He YW , Tadtong S , Sareedenchai V , Prombutara P , Qian Y
Ref : Sci Rep , 10 :11058 , 2020
Abstract : An actinomycete strain CSR-4 was isolated from the rhizosphere soil of Zingiber montanum. Taxonomic characterization revealed strain CSR-4 was a member of the genus Microbispora. Whole-genome sequence analysis exhibited the highest average nucleotide identity (ANI) value (95.34%) and digital DNA-DNA hybridization (DDH) value (74.7%) between strain CSR-4 and the closest relative M. hainanensis DSM 45428(T), which was in line with the assignment to same species. In addition, a new diterpene compound, 2alpha-hydroxy-8(14), 15-pimaradien-17, 18-dioic acid, and nine known compounds were isolated from the ethyl acetate crude extract of fermentation broth. Interestingly, a new diterpene displayed the suppressive effect on the recombinant human acetylcholinesterase (rhAChE) enzymes (IC50 96.87 +/- 2.31 mug/ml). In silico studies based on molecular docking and molecular dynamics (MD) simulations were performed to predict a binding mode of the new compound into the binding pocket of the rhAChE enzyme and revealed that some amino acids in the peripheral anions site (PAS), anionic subsite, oxyanion site and catalytic active site (CAS) of the rhAChE have interacted with the compound. Therefore, our new compound could be proposed as a potential active human AChE inhibitor. Moreover, the new compound can protect significantly the neuron cells (% neuron viability = 88.56 +/- 5.19%) from oxidative stress induced by serum deprivation method at 1 ng/ml without both neurotoxicities on murine P19-derived neuron cells and cytotoxicity against Vero cells.
ESTHER : Thawai_2020_Sci.Rep_10_11058
PubMedSearch : Thawai_2020_Sci.Rep_10_11058
PubMedID: 32632152

Title : The influence of carboxylesterase 1 polymorphism and cannabidiol on the hepatic metabolism of heroin - Qian_2019_Chem.Biol.Interact__108914
Author(s) : Qian Y , Gilliland TK , Markowitz JS
Ref : Chemico-Biological Interactions , :108914 , 2019
Abstract : Heroin (diamorphine) is a highly addictive opioid drug synthesized from morphine. The use of heroin and incidence of heroin associated overdose death has increased sharply in the US. Heroin is primarily metabolized via deacetylation (hydrolysis) forming the active metabolites 6-monoacetylmorphine (6-MAM) and morphine. A diminution in heroin hydrolysis is likely to cause higher drug effects and toxicities. In this study, we sought to determine the contribution of the major hepatic hydrolase carboxylesterase 1 (CES1) to heroin metabolism in the liver as well as the potential influence of one of its known genetic variants, G143E (rs71647871). Furthermore, given the potential therapeutic application of cannabidiol (CBD) for heroin addiction and the frequent co-abuse of cannabis and heroin, we also assessed the effects of CBD on heroin metabolism. In vitro systems containing human liver, wild-type CES1, and G143E CES1 S9 fractions were utilized in the assessment. The contribution of CES1 to the hydrolysis of heroin to 6-MAM was determined as 3.66%, and CES1 was unable to further catalyze 6-MAM under our assay conditions. The G143E variant showed a 3.2-fold lower intrinsic clearance of heroin as compared to the WT. CBD inhibited heroin and 6-MAM hydrolysis in a reversible manner, with IC50s of 14.7 and 12.1muM, respectively. Our study results suggested only minor involvement of CES1 in heroin hydrolysis in the liver. Therefore, the G143E variant is unlikely to cause significant impact despite a much lower hydrolytic activity. CBD exhibited potent in vitro inhibition toward both heroin and 6-MAM hydrolysis, which may be of potential clinical relevance.
ESTHER : Qian_2019_Chem.Biol.Interact__108914
PubMedSearch : Qian_2019_Chem.Biol.Interact__108914
PubMedID: 31837295

Title : Lactobacillus plantarum CQPC02-Fermented Soybean Milk Improves Loperamide-Induced Constipation in Mice - Yi_2019_J.Med.Food_22_1208
Author(s) : Yi R , Peng P , Zhang J , Du M , Lan L , Qian Y , Zhou J , Zhao X
Ref : J Med Food , 22 :1208 , 2019
Abstract : This study determined the ameliorative effects of the novel microorganism, Lactobacillus plantarum CQPC02 (LP-CQPC02), fermented in soybean milk, on loperamide-induced constipation in Kunming mice. High-performance liquid chromatography revealed that LP-CQPC02-fermented soybean milk (LP-CQPC02-FSM) had six types of soybean isoflavones, whereas Lactobacillus bulgaricus-fermented soybean milk (LB-FSM) and unfermented soybean milk (U-FSM) only had five types of soybean isoflavones. LP-CQPC02-FSM also contained more total and active soybean isoflavones than LB-FSM and U-FSM. Results from mouse experiments showed that the defecation factors (quantity, fecal weight and water content, gastrointestinal transit ability, and time to first black stool) in the LP-CQPC02-FSM-treated mice were better than those in the LB-FSM- and U-FSM-treated mice. The serum and small intestinal tissue experiments showed that soybean milk increased the motilin, gastrin, endothelin, acetylcholinesterase, substance P, vasoactive intestinal peptide, and glutathione levels and decreased the somatostatin, myeloperoxidase, nitric oxide, and malondialdehyde levels compared with the constipated mice in the control group. The LP-CQPC02-FSM also showed better effects than those of LB-FSM and U-FSM. Further results showed that LP-CQPC02-FSM upregulated cuprozinc-superoxide dismutase (Cu/Zn-SOD), manganese superoxide dismutase (Mn-SOD), catalase (CAT), c-Kit, stem cell factor (SCF), glial cell-derived neurotrophic factor (GDNF), neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), and aquaporin-9 (AQP9) and downregulated the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), inducible nitric oxide synthase (iNOS), and aquaporin-3 (AQP3) in the constipated mice. LP-CQPC02-FSM increased the Bacteroides and Akkermansia abundances and decreased the Firmicutes abundance in the feces of the constipated mice and decreased the Firmicutes/Bacteroides ratio. This study confirmed that LP-CQPC02-FSM partially reversed constipation in mice.
ESTHER : Yi_2019_J.Med.Food_22_1208
PubMedSearch : Yi_2019_J.Med.Food_22_1208
PubMedID: 31621475

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

Title : The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications - Qian_2019_J.Clin.Psychopharmacol_39_462
Author(s) : Qian Y , Gurley BJ , Markowitz JS
Ref : J Clin Psychopharmacol , 39 :462 , 2019
Abstract : PURPOSE: Increased cannabis use and recent drug approvals pose new challenges for avoiding drug interactions between cannabis products and conventional medications. This review aims to identify drug-metabolizing enzymes and drug transporters that are affected by concurrent cannabis use and, conversely, those co-prescribed medications that may alter the exposure to one or more cannabinoids. METHODS: A systematic literature search was conducted utilizing the Google Scholar search engine and MEDLINE (PubMed) database through March 2019. All articles describing in vitro or clinical studies of cannabis drug interaction potential were retrieved for review. Additional articles of interest were obtained through cross-referencing of published bibliographies. FINDINGS: After comparing the in vitro inhibition parameters to physiologically achievable cannabinoid concentrations, it was concluded that CYP2C9, CYP1A1/2, and CYP1B1 are likely to be inhibited by all 3 major cannabinoids Delta-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The isoforms CYP2D6, CYP2C19, CYP2B6, and CYP2J2 are inhibited by THC and CBD. CYP3A4/5/7 is potentially inhibited by CBD. Delta-Tetrahydrocannabinol also activates CYP2C9 and induces CYP1A1. For non-CYP drug-metabolizing enzymes, UGT1A9 is inhibited by CBD and CBN, whereas UGT2B7 is inhibited by CBD but activated by CBN. Carboxylesterase 1 (CES1) is potentially inhibited by THC and CBD. Clinical studies suggest inhibition of CYP2C19 by CBD, inhibition of CYP2C9 by various cannabis products, and induction of CYP1A2 through cannabis smoking. Evidence of CBD inhibition of UGTs and CES1 has been shown in some studies, but the data are limited at present. We did not identify any clinical studies suggesting an influence of cannabinoids on drug transporters, and in vitro results suggest that a clinical interaction is unlikely. CONCLUSIONS: Medications that are prominent substrates for CYP2C19, CYP2C9, and CYP1A2 may be particularly at risk of altered disposition by concomitant use of cannabis or 1 or more of its constituents. Caution should also be given when coadministered drugs are metabolized by UGT or CES1, on which subject the information remains limited and further investigation is warranted. Conversely, conventional drugs with strong inhibitory or inductive effects on CYP3A4 are expected to affect CBD disposition.
ESTHER : Qian_2019_J.Clin.Psychopharmacol_39_462
PubMedSearch : Qian_2019_J.Clin.Psychopharmacol_39_462
PubMedID: 31433338

Title : In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites - Qian_2019_Drug.Metab.Dispos_47_465
Author(s) : Qian Y , Wang X , Markowitz JS
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 47 :465 , 2019
Abstract : The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to a higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the individual major cannabinoids and metabolites 9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-nor-THC-carboxylic acid, and 11-hydroxy-THC on CES1 activity. S9 fractions from human embryonic kidney 293 cells stably expressing CES1 were used in the assessment of cannabinoid inhibitory effects. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitive-noncompetitive mechanism. The inhibition constant (K i) values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 microM (0.170, 0.306, and 0.0817 microg/ml), respectively. Inhibition potency was increased when THC, CBD, and CBN were combined. Compared with the potential unbound plasma concentrations attainable clinically, the K i values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have a limited impact on CES1. Carefully designed clinical studies are warranted to establish the clinical significance of these in vitro findings.
ESTHER : Qian_2019_Drug.Metab.Dispos_47_465
PubMedSearch : Qian_2019_Drug.Metab.Dispos_47_465
PubMedID: 30833288
Gene_locus related to this paper: human-CES1

Title : Lactobacillus plantarum YS-3 Prevents Activated Carbon-Induced Constipation in Mice - Zhao_2018_J.Med.Food_21_575
Author(s) : Zhao X , Yi R , Qian Y , Park KY
Ref : J Med Food , 21 :575 , 2018
Abstract : The aim of this study was to determine the effects of Lactobacillus plantarum YS-3 (LP-YS3) on activated carbon-induced constipation in Kunming mice. The results of the experiment show that the antigastric acid activity and bile salt tolerance of LP-YS3 were stronger than those of Lactobacillus bulgaricus (LB). LP-YS3 inhibited loss of body weight caused by constipation and further reductions in fecal weight, particle number, and water content in mice. Moreover, LP-YS3 elevated the gastrointestinal transit rate and reduced the time required for initial black stool defecation. LP-YS3 also elevated motilin (MTL), endothelin (ET), acetylcholinesterase (AChE), substance P (SP), and VIP serum levels and reduced somatostatin (SS) levels in constipated mice. Hematoxylin-eosin (H&E) staining revealed that high concentration of LP-YS3 reduced the incidence of injuries to small intestine villi and the intestinal wall compared to carbon-induced constipation groups. Reverse transcription-polymerase chain reaction and western blot experiments demonstrated that LP-YS3 upregulated c-Kit, stem cell factor, and glial cell line-derived neurotrophic factor mRNA and protein expression and downregulated transient receptor potential vanilloid 1 and nitric oxide synthase expression in small intestine tissue from constipated mice. In conclusion, high concentrations of LP-YS3 had stronger and more beneficial effects than LB. Based on these results, we conclude that LP-YS3 can effectively inhibit constipation.
ESTHER : Zhao_2018_J.Med.Food_21_575
PubMedSearch : Zhao_2018_J.Med.Food_21_575
PubMedID: 29757072

Title : Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer's Disease - Zhen_2017_Front.Neural.Circuits_11_48
Author(s) : Zhen J , Qian Y , Fu J , Su R , An H , Wang W , Zheng Y , Wang X
Ref : Front Neural Circuits , 11 :48 , 2017
Abstract : Alzheimer's disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress-related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function.
ESTHER : Zhen_2017_Front.Neural.Circuits_11_48
PubMedSearch : Zhen_2017_Front.Neural.Circuits_11_48
PubMedID: 28713248

Title : MAPK cascade-mediated regulation of pathogenicity, conidiation and tolerance to abiotic stresses in the entomopathogenic fungus Metarhizium robertsii - Chen_2016_Environ.Microbiol_18_1048
Author(s) : Chen X , Xu C , Qian Y , Liu R , Zhang Q , Zeng G , Zhang X , Zhao H , Fang W
Ref : Environ Microbiol , 18 :1048 , 2016
Abstract : Metarhizium robertsii has been used as a model to study fungal pathogenesis in insects, and its pathogenicity has many parallels with plant and mammal pathogenic fungi. MAPK (Mitogen-activated protein kinase) cascades play pivotal roles in cellular regulation in fungi, but their functions have not been characterized in M. robertsii. In this study, we identified the full complement of MAPK cascade components in M. robertsii and dissected their regulatory roles in pathogenesis, conidiation and stress tolerance. The nine components of the Fus3, Hog1 and Slt2-MAPK cascades are all involved in conidiation. The Fus3- and Hog1-MAPK cascades are necessary for tolerance to hyperosmotic stress, and the Slt2- and Fus3-MAPK cascades both mediate cell wall integrity. The Hog1 and Slt2-MAPK cascades contribute to pathogenicity; the Fus3-MAPK cascade is indispensable for fungal pathogenesis. During its life cycle, M. robertsii experiences multiple microenvironments as it transverses the cuticle into the haemocoel. RNA-seq analysis revealed that MAPK cascades collectively play a major role in regulating the adaptation of M. robertsii to the microenvironmental change from the cuticle to the haemolymph. The three MAPKs each regulate their own distinctive subset of genes during penetration of the cuticle and haemocoel colonization, but they function redundantly to regulate adaptation to microenvironmental change.
ESTHER : Chen_2016_Environ.Microbiol_18_1048
PubMedSearch : Chen_2016_Environ.Microbiol_18_1048
PubMedID: 26714892
Gene_locus related to this paper: metra-pks2

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

Title : Forebrain-selective AMPA-receptor antagonism guided by TARP gamma-8 as an antiepileptic mechanism - Kato_2016_Nat.Med_22_1496
Author(s) : Kato AS , Burris KD , Gardinier KM , Gernert DL , Porter WJ , Reel J , Ding C , Tu Y , Schober DA , Lee MR , Heinz BA , Fitch TE , Gleason SD , Catlow JT , Yu H , Fitzjohn SM , Pasqui F , Wang H , Qian Y , Sher E , Zwart R , Wafford KA , Rasmussen K , Ornstein PL , Isaac JT , Nisenbaum ES , Bredt DS , Witkin JM
Ref : Nat Med , 22 :1496 , 2016
Abstract : Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP gamma-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing gamma-8, but not gamma-2 (cerebellum) or other TARP members. Two amino acid residues unique to gamma-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.
ESTHER : Kato_2016_Nat.Med_22_1496
PubMedSearch : Kato_2016_Nat.Med_22_1496
PubMedID: 27820603

Title : Therapeutic effects of Lactobacillus casei Qian treatment in activated carbon induced constipated mice - Zhao_2015_Mol.Med.Rep_12_3191
Author(s) : Zhao X , Suo HY , Qian Y , Li GJ , Liu ZH , Li J
Ref : Mol Med Rep , 12 :3191 , 2015
Abstract : In the present study, the therapeutic effects of Lactobacillus casei Qian (LCQian), the key microorganism in Tibetan yak yoghurt, on activated carboninduced constipation were determined in vivo. ICR mice were treated with LCQian for nine days by oral administration. The body weight, defecation status, gastrointestinal transit and defecation time of mice were assessed, and the serum levels of motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) were further evaluated. Bisacodyl was used as the positive control. The time until the first black stool defecation following carbon intake of the normal, control, 100 mg/kg bisacodyltreated, Lactobacillus bulgaricus (LB)treated, LCQian (L) and LCQian (H)treated mice was 93, 231, 121, 194, 172 and 157 min, respectively. Following treatment with LCQian, the gastrointestinal transit was increased to 52.4% [LCQian (L)] and 65.8% [LCQian (H)], while that in the group treated with the common lactic acid bacteria of LB was 40.3%. The MTL, Gas, ET, AChE, SP and VIP serum levels were significantly increased and levels of SS were reduced in mice following LCQian treatment compared with those in the control mice (P<0.05). Reverse transcription quantitative polymerase chain reaction indicated that LCQian raised the cKit, GDNF as well as SCF mRNA expression levels and reduced the TRPV1 and NOS expression levels in tissue of the small intestine in mice. These results suggested that lactic acid bacteria prevent constipation in mice, among which LCQian was the most effective.
ESTHER : Zhao_2015_Mol.Med.Rep_12_3191
PubMedSearch : Zhao_2015_Mol.Med.Rep_12_3191
PubMedID: 25955533

Title : Association of Lp-PLA2 Mass and Aysmptomatic Intracranial and Extracranial Arterial Stenosis in Hypertension Patients - Wang_2015_PLoS.One_10_e0130473
Author(s) : Wang Y , Zhang J , Qian Y , Tang X , Ling H , Chen K , Gao P , Zhu D
Ref : PLoS ONE , 10 :e0130473 , 2015
Abstract : BACKGROUND AND PURPOSE: Intracranial arterial stenosis (ICAS) is a common cause of ischemic stroke in Asians, whereas whites tend to have more extracranial lesions. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been associated with ischemic stroke by a large amount of work. However, there are few studies focusing on the relationship of Lp-PLA2 and asymptomatic ICAS or extracranial arterial stenosis (ECAS). Wehereby sought to explore the relationship of Lp-PLA2 and ICAS, ECAS and concurrent stenosis in stroke-free hypertensive patients in Chinese population.
METHODS: All the subjects were evaluated for the presence and severity of ICAS and ECAS through computerized tomographic angiography (CTA) covered the whole brain down to the level of aortic arch. Lp-PLA2 mass was measured by enzyme linked immunoassay. The association of Lp-PLA2 and vascular stenosis was analyzed through multivariate logistic regression.
RESULTS: Among 414 participants, 163 (39.4%) had no ICAS or ECAS, 63 (15.2%) had ECAS only, 111 (26.8%) had ICAS only and 77 (18.6%) had concurrent extraintracranial stenosis. Lp-PLA2 mass was significantly associated with isolated ICAS (OR: 2.3; 95% CI: 1.14-4.64), and concurrent stenosis (OR: 3.93; 95% CI: 1.62-9.51), but was not related to isolated ECAS (OR: 1.54; 95% CI: 0.68-3.48). Lp-PLA2 mass was also associated with moderate to severe ICAS no matter how was the ECAS. Moreover, patients with higher Lp-PLA2 mass showed more sever ICAS and had more intracranial arterial lesions. CONCLUSION: This study revealed the association of Lp-PLA2 mass with ICAS in stroke-free hypertensive patients in Chinese population. The further long-term cohort study was warranted to elucidate the concrete effect of Lp-PLA2 on the asymptomatic ICAS.
ESTHER : Wang_2015_PLoS.One_10_e0130473
PubMedSearch : Wang_2015_PLoS.One_10_e0130473
PubMedID: 26098634

Title : Preventive Effect of Lactobacillus fermentum Zhao on Activated Carbon-Induced Constipation in Mice - Zhao_2015_J.Nutr.Sci.Vitaminol.(Tokyo)_61_131
Author(s) : Zhao X , Qian Y , Suo H , Du M , Li G , Liu Z , Li J
Ref : J Nutr Sci Vitaminol (Tokyo) , 61 :131 , 2015
Abstract : The aim of this study was to investigate the effects of Lactobacillus fermentum Zhao (LF-Zhao) on activated carbon-induced constipation in ICR mice. ICR mice were administered lactic acid bacteria by gavage for 9 d. Body weight, diet intake, drinking amount, stool status, gastrointestinal transit distance and stool time, in addition to motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) levels in serum were monitored to evaluate the preventive effects of LF-Zhao on constipation. Bisacodyl, a laxative drug, was used as a positive control. Times to the first black stool for normal (untreated), control (no lactic acid bacteria treatment but activated carbon treated), bisacodyl-treated and L. delbrueckii subsp. bulgaricus (LB), LF-Zhao (L) (low concentration of 1x10(8) CFU/mL)- and LF-Zhao (H) (high concentration of 1x10(9) CFU/mL)-treated mice induced by activated carbon were 90, 218, 117, 180, 169 and 156 min, respectively. Following the consumption of LB, LF-Zhao (L) and LF-Zhao (H) or the oral administration of bisacodyl, the gastrointestinal transit distances were reduced by 55.2%, 61.3%, 70.6% and 94.6%, respectively. The serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and the serum levels of SS were reduced in the mice treated with LF-Zhao compared with those in the control mice (p<0.05). These results demonstrated that lactic acid bacteria demonstrate preventive effects on mouse constipation and that LF-Zhao alleviated constipation symptoms better than LB.
ESTHER : Zhao_2015_J.Nutr.Sci.Vitaminol.(Tokyo)_61_131
PubMedSearch : Zhao_2015_J.Nutr.Sci.Vitaminol.(Tokyo)_61_131
PubMedID: 26052143

Title : Assessing joint toxicity of four organophosphate and carbamate insecticides in common carp (Cyprinus carpio) using acetylcholinesterase activity as an endpoint - Wang_2015_Pestic.Biochem.Physiol_122_81
Author(s) : Wang Y , Chen C , Zhao X , Wang Q , Qian Y
Ref : Pestic Biochem Physiol , 122 :81 , 2015
Abstract : Mixtures of organophosphate (OP) and carbamate (CB) pesticides are commonly detected in freshwater ecosystems. These pesticides inhibit the activity of acetylcholinesterase (AChE) and have potential to interfere with behaviors that may be essential for the survival of species. Although the effects of individual anticholinesterase insecticides on aquatic species have been studied for decades, the neurotoxicity of mixtures is still poorly understood. In the present study, brain AChE inhibition in carp (Cyprinus carpio) exposed to a series of concentrations of the organophosphates (malathion and triazophos) as well as the carbamates (fenobucarb and carbosulfan) was measured. In equitoxic mixtures, the observed AChE activity inhibition of the malathion plus triazophos, and triazophos plus carbosulfan mixtures, was synergism. In equivalent concentration mixtures, the combination of malathion plus fenobucarb mixture conformed to synergism, while the observed AChE activity inhibition of the remaining pairings was less than additive. Single pesticide risk assessments are likely to underestimate the impacts of these insecticides on carps in aquatic environment where mixtures occur. Moreover, mixtures of pesticides that have been commonly reported in aquatic ecosystems may pose a more important challenge than previously anticipated.
ESTHER : Wang_2015_Pestic.Biochem.Physiol_122_81
PubMedSearch : Wang_2015_Pestic.Biochem.Physiol_122_81
PubMedID: 26071811

Title : Preventive effect of Lee on activated carbon-induced constipation in mice - Qian_2015_Exp.Ther.Med_9_272
Author(s) : Qian Y , Suo H , Du M , Zhao X , Li J , Li GJ , Song JL , Liu Z
Ref : Exp Ther Med , 9 :272 , 2015
Abstract : The aim of this study was to investigate the effects of Lactobacillus fermentum Lee (LF-Lee) on activated carbon-induced constipation in ICR mice. ICR mice were orally administered lactic acid bacteria for nine days. Body weight, dietary and water intake, defecation status, gastrointestinal (GI) transit and defecation time, as well as levels of motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) in serum were measured to evaluate the preventive effects of LF-Lee on constipation. Bisacodyl, a laxative drug, was administered as a positive control. The time taken until the first defecation of a black stool for normal, control, bisacodyl- (100 mg/kg, oral administration), Lactobacillus bulgaricus (LB)-, LF-Lee low dose (L)- and LF-Lee high dose (H)-treated mice was 90, 218, 117, 180, 161 and 151 min, respectively. Following the consumption of LB, LF-Lee (L) or LF-Lee (H), or the oral administration of bisacodyl, the GI transit was reduced to 55.2, 65.8, 73.1 and 94.6%, respectively, of the transit in normal mice. The serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and those of SS were reduced in the mice treated with LF-Lee compared with those in the untreated control mice (P<0.05). These results demonstrate that lactic acid bacteria have preventive effects on constipation in mice and that LF-Lee has superior functional activity.
ESTHER : Qian_2015_Exp.Ther.Med_9_272
PubMedSearch : Qian_2015_Exp.Ther.Med_9_272
PubMedID: 25452815

Title : Therapeutic Effect of Activated Carbon-Induced Constipation Mice with Lactobacillus fermentum Suo on Treatment - Suo_2014_Int.J.Mol.Sci_15_21875
Author(s) : Suo H , Zhao X , Qian Y , Li G , Liu Z , Xie J , Li J
Ref : Int J Mol Sci , 15 :21875 , 2014
Abstract : The aim of this study was to investigate the effects of Lactobacillus fermentum Suo (LF-Suo) on activated carbon-induced constipation in ICR (Institute of Cancer Research) mice. ICR mice were orally administered with lactic acid bacteria for 9 days. Body weight, diet intake, drinking amount, defecation status, gastrointestinal transit and defecation time, and the serum levels of MTL (motilin), Gas (gastrin), ET (endothelin), SS (somatostatin), AChE (acetylcholinesterase), SP (substance P), VIP (vasoactive intestinal peptide) were used to evaluate the preventive effects of LF-Suo on constipation. Bisacodyl, a laxative drug, was used as a positive control. The normal, control, 100 mg/kg bisacodyl treatment, LB (Lactobacillus bulgaricus)-, LF-Suo (L)- and LF-Suo (H)-treated mice showed the time to the first black stool defecation at 90, 218, 117, 180, 155 and 137 min, respectively. By the oral administration of LB-, LF-Suo (L), LF-Suo (H) or bisacodyl (100 mg/kg), the gastrointestinal transit was reduced to 55.2%, 72.3%, 85.5% and 94.6%, respectively, of the transit in normal mice, respectively. In contrast to the control mice, the serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and the serum levels of SS were reduced in the mice treated with LF-Suo (p < 0.05). By the RT-PCR (reverse transcription-polymerase chain reaction) and western blot assays, LF-Suo increased the c-Kit, SCF (stem cell factor), GDNF (glial cell line-derived neurotrophic factor) and decreased TRPV1 (transient receptor potential vanilloid 1), NOS (nitric oxide synthase) expressions of small intestine tissue in mice. These results demonstrate that lactic acid bacteria has preventive effects on mouse constipation and LF-Suo demonstrated the best functional activity.
ESTHER : Suo_2014_Int.J.Mol.Sci_15_21875
PubMedSearch : Suo_2014_Int.J.Mol.Sci_15_21875
PubMedID: 25464378

Title : The combined toxicity assessment of carp (Cyprinus carpio) acetylcholinesterase activity by binary mixtures of chlorpyrifos and four other insecticides - Chen_2014_Ecotoxicology_23_221
Author(s) : Chen C , Wang Y , Zhao X , Wang Q , Qian Y
Ref : Ecotoxicology , 23 :221 , 2014
Abstract : Mixtures of organophosphate (OP) and carbamate (CB) insecticides are commonly detected in freshwater habitats. These insecticides inhibit the activity of acetylcholinesterase (AChE) and have potential to interfere with behaviors that may be essential for survival of species. Although the effects of individual anticholinesterase insecticides on aquatic species have been studied for decades, the combined toxicity of mixtures is still poorly understood. In the present study, we assessed whether pesticides in a mixture act in isolation (resulting in additive AChE inhibition) or whether components interact to produce either antagonistic or synergistic toxicity. Brain AChE inhibition in carp (Cyprinus carpio L.) exposed to a series of concentrations of the OP (chlorpyrifos, malathion and triazophos) as well as the CB (fenobucarb and carbosulfan) were measured. The concentration addition (CA) model and the isobole method were used to determine whether toxicological responses to binary mixtures of pesticides. In 50:50 % effect mixtures, the observed combined toxicity of chlorpyrifos and malathion was significantly higher than observed and was considered as synergistic. For equivalent dose mixtures, when chlorpyrifos mixed with fenobucarb or malathion, the observed toxicities were significantly higher than predicted, suggesting synergistic joint actions. The rest five binary combinations exhibited concentration additive or slight antagonistic joint actions. The CA model and the isobole method provided estimates of mixture toxicity that did not markedly underestimate the measured toxicity, therefore these methods are suitable to use in ecological risk assessments of pesticide mixtures.
ESTHER : Chen_2014_Ecotoxicology_23_221
PubMedSearch : Chen_2014_Ecotoxicology_23_221
PubMedID: 24363216

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

Title : Preventive effect of resistant starch on activated carbon-induced constipation in mice - Qian_2013_Exp.Ther.Med_6_228
Author(s) : Qian Y , Zhao X , Kan J
Ref : Exp Ther Med , 6 :228 , 2013
Abstract : The aim of this study was to investigate the effects of resistant starch (RS) on activated carbon-induced constipation in ICR mice. ICR mice were fed on diet containing 15% RS of type RS2, RS3 or RS4 for 9 days. Gastrointestinal transit, defecation time and intestinal tissue histopathological sections, as well as motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) levels in serum were used to evaluate the preventive effects of RS on constipation. Bisacodyl, a laxative drug, was used as a positive control. The time to the first black stool defecation for normal, control, bisacodyl-treated (100 mg/kg, oral administration) and RS2-, RS3- and RS4-treated mice was 78, 208, 109, 181, 144 and 173 min, respectively. Following the consumption of RS2, RS3 and RS4 or the oral administration of bisacodyl (100 mg/kg), the gastrointestinal transit was reduced to 37.7, 52.1, 39.3 and 87.3%, respectively, of the transit in normal mice, respectively. Histopathological sections of intestinal tissue also underscored the protective effect of RS3. The serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and the serum levels of SS were reduced in the mice treated with RS compared with those in the untreated control mice (P<0.05). These results demonstrate that RS has preventive effects on mouse constipation and RS3 demonstrated the best functional activity.
ESTHER : Qian_2013_Exp.Ther.Med_6_228
PubMedSearch : Qian_2013_Exp.Ther.Med_6_228
PubMedID: 23935751

Title : Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of beta-amyloid and ibotenic acid into the bilateral hippocampus - Feng_2012_Int.J.Pharm_423_226
Author(s) : Feng C , Zhang C , Shao X , Liu Q , Qian Y , Feng L , Chen J , Zha Y , Zhang Q , Jiang X
Ref : Int J Pharm , 423 :226 , 2012
Abstract : Basic fibroblast growth factor (bFGF) delivery to the brain of animals appears to be an emerging potential therapeutic approach to neurodegenerative diseases, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracerebroventricular infusion. A nasal spray of bFGF had been developed previously and the objective of the present study was to investigate whether bFGF nasal spray could enhance brain uptake of bFGF and ameliorate memory impairment induced by co-injection of beta-amyloid(25-35) and ibotenic acid into bilateral hippocampus of rats. The results of brain uptake study showed that the AUC(0-12h) of bFGF nasal spray in olfactory bulb, cerebrum, cerebellum and hippocampus was respectively 2.47, 2.38, 2.56 and 2.19 times that of intravenous bFGF solution, and 1.11, 1.95, 1.40 and 1.93 times that of intranasal bFGF solution, indicating that intranasal administration of bFGF nasal spray was an effective means of delivering bFGF to the brain, especially to cerebrum and hippocampus. In Morris water maze tasks, intravenous administration of bFGF solution at high dose (40 mug/kg) showed little improvement on spatial memory impairment. In contrast, bFGF solution of the same dose following intranasal administration could significantly ameliorate spatial memory impairment. bFGF nasal spray obviously improved spatial memory impairment even at a dose half (20 mug/kg) of bFGF solution, recovered their acetylcholinesterase and choline acetyltransferase activity to the sham control level, and alleviated neuronal degeneration in rat hippocampus, indicating neuroprotective effects on the central nerve system. In a word, bFGF nasal spray may be a new formulation of great potential for treating AD.
ESTHER : Feng_2012_Int.J.Pharm_423_226
PubMedSearch : Feng_2012_Int.J.Pharm_423_226
PubMedID: 22193058

Title : Activity-based proteome profiling of hepatoma cells during hepatitis C virus replication using protease substrate probes - Blais_2010_J.Proteome.Res_9_912
Author(s) : Blais DR , Brulotte M , Qian Y , Belanger S , Yao SQ , Pezacki JP
Ref : J Proteome Res , 9 :912 , 2010
Abstract : Activity-based protein profiling (ABPP) offers direct insight into changes in catalytic activity of enzyme classes in complex proteomes, rather than protein or transcript abundance. Here, ABPP was performed in Huh7 hepatoma cell lines with a group of ABPP probes composed of an N-acetylated amino acid, that mimic the P(1) position in protease peptide substrates. Five different probes bearing distinct amino acids (Ser, Thr, Phe, Glu and His) labeled 54 differentially active proteins, including proteases, other hydrolases, oxidoreductases and isomerases. Four of the six protease families were targeted based on their P(1) substrate preferences. The broader specificity of the labeling observed could be explained by the substrate-based targeting nature and the electrophilic properties of the ABPP probes. When applied to Huh7 cells stably replicating hepatitis C virus (HCV) subgenomic replicon RNA, four proteins showed reduced activity, while three proteins had increased activity during HCV replication. These differentially active hits included carboxylesterase 1, cathepsin D, HSP105, protein disulfide isomerase 1 and A6, chaperonin containing TCP1 and isochorismatase domain containing 1, which demonstrated substrate preferences by being labeled by specific substrate probes. This illustrates the broader activity-based profiling capabilities of these substrate-based probes to reveal novel enzyme candidates and their potential roles during HCV replication.
ESTHER : Blais_2010_J.Proteome.Res_9_912
PubMedSearch : Blais_2010_J.Proteome.Res_9_912
PubMedID: 19954226

Title : Organophosphorus pesticide residues in milled rice (Oryza sativa) on the Chinese market and dietary risk assessment - Chen_2009_Food.Addit.Contam.Part.A.Chem.Anal.Control.Expo.Risk.Assess_26_340
Author(s) : Chen C , Li Y , Chen M , Chen Z , Qian Y
Ref : Food Additives & Contaminants Part A Chem Anal Control Expo Risk Assess , 26 :340 , 2009
Abstract : The present study investigates the occurrence of acetylcholinesterase (AChE)-inhibiting organophosphorus (OP) pesticide residues in milled rice samples obtained form local markets in China during the period 2004-2006 and estimates their cumulative exposure. Concentrations of OP pesticides were determined by gas chromatography with flame photometric detection (GC-FPD). The results showed that 9.3% of the samples contained detectable residues of at least one of the seven target OP pesticides (chlorpyrifos, dichlorvos, omethoate, methamidophos, parathion-methyl, parathion and triazophos) mainly used for agriculture in China, with concentrations ranging 0.011-1.756 mg kg(-1). Rice consumption data was obtained from an individual food consumption survey. Relative potency factors (RPFs) for each pesticide were calculated with methamidophos as the index compound (IC), using 1- or 2-year chronic non-observed adverse effect levels (NOAEL) for AChE inhibition, mostly in rat brain, obtained from international evaluations of pesticides. Exposure to AChE-inhibiting pesticides for the population above 7 years old at P99.9 represented 52-94.5% of the acceptable daily intake (ADI) expressed as methamidophos. Estimated exposure for children aged 2-4 and 4-7 years at P99.9 were 119 and 104.3% of the ADI level, respectively. This study suggests that a yearly monitoring program for OP pesticide residues and strict implementation of the national safety standard for milled rice is necessary.
ESTHER : Chen_2009_Food.Addit.Contam.Part.A.Chem.Anal.Control.Expo.Risk.Assess_26_340
PubMedSearch : Chen_2009_Food.Addit.Contam.Part.A.Chem.Anal.Control.Expo.Risk.Assess_26_340
PubMedID: 19680907

Title : Comparison of acute neurobehavioral and cholinesterase inhibitory effects of N-methylcarbamates in rat - McDaniel_2007_Toxicol.Sci_98_552
Author(s) : McDaniel KL , Padilla S , Marshall RS , Phillips PM , Podhorniak L , Qian Y , Moser VC
Ref : Toxicol Sci , 98 :552 , 2007
Abstract : While the cholinesterase-inhibiting N-methyl carbamate pesticides have been widely used, there are few studies evaluating direct functional and biochemical consequences of exposure. In the present study of the acute toxicity of seven N-methyl carbamate pesticides, we evaluated the dose-response profiles of cholinesterase (ChE) inhibition in brain and erythrocytes (RBCs) as well as motor activity (both horizontally and vertically directed) and clinical signs of overt toxicity. The chemicals tested were carbaryl, carbofuran, formetanate, methiocarb, methomyl, oxamyl, and propoxur. All were administered orally, and rats were tested in 20-min activity sessions beginning 15 min after dosing; tissues were collected immediately after activity sessions. In general, motor activity was a sensitive measure of ChE inhibition for all these carbamate pesticides, and vertical activity showed the greatest magnitude of effect at the highest doses compared to either horizontal activity or ChE inhibition. Brain and RBC ChE activities were generally affected similarly. Pearson correlation coefficients of within-subject data showed good correlation between the behavioral and biochemical end points, with brain ChE inhibition and horizontal activity showing the highest correlation values. Determination of benchmark dose levels for 10% change in each end point also revealed that these two measures produced the lowest estimates. Thus, motor activity decreases are highly predictive of ChE inhibition for N-methyl carbamates, and vice versa.
ESTHER : McDaniel_2007_Toxicol.Sci_98_552
PubMedSearch : McDaniel_2007_Toxicol.Sci_98_552
PubMedID: 17504769

Title : Regulation of lipoprotein lipase expression by effect of hawthorn flavonoids on peroxisome proliferator response element pathway - Fan_2006_J.Pharmacol.Sci_100_51
Author(s) : Fan C , Yan J , Qian Y , Wo X , Gao L
Ref : J Pharmacol Sci , 100 :51 , 2006
Abstract : To investigate the possibility that natural medicines affect lipid metabolism by regulating lipoprotein lipase (LPL) expression, a green fluorescent protein (GFP) gene was constructed downstream of the peroxisome proliferator response element (PPRE) and the constructed plasmid was microinjected into Xenopus oocytes to establish a PPRE regulatory reporter system. Using this system, hawthorn flavonoids were quickly selected from a panel of natural medicines and found to up-regulate GFP expression by an effect on PPRE. To confirm the effect of hawthorn flavonoids, we treated mice orally with water (control), hawthorn flavonoids, and pioglitazone and measured the LPL levels in serum, adipose tissue, and muscle by an enzyme-linked immunosorbent assay. The serum LPL levels were no different from the controls after treatment with either hawthorn flavonoids or pioglitazone, but LPL increased significantly in muscular tissues and decreased in adipose tissues. These results demonstrate that hawthorn flavonoids meditate LPL expression in mice with tissue-specific differences. A novel PPRE regulatory report system was established for rapid and effective selection and evaluation of LPL-mediating drugs.
ESTHER : Fan_2006_J.Pharmacol.Sci_100_51
PubMedSearch : Fan_2006_J.Pharmacol.Sci_100_51
PubMedID: 16404131

Title : Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10) - Jerng_2004_Biophys.J_87_2380
Author(s) : Jerng HH , Qian Y , Pfaffinger PJ
Ref : Biophysical Journal , 87 :2380 , 2004
Abstract : The dipeptidyl aminopeptidase-like protein DPPX (DPP6) associates with Kv4 potassium channels, increasing surface trafficking and reconstituting native neuronal ISA-like properties. Dipeptidyl peptidase 10 (DPP10) shares with DPP6 a high amino acid identity, lack of enzymatic activity, and expression predominantly in the brain. We used a two-electrode voltage-clamp and oocyte expression system to determine if DPP10 also interacts with Kv4 channels and modulates their expression and function. Kv4.2 coimmunoprecipitated with HA/DPP10 from extracts of oocytes heterologously expressing both proteins. Coexpression with DPP10 and HA/DPP10 enhanced Kv4.2 current by approximately fivefold without increasing protein level. DPP10 also remodeled Kv4.2 kinetic and steady-state properties by accelerating time courses of inactivation and recovery (taurec: WT = 200 ms, +DPP10 = 78 ms). Furthermore, DPP10 introduced hyperpolarizing shifts in the conductance-voltage relationship (approximately 19 mV) as well as steady-state inactivation (approximately 7 mV). The effects of DPP10 on Kv4.1 were similar to Kv4.2; however, distinct biophysical differences were observed. Additional experiments suggested that the cytoplasmic N-terminal domain of DPP10 determines the acceleration of inactivation. In summary, DPP10 is a potent modulator of Kv4 expression and biophysical properties and may be a critical component of somatodendritic ISA channels in the brain.
ESTHER : Jerng_2004_Biophys.J_87_2380
PubMedSearch : Jerng_2004_Biophys.J_87_2380
PubMedID: 15454437
Gene_locus related to this paper: human-DPP6 , human-DPP10

Title : Genome sequence of Streptococcus mutans UA159, a cariogenic dental pathogen - Ajdic_2002_Proc.Natl.Acad.Sci.U.S.A_99_14434
Author(s) : Ajdic D , McShan WM , McLaughlin RE , Savic G , Chang J , Carson MB , Primeaux C , Tian R , Kenton S , Jia H , Lin S , Qian Y , Li S , Zhu H , Najar F , Lai H , White J , Roe BA , Ferretti JJ
Ref : Proceedings of the National Academy of Sciences of the United States of America , 99 :14434 , 2002
Abstract : Streptococcus mutans is the leading cause of dental caries (tooth decay) worldwide and is considered to be the most cariogenic of all of the oral streptococci. The genome of S. mutans UA159, a serotype c strain, has been completely sequenced and is composed of 2,030,936 base pairs. It contains 1,963 ORFs, 63% of which have been assigned putative functions. The genome analysis provides further insight into how S. mutans has adapted to surviving the oral environment through resource acquisition, defense against host factors, and use of gene products that maintain its niche against microbial competitors. S. mutans metabolizes a wide variety of carbohydrates via nonoxidative pathways, and all of these pathways have been identified, along with the associated transport systems whose genes account for almost 15% of the genome. Virulence genes associated with extracellular adherent glucan production, adhesins, acid tolerance, proteases, and putative hemolysins have been identified. Strain UA159 is naturally competent and contains all of the genes essential for competence and quorum sensing. Mobile genetic elements in the form of IS elements and transposons are prominent in the genome and include a previously uncharacterized conjugative transposon and a composite transposon containing genes for the synthesis of antibiotics of the gramicidin/bacitracin family; however, no bacteriophage genomes are present.
ESTHER : Ajdic_2002_Proc.Natl.Acad.Sci.U.S.A_99_14434
PubMedSearch : Ajdic_2002_Proc.Natl.Acad.Sci.U.S.A_99_14434
PubMedID: 12397186
Gene_locus related to this paper: strmu-BACT , strmu-BGLB , strmu-GBPD , strmu-pepx , strmu-SMU.118C , strmu-SMU.178 , strmu-SMU.633 , strmu-SMU.643 , strmu-SMU.737 , strmu-SMU.1028 , strmu-SMU.1071C , strmu-SMU.1280C , strmu-SMU.1314 , strmu-SMU.1319C , strmu-SMU.1337C , strmu-SMU.1393C , strmu-SMU.1443C , strmu-SMU.1482C , strmu-SMU.1678

Title : The sorption behavior of complex pollution system composed of aldicarb and surfactant--SDBS - Dai_2001_Water.Res_35_2286
Author(s) : Dai S , Liu G , Qian Y , Cheng X
Ref : Water Res , 35 :2286 , 2001
Abstract : The behavior of complex pollution system in soil composed of aldicarb, a carbamate pesticide, and sodium dodecylbenzenesulfonate (SDBS), an anionic surfactant, was studied by the experiment of shaking sorption balance. The range of concentration of aldicarb and SDBS was 0.4-5.0 and 1-1000 mg/kg of dried soil, respectively. Linear sorption isotherm was well fitted for these two chemicals. SDBS can decrease the sorption of aldicarb in soil remarkably. While the concentration of SDBS increased from 0 to 1000 mg/kg, the linear sorption coefficient can be decreased by 50%. But aldicarb showed no effect on the sorption of SDBS in experiment. In addition the mechanism of the effect of SDBS on sorption of aldicarb was discussed.
ESTHER : Dai_2001_Water.Res_35_2286
PubMedSearch : Dai_2001_Water.Res_35_2286
PubMedID: 11358309

Title : Complete genome sequence of an M1 strain of Streptococcus pyogenes - Ferretti_2001_Proc.Natl.Acad.Sci.U.S.A_98_4658
Author(s) : Ferretti JJ , McShan WM , Ajdic D , Savic DJ , Savic G , Lyon K , Primeaux C , Sezate S , Suvorov AN , Kenton S , Lai HS , Lin SP , Qian Y , Jia HG , Najar FZ , Ren Q , Zhu H , Song L , White J , Yuan X , Clifton SW , Roe BA , McLaughlin R
Ref : Proc Natl Acad Sci U S A , 98 :4658 , 2001
Abstract : The 1,852,442-bp sequence of an M1 strain of Streptococcus pyogenes, a Gram-positive pathogen, has been determined and contains 1,752 predicted protein-encoding genes. Approximately one-third of these genes have no identifiable function, with the remainder falling into previously characterized categories of known microbial function. Consistent with the observation that S. pyogenes is responsible for a wider variety of human disease than any other bacterial species, more than 40 putative virulence-associated genes have been identified. Additional genes have been identified that encode proteins likely associated with microbial "molecular mimicry" of host characteristics and involved in rheumatic fever or acute glomerulonephritis. The complete or partial sequence of four different bacteriophage genomes is also present, with each containing genes for one or more previously undiscovered superantigen-like proteins. These prophage-associated genes encode at least six potential virulence factors, emphasizing the importance of bacteriophages in horizontal gene transfer and a possible mechanism for generating new strains with increased pathogenic potential.
ESTHER : Ferretti_2001_Proc.Natl.Acad.Sci.U.S.A_98_4658
PubMedSearch : Ferretti_2001_Proc.Natl.Acad.Sci.U.S.A_98_4658
PubMedID: 11296296
Gene_locus related to this paper: strpy-ESTA , strpy-PEPXP , strpy-Q8K5W4 , strpy-SPY1308 , strpy-SPYM18.1727

Title : The DNA sequence of human chromosome 22 - Dunham_1999_Nature_402_489
Author(s) : Dunham I , Hunt AR , Collins JE , Bruskiewich R , Beare DM , Clamp M , Smink LJ , Ainscough R , Almeida JP , Babbage AK , Bagguley C , Bailey J , Barlow KF , Bates KN , Beasley OP , Bird CP , Blakey SE , Bridgeman AM , Buck D , Burgess J , Burrill WD , Burton J , Carder C , Carter NP , Chen Y , Clark G , Clegg SM , Cobley VE , Cole CG , Collier RE , Connor R , Conroy D , Corby NR , Coville GJ , Cox AV , Davis J , Dawson E , Dhami PD , Dockree C , Dodsworth SJ , Durbin RM , Ellington AG , Evans KL , Fey JM , Fleming K , French L , Garner AA , Gilbert JGR , Goward ME , Grafham DV , Griffiths MND , Hall C , Hall RE , Hall-Tamlyn G , Heathcott RW , Ho S , Holmes S , Hunt SE , Jones MC , Kershaw J , Kimberley AM , King A , Laird GK , Langford CF , Leversha MA , Lloyd C , Lloyd DM , Martyn ID , Mashreghi-Mohammadi M , Matthews LH , Mccann OT , Mcclay J , Mclaren S , McMurray AA , Milne SA , Mortimore BJ , Odell CN , Pavitt R , Pearce AV , Pearson D , Phillimore BJCT , Phillips SH , Plumb RW , Ramsay H , Ramsey Y , Rogers L , Ross MT , Scott CE , Sehra HK , Skuce CD , Smalley S , Smith ML , Soderlund C , Spragon L , Steward CA , Sulston JE , Swann RM , Vaudin M , Wall M , Wallis JM , Whiteley MN , Willey DL , Williams L , Williams SA , Williamson H , Wilmer TE , Wilming L , Wright CL , Hubbard T , Bentley DR , Beck S , Rogers J , Shimizu N , Minoshima S , Kawasaki K , Sasaki T , Asakawa S , Kudoh J , Shintani A , Shibuya K , Yoshizaki Y , Aoki N , Mitsuyama S , Roe BA , Chen F , Chu L , Crabtree J , Deschamps S , Do A , Do T , Dorman A , Fang F , Fu Y , Hu P , Hua A , Kenton S , Lai H , Lao HI , Lewis J , Lewis S , Lin S-P , Loh P , Malaj E , Nguyen T , Pan H , Phan S , Qi S , Qian Y , Ray L , Ren Q , Shaull S , Sloan D , Song L , Wang Q , Wang Y , Wang Z , White J , Willingham D , Wu H , Yao Z , Zhan M , Zhang G , Chissoe S , Murray J , Miller N , Minx P , Fulton R , Johnson D , Bemis G , Bentley D , Bradshaw H , Bourne S , Cordes M , Du Z , Fulton L , Goela D , Graves T , Hawkins J , Hinds K , Kemp K , Latreille P , Layman D , Ozersky P , Rohlfing T , Scheet P , Walker C , Wamsley A , Wohldmann P , Pepin K , Nelson J , Korf I , Bedell JA , Hillier L , Mardis E , Waterston R , Wilson R , Emanuel BS , Shaikh T , Kurahashi H , Saitta S , Budarf ML , McDermid HE , Johnson A , Wong ACC , Morrow BE , Edelmann L , Kim UJ , Shizuya H , Simon MI , Dumanski JP , Peyrard M , Kedra D , Seroussi E , Fransson I , Tapia I , Bruder CE , O'Brien KP
Ref : Nature , 402 :489 , 1999
Abstract : Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.
ESTHER : Dunham_1999_Nature_402_489
PubMedSearch : Dunham_1999_Nature_402_489
PubMedID: 10591208
Gene_locus related to this paper: human-CES5A , human-SERHL2