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Expression of matrix metalloproteinase-11 is increased under conditions of insulin resistance

World Journal of Diabetes 2017年第9期8卷 422-428页

作者： Biagio Arcidiacono Eusebio Chiefari Anna Elisa Laria Sebastiano Messineo Francesco Luciano Bilotta Domenico Britti Daniela Patrizia Foti Anna Foryst-Ludwig Ulrich Kintscher Antonio Brunetti department of Health Sciences University"Magna Gr█cia"of Catanzaro Institute of phar-macology Center for Cardiovascular Research

AIM To investigate matrix metalloproteinase-11(MMP-11) expression in adipose tissue dysfunction, using in vitro and in vivo models of insulin *** Culture of mouse 3T3-L1 preadipocytes were induced to differentiation into mature 3T3-L1 adipocytes. Cellular insulin resistance was induced by treating differentiated cultured adipocytes with hypoxia and/or tumor necrosis factor(TNF)-α, and transcriptional changes were analyzed in each condition thereafter. For the in vivo studies, MMP-11 expression levels were measured in white adipose tissue(WAT) from C57BL/6J mice that underwent low fat diet or high-fat feeding in order to induce obesity and obesity-related insulin resistance. Statistical analysis was carried out with GraphP ad Prism *** MMP-11 m RNA expression levels were significantly higher in insulin resistant 3T3-L1 adipocytes compared to control cells(1.46±0.49vs0.83±0.21, respectively;P<0.00036). The increase in MMP-11 expression was observed even in the presence of TNF-α alone(3.79±1.11vs1±0.17, P<0.01) or hypoxia alone(1.79±0.7vs0.88±0.1, P<0.00023). The results obtained in in vitro experiments were confirmed in the in vivo model of insulin resistance. In particular, MMP-11 m RNA was upregulated in WAT from obese mice compared to lean mice(5.5±2.8vs1.1±0.7, respectively; P<3.72E-08). The increase in MMP-11 levels in obese mice was accompanied by the increase in typical markers of fibrosis, such as collagen type Ⅵ alpha 3(Col6_α3), and fibroblast-specific protein *** Our results indicate that dysregulation of MMP-11 expression is an early process in the adipose tissue dysfunction, which leads to obesity and obesity-related insulin resistance.

关键词： Metalloproteinase-11 Insulin resistance Type 2 diabetes Fibrosis Hypoxia Tumor necrosis factor-α Inflammation

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Flumazenil-insensitive benzodiazepine effects in vitro and in vivo

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中国药理学与毒理学杂志 2021年第9期35卷 692-693页

作者： WANG Na LIAN Jing-jing CAO Yan-qing YU Gang SU Rui-bin State Key Laboratory of Toxicology and Medical Countermeasures Beijing Key Laboratory of Neu-ropsychopharmacologyBeijing Institute of Phar-macology and ToxicologyBeijing 100850China

OBJECTIVE To identify benzodi⁃azepine(BZD)effects that are insensitive to the classical BZD binding site antagonist,*** the flumazenil-insensitive BZD effects have selectivity on different GABAA receptor sub⁃types was also *** The high-concentration effects of BZDs and their sensitivity to flumazenil were determined on recombi⁃nant synaptic(α1β2γ2,α2β2γ2,α5β2γ2)and extra-synaptic(α4β2δ)GABAA receptors using the voltage-clamp electrophysiology *** in vivo evaluation of flumazenil-insensitive BZD effects was conducted in mice loss of right reflex(LORR)*** Diazepam induced a biphasic potentiation for theα1β2γ2,α2β2γ2 andα5β2γ2 receptor channels,but did not affect theα4β2δ*** contrast to the nanomolar com⁃ponent of potentiation,the second potentiation elicited by micromolar diazepam was insensitive to ***,clonazepam,and loraz⁃epam at 200μmol·L-1 exhibited similar flumaze⁃nil-insensitive effects onα1β2γ2,α2β2γ2 andα5β2γ2 receptors,whereas the potentiation induced by 200μmol·L-1 zolpidem or triazolam was abol⁃ished by *** with the in vitro results,flumazenil antagonized the zolpidem(50 mg·kg-1)-induced LORR,but not those induced by 50 mg·kg-1 diazepam or 100 mg·kg-1 *** The existence of non-classical BZD binding sites on certain GABAA receptor subtypes and the flumazenil-insensitive effects depend on the chemical structures of the allosteric modulators.

关键词： GABAA receptor benzodiazepine non-classical binding sites flumazenil

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Antioxidants in liver health

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World Journal of Gastrointestinal pharmacology and Therapeutics 2015年第3期6卷 59-72页

作者： Sael Casas-Grajales Pablo Muriel department of phar-macology Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional

Liver diseases are a worldwide medical problem because the liver is the principal detoxifying organ and maintains metabolic homeostasis. The liver metabolizes various compounds that produce free radicals(FR).However, antioxidants scavenge FR and maintain the oxidative/antioxidative balance in the liver. When the liver oxidative/antioxidative balance is disrupted, the state is termed oxidative stress. Oxidative stress leadsto deleterious processes in the liver and produces liver diseases. Therefore, restoring antioxidants is essential to maintain homeostasis. One method of restoring antioxidants is to consume natural compounds with antioxidant capacity. The objective of this review is to provide information pertaining to various antioxidants found in food that have demonstrated utility in improving liver diseases.

关键词： Antioxidant Oxidative stress Naringenin Quercetin Curcumin Resveratrol Silymarin Coffee Liver diseases

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11＇-Deoxyverticillin A （C42） promotes autophagy through K-Ras/GSK3 signaling pathway in HCT116 cells

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Protein & Cell 2014年第12期5卷 945-949页

作者： Shubin Niu Dongdong Yuan Xuejun Jiang Yonashena Che State Key Laboratory of Mycology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 China State Key Laboratory of Toxicology Medical Countermeasures Beijing Institute of Pharmacology Toxicology Beijing 100850 China University of Chinese Academy of Sciences Beijing 100039 China Center for New Drug Evaluation Shandong Academy of Phar- macology Jinan 250101 China

Dear Editor Macroautophagy （hereafter referred to as autophagy） is a cellular adaptation to starvation, involving the vesicular sequestration of the long-lived cytoplasmic proteins and organelles such as mitochondria （Klionsky and Emr, 2000）. However, it also results in cell death when overacUvated （Edinger and Thompson, 2004）. Stresses which affect cel- lular homeostasis including changes in oxidation status, build-up of damaged organelles and misfolded proteins, and infection by pathogens, have also been shown to induce autophagy （Rabinowitz and White, 2010）. Besides, autoph- agy was found to be involved in cancer formation and pro- gression. Depending on tumor type, stage, and cellular context, autophagy can play either anti- or pro-tumorigenic roles （Mancias and Kimmelman, 2011）.

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Roles of 5-HT2 receptors in effects of DOM,ketamine and methamphetamine on prepulse inhibition in Sprague Dawley rats

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中国药理学与毒理学杂志 2021年第9期35卷 669-670页

作者： JIANG Kai-li LI Kai-xi LIU Xiao-yan SU Rui-bin State Key Laboratory of Toxicology and Medical Countermeasures Beijing Key Laboratory of Neu-ropsychopharmacologyBeijing Institute of Phar-macology and ToxicologyBeijing 100850China Key Laboratory of Xinjiang Phytomedicine Resource and Utilization Ministry of EducationDepartment of PharmacologyShihezi UniversityShihezi 832003China

OBJECTIVE Prepulse inhibition(PPI)of the acoustic startle response provides a measure of sensorimotor gating system mecha⁃nisms,which is known to be impaired in schizo⁃phrenia *** assessed the effects of the 5-HT2A/2C receptor agonist(±)2,5-dimethoxy-4-methylamphetamine(DOM),the NMDA receptor antagonist ketamine,the dopamine receptor ago⁃nist methamphetamine(Meth)on PPI and the startle magnitude in SD *** AND RESULTS Systemic administration of the three compounds all dose-dependently reduced ***,as far as startle magnitude,only DOM at the doses of 3 mg·kg-1 reduced that,while both ketamine and Meth did not change the startle ***,to determine whether 5-HT2A receptor mediate this effect,the non-spe⁃cific 5-HT2 receptor antagonist cyproheptadine,specific 5-HT2A receptor antagonist ketanserin and specific 5-HT2C receptor antagonist SB242084 were ***,ketan⁃serin and SB242084 did not alter startle ampli⁃tude by themselves in SD rats and only ketanserin slightly increased PPI at higher dose(3 mg·kg-1).PPI impairment induced by DOM was restored by pretreatment of cyproheptadine(1 mg·kg-1)and ketanserin(1 mg·kg-1),while not by pretreat⁃ment of SB242084(1 mg·kg-1).Damage of PPI induced by ketamine and Meth was not reversed by cyproheptadine(1 and 5 mg·kg-1).CONCLU⁃SION The receptor mechanisms underlying the disruption of PPI caused by DOM,ketamine and Meth were different from each other,at least 5-HT2A receptor was not the junction receptor for which the three chemicals acted.

关键词： prepulse inhibition 5-HT2 receptor startle magnitude psychoactive substances

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Effects and mechanisms of Cryptotanshinone on rats with adjuvant arthritis

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Chinese Medical Journal 2011年第24期124卷 4293-4298页

作者： ZHENG Fu-lin CHANG Yan JIA Xiao-yi HUANG Min WEI Wei department of phar-macology Medical College Anhui Universityof Science and Technology Huainan Anhui 232001 China Institute of Clinical pharmacology Anhui Medical UniversityHefei Anhui 230032 China School of pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou Guangdong 510006 China

Background Cryptotanshinone （CT） is the major active constituent of Salvia miltiorrhiza Bunge. The present study was carried out to investigate the effects of CT on rats with adjuvant arthritis （AA）. Methods AA was induced by the metatarsal footpad injection with complete Freund＇s adjuvant in male Sprague-Dawley rats. The secondary inflammatory reaction was evaluated by hind paw swelling and the polyarthritis index. Activity of interleukin-1 （IL-1） was detected by the concanavalin A-induced thymocytes proliferation assay. The lymphocytes proliferation and IL-2 production were assayed by 3-（4,5-2dimethylthiazal-2yl）2,5-diphenyltetrazoliumbromide （MTT） and activated mouse splenocytes proliferation, respectively. Results Intragastric administration of CT （50 and 100 mg/kg） significantly decreased secondary inflammatory reactions and increased the spleen and thymus index. There was a marked immunologic and inflammatory response in the AA model, which was accompanied by the decrease of thymocyte proliferation and IL-2 production as well as the increase of IL-1 production. CT apparently enhanced thymocyte proliferation and decreased IL-1 production in AA rats. Conclusion These results indicate that CT may exert its anti-inflammatory and immunoregulatory effects through inhibiting lymphocyte proliferation and production of pro-inflammatory mediators.

关键词： cryptotanshinone adjuvant arthritis lymphocyte proliferation cytokine

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Can Na+/K+ATPase be a novel target to treat anxiety?A hint from its regulatory effect on neuroinflammation

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中国药理学与毒理学杂志 2021年第9期35卷 664-665页

作者： HUANG Song-qiang ZHU Meng-yuan LI Shan-shan NIE Xiao-wei BIAN Jin-song department of pharmacology School of Medi-cineSouthern University of Science and TechnologyShenzhen 518055China department of phar-macology Yong Loo Lin School of MedicineNational University of Singapore117600Singapore Shenzhen Institute of Respiratory Diseases the First Affiliated Hospital(Shenzhen People′s Hospi-tal)Southern University of Science and Technolo-gyShenzhen 518020China

OBJECTIVE Na+/K+-ATPase(NKA)is large membrane protein expressed uni⁃versally which is indispensable for the mainte⁃nance of ionic gradient as well as neuronal excit⁃*** role of NKA in inflammatory regula⁃tion is still *** responses are initiated upon the activation of *** order to investigate the crosslink between NKA and inflammasome,NKAα1 knockout(KO)N2a cells were generated using CRISPR/Cas9 *** AND RESULTS qPCR results showed that NLRP1 and NLRP3 were upregulated in response to NKAα1 loss while both NLRC4 and AIM2 remained ***,consistent with the change in NLRP1 and NLRP3,both the mRNA level of ASC and IL-1βwere significantly increased in NKAα1 KO *** data indicated that NKAα1 interfer⁃ence might influence the level of NLRP1 and NLRP3 inflammasomes in neuronal *** evidence indicating the potential link between NKA and inflammasome pathway were provided using cytokine array assay where all the differen⁃tiated protein detected were closely linked to NLRP1 and *** confirm this effect,we also observed the transcriptional levels of inflam⁃masome proteins in the brain cortex from both NKAα1+/+and NKAα1+/-*** line with the observation gained in NKAα1 KO cells,the mRNA level of NLRP1,NLRP3 and IL-1βwere significantly upregulated in NKAα1+/-mice ***,in the primary cultured astrocytes,treatment with LPS/ATP significantly reduced the mRNA and protein levels of NKAα1 *** data imply that a negative regulation loop between NKAα1 and inflammation may exist in the central nervous *** neuroinflam⁃matory mechanism is currently considered the most potential of interventions to target anxiety,we therefore perform behavioural experiments to investigate the role of NKAα1 in *** restraint stress(CRS)for 10 d significantly reduced the time and frequency of entering the open arm and prolonged the retention time in the closed arm in the elevated p

关键词： Na+/K+ATPase anxiety inflamma⁃some neuroinflammation

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Effects of ethanol extract of Bombax ceiba leaves and its main constituent mangiferin on diabetic nephropathy in mice

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Chinese Journal of Natural Medicines 2017年第8期15卷 597-605页

作者： XU Guang-Kai SUN Chen-Yu QIN Xiao-Ying HAN Yu LI Yi XIE Guo-Yong Qin Min-Jian department of Resources Science of Traditional Chinese Medicines State Key Laboratory of Natural MedicinesChina Phar-maceutical UniversityNanjing 211198China department of pharmacology of Chinese Materia Medica China Pharmaceutical UniversityNanjing 211198China

The present study was designed to explore the mechanism by which ethanol extract of Bombax ceiba leaves(BCE) and its main constituent mangiferin(MGF) affect diabetic nephropathy by combating oxidative stress. Oral administration of BCE and MGF to normal and streptozotocin(STZ)-induced diabetic mice were carried out. Fasting blood glucose, 24-h urinary albumin, serum creatinine, and blood urea nitrogen were tested, histopathology, and immunohistochemical analysis of kidney tissues were performed. Moreover, mesangial cells were treated with BCE and MGF for 48 h with or without 25 mmol·L^(-1) of glucose. Immunofluorescence, Western blot and apoptosis analyses were used to investigate their regulation of oxidative stress and mitochondrial function. BCE and MGF ameliorated biochemical parameters and restored STZ-induced renal injury in the model mice. In vitro study showed that high glucose stimulation increased oxidative stress and cell apoptosis in mesangial cells. BCE and MGF limited mitochondrial membrane potential(Δψm) collapse by inhibiting Nox4, mitochondrially bound hexokinase II dissociation, and subsequent ROS production, which effectively reduced oxidative stress, cleaved caspase-3 expression and cell apoptosis. Our work indicated that BCE and MGF had protective effects on diabetic caused kidney injury and prevented oxidative stress in mesangial cells by regulation of hexokinase II binding and Nox4 oxidase signaling.

关键词： Bombax ceiba Mangiferin Diabetic neprropathy Mitochondrial function Oxidative stress

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Development of a Behavioral and Imaging Model of Feeding in Planarians

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pharmacology & pharmacy 2012年第3期3卷 364-367页

作者： Robert B. Raffa Christopher S. Tallarida Shan R. Patel Scott M. Rawls Evgeny Krynetskiy department of phar- macology Temple University School of Medicine and Center for Substance Abuse Research Temple University Philadelphia PA U.S.A. department of pharmaceutical Sciences Temple University School of Pharmacy Philadelphia PA U.S.A.

Excess weight is a major risk factor for type-2 diabetes, cardiovascular disease, and other comorbidities. Animal models of feeding provide insight into the problem and provide a means for the discovery and evaluation of pharmacotherapeutic treatment. Mammalian models are the most commonly used, but recently non-mammalian models have been utilized (e.g., C. elegans). Planarians provide an intermediate model. They are the earliest extant animal with a primitive brain-like structure and are a convenient model of mammalian behavioral endpoints and drug-induced effects. The purpose of the present study was to determine if a quantitative measure of presumptive feeding behavior could be visualized using an imaging technique. Colored food pellets were prepared and in some experiments, plasmid-delivered green fluorescent protein was added. Both visible and fluorescence microscopy displayed clear indication of internalization of the red dye and localization to the digestive system. This new methodology establishes a convenient way to study normal physiological feeding behavior as well as modifications induced by drugs or other exogenous substances.

关键词： Feeding Imaging Fluorescence GFP Planarians

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Effects of probiotic bacteria on gastrointestinal motility in guinea-pig isolated tissue

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World Journal of Gastroenterology 2006年第37期12卷 5987-5994页

作者： Matteo Massi Pierfranco Ioan Roberta Budriesi Alberto Chiarini Beatrice Vitali Karen M Lammers Paolo Gionchetti Massimo Campieri Anthony Lembo Patrizia Brigidi department of phar-maceutical Sciences University of Bologna Bologna Italy department of Internal Medicine and Gastroenterology University of Bologna Bologna Italy department of Medicine Division of Gastro- enterology Harvard Medical School Boston Massachusetts United States department of phar- maceutical Sciences University of Bologna Bologna Italy

AIM: To evaluate the intestinal motility changes evoked by 8 bacterial strains belonging to Bifidobacterium , Lactobacillus and Streptococcus genera within the probiotic preparation VSL#3. METHODS: Ileum and proximal colon segments isolated from guinea-pigs were used as a study model. Entire cells and cell fractions (cell debris, cell wall fraction, cytoplasmatic fraction, proteinaceous and non- proteinaceous cytoplasmatic components) of VSL#3 strains and, as controls, Escherichia coli, Salmonella aboni and Bacillus licheniformis were tested in this in vitro model. RESULTS: Among the bacterial cell fractions tested, only the cytoplasmatic fraction modified intestinal motility. Lactobacillus strains stimulated the contraction of ileum segment, whereas all probiotic strains tested induced proximal colon relaxation response. The non-proteinaceous cytoplasmatic components were responsible for the colon relaxation. CONCLUSION: The results obtained in this study suggest that the proximal colon relaxation activity showed by the probiotic bacteria could be one of the possible mechanisms of action by which probiotics exert their positive effects in regulating intestinal motility.

关键词： Probiotics Intestinal motility Guinea-pigs Ileum Colon

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