【摘 要】
：
Acute liver failure(ALF)is a fatal clinical syndrome with no special drug.Recent evidence shows that modulation of macrophage to inhibit inflammation may be a promising strategy for ALF treatment.In this study we investigated the potential therapeutic eff
【机 构】
：
Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease,Xiangya Hospital,Centra
论文部分内容阅读
Acute liver failure(ALF)is a fatal clinical syndrome with no special drug.Recent evidence shows that modulation of macrophage to inhibit inflammation may be a promising strategy for ALF treatment.In this study we investigated the potential therapeutic effects of melittin,a major peptide component of bee venom both in mice model of ALF and in LPS-stimulated macrophages in vitro,and elucidated the underlying mechanisms.ALF was induced in mice by intraperitoneal injection of D-galactosamine/LPS.Then the mice were treated with melittin(2,4,and 8 mg/kg,ip).We showed that melittin treatment markedly improved mortality,attenuated severe symptoms and signs,and alleviated hepatic inflammation in D-galactosamine/LPS-induced ALF mice with the optimal dose being 4 mg/kg.In addition,melittin within the effective doses did not cause significant in vivo toxicity.In LPS-stimulated RAW264.7 macrophages,melittin(0.7 μM)exerted anti-oxidation and anti-inflammation effects.We showed that LPS stimulation promoted aerobic glycolysis of macrophages through increasing glycolytic rate,upregulated the levels of Warburg effect-related enzymes and metabolites including lactate,LDHA,LDH,and GLUT-1,and activated Akt/mTOR/PKM2/HIF-1α signaling.Melittin treatment suppressed M2 isoform of pyruvate kinase(PKM2),thus disrupted the Warburg effect to alleviate inflammation.Molecular docking analysis confirmed that melittin targeted PKM2.In LPS-stimulated RAW264.7 macrophages,knockdown of PKM2 caused similar anti-inflammation effects as melittin did.In D-galactosamine/LPS-induced ALF mice,melittin treatment markedly decreased the expression levels of PKM2 and HIF-1α in liver.This work demonstrates that melittin inhibits macrophage activation-mediated inflammation via inhibition of aerobic glycolysis by targeting PKM2,which highlights a novel strategy of using melittin for ALF treatment.
其他文献
Herbs and dietary supplement-induced liver injury(HILI)is the leading cause of drug-induced liver injury in China.Among different hepatotoxic herbs,the pyrrolizidine alkaloid(PA)-producing herb Gynura japonica contributes significantly to HILI by inducing
Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival.As epithelial-mesenchymal transition (EMT) is well recognized as a major factor initiating tumor metastasis,developing EMT inhibitor could be a feasibl
Group Ⅰ metabotropic glutamate receptors(mGlu1 and mGlu5)are promising targets for multiple psychiatric and neurodegenerative disorders.Understanding the subtype selectivity of mGlu1 and mGlu5 allosteric sites is essential for the rational design of novel
Proteasome inhibitors,bortezomib(BTZ),and carfilzomib(CFZ)are approved drugs for hematological malignancies,but lack anticancer activities against most solid tumors.Small cell lung cancer(SCLC)is a very aggressive neuroendocrine carcinoma of the lungs dem
Aflibercept,as a soluble decoy vascular endothelial growth factor receptor,Which has been used as a first-line monotherapy for cancers.Aflibercept often causes cardiovascular toxicities including hypertension,but the mechanisms underlying aflibercept-indu
Hemorrhagic transformation(HT)is a common serious complication of stroke after thrombolysis treatment,which limits the clinical use of tissue plasminogen activator(t-PA).Since early diagnosis and treatment for HT is important to improve the prognosis of s
Oxidative stress is intimately tied to neurodegenerative diseases,including Parkinson\'s disease and amyotrophic lateral sclerosis,and acute injuries,such as ischemic stroke and traumatic brain injury.Acid sensing ion channel 1a(ASIC1a),a proton-gated i
目的 分析阜阳市首例人感染H5N6禽流感轻症患儿流行病学特征,为做好病例诊治及防控工作提供参考.方法 调查人感染H5N6禽流感患儿发病就诊情况、密切接触者、可疑禽类及活禽市场环境情况,采集患儿及其涉及的人群、活禽和环境标本并进行流感病毒检测,应用描述性流行病学方法进行分析.结果 阜阳市1例人感染H5N6禽流感患儿为流感常规监测发现,发病约10 h服用磷酸奥司他韦,约20 h症状消失,密切接触者无感染,可疑活禽摊位环境标本检测出现H5型禽流感病毒.结论 患儿有活禽市场环境暴露史,早发现早治疗,对减轻病情,提
Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain,but there is no selective Nav1.7 inhibitor available for therapy of chronic pain.Ralfinamide has shown an
目的 采用指数平滑法预测艾滋病新报告病例的趋势,为泸州市制定预防和控制艾滋病策略提供依据.方法 根据2018-2019年泸州市每月艾滋病新报告病例资料,使用指数平滑法构建预测模型,预测2020年上半年每月新报告病例,并对预测结果进行评价.结果 综合比较指数平滑法四种模型的判断指标,确定Holt线性趋势模型为最优预测模型,模型的拟合度较高,实际值均在预测值的95％置信区间内.2020年1～6月艾滋病新报告病例数和模型预测值的平均相对误差33.19％.结论 Holt线性趋势模型可较好地拟合泸州市艾滋病新报告病