外泌体源性RNAs在中枢神经系统中的研究进展

外泌体是一种由细胞主动分泌到胞外的纳米级别囊泡,内含蛋白质、核酸、脂质等生物活性物质,与靶细胞接触后释放内容物,介导细胞间的信息交流。在中枢神经系统(CNS)中,神经细胞、神经胶质细胞、神经干细胞等细胞分泌的外泌体,负载miRNAs、mRNAs等多种核酸类活性物质,在转录后水平调控神经元的分化发育、突触的可塑性以及CNS疾病的形成与发展,如阿尔茨海默病、药物成瘾等。因外泌体源性RNAs具生物学活性及靶向特异性,不但是潜在的疾病诊断标志物,还可成为疾病新的治疗靶点。该文就外泌体的一般特性以及外泌体源性RNAs在中枢神经系统中的作用、变化与作用机制等进行阐述,旨在对中枢神经系统的分化发育及疾病的形成有新的认识。

Protective Effect of Silibinin on Lipopolysaccharide-Induced Endotoxemia by Inhibiting Caspase-11-Dependent Cell Pyroptosis

Objective:To explore the protective effect and the underlying mechanism of silibinin(SIB),one of the active compounds from Silybum marianum(L.)Gaertn in endotoxemia.Methods:Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium.Cell viability was assessed using the cell counting kit-8,while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay.The protein expressions of interleukin(IL)-1α,IL-1β,and IL-18 were determined by enzyme-linked immunosorbent assay.Intracellular lipopolysaccharide(LPS)levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry.Additionally,proximity ligation assay was employed for the LPS and caspase-11 interaction.Mice were divided into 4 groups:the control,LPS,high-dose-SIB(100 mg/kg),and low-dose-SIB(100 mg/kg)groups(n=8).Zebrafish were divided into 4 groups:the control,LPS,high-dose-SIB(200μmol/L),and low-dose-SIB(100μmol/L)groups(n=30 for survival experiment and n=10 for gene expression analysis).The expression of caspase-11,gasdermin D(GSDMD),and N-GSDMD was determined by Western blot and the expressions of caspy2,gsdmeb,and IL-1βwere detected using quantitative real-time PCR.Histopathological observation was performed through hematoxylineosin staining,and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay.Results:SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1α,IL-1β,and IL-18 induced by LPS(P<0.05).Moreover,SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS(P<0.05).SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD,inhibited the relative cytokines,prolonged the survival time,and up-regulated the survival rate in the endotoxemia models(P<0.05).Conclusions:SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model,at least in part,by inhibiting the caspase-11-mediated cleavage of GSDMD.Additionally,SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression,which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality.

Heat-Clearing Chinese Medicines in Lipopolysaccharide-Induced Inflammation

Lipopolysaccharide(LPS)-induced inflammation causes massive threatening diseases,such as sepsis,acute lung injury and multiple organ dysfunction syndrome.Efficient treatment to prevent inflammation is crucial in LPS-induced inflammatory diseases.Heat-clearing Chinese medicines(CMs)have been used to ameliorate LPS-induced inflammation in China for centuries.Heat-clearing CMs regulate inflammatory pathways,thereby inhibiting the release of inflammatory factors.This review aimed to introduce promising heat-clearing CMs countering LPS-induced inflammation in the last 5 years,exploring the underlying molecular mechanisms.

Antioxidant and Antiapoptotic Polyphenols from Green Tea Extract Ameliorate CCl4-Induced Acute Liver Injury in Mice

Objective To investigate the phenolic composition,antioxidant properties,and hepatoprotective mechanisms of polyphenols from green tea extract(GTP)in carbon tetrachloride(CCl4)-induced acute liver injury mouse model.Methods High-performance liquid chromatography was used to analyze the chemical composition of the extract.Antioxidant activity of GTP was assessed by O2∙-,OH∙,DPPH∙,and ferric-reducing antioxidant power(FRAP)assay in vitro.Sixty Kunming mice were divided into 6 groups including control,model,low-,medium-,and high-doses GTP(200,400,800 mg/kg)and vitamin E(250 mg/kg)groups,10 in each group.GTP and vitamin E were administered at a level of abovementioned doses twice per day for 7 days prior to exposure to a single injection of CCl4.Hepatoprotective effects of GTP were evaluated in a CCl4-induced mouse model of acute liver injury,using commercial enzyme linked immunosorbent assay kits,histopathological observation,terminal deoxynucleotidyl transferase-mediated dUTPNick-end labeling(TUNEL)assay and Western blot.Results GTP contained 98.56µg gallic acid equivalents per milligram extract total polyphenols,including epicatechingallate,epigallocatechin gallate,epicatechin,and epigallocatechin.Compared with the model group,low-,medium-,or high doses GTP significantly decreased serum levels of alanine aminotransferase and aspartate transaminase(P<0.01).Histopathological observation confirmed that pretreatment of GTP prevented swelling and necrosis in CCl4-exposed hepatocytes.Hepatoprotective effects of low-,medium-,and high-dose GTP were associated with eliminating free radicals and improving superoxide dismutase,catalase,and glutathione peroxidase activity in the liver.Additionally,low-,medium-,and high-dose GTP decreased cell apoptosis in the CCl4-exposed liver(P<0.01).Phosphorylated nuclear factor kappa-B(NF-κB),p53,Bcl-2 associated x protein/B-cell lymphoma/leukemia-2 gene,cytochrome C,and cleaved caspase-3 levels were downregulated compared with the model group(P<0.01).Conclusion GTP achieves hepatoprotective effects by improving hepatic antioxidant status and preventing cell apoptosis through caspase-3-dependent signaling pathways.