ABSTRACT
Hepatocytes has been confirmed to undergo EMT and can be converted into myofibroblasts during hepatic fibrogenesis. However, the mechanism of hepatocyte EMT regulation in hepatic fibrosis, particularly through HSP27 (human homologue of rodent HSP25), remains unclear. Mangiferin (MAN), a compound extracted from Mangifera indica L, has been reported to attenuate liver injury. This study aimed to investigate the mechanisms underlying HSP27 inhibition and the anti-fibrotic effect of MAN in liver fibrosis. Our results revealed that the expression of HSP27 was remarkably increased in the liver tissues of patients with liver cirrhosis and CCl4 -induced fibrotic rats. However, HSP27 shRNA treatment significantly alleviated fibrosis. Furthermore, MAN was found to inhibit CCl4 - and TGF-ß1-induced liver fibrosis and reduced hepatocyte EMT. More importantly, MAN decreased HSP27 expression to suppress the JAK2/STAT3 pathway, and subsequently blocked TGF-ß1/Smad signaling, which were consistent with its protection against CCl4 -induced EMT and liver fibrosis. Together, these results suggest that HSP27 may play a crucial role in hepatocyte EMT and liver fibrosis by activating JAK2/STAT3 signaling and TGF-ß1/Smad pathway. The suppression of HSP27 expression by MAN may be a novel strategy for attenuating the hepatocyte EMT in liver fibrosis.
Subject(s)
Epithelial-Mesenchymal Transition , Transforming Growth Factor beta1 , Animals , Humans , Rats , Fibrosis , Hepatocytes , HSP27 Heat-Shock Proteins/metabolism , Janus Kinase 2 , Liver Cirrhosis/drug therapy , STAT3 Transcription Factor/metabolism , Transforming Growth Factor beta1/metabolism , Smad Proteins/metabolismABSTRACT
Accumulating evidences suggest that inflammation-mediated neurons dysfunction participates in the initial and development of Parkinson's disease (PD), whereas mitochondria have been recently recognized as crucial regulators in NLRP3 inflammasome activation. Cordycepin, a major component of cordyceps militaris, has been shown to possess neuroprotective and anti-inflammatory activity. However, the effects of cordycepin in rotenone-induced PD models and the possible mechanisms are still not fully understood. Here, we observed that motor dysfunction and dopaminergic neurons loss induced by rotenone exposure were ameliorated by cordycepin. Cordycepin also reversed Drp1-mediated aberrant mitochondrial fragmentation through increasing AMPK phosphorylation and maintained normal mitochondrial morphology. Additionally, cordycepin effectively increased adenosine 5'-triphosphate (ATP) content, mitochondrial membrane potential (MMP), and reduced mitochondrial ROS levels, as well as inhibited complex 1 activity. More importantly, cordycepin administration inhibited the expression of NLRP3 inflammasome components and the release of pro-inflammatory cytokine in rotenone-induced rats and cultured neuronal PC12 cells. Moreover, we demonstrated that the activation of NLRP3 inflammasome within neurons could be suppressed by the mitochondrial division inhibitor (Mdivi-1). Collectively, the present study provides evidence that cordycepin exerts neuroprotective effects partially through preventing neural NLRP3 inflammasome activation induced by Drp1-dependent mitochondrial fragmentation in rotenone-injected PD models.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Deoxyadenosines/therapeutic use , Dynamins/antagonists & inhibitors , Mitochondrial Dynamics/drug effects , Neuroprotective Agents/therapeutic use , Parkinsonian Disorders/drug therapy , Rotenone/toxicity , Animals , Anti-Inflammatory Agents/pharmacology , Deoxyadenosines/pharmacology , Dose-Response Relationship, Drug , Dynamins/metabolism , Insecticides/toxicity , Male , Mitochondrial Dynamics/physiology , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neuroprotective Agents/pharmacology , PC12 Cells , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
AIM: To study the effects of human recombinant interleukin-1 receptor antagonist (IL-1ra) on isolated trachea smooth muscle (TSM) of the guinea pig. METHODS: Changes of the tension of isolated trachea were measured by force-displacement transducer and MedLab recording system in vitro. RESULTS: IL-1ra showed direct relaxed effect on TSM in normal and ovalbumin sensitized guinea pig. The EC50 values were 8.06 x 10(-8) and 5.88 x 10(-7) mol.L-1 respectively. IL-1ra (1 x 10(-7)-1 x 10(-5) mol.L-1) concentration-dependently inhibited the contraction of TSM induced by 1 x 10(-3) mol.L-1 histamine (His), 1 x 10(-3) mol.L-1 acetylcholine (ACh) and 1 x 10(-6) mol.L-1 5-hydroxytryptamine (5-HT) (P < 0.05 or 0.01). When IL-1ra was given in advance, the contractile actions of His, ACh and 5-HT were antagonized by IL-1ra (1 x 10(-7)-1 x 10(-5) mol.L-1), the pD'2 value for His was 6.6 +/- 0.3. However, the contractile action of ACh was enhanced by IL-1ra at low concentration of 1 x 10(-9)-1 x 10(-8) mol.L-1. IL-1ra significantly prevented and inhibited the contraction of sensitized TSM induced by antigen ovalbumin, the IC50 value was 4.48 x 10(-7) mol.L-1. CONCLUSION: The results indicate that IL-1ra, within certain concentration, can relax the normal, contracted and sensitized ISM of the guinea pig in vitro.
