西格列汀通过增加肾组织中SOCS 1和Podocalyxin的表达改善糖尿病肾病大鼠肾功能

目的:探讨西格列汀对糖尿病肾病大鼠肾功能及肾组织中细胞因子信号传导负调控因子1(Suppressors of cytockine signaling,SOCS 1)和足细胞特异蛋白抗体(Podocalyxin)表达的影响。方法:将大鼠随机分为4组:对照组,模型组,西格列汀组和贝那普利组。模型组、西格列汀组和贝那普利组采用腹腔注射链脲佐菌素建立模型,对照组给予腹腔注射等量生理盐水。造模成功后,西格列汀组(n=8)和贝那普利组(n=8)分别灌胃给予7 mg/kg/d的西格列汀和贝那普利。模型组(n=8)和对照组(n=10)均给予等体积的蒸馏水灌胃,连续8周。检测并对比各组大鼠代谢相关指标,肾组织纤维化程度指标,肾组织中炎症因子水平以及Podocalyxin、SOCS 1和结蛋白(Desmin)表达。结果:干预8周后,与对照组对比,模型组空腹血糖、糖化血红蛋白、甘油三酯、总胆固醇、24 h尿蛋白排泄率、肌酐、体重、肾组织转化生长因子-β1(Transforming growth factor,TGF-β1)、白介素(Interleukin,IL)-6、IL-1β、SOCS 1和Desmin水平均显著增加,Ⅳ型胶原蛋白(Collagen-Ⅳ,C-Ⅳ)、纤维连接蛋白(Fibronectin,FN)、层黏连蛋白(Laminin,LN)和Podocalyxin水平显著降低(P0.05);与模型组对比,西格列汀组和厄贝沙坦组空腹血糖、糖化血红蛋白、甘油三酯、总胆固醇、24 h尿蛋白排泄率、肌酐、体重、肾组织TGF-β1、IL-6、IL-1β和Desmin水平均显著降低,Podocalyxin和SOCS 1蛋白表达增加(P0.05)。但厄贝沙坦组与西格列汀组以上各指标对比差异无统计学意义(P0.05)。结论:西格列汀可能通过增加Podocalyxin和SOCS 1蛋白表达,降低肾组织中炎症因子和Desmin蛋白表达,进而改善糖尿病肾病大鼠肾纤维化和肾功能。     

Down-regulation of miR-let-7e attenuates LPS-induced acute lung injury in mice via inhibiting pulmonary inflammation by targeting SCOS1/NF-κB pathway

Excessive pulmonary inflammatory response is critical in the development of acute lung injury (ALI). Previously, microRNAs (miRNAs) have been recognized as an important regulator of inflammation in various diseases. However, the effects and mechanisms of miRNAs on inflammatory response in ALI remain unclear. Herein, we tried to screen miRNAs in the processes of ALI and elucidate the potential mechanism. Using a microarray assay, microRNA let-7e (let-7e) was chose as our target for its reported suppressive roles in several inflammatory diseases. Down-regulation of let-7e by antagomiR-let-7e injection attenuated LPS-induced acute lung injury. We also found that antagomiR-let-7e could obviously improve the survival rate in ALI mice. Moreover, antagomiR-let-7e treatment reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-1β and IL-6) in bronchoalveolar lavage fluid (BALF) of LPS-induced ALI mice. Luciferase reporter assays confirmed that suppressor of cytokine signaling 1 (SOCS1), a powerful attenuator of nuclear factor kappa B (NF-κB) signaling pathway, was directly targeted and suppressed by let-7e in RAW264.7 cells. In addition, it was further observed that SOCS1 was down-regulated, and inversely correlated with let-7e expression levels in lung tissues of ALI mice. Finally, down-regulation of let-7e suppressed the activation of NF-κB pathway, as evidenced by the reduction of p-IκBα, and nuclear p-p65 expressions in ALI mice. Collectively, our findings indicate that let-7e antagomir protects mice against LPS-induced lung injury via repressing the pulmonary inflammation though regulation of SOCS1/NF-κB pathway, and let-7e may act as a potential therapeutic target for ALI.     

Suppression of cytokine signaling: The SOCS perspective

The discovery of the Suppressor of Cytokine Signaling (SOCS) family of proteins has resulted in a significant body of research dedicated to dissecting their biological functions and the molecular mechanisms by which they achieve potent and specific inhibition of cytokine and growth factor signaling. The Australian contribution to this field has been substantial, with the initial discovery of SOCS1 by Hilton, Starr and colleagues (discovered concurrently by two other groups) and the following work, providing a new perspective on the regulation of JAK/STAT signaling. In this review, we reflect on the critical discoveries that have lead to our current understanding of how SOCS proteins function and discuss what we see as important questions for future research.     

Negative regulation of the hepatic fibrogenic response by suppressor of cytokine signaling 1

Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFNγ signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFNγ, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFNγ-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in HSC activation. Liver fibrosis was induced in Socs1^−/−Ifng^−/− mice with dimethylnitrosamine or carbon tetrachloride. Ifng^−/− and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1^−/−Ifng^−/− mice showed elevated serum ALT levels and increased liver fibrosis compared to Ifng^−/− mice. The latter group showed higher ALT levels and fibrosis than C57BL/6 controls. The livers of SOCS1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. SOCS1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from SOCS1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of SOCS1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFNγ and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability.     

黄连素通过SOCS1减轻Aβ淀粉样蛋白诱导的小胶质细胞激活

目的:观察黄连素(Berberine,BBR)对暴露于Aβ淀粉样蛋白(βAmyloid,Aβ)中的小胶质细胞激活的影响,并明确细胞因子沉默蛋白1(Silencing of Cytokine Signaling Factor 1, SOCS1)是否参与了BBR对小胶质细胞激活的影响。方法:将N9小胶质细胞暴露于含5μM Aβ的培养基中模拟阿尔兹海默症(Alzheimer's,AD)中的小胶质细胞激活。随后,将细胞分为5组,分别为Control组、5μM的Aβ损伤组(Aβ)、BBR+Aβ组、SOCS1-siRNA干扰组(SOCS1-siRNA+BBR+Aβ)和乱序si RNA处理组(SC-si RNA+BBR+Aβ),细胞处理24 h后,采用Western blot检测细胞诱导型一氧化氮合酶(Inducible Nitric Oxide Synthase,i NOS)、SOCS1蛋白的表达,酶联免疫吸附法(Enzyme Linked Immunosorbent Assay,ELISA)检测细胞培养基内炎症因子的水平。结果:与正常培养的Control组相比,5μM的Aβ暴露24 h可显著增加细胞i NOS蛋白表达水平和肿瘤坏死因子α(Tumor Necrosis Factorα,TNF-α)、白细胞介素1β(Interleukin 1β,IL-1β)和IL-6的释放(P0.05),但并未对SOCS1蛋白表达产生显著影响(P0.05),5μM的BBR可显著降低i NOS表达和上述3种促炎症因子的释放(P0.05),并上调SOCS1蛋白表达,而SOCS1-siRNA可显著逆转BBR对i NOS和SOCS1蛋白表达及3种炎症因子释放的影响(P0.05)。结论:BBR可能通过SOCS1减轻Aβ淀粉样蛋白对小胶质细胞的激活。     

MiR-455-5p ameliorates HG-induced apoptosis,oxidative stress and inflammatory via targeting SOCS3 in retinal pigment epithelial cells

Diabetic retinopathy (DR) remains the leading cause of blindness in adults with diabetes mellitus. Numerous microRNAs (miRNAs) have been identified to modulate the pathogenesis of DR. The main purpose of this study was to evaluate the potential roles of miR-455-5p in high glucose (HG)-treated retinal pigment epithelial (RPE) cells and underlying mechanisms. Our present investigation discovered that the expression of miR-455-5p was apparently downregulated in ARPE-19 cells stimulated with HG. In addition, forced expression of miR-455-5p markedly enhanced cell viability and restrained HG-induced apoptosis accompanied by decreased BCL2-associated X protein (Bax)/B-cell leukemia/lymphoma 2 (Bcl-2) ratio and expression of apoptotic marker cleaved caspase-3 during HG challenged. Subsequently, augmentation of miR-455-5p remarkably alleviated HG-triggered oxidative stress injury as reflected by decreased the production of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content as well as NADPH oxidase 4 expression, concomitant with enhanced the activities of superoxide dismutase, catalase, and GPX stimulated with HG. Furthermore, enforced expression of miR-455-5p effectively ameliorated HG-stimulated inflammatory response as exemplified by repressing the secretion of inflammatory cytokines interleukin 1β (IL-1β), IL-6, and tumour necrosis factor-α in ARPE-19 cells challenged by HG. Most importantly, we successfully identified suppressor of cytokine signaling 3 (SOCS3) as a direct target gene of miR-455-5p, and miR-455-5p negatively regulated the expression of SOCS3. Mechanistically, restoration of SOCS3 abrogated the beneficial effects of miR-455-5p on apoptosis, accumulation of ROS, and inflammatory factors production in response to HG. Taken together, these findings demonstrated that miR-455-5p relieved HG-induced damage through repressing apoptosis, oxidant stress, and inflammatory response by targeting SOCS3. The study gives evidence that miR-455-5p may serve as a new potential therapeutic agent for DR treatment.