细胞因子是调节机体免疫和神经内分泌功能的生物活性物质，其信号的激发、放大和持续在时间和空间上都受到严格调控 。细胞因子信号传导抑制因子（Suppressor of cytokine signaling．socs）是细胞因子信号通路的负调节因子，通过负反...细胞因子是调节机体免疫和神经内分泌功能的生物活性物质，其信号的激发、放大和持续在时间和空间上都受到严格调控 。细胞因子信号传导抑制因子（Suppressor of cytokine signaling．socs）是细胞因子信号通路的负调节因子，通过负反馈抑制细胞因子的信号传递，防止过度的信号反应干扰机体代谢平衡和细胞功能 .展开更多
The anti-inflammatory and antioxidant effects of exendin-4（Ex-4） have been reported previously.However,whether（Ex-4） has anti-inflammatory and antioxidant effects on high-altitude cerebral edema（HACE） remains po...The anti-inflammatory and antioxidant effects of exendin-4（Ex-4） have been reported previously.However,whether（Ex-4） has anti-inflammatory and antioxidant effects on high-altitude cerebral edema（HACE） remains poorly understood.In this study,two rat models of HACE were established by placing rats in a hypoxic environment with a simulated altitude of either 6000-or 7000-m above sea level（MASL） for 72 hours.An altitude of 7000 MASL with 72-hours of hypoxia was found to be the optimized experimental paradigm for establishing HACE models.Then,in rats where a model of HACE was established by introducing them to a 7000 MASL environment with 72-hours of hypoxia treatment,2,10 and,100 μg of Ex-4 was intraperitoneally administrated.The open field test and tail suspension test were used to test animal behavior.Routine methods were used to detect change in inflammatory cells.Hematoxylin-eosin staining was performed to determine pathological changes to brain tissue.Wet/dry weight ratios were used to measure brain water content.Evans blue leakage was used to determine blood-brain barrier integrity.Enzyme-linked immunosorbent assay（ELISA） was performed to measure markers of inflammation and oxidative stress including superoxide dismutase,glutathione,and malonaldehyde values,as well as interleukin-6,tumor necrosis factor-alpha,cyclic adenosine monophosphate levels in the brain tissue.Western blot analysis was performed to determine the levels of occludin,ZO-1,SOCS-3,vascular endothelial growth factor,EPAC1,nuclear factor-kappa B,and aquaporin-4.Our results demonstrate that Ex-4 preconditioning decreased brain water content,inhibited inflammation and oxidative stress,alleviated brain tissue injury,maintain blood-brain barrier integrity,and effectively improved motor function in rat models of HACE.These findings suggest that Ex-4 exhibits therapeutic potential in the treatment of HACE.展开更多
Objective:To study the effects of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in peripheral blood on CD4+T cell differentiation in children with Henoch-Schonlein purpura. Methods: Children with Henoch-Schonle...Objective:To study the effects of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in peripheral blood on CD4+T cell differentiation in children with Henoch-Schonlein purpura. Methods: Children with Henoch-Schonlein purpura who were treated in Zigong Maternal and Child Health Hospital between June 2014 and February 2018 were selected as the HSP group of the study, and healthy children who received physical examination during the same period were selected as the control group of the study. Peripheral blood was collected to determine the expression of SOCS1 and SOCS3 as well as the contents of CD4+T cell subsets, and serum was collected to determine the contents of CD4+T cytokines.Results: SOCS1 and SOCS3 mRNA expression levels as well as SOCS3/SOCS1 ratio in peripheral blood of HSP group were significantly higher than those of control group;Th1 and Treg contents in peripheral blood as well as IFN-γ and TGF-β1 contents in serum of HSP group were lower than those of control group whereas Th2 and Th17 contents in peripheral blood as well as IL-4, IL-5 and IL-17 contents in serum were higher than those of control group, and Th1 and Treg contents in peripheral blood as well as IFN-γ and TGF-β1 contents in serum of HSP children with high SOCS3/SOCS1 ratio were lower than those of HSP children with low SOCS3/SOCS1 ratio whereas Th2 and Th17 contents in peripheral blood as well as IL-4, IL-5 and IL-17 contents in serum were higher than those of HSP children with low SOCS3/SOCS1 ratio.Conclusions: Changes in SOCS1 and SOCS3 expression in peripheral blood of children with Henoch-Schonlein purpura can affect the differentiation of CD4+T cells.展开更多
目的:观察大黄泄浊方对慢性肾衰竭(CRF)大鼠信号传导抑制因子3(SOCS3)/Toll样受体4(TLR4)通路的干预作用,探讨其减轻肾组织炎症反应的分子机制。方法:取雄性SD大鼠90只,随机留取15只为假手术组,剩余75只为造模组,行5/6肾切除术复制CRF...目的:观察大黄泄浊方对慢性肾衰竭(CRF)大鼠信号传导抑制因子3(SOCS3)/Toll样受体4(TLR4)通路的干预作用,探讨其减轻肾组织炎症反应的分子机制。方法:取雄性SD大鼠90只,随机留取15只为假手术组,剩余75只为造模组,行5/6肾切除术复制CRF大鼠模型,模型复制成功后,随机分为模型组,大黄泄浊方低、中、高剂量(6.825、13.65、27.3 g·kg^(-1))组、尿毒清颗粒组(2.6 g·kg^(-1)),分别予相应剂量的药物灌胃,连续灌胃8周。给药结束后,苏木素-伊红(HE)染色及马松(Masson)染色观察大鼠肾脏组织病理形态改变;检测大鼠血肌酐(SCr)、血尿素氮(BUN)、血尿酸(UA)水平;酶联免疫吸附测定法(ELISA)检测大鼠血清中白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、C反应蛋白(CRP)含量;实时荧光定量聚合酶链式反应(Real-time PCR)检测肾组织中SOCS3和TLR4 m RNA的表达;蛋白免疫印迹法(Western blot)检测信号传导抑制因子3(SOCS3)、TLR4、核转录因子-κB(NF-κB)、髓样分化因子88(My D88)蛋白的表达;免疫组化法检测NF-κB、My D88、NOD样受体蛋白3(NLRP3)、黑色素瘤缺乏因子2(AIM2)蛋白的表达。结果:与假手术组比较,模型组大鼠肾组织发生明显的炎症反应,血SCr、BUN、UTP、IL-6、TNF-α、CRP水平明显升高(P<0.05),肾组织中SOCS3蛋白及SOCS3 m RNA含量明显下调,TLR4、NF-κB、My D88、NLRP3、AIM2蛋白及TLR4 m RNA含量均明显升高(P<0.05);与模型组比较,大黄泄浊方和尿毒清颗粒可明显减轻肾组织中的炎症反应,降低血SCr、BUN、UTP、IL-6、TNF-α、CRP的表达水平(P<0.05),肾组织中SOCS3蛋白及SOCS3 m RNA含量显著上升,TLR4、NF-κB、My D88、NLRP3、AIM2蛋白及TLR4 m RNA含量均明显下降(P<0.05)。结论:大黄泄浊方可减少炎症因子的释放和表达,抑制炎症反应,改善肾功能,其机制可能与调控SOCS3/TLR4信号通路有关。展开更多
Background Idiopathic pulmonary fibrosis （IPF） is a progressive diffuse parenchymal disease with a poor prognosis.A variety of cytokines and chemokines are involved in its pathophysiology.The aim of this study was t...Background Idiopathic pulmonary fibrosis （IPF） is a progressive diffuse parenchymal disease with a poor prognosis.A variety of cytokines and chemokines are involved in its pathophysiology.The aim of this study was to evaluate the clinical features in IPF patients with the expression of suppressor of cytokine signaling 1 （SOCS-1）,which acts as a negative regulator of cytokine signaling.Methods IPF patients （n=20） and healthy controls （n=16） were included in this study.The expression of SOCS-1 was analyzed in peripheral blood mononuclear cells （PBMC） of subjects using RT-PCR.Interleukin 4 （IL-4）,transforming growth factor β1 （TGF-β1） and type Ⅰ collagen expression were also analyzed in each individual using enzyme-linked immunosorbent assay （ELISA）.The clinical characteristics of IPF patients were delineated.These results were analyzed by SPSS13.0 statistics software.Results SOCS-1 mRNA expression was significantly decreased in the PBMC of IPF patients compared with healthy controls; serum levels of IL-4 and TGF-β1 were higher in IPF patients.The patients with lower expression of SOCS-1 developed lower percentage of forced vital capacity （FVC%） and DLCO/VA.A patients＇ SOCS-1 mRNA level was negatively correlated with serum levels of IL-4,and negatively correlated with their high-resolution computed tomography （HRCT） scores.Conclusions SOCS-1 mRNA can be detected in PBMC,and it is down-regulated in IPF patients.The expression of SOCS-1 is associated with the severity of IPF patients＇ symptoms,so it might be the predictor of disease severity.SOCS-1 might play an important role in IPF by reducing the expression of the T helper type 2 （Th2） cell-related cytokine IL-4.展开更多
目的观察血管软化丸对miRNA-155(miR-155)及细胞因子信号转导抑制剂l(suppressor of cytokine signaling 1,SOCS1)-磷酸化转录激活子3(phosphorylated signal transducer and activator of transcription 3,p-STAT3)-程序性细胞凋亡因子...目的观察血管软化丸对miRNA-155(miR-155)及细胞因子信号转导抑制剂l(suppressor of cytokine signaling 1,SOCS1)-磷酸化转录激活子3(phosphorylated signal transducer and activator of transcription 3,p-STAT3)-程序性细胞凋亡因子4(programmed cell death 4,PDCD4)信号通路和下游炎症因子的影响。方法体内实验中,将ApoE-/-小鼠分为模型组,miR-155抑制剂组,miR-155模拟物组,血管软化丸高、低剂量组;干预8周后观察小鼠主动脉病理变化,RT-PCR法检测小鼠主动脉miR-155、SOCS1、p-STAT3、PDCD4 mRNA表达水平,ELISA法检测小鼠血清肿瘤坏死因子-α(tumor necrosis factor alpha,TNF-α)、白细胞介素-6(interleukin-6,IL-6)、干扰素-γ(interferon gamma,IFN-γ)水平。体外实验中,将RAW264.7细胞随机分为对照组(空白血清)、miR-155抑制剂组、miR-155模拟物组、血管软化丸含药血清组;经药物血清干预后,RT-PCR法检测细胞miR-155、SOCS1、p-STAT3、PDCD4 mRNA表达水平。结果体内实验显示,miR-155模拟物组,血管软化丸高、低剂量组小鼠主动脉粥样硬化病变程度较模型组明显减轻;与模型组相比,miR-155模拟物组,血管软化丸高、低剂量组主动脉miR-155、SOCS1 mRNA表达水平明显升高(P<0.05),p-STAT3、PDCD4 mRNA表达水平明显降低(P<0.05),血清TNF-α、IL-6、IFN-γ水平较模型组明显降低(P<0.05)。体外实验显示,与对照组比较,miR-155模拟物组、血管软化丸含药血清组RAW264.7细胞miR-155、SOCS1 mRNA表达水平明显升高(P<0.05),p-STAT3和PDCD4 mRNA表达水平明显降低(P<0.05)。结论血管软化丸抗动脉粥样硬化的机制可能是通过miR-155调控SOCS1/STAT3/PDCD4信号通路影响炎症因子水平。展开更多
Approximately 170 million people worldwide are chronically infected with hepatitis C virus(HCV).Chronic HCV infection is the leading cause for the development of liver fibrosis,cirrhosis,hepatocellular carcinoma(HCC)a...Approximately 170 million people worldwide are chronically infected with hepatitis C virus(HCV).Chronic HCV infection is the leading cause for the development of liver fibrosis,cirrhosis,hepatocellular carcinoma(HCC)and is the primary cause for liver transplantation in the western world.Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of typeⅡdiabetes.Insulin resistance plays an important role in the development of various complications associated with HCV infection.Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis,steatosis,HCC and resistance to anti-viral treatment.Thus,HCV associated insulin resistance is a therapeutic target at any stage of HCV infection.HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway.Various mechanisms have been proposed in regard to HCV mediated insulin resistance,involving up regulation of inflammatory cytokines,like tumor necrosis factor-α,phosphorylation of insulin-receptor substrate-1,Akt,up-regulation of gluconeogenic genes like glucose 6 phosphatase,phosphoenolpyruvate carboxykinase 2,and accumulation of lipid droplets.In this review,we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.展开更多
Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor imm...Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.展开更多
Although microRNA-155(miR-155)is considered a pro-inflammatory mediator,cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells.In this study,we identified the drama...Although microRNA-155(miR-155)is considered a pro-inflammatory mediator,cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells.In this study,we identified the dramatic expression changes of more than half of potential miR-155-targeted genes upon lipopolysaccharide(LPS)stimulation;223 genes were down-regulated and 85 genes were up-regulated,including suppressor of cytokine signaling 1(SOCS1)and transforming growth factor-β-activated kinase 1-binding protein 2(TAB2),two well-known genes involved in miR-155-mediated regulation of the Toll-like receptor 4(TLR4)signaling pathway.We also found that miR-155 acted as an anti-inflammatory mediator in the initial stage of LPS-induced inflammatory response mainly through repressing TAB2 protein translation,and as a proinflammatory mediator by down-regulating SOCS1 in the later stage.Meanwhile,overexpression of TAB23'untranslated region(UTR)in macrophages promoted the development of endotoxin tolerance by competing for binding with miR-155,which resulted in an elevated expression level of SOCS1 protein.These findings provide new insights for understanding the regulatory mechanisms in fine-tuning of LPS-induced innate immune response.展开更多
基金supported by the National Key Research and Development Plan of China,No.2016YFC1101500the National Natural Science Foundation of China,No.11672332,11102235,31200809,81772018+1 种基金the Key Science and Technology Support Foundation of Tianjin City of China,No.17YFZCSY00620the Natural Science Foundation of Tianjin City of China,No.15JCYBJC28600,17JCZDJC35400
文摘The anti-inflammatory and antioxidant effects of exendin-4（Ex-4） have been reported previously.However,whether（Ex-4） has anti-inflammatory and antioxidant effects on high-altitude cerebral edema（HACE） remains poorly understood.In this study,two rat models of HACE were established by placing rats in a hypoxic environment with a simulated altitude of either 6000-or 7000-m above sea level（MASL） for 72 hours.An altitude of 7000 MASL with 72-hours of hypoxia was found to be the optimized experimental paradigm for establishing HACE models.Then,in rats where a model of HACE was established by introducing them to a 7000 MASL environment with 72-hours of hypoxia treatment,2,10 and,100 μg of Ex-4 was intraperitoneally administrated.The open field test and tail suspension test were used to test animal behavior.Routine methods were used to detect change in inflammatory cells.Hematoxylin-eosin staining was performed to determine pathological changes to brain tissue.Wet/dry weight ratios were used to measure brain water content.Evans blue leakage was used to determine blood-brain barrier integrity.Enzyme-linked immunosorbent assay（ELISA） was performed to measure markers of inflammation and oxidative stress including superoxide dismutase,glutathione,and malonaldehyde values,as well as interleukin-6,tumor necrosis factor-alpha,cyclic adenosine monophosphate levels in the brain tissue.Western blot analysis was performed to determine the levels of occludin,ZO-1,SOCS-3,vascular endothelial growth factor,EPAC1,nuclear factor-kappa B,and aquaporin-4.Our results demonstrate that Ex-4 preconditioning decreased brain water content,inhibited inflammation and oxidative stress,alleviated brain tissue injury,maintain blood-brain barrier integrity,and effectively improved motor function in rat models of HACE.These findings suggest that Ex-4 exhibits therapeutic potential in the treatment of HACE.
文摘Objective:To study the effects of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in peripheral blood on CD4+T cell differentiation in children with Henoch-Schonlein purpura. Methods: Children with Henoch-Schonlein purpura who were treated in Zigong Maternal and Child Health Hospital between June 2014 and February 2018 were selected as the HSP group of the study, and healthy children who received physical examination during the same period were selected as the control group of the study. Peripheral blood was collected to determine the expression of SOCS1 and SOCS3 as well as the contents of CD4+T cell subsets, and serum was collected to determine the contents of CD4+T cytokines.Results: SOCS1 and SOCS3 mRNA expression levels as well as SOCS3/SOCS1 ratio in peripheral blood of HSP group were significantly higher than those of control group;Th1 and Treg contents in peripheral blood as well as IFN-γ and TGF-β1 contents in serum of HSP group were lower than those of control group whereas Th2 and Th17 contents in peripheral blood as well as IL-4, IL-5 and IL-17 contents in serum were higher than those of control group, and Th1 and Treg contents in peripheral blood as well as IFN-γ and TGF-β1 contents in serum of HSP children with high SOCS3/SOCS1 ratio were lower than those of HSP children with low SOCS3/SOCS1 ratio whereas Th2 and Th17 contents in peripheral blood as well as IL-4, IL-5 and IL-17 contents in serum were higher than those of HSP children with low SOCS3/SOCS1 ratio.Conclusions: Changes in SOCS1 and SOCS3 expression in peripheral blood of children with Henoch-Schonlein purpura can affect the differentiation of CD4+T cells.
文摘目的:观察大黄泄浊方对慢性肾衰竭(CRF)大鼠信号传导抑制因子3(SOCS3)/Toll样受体4(TLR4)通路的干预作用,探讨其减轻肾组织炎症反应的分子机制。方法:取雄性SD大鼠90只,随机留取15只为假手术组,剩余75只为造模组,行5/6肾切除术复制CRF大鼠模型,模型复制成功后,随机分为模型组,大黄泄浊方低、中、高剂量(6.825、13.65、27.3 g·kg^(-1))组、尿毒清颗粒组(2.6 g·kg^(-1)),分别予相应剂量的药物灌胃,连续灌胃8周。给药结束后,苏木素-伊红(HE)染色及马松(Masson)染色观察大鼠肾脏组织病理形态改变;检测大鼠血肌酐(SCr)、血尿素氮(BUN)、血尿酸(UA)水平;酶联免疫吸附测定法(ELISA)检测大鼠血清中白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、C反应蛋白(CRP)含量;实时荧光定量聚合酶链式反应(Real-time PCR)检测肾组织中SOCS3和TLR4 m RNA的表达;蛋白免疫印迹法(Western blot)检测信号传导抑制因子3(SOCS3)、TLR4、核转录因子-κB(NF-κB)、髓样分化因子88(My D88)蛋白的表达;免疫组化法检测NF-κB、My D88、NOD样受体蛋白3(NLRP3)、黑色素瘤缺乏因子2(AIM2)蛋白的表达。结果:与假手术组比较,模型组大鼠肾组织发生明显的炎症反应,血SCr、BUN、UTP、IL-6、TNF-α、CRP水平明显升高(P<0.05),肾组织中SOCS3蛋白及SOCS3 m RNA含量明显下调,TLR4、NF-κB、My D88、NLRP3、AIM2蛋白及TLR4 m RNA含量均明显升高(P<0.05);与模型组比较,大黄泄浊方和尿毒清颗粒可明显减轻肾组织中的炎症反应,降低血SCr、BUN、UTP、IL-6、TNF-α、CRP的表达水平(P<0.05),肾组织中SOCS3蛋白及SOCS3 m RNA含量显著上升,TLR4、NF-κB、My D88、NLRP3、AIM2蛋白及TLR4 m RNA含量均明显下降(P<0.05)。结论:大黄泄浊方可减少炎症因子的释放和表达,抑制炎症反应,改善肾功能,其机制可能与调控SOCS3/TLR4信号通路有关。
基金This study was supported by the grants from Science and Technology Commission of Shanghai，National Natural Science Foundation
文摘Background Idiopathic pulmonary fibrosis （IPF） is a progressive diffuse parenchymal disease with a poor prognosis.A variety of cytokines and chemokines are involved in its pathophysiology.The aim of this study was to evaluate the clinical features in IPF patients with the expression of suppressor of cytokine signaling 1 （SOCS-1）,which acts as a negative regulator of cytokine signaling.Methods IPF patients （n=20） and healthy controls （n=16） were included in this study.The expression of SOCS-1 was analyzed in peripheral blood mononuclear cells （PBMC） of subjects using RT-PCR.Interleukin 4 （IL-4）,transforming growth factor β1 （TGF-β1） and type Ⅰ collagen expression were also analyzed in each individual using enzyme-linked immunosorbent assay （ELISA）.The clinical characteristics of IPF patients were delineated.These results were analyzed by SPSS13.0 statistics software.Results SOCS-1 mRNA expression was significantly decreased in the PBMC of IPF patients compared with healthy controls; serum levels of IL-4 and TGF-β1 were higher in IPF patients.The patients with lower expression of SOCS-1 developed lower percentage of forced vital capacity （FVC%） and DLCO/VA.A patients＇ SOCS-1 mRNA level was negatively correlated with serum levels of IL-4,and negatively correlated with their high-resolution computed tomography （HRCT） scores.Conclusions SOCS-1 mRNA can be detected in PBMC,and it is down-regulated in IPF patients.The expression of SOCS-1 is associated with the severity of IPF patients＇ symptoms,so it might be the predictor of disease severity.SOCS-1 might play an important role in IPF by reducing the expression of the T helper type 2 （Th2） cell-related cytokine IL-4.
文摘目的观察血管软化丸对miRNA-155(miR-155)及细胞因子信号转导抑制剂l(suppressor of cytokine signaling 1,SOCS1)-磷酸化转录激活子3(phosphorylated signal transducer and activator of transcription 3,p-STAT3)-程序性细胞凋亡因子4(programmed cell death 4,PDCD4)信号通路和下游炎症因子的影响。方法体内实验中,将ApoE-/-小鼠分为模型组,miR-155抑制剂组,miR-155模拟物组,血管软化丸高、低剂量组;干预8周后观察小鼠主动脉病理变化,RT-PCR法检测小鼠主动脉miR-155、SOCS1、p-STAT3、PDCD4 mRNA表达水平,ELISA法检测小鼠血清肿瘤坏死因子-α(tumor necrosis factor alpha,TNF-α)、白细胞介素-6(interleukin-6,IL-6)、干扰素-γ(interferon gamma,IFN-γ)水平。体外实验中,将RAW264.7细胞随机分为对照组(空白血清)、miR-155抑制剂组、miR-155模拟物组、血管软化丸含药血清组;经药物血清干预后,RT-PCR法检测细胞miR-155、SOCS1、p-STAT3、PDCD4 mRNA表达水平。结果体内实验显示,miR-155模拟物组,血管软化丸高、低剂量组小鼠主动脉粥样硬化病变程度较模型组明显减轻;与模型组相比,miR-155模拟物组,血管软化丸高、低剂量组主动脉miR-155、SOCS1 mRNA表达水平明显升高(P<0.05),p-STAT3、PDCD4 mRNA表达水平明显降低(P<0.05),血清TNF-α、IL-6、IFN-γ水平较模型组明显降低(P<0.05)。体外实验显示,与对照组比较,miR-155模拟物组、血管软化丸含药血清组RAW264.7细胞miR-155、SOCS1 mRNA表达水平明显升高(P<0.05),p-STAT3和PDCD4 mRNA表达水平明显降低(P<0.05)。结论血管软化丸抗动脉粥样硬化的机制可能是通过miR-155调控SOCS1/STAT3/PDCD4信号通路影响炎症因子水平。
基金Supported by The National Institutes of Health,NO.DK080812
文摘Approximately 170 million people worldwide are chronically infected with hepatitis C virus(HCV).Chronic HCV infection is the leading cause for the development of liver fibrosis,cirrhosis,hepatocellular carcinoma(HCC)and is the primary cause for liver transplantation in the western world.Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of typeⅡdiabetes.Insulin resistance plays an important role in the development of various complications associated with HCV infection.Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis,steatosis,HCC and resistance to anti-viral treatment.Thus,HCV associated insulin resistance is a therapeutic target at any stage of HCV infection.HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway.Various mechanisms have been proposed in regard to HCV mediated insulin resistance,involving up regulation of inflammatory cytokines,like tumor necrosis factor-α,phosphorylation of insulin-receptor substrate-1,Akt,up-regulation of gluconeogenic genes like glucose 6 phosphatase,phosphoenolpyruvate carboxykinase 2,and accumulation of lipid droplets.In this review,we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.
基金Supported by(in part)Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B(No.17fk0310116h0001) from the Japan Agency for Medical Research and Development(AMED)Extramural Collaborative Research Grant of Cancer Research Institute,Kanazawa University
文摘Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.
基金the National Natural Science Foundation of China(Nos.81701568,81930041,81571524,81872248,and 91842103)the Zhejiang Provincial Natural Science Foundation of China(Nos.Y15C080001 and Z19H100001)the Zhejiang Provincial Key Laboratory for Immunity and Inflammatory Diseases for its support。
文摘Although microRNA-155(miR-155)is considered a pro-inflammatory mediator,cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells.In this study,we identified the dramatic expression changes of more than half of potential miR-155-targeted genes upon lipopolysaccharide(LPS)stimulation;223 genes were down-regulated and 85 genes were up-regulated,including suppressor of cytokine signaling 1(SOCS1)and transforming growth factor-β-activated kinase 1-binding protein 2(TAB2),two well-known genes involved in miR-155-mediated regulation of the Toll-like receptor 4(TLR4)signaling pathway.We also found that miR-155 acted as an anti-inflammatory mediator in the initial stage of LPS-induced inflammatory response mainly through repressing TAB2 protein translation,and as a proinflammatory mediator by down-regulating SOCS1 in the later stage.Meanwhile,overexpression of TAB23'untranslated region(UTR)in macrophages promoted the development of endotoxin tolerance by competing for binding with miR-155,which resulted in an elevated expression level of SOCS1 protein.These findings provide new insights for understanding the regulatory mechanisms in fine-tuning of LPS-induced innate immune response.
