目的探讨果蝇双翅边缘缺刻同源基因(Notch)信号通路在慢性阻塞性肺疾病(COPD)辅助性T细胞1(Helper T cells 1,Th1)和辅助性T细胞2(Helper T cells 2,Th2)失衡中的作用及芪蛭皱肺颗粒的干预机制。方法70只Wistar大鼠随机挑选10只作为空...目的探讨果蝇双翅边缘缺刻同源基因(Notch)信号通路在慢性阻塞性肺疾病(COPD)辅助性T细胞1(Helper T cells 1,Th1)和辅助性T细胞2(Helper T cells 2,Th2)失衡中的作用及芪蛭皱肺颗粒的干预机制。方法70只Wistar大鼠随机挑选10只作为空白对照组,其余大鼠均采用香烟烟雾(CS)联合气管滴注脂多糖(Lipopolysaccharide,LPS)法建立COPD模型,空白对照组及造模组各随机挑选3只大鼠验证造模是否成功。造模结束进行灌胃给药干预,造模组大鼠随机分为模型对照组、阳性对照组(67.5μg·kg^(-1))及芪蛭皱肺颗粒高中低剂量组(3.24、1.62、0.81 g·kg^(-1)),分别给予生理盐水、醋酸地塞米松混悬液、芪蛭皱肺高、中、低剂量混悬液进行灌胃干预,空白对照组同模型对照组,灌胃等体积生理盐水。经28天造模及28天治疗后,采用动物肺功能测试系统检测吸气峰流速(Peak Inspiratory Flow,PIF)和呼气峰流速(Peak Expiratory Flow,PEF),处死大鼠提取肺脏、脾脏、血清及支气管肺泡灌洗液(BALF),苏木素-伊红(HE)染色评价肺组织病理变化,酶联免疫吸附实验法(ELISA)测定血清及BALF中肿瘤坏死因子-α(TNF-α)含量,流式细胞仪检测脾脏Th1/Th2细胞水平,免疫组织化学法(Immunohistochemistry,IHC)及蛋白免疫印迹法(Western blot)检测肺组织Notch1、Hes家族发状分裂相关增强子1(Hes1)、Hey家族发状分裂相关增强子1(Hey1)蛋白水平,实时荧光定量聚合酶链式反应(Real-time PCR,RT-PCR)检测肺组织Notch1、Hes1、Hey1基因表达水平。结果与空白对照组比较,模型对照组大鼠肺功能显著降低(P<0.05),肺组织出现炎性细胞浸润、支气管结构破坏等病变,血清及BALF中TNF-α含量显著升高(P<0.05),脾Th1细胞百分比显著降低(P<0.05),Th2细胞百分比显著升高(P<0.05),肺组织Notch1、Hes1、Hey1蛋白及mRNA表达显著升高(P<0.05),差异均具有统计学意义;与模型对照组比较,各给药组大鼠肺功能显著升高(P<0.05),肺组织病理损伤均有所减轻,血清及BALF中TNF-α含量显著降低(P<0.05),脾Th1细胞百分比显著升高(P<0.05),Th2细胞百分比显著降低(P<0.05),肺组织Notch1、Hes1、Hey1蛋白及mRNA表达显著降低(P<0.05),差异均具有统计学意义。结论芪蛭皱肺颗粒通过抑制Notch信号通路调节Th1/Th2平衡,从而改善COPD大鼠肺功能及病理损伤,影响其免疫功能。展开更多
Background:The cyclin-dependent kinase inhibitor 2a(CDKN2A)gene,identified as the multiple tumor suppressor gene,functions as a regulatory gene implicated in cancer pathogenesis.Its significance lies in its pivotal in...Background:The cyclin-dependent kinase inhibitor 2a(CDKN2A)gene,identified as the multiple tumor suppressor gene,functions as a regulatory gene implicated in cancer pathogenesis.Its significance lies in its pivotal involvement in the genesis of various tumors;notwithstanding,the precise connection between CDKN2A and c olon adenocarcinoma(COAD)remains undisclosed.Methods:The objective of this research was to assess the predictive importance of CDKN2A in COAD by analyzing data from The Cancer Genome Atlas database.Logistic regression,signed rank test,Wilcoxon test,and Kruskal-Wallis test were used to examine CDKN2A expression levels and clinicopathological features.Univariate and multivariate Cox r egression analyses and Kaplan-Meier analysis found prognostic variables.Additionally,gene set enrichment analysis identified key CDKN2A expression pathways.The study additionally examined CDKN2A expression with tumor immune infiltration using The Cancer Genome Atlas data and single sample gene set enrichment analysis.Results:The results of this investigation indicated a substantial connection between higher CDKN2A expression and negative outcomes in terms of overall survival and disease-related survival among COAD patients.Gene set enrichment analysis indicated a tight link between CDKN2A and both the cell cycle and hedgehog signaling pathways.Subsequent evaluation employing single sample gene set enrichment analysis demonstrated a positive link between CDKN2A expression with infiltration by iDCs,whereas a negative correlation was detected with infiltration by helper T cells.Conclusion:In conclusion,the present study gives strong data supporting the predictive value of CDKN2A and its possible usefulness as a biomarker for COAD.Additionally,our results show a reasonable link between CDKN2A expression and immune influx in COAD,putting light on the role of CDKN2A in the control of the tumor microenvironment.Nevertheless,additional studies are needed to confirm the underlying mechanisms of these relationships and to discover the therapeutic possibilities of targeting CDKN2A in the treatment of COAD.展开更多
The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulate...The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.展开更多
The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the ear...The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.展开更多
BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in P...BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in PI-IBS.T helper 17(Th17)polarization occurs in IBS.Adenosine and its receptors participate in intestinal inflammation and immune regulation.AIM To investigate the role of Th17 polarization of CD4+T cells regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS A PI-IBS model was established by infecting mice with Trichinella spiralis.The intestinal A2AR and CD4+T lymphocytes were detected by immunohistochemistry,and the inflammatory cytokines were detected by enzyme-linked immunoassay.CD4+T lymphocytes present in the animal’s spleen were separated and cultured with or without A2AR agonist and antagonist.Western blotting and real-time quantitative polymerase chain reaction were performed to determine the effect of A2AR on the cells and intestinal tissue.Cytokine production was determined.The protein and mRNA levels of A2AR associated signaling pathway molecules were also evaluated.Furthermore,A2AR agonist and antagonist were injected into the mouse model and the clinical features were observed.RESULTS The PI-IBS mouse model showed increased expression of ATP and A2AR(P<0.05),and inhibition of A2AR improved the clinical features in PI-IBS,including the abdominal withdrawal reflex and colon transportation test(P<0.05).The number of intestinal CD4+T cells and interleukin-17(IL-17)protein levels increased during PI-IBS,which was reversed by administration of the A2AR antagonist(P<0.05).CD4+T cells expressed A2AR and produced IL-17 in vitro,which was regulated by the A2AR agonist and antagonist.The A2AR antagonist increased the production of IL-17 by CD4+T cells via the Janus kinase-signal transducer and activator of transcriptionreceptor-related orphan receptorγsignaling pathway.CONCLUSION The results of the present study suggested that the upregulation of A2AR increases PI-IBS by promoting the Th17 polarization of CD4+T cells.展开更多
基金Guizhou Provincial Department of Science and Technology Natural Science Foundation(No Foundation-ZK[2022])the Guizhou Provincial Health Commission Science and Technology Fund(No.GZWKJ2023-135)the Science Foundation of 925th Hospital(No.2023[3],No.2022[3/4]).
文摘Background:The cyclin-dependent kinase inhibitor 2a(CDKN2A)gene,identified as the multiple tumor suppressor gene,functions as a regulatory gene implicated in cancer pathogenesis.Its significance lies in its pivotal involvement in the genesis of various tumors;notwithstanding,the precise connection between CDKN2A and c olon adenocarcinoma(COAD)remains undisclosed.Methods:The objective of this research was to assess the predictive importance of CDKN2A in COAD by analyzing data from The Cancer Genome Atlas database.Logistic regression,signed rank test,Wilcoxon test,and Kruskal-Wallis test were used to examine CDKN2A expression levels and clinicopathological features.Univariate and multivariate Cox r egression analyses and Kaplan-Meier analysis found prognostic variables.Additionally,gene set enrichment analysis identified key CDKN2A expression pathways.The study additionally examined CDKN2A expression with tumor immune infiltration using The Cancer Genome Atlas data and single sample gene set enrichment analysis.Results:The results of this investigation indicated a substantial connection between higher CDKN2A expression and negative outcomes in terms of overall survival and disease-related survival among COAD patients.Gene set enrichment analysis indicated a tight link between CDKN2A and both the cell cycle and hedgehog signaling pathways.Subsequent evaluation employing single sample gene set enrichment analysis demonstrated a positive link between CDKN2A expression with infiltration by iDCs,whereas a negative correlation was detected with infiltration by helper T cells.Conclusion:In conclusion,the present study gives strong data supporting the predictive value of CDKN2A and its possible usefulness as a biomarker for COAD.Additionally,our results show a reasonable link between CDKN2A expression and immune influx in COAD,putting light on the role of CDKN2A in the control of the tumor microenvironment.Nevertheless,additional studies are needed to confirm the underlying mechanisms of these relationships and to discover the therapeutic possibilities of targeting CDKN2A in the treatment of COAD.
文摘The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.
基金The National Natural Science Foundation of China,Nos.30871118,30971325,81270129 and 81470268(FL)grants from Department of Science and Technology of Sichuan Province,Nos.09ZQ026-020 and 2009SZ0190(FL)
文摘The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
基金Supported by National Natural Science Foundation of China,No.81160057,No.81860102,and No.82060102.
文摘BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in PI-IBS.T helper 17(Th17)polarization occurs in IBS.Adenosine and its receptors participate in intestinal inflammation and immune regulation.AIM To investigate the role of Th17 polarization of CD4+T cells regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS A PI-IBS model was established by infecting mice with Trichinella spiralis.The intestinal A2AR and CD4+T lymphocytes were detected by immunohistochemistry,and the inflammatory cytokines were detected by enzyme-linked immunoassay.CD4+T lymphocytes present in the animal’s spleen were separated and cultured with or without A2AR agonist and antagonist.Western blotting and real-time quantitative polymerase chain reaction were performed to determine the effect of A2AR on the cells and intestinal tissue.Cytokine production was determined.The protein and mRNA levels of A2AR associated signaling pathway molecules were also evaluated.Furthermore,A2AR agonist and antagonist were injected into the mouse model and the clinical features were observed.RESULTS The PI-IBS mouse model showed increased expression of ATP and A2AR(P<0.05),and inhibition of A2AR improved the clinical features in PI-IBS,including the abdominal withdrawal reflex and colon transportation test(P<0.05).The number of intestinal CD4+T cells and interleukin-17(IL-17)protein levels increased during PI-IBS,which was reversed by administration of the A2AR antagonist(P<0.05).CD4+T cells expressed A2AR and produced IL-17 in vitro,which was regulated by the A2AR agonist and antagonist.The A2AR antagonist increased the production of IL-17 by CD4+T cells via the Janus kinase-signal transducer and activator of transcriptionreceptor-related orphan receptorγsignaling pathway.CONCLUSION The results of the present study suggested that the upregulation of A2AR increases PI-IBS by promoting the Th17 polarization of CD4+T cells.
