溃疡性结肠炎(ulcerative colitis,UC)是一种以结肠黏膜及黏膜下层炎症为主要特征的慢性非特异性炎症,其致病机制复杂,易反复发作,现代医学研究认为其涉及氧化应激、免疫失衡等多方面因素。信号转导和转录激活因子3(signal transducer a...溃疡性结肠炎(ulcerative colitis,UC)是一种以结肠黏膜及黏膜下层炎症为主要特征的慢性非特异性炎症,其致病机制复杂,易反复发作,现代医学研究认为其涉及氧化应激、免疫失衡等多方面因素。信号转导和转录激活因子3(signal transducer and activator of transcription,STAT3)是调节细胞生长、分化和存活的重要因子,可被相关细胞因子激活,从而介导炎症、氧化应激及免疫反应以影响UC病理进程,并与核因子κB(nuclear factor kappa-B,NF-κB)、NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3,NLRP3)、细胞因子信号传导抑制因子(suppressor of cytokine signaling,SOCSs)等信号通路存在串扰现象。STAT3作为近年来UC相关研究的热点之一,本文综述了中药通过调控STAT3信号通路防治UC的研究进展,深入探究了STAT3激活及介导UC病理过程的分子机制,以及中药成分如何通过多途径调控STAT3信号通路,发挥其潜在的作用机制。相关研究揭示了中药通过调节STAT3信号通路,不仅有效抑制炎症、氧化应激的发生,还能在调控免疫反应、维持肠道屏障功能及完整性等方面发挥重要作用,有望为治疗UC提供新思路。展开更多
【目的】探究猪德尔塔冠状病毒(Porcine deltacoronavirus,PDCoV)感染对先天性免疫的影响及免疫信号传导的干扰机制,重点解析信号传导转录激活因子1(signal transducer and activator of transcription 1,STAT1)与三方基序蛋白21(tripar...【目的】探究猪德尔塔冠状病毒(Porcine deltacoronavirus,PDCoV)感染对先天性免疫的影响及免疫信号传导的干扰机制,重点解析信号传导转录激活因子1(signal transducer and activator of transcription 1,STAT1)与三方基序蛋白21(tripartite-motif protein 21,TRIM21)在此过程中的作用。【方法】通过倒置显微镜观察感染复数(multiplicity of infection,MOI)为1的PDCoV感染IPEC-J2细胞1、12、24、48 h后细胞形态学变化,采用实时荧光定量PCR和Western blotting分别检测PDCoV-N基因及蛋白的表达水平,以此筛选PDCoV感染IPEC-J2细胞模型的最佳条件。在PDCoV感染峰值时,通过实时荧光定量PCR和Western blotting检测STAT1、TRIM21及干扰素刺激基因(interferon-stimulated genes,ISGs)的mRNA和蛋白表达水平;通过双荧光素酶报告基因系统检测过表达或抑制STAT1对PDCoV复制及干扰素激活反应元件(interferon-stimulated response element,ISRE)启动子活性的影响;将TRIM21与STAT1真核表达载体共转染至IPEC-J2细胞,结合激光共聚焦显微镜、免疫共沉淀技术(coimmunoprecipitation,Co-IP)和Western blotting验证二者的相互作用及TRIM21对STAT1的调控效应。【结果】PDCoV在感染IPEC-J2细胞24 h达复制高峰,同时试验组细胞中STAT1、TRIM21蛋白表达及ISGs转录水平均极显著高于对照组(P<0.01)。与对照组相比,过表达STAT1后ISRE启动子活性极显著增强,PDCoV-N基因及其蛋白表达量极显著降低(P<0.01),而氟达拉滨抑制STAT1后则极显著促进病毒复制(P<0.01)。激光共聚焦显微镜观察与Co-IP结果显示,STAT1与TRIM21存在共定位及相互作用,且与对照组相比,过表达TRIM21后STAT1蛋白表达量极显著降低(P<0.01)。【结论】本研究解析了PDCoV与宿主IPEC-J2细胞先天性免疫的相互作用机制,STAT1作为关键抗病毒因子通过ISRE通路增强先天性免疫来抑制病毒复制,TRIM21则靶向STAT1并下调其表达从而帮助病毒免疫逃逸。研究结果不仅为深入理解PDCoV的致病分子机制提供了新见解,也为制定PDCoV防控策略奠定了基础。展开更多
Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodul...Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.展开更多
Breast cancer(BRCA)is characterized by high heterogeneity,with aggressive subtypes frequently showing poor prognosis and resistance to conventional therapies,making the discovery of new therapeutic targets and strateg...Breast cancer(BRCA)is characterized by high heterogeneity,with aggressive subtypes frequently showing poor prognosis and resistance to conventional therapies,making the discovery of new therapeutic targets and strategies imperative.Although elevated expression of discs large homolog 3(DLG3)has been reported in BRCA,its functional role in disease progression remains unclear.We performed bioinformatic analyses of clinical datasets to evaluate the prognostic significance of DLG3 expression in BRCA patients.In vitro gain-and loss-of-function experiments were conducted to assess the impact of DLG3 on BRCA cell proliferation,migration,and colony formation.Transcriptomic profiling,coupled with pharmacological inhibition,was employed to identify and validate downstream signaling pathways.Additionally,we extended our validation to an in vivo model to assess the role of DLG3 in tumor progression.We found that elevated DLG3 levels correlated with poor prognosis in breast cancer patients.Functionally,DLG3 overexpression significantly promoted cell proliferation and migration in estrogen receptor-positive MCF7 and triple-negative MDA-MB-231 breast cancer cells,whereas its knockdown suppressed these effects.Transcriptomic analyses revealed that DLG3 activates signal transducer and activator of transcription 3(STAT3)signaling,a finding further corroborated by Western blot.Critically,treatment with the STAT3 inhibitor Stattic attenuated DLG3-driven proliferation and migration,supporting a DLG3-STAT3 oncogenic axis.Furthermore,in vivo studies validated the role of DLG3 in promoting tumor growth and its correlation with elevated STAT3 signaling,consistent with our in vitro findings.Our findings establish DLG3 as a novel driver of breast cancer progression that directly activates STAT3 signaling.DLG3 thus represents both a potential prognostic biomarker and a promising therapeutic target for aggressive breast cancer subtypes,including triple-negative breast cancer.展开更多
文摘溃疡性结肠炎(ulcerative colitis,UC)是一种以结肠黏膜及黏膜下层炎症为主要特征的慢性非特异性炎症,其致病机制复杂,易反复发作,现代医学研究认为其涉及氧化应激、免疫失衡等多方面因素。信号转导和转录激活因子3(signal transducer and activator of transcription,STAT3)是调节细胞生长、分化和存活的重要因子,可被相关细胞因子激活,从而介导炎症、氧化应激及免疫反应以影响UC病理进程,并与核因子κB(nuclear factor kappa-B,NF-κB)、NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3,NLRP3)、细胞因子信号传导抑制因子(suppressor of cytokine signaling,SOCSs)等信号通路存在串扰现象。STAT3作为近年来UC相关研究的热点之一,本文综述了中药通过调控STAT3信号通路防治UC的研究进展,深入探究了STAT3激活及介导UC病理过程的分子机制,以及中药成分如何通过多途径调控STAT3信号通路,发挥其潜在的作用机制。相关研究揭示了中药通过调节STAT3信号通路,不仅有效抑制炎症、氧化应激的发生,还能在调控免疫反应、维持肠道屏障功能及完整性等方面发挥重要作用,有望为治疗UC提供新思路。
文摘【目的】探究猪德尔塔冠状病毒(Porcine deltacoronavirus,PDCoV)感染对先天性免疫的影响及免疫信号传导的干扰机制,重点解析信号传导转录激活因子1(signal transducer and activator of transcription 1,STAT1)与三方基序蛋白21(tripartite-motif protein 21,TRIM21)在此过程中的作用。【方法】通过倒置显微镜观察感染复数(multiplicity of infection,MOI)为1的PDCoV感染IPEC-J2细胞1、12、24、48 h后细胞形态学变化,采用实时荧光定量PCR和Western blotting分别检测PDCoV-N基因及蛋白的表达水平,以此筛选PDCoV感染IPEC-J2细胞模型的最佳条件。在PDCoV感染峰值时,通过实时荧光定量PCR和Western blotting检测STAT1、TRIM21及干扰素刺激基因(interferon-stimulated genes,ISGs)的mRNA和蛋白表达水平;通过双荧光素酶报告基因系统检测过表达或抑制STAT1对PDCoV复制及干扰素激活反应元件(interferon-stimulated response element,ISRE)启动子活性的影响;将TRIM21与STAT1真核表达载体共转染至IPEC-J2细胞,结合激光共聚焦显微镜、免疫共沉淀技术(coimmunoprecipitation,Co-IP)和Western blotting验证二者的相互作用及TRIM21对STAT1的调控效应。【结果】PDCoV在感染IPEC-J2细胞24 h达复制高峰,同时试验组细胞中STAT1、TRIM21蛋白表达及ISGs转录水平均极显著高于对照组(P<0.01)。与对照组相比,过表达STAT1后ISRE启动子活性极显著增强,PDCoV-N基因及其蛋白表达量极显著降低(P<0.01),而氟达拉滨抑制STAT1后则极显著促进病毒复制(P<0.01)。激光共聚焦显微镜观察与Co-IP结果显示,STAT1与TRIM21存在共定位及相互作用,且与对照组相比,过表达TRIM21后STAT1蛋白表达量极显著降低(P<0.01)。【结论】本研究解析了PDCoV与宿主IPEC-J2细胞先天性免疫的相互作用机制,STAT1作为关键抗病毒因子通过ISRE通路增强先天性免疫来抑制病毒复制,TRIM21则靶向STAT1并下调其表达从而帮助病毒免疫逃逸。研究结果不仅为深入理解PDCoV的致病分子机制提供了新见解,也为制定PDCoV防控策略奠定了基础。
基金funded in part by the STI2030-Major Projects(2022ZD0212200)Hainan Province Key Area R&D Program(KJRC2023C30)+1 种基金Project of Collaborative Innovation Center of One Health(XTCX2022JKB02)Sanya Yazhou Bay Science and Technology City(SKJC-JYRC-2024-38).
文摘Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.
文摘Breast cancer(BRCA)is characterized by high heterogeneity,with aggressive subtypes frequently showing poor prognosis and resistance to conventional therapies,making the discovery of new therapeutic targets and strategies imperative.Although elevated expression of discs large homolog 3(DLG3)has been reported in BRCA,its functional role in disease progression remains unclear.We performed bioinformatic analyses of clinical datasets to evaluate the prognostic significance of DLG3 expression in BRCA patients.In vitro gain-and loss-of-function experiments were conducted to assess the impact of DLG3 on BRCA cell proliferation,migration,and colony formation.Transcriptomic profiling,coupled with pharmacological inhibition,was employed to identify and validate downstream signaling pathways.Additionally,we extended our validation to an in vivo model to assess the role of DLG3 in tumor progression.We found that elevated DLG3 levels correlated with poor prognosis in breast cancer patients.Functionally,DLG3 overexpression significantly promoted cell proliferation and migration in estrogen receptor-positive MCF7 and triple-negative MDA-MB-231 breast cancer cells,whereas its knockdown suppressed these effects.Transcriptomic analyses revealed that DLG3 activates signal transducer and activator of transcription 3(STAT3)signaling,a finding further corroborated by Western blot.Critically,treatment with the STAT3 inhibitor Stattic attenuated DLG3-driven proliferation and migration,supporting a DLG3-STAT3 oncogenic axis.Furthermore,in vivo studies validated the role of DLG3 in promoting tumor growth and its correlation with elevated STAT3 signaling,consistent with our in vitro findings.Our findings establish DLG3 as a novel driver of breast cancer progression that directly activates STAT3 signaling.DLG3 thus represents both a potential prognostic biomarker and a promising therapeutic target for aggressive breast cancer subtypes,including triple-negative breast cancer.
