Objective To investigate the effect of honokiol(HON)and the role of high-mobility group protein B1(HMGB1)on the pathogenesis of severe acute pancreatitis(SAP).Methods Thirty mice were numbered according to weight,and ...Objective To investigate the effect of honokiol(HON)and the role of high-mobility group protein B1(HMGB1)on the pathogenesis of severe acute pancreatitis(SAP).Methods Thirty mice were numbered according to weight,and randomly divided into 5 groups using a random number table,including control,SAP,SAP and normal saline(SAP+NS),SAP and ethyl pyruvate(SAP+EP),or SAP+HON groups,6 mice in each group.Samples of pancreas,intestine,and blood were collected 12 h after SAP model induction for examination of pathologic changes,immune function alterations by enzyme linked immunosorbent assay(ELISA),and Western blot.In vitro experiments,macrophages were divided into 5 groups,the control,lipopolysaccharide(LPS),LPS+DMSO(DMSO),LPS+anti-HMGB1 monoclonal antibody(mAb),and LPS+HON groups.The tight connection level was determined by transmission electron microscopy and fluorescein isothiocyanate-labeled.The location and acetylation of HMGB1 were measured by Western blot.Finally,pyridone 6 and silencing signal transducer and activator of the transcription 1(siSTAT1)combined with honokiol were added to determine whether the Janus kinase(JAK)/STAT1 participated in the regulation of honokiol on HMGB1.The protein expression levels of HMGB1,JAK,and STAT1 were detected using Western blot.Results Mice with SAP had inflammatory injury in the pancreas,bleeding of intestinal tissues,and cells with disrupted histology.Mice in the SAP+HON group had significantly fewer pathological changes.Mice with SAP also had significant increases in the serum levels of amylase,lipase,HMGB1,tumor necrosis factor-α,interleukin-6,diamine oxidase,endotoxin-1,and procalcitonin.Mice in the SAP+HON group did not show these abnormalities(P<0.01).Studies of Caco-2 cells indicated that LPS increased the levels of occludin and claudin-1 as well as tight junction permeability,decreased the levels of junctional adhesion molecule C,and elevated intercellular permeability(P<0.01).HON treatment blocked these effects.Studies of macrophages indicated that LPS led to low nucl展开更多
腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)是参与调节细胞能量代谢的关键激酶,也可通过沉默信息调节因子1(silent information regulator of transcription 1,SIRT1)依赖的途径发挥抗炎效应。AMPK激活SIRT1的机制在于AMP...腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)是参与调节细胞能量代谢的关键激酶,也可通过沉默信息调节因子1(silent information regulator of transcription 1,SIRT1)依赖的途径发挥抗炎效应。AMPK激活SIRT1的机制在于AMPK促进了SIRT1的激活因子NAD+的生成,并解除了DBC1对SIRT1活性及p53对SIRT1表达的抑制效应;而SIRT1则通过催化NF-κB、AP-1和组蛋白的去乙酰化反应而降低转录因子活性、恢复染色质致密构象,这可抑制炎症相关基因的转录。此外,AMPK激活剂及临床常用降糖药二甲双胍均可通过激活AMPK而在多种炎症相关性疾病模型中发挥有效保护作用。因而,AMPKSIRT1通路有望成为抗炎治疗的新靶点。展开更多
目的探讨欣胃颗粒对胃癌前病变(precancerous lesionof gastric cancer,PLGC)大鼠信号传导及转录活化因子(signal transducers and activators of transcription,STATs)、酪氨酸磷酸化STAT3(p-STAT3)信号通路的影响。方法 96只Wistar大...目的探讨欣胃颗粒对胃癌前病变(precancerous lesionof gastric cancer,PLGC)大鼠信号传导及转录活化因子(signal transducers and activators of transcription,STATs)、酪氨酸磷酸化STAT3(p-STAT3)信号通路的影响。方法 96只Wistar大鼠随机分为空白对照组(空白组)16只,造模组80只。采用N-甲基-N′-硝基-亚硝基胍(MNNG)为主的复合因素造模法制备PLGC大鼠模型,将造模成功大鼠随机抽取75只分为模型组、维霉素组、欣胃颗粒低剂量组、欣胃颗粒中剂量组、欣胃颗粒高剂量组,每组15只。空白组随机抽取大鼠15只。空白组予普通标准饲料喂养,并予10mL/kg生理盐水灌胃;欣胃颗粒低、中、高剂量组每日分别给予1.254、2.508、5.016g/kg中药冲剂灌胃;模型组给予10mL/kg生理盐水灌胃;维酶素组将维酶素片研碎制成0.1g/mL的混悬液以10mL/kg灌胃。均每日1次,给药12周。观察各组大鼠的一般状态(包括大鼠皮毛、活动度、进食进水量、粪便、体重及存活情况)和胃黏膜组织病理学的变化,观察其对STAT3、p-STAT3表达的影响。结果与空白组比较,模型组STAT3、p-STAT3表达水平增高(P<0.05)。欣胃颗粒各剂量组大鼠活动度、进食水量、体重等一般状态较模型组好转;与模型组比较,欣胃颗粒低、中、高剂量组,STAT3、p-STAT3表达水平降低,差异均有统计学意义(P<0.05);PLGC即肠上皮化生(intestinal metaplasia,IM)和异性增生(dysplasia,DYS)发生率均显著下降,差异有统计学意义(P<0.05)。与维酶素组比较,欣胃颗粒中、高剂量组IM及DYS发生率均显著下降,差异有统计学意义(P<0.05),欣胃颗粒中、高剂量组STAT3、p-STAT3表达水平下降更显著,差异有统计学意义(P<0.05)。结论欣胃颗粒对PLGC大鼠胃黏膜组织病理具有明显改善作用,可下调STAT3、p-STAT3的表达以达到对抗PLGC的作用。展开更多
目的从白细胞介素(interleukin,IL)-27/信号转导和转录激活因子1(signal transducer and activator of transcription1,STAT1)探究针刺肺俞穴改善哮喘大鼠辅助性T细胞(helper T cell,Th)1/Th2免疫平衡的可能机制。方法取140只SD雄性大鼠...目的从白细胞介素(interleukin,IL)-27/信号转导和转录激活因子1(signal transducer and activator of transcription1,STAT1)探究针刺肺俞穴改善哮喘大鼠辅助性T细胞(helper T cell,Th)1/Th2免疫平衡的可能机制。方法取140只SD雄性大鼠,随机分为正常组、模型组、IL-27预防组、IL-27治疗组、针刺肺俞组、STAT1抑制剂组、针刺肺俞加STAT1抑制剂组,每组20只。除正常组外,其余各组均进行卵白蛋白反复致敏建立哮喘模型。肺功能仪检测气道高反应性;ELISA法检测血清及肺泡灌洗液中IL-4、干扰素γ(interferonγ,IFN-γ)、免疫球蛋白E(immunoglobulin,Ig E)水平;流式细胞仪检测脾脏Th1/Th2比例;HE染色观察肺组织病理变化;免疫组化法检测IL-4、IFN-γ、磷酸化STAT1(p-STAT1)阳性表达;Western blot法检测IL-27、STAT1、IL-4、IFN-γ、T-bet及GATA3蛋白表达。结果与正常组相比,模型组大鼠气道高反应性升高,脾脏Th1/Th2比例降低,血清及肺泡灌洗液中IL-4水平升高而IFN-γ水平降低,肺泡灌洗液中嗜酸性粒细胞比例升高,肺组织支气管黏膜水肿及炎性细胞浸润等病理损伤加重,促Th1/Th2比例平衡相关通路IL-27/STAT1处于抑制状态(P<0.05)。与模型组相比,IL-27预防组、IL-27治疗组及针刺肺俞组均可缓解大鼠肺组织损伤,促进IL-27/STAT1活化,纠正Th1/Th2平衡,改善哮喘大鼠气道高反应性(P<0.05);其中,IL-27预防组对哮喘大鼠的上述改善作用均优于针刺肺俞组(P<0.05)。此外,STAT1抑制剂可加重哮喘大鼠肺组织损伤,促进气道高反应及Th1/Th2免疫平衡紊乱,并削弱针刺肺俞穴发挥的促IL-27/STAT1活化、纠正Th1/Th2免疫平衡等作用(P<0.05)。结论针刺肺俞穴治疗哮喘大鼠的作用机制,可能与促进IL-27/STAT1通路活化,纠正Th1/Th2免疫平衡有关。展开更多
基金Supported by National Natural Science Foundation of China(No.81803920 and 81673789)Key Medical Specialty Construction Project of Shanghai Municipal Health Commission(No.ZK2019B18)Shanghai Putuo District Health Commission Characteristic Disease Construction Project(No.2020TSZB03)。
文摘Objective To investigate the effect of honokiol(HON)and the role of high-mobility group protein B1(HMGB1)on the pathogenesis of severe acute pancreatitis(SAP).Methods Thirty mice were numbered according to weight,and randomly divided into 5 groups using a random number table,including control,SAP,SAP and normal saline(SAP+NS),SAP and ethyl pyruvate(SAP+EP),or SAP+HON groups,6 mice in each group.Samples of pancreas,intestine,and blood were collected 12 h after SAP model induction for examination of pathologic changes,immune function alterations by enzyme linked immunosorbent assay(ELISA),and Western blot.In vitro experiments,macrophages were divided into 5 groups,the control,lipopolysaccharide(LPS),LPS+DMSO(DMSO),LPS+anti-HMGB1 monoclonal antibody(mAb),and LPS+HON groups.The tight connection level was determined by transmission electron microscopy and fluorescein isothiocyanate-labeled.The location and acetylation of HMGB1 were measured by Western blot.Finally,pyridone 6 and silencing signal transducer and activator of the transcription 1(siSTAT1)combined with honokiol were added to determine whether the Janus kinase(JAK)/STAT1 participated in the regulation of honokiol on HMGB1.The protein expression levels of HMGB1,JAK,and STAT1 were detected using Western blot.Results Mice with SAP had inflammatory injury in the pancreas,bleeding of intestinal tissues,and cells with disrupted histology.Mice in the SAP+HON group had significantly fewer pathological changes.Mice with SAP also had significant increases in the serum levels of amylase,lipase,HMGB1,tumor necrosis factor-α,interleukin-6,diamine oxidase,endotoxin-1,and procalcitonin.Mice in the SAP+HON group did not show these abnormalities(P<0.01).Studies of Caco-2 cells indicated that LPS increased the levels of occludin and claudin-1 as well as tight junction permeability,decreased the levels of junctional adhesion molecule C,and elevated intercellular permeability(P<0.01).HON treatment blocked these effects.Studies of macrophages indicated that LPS led to low nucl
文摘腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)是参与调节细胞能量代谢的关键激酶,也可通过沉默信息调节因子1(silent information regulator of transcription 1,SIRT1)依赖的途径发挥抗炎效应。AMPK激活SIRT1的机制在于AMPK促进了SIRT1的激活因子NAD+的生成,并解除了DBC1对SIRT1活性及p53对SIRT1表达的抑制效应;而SIRT1则通过催化NF-κB、AP-1和组蛋白的去乙酰化反应而降低转录因子活性、恢复染色质致密构象,这可抑制炎症相关基因的转录。此外,AMPK激活剂及临床常用降糖药二甲双胍均可通过激活AMPK而在多种炎症相关性疾病模型中发挥有效保护作用。因而,AMPKSIRT1通路有望成为抗炎治疗的新靶点。
文摘目的从白细胞介素(interleukin,IL)-27/信号转导和转录激活因子1(signal transducer and activator of transcription1,STAT1)探究针刺肺俞穴改善哮喘大鼠辅助性T细胞(helper T cell,Th)1/Th2免疫平衡的可能机制。方法取140只SD雄性大鼠,随机分为正常组、模型组、IL-27预防组、IL-27治疗组、针刺肺俞组、STAT1抑制剂组、针刺肺俞加STAT1抑制剂组,每组20只。除正常组外,其余各组均进行卵白蛋白反复致敏建立哮喘模型。肺功能仪检测气道高反应性;ELISA法检测血清及肺泡灌洗液中IL-4、干扰素γ(interferonγ,IFN-γ)、免疫球蛋白E(immunoglobulin,Ig E)水平;流式细胞仪检测脾脏Th1/Th2比例;HE染色观察肺组织病理变化;免疫组化法检测IL-4、IFN-γ、磷酸化STAT1(p-STAT1)阳性表达;Western blot法检测IL-27、STAT1、IL-4、IFN-γ、T-bet及GATA3蛋白表达。结果与正常组相比,模型组大鼠气道高反应性升高,脾脏Th1/Th2比例降低,血清及肺泡灌洗液中IL-4水平升高而IFN-γ水平降低,肺泡灌洗液中嗜酸性粒细胞比例升高,肺组织支气管黏膜水肿及炎性细胞浸润等病理损伤加重,促Th1/Th2比例平衡相关通路IL-27/STAT1处于抑制状态(P<0.05)。与模型组相比,IL-27预防组、IL-27治疗组及针刺肺俞组均可缓解大鼠肺组织损伤,促进IL-27/STAT1活化,纠正Th1/Th2平衡,改善哮喘大鼠气道高反应性(P<0.05);其中,IL-27预防组对哮喘大鼠的上述改善作用均优于针刺肺俞组(P<0.05)。此外,STAT1抑制剂可加重哮喘大鼠肺组织损伤,促进气道高反应及Th1/Th2免疫平衡紊乱,并削弱针刺肺俞穴发挥的促IL-27/STAT1活化、纠正Th1/Th2免疫平衡等作用(P<0.05)。结论针刺肺俞穴治疗哮喘大鼠的作用机制,可能与促进IL-27/STAT1通路活化,纠正Th1/Th2免疫平衡有关。
