Argatroban promotes recovery of spinal cord injury by inhibiting the PAR1/JAK2/STAT3 signaling pathway

Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.

Exploring the mechanism of electroacupuncture at different acupoints on acute colitis rats based on JAK2/STAT3/SOCS1 signaling pathway

Objective:To investigate the mechanism of JAK2/STAT3/SOCS1 signaling pathway in electroacupuncture of different acupoints on acute colitis rats.Methods:36 SPF SD rats were randomly divided into 6 groups,with 6 rats in each group.The rat model of acute colitis was prepared by enema with glacial acetic acid solution.After the model was established,electroacupuncture was given to each acupoint group,with density wave,frequency 2Hz-50 Hz,intensity 2 mA,muscle tremor as the degree 20 min/time,1 time/day,for 3 consecutive days.Observe the general condition of rats;the pathological changes of colonic mucosa in rats were observed by HE method.The contents of serum interleukin-4(IL-4)and interleukin-8(IL-8)were detected by ELISA.Western blot and RT-PCR were used to detect the expression of JAK2,STAT3,SOCS1 protein and mRNA in rat colon tissue.Results:In contrast to the normal group,the overall condition of the model group was worse,the colonic mucosa was severely damaged,even necrotic,and the ulcer surface was obvious.The content of IL-4 in serum was obviously reduced,and the content of IL-8 was obviously go up(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously go up,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously reduced(P<0.01).In contrast to the model group,the general condition of rats in each acupoint group was significantly improved,the damage and necrosis of colonic mucosa and ulcer surface were obviously alleviated,the content of IL-4 in serum was obviously go up,and the content of IL-8 was significantly decreased(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously reduced,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously go up(P<0.05,P<0.01).Comparison of different acupoint groups,the colonic mucosal injury in the Zusanli group was significantly reduced,the content of serum IL-4 was significantly increased,and the content of IL-8 was significantly decreased(P<0.05,P<0.01).The protein content and mRNA expression of JAK2 and STAT3 in colon tissue were significantly down-regulated,while the protein content and mRNA expression of SOCS1 were significantly go up(P<0.05,P<0.01).Conclusion:Electroacupuncture at each acupoint can improve the damage of colonic mucosa and reduce the inflammatory response.The therapeutic effect of Zusanli(ST36)is better than that of Tianshu(ST25),Dachangshu(BL25)and Shangjuxu(ST37).The mechanism may be related to the regulation of JAK2/STAT3/SOCS1 signaling pathway related proteins and inflammatory cytokines IL-4 and IL-8.

Oleanolic acid inhibits colon cancer cell stemness and reverses chemoresistance by suppressing JAK2/STAT3 signaling pathway

Background:Oleanolic acid(OA),a pentacyclic triterpenoid exhibiting specific anti-cancer properties and highly effective antioxidant activity,was isolated from traditional Chinese medicinal herbs.Conversely,the OA that impacts colon cancer(CC)cells and its underlying mechanisms remain poorly understood.Methods:The cytotoxic effect of OA alone or OA-5-Fluorouracil(5-FU)combination on normal and CC cells was analyzed by methyl thiazolyl diphenyl-tetrazolium bromide(MTT).Then,the impact of OA on CC cell lines(LoVo and HT-29)proliferation and stemness were measured using colon formation and tumorsphere formation assays.Octamer-binding transcription factor 4(Oct4),Prominin-1(CD133),Nanog,and transcription factor SOX-2(SOX2)are cell stemness-related indicators whose expression was assessed usingfluorescence qPCR assay,Western blotting,and immunohistochemistry.The effect of OA on the proliferative potency of CC cells was evaluated using an in vivo model.Results:The stem-like characteristics and clone production of colon cancer cells were markedly reduced by OA alone or in combination with OA-5-FU.Moreover,OA increases the susceptibility of CC cells to 5-FU by blocking the cell stemness-related markers(CD133,Nanog,SOX2,and Oct4)expression levels both in vitro and in vivo,as well as by inactivating the activator of transcription 3(STAT3 signaling)and Janus kinase 2/signal transducer(JAK2).Conclusion:Thesefindings imply that oleanolic acid,both in vitro and in vivo,suppresses the JAK2/STAT3 pathway,which in turn reverses chemoresistance and decreases colon cancer cell stemness.Therefore,by reducing the recommended amount of 5-FU,this strategy may improve chemotherapeutic effectiveness and minimize undesired side effects.

Effects of plumbagin on migration and invasion of human hepatoma cell line via JAK2/STAT3 signaling pathway

Objective:To study the effect of plumbagin(PL)on the migration and invasion of human hepatocellular carcinoma(HCC)cells and its possible mechanism.Methods:The cell counting kit(CCK-8)was used to detect the effects of different concentrations of plumbagin on the proliferation of human hepatocellular carcinoma Huh-7 and LM3 cells.The effect of plumbagin on the migration ability of Huh-7 and LM3 cells was detected by scratch test and Transwell migration test,and the effect of on the invasion ability of Huh-7 and LM3 cells was detected by Transwell invasion test.Western Blot was used to detect the expression of E-cadherin,N-cadherin,matrix metalloproteinase-2 and related proteins in JAK2/STAT3 signaling pathway in Huh-7 and LM3 cells.Results:Plumbagin could inhibit the proliferation of Huh-7 and LM3 cells in a time-and concentration-dependent manner.Plumbagin inhibited the migration and invasion of Huh-7 and LM3 cells in a concentration dependent manner,and it can down-regulate the expression of N-cadherin and MMP-2 protein,up-regulate the expression of E-cadherin protein,and inhibit the activation of JAK2/STAT3 signaling pathway.Conclusion:Plumbagin can inhibit the migration and invasion of human hepatocellular carcinoma Huh-7 and LM3 cells,and the molecular mechanism of this process may be related to the inhibition of JAK2/STAT3 signaling pathway activation.

To explore the mechanism of Dahuang Lingxian Formula in relieving inflammatory response of bile duct cells based on IL-6/JAK/STAT3 signaling pathway

Objective:To explore the mechanism of action of Dahuang Lingxian Formula in alleviating the inflammatory response of bile duct cells in LPS-induced intrahepatic bile duct inflammation model rats based on IL-6/JAK/STAT3 signaling pathway.Methods:Fifty SD rats were randomly divided into five groups,blank group,model group,choling tablets(0.5 g/kg),and low and high concentration groups(2.4 g/kg and 4.8 g/kg)of Dahuang Lingxian Formula,ten rats in each group.Except for the blank group,the rats in each group were injected with 1.25 mg/kg LPS at the common bile duct at one time to construct an animal model of intrahepatic bile duct infection.After gavage on day 8,liver tissues were taken from rats at the hepatic hilum,and the histopathological changes of the hepatic hilum and biliary tree were observed by HE staining.The expression levels of serum glutamic alanine transaminase(ALT),glutamic oxalacetic transaminase(AST),malondialdehyde(MDA)and superoxide dismutase(SOD)were measured by biochemical method.The expression levels of interleukin 6(IL-6),Janus protein tyrosine kinase 2(JAK2),signal transducer and activator of transcription 3(STAT3)in rat serum were measured by enzyme-linked immunosorbent assay(ELISA).Protein immunoblotting(WB)and real-time fluorescence quantitative PCR(RT-qPCR)were used to detect the expression levels of IL-6,JAK2,STAT3 protein and mRNA in biliary tree tissues.Results:①Compared with the blank group,the structures such as interlobular bile ducts in the hepatic sinusoids and portal duct area of the model rats were destroyed,and inflammatory cells infiltrated around them.The expression of ALT,AST,MDA,IL-6,JAK2 and STAT3 in the serum increased significantly,the expression level of SOD decreased,and the expression levels of IL-6,JAK2 and STAT3 proteins and mRNA increased.②Compared with the model group,the degree of liver pathological damage in rats in the Chiling Ning tablet group and the low and high concentration groups of Dahuang Lingxian Formula were improved,which could significantly reduce the expression levels of ALT,AST,MDA,IL-6,JAK2,STAT3 and up-regulate SOD in serum,and down-regulate the expression of IL-6,JAK2,STAT3 protein and mRNA,with the best effect in the high concentration group of Dahuang Lingxian Formula.③Compared with the choling tablet group,the rats in the low and high concentration groups of Dahuang Lingxian Formula tended to normalize the degree of liver pathological damage,without obvious inflammatory cell infiltration,and the expression levels of ALT,AST,MDA,IL-6,JAK2,STAT3 and the expression levels of IL-6,JAK2,STAT3 protein and mRNA in serum were reduced,and the expression levels of SOD were increased,with the best effect of Dahuang Lingxian Formula The treatment effect was best in the high concentration group.Conclusion:The mechanism may be related to the down-regulation of IL-6/JAK/STAT3 signaling pathway activation,and the best therapeutic effect was achieved by the high concentration group of Dahuang Lingxian Formula.

Elevated retinol binding protein 4 levels are associated with atherosclerosis in diabetic rats via JAK2/STAT3 signaling pathway

BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occurrence and development of diabetic atheroscerosis have not been fully elucidated.AIM To summarize the potential role of retinol binding protein 4(RBP4) in the pathogenesis of diabetic atheroscerosis,particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.METHODS Male Wistar rats were randomly divided into three groups,including a control group(NC group),diabetic rat group(DM group),and diabetic atherosclerotic rat group(DA group).The contents of total cholesterol(TC), high-density lipoprotein cholesterol(HDL-c), triglycerides(TG), low-density lipoprotein cholesterol(LDLc), fasting insulin(FINS),fasting plasma glucose,and hemoglobin A1 c(HbA1 c)were measured.Moreover,the adipose and serum levels of RBP4,along with the expression levels of JAK2, phosphorylated JAK2(p-JAK2), STAT3,phosphorylated STAT3(p-STAT3), B-cell lymphoma-2(Bcl-2), and Cyclin D1 in aortic tissues were also measured.Besides,homeostasis model assessment of insulin resistance(HOMA-IR) and atherogenic indexes(AI) were calculated.RESULTS Compared with the NC and DM groups,the levels LDL-c,TG,TC,FINS,HOMAIR,RBP4,and AI were upregulated,whereas that of HDL-c was downregulated in the DA group(P <0.05);the mRNA levels of JAK2,STAT3,Cyclin D1,and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group;P-JAK2,p-JAK2/JAK2 ratio,p-STAT3,p-STAT3/STAT3 ratio,Cyclin D1,and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group.In addition,as shown by Pearson analysis,serum RBP4 had a positive correlation with TG,TC,LDL-c,FINS,HbA1 C,p-JAK2,p-STAT3,Bcl-2,Cyclin D1,AI,and HOMA-IR but a negative correlation with HDL-c.In addition,multivariable logistic regression analysis showed that serum RBP4,p-JAK2,p-STAT3,and LDL-c were predictors of the presence of diabetic atherosclerosis.CONCLUSION RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.

3-epi-bufotalin suppresses the proliferation in colorectal cancer cells through the inhibition of the JAK1/STAT3 signaling pathway

Traditional Chinese medicine(TCM)has been increasingly employed in the last decades in China for both preventing and treating a variety of cancers.3-epi-bufotalin is an active ingredient of TCM“Chanpi”with anti-tumor potential.However,the effect and mechanism of 3-epi-bufotalin on colorectal cancers were not well disclosed.The present study demonstrated that 3-epi-bufotalin could reduce viability,trigger apoptosis,and block the cell cycle at the G2/M stage in colorectal cancer cell lines HT29,RKO,and COLO205 in vitro.Moreover,3-epi-bufotalin inhibited the JAK1/STAT3 signaling pathway.These results indicated the anti-proliferation ability of 3-epi-bufotalin in colorectal cancer cells.

补阳还五汤通过调控PI3K/Akt、JAK2/STAT3信号促进BMSC趋化迁移对外伤性脊髓损伤大鼠神经元活性及认知功能的影响

目的研究补阳还五汤通过调控磷脂酰肌醇-3激酶/蛋白激酶B(PI3K/Akt)、内源性酪氨酸激酶(JAK)2/信号传导和转录启动因子(STAT)3信号促进骨髓间充质干细胞(BMSCs)趋化迁移对外伤性脊髓损伤大鼠的神经元活性及认知功能的影响。方法选取健康大鼠53只,随机分为健康组(健康大鼠常规饲养)、损伤组(建立脊髓损伤模型)、干预组(补阳还五汤治疗)、对照组(甲泼尼龙治疗),每组12只,剩余5只大鼠用于补阳还五汤含药血清制备。流式细胞术鉴定BMSCs细胞。Transwell小室法测大鼠BMSCs迁移。高架十字迷宫和Morris水迷宫实验检测大鼠认知功能。苏木素-伊红(HE)染色检测脊髓组织病理形态。TUNEL测脊髓组织神经细胞凋亡。免疫组化检测p-JAK2、p-STAT3。Western印迹测PI3K、p-PI3K、Akt、p-Akt。结果传代后的培养细胞呈旋窝状或放射状贴壁生长,细胞多呈星形、梭形或三角状,培养3代后,细胞贴壁加快、形态均一,呈旋窝状或单层放射状生长。培养细胞表面抗原CD29、CD90为阳性,CD31、CD45为阴性,提示其为BMSCs细胞。与健康组相比,损伤组总路程、进入开臂次数、穿越平台次数显著降低,不同时间的潜伏期显著升高(P<0.05)。与损伤组相比,干预组与对照组总路程、进入开臂次数、穿越平台次数显著升高,不同时间的潜伏期显著降低(P<0.05)。干预组与对照组各指标对比无统计学差异(P>0.05)。健康组脊髓组织结构完整。损伤组脊髓组织疏松水肿,有细胞空泡变性产生。相较于损伤组,干预组与对照组大鼠脊髓组织病理形态有所改善。与健康组相比,损伤组BMSCs、PI3K、Akt、p-PI3K、p-Akt显著降低,神经细胞凋亡率、p-JAK2、p-STAT3显著升高(P<0.05)。与损伤组相比,干预组BMSCs、PI3K、Akt、p-PI3K、p-Akt显著升高,神经细胞凋亡率、p-JAK2、p-STAT3显著降低(P<0.05)。干预组与对照组各指标水平无统计学差异(P>0.05)。结论补阳还五汤通过激活PI3K/Akt通路抑制JAK2/STAT3信号通路的激活,促进BMSCs的迁移,减轻神经细胞的凋亡,起到神经保护的作用,从而改善脊髓损伤大鼠的认知功能。

Value of spiral CT perfusion parameters for evaluating acute pancreatitis and their correlation with inflammatory factor and JAK2/STAT3 signaling pathway

Objective: To study the value of spiral CT perfusion parameters for evaluating acute pancreatitis and their correlation with inflammatory factor and JAK2/STAT3 signaling pathway. Methods: Patients with acute pancreatitis and patients with pancreatic trauma who underwent surgical resection in Liaocheng Dongchangfu People's Hospital between May 2014 and March 2017 were selected and enrolled in the AP group and the control group of the research respectively;spiral CT perfusion scanning was conducted before surgery to measure the blood flow (BF), blood volume (BV), and mean transit time (MTT), and the serum was collected to determine the contents of inflammatory factors;pancreatitis tissue and normal pancreatic tissue were collected after surgical resection to determine the expression of JAK2/STAT3 signal molecules. Results: pancreatic tissue BF and BV levels of AP group were significantly lower than those of control group while MTT level was not different from that of control group;CRP, PCT, HMGB-1, Ghrelin and sTREM-1 contents in serum as well as JAK2, STAT3, Bcl-2 and Bcl-xL mRNA expression in pancreatic tissue of AP group were significantly higher than those of control group and negatively correlated with BF and BV levels in pancreatic tissue. Conclusion: Spiral CT perfusion parameters BF and BV can reflect the microcirculatory disorder of acute pancreatitis and are associated with the increased secretion of inflammatory factors and the activation of JAK2/STAT3 signaling pathway in the course of disease.

毛蕊异黄酮介导GP130/JAK/STAT通路对脊髓星形胶质细胞氧化损伤的影响

目的探究毛蕊异黄酮介导糖蛋白(GP)130/Janus酪氨酸蛋白激酶(JAK)/信号转导及转录激活因子(STAT)通路对脊髓星形胶质细胞损伤的影响。方法原代分离大鼠脊髓星形胶质细胞,并利用免疫荧光检测胶原纤维酸性蛋白(GFAP)。分别加入50、100、150μmol/L毛蕊异黄酮预处理脊髓星形胶质细胞12 h,然后加入H_(2)O_(2)处理24 h造氧化损伤模型,CCK8检测各组细胞增殖情况,选择合适的毛蕊异黄酮处理浓度。实验分组:空白对照(Control)组、模型(H_(2)O_(2))组、模型+毛蕊异黄酮预处理(H_(2)O_(2)+Calycosin)组、模型+毛蕊异黄酮预处理+抑制剂Ly294002(H_(2)O_(2)+Calycosin+Ly294002)组、模型+毛蕊异黄酮处理+抑制剂Stattic(H_(2)O_(2)+Calycosin+Stattic)组。CCK8检测各组细胞增殖情况,流式检测各组细胞凋亡和周期情况,免疫荧光检测各组细胞样本中Brdu水平;Western印迹检测各组细胞中p-JAK2、p-STAT3、p-蛋白激酶B(AKT)、GP130、白细胞介素(IL)-6蛋白表达水平。结果H_(2)O_(2)处理能够抑制脊髓星形胶质细胞的增殖并诱导其凋亡,氧化损伤模型细胞组中p-JAK2、p-STAT3、p-AKT、GP130、IL-6的蛋白表达水平显著增加,而毛蕊异黄酮预处理后能够减轻H_(2)O_(2)造成的氧化损伤,促进增殖和抑制凋亡,并显著抑制p-JAK2、p-STAT3、p-AKT、GP130、IL-6蛋白表达水平(P<0.05)。结论蕊异黄酮能够促进氧化损伤的星形胶质细胞增殖并抑制其凋亡,并能通过抑制磷脂酰肌醇-3激酶(PI3K)/AKT通路磷酸化、JAK2/STAT3通路磷酸化起作用。

JAK/STAT信号通路及其对昆虫免疫的调控

JAK/STAT信号通路参与细胞的生长、分化、凋亡和免疫调节等重要的生物学过程,是细胞因子介导的最重要的信号转导途径之一。在昆虫中,JAK/STAT是一条相对保守的信号途径,与Toll途径和Imd途径共同作为主要免疫途径以抵御病原物入侵,在昆虫免疫、激素调控和其他生理调节过程中发挥着十分重要的作用。本文介绍了细胞因子受体超家族、JAKs家族、STATs家族和JAK/STAT信号通路及其负反馈调节的作用机制,分析了寄生物、病毒和真菌感染昆虫时,JAK/STAT信号通路的重要功能及最新研究进展,并提出了JAK/STAT信号通路研究中尚待解决的问题,以期为该领域后续深入研究提供方向和参考。

JAK/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila

In multicellular organisms, biological activities are regulated by cell signaling. The various signal transduction path- ways regulate cell fate, proliferation, migration, and polarity. Miscoordination of the communicative signals will lead to disasters like cancer and other fatal diseases. The JAK/STAT signal transduction pathway is one of the pathways, which was first identified in vertebrates and is highly conserved throughout evolution. Studying the JAK/STAT signal transduc- tion pathway in Drosophila provides an excellent opportunity to understand the molecular mechanism of the cell regu- lation during development and tumor formation. In this review, we discuss the general overview of JAK/STAT signaling in Drosophila with respect to its functions in the eye development and stem cell fate determination.

Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn’s disease

In 2018,the pan-Janus kinase(JAK)inhibitor tofacitinib was launched for the treatment of ulcerative colitis(UC).Although tofacitinib has proven efficacious in patients with active UC,it failed in patients with Crohn’s disease(CD).This finding strongly hints at a different contribution of JAK signaling in both entities.Here,we review the current knowledge on the interplay between the JAK/signal transducer and activator of transcription(STAT)pathway and inflammatory bowel diseases(IBD).In particular,we provide a detailed overview of the differences and similarities of JAK/STAT-signaling in UC and CD,highlight the impact of the JAK/STAT pathway in experimental colitis models and summarize the published evidence on JAK/STAT-signaling in immune cells of IBD as well as the genetic association between the JAK/STAT pathway and IBD.Finally,we describe novel treatment strategies targeting JAK/STAT inhibition in UC and CD and comment on the limitations and challenges of the new drug class.

Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway

BACKGROUND:Exosomes and exosomal microRNAs have been implicated in tumor occurrence and metastasis.Our previous study showed that microRNA-761(miR-761)is overexpressed in hepatocellular carcinoma(HCC)tissues and that its inhibition affects mitochondrial function and inhibits HCC metastasis.The mechanism by which exosomal miR-761 modulates the tumor microenvironment has not been elucidated.METHODS:Exosomal miR-761 was detected in six cell lines.Cell counting kit-8(CCK-8)and transwell migration assays were performed to determine the function of exosomal miR-761 in HCC cells.The luciferase reporter assay was used to analyze miR-761 target genes in normal fi broblasts(NFs).The inhibitors AZD1480 and C188-9 were employed to determine the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway in the transformation of cancer-associated fi broblasts(CAFs).RESULTS:In this study,we characterized the mechanism by which miR-761 reprogrammed the tumor microenvironment.We found that HCC-derived exosomal miR-761 was taken up by NFs.Moreover,HCC exosomes aff ected the tumor microenvironment by activating NFs via suppressor of cytokine signaling 2(SOCS2)and the JAK2/STAT3 signaling pathway.CONCLUSIONS:These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs.Our fi ndings may inspire new strategies for HCC prevention and therapy.

Research progress on signaling pathways in cirrhotic portal hypertension

Portal hypertension(PHT) is an important consequence of liver cirrhosis, which can lead to complications that adversely affect a patient's quality of life and survival, such as upper gastrointestinal bleeding, ascites, and portosystemic encephalopathy. In recent years, advances in molecular biology have led to major discoveries in the pathological processes of PHT, including the signaling pathways that may be involved: PI3 K-AKT-mTOR, RhoA/Rho-kinase, JAK2/STAT3, and farnesoid X receptor. However, the pathogenesis of PHT is complex and there are numerous pathways involved. Therefore, the targeting of signaling pathways for medical management is lagging. This article summarizes the progress that has been made in understanding the signaling pathways in PHT, and provides ideas for treatment of the disorder.

川穹嗪对AngⅡ诱导的大鼠心肌肥大细胞JAK-STAT通路作用

目的:研究川穹嗪对心肌肥大JAK-STAT通路的影响。方法:建立心肌肥大动物模型,分离培养新生大鼠心肌细胞,利用RT-PCR检测试验组和对照组基因ANP相对水平、Western blot检测试验组和对照组心肌肥大信号转导途径分子pJAK2、pJAK1、pSTAT3,并进行统计学分析。结果:川芎嗪可显著抑制ANP mRNA的表达(P<0.01),可明显抑制JAK2 JAK1 STAT3的表达(P<0.01)。结论:川穹嗪能干扰大鼠心肌肥大JAK-STAT信号转导通路,为中药干扰JAK-STAT信号转导通路治疗心肌肥大奠定基础。

JAK/STAT途径调节瘦素诱导的肝星状细胞Ⅰ型胶原基因的表达

目的研究瘦素对肝星状细胞(HSC)α1(Ⅰ)型胶原mRNA表达和蛋白合成的影响,探讨Janus激酶/信号传导及活化转录因子(JAK/STAT)信号传导通路在瘦素诱导的HSC胶原基因表达过程中的作用。方法采用RT-PCR法、ELISA法和Western blot法分别检测不同浓度的瘦素对人肝星状细胞株LX-2α1(Ⅰ)型胶原mRNA表达、蛋白合成以及JAK1、STAT3磷酸化状态的影响;采用Western blot法和RT-PCR法分别观察JAK1抑制剂AG490对瘦素诱导的JAK1磷酸化和α1(Ⅰ)型胶原mRNA表达的影响;采用Western blot法分别观察AG490、LX-2转染STAT3反义寡核苷酸(STAT3-ASON)对瘦素诱导的STAT3磷酸化状态的影响;应用RT-PCR法检测LX-2转染STAT3-ASON对瘦素诱导的α1(Ⅰ)型胶原mRNA表达的影响。结果瘦素增加LX-2α1(Ⅰ)型胶原mRNA表达和蛋白合成,呈剂量效应关系,当瘦素浓度为80μg·L-1时达到最大值;瘦素促进JAK1、STAT3磷酸化,呈时间效应关系;AG490完全阻断瘦素诱导的JAK1、STAT3磷酸化和α1(Ⅰ)型胶原mRNA的表达;LX-2转染STAT3-ASON阻断瘦素诱导的STAT3磷酸化和α1(Ⅰ)型胶原mRNA的表达。结论瘦素通过增加HSCα1(Ⅰ)型胶原mRNA表达和蛋白合成而在肝纤维化发生发展过程中发挥重要的作用,JAK/STAT信号传导通路参与并调节该过程,AG490和LX-2转染STAT3-ASON可有效阻滞此传导途径。在人HSC中,活化的JAK1和STAT3信号可作为肝纤维化治疗新的分子靶点。

腹腔感染大鼠JAK/STAT对肺TNF-α表达的介导作用

目的探讨Janus激酶/信号转导和转录激活(janus kinase/signal transducer and activator of transcription,JAK/STAT)通路对严重腹腔感染大鼠肺组织TNF-α表达的调节作用及其在ARDS中的意义。方法采用CLP模型,大鼠随机分为正常对照组、CLP脓毒症组、JAK激酶抑制剂处理组和STAT抑制剂处理组。采用逆转录多聚酶链式反应测定肺组织TNF-αmRNA水平,酶联免疫吸附试验检测试剂盒检测TNF-α蛋白含量。结果与正常对照组相比,CLP后各时间点TNF-αmRNA和蛋白含量升高明显(P<0.01)。JAK和STATA抑制剂预处理后,与CLP组相应时间点相比,CLP后多个时间点TNF-αmRNA表达和蛋白含量显著下降(P<0.05或0.01);呼吸功能同时有所改善。结论腹腔脓毒症时肺组织TNF-α表达明显升高,抑制JAK/STAT通路的活化可下调肺组织TNF-α的表达,这可能有助于防止脓毒症所致肺组织损伤。

JAK/STAT信号转导通路及中药干预在缺血性脑卒中的研究进展

缺血性脑卒中是老年人常见疾病,该疾病的高发病率、高死亡率以及高致残率特点使其成为全球关注的健康难题。JAK/STAT途径作为一条新近发现的信号转导通路,广泛参与神经元生长、分化、凋亡等过程,并且与脑卒中的病理生理过程密切相关,但目前对该通道在缺血性脑卒中疾病中的功能和作用机制尚未能完全阐明。该文将结合国内外JAK/STAT通路与缺血性脑卒中疾病的最新研究报道,对JAK/STAT信号转导途径在缺血脑卒中疾病过程中的作用和机制进行综述,并系统绘制缺血性脑卒中神经病变过程各种相关信号分子的网络关系图,以便更深入了解脑卒中病理发生过程,为寻找抗脑缺血疾病治疗新药,提供较为系统的科学文献支持。

感染性休克大鼠JAK/STAT对组织IFN-γ表达的影响

目的探讨Janus激酶/信号转导和转录激活子(janus kinase/signal transducer and activator of transcription,JAK/STAT)通路对严重腹腔感染肝、肺中干扰素-γ(interferon-,γIFN-γ)表达的调节作用。方法采用盲肠结扎穿孔(CLP)模型,大鼠分为CLP组、JAK激酶抑制剂(AG490)处理组和STAT抑制剂(RPM)处理组。采用RT-PCR技术和ELISA检测试剂盒检测肝、肺IFN-γmRNA表达水平和蛋白含量。结果与CLP 0时相点相比,CLP后各时相点IFN-γmRNA表达水平和蛋白含量不同程度升高(P<0.05,P<0.01)。经JAK和STATA抑制剂预处理后,与CLP组相应时相点相比,CLP后多个时相点IFN-γmRNA表达水平和蛋白含量显著下降(P<0.05,P<0.01)。结论腹腔脓毒症时肝、肺IFN-γ表达明显升高,抑制JAK/STAT通路的活化可下调肝、肺IFN-γ的表达,这可能是防止及治疗多器官功能衰竭的一个新的干预途径。