The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, th...The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, the cellular and molecular mechanisms underlying sepsis-induced brain damage remain elusive. In the present study, we found severe loss of neurons in the hippocampal CA1 region in rats with sepsis-induced brain damage following intraperitoneal injection of endotoxin, The expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 was significantly increased in brain tissues following lipopolysaccharide exposure. AG490 （JAK2 antagonist） and rapamycin （STAT3 antagonist） significantly reduced neuronal loss and suppressed the increased expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 in the hippocampal CA1 region in sepsis-induced brain damaged rats. Overall, these data suggest that blockade of the JAK/STAT signal transduction pathway is neuroprotective in sepsis-induced brain damage via the inhibition of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 exoression.展开更多
Background:Galectin 2(LGALS2)is a protein previously reported to serve as a mediator of disease progression in a range of cancers.The function of LGALS2 in oral squamous cell carcinoma(OSCC),however,has yet to be expl...Background:Galectin 2(LGALS2)is a protein previously reported to serve as a mediator of disease progression in a range of cancers.The function of LGALS2 in oral squamous cell carcinoma(OSCC),however,has yet to be explored,prompting the present study to address this literature gap.Methods:Overall,144 paired malignant tumor tissues and paracancerous OSCC patient samples were harvested and the LGALS2 expression levels were examined through qPCR and western immunoblotting.The LGALS2 coding sequence was introduced into the pcDNA3.0 vector,to enable the overexpression of this gene,while an LGALS2-specific shRNA and corresponding controls were also obtained.The functionality of LGALS2 as a regulator of the ability of OSCC cells to grow and undergo apoptotic death in vitro was assessed through EdU uptake and CCK-8 assays,and flow cytometer,whereas a Transwell system was used to assess migratory activity and invasivity.An agonist of the Janus Kinase 2(JAK2)/Signal Transducer and Activator of Transcription 3(STAT3)pathway was also used to assess the role of this pathway in the context of LGALS2 signaling.Results:Here,we found that lower LGALS2 protein and mRNA expression were evident in OSCC tumor tissue samples,and these expression levels were associated with clinicopathological characteristics and patient survival outcomes.Silencing LGALS2 enhanced proliferation in OSCC cells while rendering these cells better able to resist apoptosis.The opposite was instead observed after LGALS2 was overexpressed.Mechanistically,the ability of LGALS2 to suppress the progression of OSCC was related to its ability to activate the JAK/STAT3 signaling axis.Conclusion:Those results suggest a role for LGALS2 as a suppressor of OSCC progression through its ability to modulate JAK/STAT3 signaling,supporting the potential utility of LGALS2 as a target for efforts aimed at treating OSCC patients.展开更多
Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(...Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.展开更多
Objectives： To investigate the mechanism of Liuwei Dihuang Pill （六味地黄丸, LDP） in treating postmenopausal osteoporosis （PMOP） with Shen （Kidney） yin deficiency. Methods： In this study, 205 cases of PMOP wer...Objectives： To investigate the mechanism of Liuwei Dihuang Pill （六味地黄丸, LDP） in treating postmenopausal osteoporosis （PMOP） with Shen （Kidney） yin deficiency. Methods： In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group （Group A）, PMOP Shen-yang deficiency group （Group B）, PMOP without Shen deficiency group （Group C）, and control group （Group N）. Real-time polymerase chain reaction （RT-PCR） and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 （CLCF1）, ankyrin repeat and SOCS box containing 1 （ASB1）, and proldneticin 2 （PROK2） genes and the Janus kinase/signal transducer and activator of transcription （JAK/STAT） signaling pathway. Results： The mRNA （P〈0.05） and protein （P〈0.01） expression levels of the CLCF1 gone in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gone were obviously up-regulated （P〈0.01）. After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated （both P〈0.01）, and the average bone density of the top femur had significantly increased （P〈0.05）. In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3. Conclusions： The CLCF1 gone is an important gone associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gone expression and activation of the JAK/STAT signaling pathway.展开更多
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’...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.展开更多
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 ...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.展开更多
Objective: To observe the effect of electroacupuncture (EA) on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in knee joint synovial tissues of rats with rheumatoid arthritis (R...Objective: To observe the effect of electroacupuncture (EA) on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in knee joint synovial tissues of rats with rheumatoid arthritis (RA) and to explore the action mechanism of EA on RA. Methods: Twelve of the 48 SPF male Sprague-Dawley (SD) rats were assigned to a normal group by the random number table method. The remaining 36 rats were subjected to RA model preparation by intradermal injection of the Freund's complete adjuvant into the right hind foot pad of each rat under sterile conditions. After the model was successfully prepared, rats were then divided into a model group, a drug group and an EA group according to a random number table method (n=12). Rats in the drug group were treated with 2 mL aqueous solution of tripterygium glycosides [8.1 mg/(kg?bw)];rats in the EA group were treated with EA at bilateral Yanglingquan (GB 34) and Zusanli (ST 36), for 30 min each time;rats in the normal group and the model group were placed in a special rat fixation tank for 30 min each time, and received the same dose of normal saline as those in the drug group. Rats in all groups received intervention once a day for 4 weeks. Diameter of rat ankle joint and rat arthritis index were measured before and after the intervention. At the end of the experiment, the expressions of phospho-JAK2 and phospho-STAT3 were determined by immunohistochemistry. Quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect JAK2 and STAT3 mRNAs expressions. Results: After the model was produced, the arthritis index >2 was considered successful in model preparation. Compared with the model group, the ankle joint diameters and arthritis indexes of rats in the drug group and the EA group were significantly lower (all P<0.01);immunohistochemical staining cells with phospho-JAK2 and phospho-STAT3 were significantly decreased (all P<0.01);the expression levels of JAK2 and STAT3 mRNAs were decreased with statistical differences (all P<0.01). There were no significant differences between the EA group and the drug group (all P>0.05). Conclusion: EA can alleviate the inflammatory response of RA rats, improve their pathological conditions, reduce the expressions of phospho-JAK2 and phospho-STAT3 in the synovial tissue of knee joint, and decrease the expressions of JAK2 and STAT3 mRNAs. The therapeutic effect of EA is comparable to that of the tripterygium glycosides. The mechanism of EA treatment may be related to the inactivation of the JAK2/STAT3 pathway.展开更多
Aberrant activation of signal transducer and activator of transcription(STAT)proteins is associated with the development and progression of solid tumors.However,as transcription factors,these proteins are difficult to...Aberrant activation of signal transducer and activator of transcription(STAT)proteins is associated with the development and progression of solid tumors.However,as transcription factors,these proteins are difficult to target directly.In this review,we summarize the role of targeting Janus kinases(JAKs),upstream activators of STATs,as a strategy for decreasing STAT activation in solid tumors.Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation,cell proliferation,and cell survival;in in vivo models,they also inhibit tumor growth.JAK inhibitors,particularly the JAK1/2 inhibitor ruxolitinib,sensitize cell lines and murine models to chemotherapy,immunotherapy,and oncolytic viral therapy.Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors;two of these inhibitors are already Food and Drug Administration(FDA)approved for the treatment of myeloproliferative disorders and rheumatoid arthritis,making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated.Four JAK inhibitors(two of which are FDA approved for other indications)have exhibited promising anti-cancer effects in preclinical studies;however,clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted.In summary,JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.展开更多
目的:观察扶元散加减联合耳穴压豆治疗Ⅱ,Ⅲ期糖尿病肾病的疗效及对血清酪氨酸激酶/信号转导子及转录激活因子(JAK/STAT)信号通路的影响。方法:180例患者随机分为对照组和观察组,各90例。两组分别给予氯沙坦钾,扶元散加减联合耳穴压豆,...目的:观察扶元散加减联合耳穴压豆治疗Ⅱ,Ⅲ期糖尿病肾病的疗效及对血清酪氨酸激酶/信号转导子及转录激活因子(JAK/STAT)信号通路的影响。方法:180例患者随机分为对照组和观察组,各90例。两组分别给予氯沙坦钾,扶元散加减联合耳穴压豆,疗程均为12周。治疗前后分别观察两组肾功能指标血尿素氮(BUN),肌酐(SCr),尿白蛋白排泄率(UAER),24 h尿蛋白定量(24 h Upor);肠道菌群(疣微菌门菌、硬壁菌门菌、脱铁杆菌门菌、变形菌门菌)相对丰度;氧化应激指标晚期蛋白氧化产物(AOPPs),活性氧(ROS),谷胱甘肽过氧化物酶(GSH-Px),总超氧化物歧化酶(TSOD);肾血流指标舒张末期的血流速度(EDV),肾段动脉的收缩期峰值(PSV),搏动指数(PI),血流阻力指数(RI);JAK/STAT信号通路JAK,磷酸化JAK(p-JAK),STAT,磷酸化STAT(p-STAT)水平。观察两组安全性,治疗后及随访1年,2年临床疗效。结果:治疗后及随访1年,2年,观察组总有效率分别为97.8%(87/89),81.6%(71/87),59.8%(49/82),明显高于同期对照组的79.3%(69/87),57.8%(48/83),37.2%(29/78)(χ^(2)=4.016,χ^(2)=4.503,χ^(2)=4.769,P<0.05)。治疗后与对照组比较,观察组BUN,SCr,UAER,24 h Upor,硬壁菌门菌,脱铁杆菌门菌,变形菌门菌,AOPPs,ROS,PI,RI,p-JAK,p-STAT3明显降低(P<0.05,P<0.01),疣微菌门菌,GSH-Px,TSOD,JAK,STAT3明显升高(P<0.05,P<0.01),EDV,PSV明显加快(P<0.05,P<0.01)。观察组不良反应发生率1.1%(1/89),低于对照组的13.8%(12/87)(χ^(2)=5.127,P<0.05)。结论:扶元散加减联合耳穴压豆可明显改善Ⅱ,Ⅲ期糖尿病肾病的临床疗效,其作用机制可能与调节血清JAK/STAT信号通路有关。展开更多
文摘The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, the cellular and molecular mechanisms underlying sepsis-induced brain damage remain elusive. In the present study, we found severe loss of neurons in the hippocampal CA1 region in rats with sepsis-induced brain damage following intraperitoneal injection of endotoxin, The expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 was significantly increased in brain tissues following lipopolysaccharide exposure. AG490 （JAK2 antagonist） and rapamycin （STAT3 antagonist） significantly reduced neuronal loss and suppressed the increased expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 in the hippocampal CA1 region in sepsis-induced brain damaged rats. Overall, these data suggest that blockade of the JAK/STAT signal transduction pathway is neuroprotective in sepsis-induced brain damage via the inhibition of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 exoression.
基金supported by grants from Key R&D Project of Science and Technology Foundation of Sichuan Province(2022YFS0290).
文摘Background:Galectin 2(LGALS2)is a protein previously reported to serve as a mediator of disease progression in a range of cancers.The function of LGALS2 in oral squamous cell carcinoma(OSCC),however,has yet to be explored,prompting the present study to address this literature gap.Methods:Overall,144 paired malignant tumor tissues and paracancerous OSCC patient samples were harvested and the LGALS2 expression levels were examined through qPCR and western immunoblotting.The LGALS2 coding sequence was introduced into the pcDNA3.0 vector,to enable the overexpression of this gene,while an LGALS2-specific shRNA and corresponding controls were also obtained.The functionality of LGALS2 as a regulator of the ability of OSCC cells to grow and undergo apoptotic death in vitro was assessed through EdU uptake and CCK-8 assays,and flow cytometer,whereas a Transwell system was used to assess migratory activity and invasivity.An agonist of the Janus Kinase 2(JAK2)/Signal Transducer and Activator of Transcription 3(STAT3)pathway was also used to assess the role of this pathway in the context of LGALS2 signaling.Results:Here,we found that lower LGALS2 protein and mRNA expression were evident in OSCC tumor tissue samples,and these expression levels were associated with clinicopathological characteristics and patient survival outcomes.Silencing LGALS2 enhanced proliferation in OSCC cells while rendering these cells better able to resist apoptosis.The opposite was instead observed after LGALS2 was overexpressed.Mechanistically,the ability of LGALS2 to suppress the progression of OSCC was related to its ability to activate the JAK/STAT3 signaling axis.Conclusion:Those results suggest a role for LGALS2 as a suppressor of OSCC progression through its ability to modulate JAK/STAT3 signaling,supporting the potential utility of LGALS2 as a target for efforts aimed at treating OSCC patients.
基金The Sixth Batch of Special Support Plans in Anhui Province(No.dlPtzjh20200050)Key Natural Science Research Project of Higher Education Institutions in Anhui Province(No.KJ2020A0426)。
文摘Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.
基金Supported by National Natural Science Foundation of China(Nos.81173280,81302995,81403420)Fujian Medical Innovation project(No.2011-CX-30)+1 种基金Science and Technology Department of Fujian Province autonomous non-profit research institutes topics project(No.2011R1038-5)Fujian Academy of Traditional Chinese autonomous topics Project(No.2012fjzyyk-5)
文摘Objectives： To investigate the mechanism of Liuwei Dihuang Pill （六味地黄丸, LDP） in treating postmenopausal osteoporosis （PMOP） with Shen （Kidney） yin deficiency. Methods： In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group （Group A）, PMOP Shen-yang deficiency group （Group B）, PMOP without Shen deficiency group （Group C）, and control group （Group N）. Real-time polymerase chain reaction （RT-PCR） and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 （CLCF1）, ankyrin repeat and SOCS box containing 1 （ASB1）, and proldneticin 2 （PROK2） genes and the Janus kinase/signal transducer and activator of transcription （JAK/STAT） signaling pathway. Results： The mRNA （P〈0.05） and protein （P〈0.01） expression levels of the CLCF1 gone in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gone were obviously up-regulated （P〈0.01）. After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated （both P〈0.01）, and the average bone density of the top femur had significantly increased （P〈0.05）. In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3. Conclusions： The CLCF1 gone is an important gone associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gone expression and activation of the JAK/STAT signaling pathway.
文摘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.
基金This work was supported by the National Natural Science Foundation of China(82072203)Natural Science Foundation of Zhejiang Province(LQ19H160025).
文摘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.
文摘Objective: To observe the effect of electroacupuncture (EA) on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in knee joint synovial tissues of rats with rheumatoid arthritis (RA) and to explore the action mechanism of EA on RA. Methods: Twelve of the 48 SPF male Sprague-Dawley (SD) rats were assigned to a normal group by the random number table method. The remaining 36 rats were subjected to RA model preparation by intradermal injection of the Freund's complete adjuvant into the right hind foot pad of each rat under sterile conditions. After the model was successfully prepared, rats were then divided into a model group, a drug group and an EA group according to a random number table method (n=12). Rats in the drug group were treated with 2 mL aqueous solution of tripterygium glycosides [8.1 mg/(kg?bw)];rats in the EA group were treated with EA at bilateral Yanglingquan (GB 34) and Zusanli (ST 36), for 30 min each time;rats in the normal group and the model group were placed in a special rat fixation tank for 30 min each time, and received the same dose of normal saline as those in the drug group. Rats in all groups received intervention once a day for 4 weeks. Diameter of rat ankle joint and rat arthritis index were measured before and after the intervention. At the end of the experiment, the expressions of phospho-JAK2 and phospho-STAT3 were determined by immunohistochemistry. Quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect JAK2 and STAT3 mRNAs expressions. Results: After the model was produced, the arthritis index >2 was considered successful in model preparation. Compared with the model group, the ankle joint diameters and arthritis indexes of rats in the drug group and the EA group were significantly lower (all P<0.01);immunohistochemical staining cells with phospho-JAK2 and phospho-STAT3 were significantly decreased (all P<0.01);the expression levels of JAK2 and STAT3 mRNAs were decreased with statistical differences (all P<0.01). There were no significant differences between the EA group and the drug group (all P>0.05). Conclusion: EA can alleviate the inflammatory response of RA rats, improve their pathological conditions, reduce the expressions of phospho-JAK2 and phospho-STAT3 in the synovial tissue of knee joint, and decrease the expressions of JAK2 and STAT3 mRNAs. The therapeutic effect of EA is comparable to that of the tripterygium glycosides. The mechanism of EA treatment may be related to the inactivation of the JAK2/STAT3 pathway.
基金NIH(R35CA231998)(to Grandis JR),(R01DE028289)(to Johnson DE,Grandis JR)a Yearlong Research Fellowship awarded by the University of California San Francisco School of Medicine(to Qureshy Z).
文摘Aberrant activation of signal transducer and activator of transcription(STAT)proteins is associated with the development and progression of solid tumors.However,as transcription factors,these proteins are difficult to target directly.In this review,we summarize the role of targeting Janus kinases(JAKs),upstream activators of STATs,as a strategy for decreasing STAT activation in solid tumors.Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation,cell proliferation,and cell survival;in in vivo models,they also inhibit tumor growth.JAK inhibitors,particularly the JAK1/2 inhibitor ruxolitinib,sensitize cell lines and murine models to chemotherapy,immunotherapy,and oncolytic viral therapy.Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors;two of these inhibitors are already Food and Drug Administration(FDA)approved for the treatment of myeloproliferative disorders and rheumatoid arthritis,making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated.Four JAK inhibitors(two of which are FDA approved for other indications)have exhibited promising anti-cancer effects in preclinical studies;however,clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted.In summary,JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.
文摘目的:观察扶元散加减联合耳穴压豆治疗Ⅱ,Ⅲ期糖尿病肾病的疗效及对血清酪氨酸激酶/信号转导子及转录激活因子(JAK/STAT)信号通路的影响。方法:180例患者随机分为对照组和观察组,各90例。两组分别给予氯沙坦钾,扶元散加减联合耳穴压豆,疗程均为12周。治疗前后分别观察两组肾功能指标血尿素氮(BUN),肌酐(SCr),尿白蛋白排泄率(UAER),24 h尿蛋白定量(24 h Upor);肠道菌群(疣微菌门菌、硬壁菌门菌、脱铁杆菌门菌、变形菌门菌)相对丰度;氧化应激指标晚期蛋白氧化产物(AOPPs),活性氧(ROS),谷胱甘肽过氧化物酶(GSH-Px),总超氧化物歧化酶(TSOD);肾血流指标舒张末期的血流速度(EDV),肾段动脉的收缩期峰值(PSV),搏动指数(PI),血流阻力指数(RI);JAK/STAT信号通路JAK,磷酸化JAK(p-JAK),STAT,磷酸化STAT(p-STAT)水平。观察两组安全性,治疗后及随访1年,2年临床疗效。结果:治疗后及随访1年,2年,观察组总有效率分别为97.8%(87/89),81.6%(71/87),59.8%(49/82),明显高于同期对照组的79.3%(69/87),57.8%(48/83),37.2%(29/78)(χ^(2)=4.016,χ^(2)=4.503,χ^(2)=4.769,P<0.05)。治疗后与对照组比较,观察组BUN,SCr,UAER,24 h Upor,硬壁菌门菌,脱铁杆菌门菌,变形菌门菌,AOPPs,ROS,PI,RI,p-JAK,p-STAT3明显降低(P<0.05,P<0.01),疣微菌门菌,GSH-Px,TSOD,JAK,STAT3明显升高(P<0.05,P<0.01),EDV,PSV明显加快(P<0.05,P<0.01)。观察组不良反应发生率1.1%(1/89),低于对照组的13.8%(12/87)(χ^(2)=5.127,P<0.05)。结论:扶元散加减联合耳穴压豆可明显改善Ⅱ,Ⅲ期糖尿病肾病的临床疗效,其作用机制可能与调节血清JAK/STAT信号通路有关。
