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
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
Regulatory T cells （Tregs） are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes （TID）. Pharmacological inhibition of Janus tyrosine kinase 3 （JAK...Regulatory T cells （Tregs） are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes （TID）. Pharmacological inhibition of Janus tyrosine kinase 3 （JAK3） has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses. Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T 1D in non-obese diabetic （NOD） mice. As the mechanism of such preventative action has been unknown, we hypothesized that JAK3 inhibition induces generation of Tregs. Here, we show that the JAK3 inhibitor 4-（4＇-hydroxyphenyl）-amino-6,7-dimethoxyquinazoline （WHI-P131） suppresses proliferation of short-term cultured NOD CD4＋ T cells through induction of apoptosis, while promoting survival of a particular population of long-term cultured cells. It was found that the surviving cells were not of the CD4＋CD25＋FoxP3＋ phenotype. They secreted decreased amounts of IL-IO, IL-4 and interferon （IFN）-y compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor. However, an elevated transforming growth factor （TGF）-β secretion was detected in their supernatants. In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4＋FoxP3＋ Tregs, while generating an elevated numbers of CD4＋FoxP3- TGF-β-secreting T cells. In conclusion, our data suggest an induction of TGF-β-secreting CD4＋ T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor. To our knowledge, this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs.展开更多
A 4-anilinoquinazoline derivative(1) designed as a JAK3 inhibitor was synthesized in high yield by a practical and efficient method.The molecular docking study was also performed to elucidate the molecular mechanism o...A 4-anilinoquinazoline derivative(1) designed as a JAK3 inhibitor was synthesized in high yield by a practical and efficient method.The molecular docking study was also performed to elucidate the molecular mechanism of the JAK3 inhibitory potency of compound 1.The results indicated that compound 1 had various interactions with the key amino acid residues at the ATP-binding cavity of JAK3 protein and presented high affinity to JAK3 protein,which was even higher than JANEX-1 and Tasocitinib.展开更多
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, asc...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.展开更多
A 4-anilinoquinazoline derivative （1） designed as a JAK3 inhibitor was synthesized in high yield by a practical and efficient method. The molecular docking study was also performed to elucidate the molecular mechani...A 4-anilinoquinazoline derivative （1） designed as a JAK3 inhibitor was synthesized in high yield by a practical and efficient method. The molecular docking study was also performed to elucidate the molecular mechanism of the JAK3 inhibitory potency of compound 1. The results indicated that compound 1 had various interactions with the key amino acid residues at the ATP-binding cavity of JAK3 protein and presented high affinity to JAK3 protein, which was even higher than JANEX-1 and Tasocitinib.展开更多
C myc gene expression can be rapidly induced by IL 2 through intracellular signal transduction which is triggered by the interaction between IL 2 and its receptor （IL 2R）. JAK3 which associates to the intracellular ...C myc gene expression can be rapidly induced by IL 2 through intracellular signal transduction which is triggered by the interaction between IL 2 and its receptor （IL 2R）. JAK3 which associates to the intracellular domain of IL2R γ may play a critical role in this process. To reveal the action of JAK3 in c myc induction, a chimeric receptor gene IL2R α/γ/Δ NJAK3 is constructed which consists of extracellular domain derived from IL 2R α subunit （IL2R α）, the transmembrane sequence derived from IL2R γ and the cytoplasmic domain derived from the catalytic domain of JAK3 （Δ NJAK3）, and then transfected this chimeric gene into mouse fibroblast cell line L929 β which had been transfected with IL2R β gene and stably expressed IL2R β in high level. In the transfectants coexpressing IL2R β and α/γ/Δ NJAK3, the stimulation of IL2 could intensively induce c myc gene expression. Because the whole cytoplasmic domain of IL2R γ which could recruit signaling molecules was replaced by JAK3 and the c myc could be still induced by IL2 in this situation, the results here gave the direct evidence demonstrating that JAK3 plays an important role in c myc gene expression induced by IL2.展开更多
信号转导和转录激活因子(signal transducer and activatorof transcription,STAT)3是信号转导与转录活化因子家族重要成员,作为JAK-STAT(Janus kinase signal transducer and activator of transcription)途径中JAK的底物,接受生长因...信号转导和转录激活因子(signal transducer and activatorof transcription,STAT)3是信号转导与转录活化因子家族重要成员,作为JAK-STAT(Janus kinase signal transducer and activator of transcription)途径中JAK的底物,接受生长因子与细胞因子等细胞外信号刺激激活。活化的信号转导和转录激活因子3蛋白进入细胞核,结合靶基因,修饰靶基因的表达,从而调节细胞增殖、分化及凋亡。研究表明,信号转导和转录激活因子异常激活可通过抑制凋亡,促进细胞增殖等促进细胞恶性转化与进展。多种人类恶性肿瘤中均存在信号转导与转录活化因子家族成员的异常激活。通过阻断该途径,能抑制肿瘤细胞增殖,促进细胞凋亡。JAK-STAT信号转导途径,可参与妇科恶性肿瘤发生发展。随着对信号转导和转录激活因子3更深入研究,可能为妇科恶性肿瘤的早期诊断及预后提供线索,并为卵巢癌等妇科恶性肿瘤的耐药及治疗提供新靶点。展开更多
JAK-3激酶(Janus kinase 3)作为酪氨酸蛋白激酶家族成员,在JAK-STAT(Janus kinase-signal transducer and activator of transcription)信号通路中起着非常重要的作用,研究证实JAK-3活性的调控在多种疾病的治疗中起着关键作用,针对该激...JAK-3激酶(Janus kinase 3)作为酪氨酸蛋白激酶家族成员,在JAK-STAT(Janus kinase-signal transducer and activator of transcription)信号通路中起着非常重要的作用,研究证实JAK-3活性的调控在多种疾病的治疗中起着关键作用,针对该激酶的抑制剂已经有许多相关研究,并有多个JAK-3激酶抑制剂进入临床研究,表现出很好的JAK-3选择性和抑制活性,其中tofacitinib等抑制剂已经通过临床试验,被批准用于类风湿性关节炎的治疗。很多JAK-3抑制剂表现出良好抑制活性的同时,伴有一定的不良反应,有待于改进。本文综述了JAK-3激酶的结构功能以及JAK-3激酶抑制剂的研究进展,为后续研究提供参考。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
Objective:To observe the lipid-lowering effect of different transdermal absorption enhancers applied to the herbal cake-partitioned moxibustion in hyperlipidemia model rabbits,and to explore the possible mechanism.Met...Objective:To observe the lipid-lowering effect of different transdermal absorption enhancers applied to the herbal cake-partitioned moxibustion in hyperlipidemia model rabbits,and to explore the possible mechanism.Methods:Forty New-Zea I a nd rabbits were ran domly divided into 5 groups using the ran dom nu mber table method,with 8 rats in each group.Rabbits in the blank group were fed routinely with normal diet;rabbits in the other groups were fed with high-fat diet for 12 weeks to establish the hyperlipidemia model.Rabbits in the blank and the model groups were not treated.After the model was prepared,rabbits in the non-transdermal absorption enhancer group received herbal cake-partitioned moxibustion without transdermal absorption enhancer;rabbits in the laurocapram group and the borneol group received herbal cake-partitioned moxibustion with laurocapram or borneol respectively.After 4 weeks of treatment,serum was collected for enzyme-linked immunosorbent assay(ELISA),and the liver tissues were isolated for imm uno histochemistry,qua ntitative polymerase chain reactio n(qPCR)and Western-blotting(WB)detecti on.Results:Serum ELISA results showed that leptin was significantly decreased in the model group compared with the blank group(P<0.05);compared with the model group,lepti n was significa ntly in creased in the non-tran sdermal absorpti on enhanee。the laurocapram and the borneol groups(all P<0.05);compared with the non-transdermal absorption enhancer group,leptin was significantly increased in the laurocapram group and the borneol group(both P<0.05);there was no significant differenee in leptin between the laurocapram and the borneol groups(P>0.05).The qPCR results of rabbit liver tissues showed that the mRNA expressions of leptin,Janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STOT3)in the model group were significantly lower than those in the blank group(all P<0.05);compared with the model group,the mRNA expressions of leptin,leptin receptor(LR),JAK2 and S1AT3 in the non-transdermal absorptio n enhan cer,the laurocapram and the born eol groups were significantly in creased(all P<0.05);compared with the non-transdermal absorption enhancer group,the mRNA expressions of leptin,LR,JAK2 and S77VT3 in the laurocapram and the bor neol groups were sign ificantly in creased(all P<0.05);compared with the laurocapram group,the mRNA expressi ons of lepti n,LR,JAK2 and SW3 in the bor neol group were significa ntly in creased(P<0.05).The trend of immun ohistochemistry and WB detecti on results was basically con siste nt with the qPCR assay results.The immuno histochemistry and WB detection results of phosphorylated JAK2(phospho-JAK2)and phosphorylated S7AT3(phospho-STAT3)were basically consistent with those of JAK2 and S7AT3.Conclusion:The molecular expression of Leptin/JAK"S7AT3 pathway in the hyperlipidemia model rabbits was decreased.The molecular expression of Leptin/JAK0STCT3 pathway was significantly increased after the herbal cake-partitioned moxibustion.The application of laurocapram and borneol,as transdermal absorption enhancers,in the herbal cake-partitioned moxibustion could more obviously up-regulate the factors of the Leptin/JAK^SIAT3 lipid-regulating pathway than the herbal cake-partitioned moxibustion alone.展开更多
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Regulatory T cells （Tregs） are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes （TID）. Pharmacological inhibition of Janus tyrosine kinase 3 （JAK3） has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses. Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T 1D in non-obese diabetic （NOD） mice. As the mechanism of such preventative action has been unknown, we hypothesized that JAK3 inhibition induces generation of Tregs. Here, we show that the JAK3 inhibitor 4-（4＇-hydroxyphenyl）-amino-6,7-dimethoxyquinazoline （WHI-P131） suppresses proliferation of short-term cultured NOD CD4＋ T cells through induction of apoptosis, while promoting survival of a particular population of long-term cultured cells. It was found that the surviving cells were not of the CD4＋CD25＋FoxP3＋ phenotype. They secreted decreased amounts of IL-IO, IL-4 and interferon （IFN）-y compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor. However, an elevated transforming growth factor （TGF）-β secretion was detected in their supernatants. In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4＋FoxP3＋ Tregs, while generating an elevated numbers of CD4＋FoxP3- TGF-β-secreting T cells. In conclusion, our data suggest an induction of TGF-β-secreting CD4＋ T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor. To our knowledge, this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs.
基金Natural Science Foundation of Guangdong Province,China(Grant No.04009620).
文摘A 4-anilinoquinazoline derivative(1) designed as a JAK3 inhibitor was synthesized in high yield by a practical and efficient method.The molecular docking study was also performed to elucidate the molecular mechanism of the JAK3 inhibitory potency of compound 1.The results indicated that compound 1 had various interactions with the key amino acid residues at the ATP-binding cavity of JAK3 protein and presented high affinity to JAK3 protein,which was even higher than JANEX-1 and Tasocitinib.
基金Supported by the National Natural Science Foundation of China,No.81573948
文摘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.
基金Foundation item： Natural Science Foundation of Guangdong Province, China （Grant No. 04009620）.
文摘A 4-anilinoquinazoline derivative （1） designed as a JAK3 inhibitor was synthesized in high yield by a practical and efficient method. The molecular docking study was also performed to elucidate the molecular mechanism of the JAK3 inhibitory potency of compound 1. The results indicated that compound 1 had various interactions with the key amino acid residues at the ATP-binding cavity of JAK3 protein and presented high affinity to JAK3 protein, which was even higher than JANEX-1 and Tasocitinib.
文摘C myc gene expression can be rapidly induced by IL 2 through intracellular signal transduction which is triggered by the interaction between IL 2 and its receptor （IL 2R）. JAK3 which associates to the intracellular domain of IL2R γ may play a critical role in this process. To reveal the action of JAK3 in c myc induction, a chimeric receptor gene IL2R α/γ/Δ NJAK3 is constructed which consists of extracellular domain derived from IL 2R α subunit （IL2R α）, the transmembrane sequence derived from IL2R γ and the cytoplasmic domain derived from the catalytic domain of JAK3 （Δ NJAK3）, and then transfected this chimeric gene into mouse fibroblast cell line L929 β which had been transfected with IL2R β gene and stably expressed IL2R β in high level. In the transfectants coexpressing IL2R β and α/γ/Δ NJAK3, the stimulation of IL2 could intensively induce c myc gene expression. Because the whole cytoplasmic domain of IL2R γ which could recruit signaling molecules was replaced by JAK3 and the c myc could be still induced by IL2 in this situation, the results here gave the direct evidence demonstrating that JAK3 plays an important role in c myc gene expression induced by IL2.
文摘信号转导和转录激活因子(signal transducer and activatorof transcription,STAT)3是信号转导与转录活化因子家族重要成员,作为JAK-STAT(Janus kinase signal transducer and activator of transcription)途径中JAK的底物,接受生长因子与细胞因子等细胞外信号刺激激活。活化的信号转导和转录激活因子3蛋白进入细胞核,结合靶基因,修饰靶基因的表达,从而调节细胞增殖、分化及凋亡。研究表明,信号转导和转录激活因子异常激活可通过抑制凋亡,促进细胞增殖等促进细胞恶性转化与进展。多种人类恶性肿瘤中均存在信号转导与转录活化因子家族成员的异常激活。通过阻断该途径,能抑制肿瘤细胞增殖,促进细胞凋亡。JAK-STAT信号转导途径,可参与妇科恶性肿瘤发生发展。随着对信号转导和转录激活因子3更深入研究,可能为妇科恶性肿瘤的早期诊断及预后提供线索,并为卵巢癌等妇科恶性肿瘤的耐药及治疗提供新靶点。
文摘JAK-3激酶(Janus kinase 3)作为酪氨酸蛋白激酶家族成员,在JAK-STAT(Janus kinase-signal transducer and activator of transcription)信号通路中起着非常重要的作用,研究证实JAK-3活性的调控在多种疾病的治疗中起着关键作用,针对该激酶的抑制剂已经有许多相关研究,并有多个JAK-3激酶抑制剂进入临床研究,表现出很好的JAK-3选择性和抑制活性,其中tofacitinib等抑制剂已经通过临床试验,被批准用于类风湿性关节炎的治疗。很多JAK-3抑制剂表现出良好抑制活性的同时,伴有一定的不良反应,有待于改进。本文综述了JAK-3激酶的结构功能以及JAK-3激酶抑制剂的研究进展,为后续研究提供参考。
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.
文摘Objective:To observe the lipid-lowering effect of different transdermal absorption enhancers applied to the herbal cake-partitioned moxibustion in hyperlipidemia model rabbits,and to explore the possible mechanism.Methods:Forty New-Zea I a nd rabbits were ran domly divided into 5 groups using the ran dom nu mber table method,with 8 rats in each group.Rabbits in the blank group were fed routinely with normal diet;rabbits in the other groups were fed with high-fat diet for 12 weeks to establish the hyperlipidemia model.Rabbits in the blank and the model groups were not treated.After the model was prepared,rabbits in the non-transdermal absorption enhancer group received herbal cake-partitioned moxibustion without transdermal absorption enhancer;rabbits in the laurocapram group and the borneol group received herbal cake-partitioned moxibustion with laurocapram or borneol respectively.After 4 weeks of treatment,serum was collected for enzyme-linked immunosorbent assay(ELISA),and the liver tissues were isolated for imm uno histochemistry,qua ntitative polymerase chain reactio n(qPCR)and Western-blotting(WB)detecti on.Results:Serum ELISA results showed that leptin was significantly decreased in the model group compared with the blank group(P<0.05);compared with the model group,lepti n was significa ntly in creased in the non-tran sdermal absorpti on enhanee。the laurocapram and the borneol groups(all P<0.05);compared with the non-transdermal absorption enhancer group,leptin was significantly increased in the laurocapram group and the borneol group(both P<0.05);there was no significant differenee in leptin between the laurocapram and the borneol groups(P>0.05).The qPCR results of rabbit liver tissues showed that the mRNA expressions of leptin,Janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STOT3)in the model group were significantly lower than those in the blank group(all P<0.05);compared with the model group,the mRNA expressions of leptin,leptin receptor(LR),JAK2 and S1AT3 in the non-transdermal absorptio n enhan cer,the laurocapram and the born eol groups were significantly in creased(all P<0.05);compared with the non-transdermal absorption enhancer group,the mRNA expressions of leptin,LR,JAK2 and S77VT3 in the laurocapram and the bor neol groups were sign ificantly in creased(all P<0.05);compared with the laurocapram group,the mRNA expressi ons of lepti n,LR,JAK2 and SW3 in the bor neol group were significa ntly in creased(P<0.05).The trend of immun ohistochemistry and WB detecti on results was basically con siste nt with the qPCR assay results.The immuno histochemistry and WB detection results of phosphorylated JAK2(phospho-JAK2)and phosphorylated S7AT3(phospho-STAT3)were basically consistent with those of JAK2 and S7AT3.Conclusion:The molecular expression of Leptin/JAK"S7AT3 pathway in the hyperlipidemia model rabbits was decreased.The molecular expression of Leptin/JAK0STCT3 pathway was significantly increased after the herbal cake-partitioned moxibustion.The application of laurocapram and borneol,as transdermal absorption enhancers,in the herbal cake-partitioned moxibustion could more obviously up-regulate the factors of the Leptin/JAK^SIAT3 lipid-regulating pathway than the herbal cake-partitioned moxibustion alone.
