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: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
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
Angiogenesis is an essential process in tumor growth,invasion and metastasis.VEGF receptor 2(VEGFR2)inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment.However,most of ...Angiogenesis is an essential process in tumor growth,invasion and metastasis.VEGF receptor 2(VEGFR2)inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment.However,most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration.Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view.Here we report the discovery and characterization of a novel VEGFR2 inhibitor(CHMFLVEGFR2-002),which exhibited high selectivity among structurally closed kinases including PDGFRs,FGFRs,CSF1 R,etc.CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay(IC50=66 nmol/L)and VEGFR2 autophosphorylation in cells(EC50s^100 nmol/L)as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells(GI50=150 nmol/L).In addition,CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK(pharmacokinetics)profile with bioavailability over 49%and antiangiogenesis efficacy in both zebrafish and mouse models without apparent toxicity.These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.展开更多
The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors i...The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic.In this paper,a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design,synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib.Among them,21 b exhibited high inhibitory activity against JAK2 with an IC_(50)of 9 nmol/L,moreover,it showed 276-and 184-fold selectivity over JAK1 and JAK3,respectively.Besides,21 b had a significant antiproliferative activity against HEL cells,and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway.These results indicated that2-aminopyridine compound 21 b had the potential to be developed as a selective JAK2 inhibitor for further study.展开更多
The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase 1/2(ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the pr...The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase 1/2(ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.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
Background and Aims:Acute liver failure(ALF)is a potentially fatal clinical syndrome with no effective treatment.This study aimed to explore the role of Janus kinase 2/signal transducer and activator of transcription ...Background and Aims:Acute liver failure(ALF)is a potentially fatal clinical syndrome with no effective treatment.This study aimed to explore the role of Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in modulating the phenotype and immune function of endotoxin-tolerant dendritic cells(ETDCs).In addition,we explored the use of EDTCs in an experimental model of ALF and investigated the associated mechanisms.Methods:In the in vitro experiment,ETDCs were transfected with adenovirus to induce SOCS1^(+/+)ETDCs and SOCS1^(−/−)ETDCs.Thereafter,costimulatory molecules and mixed lymphocyte reaction were assessed.Experimental mice were randomly divided into normal control,ALF,ALF+mock-ETDCs,ALF+SOCS1^(+/+)ETDCs,ALF+AG490,and ALF+AG490+SOCS1^(+/+)ETDCs groups.We examined the therapeutic effect of adoptive cellular immunotherapy by tail-vein injection of target ETDCs 12 h before ALF modeling.AG490,a JAK2/STAT3 inhibitor,was used in the in vivo experiment to further explore the protective mechanism of SOCS1^(+/+)ETDCs.Results:Compared with control ETDCs,SOCS1^(+/+)ETDCs had lower expression of costimulatory molecules,weaker allostimulatory ability,lower levels of IL-6 and TNF-αexpression and higher IL-10 secretion.SOCS1^(−/−)ETDCs showed the opposite results.In the in vivo experiments,the ALF+SOCS1^(+/+)ETDCs and ALF+AG490+SOCS1^(+/+)ETDCs groups showed less pathological damage and suppressed activation of JAK2/STAT3 pathway.The changes were more pronounced in the ALF+AG490+SOCS1^(+/+)ETDCs group.Infusion of SOCS1^(+/+)ETDCs had a protective effect against ALF possibly via inhibition of JAK2 and STAT3 phosphorylation.Conclusions:The SOCS1 gene had an important role in induction of endotoxin tolerance.SOCS1^(+/+)ETDCs alleviated lipopolysaccharide/D-galactosamine-induced ALF by downregulating the JAK2/STAT3 signaling pathway.展开更多
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 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.
基金supported by the National Natural Science Foundation of China(Grant Nos.81773777,81673469,81603123,81803366)the China Postdoctoral Science Foundation(Grant Nos.2018T110634,2018M630720)+2 种基金the Anhui Province Postdoctoral Science Foundation(Grant No.2018B279)the CASHIPS Director’s Fund(Grant No.BJPY2019A03)the Key Program of 13th five-year plan,CASHIPS(Grant No.KP-2017-26).
文摘Angiogenesis is an essential process in tumor growth,invasion and metastasis.VEGF receptor 2(VEGFR2)inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment.However,most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration.Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view.Here we report the discovery and characterization of a novel VEGFR2 inhibitor(CHMFLVEGFR2-002),which exhibited high selectivity among structurally closed kinases including PDGFRs,FGFRs,CSF1 R,etc.CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay(IC50=66 nmol/L)and VEGFR2 autophosphorylation in cells(EC50s^100 nmol/L)as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells(GI50=150 nmol/L).In addition,CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK(pharmacokinetics)profile with bioavailability over 49%and antiangiogenesis efficacy in both zebrafish and mouse models without apparent toxicity.These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.
基金the National Key Research and Development Program(No.2016YFA0502304)the National Natural Science Foundation of China(No.81825020)+3 种基金the Shanghai Committee of Science and Technology(No.20S11901000)the Fundamental Research Funds for the Central Universitiessponsored by the National Program for Special Supports of Eminent Professionalsthe National Program for Support of Top-Notch Young Professionals。
文摘The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic.In this paper,a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design,synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib.Among them,21 b exhibited high inhibitory activity against JAK2 with an IC_(50)of 9 nmol/L,moreover,it showed 276-and 184-fold selectivity over JAK1 and JAK3,respectively.Besides,21 b had a significant antiproliferative activity against HEL cells,and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway.These results indicated that2-aminopyridine compound 21 b had the potential to be developed as a selective JAK2 inhibitor for further study.
基金supported by grants from the National Natural Science Foundation of China (Grants 22177083,81922064,81874290,and 81803755)Sichuan Science and Technology Program (Grant No.2020JDRC0053,China)+1 种基金Fundamental Research Funds for the Central Universities (Grant No.2682020CX56,China)National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University (Grant Z20201004,China)。
文摘The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase 1/2(ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.
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supported by Zhejiang Provincial Natural Science Foundation of China under Grant No.LY18H030010.
文摘Background and Aims:Acute liver failure(ALF)is a potentially fatal clinical syndrome with no effective treatment.This study aimed to explore the role of Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in modulating the phenotype and immune function of endotoxin-tolerant dendritic cells(ETDCs).In addition,we explored the use of EDTCs in an experimental model of ALF and investigated the associated mechanisms.Methods:In the in vitro experiment,ETDCs were transfected with adenovirus to induce SOCS1^(+/+)ETDCs and SOCS1^(−/−)ETDCs.Thereafter,costimulatory molecules and mixed lymphocyte reaction were assessed.Experimental mice were randomly divided into normal control,ALF,ALF+mock-ETDCs,ALF+SOCS1^(+/+)ETDCs,ALF+AG490,and ALF+AG490+SOCS1^(+/+)ETDCs groups.We examined the therapeutic effect of adoptive cellular immunotherapy by tail-vein injection of target ETDCs 12 h before ALF modeling.AG490,a JAK2/STAT3 inhibitor,was used in the in vivo experiment to further explore the protective mechanism of SOCS1^(+/+)ETDCs.Results:Compared with control ETDCs,SOCS1^(+/+)ETDCs had lower expression of costimulatory molecules,weaker allostimulatory ability,lower levels of IL-6 and TNF-αexpression and higher IL-10 secretion.SOCS1^(−/−)ETDCs showed the opposite results.In the in vivo experiments,the ALF+SOCS1^(+/+)ETDCs and ALF+AG490+SOCS1^(+/+)ETDCs groups showed less pathological damage and suppressed activation of JAK2/STAT3 pathway.The changes were more pronounced in the ALF+AG490+SOCS1^(+/+)ETDCs group.Infusion of SOCS1^(+/+)ETDCs had a protective effect against ALF possibly via inhibition of JAK2 and STAT3 phosphorylation.Conclusions:The SOCS1 gene had an important role in induction of endotoxin tolerance.SOCS1^(+/+)ETDCs alleviated lipopolysaccharide/D-galactosamine-induced ALF by downregulating the JAK2/STAT3 signaling pathway.
