INTERNATIONAL IMMUNOPHARMACOLOGY
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2016
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IF 2.551
Zhilin Qi,Shimei Qi,Liefeng Ling,Jun Lv,Zunyong Feng
Salidroside (SAL) is an active ingredient isolated from the Rhodiola rosea , has potent anti-inflammatory effect, but the mechanism is still elusive. The purpose of this study is to verify the effects of SAL on LPS-induced inflammatory response and investigate the possible underlying molecular mechanism. RAW264.7 cells were pre-incubated with SAL for 2 h, then stimulated with or without LPS for another 16 h. The levels of TNF-α, MCP-1, IL-6, and PGE2 were detected by ELISA , and the production of NO was determined by nitrite analysis. The expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by Western blotting . In RAW264.7 cells and murine peritoneal macrophages, the activation of signal molecules was also measured by Western blot. The nuclear translocation of STAT3 was determined by Laser confocal and nucleocytoplasmic separation experiments. Our results showed that SAL attenuated the productions of TNF-α, IL-6, MCP-1, PGE2 and NO dose dependently. SAL also suppressed LPS-induced expressions of iNOS and COX-2 significantly. Further studies revealed that SAL down-regulated the phosphorylation of JAK2-STAT3 signaling pathway and reduced the nuclear translocation of STAT3 induced by LPS in RAW264.7 cells and primary peritoneal macrophages. In addition, consistent with the results in vitro, in the model of mice acute lung injury (ALI) induced by LPS, SAL reduced the infiltration of inflammatory cells and decreased the levels of serum TNF-α and IL-6 obviously. Taken together, these data indicated that SAL exerted anti-inflammatory action via down-regulating LPS-induced activation of JAK2-STAT3 pathway and suppressing STAT3 transfer into the nucleus at least in part.
研究领域:
药理学
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免疫学
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细胞生物学
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炎症
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DOI
PubMed
高影响因子
Scientific Reports
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2015
·Vol. 5
·期 1
·1-17
·
IF 5.578
Cao Wei,Liu Ying,Zhang Ran,Zhang Bo,Wang Teng,Zhu Xianbing,Mei Lin,Chen Hongbo,Zhang Hongling,Ming Pinghong,Huang Laiqiang
Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia , on Gefitinib-resistant NSCLC cell lines in vitro and in viv o. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGFβ signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo . Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2019
·Vol. 38
·期 1
·1-13
·
IF 5.646
Yang Lehe,Lin Shichong,Kang Yanting,Xiang Youqun,Xu Lingyuan,Li Jifa,Dai Xuanxuan,Liang Guang,Huang Xiaoying,Zhao Chengguang
Background Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that rhein has significant antitumor effects, supporting its potential use as an antitumor agent. The IL6/STAT3 signaling pathway has been suggested as an attractive target for the discovery of novel cancer therapeutics.Methods The human pancreatic cancer cell lines AsPC-1, Patu8988T, BxPC-3 and PANC-1, and immunodeficient mice were chosen as models to study the effects of rhein. The potent antiproliferative and proapoptotic effects of rhein were examined by cell viability, cellular morphology, apoptosis and colony formation assays. The STAT3 luciferase report assay, immunostaining analysis and Western blot analysis revealed the inhibition of the IL6/STAT3 signaling axis.Results Apoptosis was induced by adjunctive use of rhein with epidermal growth factor receptor (EGFR) inhibitors in pancreatic cancer cells as verified by cell apoptosis analysis and changes in the expression level of apoptotic/anti-apoptotic proteins BCL-2, BAX, Caspase 3 and Cl-PARP. Suppression of the phosphorylation of STAT3 and EGFR were also observed as a result of the treatment with a combination of rhein and EGFR inhibitors. Most interestingly, it was found that rhein considerably sensitized cells to erlotinib, thus suppressing tumor growth in PANC-1 and BxPC-3 xenograft models. The in vivo anti-tumor effect was associated with increased apoptosis and combined inhibition of the STAT3 and EGFR pathways in tumor remnants.Conclusion sRhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Physiology
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2020
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IF 3.367
Song Manyu,Wang Chaoran,Yang Haotian,Chen Yongping,Feng Xiujing,Li Bei,Fan Honggang
Chronic stress leads to immunosuppression and induces splenocyte apoptosis. STAT3 is a transcription factor that regulates immunity and apoptosis; however, it is unclear whether the increased expression of phosphorylated STAT3 (p-STAT3) observed in chronic stress is related to splenocyte apoptosis. To explore the relationship between splenocyte apoptosis and STAT3 in chronic stress, we treated rats undergoing a 21-day chronic restraint stress program with the STAT3 inhibitor S3I-201. This chronic stress model was verified by observing rats’ behavior and measuring their serum corticosterone levels. Chronic stress led to increased expression of anti-inflammatory cytokines, and p-STAT3 inhibition enhanced splenocyte apoptosis in chronic stress. We detected key proteins in three apoptotic pathways to determine which pathway mediated increasing splenocyte apoptosis and found that the death receptor pathway was the main apoptotic pathway that occurred in the spleen during chronic stress. The unfolded protein response (UPR) was also activated, but the Bcl-2 family was not involved in chronic stress. P-STAT3 inhibition had no influence on the Bcl-2 family and the death receptor pathway; however, p-STAT3 inhibition disrupted the pro-survival function of the UPR by decreasing the expression of ATF6α and p-IRE1α. Furthermore, p-STAT3 inhibition activated endoplasmic reticulum stress by promoting the expression of CHOP, p-JNK, and procaspase-12. Collectively, these findings indicate that the increased p-STAT3 expression during chronic stress may promote splenocyte survival by activating the UPR. Consequently, STAT3 and the UPR may be considered as potential therapeutic targets for chronic stress in the future.
研究领域:
免疫学
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压力生物学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2022
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IF 4.271
Yishuang Luo,Jinyu Kang,Jia Luo,Zheng Yan,Shengtao Li,Zhuoheng Lu,Yufei Song,Xie Zhang,Julin Yang,Aiming Liu
The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188–9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl 3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid . The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis . The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl 3 , there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI.
研究领域:
肝病学
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免疫学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Heliyon
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2023
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IF 4
Nanyu Cao,Heyang Wang
Regular insulin therapy is significantly related to worse cardiovascular outcomes in patients with type 2 diabetes and heart failure. However, the mechanisms of the causal relationship remain unclear. In this study, we observed the effect of insulin on cardiac structure and function and found that insulin dramatically augmented angiotensin II (Ang II)-induced cardiac dysfunction, as well as the proliferation and collagen production of primary cardiac fibroblasts. Total STAT3 expression, but not activation was stimulated by insulin; the effect of insulin on Ang II-induced fibrosis disappeared when STAT3 was blocked and could be entirely suppressed by the MEK inhibitor PD0325901. Our findings suggest a noninsulin-dependent glucose-lowering regimen for patients with type 2 diabetes (T2DM) and heart failure (HF).
研究领域:
心血管病学
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内分泌学
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分子生物学
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DOI
高影响因子
Chemical Biology & Drug Design
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2025
·Vol. 105
·期 1
·e70054
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IF 3.3
Lichao Ji,Yingjie Chai,Chenhao Tong,Yanxin Hu,Jiandong Li,Baochun Lu,Jianhua Yu
Gallbladder cancer is the most prevalent malignancy of the biliary tract and has a dismal overall survival even in the present day. The development of new drugs holds promise for improving the prognosis of this lethal disease. The possible anti-neoplastic role of morusin was investigated both in vitro and in vivo. Through cell viability and colony formation assays, we observed that morusin inhibited the proliferation of gallbladder cancer cells in vitro. Wound healing and transwell assays revealed that morusin impeded the migration and invasion of gallbladder cancer cells. Given the observed morphological changes, we examined epithelial-mesenchymal transition (EMT) markers. Subsequent investigations demonstrated that morusin treatment, both in vitro and in vivo, downregulated the expression of phospho-STAT3 (Signal transducer and activator of transcription 3) and HIF-1α (Hypoxia-inducible factor 1α) in gallbladder cancer cells. Furthermore, morusin effectively reversed EMT induced by phospho-STAT3 or HIF-1α. Morusin has a reversing effect on the EMT of gallbladder cancer cells by modulating STAT3/HIF-1α signaling.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
·
IF 9.7
Mingyu Xia,Songsong Zhao,Zhiwei Sun,Yan Shi,Wenhai Lin,Zhiyuan Zhong,Fenghua Meng
Glioblastoma (GBM) is among the most aggressive brain tumors, presenting significant therapeutic challenges due to intrinsic and acquired resistance to treatment, alongside a highly immunosuppressive tumor microenvironment (TME). While temozolomide (TMZ) is the standard chemotherapeutic agent with the ability to penetrate the blood–brain barrier (BBB), its clinical efficacy is often limited. Here, we report a strategy employing Apolipoprotein E (ApoE) peptide-functionalized polymersomes loaded with small interfering RNA (siRNA) targeting signal transducer and activator of transcription 3 (Apstat3) to amplify the anti-GBM effects of TMZ and immunotherapy. Apstat3 demonstrated small, uniform particle sizes, stability in siRNA encapsulation, and effective downregulation of STAT3 and O⁶-methylguanine-DNA methyltransferase (MGMT) in GL261 cells, sensitizing these tumor cells to TMZ. The combinatorial approach not only significantly inhibited GBM cell proliferation, migration and invasion but also improved dendritic cells (DCs) maturation under TME-mimicking environment. In orthotopic GL261 mouse models, intravenous injection of Apstat3 co-administered with oral TMZ resulted in a twofold increase in median survival and reshaped the TME. Notably, combined treatment with anti-CTLA4 therapy tripled median survival to 64 days, achieving complete remission observed in 20 % of the mice. This siSTAT3 delivery strategy holds promise for enhancing GBM treatment outcomes.
研究领域:
肿瘤学
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药剂学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2025
·
IF 2.2
Xiaoyun Yang,Yi Wang,Yujin Feng,Feng Wang,Lijuan Gao,Yueheng Wang
Myocardial infarction is often accompanied by symptoms of myocardial fibrosis, causing myocardial systolic and diastolic dysfunction. High levels of TMAO are considered to be strongly connected to cardiovascular diseases occurrence. The objective of this investigation was to determine whether formal TMAO affects the development of cardiac muscle fibers. The left anterior descending (LAD) coronary artery was ligated to construct myocardial infarction mouse model, while the control group mouse was only operated vessel separation. According to whether or not TMAO intervention is given, mice were divided into control, TMAO, myocardial infarction model(model), and myocardial infarction model + TMAO(model + TMAO). TMAO and model + TMAO group received 0.24 % TMAO in drinking water for one month. After modeling, echocardiography assessed cardiac function, and cardiac tissues were collected for analysis. Masson staining observed collagen deposition, while immunohistochemistry was conducted to identify fibronectin, collagen III, collagen I, and JAK/STAT pathway related proteins levels. In vitro, mouse cardiac fibroblasts were cultured and treated with varying TMAO concentrations (0, 300, 600, 900 μM), and Western blot was carried out to analyse changes in fibronectin, collagen III, and collagen I. Subsequently, the JAK2/STAT3 pathway inhibitor AG490 was utilized to treat cells and further examine the changes of fibronectin and collagen. The in vivo data showed TMAO significantly increases fibrosis and upregulates fibronectin, collagen III, and collagen I. In vitro experiments indicated that TMAO promotes fibronectin, collagen III, and collagen I levels through regulating the JAK2/STAT3 pathway, ultimately accelerating fibrosis.
研究领域:
心血管疾病研究
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2025
·
IF 8.3
Penghong Xu,Yuping Qian,Guo Xu,Jianlin Chu,Bingfang He
Background Inflammatory bowel disease (IBD), a chronic inflammatory condition categorized into ulcerative colitis (UC) and Crohn's disease (CD), affects a growing global patient population. Despite the prevalence, clinically there is a scarcity of effective therapeutic agents. Purpose This study investigated the therapeutic effects of fructosyl mangiferin (FM) on UC and elucidated its underlying mechanisms through in vivo and in vitro experiments. Methods In vivo , a UC model of C57BL/6J mice was established via dextran sulfate sodium (DSS) induction, and the therapeutic effects were assessed through intragastric administration. In vitro , the murine macrophage cell line RAW264.7 was stimulated with lipopolysaccharide (LPS) to establish an M1 polarization model and introduced to explore the role of FM in immune cells. Molecular docking was further employed to investigate the specific molecular mechanisms of FM. Results In vivo experimental findings indicate that FM, like mangiferin (M), preserves mucin secretion and the expression of occludin protein, and both significantly impede the progression of fibrosis associated with colitis. Additionally, FM effectively suppresses M1 macrophage polarization and exerts a pronounced inhibitory effect on the adaptive immune response, outperforming M in mitigating UC. In vitro results corroborate FM's inhibitory action on M1 polarization. Molecular docking studies identified FM as a potential signal transducer and activator of transcription 3 (STAT3) inhibitor, aligning with western blot analyses from both in vivo and i n vitro experiments. Conclusion In conclusion, following fructosylation, FM exhibits remarkable anti-inflammatory and colonic protective effects. FM's ability to control the progression of UC offers a novel strategy for its potential treatment, warranting further investigation into its clinical application.
研究领域:
免疫学
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药理学
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消化病学
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DOI
PubMed
高影响因子
Canadian Respiratory Journal
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2019
·
IF 1.803
Sheng Zuo,Zhen Zhu,Yi Liu,Hong Li,Shuang Song,Shaojun Yin
Aim. The transmembrane chemokine (C-X-C motif) ligand 16 (CXCL16) plays a vital role in the pathogenesis of organ fibrosis, including the liver and kidney. However, the detailed biological function of CXCL16 is still not fully understood in the progression of pulmonary fibrosis (PF). The aim of present study is to examine the function of CXCL16 in PF. Materials and Methods. In this study, we constructed the PF model on mouse by using bleomycin and analyzed the effect of the mouse recombinant protein CXCL16 on mouse lung fibroblast L929 (LF) as well. To further examine the connection between CXCL16 and STAT3 in mouse LF cells, the STAT3 inhibitor AG490 was utilized to inhibit the expression of STAT3. Meanwhile, lipopolysaccharide was used to enhance the phosphorylation of STAT3 (p-STAT3) in mouse LF cells. Results. Our results indicated that the level of CXCL16/CXCR6 was significantly upregulated in the mouse PF model. Moreover, the level of p-STAT3 was also promoted. In addition, the mouse recombinant protein CXCL16 not only contributed to the proliferation of mouse LF cells but also induced the expression of p-STAT3 in LF cells. However, the effect of CXCL16 was deeply abolished by the STAT3 inhibitor AG490 in LF cells. Meanwhile, the antibody of CXCL16 deeply reduced the phosphorylation of STAT3 in lipopolysaccharide (LPS) cultured cells. Conclusions. All these results demonstrated that CXCL16 promoted the phosphorylation of STAT3 and further demonstrated that STAT3 was a critical component in CXCL16/CXCR6 signaling pathway. This research not only enhanced the comprehension of CXCL16 but also indicated its potential value as a target in the treatment for human PF.
研究领域:
肺科学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
NEUROTOXICITY RESEARCH
·
2022
·Vol. 40
·期 1
·78-88
·
IF 3.978
Ji Na,Wu Lirong,Shi Hui,Li Qianlu,Yu Anyong,Yang Zhao
Intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease. Neuroinflammation plays an important pathological role in brain injury after ICH. NLRP3 contributes to the pathogenesis of ICH, but the underlying mechanisms regulating of NLRP3 remain elusive. V-set and immunoglobulin domain containing 4 (VSIG4), specifically expressed in resting tissue-resident macrophages, can deliver anti-inflammatory signals into various inflammatory diseases. However, the interaction between VSIG4 and NLRP3, as well as the underlying mechanisms after ICH have not been reported. C57BL/6 mice were subjected to the autologous blood injection ICH model. VSIG4 and NLRP3 levels of macrophages were detected following ICH. Ad-VSIG4 or controls were administered via intracerebroventricular (i.c.v) injection before ICH induction. STAT3 inhibitor (S31-201), JAK2 inhibitor (TG101348), or Ad-A20 RNAi was administered to investigate the role of JAK2-STAT3-A20 pathway in VSIG4-mediated neuroinflammation after ICH. Pro-inflammatory cytokine production, BBB disruption, brain water content, and neurological test were examined in ICH mice. VSIG4 levels were significantly decreased, and NLRP3 levels were significantly increased in the perihematomal brain tissues after ICH. Ad-VSIG4 attenuated NLRP3 levels and inhibited inflammation, as well as improved neurological function and reduced BBB disruption and brain water content. Furthermore, Ad-VSIG4 increased the protein levels of phosphorylated JAK2 and STAT3, and A20 levels at 24 h after ICH. STAT3 inhibitor, JAK2 inhibitor, and A20 RNAi abolished the beneficial effects of Ad-VSIG4 after ICH. In summary, these data suggested that VSIG4 attenuated NLRP3 and ameliorated neuroinflammation via JAK2-STAT3-A20 pathway after intracerebral hemorrhage in mice. VSIG4 might be an ideal therapeutic target for ICH patients.
研究领域:
神经科学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
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