Urantide alleviates the symptoms of atherosclerotic rats in vivo and in vitro models through the JAK2/STAT3 signaling pathway

2021 ◽  
Vol 902 ◽  
pp. 174037
Author(s):  
Tu Wang ◽  
Lide Xie ◽  
Hongdong Bi ◽  
Ying Li ◽  
Ying Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
In Vitro Models ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

scholarly journals Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Binlong Zhong ◽  
Deyao Shi ◽  
Fashuai Wu ◽  
Shangyu Wang ◽  
Hongzhi Hu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
G1 Arrest ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Candidate Drug

Abstract Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients’ health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.

scholarly journals Escin Sodium Improves the Prognosis of Acute Pancreatitis via Promoting Cell Apoptosis by Suppression of the ERK/STAT3 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-26
Author(s):  
Qian Zhang ◽  
Chen Zhao ◽  
Lei Zhang ◽  
Kai Sun ◽  
Linlin Yu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Inflammatory Responses ◽  
Horse Chestnut ◽  
Inflammatory Disorder ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Acute pancreatitis (AP), an inflammatory disorder of the pancreas, can cause systemic inflammatory responses. Escin Sodium (ES), a natural mixture of triterpene saponins extracted from the dry ripe fruit of Fructus Aesculi or horse chestnut crude, has been demonstrated to have antiedematous, anti-inflammatory, and antiexudative effects. We here aim to investigate the effects of ES pretreatment on AP in vivo and in vitro and explore its potential molecular mechanism. In the present study, we demonstrated that ES pretreatment could apparently decrease amylase and lipase, downregulate inflammatory cytokines, and attenuate pancreatic damage. Additionally, the increased expression of apoptotic-related proteins and the results of flow cytometry demonstrated the effects of ES on promoting apoptosis in acinar cells. Moreover, ES could enhance mitochondrial membrane potential (MMP, ΔΨm) and reactive oxygen species (ROS) level and reduce intracellular calcium concentration, which are closely related to mitochondrial-mediated death. The effect of ES pretreatment on acinar cell apoptosis was furtherly confirmed by the regulatory pathway of the ERK/STAT3 axis. These results suggest that ES attenuates the severity of AP by enhancing cell apoptosis via suppressing the ERK/STAT3 signaling pathway. These findings provide evidence for ES which is treated as a novel and potent therapeutic for the treatment of AP.

scholarly journals Bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway

2021 ◽  
Author(s):  
Ke Xu ◽  
Kai Fang ◽  
Yueping Zhan ◽  
Yuqian Wang ◽  
Chengqi Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Umbilical Vein ◽  
Tumour Microenvironment ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background Anti-angiogenesis therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that tumor microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active compound whose anti-tumor efficacy has been proven by previous studies. However, there are very few studies on the anti-angiogenic effects of bufalin. Methods Herein, human umbilical vein endothelial cells (HUVEC) tube formation, migration and adhesion test were used to assess angiogenesis in vitro. Western blot and quantitative PCR were used to detect relevant protein levels and the expressions of mRNAs. Subcutaneous xenograft tumor model and hepatic metastasis model in mice were established to investigate the influence of bufalin on angiogenesis-mediated by TME in vivo. Results We found that the angiogenesis mediated by tumor microenvironment cells was significantly inhibited in the present of bufalin. The results demonstrated that the pro-angiogenic gene in HUVEC such as VEGF, PDGFA, E-selectin and P-selectin were downregulated by bufalin, and the downregulation was regulated by inhibiting the STAT3 pathway. Overexpression STAT3 could reverse the inhibitory effect of bufalin on angiogenesis. What is more, few reduction of angiogenesis when bufalin directly acted on tumor microenvironment cells. Conclusion Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway of vascular endothelial cells, which reveals that bufalin may be used as a new anti-angiogenic adjuvant therapy medicine in the treatment of colorectal cancer.

scholarly journals HBD Inhibits the Development of Colitis-Associated Cancer in Mice via the IL-6R/STAT3 Signaling Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 1069 ◽  
Author(s):  
Song Deng ◽  
Aiping Wang ◽  
Xi Chen ◽  
Qun Du ◽  
Yanli Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intestinal Inflammation ◽  
Underlying Mechanism ◽  
Peptic Ulcers ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Hct 116 ◽  
Chronic Intestinal Inflammation

Colitis-associated cancer (CAC) is a malignant disease of the colon that is caused by recurrent episodes of chronic intestinal inflammation. Huangqi Baizhu decoction (HBD) is a classic prescription comprised of Radix Astragali and Rhizoma Atractylodis, which are usually used to treat digestive conditions, such as peptic ulcers, colitis, or colorectal carcinoma in clinics. HBD is well known for “tonifying qi and spleen” based on the theories of traditional Chinese medicine, and has the preponderant effect of alleviating chronic intestinal mucosa damage associated with disease. However, the underlying mechanism behind this is still unknown. In the current study, we employed the AOM/DSS mouse model to analyze the effects of HBD on the development of inflammation in colonic carcinoma. The in vivo study showed that HBD could significantly reduce the mortality of mice and control the incidence and size of colonic tumors by inhibiting the IL-6/STAT3 signaling pathway. In vitro, Astragaloside and Atractylenolide (CAA), the main components of HBD, inhibited the proliferation of HCT-116 cells as determined by an MTT assay. Furthermore, CAA notably suppressed the protein expression of IL-6R, STAT3, Survivin, and Cyclin D1 induced by IL-6 in HCT-116 and RAW264.7 cells. These results suggested that HBD exhibits anti-inflammatory and anti-proliferative effects, inhibiting the development of CAC in mice.

scholarly journals ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Sipei Nie ◽  
Lin Zhang ◽  
Jinhui Liu ◽  
Yicong Wan ◽  
Yi Jiang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cisplatin Resistance ◽  
Rna Seq ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Rna Immunoprecipitation

Abstract Background Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. Methods Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. Results ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. Conclusions The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

scholarly journals ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and platinum resistance in epithelial ovarian cancer

2021 ◽  
Author(s):  
Sipei Nie ◽  
Lin Zhang ◽  
Jinhui Liu ◽  
Yicong Wan ◽  
Yi Jiang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Platinum Resistance ◽  
Rna Seq ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Rna Immunoprecipitation

Abstract Background: Chemotherapy resistance remains a barrier in improving the prognosis of epithelial ovarian cancer (EOC), but its mechanism remains to be elucidated. ALKBH5 has been recently proven to be an RNA N6-methyladenosine (m6A) demethyltransferase associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in platinum-resistant EOC.Methods: Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop.Results: ALKBH5 was upregulated in platinum-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 was found to be the upstream transcription factor of ALKBH5 and formed a loop with ALKBH5., and its overexpression facilitated EOC cell chemoresistance both in vivo and in vitro. HOXA10 overexpression was found to facilitate EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is an m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, and this resulted in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10.Conclusions: The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to platinum. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop maybe a potential strategy to overcome platinum resistance in EOC.

scholarly journals Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Zhongzhong Tu ◽  
Mengxian Xu ◽  
Jian Zhang ◽  
Ye Feng ◽  
Zhuo Hao ◽  
...  
Keyword(s):  
Viral Replication ◽  
Signaling Pathway ◽  
Rabies Virus ◽  
Antiviral Effect ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

ABSTRACT Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3′ untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3. IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3′ UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo. Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.

scholarly journals HNF1α Controls Liver Lipid Metabolism and Insulin Resistance via Negatively Regulating the SOCS-3-STAT3 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Jiaorong Tan ◽  
Jiahong Xu ◽  
Guohua Wei ◽  
Lijuan Zhang ◽  
Long’e Sun ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Liver Lipid ◽  
Fatty Degeneration ◽  
Glycolipid Metabolism ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

This study is aimed at evaluating the effects, functions, and mechanism of HNF1α on hepatic glycolipid metabolism. In this study, free fatty acid- (FFA-) induced steatosis of hepatocyte liver cell LO2 was used as an in vitro model. The methods of Oil Red O staining, RT-qPCR, western blot, and immunofluorescence staining were used to detect LO2-regulated HNF1α expression and its effects on FFA-induced LO2 cell steatosis, the insulin signaling and SOCS-3-STAT3 signaling pathways, the expression of lipid metabolism-related regulators, and phosphorylation. With increased FFA induction time, the expression of HNF1α in the LO2 fatty degeneration hepatic cells gradually decreased. Downregulation of HNF1α expression aggravated FFA-induced steatosis of LO2 hepatocytes. HNF1α promotes activation of the insulin pathway and oxidative breakdown of fat and inhibits lipid anabolism. Inhibitors of STAT3 can reverse the regulation of decreased HNF1α expression on the insulin signaling pathway and fat metabolism. We also confirmed this pathway using HNF1α-/- mice combining treatment with STAT3 inhibitor NSC 74859 in vivo. HNF1α regulates hepatic lipid metabolism by promoting the expression of SOCS-3 and negatively regulating the STAT3 signaling pathway.

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