Cancer Communications
·
2022
·Vol. 43
·期 1
·100-122
·
IF 15.283
Yufei Yang,Dakui Luo,Yang Shao,Zezhi Shan,Qi Liu,Junyong Weng,Weijing He,Ruoxin Zhang,Qingguo Li,Ziliang Wang,Xinxiang Li
Background Circular RNAs (circRNAs) generated by back-splicing of precursor mRNAs (pre-mRNAs) are often aberrantly expressed in cancer cells. Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers, including colorectal cancer (CRC). However, the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited. Here, we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis. Methods circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients. The expression of circRNAs were determined by quantitative PCR (qPCR) and in situ hybridization (ISH). The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs. The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array, RNA pull-down/mass spectrometry, RNA immunoprecipitation assay, luciferase reporter assay, chromatin immunoprecipitation analysis, and fluorescence in situ hybridization (FISH). Results Among circRNAs, circCAPRIN1 was most significantly upregulated in CRC tissue specimens. circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients. Downregulation of circCAPRIN1 suppressed proliferation, migration, and epithelial-mesenchymal transition of CRC cells, while circCAPRIN1 overexpression had opposite effects. RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism. Moreover, circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1 (ACC1) expression. Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2 (STAT2) to activate ACC1 transcription, thus regulating lipid metabolism and facilitating CRC tumorigenesis. Conclusions These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC. circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1. circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Risheng Zhao,Min Zhang,Gege Yang,Wei Liu,Hui Yu,Shuang Yan,Ting Ren,Linxin Zhang,Mengyang Wang,Haiming Sun
Hypertensive heart failure pathogenesis involves angiotensin II (Ang II)-mediated mechanisms through both hemodynamic overload and direct cellular signaling pathways. This study investigates the therapeutic potential of Portulaca oleracea L. (POL) extract and its active constituent Oleracein E (OE) in attenuating Ang II-induced pathological cardiac remodeling and subsequent heart failure progression. An experimental model of hypertensive heart failure was established in C57BL/6 mice through continuous subcutaneous infusion of Ang II for 4 weeks, with Oleracein E (OE) intervention administered during the final 2 weeks of the protocol. To elucidate the molecular mechanisms underlying OE's cardioprotective effects, we employed an integrated approach combining RNA sequencing analysis, molecular docking simulations, and target validation through drug affinity response target stability (DARTS) and cellular thermal shift assay (CETSA) techniques. The experimental results demonstrated that both POL extract and its active component OE exerted significant cardioprotective effects against Ang II-induced cardiac dysfunction in murine models, primarily through attenuation of pathological cardiac hypertrophy and suppression of inflammatory responses. Transcriptomic profiling via RNA sequencing identified the MAPK signaling pathway as a critical mediator of these protective effects. Subsequent transcription factor analysis revealed STAT2 as a key regulatory component in this pathway. Importantly, OE treatment effectively mitigated inflammatory responses in both in vivo cardiac tissues and in vitro cultured cardiomyocytes by specifically inhibiting the Ang II-activated MAPKs/STAT2 signaling cascade. Genetic ablation experiments further confirmed the essential role of this pathway, as the anti-inflammatory efficacy of OE was completely abolished in cardiomyocytes with MAPKs or STAT2 deficiency. Molecular interaction studies employing in silico docking simulations combined with experimental validation through DARTS and CETSA techniques provided direct evidence of physical binding between OE and the STAT2 protein. Our findings demonstrate that Oleracein E (OE) confers cardioprotection against Ang II-induced myocardial injury through a novel mechanism involving STAT2 targeting and subsequent suppression of MAPK signaling-mediated inflammatory cascades. These results not only elucidate a previously unrecognized pharmacological pathway but also suggest that OE and its derivatives hold significant therapeutic promise for the clinical management of hypertensive heart failure, potentially offering a targeted approach to modulate pathological cardiac remodeling.
研究领域:
药理学
·
心血管病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Xin Qiao,Lei Zhang,Ting Wang,Xinyi Liang,Shenmeng Yao,Lei Wang,Gaoxiang Ma,Jie Yang,Xiaodong Wen
Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising global prevalence, posing ongoing therapeutic challenges. Diosgenin (DSG), a natural steroidal saponin, exhibits anti-inflammatory properties. However, its molecular mechanisms in UC are poorly understood. Purpose This study sought to clarify the molecular mechanisms and therapeutic targets responsible for DSG's protective effects against UC. Methods A murine colitis model induced by dextran sulfate sodium was used to assess DSG efficacy. Mechanistic insights were obtained from RNA sequencing analysis and confirmed in RAW264.7 and bone marrow-derived macrophages through Stat2 knockdown/overexpression experiment. Chromatin immunoprecipitation and surface plasmon resonance assays were used to investigate DSG-STAT2 interactions. Results DSG markedly alleviated colonic inflammation and tissue damage in DSS-treated mice. It significantly modulated macrophage polarization in colonic lamina propria lymphocytes. RNA-seq and Western blotting revealed that DSG selectively suppressed STAT2 phosphorylation and CMPK2 expression in macrophages, while attenuated LPS-induced mitochondrial DNA (mtDNA) synthesis and mitochondrial ROS (mtROS) production. STAT2 directly bound to the Cmpk2 promoter, and Stat2 silencing abolished LPS-driven Cmpk2 transcription and mtDNA synthesis. DSG interacted with STAT2 at Pro630 and Lys689 residues, and its inhibitory effects on CMPK2 and mtDNA were reversed by STAT2 overexpression. Conclusions DSG exerts its anti-colitis effects by selectively targeting STAT2 at Pro630 and Lys689, thereby suppressing CMPK2-mediated mtDNA overproduction. The discovery of a STAT2-dependent mechanism in DSG presents a potential therapeutic approach for UC.
研究领域:
免疫学
·
分子生物学
·
药理学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Mengyang Wang,Wei Liu,Zhuoqun Wang,Linxin Zhang,Jie Zhao,Yongwei Lai,Xiaoli Cui
Background Hypertension is an important risk factor for heart failure. Zhenwu Decoction (ZWD) is a classical Chinese medicinal recipe that has been extensively used to manage cardiovascular disorders throughout history. However, the fundamental processes involved in its effects were not clear. Objective In this study, we investigated the effects of ZWD on Ang II-induced cardiac remodeling and heart failure. Methods A hypertensive heart failure (HF) mice model was established via the micro-osmotic pump infusion of Ang II in C57BL/6 mice for 4 weeks. After two weeks of infusion, ZWD and valsartan were administered intragastrically for another two weeks to investigate their mechanisms of action.RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of ZWD, and potential binding proteins of Galloypaeoniflorin (GAL), an effective monomer component of ZWD, were verified by molecular docking, DARTS, CETSA and SPR. Results The results showed that ZWD conferred a protective effect against Ang II-induced cardiac dysfunction in mice by inhibiting cardiac hypertrophy and inflammation. RNA sequencing revealed that this cardioprotective effect was associated with the MAPKs/STAT2-NLRC5 signaling pathway. GAL alleviated the inflammatory response in mouse heart tissues and in vitro cultured cardiomyocytes by inhibiting the Ang II-stimulated MAPKs/STAT2-NLRC5 signaling pathway. The data suggest that deficiency of MAPKs or STAT2 in cardiomyocytes abolished the anti-inflammatory effects of GAL. Molecular docking, DARTS, CETSA and SPR techniques confirmed the binding of GAL and STAT2. Conclusion Our study suggests that ZWD protects the heart from damage caused by Ang II stimulation by targeting STAT2 through inhibiting the inflammatory response driven by the MAPK signaling pathway, indicating its promising application in the treatment of hypertensive heart failure.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Yajie Cai,Bing Xu,Fei Zhou,Jianzhi Wu,Shuo Li,Qi Zheng,Yajing Li,Xiaojiaoyang Li,Feng Gao,Shifen Dong,Runping Liu
Background Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that markedly elevates the risk of colon cancers and results in disability. The disrupted immune homeostasis has been recognized as a predominant player in the pathogenesis of UC. However, the overall remission rate of current therapies based on immunoregulation is still unsatisfactory. Si-Ni-San (SNS) has been found effective in relieving UC through thousands of years of clinical practice, yet the specific mechanisms of the protective effect of SNS were not fully elucidated. Purpose We aim to investigate the therapeutic effects of SNS against the development of chronic colitis and the underlying mechanisms. Methods We established a DSS-induced chronic experimental colitis mouse model to evaluate the effect of SNS. RNA-sequencing, bioinformatic analysis, and in vitro studies were performed to investigate the underlying mechanisms. Results Our data demonstrated that SNS significantly ameliorated chronic experimental colitis via inhibiting the expression of genes associated with inflammatory responses. Interestingly, SNS significantly suppressed DSS-induced type I interferon (IFN) responses instead of directly downregulating the production of pro-inflammatory cytokines, such as Il-6. In vitro study further found that SNS selectively inhibited STING and RIG-I pathway-induced type I IFN responses by modulating TBK1- and IRF3-dependent signaling transduction. SNS also suppressed the expression of IFN-stimulated genes by directly inhibiting STAT1 and STAT2 activation. Conclusion Our study not only provides novel insights into the pathogenic role of type I IFN responses in colitis but also suggested that SNS or bioactive compounds derived from SNS may serve as novel therapeutic strategies for the treatment of UC via interfering type I IFN-mediated inflammation.
研究领域:
药理学
·
免疫学
·
胃肠病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Physical Science
·
2024
·
IF 7.9
Yuzhuo Fan,Fanfan Chen,Wanzhong Yuan,Yuchun Sun,Jiarui Li,Yan Li,Mingwei Zhao,Xu Zhang,Kai Wang
Contact lens (CL)-associated bacterial keratitis (BK), a prevalent and underestimated disorder caused by unhygienic CL wear, poses a risk to permanent loss of visual acuity. Clinically, low drug-delivery efficiency, frequent administration, hormone complications, and antibiotic resistance remain the major unsolved challenges. Here, we introduce a chlorogenic acid (CGA)-conjugated CL material based on gelatin methacrylate via cryogelation(cGelMA/CGA-CL) to strengthen the prevention and treatment of BK. The cGelMA/CGA-CL features a highly moist, macroporous, adjustable structure for sustained release of CGA and is favorably biocompatible to cells, providing antimicrobial protection against opportunistic pathogens and inhibiting excessive ocular inflammatory responses through the JAK2-STAT1/STAT2 signaling pathway. Furthermore, the cGelMA/CGA-CL effectively alleviates the symptoms of BK with immunoregulation of macrophage recruitment and anti-inflammatory factor release in a mouse model of BK. The cGelMA/CGA-CL offers a promising candidate for the prevention and treatment of BK, which may significantly reduce the risk of infection for CL wearers.
研究领域:
眼科学
·
生物材料
·
药学
·
免疫学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）