Journal of Hepatocellular Carcinoma
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2025
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IF 3.4
Jiayuan Zhang,Tian Tian,Shanshan Tian,Jinhai Yao,Yingwan Zhang,Rujia Xie,Ting Yang,Bing Han
Purpose This study aims to investigate the mechanism of action of arsenic-based agents against hepatocellular carcinoma (HCC) and to identify effective drug targets for HCC treatment.Methods Huh7 and HepG2 cells treated with NaAsO2 were assessed for cell viability, pyroptosis, migration, and invasion after undergoing lentiviral transfection. An orthotopic liver tumor model was established and divided into a model group and a treatment group. Proteins associated with QRICH1, PRMT1, cGAS-STING, and the classical pyroptosis pathway were quantified using Western blotting. The intracellular expression and localization of PRMT1 and NLRP3 in HCC were analyzed through cellular immunofluorescence. Co-immunoprecipitation (Co-IP) was performed to examine the protein interactions between PRMT1 and cGAS, as well as between STING and NLRP3. Chromatin immunoprecipitation (ChIP) was used to confirm QRICH1 enrichment in the PRMT1 promoter region.Results NaAsO2 treatment significantly inhibited the proliferation of Huh7 and HepG2 cells and effectively blocked their migration and invasion capabilities, while promoting cellular pyroptosis. Quantitative polymerase chain reaction(QRCR) and ChIP assays confirmed that NaAsO2 regulates PRMT1 expression by down-regulate QRICH1 binding in the PRMT1 promoter region. Additionally, NaAsO2 decreased the expression of the QRICH1-PRMT1 complex and upregulated the cGAS-STING signaling pathway, activating the downstream NLRP3-dependent classical pyroptosis pathway. Overexpression of QRICH1 reversed these effects.Conclusion NaAsO2 inhibits the expression of the QRICH1-PRMT1 axis, activates cGAS-STING signaling pathway transduction, and induces pyroptosis in HCC cells, thereby increasing the infiltration of immune cells in liver cancer tissues.
研究领域:
分子生物学
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肿瘤学
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药理学
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产品关联
DOI
PubMed
高影响因子
CELL
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2019
·
IF 36.216
Jiang Dai,Yi-Jiao Huang,Xinhua He,Ming Zhao,Xinzheng Wang,Zhao-Shan Liu,Wen Xue,Hong Cai,Xiao-Yan Zhan,Shao-Yi Huang,Kun He,Hongxia Wang,Na Wang,Zhihong Sang,Tingting Li,Qiu-Ying Han,Jie Mao,Xinwei Diao,Nan Song,Yuan Chen,Wei-Hua Li,Jiang-Hong Man,Ai-Ling Li,Tao Zhou,Zheng-Gang Liu,Xue-Min Zhang,Tao Li
Summary The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.
研究领域:
免疫学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Biomaterials Science
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2025
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IF 5.7
Xinyu Wang,Qingbin He,Lining Wang,Chengzhilin Li,Wenyu Zhang,Zhonghou Rong,Qingqing Yin,Yingchun Zhao
Sepsis, an inflammatory disease caused by bacterial infection, has become a global public health crisis. Excessive reactive oxygen species (ROS) in sepsis patients act as the primary trigger for activating intracellular immune pathways, ultimately leading to multiple organ dysfunction syndrome. The overexpression of acidic metabolites and ROS, characteristic of the infected microenvironment, significantly impedes sepsis treatment. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, plays a key role in inflammatory diseases. The detrimental effects of STING in sepsis have been well documented. Here, we developed a pH-responsive nanotherapy platform (DMSNM@C-178/PAA) that combines ROS scavenging with cGAS-STING pathway inhibition for anti-inflammatory therapy. This nanoparticle is selectively released in the infected microenvironment, where reduced molybdenum-based polyoxometalates (Mo-POM) efficiently neutralize toxic ROS in vivo, while C-178 selectively inhibits the cGAS-STING pathway, thereby attenuating the inflammatory response and preventing organ deterioration. In vitro and in vivo studies demonstrate that DMSNM@C-178/PAA treats sepsis by eliminating excess ROS and modulating autoimmune dysfunction via the cGAS-STING pathway, providing a novel therapeutic strategy for sepsis management.
研究领域:
医学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Jingwen Xiao,Shilin Zhou,Fengshu Fei,Lin Long,Chuanlong Guo
Ulcerative colitis (UC) is a persistent intestinal disorder featuring periodic flare-ups of the colon's inner lining inflammation. Current therapeutic strategies, while effective in managing symptoms, are often limited by side effects and high costs. This study investigates the potential of pectin-loaded ferulic acid (PC-FA) nanoparticles as a novel therapeutic approach for UC, focusing on their ability to modulate the cGAS-STING pathway, a key mediator in the inflammation associated with UC. PC-FA nanoparticles were prepared and characterized for their physicochemical properties, antioxidant capacity, biocompatibility, and influence on the cGAS-STING pathway. In vitro experiments demonstrated that PC-FA nanoparticles enhanced the solubility and bioavailability of ferulic acid (FA), reduced oxidative stress, and protected colon epithelial cells from damage caused by the administration of dextran sulfate sodium (DSS). In vivo studies in a DSS-induced colitis mouse model showed that PC-FA nanoparticles mitigated weight reduction, lowered disease activity index (DAI) scores, and sustained colon length, and ameliorated histopathological changes. Additionally, PC-FA nanoparticles effectively targeted DNA damage and inhibited the cGAS-STING pathway, leading to a significant reduction in pro-inflammatory cytokines. Pharmacokinetic studies revealed rapid absorption of PC-FA in the bloodstream, with a predominant distribution in the intestines. The study concludes that PC-FA nanoparticles are a promising therapeutic strategy for UC, offering targeted drug delivery, enhanced bioavailability, and anti-inflammatory effects.
研究领域:
药理学
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免疫学
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消化系统疾病
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Xiao Xiao,Song Wang,Xin Zhang,Junyong Zheng,Dazhi Yang,Songlin Peng
The pollution issue of chlorinated paraffins has garnered widespread attention, with short-chain chlorinated paraffins (SCCPs) being comprehensively banned by the Stockholm Convention due to environmental contamination concerns. Currently, long-chain chlorinated paraffins (LCCPs) are widely used, necessitating an assessment of their toxicological impact. Bone marrow mesenchymal stem cells (MSCs) are a type of multipotent stem cell with self-renewal, immunoregulatory, and tissue repair capabilities, exhibiting important biological functions. In this study, MSCs were used as a model to evaluate the toxicological effects of LCCP. Initially, cell proliferation experiments were conducted to assess the impact of LCCP on MSC proliferation. The results indicated a significant reduction in cell proliferation capacity. Further work revealed that LCCP treatment induced cell senescence, as evidenced by Sa-β-gal staining and the evaluation of senescence markers, including p16, p21, and p53. Furthermore, LCCP treatment led to inflammation and oxidative stress, as analyzed by corresponding marker molecules, and ultimately resulted in cell death. Based on these findings, we investigated the molecular mechanisms underlying LCCP-induced MSC senescence. In summary, this paper is the first study to systematically investigate the toxicological effects of LCCPs on stem cells. The current study demonstrates that LCCP induces MSC senescence, highlighting its potential toxicity. This research lays the foundation for further elucidating the toxicology of LCCP. This finding suggests that the use of LCCPs should be strictly controlled under rigorous regulation.
研究领域:
毒理学
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细胞生物学
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环境科学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-18
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IF 12.6
Wen E.,Tian Yu,Chen Yu,Wang Zhigang,Feng Yi,Liao Zhen
Despite the encouraging developments in tumor immunotherapy, the complex tumor microenvironment (TME) and abnormal energy metabolism persist as key factors facilitating immune escape. Recent research has emphasized the significant potential of the Manganese ions (Mn 2+ ) as a “immune ion reactors” have the potential to stimulate cGAS-STING signaling pathway in modulating tumor immunotherapy. However, their efficacy is limited by insufficient targeting and lack of tumor specificity. To address these challenges, we have developed a nano-drug named as LT@MnO@MON-HA (LMMH), which incorporates manganese oxide (MnO) nanoparticles as the core and organic mesoporous silica as the outer layer. The mitochondrial glycolysis inhibitor lonidamine (LT) is encapsulated within the mesopores of LMMH and subsequently coated with hyaluronic acid to achieve precise tumor-targeted drug delivery. After reaching the tumor site, LMMH can decompose in the reducing and acidic TME, releasing LT and Mn 2+ . Once internalized by cells, LT rapidly localizes to mitochondria via functional groups, disrupting mitochondrial metabolism and increasing intracellular reactive oxygen species levels. Mn 2+ catalyze the conversion of hydrogen peroxide (H₂O₂) into more cytotoxic hydroxyl radicals (·OH), thereby enhancing chemodynamic therapy (CDT). The mesoporous silica shell of LMMH is capable of depleting glutathione in the TME, enhancing CDT. Moreover, LMMH functions as an agonist of the cGAS-STING pathway, stimulating cytokine release and activating effector T cells, which in turn triggering systemic immune responses against primary and metastatic cancers. Collectively, these finding highlights the dual mechanisms by which LMMH enhances combination immunotherapy by regulating the TME and tumor metabolism. Graphical
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
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2025
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IF 26.8
Nailin Yang,Shumin Sun,Jiachen Xu,Fei Gong,Huali Lei,Yu Hao,Zifan Pei,Chenya Wang,Qiao Yu,Jihu Nie,Nan Jiang,Caifang Ni,Liang Cheng
The cGAS-STING pathway is pivotal in initiating antitumor immunity. However, tumor metabolism, particularly glycolysis, negatively regulates the activation of the cGAS-STING pathway. Herein, Mn galvanic cells (MnG) are prepared via liquid-phase exfoliation and in situ galvanic replacement to modulate tumor metabolism, thereby enhancing cGAS-STING activation for bidirectional synergistic H 2 -immunotherapy. The obtained MnG can be etched by water, enabling efficient and sustained generation of H 2 gas and Mn 2+ . MnG not only activated and amplified the cGAS-STING pathway through the sustained release of Mn 2+ but also regulated tumor glucose metabolism to inhibit the expression of three prime repair exonuclease 2 (TREX2), thereby synergistically enhancing the activation of the cGAS-STING pathway. The injection of MnG into tumors resulted in a robust immune response, thereby providing favorable support for antitumor therapy. Consequently, the combination of MnG with immune checkpoint blockade therapy resulted in significant suppression of both primary tumors and distant tumors. Furthermore, the MnG-lipiodol dispersion exhibited remarkable efficacy in combination with transarterial embolization (TAE)-gas-immunotherapy in a rabbit orthotopic liver tumor model. The present study underscores the significance of employing a metal galvanic cell strategy for enhanced immunotherapy, thereby offering a novel approach for rational design of bioactive materials to augment immunotherapeutic effectiveness.
研究领域:
肿瘤学
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免疫学
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生物化学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
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2022
·Vol. 59
·期 11
·7006-7024
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IF 5.682
Han Chengzhi,Qian Xinyi,Ren Xiaorong,Zhang Shutian,Hu Li,Li Jingyao,Huang Yijun,Huang Renhui,Ooi Kokwin,Lin Hong,Xia Chunmei
Neuroinflammation in the cardiovascular center plays a critical role in the progression of hypertensive heart disease. And microglial autophagy is involved in the regulation of neuroinflammation. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, senses mitochondrial DNA (mtDNA) and regulates autophagy. The detailed mechanisms of central cGAS affects neuroinflammatory response in hypertensive heart disease via regulating autophagy remain unknown. Angiotensin II (Ang II, 1.5 mg·kg −1 ·12 h −1 , 2 weeks) was intraperitoneally injected to induce hypertension in mice. The cGAS-STING pathway was activated in the paraventricular nucleus (PVN) of Ang II-induced hypertensive mice. The contractile dysfunction of heart was alleviated in Ang II-induced hypertensive cGAS −/− mice. To observe the central effects of cGAS on regulating hypertensive heart disease, the RU.521 (a cGAS inhibitor) was intracisternally infused in hypertensive mice. Intracisternal infusion of the RU.521-alleviated myocardial interstitial fibrosis, cardiomyocyte hypertrophy, and the contractile dysfunction in Ang II-induced hypertensive mice. Intracisternal infusion of RU.521 attenuated the microglial activation, neuroinflammation, sympathetic/parasympathetic activity ratio, and lowered blood pressure. The autophagic flux in the PVN cells was blocked, while intracisternal infusion of RU.521 alleviated this effect in the Ang II-induced hypertensive mice. In vitro, it was found that cGAS-STING activation-induced autophagic flux blockage, while when the impaired autophagic flux was facilitated by rapamycin, an autophagy inducer, the microglial M1 polarization was decreased correspondingly. In conclusion, cGAS induces the inflammatory phenotype of microglia via impairing autophagic flux, thereby participating in neuroinflammation, which leads to sympathetic overactivation in hypertension and further caused hypertensive myocardial injury.
研究领域:
心血管疾病
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神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2021
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IF 9.776
Chao Wang,Zhaoyi Sun,Chenxuan Zhao,Zhewei Zhang,Haoran Wang,Yang Liu,Yunfei Guo,Bingtao Zhang,Lihong Gu,Yue Yu,Yiqiao Hu,Jinhui Wu
Radiotherapy (RT)-induced DNA damage leaked into cytosol can elicit host antitumor immune response. However, such response rate is unpromising due to limited cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA, which could be digested inherently by host DNases . Here we show that synchronizing Mn 2+ delivery with accumulated cytosolic DNA after RT can promote the activation of cGAS-STING pathway, thereby enhancing RT-induced antitumor immunity. Intratumoral Mn 2+ injection immediately after RT cannot enhance RT, while intratumoral Mn 2+ injection 24 h after RT can. Direct-injected Mn 2+ can be metabolized out from tumor in minutes while RT-induced DNA damage need cells mitotic progression for up to 24 h to accumulate into cytosol. Alginate can maintain Mn 2+ in tumor for up to 24 h due to it can chelate divalent cations . When the release profile of Mn 2+ is controlled by alginate (Alg) and synchronized with the accumulation of RT-induced DNA damage, over 90% inhibition rate can be obtained even in the unirradiated tumor, and survival time is significantly extended. This synchronizing strategy provides a simple and novel approach to effectively activate cGAS-STING pathway in tumor and promote RT-induced immunity.
研究领域:
肿瘤学
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免疫学
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放射生物学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
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2024
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IF 14.3
Zhen Tong,Jia-Peng Zou,Su-Yun Wang,Wei-Wei Luo,Yan-Yi Wang
Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (β) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-β and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-β and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-β- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.
研究领域:
免疫学
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分子生物学
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微生物学
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癌症研究
✓ 已验证
DOI
PubMed
高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
·
2025
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IF 3.7
Fa Wang,Zhiyang Wang,Shuqi Huang,Jinrong Yang,Yu Chen,Hui Chao
Graphical A convenient strategy by synergistic delivering DNA and DNA photocleavage agents to tumor cells was developed for effective photodynamic immunotherapy under hypoxia. Plasmid DNAs intercalated with Ru(II) complexes were encapsulated in liposomes to create nano-photosensitizers. Upon light exposure, the ruthenium complex photo-cleavages DNA. The DNA fragments specifically stimulate the cGAS-STING pathway and induce immunogenic death. This study presents a convenient strategy for photodynamic immunotherapy against cisplatin-resistant tumor cells under hypoxia.
研究领域:
生物化学
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肿瘤学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2022
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IF 10.334
Xiaohua Xie,Xiaofeng Wu,Dongsheng Zhao,Ying Liu,Qiyue Du,Yitian Li,Yaping Xu,Yuhang Li,Yan Qiu,Yungang Yang
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with high mortality and limited effective therapy. Herein, we reported that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), used in depression and anxiety treatment, also exhibited therapeutic activities in IPF. Fluvoxamine inhibited cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), restrained the activation of their downstream targets, including PERK/ eIF2α/ c-Myc/ miR-9–5p/ TBPL1 and TBK1/ YAP/ JNK1/2/ Bnip3/ CaMKII/ cofilin signaling, thus attenuated the activation and migration of fibroblasts upon TGF-β1 challenge. Fluvoxamine dose-dependently improved pulmonary function, decreased the expression of inflammatory factors, reduced excessive production of extracellular matrix, and thus alleviated bleomycin (BLM)-induced lung fibrosis in mice. Moreover, fluvoxamine at a dose of 10 mg/ kg showed similar efficacy as pirfenidone (PFD) at a dose of 30 mg/kg in a mice model of lung fibrosis. In summary, our results suggest that fluvoxamine is an effective anti-fibrotic agent for IPF.
研究领域:
药理学
·
肺科学
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免疫学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）