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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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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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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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
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高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
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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
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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
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肺科学
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免疫学
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病理学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Ru-Yang Zhao,Mu-Zi Li,Qi-Qian Wang,Fu-Wei Jiang,Yi Zhao,Jin-Long Li
Butachlor (BTR), a globally prevalent amide herbicide, poses significant environmental health risks due to its bioaccumulation potential and documented chronic toxicity in mammalian systems. Given the spleen's pivotal role in orchestrating systemic immune homeostasis, this study investigated BTR-induced immunopathological mechanisms in ICR mice following 28-day subacute exposure (10 mg/kg). Histopathological examination revealed significant disorganization of the splenic marginal zone architecture, concomitant with ultrastructural mitochondrial abnormalities and a reduction in mitochondrial membrane potential (ΔΨm). Mitochondrial permeability transition pore opening triggered cytoplasmic translocation of mitochondrial DNA (mtDNA), activating the stimulator of interferon genes (STING) pathway—a master regulator of innate immunity. STING activation initiated bifurcated downstream signaling, evidenced by TBK1 phosphorylation and subsequent IRF3 / NF-κB nuclear translocation. This dual signaling cascade simultaneously executed immunogenic cell death via Gasdermin D-dependent pyroptosis (cleaved GSDMD-NT) and drove macrophage polarization (IFN-α / β, IL-1β, TNF-α). Crucially, pharmacological STING inhibition with C-176 attenuated both pyroptosis (GSDMD cleavage reduced) and inflammatory cytokine surge. Our findings not only pioneer the identification of the mtDNA-STING axis as the central mechanism underlying BTR-induced splenic immunotoxicity but also validate STING inactivation as a targeted strategy to mitigate herbicide-associated immune dysfunction. This work provides critical insights for environmental toxicant risk assessment and immunomodulatory.
研究领域:
环境毒理学
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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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细胞生物学
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PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Qingdong Li,Yuanyuan Cui,Zhenhong Xia,Wenjuan Gao,Jianmin Xiao,Zhen Zhao,Lei Yang,Guilong Zhang,Zhengyan Wu
Immunotherapy has emerged as a promising approach for melanoma treatment. However, the efficacy of traditional immune checkpoint inhibitors (ICIs) remains limited due to the immunosuppressive tumor microenvironment. In this study, a novel nano-immune agonist, pLCGM-OVA, was developed to induce cuproptosis and activate the cGAS-STING pathway, thereby enhancing melanoma immunotherapy. The pLCGM-OVA was synthesized by conjugating PDGFB with liposomes that encapsulate CuGdMn nanoclusters (CGM) and ovalbumin (OVA). Upon exposure to the acidic microenvironment of tumours, pLCGM-OVA undergoes degradation, releasing Cu ions, Mn ions, and free OVA. This release triggers reactive oxygen species-mediated cuproptosis and activates the cGAS-STING pathway via Mn, leading to the subsequent induction of immunogenic cell death (ICD). Simultaneously, free OVA and ICD antigens are presented to dendritic cells (DCs), promoting their maturation and enhancing cytotoxic T lymphocyte infiltration, thus improving the efficacy of tumour immunotherapy. In vitro and in vivo studies demonstrated that pLCGM-OVA significantly inhibited tumour growth and recurrence with minimal systemic toxicity, owing to the combined effects of cuproptosis and immunotherapy. Moreover, pLCGM-OVA exhibited excellent T 1 contrast (9.26 mM −1 s −1 ), significantly enhancing T 1 -weighted magnetic resonance imaging signals of tumours, facilitating accurate melanoma diagnosis. Overall, this work presents a highly promising candidate for the development of potent immune agonists for melanoma treatment.
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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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
·
IF 12.2
Li Mou,Daguang Sun,Jiayuan Qu,Xiaoyin Tan,Suli Wang,Qiang Zeng,Changjiang Liu
Iodoacetic acid (IAA) is an emerging unregulated iodinated disinfection byproduct with high toxicity and widespread exposure. IAA has potential reproductive toxicity and could damage male reproduction. However, the underlying mechanisms and toxicological targets of IAA on male reproductive impairment are still unclear, and thus Sprague-Dawley rats and Leydig cells were used in this work to decode these pending concerns. Results showed that after IAA exposure, the histomorphology and ultrastructure of rat testes were abnormally changed, numbers of Leydig cells were reduced, the hypothalamic-pituitary-testis (HPT) axis was disordered, and testosterone biosynthesis was inhibited. Proteomics analyses displayed that oxidative stress, endoplasmic reticulum stress, and steroid hormone biosynthesis were involved in IAA-caused reproductive injury. Antioxidant enzymes were depleted, while levels of ROS, MDA, 8-OHdG, and γ-H2A.X were increased by IAA. IAA triggered oxidative stress and DNA damage, and then activated the GRP78/IRE1/XBP1s and cGAS/STING/NF-κB pathways in Leydig cells. The two signaling pathways constructed an interactive network by synergistically regulating the downstream transcription factor CHOP, which in turn directly bound to and negatively modulated steroidogenic StAR, finally refraining testosterone biosynthesis in Leydig cells. Collectively, IAA as a reproductive toxicant has anti-androgenic effects, and the GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP facilitates IAA-mediated testosterone decline.
研究领域:
生殖毒理学
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分子生物学
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内分泌学
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PubMed
高影响因子
Journal of Translational Medicine
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2024
·Vol. 22
·期 1
·1-16
·
IF 6.1
Xiong Yi,Chen Jiawen,Liang Wei,Li Kun,Huang Yingqi,Song Jingwen,Zhang Baoyu,Qiu Xiusheng,Qiu Dongbo,Zhang Qi,Qin Yunfei
Background Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated. Methods Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models. Results Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization. Conclusions The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.
研究领域:
免疫学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2025
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IF 9.6
Xiaoyu Pan,Yan Lin,Chunlin Lin,Songyi Liu,Penghang Lin,Xiang Lin,Ruofan He,ZiChen Ye,Jianxin Ye,Guangwei Zhu
The cGAS-STING signaling pathway is a pivotal immune response mechanism that bridges tumor and immune cell interactions. This study describes a multifunctional LPDAM nanoplatform integrating Lapachone, polydopamine (PDA), and Mn 2+ , which synergistically kills tumor cells and activates the cGAS-STING pathway, thereby inducing DC maturation and T cell activation to achieve potent antitumor immunity. In the tumor microenvironment, Lapachone generates H 2 O 2 via the NAD(P)H:quinone oxidoreductase 1 (NQO1 enzyme), while Mn 2+ catalyze H 2 O 2 conversion into •OH through chemodynamic effects (CDT). The photothermal effects (PTT) of PDA further amplify this cascade reaction, producing reactive oxygen species (ROS) that damage tumor mitochondria and release mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING pathway, while Mn 2+ enhances the sensitivity of cGAS to mtDNA, leading to robust antitumor immunity. Concurrently, photothermal-induced immunogenic cell death (ICD) promotes d endritic cells ( DCs) maturation, further strengthening immune responses. Moreover, Mn 2 ⁺ also serves as a contrast agent for T1-weighted magnetic resonance imaging (MRI), offering precise tumor visualization. This study demonstrates that the LPDAM nanoplatform facilitates Lapachone/CDT/PTT synergistic therapy under MRI guidance, showcasing its potential as an innovative strategy for combined immunotherapy in clinical oncology.
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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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2024
·
IF 2.7
Xiaodong Liu,Tianyi Jiang,Huiyun Jin,Chenxi Yan,Yuqi Tong,Jiaquan Ding,Yaqi Li,Lian Huang,Zhaohui Zhang
Beryllium sulfate (BeSO 4 ) can cause inflammation through the mechanism, which has not been elucidated. Mitochondrial DNA (mtDNA) is a key contributor of inflammation. With mitochondrial damage, released mtDNA can bind to specific receptors (e.g., cGAS) and then activate related pathway to promote inflammatory responses. To investigate the mechanism of mtDNA in BeSO 4 -induced inflammatory response in 16HBE cells, we established the BeSO 4 -induced 16HBE cell inflammation model and the ethidium bromide (EB)-induced ρ 0 16HBE cell model to detect the mtDNA content, oxidative stress-related markers, mitochondrial membrane potential, the expression of the cGAS-STING pathway, and inflammation-related factors. Our results showed that BeSO 4 caused oxidative stress, decline of mitochondrial membrane potential, and the release of mtDNA into the cytoplasm of 16HBE cells. In addition, BeSO 4 induced inflammation in 16HBE cells by activating the cGAS-STING pathway. Furthermore, mtDNA deletion inhibited the expression of cGAS-STING pathway, IL-10, TNF-α, and IFN-β. This study revealed a novel mechanism of BeSO 4 -induced inflammation in 16HBE cells, which contributes to the understanding of the molecular mechanism of beryllium and its compounds-induced toxicity.
研究领域:
毒理学
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细胞生物学
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免疫学
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PubMed
高影响因子
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