BIOLOGICAL TRACE ELEMENT RESEARCH
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2025
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IF 3.6
Xu Hao,Yang Jingyi,Ye Ruiqi,Cao Mixia,Li Shenghe,Liu Chang,Li Lei
Acute cadmium (Cd) exposure induces hepatic toxicity in murine models, where oxidative stress and subsequent inflammatory responses are recognized as principal contributors to hepatocyte damage. The NLRP3 inflammasome, a pivotal member of the NOD-like receptor family, mediates pyroptotic cell death in diverse hepatic inflammatory pathologies. While murine liver exhibits heightened susceptibility to heavy metal toxicity, the mechanistic basis of Cd-induced hepatocyte injury remains incompletely characterized. This study aims to clarify the cytotoxic effects of Cd on murine hepatocyte line BNL CL.2 and systematically dissect the underlying molecular mechanisms. Via molecular and cellular assays, we evaluated mitochondrial function, reactive oxygen species (ROS) levels, NLRP3 inflammasome activation, and pyroptotic features in BNL CL.2 cells post Cd exposure; intervened with ROS scavengers N-acetylcysteine (NAC) and Mito-TEMPO, and detected transcriptional activity of the antioxidant regulator Nrf2. Experimental data demonstrate that Cd exposure triggers mitochondrial dysfunction coupled with excessive ROS production, concomitant NLRP3 inflammasome activation, and characteristic plasma membrane rupture confirming pyroptosis. Notably, NAC and Mito-TEMPO effectively attenuate these pathological responses, establishing ROS as critical regulators of Cd-induced NLRP3 inflammasome activation; mechanistically, Cd suppresses Nrf2 transcriptional activity and downstream antioxidant gene expression, thereby disrupting redox homeostasis. These findings collectively delineate a pathogenic cascade where Cd impairs mitochondrial integrity and disrupts Nrf2-dependent antioxidant defenses, synergistically driving ROS-mediated NLRP3 inflammasome activation and subsequent hepatocyte pyroptosis. This mechanism provides novel insights into heavy metal hepatotoxicity and identifies potential targets for treating Cd-induced liver injury.
研究领域:
毒理学
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分子生物学
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肝病学
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氧化应激
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炎症与免疫
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Yishi Lu,Ziyue Zu,Nan Zhong,Yang Li,Xuan Sha,Shangyu Lu,Jie Zhang,Hanyao Sun,Xi Luo,Ziqing Xu,Feiyun Wu,Yuxia Tang,Shouju Wang
Autophagy blockade has emerged as a promising strategy to enhance the antitumor efficacy of pancreatic ductal adenocarcinoma (PDAC). However, autophagy inhibition in PDAC may induce compensatory macropinocytosis to maintain cellular homeostasis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, lysosomal-activated nanoreactors loaded with the NRF2 inhibitor ML385 (CPZI-Ms) are developed to spatiotemporally block autophagy and inhibit macropinocytosis. The nanoreactors, which preferentially accumulate in lysosomes, undergo degradation in the acidic lysosomal environment, triggering a Fenton-like reaction between the released Cu 2 ⁺ ions and H₂O₂ to generate hydroxyl radicals. This results in lysosomal membrane permeabilization, which further leads to not only lysosomal autophagy blockade, but also the leakage of Cu 2 ⁺ and ML385 into the cytoplasm. Cu 2 ⁺ induces extensive oxidative stress throughout the whole cell, while ML385 suppresses compensatory macropinocytosis response activated by autophagy blocking. As a result, the Panc02 cells become a “besieged fortress”, with impaired autophagic clearance and restricted nutrient uptake. In vivo, CPZI-Ms effectively suppress tumor growth in Panc02-bearing mice, offering a promising nanoplatform for enhancing cancer cell killing. Taken together, the present work provides an innovative anti-tumor insight by spatiotemporally blocking autophagic flux and inhibiting compensatory macropinocytosis.
研究领域:
肿瘤学
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药理学
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纳米医学
✓ 已验证
产品关联
DOI
高影响因子
ACS Omega
·
2024
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IF 3.7
Chenxin Xu,Yinghua Chen,Zhuoen Zhou,Ying Yan,Wenying Fu,Peng Zou,Daoyong Ni
Lung cancer is one of the leading causes of death. Celastrol is a natural product that has shown anticancer activity but has not yet been applied in clinical settings due to its narrow therapeutic window. In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol. At the same time, celastrol upregulated the expression of cytoprotective transcription factor Nrf2 and its downstream proteins, which are effective in preventing the oxidative damage caused by ROS accumulation. Notably, we found that the overexpression of Nrf2 enhances the tolerance of lung cancer cells to celastrol and that lung cancer cells H460 with a Keap1 mutation are insensitive to celastrol. This indicates that the increase in Nrf2 contributes to the survival of lung cancer cells. Thus, we brought in an Nrf2 inhibitor ML385 to suppress the activation of Nrf2. We found that when ML385 and celastrol were added together the survival rates of lung cancer cells decreased more and the detected ROS level became much higher compared to treatment with celastrol alone. We also discovered that ML385 suppressed the expression of HO-1 and GCLC, which amplified celastrol-induced ATF4/CHOP-dependent endoplasmic reticulum stress (ER stress). Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF SURGICAL RESEARCH
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2022
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IF 2.417
Ming Deng,Ping Xie,Junqi Liu,Yan Zhou,Zhonghui Chen,Yonggang Ma,Jianwei Yang
Introduction α-Cyperone has anti-inflammatory activities, but its effects on spinal cord injury (SCI) remain obscure. Thus, this study attempts to investigate the effects and modulatory mechanisms of α-Cyperone on SCI. Materials and methods An SCI model was established in rats which were further treated with α-Cyperone. Basso-Beattie-Bresnahan (BBB) scoring was used to assess motor rehabilitation of rats modeled with SCI. The spinal cord tissues were collected, and the effect of α-Cyperone on the histopathology of rats modeled with SCI was detected by hematoxylin-eosin staining. Rat primary cortical neuron was stimulated with H 2 O 2 and further treated with α-Cyperone and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. The levels of Nrf2, interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), Akt, toll-like receptor 4 (TLR4), and tumor necrosis factor-alpha (TNF-α) were detected by immunofluorescence staining and western blotting . Results α-Cyperone elevated the BBB score and ameliorated the damage of spinal cord tissue in rats modeled with SCI. The levels of IL-6, Nrf2, NF-κB, TLR4, and TNF-α were upregulated, whereas that of Akt was downregulated in rats and cells modeled with SCI. Furthermore, α-Cyperone diminished the levels of IL-6, NF-κB, TLR4, and TNF-α, while augmenting those of Nrf2 and Akt in rats and cells modeled with SCI. ML385 inhibited the Nrf2 level that had been promoted by α-Cyperone in the nucleus and elevated the Nrf2 level that had been suppressed by α-Cyperone in the cytosol of cells modeled with SCI. ML385 increased the levels of IL-6, NF-κB, TLR4, and TNF-α that had been inhibited by α-Cyperone and decreased the Akt level that had been enhanced by α-Cyperone in cells modeled with SCI. Conclusions α-Cyperone suppressed SCI-induced inflammation and spinal cord tissue damage via activating Akt/Nrf2 and suppressing NF-κB pathways.
研究领域:
神经科学
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药理学
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分子生物学
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病理学
✓ 已验证
DOI
PubMed
高影响因子
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