Cell Metabolism
·
2020
·
IF 21.567
Wanfeng Xu,Yuan Che,Quan Zhang,Hai Huang,Chujie Ding,Yun Wang,Guangji Wang,Lijuan Cao,Haiping Hao
Summary Caspase-4 is an intracellular sensor for cytosolic bacterial lipopolysaccharide (LPS) and underlies infection-elicited pyroptosis. It is unclear whether and how caspase-4 detects host-derived factors to trigger pyroptosis. Here we show that mitochondrial permeability transition (MPT) activates caspase-4 by promoting the assembly of a protein complex, which we term the Apaf-1 pyroptosome, for the execution of facilitated pyroptosis. MPT, when induced by bile acids, calcium overload, or an adenine nucleotide translocator 1 (ANT1) activator, triggers assembly of the pyroptosome comprised of Apaf-1 and caspase-4 with a stoichiometry ratio of 7:2. Unlike the direct cleavage of gasdermin D (GSDMD) by caspase-4 upon LPS ligation, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby GSDME to induce pyroptosis. Caspase-4-initiated and GSDME-executed pyroptosis underlies cholestatic liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed light on understanding how cells execute intrinsic pyroptosis under sterile conditions.
研究领域:
免疫学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2024
·Vol. 31
·期 13
·19396-19408
·
IF 0
Pan Enzhuang,Xin Yue,Li Xueqing,Ping Kaixin,Li Xing,Sun Ying,Xu Xuhui,Dong Jingquan
As a broad-spectrum and efficient triazole fungicide, difenoconazole is widely used, which not only pollutes the environment but also exerts toxic effects on non-target organisms. The spleen plays an important role in immune protection as an important secondary lymphoid organ in carp. In this study, we assessed the protective impact of silybin as a dietary additive on spleen tissues of carp during exposure to difenoconazole. Sixty carp were separated into four groups for this investigation including control group, difenoconazole group, silybin group, and silybin and difenoconazole group. By hematoxylin-eosin staining, dihydroethidium staining, immunohistochemical staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, quantitative real-time PCR assay, Western blot analysis, biochemical assays, and immune function indicator assays, we found that silybin could prevent difenoconazole-induced spleen tissue damage, oxidative stress, and immune dysfunction, and inhibited apoptosis of carp spleen tissue cells by suppressing the formation of p53-driven caspase-9-apoptotic protease activating factor-1-cytochrome C complex. The results suggested that silybin as a dietary additive could improve spleen tissue damage and immune dysfunction induced by difenoconazole in aquaculture carp.
研究领域:
环境毒理学
·
免疫学
·
水产养殖学
✓ 已验证
DOI
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Liang Hang-fei,Yang Xiao,Li Hui-lin,Li Xuan,Tian Jia-ning,Su Hai-guo,Huang Min,Fang Jian-hong,Bi Hui-chang
Our previous study shows that activation of pregnane X receptor (PXR) exerts hepatoprotection against lithocholic acid (LCA)-induced cholestatic liver injury. In this study we investigated whether PXR activation could inhibit hepatocyte pyroptosis, as well as the underlying mechanisms. Male mice were treated with mouse PXR agonist pregnenolone 16α-carbonitrile (PCN, 50 mg·kg −1 ·d −1 , i.p.) for 7 days, and received LCA (125 mg/kg, i.p., bid) from D4, then sacrificed 12 h after the last LCA injection. We showed that LCA injection resulted in severe cholestatic liver injury characterized by significant increases in gallbladder size, hepatocellular necrosis, and neutrophil infiltration with a mortality rate of 68%; PCN treatment significantly inhibited hepatocyte pyroptosis during LCA-induced cholestatic liver injury, as evidenced by reduced serum lactic dehydrogenase (LDH) levels, TUNEL-positive cells and hepatocyte membrane damage. Furthermore, PXR activation suppressed both the NOD-like receptor protein 3 (NLRP3) inflammasome-induced canonical pyroptosis and the apoptosis protease activating factor-1 (APAF-1) pyroptosome-induced non-canonical pyroptosis. Inhibition of the nuclear factor kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways was also observed following PXR activation. Notably, dual luciferase reporter assay showed that PXR activation inhibited the transcriptional effects of NF-κB on NLRP3, as well as FOXO1 on APAF-1. Our results demonstrate that PXR activation protects against cholestatic liver injury by inhibiting the canonical pyroptosis through the NF-κB-NLRP3 axis and the non-canonical pyroptosis through the FOXO1-APAF-1 axis, providing new evidence for PXR as a prospective anti-cholestatic target.
研究领域:
肝病学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AQUACULTURE
·
2022
·
IF 5.135
Min Li,Xueqin Wu,Jixing Zou,Yingqian Lai,Jiawen Zhang,Xiumei Chen,Xiaotian Niu,Yidi Kong,Guiqin Wang
This study was aimed to evaluate the ameliorative effects of thymol-supplemented diets on the toxicity damage of Channa argus induced by deltamethrin (DEL). After 28 d, the results are as follows: thymol can attenuate DEL-induced oxidative stress by reversing the decrease of the activities of antioxidant enzyme (SOD, CAT , GSH , GST and GSH-Px) and the increase of the MDA content in the tissues (liver and spleen), and also by reversing the decrease of the mRNA expression levels of Nrf2, Cu/Zn SOD and HO-1, and the increase of the Keap1 mRNA expression level in the tissues (liver and spleen). Thymol can attenuate DEL-induced immunotoxicity of fish by reverse the decrease of the levels of humoral immune parameters (C4, C3, IgM and LYS) in the serum, and by reversing the increase of the expression levels of NF-κB p65, TNF-α, IL-1β, IL-8 and IL-6, and the decrease of the IL-10 expression level in the tissues (liver and spleen). Thymol can attenuate DEL-caused apoptosis reversing the increase of the expression levels of pro-apoptosis (p53, Bax and Apaf-1) and the decrease of the expression level of anti-apoptosis Bcl-2 in the tissues (liver and spleen). Therefore, this study reveals that dietary supplementation of thymol alleviates DEL-caused immunotoxicity, oxidative stress, and apoptosis of C. argus in association with the NF-κB/Nrf2/p53 pathway.
研究领域:
水产养殖
·
毒理学
·
免疫学
·
分子生物学
✓ 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）