DNA AND CELL BIOLOGY
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2022
·Vol. 41
·期 12
·1038-1052
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IF 3.55
Qianyu Tang,Wenhui Liu,Xuefeng Yang,Yaying Tian,Jiacheng Chen,Yang Hu,Nian Fu
Despite activated autophagy ameliorating hepatocyte steatosis and metabolic associated fatty liver disease (MAFLD), mechanisms underlying the beneficial roles of autophagy in hepatic deregulation of lipid metabolism remain undefined. We explored whether autophagy can ameliorate oleic acid (OA)-induced hepatic steatosis by suppressing pyroptosis. Pyroptosis is involved in hepatocyte steatosis induced by OA. In addition, autophagy flux was blocked in OA-treated hepatocytes. Treatment with OA induced lipid accumulation in liver cell line L-02, which was attenuated by rapamycin (Rap), an autophagy agonist, while aggravated by autophagy inhibitor bafilomycin A1 (Baf A1). Inversely, treatment with pyroptotic agonist Nigericin aggravated OA-induced hepatic steatosis, while pyroptosis antagonist disulfiram ameliorated this effect. Mechanistically, treatment with Rap downregulated the expression of pyroptosis-related proteins, including NLRP3, Caspase-1, IL-18, GSDMD expression evoked by OA, thus improving pyroptosis in hepatic steatosis. Significantly, overexpression of ATG5 obviously downregulated cleaved caspase-1 expressions without altering the total caspase1 expressions in hepatic cell steatosis. Taken together, our studies strongly demonstrated that the activation of ATG5 inhibits pyroptosis to improve hepatic steatosis and suggest autophagy activation as a potential therapeutic strategy for pyroptosis-mediated MAFLD.
研究领域:
肝脏病学
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细胞生物学
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分子生物学
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药理学
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高影响因子
MOLECULAR NEUROBIOLOGY
·
2020
·Vol. 57
·期 12
·5324-5335
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IF 4.5
Chen Guang,Gao Cheng,Yan Ya’nan,Wang Tao,Luo Chengliang,Zhang Mingyang,Chen Xiping,Tao Luyang
Intracerebral hemorrhage (ICH) is a form of stroke, characterized by high morbidity and mortality and currently lacks specific therapy. ICH leads to endoplasmic reticulum (ER) stress, which can induce neurological impairment through crosstalk with programmed cell death (PCD). Pyroptosis, a newly discovered form of PCD, has received attention because of its close relationship with some certain diseases, such as traumatic brain injury and ischemic and hemorrhagic stroke. However, the relationship between ER stress and pyroptosis in ICH remains unclear. In this study, we investigated the role of ER stress in evoking neuronal pyroptosis and related mechanisms in a mouse ICH model. We used tauroursodeoxycholic acid (TUDCA) to inhibit ER stress and observed that TUDCA reduces neuronal pyroptosis and has a neuroprotective role. We explored the potential mechanisms underlying the regulation of neuronal pyroptosis by ER stress through testing the expression of interleukin-13 (IL-13). We found that ER stress inhibition alleviates neuronal pyroptosis through decreasing the expression of IL-13 after ICH. In summary, this study revealed that IL-13 is involved in ER stress–induced neuronal pyroptosis after ICH, pointing to IL-13 as a novel therapeutic target for ICH treatment.
研究领域:
神经科学
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分子生物学
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中风研究
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Cell Death & Disease
·
2024
·Vol. 15
·期 10
·1-10
·
IF 8.1
Li Ming-Qiao,He Yu-Qi,Zhang Meng-Ni,Tang Wan,Tan Ya,Cheng Yue,Yang Mei,Zhao Nan,Li Ling,Yu Si-Rui,Li Ruo-Lan,Pan Qiong,Wu Ming-Yue,Chai Jin
Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.
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
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IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2022
·
IF 3.712
Hairui Zhou,Jingru Wu,Yu Gong,Zilong Zhou,Jingtao Wang
Purpose: Sleep deprivation (SD) leads to memory and cognitive impairment due to damage to the hippocampus. Isoquercetin possesses neuron-protective properties. Our study aimed to investigate the effects of isoquercetin on SD-induced hippocampal neurons damage and the underlying mechanism.Materials and methods: Herein, the cognitive competence was evaluated by Morris water maze test after SD. The morphology of the hippocampus was observed after Nissl staining. Moreover, the level of NLRP3 was detected by Immunofluorescent staining and western blot. In vitro study, pyroptosis was tested by TUNEL assay and flow cytometry. The levels of pyroptosis-related factors were measured by western blot.Results: The results indicated that isoquercetin improved spatial memory and prevented change of hippocampal neurons of SD mice. Moreover, SD upregulated NLRP3 level, which was downregulated by isoquercetin. Additionally, isoquercetin rescued the increase of pyroptosis and the upregulation of NLRP3, caspase-1, ASC, IL-1β, IL-18, and GSDMD levels induced by LPS.Conclusions: In conclusion, isoquercetin improved learning and cognitive capability of SD mice via suppressing NLRP3-induced pyroptosis of hippocampal neurons cells, suggesting that isoquercetin might be an efficacious drug for memory disorders caused by SD.
研究领域:
神经科学
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药理学
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细胞生物学
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JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-17
·
IF 10.2
Liu Kaiyuan,Zhang Li,Lu Hengli,Wen Yingfei,Bi Bo,Wang Guocheng,Jiang Yingying,Zeng Leli,Zhao Jing
Background Mild-temperature photothermal therapy (mild PTT) is a safe and promising tumor therapeutic modality by alleviating the damage of healthy tissues around the tumor due to high temperature. However, its therapeutic efficiency is easily restricted by heat shock proteins (HSPs). Thus, exploitation of innovative approaches of inhibiting HSPs to enhance mild PTT efficiency is crucial for the clinical application of PTT.Results Herein, an innovative strategy is reported: pyroptosis-boosted mild PTT based on a Mn-gallate nanoformulation. The nanoformulation was constructed via the coordination of gallic acid (GA) and Mn2+. It shows an acid-activated degradation and releases the Mn2+ and GA for up-regulation of reactive oxygen species (ROS), mitochondrial dysfunction and pyroptosis, which can result in cellular ATP deprivation via both the inhibiton of ATP generation and incresed ATP efflux. The reduction of ATP and accumulation of ROS provide a powerful approach for inhibiting the expression of HSPs, which enables the nanoformulation-mediated mild PTT.Conclusion sOur in-vitro and in-vivo results demonstrate that this strategy of pyroptosis-assited PTT can achieve efficient mild PTT efficiency for osteosarcoma therapy.Graphical Abstract
研究领域:
癌症治疗
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纳米技术
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生物医学工程
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IMMUNITY
·
2023
·
IF 32.4
Rui Miao,Cong Jiang,Winston Y. Chang,Haiwei Zhang,Jinsu An,Felicia Ho,Pengcheng Chen,Han Zhang,Caroline Junqueira,Dulguun Amgalan,Felix G. Liang,Junbing Zhang,Charles L. Evavold,Iva Hafner-Bratkovič,Zhibin Zhang,Pietro Fontana,Shiyu Xia,Markus Waldeck-Weiermair,Youdong Pan,Thomas Michel,Liron Bar-Peled,Hao Wu,Jonathan C. Kagan,Richard N. Kitsis,Peng Zhang,Xing Liu,Judy Lieberman
Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.
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JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-15
·
IF 10.2
Jin Nianqiang,Wang Binhang,Liu Xinyao,Yin Chengcheng,Li Xing,Wang Zilin,Chen Xi,Liu Yunling,Bu Wenhuan,Sun Hongchen
Background The implementation of pyroptosis exhibits significant potential as a tactic to enhance tumor immune microenvironments. Previous applications of pyroptosis inducers have encountered various limitations, such as the development of drug resistance, manifestation of toxic side effects, and a deficiency in targeting capabilities. As a result, there is a growing demand for tumor therapeutic molecules that can overcome these obstacles. Therefore, the objective of this study is to develop a multifunctional nanospheres that addresses these challenges by enabling high-precision targeting of tumor cells and inducing effective pyroptosis. Results We prepared a mannose-modified MOF called mannose-doped Fe 3 O 4 @NH 2 -MIL-100 (M-FNM). M-FNM could enter CAL27 cells through MR-mediated endocytosis, which caused in a significant increase in the level of intracellular ROS. This increase subsequently triggered ER stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway. CHOP then mediated the downstream cascade of Caspase-1, inducing pyroptosis. In in vivo experiments, M-FNM demonstrated excellent targeting ability and exhibited anti-tumor effects. Additionally, M-FNM reshaped the immune microenvironment by promoting the infiltration of anti-tumor immune cells, primarily T lymphocytes. Conclusions M-FNM significantly decreased tumor growth. This novel approach to induce pyroptosis in tumor cells using M-FNM may offer new avenues for the development of effective immunotherapies against cancer.
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PHYTOMEDICINE
·
2023
·
IF 7.9
Shanshan Dai,Yunxuan Chen,Xiaoxi Fan,Jibo Han,Lingfeng Zhong,Yucong Zhang,Qingran Liu,Jiahui Lin,Weijian Huang,Lan Su,Zhouqing Huang,Bozhi Ye
Background Doxorubicin (Dox), which is an anticancer drug, has significant cardiac toxicity and side effects. Pyroptosis occurs during Dox-induced cardiotoxicity (DIC), and drug inhibition of this process is one therapeutic approach for treating DIC. Previous studies have indicated that emodin can reduce pyroptosis. However, the role of emodin in DIC and its molecular targets remain unknown. Hypothesis/Purpose We aimed to clarify the protective role of emodin in mitigating DIC, as well as the mechanisms underlying this effect. Methods The model of DIC was established via the intraperitoneal administration of Dox at a dosage of 5 mg/kg per week for a span of 4 weeks. Emodin at two different doses (10 and 20 mg/kg) or a vehicle was intragastrically administered to the mice once per day throughout the Dox treatment period. Cardiac function, myocardial injury markers, pathological morphology of the heart, level of pyroptosis and mitochondrial function were assessed. Protein microarray, biolayer interferometry and pull-down assays were used to confirm the target of emodin. Moreover, GSDMD-overexpressing plasmids were transfected into GSDMD −/− mice and HL-1 cells to further verify whether emodin suppressed GSDMD activation. Results Emodin therapy markedly enhanced cardiac function and reduced cardiomyocyte pyroptosis in mice induced by Dox. Mechanistically, emodin binds to GSDMD and inhibits the activation of GSDMD by targeting the Trp415 and Leu290 residues. Moreover, emodin was able to mitigate Dox-induced cardiac dysfunction and myocardial injury in GSDMD −/− mice overexpressing GSDMD, as shown by increased EF and FS, decreased serum levels of CK-MB, LDH and IL-1β and mitigated cell death and cell morphological disorder. Additionally, emodin treatment significantly reduced GSDMD-N expression and plasma membrane disruption in HL-1 cells overexpressing GSDMD induced by Dox. In addition, emodin reduced mitochondrial damage by alleviating Dox-induced GSDMD perforation in the mitochondrial membrane. Conclusion Emodin has the potential to attenuate DIC by directly binding to GSDMD to inhibit pyroptosis. Emodin may become a promising drug for prevention and treatment of DIC.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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Biomaterials Science
·
2023
·
IF 6.6
Weichu Zhu,Jian Xu,Xianxian Yao,Shuting Mai,Dan Shu,Wuli Yang
Pyroptosis is a proinflammatory form of cell death mediated by members of the gasdermin family, and is a powerful tool against cancer. Herein, a pH-responsive doxorubicin (DOX)-encapsulating zeolitic imidazolate framework-8 (ZIF-8) nanoparticle coated with a carboxybetaine-based zwitterionic polymer (DOX@ZIF-8@PCBMA) was prepared. Furthermore, decitabine (DAC) was loaded to obtain a pyroptosis nanotuner (DOX@ZIF-8@PCBMA-DAC). This nanotuner displayed extended blood circulation and enhanced tumor accumulation. In addition, the ZIF-8 structure and disulfide-crosslinked PCBMA coating endowed DOX@ZIF-8@PCBMA-DAC with acidic-pH- and glutathione-responsive degradation. The nanotuner could robustly activate caspase-3 to induce gasdermin E (GSDME)-dependent pyroptosis via the sustained release of DAC and DOX, contributing to excellent tumor suppression with negligible side effects, which may provide novel insights into traditional chemotherapy.
研究领域:
纳米技术
·
药学
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癌症治疗
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生物医学工程
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CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
E Zhang,Chuangeng Shang,Mingtao Ma,Xuanfeng Zhang,Yu Liu,Shuliang Song,Xia Li
Polyguluronic acid (PG), a polysaccharide from alginate , possesses excellent bioactivities. We prepared high-purity PG with 10.41 kDa molecular weight (Mw) and a 59 average degree of polymerization (DP) by acid hydrolysis , three pH grades, Q-Sepharose column elution, and Sephadex G-25 column desalination . Then, we evaluated the PG protective effects on doxorubicin-induced cardiotoxicity (DIC) in vitro and in vivo. The nontoxic PG enhanced cellular viability , reduced cell pyroptosis morphology, diminished the LDH and IL-1β release, and downregulated expressions of ASC oligomerization , NLRP3 , cl-CASP1, and GSDMD, by which PG protected the cardiomyocytes from NLRP3 inflammasome-mediated pyroptosis in doxorubicin-stimulated HL-1 cells and C57BL/6J mice. The probable underlying mechanism may be that PG downregulated doxorubicin -induced Peli1, the deficiency of which could inhibit doxorubicin-induced NLRP3 inflammasome-mediated pyroptosis. These results suggested that polysaccharide PG from alginate could prevent DIC and may be a potential therapeutic agent or bioactive material for preventing DIC.
研究领域:
药理学
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心脏病学
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免疫学
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生物化学
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分子生物学
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ACTA PHARMACOLOGICA SINICA
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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
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药理学
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分子生物学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Jinzhao Zhou,Yanwei Zhang,Ling Zeng,Xiaofei Wang,Wenpei Xiang,Ping Su
Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11–7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.
研究领域:
毒理学
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细胞生物学
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生殖健康
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