BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Yuge Long,Xiaoyuan Jia,Liang Chu
Gasdermin E ( GSDME ), which is also known as DFNA5 , was first identified as a deafness-related gene that is expressed in cochlear hair cells, and mutation of this gene causes autosomal dominant neurogenic hearing loss. Later studies revealed that GSDME is mostly expressed in the kidney, placenta, muscle and brain cells, but it is expressed at low levels in tumor cells. The GSDME gene encodes the GSDME protein, which is a member of the gasdermin (GSDM) family and has been shown to participate in the induction of apoptosis and pyroptosis. The current literature suggests that Caspase-3 and Granzyme B (Gzm B) can cleave GSDME to generate the active N-terminal fragment (GSDME-NT), which integrates with the cell membrane and forms pores in this membrane to induce pyroptosis. Furthermore, GSDME also forms pores in mitochondrial membranes to release apoptosis factors, such as cytochrome c (Cyt c ) and high-temperature requirement protein A2 (HtrA2/Omi), and subsequently activates the intrinsic apoptosis pathway. In recent years, GSDME has been shown to exert tumor-suppressive effects, suggesting that it has potential therapeutic effects on tumors. In this review, we introduce the structure and function of GSDME and the mechanism by which it induces cell death, and we discuss its tumor suppressive effect.
研究领域:
分子生物学
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细胞生物学
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肿瘤学
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遗传学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2026
·
IF 3.6
Shangxiang Feng,Kun Song,Hao Zhang,Zhuoqun Wang,Yuchi Zhao,Zhongyuan Zhao,Chao Wan
This study investigated the effects of Aureusidin on extracellular matrix (ECM) degradation and pyroptosis of chondrocytes in osteoarthritis. Network pharmacology, molecular docking, and pull-down assays were initially conducted to explore the target of Aureusidin. Subsequently, Sprague-Dawley rats underwent anterior cruciate ligament transection (ACLT) received oral administration of Aureusidin. Cartilage damage was evaluated histopathologically by H&E and Safranin O-fast green staining. Primary rat chondrocytes were treated with Aureusidin under IL-1β stimulation. Pyroptotic morphology was observed under light microscopy. Propidium iodide staining and flow cytometry were conducted to evaluate membrane rupture. The expression of markers associated with ECM degradation and pyroptosis was analyzed by qRT-PCR, Western blot, immunohistochemistry, and ELISA. Caspase-3 was identified as a target for Aureusidin. Aureusidin (5, 10, 20 mg/kg) alleviated ACLT-induced cartilage damage and ECM degradation. It reduced the OARSI score and serum levels of CTX-II and COMP, while upregulating the expression of Col2a1 and Acan , and downregulating Adamts5 , Mmp13 , and Mmp3 . Aureusidin also mitigated atypical pyroptosis, evidenced by inhibited expression of GSDME-N, Caspase-3, and Cleaved-Caspase-3, and decreased levels of IL-1β and IL-18. In IL-1β-stimulated primary chondrocytes, Aureusidin (5, 10, 20 μM) attenuated ECM degradation and Caspase-3/GSDME-mediated pyroptosis. Treating chondrocytes with the Caspase-3 inhibitor Z -DEVD-FMK under IL-1β-stimulated conditions alleviated ECM degradation and pyroptosis, but the additional application of Aureusidin did not provide further inhibition. Aureusidin has the potential to inhibit ECM degradation and Caspase-3/GSDME-mediated chondrocyte pyroptosis during osteoarthritis progression. Its therapeutic effects are dependent on binding to and modulating the Caspase-3.
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DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2021
·Vol. 298
·期 2
·
IF 5.157
Binxiang Cai,Chunyan Liao,Danxue He,Jingmeng Chen,Jiahuai Han,Jiaying Lu,Kaiqi Qin,Wenxu Liang,Xiaoling Wu,Zuguo Liu,Yalin Wu
The breakdown of all-trans-retinal (atRAL) clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its mechanisms remain elusive. Here, we demonstrate that activation of gasdermin E (GSDME) but not gasdermin D promotes atRAL-induced photoreceptor damage by activating pyroptosis and aggravating apoptosis through a mitochondria-mediated caspase-3-dependent signaling pathway. Activation of c-Jun N-terminal kinase was identified as one of the major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells, resulting in the release of cytochrome c from mitochondria to the cytosol, where it stimulated caspase-3 activation required for cleavage of GSDME. Aggregation of the N-terminal fragment of GSDME in the mitochondria revealed that GSDME was likely to penetrate mitochondrial membranes in photoreceptor cells after atRAL exposure. ABC (subfamily A, member 4) and all-trans-retinol dehydrogenase 8 are two key proteins responsible for clearing atRAL in the retina. Abca4−/−Rdh8−/− mice exhibit serious defects in atRAL clearance upon light exposure and serve as an acute model for dry AMD and STGD1. We found that N-terminal fragment of GSDME was distinctly localized in the photoreceptor outer nuclear layer of light-exposed Abca4−/−Rdh8−/− mice. Of note, degeneration and caspase-3 activation in photoreceptors were significantly alleviated in Abca4−/−Rdh8−/−Gsdme−/− mice after exposure to light. The results of this study indicate that GSDME is a common causative factor of photoreceptor pyroptosis and apoptosis arising from atRAL overload, suggesting that repressing GSDME may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.
研究领域:
眼科学
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分子生物学
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细胞生物学
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Kaiyuan Chen,Yahui Tang,Linhua Lan,Mengxuan Li,Zhongqiu Lu
Acute kidney injury (AKI) induced by diquat (DQ) progresses rapidly, leading to high mortality, and there is no specific antidote for this chemical. Our limited knowledge of the pathogenic toxicological mechanisms of DQ has hindered the development of treatments against DQ poisoning. Pyroptosis is a form of programmed cell death and was recently identified as a novel molecular mechanism of drug-induced AKI. To explore the role of pyroptosis in HK-2 cells exposed to DQ, the plasma membrane damage of the cells was detected by LDH release assay. Western blot was performed to detect the cleavage of GSDME. Proteomics analysis was performed to explore the mechanism of DQ induced nephrotoxicity . FerroOrange probe was used to measure the intracellular Fe 2+ levels. Herein, we show that DQ induces pyroptosis in HK-2 cells. Mechanistically, DQ induces the accumulation of mitochondrial ROS and initiates the cleavage of gasdermin E (GSDME) in an intrinsic mitochondrial pathway. Knockout of GSDME attenuated DQ-induced cell death. Further analysis revealed that loss of FTH1 induces Fe 2+ accumulation, contributing to DQ-induced pyroptosis. Knockdown LC3B could help restore the expression of FTH1 and improve cell viability . Moreover, we found DFO , an iron chelator , could reduce cellular Fe 2+ levels and inhibit pyroptosis. Collectively, these findings suggest an unrecognized mechanism for GSDME-dependent pyroptosis in DQ-induced AKI.
研究领域:
毒理学
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细胞生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Wenying Li,Dong Chen,Yanmei Zhu,Qiange Ye,Yang Hua,Ping Jiang,Ying Xiang,Yuejie Xu,Yinya Pan,Hua Yang,Yichun Ma,Hang Xu,Cheng Zhao,Chang Zheng,Changrong Chen,Yun Zhu,Guifang Xu
Current therapies primarily targeting inflammation often fail to address the root relationship between intestinal mucosal integrity and the resulting dysregulated cell death and ensuing inflammation in ulcerative colitis (UC). First, UC tissues from human and mice models in this article both emphasize the crucial role of Gasdermin E (GSDME)-mediated pyroptosis in intestinal epithelial cells (IECs) as it contributes to colitis by releasing proinflammatory cytokines, thereby compromising the intestinal barrier. Then, 4-octyl-itaconate (4-OI), exhibiting potential for anti-inflammatory activity in inhibiting pyroptosis, was encapsulated by butyrate-modified liposome (4-OI/BLipo) to target delivery for IECs. In brief, 4-OI/BLipo exhibited preferential accumulation in inflamed colonic epithelium, attributed to over 95% of butyrate being produced and absorbed in the colon. As expected, epithelium barriers were restored significantly by alleviating GSDME-mediated pyroptosis in colitis. Accordingly, the permeability of IECs was restored, and the resulting inflammation, mucosal epithelium, and balance of gut flora were reprogrammed, which offers a hopeful approach to the effective management of UC.
研究领域:
药理学
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免疫学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Shiquan Sun,Yong He,Jiaqi Xu,Shaolong Leng,Yu Liu,Huanhuan Wan,Leping Yan,Yunsheng Xu
Despite the fact that immunotherapy has significantly improved the prognosis of melanoma patients, the non-response rate of monoimmunotherapy is considerably high due to insufficient tumor immunogenicity . Therefore, it is necessary to develop alternative methods of combination therapy with enhanced antitumor efficiency and less systemic toxicity. In this study, we reported a cancer cell membrane-coated zeolitic imidazole framework-8 (ZIF-8) encapsulating pyroptosis-inducer oxaliplatin (OXA) and immunomodulator imiquimod (R837) for chemoimmunotherapy. With the assistance of DNA methyltransferase inhibitor decitabine (DCT), upregulated Gasdermin E (GSDME) was cleaved by OXA-activated caspase-3, further inducing tumor cell pyroptosis , then localized antitumor immunity was enhanced by immune adjuvant R837, followed by triggering systemic antitumor immune responses. These results provided a proof-of-concept for the use of cell membrane-coated biomimetic nanoparticles as a promising drug carrier of combination therapy and a potential insight for pyroptosis-based melanoma chemo-immunotherapy.
研究领域:
肿瘤学
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免疫疗法
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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