Browsing by Subject "Pyroptosis"

Now showing 1 - 11 of 11
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    Cardioprotective mechanisms of Jiangfu Decoction against myocardial ischemia may involve regulation of the AMPK/PINK1/ Parkin mitochondrial autophagy pathway
    (2026) Yiwei Hao; Chen Li; Haoying Li; Xue Han; Hefei Wang; Xi Chu; Zhiwei Su; Shijiang Sun; Yawei Zhao; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologia
    Background. Jiangfu Decoction (JFD) is a classical traditional herbal medicine used to clinically treat ischemic heart disease (IHD). Nonetheless, the influence of JFD on myocardial ischemia (MI), along with its precise underlying mechanism, is still unclear. The objective of this research was to investigate the potential mechanisms by which JFD exerts cardio protective effects on MI induced by isoproterenol (ISO). Methods. An acute MI model was established by subcutaneous injection of ISO (85 mg/kg/d). To evaluate alterations in myocardial structure, electrocardiogram recordings and heart histology examinations were employed. The myocardial ultrastructure was observed by transmission electron microscopy (TEM). Using specific kits, the levels and activities of oxidative stress markers as well as inflammatory cytokines were separately assessed. Western blotting was employed to assess the expression levels of proteins related to adenosine monophosphate activated protein kinase (AMPK), PTEN-induced putative kinase 1 (PINK1), Parkin, Nod-like receptor protein 3 (NLRP3), and Caspase-1. Results. The findings show that JFD treatments markedly diminished heart rate, pathological alterations in cardiac tissue, chondriosome injury, and serum concentrations of creatine kinase, creatine kinasemyocardial band, lactate dehydrogenase, malon dialdehyde, interleukin-1β, and interleukin-18. Concurrently, these treatments augmented the activation of superoxide dismutase, catalase, and glutathione peroxidase in the serum of animals subjected to ISO treatment. Additionally, JFD also reversed the ISO induced changes in the levels of AMPK, PINK1, Parkin, NLRP3, and Caspase-1. Conclusion. JFD exhibits a notable safeguarding influence on MI via a mechanism that involves regulation of the AMPK/PINK1/Parkin mitochondrial autophagy pathway, inhibition of pyroptosis, and reduction of oxidative stress and inflammation.
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    Electroacupuncture ameliorates learning and memory impairment by inhibiting inflammation and promoting synaptic plasticity via inhibition of the NF-KB/NLRP3 signaling pathway in cerebral ischemic rats
    (2026) Guoyuan Pan; Dan Lu1; Mingjin Zhu; Guifen Yang; Chenyi Huang; Yisu Shou; Xiong Jiangnan; Fang Luo; Sun Di; Chuchu Huang; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologia
    Objective. Electroacupuncture (EA) has a protective effect on cerebral ischemic injury. However, the specific mechanism of action of EA has not been studied. In this study, we investigated whether EA was involved in the treatment of learning and memory impairment in rats with cerebral ischemia‒reperfusion injury (CIRI) through the NF-KB/NLRP3 signaling pathway. Methods. Ninety-five male Sprague–Dawley (SD) rats were randomly divided into five groups, each consisting of 19 rats. A rat model of cerebral ischemia was established using transient middle cerebral artery occlusion (tMCAO) combined with cerebral blood flow monitoring. Intervention treatments consisted of electroacupuncture and lipopolysaccharide (an NF-κB agonist) injection. The behavior, spatial learning, and memory ability of the rats were evaluated with the Morris water maze method. The degree of brain injury in the rats was observed via triphenyl tetrazolium chloride (TTC), hematoxylin-eosin (H&E), and Fluoro-Jade B (FJB) staining. The expression levels of proteins related to the inflammatory response, pyroptosis, and synaptic plasticity were determined via western blotting and immunofluorescence staining. Changes in dendrites and spines were observed via Golgi-Cox staining. Results. Compared with those of the tMCAO group, the neural function scores and escape latency of the EA+tMCAO group were reduced. The cerebral infarct volume and the number of denatured neurons decreased. NF-κB, caspase-1, NLRP3, and IL-18 expression levels were significantly decreased. PSD95, SYP, and BDNF expression levels were significantly increased. The total number of dendrite junctions and the total length of dendrites increased. Compared with the EA+tMCAO and NS+EA+tMCAO groups, the escape latency in the lipopolysaccharide (LPS)+EA+tMCAO group was significantly increased. NF-κB, IL-18, and cleaved caspase-1 expression levels were elevated. Conclusion. EA may inhibit NF-κB/NLRP3 pathway proteins; regulate the neuroinflammatory response; promote the expression of PSD-95, SYN, and BDNF; improve the structure of dendrites and dendritic spines; and alleviate cognitive impairment in rats with CIRI.
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    Electroacupuncture pretreatment inhibits ferroptosis and inflammation after middle cerebral artery occlusion in rats by activating Nrf2
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Pu, Yanpeng; Cheng, Jingyan; Wang, Zhenya; Zhang, Jingbo; Liang, Fajun; Zhang, Xianbao; Zheng, Zhijun; Yin, Miaomiao; Wang, Zhen
    Objective. Electroacupuncture (EA) pretreatment can effectively increase the tolerance of the brain to ischemic stroke. The mechanism of ischemic tolerance induced by EA is related to Nrf2, but its specific mechanism has not been elucidated. This paper was designed to explore the effect of EA pretreatment on brain injury and the related mechanisms. Methods. Rats were pretreated with EA before middle cerebral artery occlusion (MCAO) modeling. The symptoms of neurological deficit and the volume of cerebral infarction were measured. The levels of inflammatory factors, oxidative stress-related factors, LPO, ROS, and Fe2+ were evaluated by the corresponding kits. Cell apoptosis was determined through TUNEL staining. The mRNA expression of inflammatory factors was examined by RT-qPCR, and the protein expression of ferroptosis-related factors, pyroptosis-related proteins, Keap1, Nrf2, HO-1, and NQO1 by western blotting. Results. EA pretreatment improved the symptoms of neurological deficit and reduced the volume of cerebral infarction. EA pretreatment significantly inhibited oxidative stress, inflammatory response, ferroptosis, pyroptosis, and apoptosis in brain tissues of MCAO rats. Mechanistically, EA pretreatment could activate Nrf2 expression and reduce Keap1 expression. Conclusion. EA pretreatment reduced inflammation and oxidative stress and inhibited ferroptosis by activating Nrf2 expression, ultimately delaying the development of ischemic stroke.
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    Evolution of the gasdermin family and pyroptosis
    (Elsevier, 2023-09-19) Angosto-Bazarra, Diego; Guijarro, Adriana; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
    Gasdermins have been identified as playing a prominent role in the innate immune response as the executors of a specific type of cell death called pyroptosis. Specific proteolytic cleavage of gasdermins generates an N-terminal that oligomerizes and forms pores in the cell membrane. Although pyroptosis has been widely described in mammals, the importance of gasdermins and gasdermin-like proteins in inducing cell death in other vertebrates, in invertebrates and in other taxa including fungi and bacteria is still being determined. Mammalian, fungal and bacterial gasdermins have in common the fact that they go through the same stages (such as proteolytic activation) when inducing membrane rupture, which suggests that pyroptosis is as an ancient mechanism. In this review, we summarize the evolution and function of the gasdermin and gasdermin-like proteins in animals, fungi and bacteria.
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    Gasdermin D mediates a fast transient release of ATP after NLRP3 inflammasome activation before ninjurin 1-induced lytic cell death
    (Cell Press, 2025) Schachter, Julieta; Guijarro, Adriana; Angosto-Bazarra, Diego; Pinilla, Miriam; Hurtado-Navarro, Laura; Meunier, Etienne; Perez-Oliva, Ana Belen; Schwarzbaum, Pablo J; Pelegrín Vivancos, Pablo; Pinilla Marquinez, Míriam; Bioquímica y Biología Molecular B e Inmunología
    Pyroptosis is a lytic cell death triggered by the cleavage of gasdermin (GSDM) proteins and subsequent pore formation by the N-terminal domain oligomerization in the plasma membrane. GSDMD is cleaved by caspase-1/-4/-5/-11 upon inflammasome activation and mediates interleukin (IL)-1β and IL-18 release. GSDMD pores favor ninjurin 1 (NINJ1)-induced plasma membrane rupture and cell death. Here, we demonstrate that GSDMD mediates early ATP release upon NLRP3 inflammasome activation independently of NINJ1, occurring before IL-1β release and cell death and constituting an early danger signal. The release of ATP is a transient signal terminated before the cells continue to permeabilize and die. The different N termini of GSDMA to -E are also able to release ATP and induce monocyte migration toward pyroptotic cells. This study reveals ATP release as an early and transient danger signal depending on GSDMD plasma membrane permeabilization, independently of the late stages of lytic cell death.
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    Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis
    (Wiley, 2021-08) Torre-Minguela, Carlos de; Gomez, Ana I.; Couillin, Isabelle; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
    Pyroptosis and intrinsic apoptosis are two forms of regulated cell death driven by active caspases where plasma membrane permeabilization is induced by gasdermin pores. Caspase-1 induces gasdermin D pore formation during pyroptosis whereas caspase-3 promotes gasdermin E pore formation during apoptosis. These two types of cell death are accompanied by mitochondrial outer membrane permeabilization due to BAK/BAX pore formation in the external membrane of mitochondria, and to some extent this complex also affects the inner mitochondrial membrane facilitating mitochondrial DNA relocalisation from the matrix to the cytosol. However, the detailed mechanism responsible for this process has not been investigated. Herein, we reported that gasdermin processing is required to induce mitochondrial DNA release from cells during pyroptosis and apoptosis. Gasdermin targeted at the plasma membrane promotes a fast mitochondrial collapse along with the initial accumulation of mitochondrial DNA in the cytosol and then facilitates the DNA’s release from the cell when the plasma membrane ruptures. These findings demonstrate that gasdermin action has a critical effect on the plasma membrane and facilitates the release of mitochondrial DNA as a damage-associated molecular pattern.
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    Gentiopicroside alleviates neuroinflammation in Parkinson's disease by mediating microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway
    (Universidad de Murcia, Departamento de Histología e Histopatología, 2025) Shen Hong; Song Hui; Sun Qiang; Biología Celular e Histología
    Objective. The study aimed to evaluate the therapeutic potential of gentiopicroside (GPS) in Parkinson's disease (PD) through both in vitro and in vivo experiments, focusing on elucidating the underlying mechanisms of its action. Methods. To achieve this, a PD model was established in C57BL6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by assessment of behavioral changes, pathological alterations, microglial activation, and neuro-inflammation. Simultaneously, a cellular PD model was developed in the BV-2 mouse microglia cell line by exposing them to 1-methyl-4-phenyl-pyridinium (MPP+). The expression of pro-inflammatory molecules was quantified using enzyme-linked immunosorbent assay (ELISA), while pyroptosis was analyzed by flow cytometry with caspase-1/PI double staining. The expression of key factors in the nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway was determined by immunoblotting. Results. The findings revealed that GPS effectively mitigated motor deficits, neurological impairments, microglial activation, and neuroinflammation in the MPTP-induced mouse model of PD. Additionally, GPS protected BV-2 cells from MPP+-induced inflammatory cytokine production and pyroptosis. Mechanistic studies indicated that GPS may exert its neuroprotective effects by inactivating the NF-κB/NLRP3/GSDMD-mediated pyroptotic pathway in both in vivo and in vitro settings. Conclusion. GPS exhibits neuroprotective effects in PD by suppressing microglia-mediated neuro-inflammation and pyroptosis, suggesting its potential as a favorable therapeutic agent for PD treatment
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    METTL1 aggravates sepsis-acute kidney injury by promoting m7G methylation of NLRP3-mediated pyroptosis
    (2025) Yuexuan Chen; Ming Fang; Jingjing Hu; Lu Wang; Biología Celular e Histología
    Sepsis is a major cause of acute kidney injury (AKI). Dysregulation of N7-methyladenosine (m7G) methylation is a pathogenic mechanism of sepsis. However, the role of m7G methylation in renal damage remains poorly understood. In this study, we investigated the regulation of METTL1, an m7G "writer", on pyroptosis in sepsis-induced AKI. HK-2 cells were treated with lipopolysaccharide (LPS), and pyroptosis was assessed using enzyme-linked immunosorbent assays and western blotting. The m7G methylation status of NLRP3 was analyzed through methylated-RNA immunoprecipitation (Me-RIP), RNA immuno-precipitation (RIP), and dual-luciferase reporter assays. Renal injury in mice subjected to cecal ligation and puncture (CLP) was evaluated using hematoxylin and eosin (H&E) staining. Our results demonstrated that METTL1 expression was significantly upregulated in both LPS-treated HK-2 cells and the CLP-induced mouse model. Interfering with METTL1 suppressed LPS-induced pyroptosis in vitro and attenuated kidney damage and pyroptosis in vivo. Furthermore, METTL1 knockdown inhibited m7G methylation of NLRP3, thereby reducing its stability. Overexpression of NLRP3 abrogated the inhibition of pyroptosis caused by METTL1 knockdown. In conclusion, silencing of METTL1 alleviates sepsis-induced AKI by inhibiting m7G methylated NLRP3-mediated pyroptosis in renal tubular epithelial cells. These findings suggest that targeting METTL1 may represent a promising therapeutic strategy for managing sepsis-associated AKI.
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    Penning decoction ameliorated pyroptosis in mice with lipopolysaccharide-induced endometritis through inhibition of the TLR4/NF-κB/NLRP3 pathway
    (2026) Chen Chen; Yuqiong Yuan; Zhihui Liu; Qianru Zhou; Jiani Shi; Biología Celular e Histología; Universidad de Murcia, Departamento de Biología Celular e Histología
    Objectives. Endometritis, stemming from bacterial infection, manifests as persistent inflammation and may cause infertility. Penning decoction (PND) has been approved for clinical treatment of patients with endometritis. However, the mechanism by which it prevents endometritis remains unknown. This study aimed to examine the impact of PND on lipopoly saccharide (LPS)-induced endometritis and elucidate the underlying mechanisms involved. Methods. Firstly, ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) analysis, in which both positive and negative ion modes were used to identify the chemical compounds in PND, was performed. The antipyroptotic effects of PND were validated in LPS-induced endometritis mice. Additionally, mouse endometrial epithelial cells (MEECs) were used to explore the molecular mechanism of PND in serum in vitro. Results. A total of 145 chemical compounds, including flavones, saponins, polysaccharides, alkaloids, and glycosides, were identified in positive and negative ion modes. The results showed that LPS could induce pyroptosis in endometritis in vivo and in vitro. Treatment with PND or serum containing PND could significantly ameliorate LPS-induced pyroptosis by inhibiting the activation of the TLR4/NF-κB/NLRP3 signaling pathway. Conclusion. Our results demonstrated that PND may improve LPS-induced endometritis by inhibiting the TLR4/NF-κB/NLRP3 pathway, which provides a potentially effective drug for the clinical treatment of endometritis.
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    Transcription factor YY1 accelerates hepatic fibrosis development by activating NLRP3 inflammasome-mediated pyroptosis
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Fu, Xiao; Xiao, Ping; Luo, Xin; Guo, Ninghong
    y. Hepatic fibrosis is the basis of multiple liver diseases and may eventually develop into hepatocellular carcinoma. Hepatic stellate cell (HSC) activation is a driving factor of hepatic fibrogenesis. In the liver microenvironment, liver cells and others play a crucial role in HSC activation. The liver tissues of CCl4- induced rats show excessive fibrosis, inflammation, and cell apoptosis. Yin Yang 1 (YY1) was highly expressed in hepatic fibrosis rats and TGF-β1-treated liver cells. In animal experiments, YY1 knockdown effectively attenuated CCl4-induced liver injury and pyroptosisrelated IL-1β and IL-18 expression. In cellular experiments, NLRP3 inflammasome-mediated pyroptosis was activated by TGF-β1 treatment, while YY1 knockdown significantly inhibited the activation of the NLRP3 inflammasome, pyroptosis, and the secretion of IL-1β and IL-18. In addition, our data showed that TGF-β1-treated liver cell conditional medium markedly induced HSC activation, which was rescued by YY1 knockdown in liver cells. YY1 overexpression in liver cells contributed to the activation of TGF-β1-treated liver cell conditional medium in HSCs, however, this effect of YY1 was attenuated by NLRP3 inhibition. Overall, YY1 overexpression in liver cells contributed to HSC activation by facilitating IL-1β and IL-18 production via activating NLRP3 inflammasomemediated pyroptosis, thus aggravating hepatic fibrogenesis. Our data indicate that YY1 may be a novel target for the treatment of hepatic fibrosis and associated liver diseases.
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    USP33 promotes pulmonary microvascular endothelial cell pyroptosis by stabilizing TRAF2 through deubiquitination
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Liang, Jianping; Chen, Junbo; Xu, Pengfei; Biología Celular e Histología
    Objective. Inhibiting the pyroptosis of human pulmonary microvascular endothelial cells (HPMECs) is a promising therapeutic modality for acute lung injury (ALI). Given the undefined effect of ubiquitin-specific protease 33 (USP33) and tumor necrosis factor receptor-associated factor 2 (TRAF2) on pyroptosis in lung injury, this study investigates their roles in the pyroptosis of HPMECs during ALI. Methods. The hypoxia/reoxygenation (H/R)-induced model was constructed in HPMECs. Cell viability, cytotoxicity, and cell death were determined by the cell counting kit-8 (CCK-8), Lactate dehydrogenase (LDH), and Hoechst-PI staining, respectively. Western blot and qRT-PCR were used to detect protein and gene expression levels of pyroptosis-related markers, respectively. The TRAF2 ubiquitination level was measured via immunoprecipitation. Results. USP33 and TRAF2 expressions were elevated in H/R-induced HPMECs. Knockdown of USP33 increased cell viability and inhibited cellular pyroptosis, accompanied by decreases in IL-1β, IL-18, and Caspase-1. USP33 stabilized TRAF2 by deubiquitination. TRAF2 overexpression reversed the effect of USP33 silencing on suppressing HPMEC pyroptosis. Conclusion. USP33 stabilizes TRAF2 by de-ubiquitination to promote HPMEC pyroptosis during ALI.