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12 pages, 880 KB  
Review
The Role of Inflammasomes in LPS and Gram-Negative Bacterial Sepsis
by Eduardo Hernández-Cuellar, Kohsuke Tsuchiya, Oscar Medina-Contreras and Ricardo Valle-Ríos
J. Clin. Med. 2025, 14(19), 7102; https://doi.org/10.3390/jcm14197102 - 9 Oct 2025
Viewed by 343
Abstract
Background/Objectives: Sepsis is a life-threatening condition characterized by an uncontrolled immune response due to systemic infections. It is responsible for millions of deaths worldwide. Although inflammasomes play an important role in host defense, they have a detrimental role in sepsis induced by [...] Read more.
Background/Objectives: Sepsis is a life-threatening condition characterized by an uncontrolled immune response due to systemic infections. It is responsible for millions of deaths worldwide. Although inflammasomes play an important role in host defense, they have a detrimental role in sepsis induced by LPS or Gram-negative bacteria. We aimed to revise the molecular mechanisms of inflammasome activation in sepsis by LPS and Gram-negative bacteria other than cytokine release as treatments blocking TNF-α and IL-1 cytokines have been ineffective even though cytokine storm is associated with lethality. Results: Studies with knockout mice deficient in inflammasome-derived cytokines have shown contrasting results on the role of these proinflammatory cytokines in the lethality of LPS- and Gram-negative-induced sepsis. However, DAMPs released after non-canonical inflammasome activation such as extracellular DNA, histones, HMGB1, and tissue factor result in disseminated-intravascular coagulation (DIC) and mortality in mice. Blocking these products in preclinical studies with animal models showed improved clinical scores and survival after LPS-induced sepsis or polymicrobial sepsis induced by Cecal Ligation and Puncture. Conclusions: Even though immunomodulatory drugs have shown inconclusive results as therapies for sepsis, blocking DAMPs associated with DIC may be considered for clinical trials in the future, especially in patients presenting biomarkers of coagulopathies. Full article
(This article belongs to the Special Issue Sepsis: New Insights into Diagnosis and Treatment)
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20 pages, 4640 KB  
Article
Probing the Cardiovascular Toxic Effects of Long-Term Exposure to Dibutyl Phthalate in Sprague-Dawley Rats Based on Oxidative Inflammation and Metabolic Pathways: Implications for the Heart and Blood Vessel
by Xiao Liang, Qi Huang, Yang Wu, Deyu Zhu, Zhuangzhuang Wei, Qing Feng, Ping Ma, Xu Yang, Cuiyu Bao and Xinyu Bao
Toxics 2025, 13(10), 815; https://doi.org/10.3390/toxics13100815 - 25 Sep 2025
Viewed by 433
Abstract
Background: Dibutyl phthalate (DBP) is a prevalent environmental pollutant that can accumulate in organisms, becoming amplified after the food cycle and ultimately affecting human health. Recent studies have provided evidence suggesting a potential association between exposure to DBP and cardiovascular diseases (CVDs). Objectives: [...] Read more.
Background: Dibutyl phthalate (DBP) is a prevalent environmental pollutant that can accumulate in organisms, becoming amplified after the food cycle and ultimately affecting human health. Recent studies have provided evidence suggesting a potential association between exposure to DBP and cardiovascular diseases (CVDs). Objectives: This study’s objective is to investigate the toxic cardiovascular effects of long-term exposure to DBP, particularly its impact on the heart and blood vessels. To be specific, we hypothesized and verified the potential mechanisms underlying DBP-induced cardiac and vascular injuries, focusing on oxidative stress, pyroptosis, inflammatory responses, and metabolic pathways. Methods: The rats were divided into 5 groups: Control group, DBP-Low group, DBP-Medium group, DBP-High group, and DBP-High + Vitamin E group. The entire experimental period lasted 12 weeks. We conducted examinations on echocardiography, histopathology, oxidative stress biomarkers, pyroptosis-related biomarkers, and inflammatory cytokine biomarkers. Additionally, we carried out serum metabolomics analysis. Result: Our research findings indicate that long-term exposure to DBP can cause significant toxic effects on the cardiovascular system. Specifically, DBP leads to changes in oxidative stress indicators (ROS and an increase in MDA levels, alongside a decrease in GSH levels) and protein levels related to pyroptosis (NLRP3, Caspase-1 and GSDMD levels increase) in cardiac and vascular tissues, triggering oxidative inflammatory responses (IL-1β and IL-18 levels increase), damaging the heart and blood vessels (organizational structure deformation and collagen fiber infiltration) and ultimately affecting their functions (abnormalities in cardiac function and hemodynamics). Additionally, the results of metabolomics studies suggest that metabolic pathways (Biotin metabolism, TCA cycle, Vitamin B6 metabolism, Pantothenate and CoA biosynthesis, and Riboflavin metabolism) and metabolites may also be of great significance. Conclusion: Long-term exposure to DBP can induce cardiovascular toxicity in rats, manifesting as cardiac and vascular damage, as well as alterations in organ function. This process is characterized by oxidative stress, activation of the pyroptosis pathway, inflammatory responses, and modifications to metabolic pathways. Full article
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20 pages, 6268 KB  
Article
Homocysteine-Mediated Neuronal Pyroptosis Contributes to Brain Injury in Heatstroke Rats by Activating the m6A-YTHDF2-NLRP3 Pathway
by Shijia Zhang, Fang Xie, Xue Wang, Zhaowei Sun, Ling Zhang, Weiwei Liu, Xiaobing Chen, Lingjia Qian and Yun Zhao
Cells 2025, 14(18), 1437; https://doi.org/10.3390/cells14181437 - 15 Sep 2025
Viewed by 583
Abstract
Heat stroke (HS) is a life-threatening condition that leads to neuronal injury, particularly in the prefrontal cortex, though its mechanisms remain unclear. In this study, we established a rat HS model and observed significant inflammatory responses and neuronal pyroptosis in the prefrontal cortex [...] Read more.
Heat stroke (HS) is a life-threatening condition that leads to neuronal injury, particularly in the prefrontal cortex, though its mechanisms remain unclear. In this study, we established a rat HS model and observed significant inflammatory responses and neuronal pyroptosis in the prefrontal cortex 6 h post-heat exposure, with the injury severity increasing over time. Mechanistically, HS activated the caspase-1/GSDMD-dependent pyroptosis pathway through NLRP3 inflammasome activation, resulting in IL-1β and IL-18 release. Additionally, HS caused a marked increase in homocysteine (Hcy) levels in both the serum and the prefrontal cortex, accompanied by reduced expression of the Hcy metabolic enzymes MTHFR and CSE, suggesting Hcy metabolism disruption. In vitro, Hcy induced pyroptosis in PC12 cells, elevating IL-1β, IL-18, and LDH levels. Notably, the NLRP3 inhibitor MCC950 mitigated this effect by reducing IL-18 and LDH release. Reducing Hcy in vivo alleviated neuronal pyroptosis and counteracted the YTHDF2-mediated decrease in NLRP3 mRNA m6A modification. Hcy reduced global m6A modification, YTHDF2 expression, and NLRP3 m6A modification in PC12 cells. This study reveals that the activation of a novel m6A-YTHDF2-NLRP3 pathway by Hcy underlies HS-induced neuronal injury, suggesting potential therapeutic targets for HS intervention. Full article
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21 pages, 1140 KB  
Article
Gasdermin-Mediated Pyroptosis in Hidradenitis Suppurativa: Molecular Insights and Therapeutic Implications
by Kinga Tyczyńska, Piotr K. Krajewski, Aleksandra Sójka, Danuta Nowicka-Suszko, Iwona Bednarz-Misa, Mariusz Fleszar, Małgorzata Krzystek-Korpacka and Jacek C. Szepietowski
Biology 2025, 14(9), 1258; https://doi.org/10.3390/biology14091258 - 12 Sep 2025
Viewed by 467
Abstract
Hidradenitis suppurativa (HS) is a debilitating inflammatory skin condition with unclear underlying mechanisms. Recent studies suggest pyroptosis, a highly inflammatory form of programmed cell death, could significantly contribute to the disease process. This study aimed to investigate the roles of gasdermin D (GSDMD) [...] Read more.
Hidradenitis suppurativa (HS) is a debilitating inflammatory skin condition with unclear underlying mechanisms. Recent studies suggest pyroptosis, a highly inflammatory form of programmed cell death, could significantly contribute to the disease process. This study aimed to investigate the roles of gasdermin D (GSDMD) and gasdermin E (GSDME), two key mediators of pyroptosis, in HS pathogenesis. Serum and skin samples from HS patients and healthy individuals were analyzed. Serum gasdermin D levels were significantly elevated in HS patients, although gasdermin E showed no significant difference compared to controls. Skin tissue analysis revealed increased expression of both GSDMD and GSDME in inflamed HS lesions compared to unaffected skin from the same patients and healthy control skin. However, these molecules did not correlate directly with disease severity. Interestingly, systemic metabolic markers showed some associations with gasdermin expression, suggesting potential connections between systemic health and inflammation in HS. These findings confirm a critical role of gasdermins in HS-related inflammation and identify pyroptosis as a promising therapeutic target. Further exploration of these pathways could yield valuable treatment strategies for managing this challenging skin condition. Full article
(This article belongs to the Special Issue Biology and Function of Inflammasomes)
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24 pages, 4260 KB  
Article
Distinct Inflammatory Responses of hiPSC-Derived Endothelial Cells and Cardiomyocytes to Cytokines Involved in Immune Checkpoint Inhibitor-Associated Myocarditis
by Samantha Conte, Isaure Firoaguer, Simon Lledo, Thi Thom Tran, Claire El Yazidi, Stéphanie Simoncini, Zohra Rebaoui, Claire Guiol, Christophe Chevillard, Régis Guieu, Denis Puthier, Franck Thuny, Jennifer Cautela and Nathalie Lalevée
Cells 2025, 14(17), 1397; https://doi.org/10.3390/cells14171397 - 7 Sep 2025
Viewed by 803
Abstract
Inflammatory cytokines, particularly interferon-γ (IFN-γ), are markedly elevated in the peripheral blood of patients with immune checkpoint inhibitor-induced myocarditis (ICI-M). Endomyocardial biopsies from these patients also show GBP-associated inflammasome overexpression. While both factors are implicated in ICI-M pathophysiology, their interplay and cellular targets [...] Read more.
Inflammatory cytokines, particularly interferon-γ (IFN-γ), are markedly elevated in the peripheral blood of patients with immune checkpoint inhibitor-induced myocarditis (ICI-M). Endomyocardial biopsies from these patients also show GBP-associated inflammasome overexpression. While both factors are implicated in ICI-M pathophysiology, their interplay and cellular targets remain poorly characterized. Our aim was to elucidate how ICI-M-associated cytokines affect the viability and inflammatory responses of endothelial cells (ECs) and cardiomyocytes (CMs) using human induced pluripotent stem cell (hiPSC)-derived models. ECs and CMs were differentiated from the same hiPSC line derived from a healthy donor. Cells were exposed either to IFN-γ alone or to an inflammatory cytokine cocktail (CCL5, GZMB, IL-1β, IL-2, IL-6, IFN-γ, TNF-α). We assessed large-scale transcriptomic changes via microarray and evaluated inflammatory, apoptotic, and cell death pathways at cellular and molecular levels. hiPSC-ECs were highly sensitive to cytokine exposure, displaying significant mortality and marked transcriptomic changes in immunity- and inflammation-related pathways. In contrast, hiPSC-CM showed limited transcriptional changes and reduced susceptibility to cytokine-induced death. In both cell types, cytokine treatment upregulated key components of the inflammasome pathway, including regulators (GBP5, GBP6, P2X7, NLRC5), a core component (AIM2), and the effector GSDMD. Increased GBP5 expression and CASP-1 cleavage mirrored the findings found elsewhere in endomyocardial biopsies from ICI-M patients. This hiPSC-based model reveals a distinct cellular sensitivity to ICI-M-related inflammation, with endothelial cells showing heightened vulnerability. These results reposition endothelial dysfunction, rather than cardiomyocyte injury alone, as a central mechanism in ICI-induced myocarditis. Modulating endothelial inflammasome activation, particularly via AIM2 inhibition, could offer a novel strategy to mitigate cardiac toxicity while preserving antitumor efficacy. Full article
(This article belongs to the Special Issue New Research on Immunity and Inflammation in Cardiovascular Disease)
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18 pages, 12613 KB  
Article
7-Methoxyflavanone Alleviates LPS-Induced Acute Lung Injury by Suppressing TLR4/NF-κB p65 and ROS/Txnip/NLRP3 Signaling
by Kongyan Wang, Huiyu Hu, Zaibin Xu, Yan Chen, Yi Qiu, Yingjie Hu, Jiawen Huang and Zhuohui Luo
Biology 2025, 14(9), 1170; https://doi.org/10.3390/biology14091170 - 2 Sep 2025
Viewed by 602
Abstract
Background: Acute lung injury (ALI) is a serious respiratory condition. The natural compound 7-Methoxyflavanone (7MF) has a broad spectrum of anti-inflammatory and antioxidant properties. However, its pharmacological effects and underlying mechanisms in alleviating ALI remain poorly understood. Methods: An in vitro LPS-induced RAW264.7 [...] Read more.
Background: Acute lung injury (ALI) is a serious respiratory condition. The natural compound 7-Methoxyflavanone (7MF) has a broad spectrum of anti-inflammatory and antioxidant properties. However, its pharmacological effects and underlying mechanisms in alleviating ALI remain poorly understood. Methods: An in vitro LPS-induced RAW264.7 macrophage inflammatory injury assay and an in vivo lipopolysaccharide (LPS)-induced ALI assay in mice were conducted. Results: In vitro experiments showed that 7MF significantly reduced levels of IL1β, IL6, and TNF-α; decreased the expression of COX2 and iNOS, as well as TLR4 and MyD88; suppressed the phosphorylation and degradation of IκBα; and blocked the entry of NF-κB p65 into the nucleus, thereby inhibiting NF-κB signaling. Meanwhile, 7MF also decreased ROS levels; prevented the dissociation of Txnip from Trx-1; and suppressed NLRP3, Caspase-1, Cleaved Caspase-1 p10, NEK7, Caspase-8, Cleaved Caspase-8, IL18, GSDMD, and GSDMD N-terminal expression, and thus inhibited NLRP3 signaling. MCC950, a specific inhibitor of NLRP3, significantly enhanced the pharmacological inhibition of NLRP3 by 7MF. Notably, similar results were confirmed in LPS-induced ALI experiments in mice. Conclusions: The compound 7MF effectively alleviated LPS-induced ALI by suppressing TLR4/NF-κB p65 and ROS/Txnip/NLRP3 signaling pathways. Our findings provide scientific evidence for drug development and treatment of ALI. Full article
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33 pages, 20134 KB  
Article
Paclitaxel and Cephalomannine Synergistically Induce PANoptosis in Triple-Negative Breast Cancer Through Oxygen-Regulated Cell Death Pathways
by Xinyu Gao, Kuilin Chen, Shuhui Jia, Jiapeng Li, Huan Zhang, Yuwei Wang and Weidong Xie
Antioxidants 2025, 14(9), 1037; https://doi.org/10.3390/antiox14091037 - 22 Aug 2025
Viewed by 1060
Abstract
Triple-negative breast cancer (TNBC) urgently requires new therapeutic strategies due to the limited efficacy of conventional treatments. Recently, PANoptosis, an integrated form of apoptosis, necroptosis, and pyroptosis, has emerged as a promising target in cancer therapy, though effective agents remain scarce. Paclitaxel, a [...] Read more.
Triple-negative breast cancer (TNBC) urgently requires new therapeutic strategies due to the limited efficacy of conventional treatments. Recently, PANoptosis, an integrated form of apoptosis, necroptosis, and pyroptosis, has emerged as a promising target in cancer therapy, though effective agents remain scarce. Paclitaxel, a Taxus-derived natural product, is often combined with other drugs to enhance efficacy, yet optimal combinations are limited. This study investigates the synergistic antitumor effects of paclitaxel and cephalomannine in TNBC, focusing on oxygen-regulated cell death pathways. Network pharmacology and molecular docking revealed that the combination targets multiple cell death- and inflammation-related proteins, including BCL2L1, MAPK14, SYK, TNF, and ADAM17, suggesting multi-target synergy. In vitro, the combination significantly inhibited MDA-MB-231 cell viability, proliferation, and migration, while inducing apoptosis and necrosis. Mechanistically, co-treatment markedly increased intracellular ROS levels and γ-H2AX expression, indicating oxidative stress and DNA damage, both of which were reversible by ROS inhibition. Further analysis demonstrated that the treatment activated the p38 and p53 pathways, regulated the Bax/Bcl-2 ratio, and initiated mitochondrial apoptosis. It also promoted RIPK1/RIPK3/MLKL phosphorylation and MLKL membrane translocation, triggering necroptosis, as well as upregulated NLRP3, cleaved Caspase-1, and GSDMD, inducing pyroptosis. The use of specific inhibitors partially reversed these effects, confirming the involvement of ROS-mediated PANoptosis. Similar antitumor effects were also observed in BT-549 cells, indicating the broad applicability of this combination in TNBC. MCF-10A cells exhibited mild but acceptable cytotoxicity, reflecting manageable side effects typical of chemotherapeutic agents. In vivo experiments further validated the combination’s antitumor efficacy and safety. In summary, paclitaxel and cephalomannine synergistically induce PANoptosis in TNBC through oxygen-regulated cell death pathways, offering a novel therapeutic strategy based on oxidative stress modulation by natural compounds. Full article
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
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15 pages, 24794 KB  
Article
CDK5RAP3 Deficiency Is Associated with Hepatic Inflammation and Increased Expression of NLRP3 Inflammasome Components
by Xinjin Chen, Yaqi Huang, Yilin Wu, Le Sheng, Hongchen Yan, Fanghui Chen, Fengwei Li, Hirpha Ketema and Yafei Cai
Biomedicines 2025, 13(8), 2030; https://doi.org/10.3390/biomedicines13082030 - 21 Aug 2025
Viewed by 674
Abstract
Background/Objectives: CDK5RAP3 (CDK5 regulatory subunit-associated protein 3), is a ubiquitously expressed protein in mammalian tissues, with emerging evidence suggesting its critical role in liver hypoplasia. CDK5RAP3 knockout results in liver hypoplasia and liver injury in mice, and most liver injuries are associated [...] Read more.
Background/Objectives: CDK5RAP3 (CDK5 regulatory subunit-associated protein 3), is a ubiquitously expressed protein in mammalian tissues, with emerging evidence suggesting its critical role in liver hypoplasia. CDK5RAP3 knockout results in liver hypoplasia and liver injury in mice, and most liver injuries are associated with inflammation. However, the connection between its deficiency and liver inflammation remains unclear. The NLRP3 inflammasome is a ubiquitously expressed inflammatory pathway, and growing evidence links it to liver diseases. Therefore, we aim to investigate the relationship between CDK5RAP3 deficiency in the liver and the NLRP3 inflammasome. Methods: To clarify the pathological link between CDK5RAP3 deficiency and liver inflammation, we developed liver-specific CDK5RAP3 knockout mouse models and mouse embryonic fibroblasts (MEFs) from conditional knockout mice. Results: CDK5RAP3 deficiency induces hepatic injury and inflammation in mice, with increased expression of NLRP3 inflammasome components (NLRP3, ASC, Caspase-1) and GSDMD, all of which promote pyroptosis. Notably, CDK5RAP3-deficient MEFs exhibit compromised proliferative capacity and elevated apoptotic rates. Conclusions: Our findings demonstrate that CDK5RAP3 is indispensable for maintaining hepatic homeostasis. Its deficiency can induce liver damage and inflammatory cell death in mice. Therefore, CDK5RAP3 may be a candidate for further investigation in inflammatory liver disease models. Full article
(This article belongs to the Section Cell Biology and Pathology)
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14 pages, 1584 KB  
Article
Murine Cytomegalovirus and Human Cytomegalovirus Differ in Pyroptosis Induction in Different Cell Types During Productive Replication
by Jessica J. Carter, Daniel H. Schneider, Arshaan M. Hisamuddin and Richard D. Dix
Viruses 2025, 17(8), 1106; https://doi.org/10.3390/v17081106 - 12 Aug 2025
Cited by 1 | Viewed by 763
Abstract
Pyroptosis is a proinflammatory programmed cell death (PCD) that protects the host against invading viruses. We previously reported that pyroptosis plays a prominent role in the pathogenesis of murine cytomegalovirus (MCMV) retinal necrosis using mice with MAIDS as a mouse model for AIDS-related [...] Read more.
Pyroptosis is a proinflammatory programmed cell death (PCD) that protects the host against invading viruses. We previously reported that pyroptosis plays a prominent role in the pathogenesis of murine cytomegalovirus (MCMV) retinal necrosis using mice with MAIDS as a mouse model for AIDS-related human cytomegalovirus (HCMV) retinal necrosis. Because MCMV and HCMV exhibit species specificity, we sought to determine if pyroptosis induction extends to different cell types of murine or human origin. In vitro studies were therefore performed in which MCMV-infected mouse fibroblasts and mouse macrophages were compared with HCMV-infected human fibroblasts and human ARPE-19 cells for stimulation of caspase-1, gasdermin G (GSDMD), and interleukin (IL)-18 and/or IL-1β transcripts as markers for canonical pyroptosis operation. Whereas MCMV stimulated significant stimulation of pyroptosis-associated transcripts during productive replication of mouse fibroblasts and mouse macrophages, significant stimulation of these transcripts was not detected during HCMV productive replication of human fibroblasts or ARPE-19 cells. Additional studies using UV-inactivated MCMV suggested that virion tegument proteins are not involved in the induction of pyroptosis in MCMV-infected mouse fibroblasts. We conclude that pyroptosis induction during productive replication of MCMV or HCMV is host cell type-dependent and may extend to species specificity, although virus-encoded PCD suppressors must be considered. Full article
(This article belongs to the Special Issue Viruses and Eye Diseases)
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16 pages, 9832 KB  
Article
Gestational GenX Exposure Induces Maternal Hepatotoxicity by Disrupting the Lipid and Bile Acid Metabolism Distinguished from PFOA-Induced Pyroptosis
by Jin-Jin Zhang, Yu-Kui Chen, Ya-Qi Chen, Qin-Yao Zhang, Yu Liu, Qi Wang and Xiao-Li Xie
Toxics 2025, 13(8), 617; https://doi.org/10.3390/toxics13080617 - 24 Jul 2025
Viewed by 696
Abstract
Perfluorooctanoic acid (PFOA) and its replacement, GenX, are per- and polyfluoroalkyl substances (PFASs) widely used in industrial and consumer applications. Pregnant women are a vulnerable population to environmental pollutants. The maternal effects of GenX and PFOA exposure during pregnancy have not been fully [...] Read more.
Perfluorooctanoic acid (PFOA) and its replacement, GenX, are per- and polyfluoroalkyl substances (PFASs) widely used in industrial and consumer applications. Pregnant women are a vulnerable population to environmental pollutants. The maternal effects of GenX and PFOA exposure during pregnancy have not been fully elucidated. In this study, pregnant mice received daily oral doses of GenX (2 mg/kg/day), PFOA (1 mg/kg/day), or Milli-Q water (control) throughout gestation. Histopathological analyses revealed significant liver abnormalities in both exposure groups, including hepatocyte swelling, cellular disarray, eosinophilic degeneration, karyopyknosis, lipid vacuolation, and increased inflammatory responses. Through transcriptomics analyses, it was found that multiple metabolic and inflammatory pathways were enriched in both exposure groups. In the GenX group, overexpression of CYP4A, c-Myc, and Oatp2 proteins and decreased expression of EGFR and β-catenin in the liver suggested disruption of lipid and bile acid metabolism. In the PFOA group, significantly upregulated protein levels of NLRP3, GSDMD, caspase-1, IL-18, and IL-1β indicated hepatic pyroptosis. Despite these distinct pathways, both compounds triggered inflammatory cytokine release in the liver, consistent with the results of the transcriptomics analysis, suggesting shared mechanisms of inflammatory liver injury. Taken together, our findings provided novel insights into the hepatotoxicity mechanisms of GenX and PFOA exposure during pregnancy, underscoring the potential health risks associated with PFAS exposure. Full article
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16 pages, 10508 KB  
Article
Pharmacological Evaluation of Polygoni Multiflori Radix Praeparata Extract: Inhibition of PANoptosis in Alleviating Premature Ovarian Insufficiency
by Can Zhu, Jinhong Li, Yaofeng Li, Daiyong Chen and Chang Lin
Curr. Issues Mol. Biol. 2025, 47(7), 569; https://doi.org/10.3390/cimb47070569 - 19 Jul 2025
Viewed by 892
Abstract
Polygoni Multiflori Radix Praeparata (PMRP), a processed root of Polygonum multiflorum Thunb. (known as Zhiheshouwu in Chinese medicine), exhibits anti-aging properties and is used to improve ovarian aging. However, its therapeutic mechanism against premature ovarian insufficiency (POI) remains unclear. This study investigates whether [...] Read more.
Polygoni Multiflori Radix Praeparata (PMRP), a processed root of Polygonum multiflorum Thunb. (known as Zhiheshouwu in Chinese medicine), exhibits anti-aging properties and is used to improve ovarian aging. However, its therapeutic mechanism against premature ovarian insufficiency (POI) remains unclear. This study investigates whether PMRP alleviates POI by inhibiting PANoptosis—a cell death pathway characterized by the concurrent occurrence and interplay of pyroptosis, apoptosis, and necroptosis. POI was induced in rats using tripterygium glycosides. We evaluated the estrous cycle, serum hormone levels (follicle-stimulating hormone [FSH], estrogen [E2], anti-Müllerian hormone [AMH]), follicular development, and the ultrastructure of granulosa cells. PANoptosome assembly (apoptosis-associated speck-like protein containing a CARD [ASC]/caspase-8/receptor-interacting protein kinase 3 [RIPK3] co-localization) and key effectors of PANoptosis (caspase 3, cleaved caspase 3, gasdermin D [GSDMD], cleaved GSDMD, GSDME, RIPK1, mixed-lineage kinase domain-like protein [MLKL], and p-MLKL) were analyzed. PMRP restored the estrous cycle, lowered FSH levels, and increased E2 and AMH levels in POI rats. It reduced follicular atresia, preserved primordial follicles, and suppressed PANoptosis-like death in granulosa cells. Mechanistically, PMRP disrupted PANoptosome assembly and downregulated key effectors of PANoptosis. PMRP alleviates POI by inhibiting PANoptosis in granulosa cells, overcoming the previous limitations of targeting single death pathways and providing novel insights into the pathogenesis and treatment strategies for POI. Full article
(This article belongs to the Section Molecular Pharmacology)
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21 pages, 16995 KB  
Article
Vitamin D Attenuates Hepatic Sinusoidal Capillarization in Type 2 Diabetes Mellitus– Metabolic Dysfunction-Associated Fatty Liver Disease via Dual Autophagy Activation and Pyroptosis Suppression in Liver Sinusoidal Endothelial Cells
by Panpan Jiang, Yang Liu, Juxiang Liu and Jinxing Quan
Biomedicines 2025, 13(6), 1459; https://doi.org/10.3390/biomedicines13061459 - 13 Jun 2025
Viewed by 886
Abstract
Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with type 2 diabetes mellitus (T2DM), where T2DM serves as a crucial driving factor for MAFLD progression. While vitamin D (VD) demonstrates protective effects against MAFLD, the underlying mechanisms through which it influences [...] Read more.
Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with type 2 diabetes mellitus (T2DM), where T2DM serves as a crucial driving factor for MAFLD progression. While vitamin D (VD) demonstrates protective effects against MAFLD, the underlying mechanisms through which it influences MAFLD-related liver sinusoidal endothelial cell (LSEC) capillarization remain to be elucidated. This study aimed to explore how vitamin D ameliorates LSEC capillarization in T2DM-associated MAFLD. Methods: Culture human liver sinusoidal endothelial cells (HLSECs) according to the established protocol. After 1,25(OH)2D3 intervention in high glucose (HG)-induced HLSECs, determine the changes in liver sinusoidal capillarization-related proteins (LN, PLVAP), autophagy and pyroptosis levels. Observe the changes in cell lipid accumulation and fenestration structures. After adding Bafilomycin A1, MCC950, compound C and rapamycin to HLSECs, explore the therapeutic mechanism of 1,25(OH)2D3. After supplementing VD to MAFLD model mice, further verify the therapeutic mechanism of VD on MAFLD. Results: HG can induce the capillarization and lipid accumulation of HLSEC, increase the level of pyroptosis, and simultaneously reduce the autophagy level. Vitamin D alleviated high-glucose-induced pyroptosis (by suppressing GSDMD/NLRP3) and autophagic inhibition by activating the AMPK-mTOR axis (upregulating p-AMPK and downregulating mTOR), and improved lipid accumulation and hepatic sinusoidal capillarization. In the mouse model of MAFLD, VD supplementation can induce autophagy, inhibit pyroptosis and capillarization, and improve MAFLD. Conclusions: These results demonstrate, for the first time, that VD mitigates LSEC dysfunction through dual mechanisms: activating AMPK-dependent autophagy and inhibiting pyroptosis, providing a therapeutic rationale for VD in treating MAFLD-related sinusoidal pathology. Full article
(This article belongs to the Section Cell Biology and Pathology)
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20 pages, 1383 KB  
Article
Determination of the Roles of H. pylori Outer Membrane Virulence Factors and Pyroptosis-Associated NLRP3, ASC, Caspase-1, Gasdermin D, IL-1β, and IL-18 in Ulcer and Gastritis Pathogenesis
by Yaren Buyukcolak-Cebeci, Emel Timucin, Sumeyye Akcelik-Deveci, Nesteren Mansur-Ozen, Tuana Aydinlar, Arzu Tiftikci and Sinem Oktem-Okullu
Biology 2025, 14(6), 634; https://doi.org/10.3390/biology14060634 - 30 May 2025
Viewed by 928
Abstract
Background: This study aims to investigate the association between pyroptosis and the outer membrane virulence factor of H. pylori in patients with gastritis and ulcers. Methods: DNA, RNA, and protein were extracted from a single tissue sample taken from the antrum region of [...] Read more.
Background: This study aims to investigate the association between pyroptosis and the outer membrane virulence factor of H. pylori in patients with gastritis and ulcers. Methods: DNA, RNA, and protein were extracted from a single tissue sample taken from the antrum region of the stomach of volunteer patients. The expression of bacterial outer membrane virulence genes was analyzed at the gene level, and the expression levels of key pyroptosis markers were compared between H. pylori-infected and uninfected gastritis and ulcer patient groups. Results: H. pylori infection induced significant alterations in the expression levels of pyroptosis markers, including ASC, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β, indicating a strong association with gastritis and ulcer pathology. Statistically significant correlations were observed between elevated levels of these markers and the activation of caspase-1 across different patient cohorts, supporting effective detection of pyroptosis. Both pro and active forms of caspase-1, GSDMD, IL-18, and IL-1β were assessed, revealing pyroptotic activity in specific patient samples. The vacA m2 allele showed a distinct ASC response in gastritis versus ulcer patients and was associated with increased GSDMD expression in ulcerative cases. Along with the babB gene, this allele appears to play a critical role in the interaction between H. pylori virulence and host pyroptotic responses. A statistically significant negative association was identified between the presence of the H. pylori alpA gene and Gasdermin D expression (odds ratio = 0, p < 0.01), suggesting that Gasdermin D was absent in all alpA-positive samples. Conclusion: This study provides novel insights into the interrelation between the virulence factors of H. pylori and pyroptosis in gastritis and ulcer diseases. Our findings demonstrate that H. pylori infection significantly alters the expression levels of pyroptosis markers, including ASC, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β, in gastric tissues. Notably, the vacA m2 allele was associated with a differential response in ASC expression among patients with gastritis and ulcers, correlating with increased GSDMD levels in ulcerative conditions. The presence of the H. pylori alpA gene is markedly associated with the lack of Gasdermin D activation, indicating a possible suppressive function or immune evasion tactic. These results underscore the critical role of H. pylori virulence determinants in modulating pyroptosis and suggest that understanding this relationship may pave the way for developing targeted therapeutic strategies to mitigate H. pylori-associated pathologies. Full article
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14 pages, 5970 KB  
Article
Impaired Mitophagy Contributes to Pyroptosis in Sarcopenic Obesity Zebrafish Skeletal Muscle
by Xiangbin Tang, Yunyi Zou, Siyuan Yang, Zhanglin Chen, Zuoqiong Zhou, Xiyang Peng and Changfa Tang
Nutrients 2025, 17(10), 1711; https://doi.org/10.3390/nu17101711 - 18 May 2025
Cited by 1 | Viewed by 905
Abstract
Background: Growing evidence suggests that the prevalence of sarcopenic obesity (SOB) is on the rise across the globe. However, the key molecular mechanisms behind this disease have not been clarified. Methods: In this experiment, we fed zebrafish a high-fat diet (HFD) for 16 [...] Read more.
Background: Growing evidence suggests that the prevalence of sarcopenic obesity (SOB) is on the rise across the globe. However, the key molecular mechanisms behind this disease have not been clarified. Methods: In this experiment, we fed zebrafish a high-fat diet (HFD) for 16 weeks to induce sarcopenic obesity. Results: After a dietary trial, HFD zebrafish exhibited an obese phenotype with skeletal muscle atrophy and decreased swimming capacity. We demonstrated that mitochondrial content and function were abnormal in SOB zebrafish skeletal muscle. These results may be associated with the impairment of mitophagy regulated by the PTEN-induced putative kinase 1 (PINK1)/Parkin (PRKN) pathway. In addition, we also found that NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) signaling was activated with the upregulation of NLRP3, GSDMD-NT, and mature-IL1β, which indicated that pyroptosis was induced in SOB zebrafish skeletal muscle. Conclusions: Our study identified that impaired mitophagy and pyroptosis were associated with the pathogenesis of SOB. These results could potentially offer novel therapeutic objectives for the treatment of sarcopenic obesity. Full article
(This article belongs to the Special Issue Effects of Diet and Nutrition on Musculoskeletal Health)
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Article
Effects of Adipose-Derived Mesenchymal Stem Cell-Secretome on Pyroptosis of Laparoscopic Hepatic Ischemia Reperfusion Injury in a Porcine Model
by Yajun Ma, Lei Cao, Pujun Li, Zhihui Jiao, Xiaoning Liu, Xiangyu Lu, Tao Liu and Hongbin Wang
Cells 2025, 14(10), 722; https://doi.org/10.3390/cells14100722 - 15 May 2025
Cited by 1 | Viewed by 791
Abstract
Extensive research has been conducted on mesenchymal stem cells (MSCs) regarding their ability to modify the immune response and reduce tissue damage. Many researchers have found that the regulatory capacity of MSCs primarily comes from their secretome. As a result, there has been [...] Read more.
Extensive research has been conducted on mesenchymal stem cells (MSCs) regarding their ability to modify the immune response and reduce tissue damage. Many researchers have found that the regulatory capacity of MSCs primarily comes from their secretome. As a result, there has been much interest in utilizing “cell-free” therapies as alternatives to stem cell treatments. In this study, the secretome from adipose mesenchymal stem cells (ADSC-secretome) was extracted and injected into minipigs with established liver injury models. Blood and liver tissue samples were obtained prior to the procedure, as well as on days 1, 3, and 7 after surgery. It was found that ADSC-secretome effectively suppressed the synthesis of the NOD-like receptor protein 3 (NLRP3) inflammasome, leading to a downregulation of gasdermin-D (GSDMD) expression, and demonstrated a more prominent anti-pyroptosis effect compared to ADSCs. Furthermore, ADSC-secretome inhibited the high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) inflammatory pathway. In summary, both ADSC-secretome and ADSCs inhibited pyroptosis in right hemihepatic ischemia–reperfusion combined with left hemihepatectomy injury, and ADSC-secretome exhibited a stronger therapeutic effect. ADSC-secretome exerted these therapeutic effects through the inhibition of the HMGB1/TLR4/NF-κB inflammatory pathway. In the future, “cell-free” therapy is expected to replace cell-based methods. Full article
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