NLRP3 Inflammasome Targeting Offers a Novel Therapeutic Paradigm for Sepsis-Induced Myocardial Injury

Drug Design Development and Therapy, Journal Year: 2025, Volume and Issue: Volume 19, P. 1025 - 1041

Published: Feb. 1, 2025

Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy injury (SIMI), is a common complication of sepsis and associated with poor outcomes. However, the pathogenesis molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds inhibit NLRP3-associated pyroptosis may exert therapeutic effects against In this review, we first outlined principal elements NLRP3 signaling cascade summarized recent studies highlighting how activation contributes We selective small-molecule modulators function inhibitors delineated their action attenuate Finally, discuss major limitations current paradigm propose possible strategies overcome them. This review highlights pharmacological inhibition promising strategy.

Language: Английский

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G protein-coupled estrogen receptor biased signaling in health and disease

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108822 - 108822

Published: Feb. 1, 2025

Language: Английский

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Role and Mechanism of Mitochondrial Ribosomal Proteins in Septic Myocardial Injury

Journal of Inflammation Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 2677 - 2698

Published: Feb. 1, 2025

To investigate the role of mitochondrial ribosomal proteins (MRPs) in pathogenesis and progression septic myocardial injury. Additionally, we aim to propose new technical strategies experimental foundations for prevention treatment Animal cell models injury were established. Aberrantly expressed MRPs screened using transcriptome sequencing, their expression was verified by RT-qPCR Western blot. Subsequently, overexpressed knockdown constructed. The effects on CO I, PGC-1α, ATP content, ROS fluorescence intensity, membrane potential, GSDMD assessed, along with changes caspase-4 IL-1β levels. Transcriptome sequencing revealed a reduction mice Both blot analysis confirmed decreased animal Furthermore, overexpression both MRPS16 MRPL47 mitigated decrease I PGC-1α levels induced alleviated elevated IL-1β, caspase-4, caused findings suggest that can mitigate attenuating biosynthesis dysfunction, energy metabolism disorders, Ca2+ disturbances This ultimately reduces cellular damage alleviates

Language: Английский

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Estrogen via GPER downregulated HIF-1a and MIF expression, attenuated cardiac arrhythmias, and myocardial inflammation during hypobaric hypoxia

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: March 20, 2025

Abstract Background The human body is highly dependent on adequate oxygenation of the cellular space for physiologic homeostasis mediation. insufficient leads to hypoxia. Hypobaric hypoxia (HH) reduction in oxygen partial pressure and atmospheric during ascent high altitudes. This state induces a maladaptive response. Women how hormones like estrogen influence have not been explored with most research being conducted males. In this study, we investigated effects GPER HIF-1a MIF expression, cardiac arrhythmias, inflammation hypobaric Methods Ovariectomy SHAM operations were done FVB wild-type (WT) female mice. 2 weeks after operation, mice treated (40 mg/kg) as therapeutic intervention placed hypoxic chamber at an altitude 6000 m 7 days. Cardiac electrical activity was assessed using electrocardiography. Alterations protein inflammatory, pathways western blotting, ELISA, immunofluorescence. Histological assessment performed Masson’s trichrome staining. Peritoneal macrophages isolated vitro study. Results Under (HH), ovariectomized (OVX) group showed increased macrophage migration inhibitory factor (MIF) hypoxia-inducible factor-1 alpha (HIF-1α) expression. contrast, these factors downregulated estrogen-treated control groups. HH also caused fibrosis, especially OVX + group, which had elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) decreased anti-inflammatory (TGF-β, IL-10). Inhibition G15 (a antagonist) HIF-1α, whereas activation G1 agonist) their highlighting GPER’s crucial role regulating HH. Conclusion Estrogen regulates HIF-1α expression through hypoxia, suggesting potential pathway mitigate responses high-altitude ascent. Graphical

Language: Английский

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Pleiotropic Role of TNIK in Sepsis‐Induced Cardiomyopathy

Journal of Cellular Physiology, Journal Year: 2025, Volume and Issue: 240(4)

Published: April 1, 2025

ABSTRACT Heart failure induced by sepsis is considered one of the foremost contributors to mortality in intensive care unit (ICU) patients. However, molecular mechanism myocardial damage has not been fully elucidated at present. TNF receptor‐associated factor‐2 and Nck‐interacting protein kinase (TNIK) are members germinal center superfamily. TNIK exhibits a pivotal role as conserved modulator glucose lipid homeostasis. Here, we aimed investigate potential direct roles whether exerts anti‐septic regulating NLRP3 pathway. We initially revealed that was crucial involvement septic injury. Subsequently, constructed cecal ligation puncture (CLP) mouse model employed LPS‐induced injury HL‐1 cardiomyocytes. Our observations an upregulation levels both CLP‐injured mice LPS‐treated cells. inhibitor TNIK‐IN‐7 or siRNA attenuated cardiomyocyte LPS Especially, can significantly downregulate well decrease IL‐1β mRNA levels, though explicit mechanisms TNIK‐NLRP3 require further investigation. Together, our investigation presents novel evidence suggesting therapeutic target for prevention intervention sepsis‐induced cardiomyopathy.

Language: Английский

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Maternal Nutritional Programming: Sex-Specific Cardiovascular and Immune Outcomes Following Perinatal High-Fat Diet Exposure

Nutrients, Journal Year: 2025, Volume and Issue: 17(9), P. 1464 - 1464

Published: April 26, 2025

Background: The long-term effects of a perinatal high-fat diet on the cardiovascular function offspring are not well elucidated. We hypothesize that exposure to alters adult and immune responses in sex-specific manner. Methods: Male female were born (pHFD) or control (pCD)-fed C57BL/6 mothers weaned diet. Cardiovascular (baseline response an acute isoproterenol stress test) was quantified at 8 weeks age, blood inflammatory single low dose lipopolysaccharide 9 age. Results: pHFD had identical baseline compared pCD mice but blunted (20-45% reductions cardiac output, stroke volume, left ventricular fractional shortening). In contrast, parameters reduced offspring, there no effect isoproterenol. Concentrations TNF-α IL-6 plasma two hours after low-dose LPS administration highest mice. Conclusions: Perinatal resulted adaptations response. Female displayed impairments, whereas male showed latent vulnerability under stress. These differences may reflect underlying hormonal epigenetic mechanisms diverge by sex. Future studies should examine roles sex hormones gene regulation pathways better understand these dimorphic outcomes. findings emphasize importance maternal shaping cardiometabolic risks highlight potential avenues for nutritional interventions during pregnancy.

Language: Английский

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Mitochondria at the Heart of Sepsis: Mechanisms, Metabolism, and Sex Differences

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4211 - 4211

Published: April 29, 2025

Sepsis is a life-threatening condition that occurs when the body unable to effectively combat infection, leading systemic inflammation and multi-organ failure. Interestingly, females exhibit lower sepsis incidence improved clinical outcomes compared males. However, mechanisms underlying these sex-specific differences remain poorly understood. While sex hormones have been primary focus, emerging evidence suggests non-hormonal factors also play contributory roles. Despite in sepsis, management same for both males females, with treatment focused on combating infection using antibiotics hemodynamic support through fluid therapy. even interventions, mortality remains high, highlighting need more effective targeted therapeutic strategies. Sepsis-induced cardiomyopathy (SIC) key contributor failure characterized by left ventricular dilation impaired cardiac contractility. In this review, we explore SIC, particular focus mitochondrial metabolism. Mitochondria generate ATP required function fatty acid glucose oxidation, recent studies revealed distinct metabolic profiles between which can further differ context of SIC. Targeting pathways could provide new avenues treatment.

Language: Английский

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The key players of inflammasomes and pyroptosis in sepsis-induced pathogenesis and organ dysfunction

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: May 19, 2025

Pyroptosis is an inflammatory form of cell death involving caspase-1 or caspase-4/5/11, initiated by inflammasomes cytoplasmic endotoxins as part the immune defense. It specifically characterized Gasdermin-mediated pore formation leading to lysis, pyroptosis also entails release pro-inflammatory cytokines. As a natural mechanism system, it activates in response harmful stimuli eliminate threats and facilitate tissue repair. However, excessive can lead detrimental outcomes, such infectious shock, multiple organ dysfunction syndrome (MODS), increased susceptibility secondary infections. Sepsis, unchecked infection, remains cause MODS among critically ill patients. The pathogenesis sepsis complex multifaceted, innate inflammation that kills infected cells releases Recent research has increasingly explored link between sepsis, focusing on its mechanisms, roles, potential therapeutic targets. There been significant advancement understanding pyroptosis, highlighting vital role development sepsis. This review delves into molecular pathophysiological roles with particular emphasis impact specific organs heart, lungs, liver, kidney brain, aiming identify new diagnostic markers targets for management.

Language: Английский

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Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

Language: Английский

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The Identification of Key Genes and Biological Pathways in Cardiac Arrest by Integrated Bioinformatics and Next Generation Sequencing Data Analysis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Abstract Cardiac arrest (CA) is a common cause of death world wide. The disease has lacks effective treatment. Efforts have been made to elucidate the molecular pathogenesis CA, but mechanisms remain elusive. To identify key genes and pathways in next generation sequencing (NGS) GSE200117 dataset was downloaded from Gene Expression Omnibus (GEO) database. DESeq2 tool used recognize differentially expressed (DEGs). ontology (GO) REACTOME pathway enrichment analyses were performed analyze DEGs associated signal g:Profiler IID database construct protein-protein interaction (PPI) network, modules analysis using Cytoscape. A miRNA-hub gene regulatory network TF-hub then constructed screen miRNAs, TFs hub by miRNet NetworkAnalyst Cityscape software. Receiver operating characteristic curve (ROC) verified genes. In total, 844 identified, comprising 414 up regulated 430 down GO indicated that for CA mainly enriched organonitrogen compound metabolic process, response stimulus, translation immune system. Ten (up-regulated: HSPA8, HOXA1, INCA1 TP53; down-regulated: HSPB1, LMNA, SNCA, ADAMTSL4 PDLIM7) screened. We also predicted miRNAs (hsa-mir-1914-5p hsa-mir-598-3p) (JUN PRRX2) targeting This study uses series bioinformatics technologies obtain hug genes, TFs, related CA. These results provide us with new ideas finding biomarkers treatment methods

Language: Английский

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