S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(6)

Published: June 28, 2024

Abstract S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in variety inflammatory diseases. Although S100a8/a9 has been reported trigger endothelial cell apoptosis, mechanisms S100a8/a9-induced dysfunction during sepsis require in-depth research. We demonstrate that high expression levels suppress Ndufa3 mitochondrial complex I via downregulation Nrf1 expression. Mitochondrial deficiency contributes NAD + -dependent Sirt1 suppression, which induces disorders, including excessive fission blocked mitophagy, mtDNA from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis cells. Moreover, based on comprehensive scRNA-seq bulk RNA-seq analyses, S100A8/A9 hi are closely associated with circulating count (a useful marker damage), S100A8 is an independent risk factor for poor prognosis patients.

Language: Английский

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Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 12, 2025

Abstract Disruption of nicotinamide adenine dinucleotide (NAD) biosynthesis and function during infection may impair host defenses aggravate inflammatory oxidative organ injury. Increasingly, studies are investigating whether niacin or NAD metabolite treatment is beneficial in sepsis animal models. We examined this preclinical experience supports clinical trials. A systematic review three data bases was conducted through 2/29/2024 a meta-analysis performed comparing to control adult models employing microbial challenges. Fifty-six met inclusion criteria, with 24 published after 2019. Most employed mouse (n = 40 studies) rat 12) administered either bacterial toxin 28) 19) challenge. Four viral fungal challenges respectively. Studies investigated an alone 44), 9), both 3), usually before within 24h challenge 50). Only four included standard antimicrobial support started > In similar patterns differing types (p ≥ 0.06), compared across those the parameter, decreased odds ratio mortality [95% confidence interval (CI)] [0.28 (0.17, 0.49)] blood tissue increased antioxidant levels [standardized mean differences (95%CI)] (SMD) [3.61 (2.20,5.02)] microbes [− 2.44 (− 3.34, − 1.55)], histologic permeability injury scoring 1.62 2.27, 0.98) 1.31(− 1.77, 0.86) respectively], TNFα, IL-6 IL-1β 2.47 3.30, 1.64), 3.17 4.74, 1.60) 8.44 12.4, 4.5) respectively] myeloperoxidase (MPO) 1.60 2.06, 1.14)], although significant, primarily quantitative heterogeneity for each (I 2 53%, p < 0.01) except MPO. Treatment + chemical measures oxidation markers but differently species ≤ 0.05). 9 survival described power analyses randomization respectively no study non-histologic outcome measure blinding. Among studies, Egger’s analysis 0.002) suggested publication bias. While suggestive, do not yet trials testing sepsis. Animal simulating conditions randomized, blinded designs needed investigate potentially promising therapeutic approach.

Language: Английский

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Supplementing Boar Diet with Nicotinamide Mononucleotide Improves Sperm Quality Probably through the Activation of the SIRT3 Signaling Pathway

Antioxidants, Journal Year: 2024, Volume and Issue: 13(5), P. 507 - 507

Published: April 24, 2024

Sperm quality is an important indicator to evaluate the reproduction ability of animals. Nicotinamide mononucleotide (NMN) participates in cell energy metabolism and reduces oxidative stress. However, effect regulatory mechanism NMN on porcine sperm are still unknown. Here, 32 Landrace boars were randomly assigned four groups (n = 8) fed with different levels (0, 8, 16 or mg/kg/d) for 9 weeks, then serum semen samples collected investigate function molecular quality. The results showed that dietary supplementation significantly increased volume, density motility (p < 0.05). Interestingly, apparently improved antioxidative indexes testosterone 0.05) serum. Furthermore, upregulated protein sirtuin 3 (SIRT3), antioxidation phosphorylation (OXPHOS), but downregulated apoptosis semen. Mechanically, protected from H2O2-induced stress through SIRT3 deacetylation. Importantly, SIRT3-specific inhibitor 3-TYP attenuated antiapoptosis sperm. Therefore, exerts improve boar via signaling pathway. Our findings suggest a novel potential feed additive produce high-quality

Language: Английский

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The Role of Nicotinamide Mononucleotide Supplementation in Psoriasis Treatment

Antioxidants, Journal Year: 2024, Volume and Issue: 13(2), P. 186 - 186

Published: Feb. 1, 2024

Psoriasis is one of several chronic inflammatory skin diseases with a high rate recurrence, and its pathogenesis remains unclear. Nicotinamide mononucleotide (NMN), as an important precursor nicotinamide adenine dinucleotide (NAD+), has been reported to be promising agent in treating various diseases, positive effects including those induced via anti-inflammatory antioxidant properties. For this reason, we have aimed explore the possible role NMN treatment psoriasis. models were constructed imiquimod (IMQ) stimulation for 5 days vivo M5 keratinocyte cell lines vitro. during IMQ application period markedly attenuated excess epidermal proliferation, splenomegaly, responses. According GEO databases, Sirtuin1 (SIRT1) levels significantly decreased psoriasis patients’ lesion tissues; was also case IMQ-treated mice, while reversed SIRT1 decline mouse model. Moreover, supplementation improved prognoses mice after stimulation, compared untreated group elevated levels. In HEKa HaCaT cells, co-culturing expression proinflammation factors, phosphorylation NF-κB, stimulator interferon genes (STING) levels, reactive oxygen species recovered decrease mitochondrial membrane potential respiration ability reduced mtDNA cytoplasm, leading inhibition autoimmune inflammation. The knockdown vitro eliminated protective therapeutic against M5. To conclude, our results indicate that protects IMQ-induced psoriatic inflammation, oxidative stress, dysfunction by activating pathway.

Language: Английский

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Advancements in NMN biotherapy and research updates in the field of digestive system diseases

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Aug. 30, 2024

Nicotinamide mononucleotide (NMN), a crucial intermediate in NAD + synthesis, can rapidly transform into within the body after ingestion. NMN plays pivotal role several important biological processes, including energy metabolism, cellular aging, circadian rhythm regulation, DNA repair, chromatin remodeling, immunity, and inflammation. has emerged as key focus of research fields biomedicine, health care, food science. Recent years have witnessed extensive preclinical studies on NMN, offering valuable insights pathogenesis age- aging-related diseases. Given sustained global interest substantial market expectations for future, here, we comprehensively review milestones biotherapy over past 10 years. Additionally, highlight current field digestive system diseases, identifying existing problems challenges research. The overarching aim this is to provide references further exploration spectrum

Language: Английский

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Nicotinamide mononucleotide as a therapeutic agent to alleviate multi-organ failure in sepsis

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Dec. 6, 2023

Abstract Background Sepsis-caused multi-organ failure remains the major cause of morbidity and mortality in intensive care units with limited therapeutics. Nicotinamide mononucleotide (NMN), a precursor nicotinamide adenine dinucleotide (NAD + ), has been recently reported to be protective sepsis; however, its therapeutic effects remain determined. This study sought investigate NMN septic organ underlying mechanisms. Methods Sepsis was induced by feces-injection-in-peritoneum mice. given after an hour sepsis onset. Cultured neutrophils, macrophages endothelial cells were incubated various agents. Results We demonstrate that administration elevated NAD levels reduced serum lactate levels, oxidative stress, inflammation, caspase-3 activity multiple organs mice, which correlated attenuation heart dysfunction, pulmonary microvascular permeability, liver injury, kidney leading lower mortality. The associated bacterial burden blood, less ROS production improved phagocytosis bactericidal neutrophils while reducing lipopolysaccharides-induced inflammatory response macrophages. In cultured cells, mitigated mitochondrial apoptosis, barrier dysfunction conditions, all offset SIRT3 inhibition. Conclusion repletion prevents restrains dissemination limiting damage through signaling sepsis. Thus, may represent option for

Language: Английский

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The role and therapeutic potential of SIRTs in sepsis

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 16, 2024

Sepsis is a life-threatening organ dysfunction caused by the host’s dysfunctional response to infection. Abnormal activation of immune system and disturbance energy metabolism play key role in development sepsis. In recent years, Sirtuins (SIRTs) family has been found an important pathogenesis SIRTs, as class histone deacetylases (HDACs), are widely involved cellular inflammation regulation, oxidative stress. The effects SIRTs on cells mainly reflected regulation inflammatory pathways. This helps balance may lessen cell damage terms metabolism, can immunophenotypic transformation regulating improve mitochondrial function, increase production, maintain balance. also regulate production reactive oxygen species (ROS), protecting from stress activating antioxidant defense pathways maintaining between oxidants reducing agents. Current studies have shown that several potential drugs, such Resveratrol melatonin, enhance activity SIRT. It help reduce response, stress, showing clinical application prospects for treatment review focuses SIRT cells, well its influence multiple sepsis, discusses summarizes related drugs compounds sepsis through pathway involving SIRTs. become new target resulting dysfunction, providing ideas possibilities this disease.

Language: Английский

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N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABA _B R1 mRNA in sepsis-associated encephalopathy

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(36)

Published: Aug. 27, 2024

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents crucial factor contributing to high mortality adverse prognosis in septic patients. This study explored the contribution NAT10-mediated messenger RNA (mRNA) acetylation cognitive dysfunction associated with SAE, utilizing cecal ligation puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression mRNA excitatory neurons hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved function mice, highlighting its role SAE. Proteomic analysis, immunoprecipitation, real-time qPCR identified GABA B R1 as key downstream target NAT10. deletion reduced expression, subsequently weakened inhibitory postsynaptic currents DG neurons. Further analysis revealed microglia activation release inflammatory mediators lead increased Microglia depletion PLX3397 effectively neurons, ameliorated induced by In summary, our after CLP, promotes through acetylation, leading dysfunction.

Language: Английский

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Hydrogen-rich saline regulates NLRP3 inflammasome activation in sepsis-associated encephalopathy rat model

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 123, P. 110758 - 110758

Published: Aug. 8, 2023

Sepsis-associated encephalopathy (SAE) is characterised by long-term cognitive impairment and psychiatric illness in sepsis survivors, associated with increased morbidity mortality. There a lack of effective therapeutics for SAE. Molecular hydrogen (H2) plays multiple roles septic diseases regulating neuroinflammation, reducing oxidative stress parameters, signalling pathways, improving mitochondrial dysfunction, astrocyte microglia activation. Here we report the protective effect hydrogen-rich saline juvenile SAE rat model its possible underlying mechanisms. Rats were injected intraperitoneally lipopolysaccharide at dose 5 mg/kg to induce sepsis; Hydrogen-rich (HRS) was administered 1 h after LPS induction ml/kg nigericin before injection. H&E staining neuronal damage, TUNEL assay detection apoptotic cells, immunofluorescence, ELISA protocol inflammatory cytokines 8-OHdG determination western blot analysis determine HRS LPS-induced rats. treated showed decreased TNF-α IL-1β expression levels. treatment enhanced activities antioxidant enzymes (SOD, CAT GPX) MDA MPO activities. The number MMP-9 NLRP3 positive immunoreactivity cells HRS-treated group. Subsequently, GFAP, IBA-1 CD86 reduced, CD206 treatment. Western NLRP3, ASC, caspase-1, MMP-2/9, TLR4 Bax protein levels treatment, while Bcl-2 These data demonstrated that attenuated inflammasome activation, injury, damage via NLRP3/Caspase-1/TLR4 model, making it potential therapeutic agent paediatric

Language: Английский

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NHH promotes Sepsis-associated Encephalopathy with the expression of AQP4 in astrocytes through the gut-brain Axis

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: May 27, 2024

Abstract Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact remains unclear. Our previous research indicated relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the NHH SAE potential mechanisms causing cognitive impairment. In vivo experimental results, there were no abnormalities livers mice moderate cecal ligation perforation (CLP); however, ammonia levels elevated hippocampal tissue serum. The ELISA suggest that fecal microbiota transplantation CLP can reduce levels. Reduction improved dysfunction neurological impairment through behavioral, neuroimaging, molecular biology studies. Further studies have shown enters brain regulate expression aquaporins-4 (AQP4) astrocytes, which may be mechanism underlying mice. results vitro experiments showed up-regulated AQP4 resulting astrocyte damage. this up-regulates gut-brain axis, for occurrence

Language: Английский

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