Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways

Gandhirajan, Anugraha; Roychowdhury, Sanjoy; Vachharajani, Vidula

doi:10.3390/antiox11010003

Cited by 7 publications

(5 citation statements)

References 204 publications

(262 reference statements)

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“…PKM2-dependent aerobic glycolysis promoted macrophages stimulated by lipopolysaccharide to release HMGB1 and IL-1β ( Xie et al., 2016 ). Numerous studies have indicated that immunosuppression was a factor for increased susceptibility to mortality and secondary infection in sepsis, and most sepsis-mortality occurred in hypo-inflammation ( Gandhirajan et al., 2021 ; Torres et al., 2022 ). Severe depletion of dendritic cells might be used to predict sepsis outcome in the early stage ( Weber et al., 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Classification of subtypes and identification of dysregulated genes in sepsis

Tong,

Ding,

Liu

et al. 2023

Front. Cell. Infect. Microbiol.

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BackgroundSepsis is a clinical syndrome with high mortality. Subtype identification in sepsis is meaningful for improving the diagnosis and treatment of patients. The purpose of this research was to identify subtypes of sepsis using RNA-seq datasets and further explore key genes that were deregulated during the development of sepsis.MethodsThe datasets GSE95233 and GSE13904 were obtained from the Gene Expression Omnibus database. Differential analysis of the gene expression matrix was performed between sepsis patients and healthy controls. Intersection analysis of differentially expressed genes was applied to identify common differentially expressed genes for enrichment analysis and gene set variation analysis. Obvious differential pathways between sepsis patients and healthy controls were identified, as were developmental stages during sepsis. Then, key dysregulated genes were revealed by short time-series analysis and the least absolute shrinkage and selection operator model. In addition, the MCPcounter package was used to assess infiltrating immunocytes. Finally, the dysregulated genes identified were verified using 69 clinical samples.ResultsA total of 898 common differentially expressed genes were obtained, which were chiefly related to increased metabolic responses and decreased immune responses. The two differential pathways (angiogenesis and myc targets v2) were screened on the basis of gene set variation analysis scores. Four subgroups were identified according to median expression of angiogenesis and myc target v2 genes: normal, myc target v2, mixed-quiescent, and angiogenesis. The genes CHPT1, CPEB4, DNAJC3, MAFG, NARF, SNX3, S100A9, S100A12, and METTL9 were recognized as being progressively dysregulated in sepsis. Furthermore, most types of immune cells showed low infiltration in sepsis patients and had a significant correlation with the key genes. Importantly, all nine key genes were highly expressed in sepsis patients.ConclusionThis study revealed novel insight into sepsis subtypes and identified nine dysregulated genes associated with immune status in the development of sepsis. This study provides potential molecular targets for the diagnosis and treatment of sepsis.

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Section: Discussionmentioning

confidence: 99%

Classification of subtypes and identification of dysregulated genes in sepsis

Tong,

Ding,

Liu

et al. 2023

Front. Cell. Infect. Microbiol.

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“…It is capable of histone deacetylation to regulate chromatin function and promote alterations in histone and DNA methylation, leading to transcriptional repression through its anti-inflammatory and antioxidant properties and regulation of the sepsis-induced immune response. 97 Further, metabolic shifts are controlled by AMPK disruption of mTOR-dependent protein synthesis and combined sirtuin 1, 3, and 6 reactions that support catabolic energizers. 98 SIRT1 promotes heterochromatin formation and NF-κB inactivation of key inflammatory genes such as TNF and IL-1β.…”

Section: Immunosuppression Of Sepsismentioning

confidence: 99%

Advances in the Study of Immunosuppressive Mechanisms in Sepsis

Fu,

Liu,

Wang

2023

JIR

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Sepsis is a life-threatening disease caused by a systemic infection that triggers a dysregulated immune response. Sepsis is an important cause of death in intensive care units (ICUs), poses a major threat to human health, and is a common cause of death in ICUs worldwide. The pathogenesis of sepsis is intricate and involves a complex interplay of pro- and anti-inflammatory mechanisms that can lead to excessive inflammation, immunosuppression, and potentially long-term immune disorders. Recent evidence highlights the importance of immunosuppression in sepsis. Immunosuppression is recognized as a predisposing factor for increased susceptibility to secondary infections and mortality in patients. Immunosuppression due to sepsis increases a patient’s chance of re-infection and increases organ load. In addition, antibiotics, fluid resuscitation, and organ support therapy have limited impact on the prognosis of septic patients. Therapeutic approaches by suppressing excessive inflammation have not achieved the desired results in clinical trials. Research into immunosuppression has brought new hope for the treatment of sepsis, and a number of therapeutic approaches have demonstrated the potential of immunostimulatory therapies. In this article, we will focus on the mechanisms of immunosuppression and markers of immune monitoring in sepsis and describe various targets for immunostimulatory therapy in sepsis.

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“…Emerging evidence supports the role of sirtuins (SIRT1-7) in the progression and prognosis of sepsis acting on epigenetic profile [ 39 – 42 ], even if the involvement of SIRT4 in endothelial septic disorder is widely debated. Of note, SIRT4 emerges as a physiological player leading to hypo-inflammation and promoting sepsis recovery [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

MiR-15b-5p and PCSK9 inhibition reduces lipopolysaccharide-induced endothelial dysfunction by targeting SIRT4

et al. 2023

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Background Endothelial dysfunction and deregulated microRNAs (miRNAs) participate in the development of sepsis and are associated with septic organ failure and death. Here, we explored the role of miR-15b-5p on inflammatory pathways in lipopolysaccharide (LPS)-treated human endothelial cells, HUVEC and TeloHAEC. Methods The miR-15b-5p levels were evaluated in LPS-stimulated HUVEC and TeloHAEC cells by quantitative real-time PCR (qRT–PCR). Functional experiments using cell counting kit-8 (CCK-8), transfection with antagomir, and enzyme-linked immunosorbent assays (ELISA) were conducted, along with investigation of pyroptosis, apoptosis, autophagy, and mitochondrial reactive oxygen species (ROS) by cytofluorometric analysis and verified by fluorescence microscopy. Sirtuin 4 (SIRT4) levels were detected by ELISA and immunoblotting, while proprotein convertase subtilisin-kexin type 9 (PCSK9) expression was determined by flow cytometry (FACS) and immunofluorescence analyses. Dual-luciferase reporter evaluation was performed to confirm the miR-15b-5p–SIRT4 interaction. Results The results showed a correlation among miR-15b-5p, PCSK9, and SIRT4 levels in septic HUVEC and TeloHAEC. Inhibition of miR-15b-5p upregulated SIRT4 content, alleviated sepsis-related inflammatory pathways, attenuated mitochondrial stress, and prevented apoptosis, pyroptosis, and autophagic mechanisms. Finally, a PCSK9 inhibitor (i-PCSK9) was used to analyze the involvement of PCSK9 in septic endothelial injury. i-PCSK9 treatment increased SIRT4 protein levels, opposed the septic inflammatory cascade leading to pyroptosis and autophagy, and strengthened the protective role of miR-15b-5p inhibition. Increased luciferase signal validated the miR-15b-5p–SIRT4 binding. Conclusions Our in vitro findings suggested the miR-15b-5p–SIRT4 axis as a suitable target for LPS-induced inflammatory pathways occurring in sepsis, and provide additional knowledge on the beneficial effect of i-PCSK9 in preventing vascular damage by targeting SIRT4. Graphical Abstract

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Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways

Cited by 7 publications

References 204 publications

Classification of subtypes and identification of dysregulated genes in sepsis

Classification of subtypes and identification of dysregulated genes in sepsis

Advances in the Study of Immunosuppressive Mechanisms in Sepsis

MiR-15b-5p and PCSK9 inhibition reduces lipopolysaccharide-induced endothelial dysfunction by targeting SIRT4

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