Mechanisms of Ataxia Telangiectasia Mutated (ATM) Control in the DNA Damage Response to Oxidative Stress, Epigenetic Regulation, and Persistent Innate Immune Suppression Following Sepsis

Huff, Laura A; Shan, Yan Shen; Clemens, Mark G.

doi:10.3390/antiox10071146

Cited by 9 publications

(4 citation statements)

References 144 publications

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“…The results of GO, KEGG, and Reactome enrichment analysis revealed that the immune response may be closely connected with the severity of sepsis. Therefore, we speculated that the interaction of immune response with autophagy, VEGF, oxidative stress, and metabolic pathways may be the major factor leading to the progression of sepsis (Minion and Tewari, 2018;Yin et al, 2019;McBride et al, 2020;Huff et al, 2021). These results, combined with our findings, indicate that these differentially activated pathways could develop potential therapeutic targets for sepsis patients with distinctive molecular subtypes.…”

Section: Discussionsupporting

confidence: 62%

Comprehensive Analysis of Molecular Subtypes and Hub Genes of Sepsis by Gene Expression Profiles

Lai

Lin²,

Lin³

et al. 2022

Front. Genet.

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Background: Sepsis is a systemic inflammatory response syndrome (SIRS) with heterogeneity of clinical symptoms. Studies further exploring the molecular subtypes of sepsis and elucidating its probable mechanisms are urgently needed.Methods: Microarray datasets of peripheral blood in sepsis were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) analysis was conducted to screen key module genes. Consensus clustering analysis was carried out to identify distinct sepsis molecular subtypes. Subtype-specific pathways were explored using gene set variation analysis (GSVA). Afterward, we intersected subtype-related, dramatically expressed and module-specific genes to screen consensus DEGs (co-DEGs). Enrichment analysis was carried out to identify key pathways. The least absolute shrinkage and selection operator (LASSO) regression analysis was used for screen potential diagnostic biomarkers.Results: Patients with sepsis were classified into three clusters. GSVA showed these DEGs among different clusters in sepsis were assigned to metabolism, oxidative phosphorylation, autophagy regulation, and VEGF pathways, etc. In addition, we identified 40 co-DEGs and several dysregulated pathways. A diagnostic model with 25-gene signature was proven to be of high value for the diagnosis of sepsis. Genes in the diagnostic model with AUC values more than 0.95 in external datasets were screened as key genes for the diagnosis of sepsis. Finally, ANKRD22, GPR84, GYG1, BLOC1S1, CARD11, NOG, and LRG1 were recognized as critical genes associated with sepsis molecular subtypes.Conclusion: There are remarkable differences in and enriched pathways among different molecular subgroups of sepsis, which may be the key factors leading to heterogeneity of clinical symptoms and prognosis in patients with sepsis. Our current study provides novel diagnostic and therapeutic biomarkers for sepsis molecular subtypes.

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Section: Discussionsupporting

confidence: 62%

Comprehensive Analysis of Molecular Subtypes and Hub Genes of Sepsis by Gene Expression Profiles

Lai

Lin²,

Lin³

et al. 2022

Front. Genet.

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“…This is surprising because we previously reported that mutation of tp53 has an opposite effect [ 38 ]. We thus investigated the non-canonical role of Atm in sensing and mitigating oxidative stress [ 14 , 18 , 57 ], and the data we present here suggests that this function, instead of its canonical role in the DDR, interacts with hUHRF1 overexpression, and paradoxically this role increases the survival or expansion of hUHRF1 overexpressing hepatocytes. In support of this, our data show that oxidative stress also enhances the small liver phenotype of hUHRF1 transgenics and that antioxidant treatment partially rescued this phenotype.…”

Section: Discussionmentioning

confidence: 99%

atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers

Ajouaou

Magnani

Madakashira

et al. 2023

Cancers

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The ataxia-telangiectasia mutated (atm) gene is activated in response to genotoxic stress and leads to activation of the tp53 tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in tp53-dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of atm on UHRF1-mediated phenotypes by generating zebrafish atm mutants. atm−/− adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or H2O2 exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, atm mutation and exposure to H2O2 further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of atm further enhances this, triggering elimination of these precancerous cells, leading to a small liver.

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“…Oxygen radicals can trigger lipid peroxidation, producing large amounts of reactive oxygen (ROS) and reactive nitrogen species (RNS), causing severe damage to mitochondria in hepatocytes and inducing apoptosis or necrosis in hepatocytes, eventually leading to liver injury or even failure. [59][60][61] Therefore, antioxidant therapy can be one of the strategies for the treatment of SRLI. Melatonin (Mel) is a multifunctional hormone with strong antioxidant effects, and some studies have shown that systemic administration of free Mel could reduce sepsis-induced tissue damage.…”

Section: Hepatic Oxidative Stressmentioning

confidence: 99%

An Overview of Drug Delivery Nanosystems for Sepsis-Related Liver Injury Treatment

Lu¹,

Shi²,

Wu³

et al. 2023

IJN

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Sepsis, which is a systemic inflammatory response syndrome caused by infection, has high morbidity and mortality. Sepsis-related liver injury is one of the manifestations of sepsis-induced multiple organ syndrome. To date, an increasing number of studies have shown that the hepatic inflammatory response, oxidative stress, microcirculation coagulation dysfunction, and bacterial translocation play extremely vital roles in the occurrence and development of sepsis-related liver injury. In the clinic, sepsis-related liver injury is mainly treated by routine empirical methods on the basis of the primary disease. However, these therapies have some shortcomings, such as serious side effects, short duration of drug effects and lack of specificity. The emergence of drug delivery nanosystems can significantly improve drug bioavailability and reduce toxic side effects. In this paper, we reviewed drug delivery nanosystems designed for the treatment of sepsis-related liver injury according to their mechanisms (hepatic inflammation response, oxidative stress, coagulation dysfunction in the microcirculation, and bacterial translocation). Although much promising progress has been achieved, translation into clinical practice is still difficult. To this end, we also discussed the key issues currently facing this field, including immune system rejection and single treatment modalities. Finally, with the rigorous optimization of nanotechnology and the deepening of research, drug delivery nanosystems have great potential for the treatment of sepsis-related liver injury.

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Mechanisms of Ataxia Telangiectasia Mutated (ATM) Control in the DNA Damage Response to Oxidative Stress, Epigenetic Regulation, and Persistent Innate Immune Suppression Following Sepsis

Cited by 9 publications

References 144 publications

Comprehensive Analysis of Molecular Subtypes and Hub Genes of Sepsis by Gene Expression Profiles

Comprehensive Analysis of Molecular Subtypes and Hub Genes of Sepsis by Gene Expression Profiles

atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers

An Overview of Drug Delivery Nanosystems for Sepsis-Related Liver Injury Treatment

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