The ERK-p38MAPK-STAT3 Signalling Axis Regulates iNOS Expression and Salmonella Infection in Senescent Cells

Fernandes, Sheryl Erica; Saini, Deepak Kumar

doi:10.3389/fcimb.2021.744013

Cited by 7 publications

(8 citation statements)

References 63 publications

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“…Fernandes et al. also demonstrated that MAP kinase/ERK rewired in senescent cells rendering them phenotypically different ( 65 ). Furthermore, studies implied that MAPK influenced cell survival in the endometrium ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the endometrial immune landscape of RIF during the window of implantation from cellular senescence by integrated bioinformatics analysis and machine learning

Zhao

Zhao²,

Jiang³

et al. 2022

Front. Immunol.

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Recurrent implantation failure (RIF) is an extremely thorny issue in in-vitro fertilization (IVF)-embryo transfer (ET). However, its intricate etiology and pathological mechanisms are still unclear. Nowadays, there has been extensive interest in cellular senescence in RIF, and its involvement in endometrial immune characteristics during the window of implantation (WOI) has captured scholars’ growing concerns. Therefore, this study aims to probe into the pathological mechanism of RIF from cellular senescence and investigate the correlation between cellular senescence and endometrial immune characteristics during WOI based on bioinformatics combined with machine learning strategy, so as to elucidate the underlying pathological mechanisms of RIF and to explore novel treatment strategies for RIF. Firstly, the gene sets of GSE26787 and GSE111974 from the Gene Expression Omnibus (GEO) database were included for the weighted gene correlation network analysis (WGCNA), from which we concluded that the genes of the core module were closely related to cell fate decision and immune regulation. Subsequently, we identified 25 cellular senescence-associated differentially expressed genes (DEGs) in RIF by intersecting DEGs with cellular senescence-associated genes from the Cell Senescence (CellAge) database. Moreover, functional enrichment analysis was conducted to further reveal the specific molecular mechanisms by which these molecules regulate cellular senescence and immune pathways. Then, eight signature genes were determined by the machine learning method of support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and artificial neural network (ANN), comprising LATS1, EHF, DUSP16, ADCK5, PATZ1, DEK, MAP2K1, and ETS2, which were also validated in the testing gene set (GSE106602). Furthermore, distinct immune microenvironment abnormalities in the RIF endometrium during WOI were comprehensively explored and validated in GSE106602, including infiltrating immunocytes, immune function, and the expression profiling of human leukocyte antigen (HLA) genes and immune checkpoint genes. Moreover, the correlation between the eight signature genes with the endometrial immune landscape of RIF was also evaluated. After that, two distinct subtypes with significantly distinct immune infiltration characteristics were identified by consensus clustering analysis based on the eight signature genes. Finally, a “KEGG pathway–RIF signature genes–immune landscape” association network was constructed to intuitively uncover their connection. In conclusion, this study demonstrated that cellular senescence might play a pushing role in the pathological mechanism of RIF, which might be closely related to its impact on the immune microenvironment during the WOI phase. The exploration of the molecular mechanism of cellular senescence in RIF is expected to bring new breakthroughs for disease diagnosis and treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Deciphering the endometrial immune landscape of RIF during the window of implantation from cellular senescence by integrated bioinformatics analysis and machine learning

Zhao

Zhao²,

Jiang³

et al. 2022

Front. Immunol.

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“…Nitric Oxide (NO) is one of the key anti‐bacterial free radicals generated enzymatically by inducible nitric oxide synthetase, whose levels increase in response to an infection (Nathan & Hibbs, 1991) as well as naturally during aging (Donato et al, 2007). It was also recently shown that in aged cells and animals, the bacterial burden can be controlled naturally by elevated free radicals, primarily nitric oxide or NO (Fernandes & Saini, 2021), thereby demonstrating that free radicals in the aged tissue microenvironment function as a protective barrier to infection.…”

Section: Aging and Oxidative Stressmentioning

confidence: 99%

“…Enhanced inflammation in the elderly also results in higher tissue injury and impairment of the immune system, further accelerating aging (Weyand & Goronzy, 2016). Recently, it was also shown that for many intracellular pathogens, reactive free radicals (RNS specifically) strengthen inflammatory and defense responses as they can limit the intracellular proliferation of bacterial cells probably by causing mutagenic DNA damage (Fernandes & Saini, 2021). In this article, we highlight the importance of examining and understanding the link between increased lifespan, age‐associated diseases, and the emergence of AMR.…”

Section: Introductionmentioning

confidence: 99%

Anti‐microbial resistance and aging—A design for evolution

Nepalia

Fernandes

Singh

et al. 2023

WIREs Mechanisms of Disease

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The emergence of resistance to anti‐infective agents poses a significant threat to successfully treating infections caused by bacteria. Bacteria acquire random mutations due to exposure to environmental stresses, which may increase their fitness to other selection pressures. Interestingly, for bacteria, the frequency of anti‐microbial resistance (AMR) seems to be increasing in tandem with the human lifespan. Based on evidence from previous literature, we speculate that increased levels of free radicals (Reactive Oxygen Species‐ROS and Reactive Nitrosative Species‐RNS), elevated inflammation, and the altered tissue microenvironment in aged individuals may drive pathogen mutagenesis. If these mutations result in the hyperactivation of efflux pumps or alteration in drug target binding sites, it could confer AMR, thus rendering antibiotic therapy ineffective while leading to the selection of novel drug‐resistant variants.This article is categorized under: Immune System Diseases > Genetics/Genomics/Epigenetics Infectious Diseases > Environmental Factors Metabolic Diseases > Environmental Factors

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“…Control of SASP expression through the enhanced translation of MAPK-activated protein kinase 2 (MAPKAPK2 or MK2) has also been reported ( 34 , 35 ). MK2 kinase is also activated upon stress through the activation of p38 mitogen-activated protein kinases (p38MAPK) and this promotes the activation of NF-κB ( 36 , 37 ). Tumor necrosis factor (TNF)-α induces phosphorylation of AK kinase, resulting in signal transducers and activators of transcription 3 (STAT3) phosphorylation that translocate to the nucleus, contributing to persistent NF-κB activation and enhanced SASP expression ( 36 ) also promoted by the PI3k/Akt pathway.…”

Section: Introductionmentioning

confidence: 99%

Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging – from theory to practice

et al. 2022

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Aging is a natural physiological process, but one that poses major challenges in an increasingly aging society prone to greater health risks such as diabetes, cardiovascular disease, cancer, frailty, increased susceptibility to infection, and reduced response to vaccine regimens. The loss of capacity for cell regeneration and the surrounding tissue microenvironment itself is conditioned by genetic, metabolic, and even environmental factors, such as nutrition. The senescence of the immune system (immunosenescence) represents a challenge, especially when associated with the presence of age-related chronic inflammation (inflammaging) and affecting the metabolic programming of immune cells (immunometabolism). These aspects are linked to poorer health outcomes and therefore present an opportunity for host-directed interventions aimed at both eliminating senescent cells and curbing the underlying inflammation. Senotherapeutics are a class of drugs and natural products that delay, prevent, or reverse the senescence process – senolytics; or inhibit senescence-associated secretory phenotype – senomorphics. Natural senotherapeutics from food sources – nutritional senotherapeutics – may constitute an interesting way to achieve better age-associated outcomes through personalized nutrition. In this sense, the authors present herein a framework of nutritional senotherapeutics as an intervention targeting immunosenescence and immunometabolism, identifying research gaps in this area, and gathering information on concluded and ongoing clinical trials on this subject. Also, we present future directions and ideation for future clinical possibilities in this field.

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The ERK-p38MAPK-STAT3 Signalling Axis Regulates iNOS Expression and Salmonella Infection in Senescent Cells

Cited by 7 publications

References 63 publications

Deciphering the endometrial immune landscape of RIF during the window of implantation from cellular senescence by integrated bioinformatics analysis and machine learning

Deciphering the endometrial immune landscape of RIF during the window of implantation from cellular senescence by integrated bioinformatics analysis and machine learning

Anti‐microbial resistance and aging—A design for evolution

Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging – from theory to practice

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