Special Issue "Molecular Mechanism of Stress, Stress Response, and Adaptation"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (5 January 2023) | Viewed by 17770

Special Issue Editor

Prof. Dr. Michitaka Ozaki
E-Mail Website
Guest Editor
Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan
Interests: oxidative stress; ischemia/reperfusion(hypoxia/reoxygenation)-induced injury; programmed cell death; redox signaling; optogenetics

Special Issue Information

Dear Colleagues, 

Stress is an unavoidable event in a living body. Moderate stress is necessary in many physiological events such as development, growth, and aging (differentiation, proliferation, and cell death at cellular level, respectively). However, excessive stress may cause various kinds of pathological conditions, including inflammation, degeneration, and cancer. Cells or organs try to survive with clever and delicate mechanisms, sometimes by responding to and sometimes by adapting to excessive stresses. By contrast, cells or organs will respectively respond to stress by dying or falling into dysfunction. Very smartly, cells or organs suffering from properly managed, nonlethal stress will learn how to withstand stress and prepare for lethal stress coming in the near future.

This Special Issue will focus especially on stress “response” and “adaptation” in excessively stressed cells/organs, including basic response (differentiation, proliferation, growth, programmed death, etc.) at the cellular level and adaptive response (preconditioning, regeneration, degeneration, etc.) at the organ level. Studies on the pathogenesis and prevention of various stress-associated diseases at the cellular/molecular levels are also welcome. 

Prof. Dr. Michitaka Ozaki
Guest Editor

Manuscript Submission Information

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Keywords

  • cell proliferation
  • cell growth, programmed cell death
  • preconditioning
  • sterile inflammation
  • oxidative stress
  • hypoxia (ischemia)
  • reoxygenation (reperfusion), metabolic stress
  • heat stress
  • ER stress
  • osmotic stress
  • mechanical stress

Published Papers (17 papers)

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Research

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Article
Renal Ischemia Tolerance Mediated by eIF5A Hypusination Inhibition Is Regulated by a Specific Modulation of the Endoplasmic Reticulum Stress
Cells 2023, 12(3), 409; https://doi.org/10.3390/cells12030409 - 25 Jan 2023
Viewed by 225
Abstract
Through kidney transplantation, ischemia/reperfusion is known to induce tissular injury due to cell energy shortage, oxidative stress, and endoplasmic reticulum (ER) stress. ER stress stems from an accumulation of unfolded or misfolded proteins in the lumen of ER, resulting in the unfolded protein [...] Read more.
Through kidney transplantation, ischemia/reperfusion is known to induce tissular injury due to cell energy shortage, oxidative stress, and endoplasmic reticulum (ER) stress. ER stress stems from an accumulation of unfolded or misfolded proteins in the lumen of ER, resulting in the unfolded protein response (UPR). Adaptive UPR pathways can either restore protein homeostasis or can turn into a stress pathway leading to apoptosis. We have demonstrated that N1-guanyl-1,7-diamineoheptane (GC7), a specific inhibitor of eukaryotic Initiation Factor 5A (eIF5A) hypusination, confers an ischemic protection of kidney cells by tuning their metabolism and decreasing oxidative stress, but its role on ER stress was unknown. To explore this, we used kidney cells pretreated with GC7 and submitted to either warm or cold anoxia. GC7 pretreatment promoted cell survival in an anoxic environment concomitantly to an increase in xbp1 splicing and BiP level while eiF2α phosphorylation and ATF6 nuclear level decreased. These demonstrated a specific modulation of UPR pathways. Interestingly, the pharmacological inhibition of xbp1 splicing reversed the protective effect of GC7 against anoxia. Our results demonstrated that eIF5A hypusination inhibition modulates distinctive UPR pathways, a crucial mechanism for the protection against anoxia/reoxygenation. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
NEK6 Regulates Redox Balance and DNA Damage Response in DU-145 Prostate Cancer Cells
Cells 2023, 12(2), 256; https://doi.org/10.3390/cells12020256 - 07 Jan 2023
Viewed by 606
Abstract
NEK6 is a central kinase in developing castration-resistant prostate cancer (CRPC). However, the pathways regulated by NEK6 in CRPC are still unclear. Cancer cells have high reactive oxygen species (ROS) levels and easily adapt to this circumstance and avoid cell death by increasing [...] Read more.
NEK6 is a central kinase in developing castration-resistant prostate cancer (CRPC). However, the pathways regulated by NEK6 in CRPC are still unclear. Cancer cells have high reactive oxygen species (ROS) levels and easily adapt to this circumstance and avoid cell death by increasing antioxidant defenses. We knocked out the NEK6 gene and evaluated the redox state and DNA damage response in DU-145 cells. The knockout of NEK6 decreases the clonogenic capacity, proliferation, cell viability, and mitochondrial activity. Targeting the NEK6 gene increases the level of intracellular ROS; decreases the expression of antioxidant defenses (SOD1, SOD2, and PRDX3); increases JNK phosphorylation, a stress-responsive kinase; and increases DNA damage markers (p-ATM and γH2AX). The exogenous overexpression of NEK6 also increases the expression of these same antioxidant defenses and decreases γH2AX. The depletion of NEK6 also induces cell death by apoptosis and reduces the antiapoptotic Bcl-2 protein. NEK6-lacking cells have more sensitivity to cisplatin. Additionally, NEK6 regulates the nuclear localization of NF-κB2, suggesting NEK6 may regulate NF-κB2 activity. Therefore, NEK6 alters the redox balance, regulates the expression of antioxidant proteins and DNA damage, and its absence induces the death of DU-145 cells. NEK6 inhibition may be a new strategy for CRPC therapy. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
Systematic Interrogation of the Temperature Perturbation in the Insulin Signaling Pathway for Optogenetic Stimulation
Cells 2022, 11(19), 3136; https://doi.org/10.3390/cells11193136 - 05 Oct 2022
Viewed by 685
Abstract
The application of NIR to optogenetic systems is in great demand due to its superior properties enabling in vivo deep tissue penetration. Irradiation of NIR to tissue samples or cells rapidly generates heat locally. The resultant elevation in temperature affects cells at the [...] Read more.
The application of NIR to optogenetic systems is in great demand due to its superior properties enabling in vivo deep tissue penetration. Irradiation of NIR to tissue samples or cells rapidly generates heat locally. The resultant elevation in temperature affects cells at the molecular level because of the activation of the heat shock pathway and ROS generation. Nevertheless, few reports have presented detailed comparisons of the effects of the temperature change rate on signaling pathway biomolecules, especially those of rapid heat changes. Aiming at broadening the understanding of temperature sensitivity, we investigated seven insulin signaling pathway biomolecules (INSR, IRS1, Akt, GSK3β, p70S6K, FoxO1, and ERK1/2) in three cell lines (C2C12, HepG2, and Fao) at temperatures between 25 and 45 °C. The results show that, except for INSR, pAkt(T308), and FoxO1, biomolecules are sensitive to rapid temperature changes at temperatures higher than 42 °C, at which they are significantly phosphorylated. At 25 °C, around a 50% reduction in phosphorylation occurred. Moreover, p70S6K is sensitive over time. It dephosphorylates quickly (5 min) and then phosphorylates over time. Our findings extend the temperature range to 45 °C, while providing additional time course information about the signaling pathway biomolecule response necessary to advance NIR optogenetic research. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
Mechanical Stretch Induced Osteogenesis on Human Annulus Fibrosus Cells through Upregulation of BMP-2/6 Heterodimer and Activation of P38 and SMAD1/5/8 Signaling Pathways
Cells 2022, 11(16), 2600; https://doi.org/10.3390/cells11162600 - 20 Aug 2022
Cited by 1 | Viewed by 928
Abstract
Degenerative disc disease (DDD) is an important cause of low back pain. Repetitive tensile stress from the daily motion of the spine predisposes it to injury of the annulus fibrosus (AF) which causes IVD degeneration. This study aims to determine the causal relationship [...] Read more.
Degenerative disc disease (DDD) is an important cause of low back pain. Repetitive tensile stress from the daily motion of the spine predisposes it to injury of the annulus fibrosus (AF) which causes IVD degeneration. This study aims to determine the causal relationship between mechanical stretch and osteogenesis in the AF cells of IVD as affected by bone morphogenic proteins (BMPs), specifically BMP-2/6 heterodimers. Our results found that 15% tensile stress (high cyclic stretching, HCS) may induce the expression of osteogenesis-related markers (Runx2, osterix) by upregulating BMP-2/6 heterodimeric ligands and their receptors on the human AF cell line. HCS also induced transient phosphorylation of p38 mitogen-activated protein (MAP) kinase and SMAD1/5/8. Neutralizing antibodies to the BMP-2/6 receptor (ALK3) blocked the expression of Runx2 and osterix, as well as the phosphorylation of p38 and SMAD1/5/8. In addition, treatment with a p38 MAPK inhibitor (SB203580) or siRNA to neutralize the effects of SMAD1/5/8 suppressed tensile stress-induced Runx2 and osterix expression. Mechanical stretching induces activation of p38 MAP kinase and SMAD1/5/8 signaling pathways, followed by the upregulation of BMP-2/6 heterodimer expression, thereby stimulating osteogenic Runx2 and osterix expression on AF cells. HCS may accelerate the progression of IVD degeneration by promoting an osteogenic response. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
HSF1 Can Prevent Inflammation following Heat Shock by Inhibiting the Excessive Activation of the ATF3 and JUN&FOS Genes
Cells 2022, 11(16), 2510; https://doi.org/10.3390/cells11162510 - 12 Aug 2022
Cited by 1 | Viewed by 1348
Abstract
Heat Shock Factor 1 (HSF1), a transcription factor frequently overexpressed in cancer, is activated by proteotoxic agents and participates in the regulation of cellular stress response. To investigate how HSF1 level affects the response to proteotoxic stress, we integrated data from functional genomics [...] Read more.
Heat Shock Factor 1 (HSF1), a transcription factor frequently overexpressed in cancer, is activated by proteotoxic agents and participates in the regulation of cellular stress response. To investigate how HSF1 level affects the response to proteotoxic stress, we integrated data from functional genomics analyses performed in MCF7 breast adenocarcinoma cells. Although the general transcriptional response to heat shock was impaired due to HSF1 deficiency (mainly chaperone expression was inhibited), a set of genes was identified, including ATF3 and certain FOS and JUN family members, whose stress-induced activation was stronger and persisted longer than in cells with normal HSF1 levels. These genes were direct HSF1 targets, suggesting a dual (activatory/suppressory) role for HSF1. Moreover, we found that heat shock-induced inflammatory response could be stronger in HSF1-deficient cells. Analyses of The Cancer Genome Atlas data indicated that higher ATF3, FOS, and FOSB expression levels correlated with low HSF1 levels in estrogen receptor-positive breast cancer, reflecting higher heat shock-induced expression of these genes in HSF1-deficient MCF7 cells observed in vitro. However, differences between the analyzed cancer types were noted in the regulation of HSF1-dependent genes, indicating the presence of cell-type-specific mechanisms. Nevertheless, our data indicate the existence of the heat shock-induced network of transcription factors (associated with the activation of TNFα signaling) which includes HSF1. Independent of its chaperone-mediated cytoprotective function, HSF1 may be involved in the regulation of this network but prevents its overactivation in some cells during stress. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
Deltamethrin-Evoked ER Stress Promotes Neuroinflammation in the Adult Mouse Hippocampus
Cells 2022, 11(12), 1961; https://doi.org/10.3390/cells11121961 - 18 Jun 2022
Cited by 2 | Viewed by 1246
Abstract
Endoplasmic reticulum (ER) stress and neuroinflammation are involved in the pathogenesis of many neurodegenerative disorders. Previously, we reported that exposure to pyrethroid insecticide deltamethrin causes hippocampal ER stress apoptosis, a reduction in neurogenesis, and learning deficits in adult male mice. Recently, we found [...] Read more.
Endoplasmic reticulum (ER) stress and neuroinflammation are involved in the pathogenesis of many neurodegenerative disorders. Previously, we reported that exposure to pyrethroid insecticide deltamethrin causes hippocampal ER stress apoptosis, a reduction in neurogenesis, and learning deficits in adult male mice. Recently, we found that deltamethrin exposure also increases the markers of neuroinflammation in BV2 cells. Here, we investigated the potential mechanistic link between ER stress and neuroinflammation following exposure to deltamethrin. We found that repeated oral exposure to deltamethrin (3 mg/kg) for 30 days caused microglial activation and increased gene expressions and protein levels of TNF-α, IL-1β, IL-6, gp91phox, 4HNE, and iNOS in the hippocampus. These changes were preceded by the induction of ER stress as the protein levels of CHOP, ATF-4, and GRP78 were significantly increased in the hippocampus. To determine whether induction of ER stress triggers the inflammatory response, we performed an additional experiment with mouse microglial cell (MMC) line. MMCs were treated with 0–5 µM deltamethrin for 24–48 h in the presence or absence of salubrinal, a pharmacological inhibitor of the ER stress factor eIF2α. We found that salubrinal (50 µM) prevented deltamethrin-induced ER stress, as indicated by decreased levels of CHOP and ATF-4, and attenuated the levels of GSH, 4-HNE, gp91phox, iNOS, ROS, TNF-α, IL-1β, and IL-6 in MMCs. Together, these results demonstrate that exposure to deltamethrin leads to ER stress-mediated neuroinflammation, which may subsequently contribute to neurodegeneration and cognitive impairment in mice. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
Depletion of HIF-1α by Inducible Cre/loxP Increases the Sensitivity of Cultured Murine Hepatocytes to Ionizing Radiation in Hypoxia
Cells 2022, 11(10), 1671; https://doi.org/10.3390/cells11101671 - 18 May 2022
Viewed by 1184
Abstract
The transcription factor hypoxia-inducible factor (HIF) is the main oxygen sensor which regulates adaptation to cellular hypoxia. The aim of this study was to establish cultured murine hepatocyte derived cells (mHDC) as an in vitro model and to analyze the role of HIF-1α [...] Read more.
The transcription factor hypoxia-inducible factor (HIF) is the main oxygen sensor which regulates adaptation to cellular hypoxia. The aim of this study was to establish cultured murine hepatocyte derived cells (mHDC) as an in vitro model and to analyze the role of HIF-1α in apoptosis induction, DNA damage repair and sensitivity to ionizing radiation (IR). We have crossed C57/BL6 mice that bear loxP sites flanking exon 2 of Hif1a with mice which carry tamoxifen-inducible global Cre expression. From the offspring, we have established transduced hepatocyte cultures which are permanently HIF-1α deficient after tamoxifen treatment. We demonstrated that the cells produce albumin, acetylcholine esterase, and the cytokeratins 8 and 18 which functionally characterizes them as hepatocytes. In moderate hypoxia, HIF-1α deficiency increased IR-induced apoptosis and significantly reduced the surviving fraction of mHDC as compared to HIF-1α expressing cells in colony formation assays. Furthermore, HIF-1α knockout cells displayed increased IR-induced DNA damage as demonstrated by increased generation and persistence of γH2AX foci. HIF-1α deficient cells showed delayed DNA repair after IR in hypoxia in neutral comet assays which may indicate that non-homologous end joining (NHEJ) repair capacity was affected. Overall, our data suggest that HIF-1α inactivation increases radiation sensitivity of mHDC cells. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
Effect of Prenatal Glucocorticoid Exposure on Circadian Rhythm Gene Expression in the Brains of Adult Rat Offspring
Cells 2022, 11(10), 1613; https://doi.org/10.3390/cells11101613 - 11 May 2022
Cited by 1 | Viewed by 1019
Abstract
Circadian clocks control many vital aspects of physiology from the sleep-wake cycle to metabolism. The circadian clock operates through transcriptional-translational feedback loops. The normal circadian signaling relies on a ‘master clock’, located in the suprachiasmatic nucleus (SCN), which synchronizes peripheral oscillators. Glucocorticoid receptor [...] Read more.
Circadian clocks control many vital aspects of physiology from the sleep-wake cycle to metabolism. The circadian clock operates through transcriptional-translational feedback loops. The normal circadian signaling relies on a ‘master clock’, located in the suprachiasmatic nucleus (SCN), which synchronizes peripheral oscillators. Glucocorticoid receptor (GR) signaling has the ability to reset the phase of peripheral clocks. It has been shown that maternal exposure to glucocorticoids (GCs) can lead to modification of hypothalamic-pituitary-adrenal (HPA) function, impact stress-related behaviors, and result in a hypertensive state via GR activation. We previously demonstrated altered circadian rhythm signaling in the adrenal glands of offspring exposed to the synthetic GC, dexamethasone (Dex). Results from the current study show that prenatal exposure to Dex affects circadian rhythm gene expression in a brain region-specific and a sex-specific manner within molecular oscillators of the amygdala, hippocampus, paraventricular nucleus, and prefrontal cortex, as well as the main oscillator in the SCN. Results also show that spontaneously hypertensive rats (SHR) exhibited dysregulated circadian rhythm gene expression in these same brain regions compared with normotensive Wistar-Kyoto rats (WKY), although the pattern of dysregulation was markedly different from that seen in adult offspring prenatally exposed to GCs. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
Article
Transcriptome Reveals Granulosa Cells Coping through Redox, Inflammatory and Metabolic Mechanisms under Acute Heat Stress
Cells 2022, 11(9), 1443; https://doi.org/10.3390/cells11091443 - 25 Apr 2022
Cited by 5 | Viewed by 1879
Abstract
Heat stress affects granulosa cells (GCs) and the ovarian follicular microenvironment, causing poor oocyte developmental competence and fertility. This study aimed to investigate the physical responses and global transcriptomic changes in bovine GCs to acute heat stress (43 °C for 2 h) in [...] Read more.
Heat stress affects granulosa cells (GCs) and the ovarian follicular microenvironment, causing poor oocyte developmental competence and fertility. This study aimed to investigate the physical responses and global transcriptomic changes in bovine GCs to acute heat stress (43 °C for 2 h) in vitro. Heat-stressed GCs exhibited transient proliferation senescence and resumed proliferation at 48 h post-stress, while post-stress immediate culture-media change had a relatively positive effect on proliferation resumption. Increased accumulation of reactive oxygen species and apoptosis was observed in the heat-stress group. In spite of the upregulation of inflammatory (CYCS, TLR2, TLR4, IL6, etc.), pro-apoptotic (BAD, BAX, TNFSF9, MAP3K7, TNFRSF6B, FADD, TRADD, RIPK3, etc.) and caspase executioner genes (CASP3, CASP8, CASP9), antioxidants and anti-apoptotic genes (HMOX1, NOS2, CAT, SOD, BCL2L1, GPX4, etc.) were also upregulated in heat-stressed GCs. Progesterone and estrogen hormones, along with steroidogenic gene expression, declined significantly, in spite of the upregulation of genes involved in cholesterol synthesis. Out of 12,385 differentially expressed genes (DEGs), 330 significant DEGs (75 upregulated, 225 downregulated) were subjected to KEGG functional pathway annotation, gene ontology enrichment, STRING network analyses and manual querying of DEGs for meaningful molecular mechanisms. High inflammatory response was found to be responsible for oxidative-stress-mediated apoptosis of GCs and nodes towards the involvement of the NF-κB pathway and repression of the Nrf2 pathway. Downregulation of MDM4, TP53, PIDD1, PARP3, MAPK14 and MYC, and upregulation of STK26, STK33, TGFB2, CDKN1A and CDKN2A, at the interface of the MAPK and p53 signaling pathway, can be attributed to transient cellular senescence and apoptosis in GCs. The background working of the AMPK pathway through upregulation of AKT1, AMPK, SIRT1, PYGM, SLC2A4 and SERBP1 genes, and downregulation of PPARGCIA, IGF2, PPARA, SLC27A3, SLC16A3, TSC1/2, KCNJ2, KCNJ16, etc., evidence the repression of cellular transcriptional activity and energetic homeostasis modifications in response to heat stress. This study presents detailed responses of acute-heat-stressed GCs at physical, transcriptional and pathway levels and presents interesting insights into future studies regarding GC adaptation and their interaction with oocytes and the reproductive system at the ovarian level. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Article
Osmotic Stress Interferes with DNA Damage Response and H2AX Phosphorylation in Human Keratinocytes
Cells 2022, 11(6), 959; https://doi.org/10.3390/cells11060959 - 11 Mar 2022
Viewed by 1507
Abstract
The human skin and in particular its outermost layer, the epidermis, protects the body from potentially harmful substances, radiation as well as excessive water loss. However, the interference between the various stress responses of the epidermal keratinocytes, which often occur simultaneously, is largely [...] Read more.
The human skin and in particular its outermost layer, the epidermis, protects the body from potentially harmful substances, radiation as well as excessive water loss. However, the interference between the various stress responses of the epidermal keratinocytes, which often occur simultaneously, is largely unknown. The focus of this study was to investigate the interference between osmotic stress and DNA damage response. In addition to revealing the already well-described regulation of diverse gene sets, for example, cellular processes such as transcription, translation, and metabolic pathways (e.g., the KEGG citrate cycle and Reactome G2/M checkpoints), gene expression analysis of osmotically stressed keratinocytes revealed an influence on the transcription of genes also related to UV-induced DNA damage response. A gene network regulating the H2AX phosphorylation was identified to be regulated by osmotic stress. To analyze and test the interference between osmotic stress and DNA damage response, which can be triggered by UV stress on the one hand and oxidative stress on the other, in more detail, primary human keratinocytes were cultured under osmotic stress conditions and subsequently exposed to UV light and H2O2, respectively. γH2AX measurements revealed lower γH2AX levels in cells previously cultured under osmotic stress conditions. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Review

Jump to: Research

Review
Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-dependent Antioxidant Defense System
Cells 2023, 12(3), 418; https://doi.org/10.3390/cells12030418 - 26 Jan 2023
Viewed by 173
Abstract
Circulating glucocorticoids increase during stress. Chronic stress, characterized by a sustained increase in serum levels of cortisol, has been associated in different cases with an increased risk of cancer and a worse prognosis. Glucocorticoids can promote gluconeogenesis, mobilization of amino acids, fat breakdown, [...] Read more.
Circulating glucocorticoids increase during stress. Chronic stress, characterized by a sustained increase in serum levels of cortisol, has been associated in different cases with an increased risk of cancer and a worse prognosis. Glucocorticoids can promote gluconeogenesis, mobilization of amino acids, fat breakdown, and impair the body’s immune response. Therefore, conditions that may favor cancer growth and the acquisition of radio- and chemo-resistance. We found that glucocorticoid receptor knockdown diminishes the antioxidant protection of murine B16-F10 (highly metastatic) melanoma cells, thus leading to a drastic decrease in their survival during interaction with the vascular endothelium. The BRAFV600E mutation is the most commonly observed in melanoma patients. Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAFV600E) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAFV600E human melanoma cell lines. Early-stage cancer cells lacking Nrf2 generate high ROS levels and exhibit a senescence-like growth arrest. Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated melanoma. In fact, during early progression of skin melanoma metastases, RU486 and VMF induced metastases regression. However, treatment at an advanced stage of growth found resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in different human models). Moreover, melanoma resistance was decreased if AKT and NF-κB signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
Review
Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease
Cells 2023, 12(1), 88; https://doi.org/10.3390/cells12010088 - 25 Dec 2022
Viewed by 714
Abstract
The kidney contains many mitochondria that generate ATP to provide energy for cellular processes. Oxidative stress injury can be caused by impaired mitochondria with excessive levels of reactive oxygen species. Accumulating evidence has indicated a relationship between oxidative stress and kidney diseases, and [...] Read more.
The kidney contains many mitochondria that generate ATP to provide energy for cellular processes. Oxidative stress injury can be caused by impaired mitochondria with excessive levels of reactive oxygen species. Accumulating evidence has indicated a relationship between oxidative stress and kidney diseases, and revealed new insights into mitochondria-targeted therapeutics for renal injury. Improving mitochondrial homeostasis, increasing mitochondrial biogenesis, and balancing mitochondrial turnover has the potential to protect renal function against oxidative stress. Although there are some reviews that addressed this issue, the articles summarizing the relationship between mitochondria-targeted effects and the risk factors of renal failure are still few. In this review, we integrate recent studies on oxidative stress and mitochondrial function in kidney diseases, especially chronic kidney disease. We organized the causes and risk factors of oxidative stress in the kidneys based in their mitochondria-targeted effects. This review also listed the possible candidates for clinical therapeutics of kidney diseases by modulating mitochondrial function. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Review
Ethylene: A Master Regulator of Plant–Microbe Interactions under Abiotic Stresses
Cells 2023, 12(1), 31; https://doi.org/10.3390/cells12010031 - 21 Dec 2022
Cited by 1 | Viewed by 885
Abstract
The plant phytohormone ethylene regulates numerous physiological processes and contributes to plant–microbe interactions. Plants induce ethylene production to ward off pathogens after recognition of conserved microbe-associated molecular patterns (MAMPs). However, plant immune responses against pathogens are essentially not different from those triggered by [...] Read more.
The plant phytohormone ethylene regulates numerous physiological processes and contributes to plant–microbe interactions. Plants induce ethylene production to ward off pathogens after recognition of conserved microbe-associated molecular patterns (MAMPs). However, plant immune responses against pathogens are essentially not different from those triggered by neutral and beneficial microbes. Recent studies indicate that ethylene is an important factor for beneficial plant–microbial association under abiotic stress such as salt and heat stress. The association of beneficial microbes with plants under abiotic stresses modulates ethylene levels which control the expression of ethylene-responsive genes (ERF), and ERFs further regulate the plant transcriptome, epi-transcriptome, Na+/K+ homeostasis and antioxidant defense mechanisms against reactive oxygen species (ROS). Understanding ethylene-dependent plant–microbe interactions is crucial for the development of new strategies aimed at enhancing plant tolerance to harsh environmental conditions. In this review, we underline the importance of ethylene in beneficial plant–microbe interaction under abiotic stresses. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Review
Liver Injury and Cell Survival in Non-Alcoholic Steatohepatitis Regulated by Sex-Based Difference through B Cell Lymphoma 6
Cells 2022, 11(23), 3751; https://doi.org/10.3390/cells11233751 - 24 Nov 2022
Viewed by 454
Abstract
The liver is a crucial organ for maintaining homeostasis in living organisms and is the center of various metabolic functions. Therefore, abnormal metabolic activity, as in metabolic syndrome, leads to pathological conditions, such as abnormal accumulation of lipids in the liver. Inflammation and [...] Read more.
The liver is a crucial organ for maintaining homeostasis in living organisms and is the center of various metabolic functions. Therefore, abnormal metabolic activity, as in metabolic syndrome, leads to pathological conditions, such as abnormal accumulation of lipids in the liver. Inflammation and cell death are induced by several stresses in the fatty liver, namely steatohepatitis. In recent years, an increase in non-alcoholic steatohepatitis (NASH), which is not dependent on excessive alcohol intake, has become an issue as a major cause of liver cirrhosis and liver cancer. There are several recent findings on functional sex-based differences, NASH, and cell stress and death in the liver. In particular, NASH-induced liver injury and tumorigeneses were suppressed by B cell lymphoma 6, the transcriptional factor regulating sex-based liver functional gene expression. In this review, we discuss cell response to stress and lipotoxicity in NASH and its regulatory mechanisms. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Review
Integration of O-GlcNAc into Stress Response Pathways
Cells 2022, 11(21), 3509; https://doi.org/10.3390/cells11213509 - 05 Nov 2022
Viewed by 1082
Abstract
The modification of nuclear, mitochondrial, and cytosolic proteins by O-linked βN-acetylglucosamine (O-GlcNAc) has emerged as a dynamic and essential post-translational modification of mammalian proteins. O-GlcNAc is cycled on and off over 5000 proteins in response to diverse stimuli impacting protein function and, in [...] Read more.
The modification of nuclear, mitochondrial, and cytosolic proteins by O-linked βN-acetylglucosamine (O-GlcNAc) has emerged as a dynamic and essential post-translational modification of mammalian proteins. O-GlcNAc is cycled on and off over 5000 proteins in response to diverse stimuli impacting protein function and, in turn, epigenetics and transcription, translation and proteostasis, metabolism, cell structure, and signal transduction. Environmental and physiological injury lead to complex changes in O-GlcNAcylation that impact cell and tissue survival in models of heat shock, osmotic stress, oxidative stress, and hypoxia/reoxygenation injury, as well as ischemic reperfusion injury. Numerous mechanisms that appear to underpin O-GlcNAc-mediated survival include changes in chaperone levels, impacts on the unfolded protein response and integrated stress response, improvements in mitochondrial function, and reduced protein aggregation. Here, we discuss the points at which O-GlcNAc is integrated into the cellular stress response, focusing on the roles it plays in the cardiovascular system and in neurodegeneration. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Review
Metabolomics in Diabetic Retinopathy: From Potential Biomarkers to Molecular Basis of Oxidative Stress
Cells 2022, 11(19), 3005; https://doi.org/10.3390/cells11193005 - 26 Sep 2022
Cited by 4 | Viewed by 1079
Abstract
Diabetic retinopathy (DR), the leading cause of blindness in working-age adults, is one of the most common complications of diabetes mellitus (DM) featured by metabolic disorders. With the global prevalence of diabetes, the incidence of DR is expected to increase. Prompt detection and [...] Read more.
Diabetic retinopathy (DR), the leading cause of blindness in working-age adults, is one of the most common complications of diabetes mellitus (DM) featured by metabolic disorders. With the global prevalence of diabetes, the incidence of DR is expected to increase. Prompt detection and the targeting of anti-oxidative stress intervention could effectively reduce visual impairment caused by DR. However, the diagnosis and treatment of DR is often delayed due to the absence of obvious signs of retina imaging. Research progress supports that metabolomics is a powerful tool to discover potential diagnostic biomarkers and therapeutic targets for the causes of oxidative stress through profiling metabolites in diseases, which provides great opportunities for DR with metabolic heterogeneity. Thus, this review summarizes the latest advances in metabolomics in DR, as well as potential diagnostic biomarkers, and predicts molecular targets through the integration of genome-wide association studies (GWAS) with metabolomics. Metabolomics provides potential biomarkers, molecular targets and therapeutic strategies for controlling the progress of DR, especially the interventions at early stages and precise treatments based on individual patient variations. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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Review
Iron-Induced Oxidative Stress in Human Diseases
Cells 2022, 11(14), 2152; https://doi.org/10.3390/cells11142152 - 08 Jul 2022
Cited by 2 | Viewed by 1085
Abstract
Iron is responsible for the regulation of several cell functions. However, iron ions are catalytic and dangerous for cells, so the cells sequester such redox-active irons in the transport and storage proteins. In systemic iron overload and local pathological conditions, redox-active iron increases [...] Read more.
Iron is responsible for the regulation of several cell functions. However, iron ions are catalytic and dangerous for cells, so the cells sequester such redox-active irons in the transport and storage proteins. In systemic iron overload and local pathological conditions, redox-active iron increases in the human body and induces oxidative stress through the formation of reactive oxygen species. Non-transferrin bound iron is a candidate for the redox-active iron in extracellular space. Cells take iron by the uptake machinery such as transferrin receptor and divalent metal transporter 1. These irons are delivered to places where they are needed by poly(rC)-binding proteins 1/2 and excess irons are stored in ferritin or released out of the cell by ferroportin 1. We can imagine transit iron pool in the cell from iron import to the export. Since the iron in the transit pool is another candidate for the redox-active iron, the size of the pool may be kept minimally. When a large amount of iron enters cells and overflows the capacity of iron binding proteins, the iron behaves as a redox-active iron in the cell. This review focuses on redox-active iron in extracellular and intracellular spaces through a biophysical and chemical point of view. Full article
(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)
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