Research

Jump to: Review

13 pages, 1573 KiB

Open AccessFeature PaperArticle

Analysis of the Anticipatory Behavior Formation Mechanism Induced by Methamphetamine Using a Single Hair

by Riku Sato, Megumi Kanai, Yukina Yoshida, Shiori Fukushima, Masahiro Nogami, Takeshi Yamaguchi, Norio Iijima, Kenneth Sutherland, Sanae Haga, Michitaka Ozaki, Kazuko Hamada and Toshiyuki Hamada

Cells 2023, 12(4), 654; https://doi.org/10.3390/cells12040654 - 17 Feb 2023

Viewed by 1386

Abstract

While the suprachiasmatic nucleus (SCN) coordinates many daily rhythms, some circadian patterns of expression are controlled by SCN-independent systems. These include responses to daily methamphetamine (MAP) injections. Scheduled daily injections of MAP resulted in anticipatory activity, with an increase in locomotor activity immediately [...] Read more.

While the suprachiasmatic nucleus (SCN) coordinates many daily rhythms, some circadian patterns of expression are controlled by SCN-independent systems. These include responses to daily methamphetamine (MAP) injections. Scheduled daily injections of MAP resulted in anticipatory activity, with an increase in locomotor activity immediately prior to the time of injection. The MAP-induced anticipatory behavior is associated with the induction and a phase advance in the expression rhythm of the clock gene Period1 (Per1). However, this unique formation mechanism of MAP-induced anticipatory behavior is not well understood. We recently developed a micro-photomultiplier tube (micro-PMT) system to detect a small amount of Per1 expression. In the present study, we used this system to measure the formation kinetics of MAP-induced anticipatory activity in a single whisker hair to reveal the underlying mechanism. Our results suggest that whisker hairs respond to daily MAP administration, and that Per1 expression is affected. We also found that elevated Per1 expression in a single whisker hair is associated with the occurrence of anticipatory behavior rhythm. The present results suggest that elevated Per1 expression in hairs might be a marker of anticipatory behavior formation. Full article

(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)

► Show Figures

Figure 1

14 pages, 1147 KiB

Open AccessArticle

Kinetics of Plasma Cell-Free DNA under a Highly Standardized and Controlled Stress Induction

by Benedict Herhaus, Elmo Neuberger, Ema Juškevičiūtė, Perikles Simon and Katja Petrowski

Cells 2023, 12(4), 564; https://doi.org/10.3390/cells12040564 - 09 Feb 2023

Cited by 3 | Viewed by 1510

Abstract

Psychological stress affects the immune system and activates peripheral inflammatory pathways. Circulating cell-free DNA (cfDNA) is associated with systemic inflammation, and recent research indicates that cfDNA is an inflammatory marker that is sensitive to psychological stress in humans. The present study investigated the [...] Read more.

Psychological stress affects the immune system and activates peripheral inflammatory pathways. Circulating cell-free DNA (cfDNA) is associated with systemic inflammation, and recent research indicates that cfDNA is an inflammatory marker that is sensitive to psychological stress in humans. The present study investigated the effects of acute stress on the kinetics of cfDNA in a within-subjects design. Twenty-nine males (mean age: 24.34 ± 4.08 years) underwent both the Trier Social Stress Test (TSST) and a resting condition. Blood samples were collected at two time points before and at 9 time points up to 105 min after both conditions. The cfDNA immediately increased 2-fold after the TSST and returned to baseline levels after 30 min after the test, showing that a brief psychological stressor was sufficient to evoke a robust and rapid increase in cfDNA levels. No associations were detected between perceived stress, whereas subjects with higher basal cfDNA levels showed higher increases. The rapid cfDNA regulation might be attributed to the transient activation of immune cells caused by neuroendocrine-immune activation. Further research is required to evaluate the reliability of cfDNA as a marker of neuroendocrine-immune activation, which could be used for diagnostics purposes or monitoring of treatment progression. Full article

(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)

► Show Figures

Figure 1

15 pages, 3742 KiB

Open AccessArticle

Renal Ischemia Tolerance Mediated by eIF5A Hypusination Inhibition Is Regulated by a Specific Modulation of the Endoplasmic Reticulum Stress

by Nicolas Melis, Isabelle Rubera, Sebastien Giraud, Marc Cougnon, Christophe Duranton, Mallorie Poet, Gisèle Jarretou, Raphaël Thuillier, Laurent Counillon, Thierry Hauet, Luc Pellerin, Michel Tauc and Didier F. Pisani

Cells 2023, 12(3), 409; https://doi.org/10.3390/cells12030409 - 25 Jan 2023

Viewed by 1623

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)

► Show Figures

Graphical abstract

20 pages, 2279 KiB

Open AccessArticle

NEK6 Regulates Redox Balance and DNA Damage Response in DU-145 Prostate Cancer Cells

by Isadora Carolina Betim Pavan, Fernanda Luisa Basei, Matheus Brandemarte Severino, Ivan Rosa e Silva, Luidy Kazuo Issayama, Mariana Camargo Silva Mancini, Mariana Marcela Góis, Luiz Guilherme Salvino da Silva, Rosangela Maria Neves Bezerra, Fernando Moreira Simabuco and Jörg Kobarg

Cells 2023, 12(2), 256; https://doi.org/10.3390/cells12020256 - 07 Jan 2023

Cited by 3 | Viewed by 2206

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)

► Show Figures

Figure 1

15 pages, 1481 KiB

Open AccessArticle

Systematic Interrogation of the Temperature Perturbation in the Insulin Signaling Pathway for Optogenetic Stimulation

by Qi Dong, Mizuki Endo, Genki Kawamura and Takeaki Ozawa

Cells 2022, 11(19), 3136; https://doi.org/10.3390/cells11193136 - 05 Oct 2022

Viewed by 1696

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)

► Show Figures

Graphical abstract

15 pages, 2468 KiB

Open AccessArticle

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

by Cheng-Nan Chen, Hsin-I Chang, Chia-Kung Yen, Wen-Lung Liu and Kuo-Yuan Huang

Cells 2022, 11(16), 2600; https://doi.org/10.3390/cells11162600 - 20 Aug 2022

Cited by 6 | Viewed by 1987

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)

► Show Figures

Figure 1

19 pages, 3146 KiB

Open AccessArticle

HSF1 Can Prevent Inflammation following Heat Shock by Inhibiting the Excessive Activation of the ATF3 and JUN&FOS Genes

by Patryk Janus, Paweł Kuś, Natalia Vydra, Agnieszka Toma-Jonik, Tomasz Stokowy, Katarzyna Mrowiec, Bartosz Wojtaś, Bartłomiej Gielniewski and Wiesława Widłak

Cells 2022, 11(16), 2510; https://doi.org/10.3390/cells11162510 - 12 Aug 2022

Cited by 4 | Viewed by 2680

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)

► Show Figures

Graphical abstract

21 pages, 4676 KiB

Open AccessFeature PaperArticle

Deltamethrin-Evoked ER Stress Promotes Neuroinflammation in the Adult Mouse Hippocampus

by Muhammad M. Hossain, Abigail C. Toltin, Laura M. Gamba and Maria A. Molina

Cells 2022, 11(12), 1961; https://doi.org/10.3390/cells11121961 - 18 Jun 2022

Cited by 12 | Viewed by 2340

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, gp91^phox, 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, gp91^phox, 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)

► Show Figures

Figure 1

18 pages, 5317 KiB

Open AccessArticle

Depletion of HIF-1α by Inducible Cre/loxP Increases the Sensitivity of Cultured Murine Hepatocytes to Ionizing Radiation in Hypoxia

by Akram Hamidi, Alexandra Wolf, Rositsa Dueva, Melanie Kaufmann, Kirsten Göpelt, George Iliakis and Eric Metzen

Cells 2022, 11(10), 1671; https://doi.org/10.3390/cells11101671 - 18 May 2022

Cited by 3 | Viewed by 2492

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)

► Show Figures

Figure 1

12 pages, 294 KiB

Open AccessArticle

Effect of Prenatal Glucocorticoid Exposure on Circadian Rhythm Gene Expression in the Brains of Adult Rat Offspring

by Alyssa Murray, Sujeenthar Tharmalingam, Sandhya Khurana, Christine Lalonde, Phong Nguyen and T. C. Tai

Cells 2022, 11(10), 1613; https://doi.org/10.3390/cells11101613 - 11 May 2022

Cited by 4 | Viewed by 2044

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)

20 pages, 30659 KiB

Open AccessArticle

Transcriptome Reveals Granulosa Cells Coping through Redox, Inflammatory and Metabolic Mechanisms under Acute Heat Stress

by Abdul Sammad, Hanpeng Luo, Lirong Hu, Huabin Zhu and Yachun Wang

Cells 2022, 11(9), 1443; https://doi.org/10.3390/cells11091443 - 25 Apr 2022

Cited by 18 | Viewed by 3923

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)

► Show Figures

Figure 1

12 pages, 1678 KiB

Open AccessArticle

Osmotic Stress Interferes with DNA Damage Response and H2AX Phosphorylation in Human Keratinocytes

by Laura Hoen, Christoph Rudisch, Michael Wick, Daniela Indenbirken, Adam Grundhoff, Florian Wegwitz, Stefan Kalkhof and Janosch Hildebrand

Cells 2022, 11(6), 959; https://doi.org/10.3390/cells11060959 - 11 Mar 2022

Cited by 3 | Viewed by 2850

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)

► Show Figures

Figure 1

Review

Jump to: Research

22 pages, 1978 KiB

Open AccessReview

Molecular Mechanisms of Lipid-Based Metabolic Adaptation Strategies in Response to Cold

by Gang Wu, Ralf Baumeister and Thomas Heimbucher

Cells 2023, 12(10), 1353; https://doi.org/10.3390/cells12101353 - 10 May 2023

Cited by 2 | Viewed by 3006

Abstract

Temperature changes and periods of detrimental cold occur frequently for many organisms in their natural habitats. Homeothermic animals have evolved metabolic adaptation strategies to increase mitochondrial-based energy expenditure and heat production, largely relying on fat as a fuel source. Alternatively, certain species are [...] Read more.

Temperature changes and periods of detrimental cold occur frequently for many organisms in their natural habitats. Homeothermic animals have evolved metabolic adaptation strategies to increase mitochondrial-based energy expenditure and heat production, largely relying on fat as a fuel source. Alternatively, certain species are able to repress their metabolism during cold periods and enter a state of decreased physiological activity known as torpor. By contrast, poikilotherms, which are unable to maintain their internal temperature, predominantly increase membrane fluidity to diminish cold-related damage from low-temperature stress. However, alterations of molecular pathways and the regulation of lipid-metabolic reprogramming during cold exposure are poorly understood. Here, we review organismal responses that adjust fat metabolism during detrimental cold stress. Cold-related changes in membranes are detected by membrane-bound sensors, which signal to downstream transcriptional effectors, including nuclear hormone receptors of the PPAR (peroxisome proliferator-activated receptor) subfamily. PPARs control lipid metabolic processes, such as fatty acid desaturation, lipid catabolism and mitochondrial-based thermogenesis. Elucidating the underlying molecular mechanisms of cold adaptation may improve beneficial therapeutic cold treatments and could have important implications for medical applications of hypothermia in humans. This includes treatment strategies for hemorrhagic shock, stroke, obesity and cancer. Full article

(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)

► Show Figures

Figure 1

18 pages, 1175 KiB

Open AccessReview

Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System

by Elena Obrador, Rosario Salvador-Palmer, Rafael López-Blanch, María Oriol-Caballo, Paz Moreno-Murciano and José M. Estrela

Cells 2023, 12(3), 418; https://doi.org/10.3390/cells12030418 - 26 Jan 2023

Cited by 5 | Viewed by 2660

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 BRAF^V600E mutation is the most commonly observed in melanoma patients. Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAF^V600E) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAF^V600E 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 BRAF^V600E-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)

► Show Figures

Figure 1

29 pages, 4301 KiB

Open AccessReview

Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease

by Hsin-Jung Ho and Hitoshi Shirakawa

Cells 2023, 12(1), 88; https://doi.org/10.3390/cells12010088 - 25 Dec 2022

Cited by 25 | Viewed by 4971

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)

► Show Figures

Figure 1

15 pages, 932 KiB

Open AccessReview

Ethylene: A Master Regulator of Plant–Microbe Interactions under Abiotic Stresses

by Kirti Shekhawat, Katja Fröhlich, Gabriel X. García-Ramírez, Marilia A. Trapp and Heribert Hirt

Cells 2023, 12(1), 31; https://doi.org/10.3390/cells12010031 - 21 Dec 2022

Cited by 14 | Viewed by 3268

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)

► Show Figures

Graphical abstract

11 pages, 867 KiB

Open AccessReview

Liver Injury and Cell Survival in Non-Alcoholic Steatohepatitis Regulated by Sex-Based Difference through B Cell Lymphoma 6

by Akihide Kamiya and Kinuyo Ida

Cells 2022, 11(23), 3751; https://doi.org/10.3390/cells11233751 - 24 Nov 2022

Cited by 1 | Viewed by 1427

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)

► Show Figures

Figure 1

37 pages, 1443 KiB

Open AccessFeature PaperReview

Integration of O-GlcNAc into Stress Response Pathways

by Kamau M. M. Fahie, Kyriakos N. Papanicolaou and Natasha E. Zachara

Cells 2022, 11(21), 3509; https://doi.org/10.3390/cells11213509 - 05 Nov 2022

Cited by 15 | Viewed by 3966

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)

► Show Figures

Graphical abstract

19 pages, 1709 KiB

Open AccessReview

Metabolomics in Diabetic Retinopathy: From Potential Biomarkers to Molecular Basis of Oxidative Stress

by Qizhi Jian, Yingjie Wu and Fang Zhang

Cells 2022, 11(19), 3005; https://doi.org/10.3390/cells11193005 - 26 Sep 2022

Cited by 18 | Viewed by 2973

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)

► Show Figures

Figure 1

16 pages, 1285 KiB

Open AccessReview

Iron-Induced Oxidative Stress in Human Diseases

by Teruyuki Kawabata

Cells 2022, 11(14), 2152; https://doi.org/10.3390/cells11142152 - 08 Jul 2022

Cited by 17 | Viewed by 2837

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)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Molecular Mechanism of Stress, Stress Response, and Adaptation

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (20 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI