Candida albicans is a fungus that is predominantly detected in the oral cavity and causes opportunistic infections. Among the elderly, a decline in the host's resistance to pathogens due to immunosenescence makes them more susceptible to oral candidiasis, which eventually may progress to systemic candidiasis. Allyl isothiocyanate (AITC) is a component found in Brassicaceae plants (such as wasabi), which possesses strong antibacterial properties and is used as a food preservative. In this study, the effects of AITC on C. albicans were investigated though: (1) inhibition of growth and biofilm formation, (2) inhibition of adhesion to denture base resin, (3) inhibition of dimorphic transformation that exacerbates pathogenicity, and (4) inhibition of the production of secretory aspartic protease and lipase. Taken together, this suggests that AITC suppresses the growth and pathogenicity of this fungus. Further investigation of the mechanism revealed a decrease in hyphae-specific gene expression in the intracellular signaling MAP kinase cascade and cAMP pathway, as well as the induction of oxidative stress and a tendency toward apoptosis within C. albicans cells. Based on these findings, we propose that AITC may be beneficial for the prevention and suppression of oral candidiasis and has the potential for clinical application aimed at improving oral care and quality of life.
{"title":"Allyl isothiocyanate suppresses the growth and pathogenicity of Candida albicans","authors":"Hideki Nishiura , Muneaki Tamura , Rieko Matsuike , Marni C. Cueno , Tomoka Ito , Yasuhiro Namura , Toshimitsu Iinuma , Kenichi Imai","doi":"10.1016/j.cstres.2025.100125","DOIUrl":"10.1016/j.cstres.2025.100125","url":null,"abstract":"<div><div><em>Candida albicans</em> is a fungus that is predominantly detected in the oral cavity and causes opportunistic infections. Among the elderly, a decline in the host's resistance to pathogens due to immunosenescence makes them more susceptible to oral candidiasis, which eventually may progress to systemic candidiasis. Allyl isothiocyanate (AITC) is a component found in Brassicaceae plants (such as wasabi), which possesses strong antibacterial properties and is used as a food preservative. In this study, the effects of AITC on <em>C. albicans</em> were investigated though: (1) inhibition of growth and biofilm formation, (2) inhibition of adhesion to denture base resin, (3) inhibition of dimorphic transformation that exacerbates pathogenicity, and (4) inhibition of the production of secretory aspartic protease and lipase. Taken together, this suggests that AITC suppresses the growth and pathogenicity of this fungus. Further investigation of the mechanism revealed a decrease in hyphae-specific gene expression in the intracellular signaling MAP kinase cascade and cAMP pathway, as well as the induction of oxidative stress and a tendency toward apoptosis within <em>C. albicans</em> cells. Based on these findings, we propose that AITC may be beneficial for the prevention and suppression of oral candidiasis and has the potential for clinical application aimed at improving oral care and quality of life.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100125"},"PeriodicalIF":3.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-20DOI: 10.1016/j.cstres.2025.100118
Sarah J. Backe , Jennifer A. Heritz , Mehdi Mollapour
Molecular chaperones maintain proteostasis by assisting protein folding, stability, and activity. Heat shock protein 70 (Hsp70) and Hsp90 (Hsp90) are ATP-dependent chaperones essential for protein quality control, signaling, and stress adaptation. Their activities are controlled not only by co-chaperones, but also by dynamic post-translational modifications (PTMs). This review dissects phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and other PTMs of Hsp70 and Hsp90 across systems. These PTMs regulate the ATPase activity, localization, and interactions of the molecular chaperones with major implications in health and disease. The term “chaperone code” describes the PTM landscape that fine-tunes chaperone function. This code governs client fate, drug sensitivity, and stress responses. Importantly, combinatorial PTMs introduce regulatory complexity and flexibility, especially in cancer, neurodegeneration, and inflammation. The crosstalk between various PTMs and feedback loops add new regulatory layers to chaperone function. Additionally, these PTMs impact the function of the clients that are central in regulating specific cellular processes or pathways, such as transcription, autophagy, metabolism, and immune regulation. These pathways are usually affected in different maladies, such cancer, neurodegenerative, infectious and chronic diseases. Unlocking the chaperone code is essential for directing chaperone activity toward therapeutic benefit. This can be achieved by targeting enzymes that write, erase, or read the chaperone code, thereby offering new therapeutic strategies.
{"title":"Hsp70 and Hsp90 post-translational modifications and translating the chaperone code","authors":"Sarah J. Backe , Jennifer A. Heritz , Mehdi Mollapour","doi":"10.1016/j.cstres.2025.100118","DOIUrl":"10.1016/j.cstres.2025.100118","url":null,"abstract":"<div><div>Molecular chaperones maintain proteostasis by assisting protein folding, stability, and activity. Heat shock protein 70 (Hsp70) and Hsp90 (Hsp90) are ATP-dependent chaperones essential for protein quality control, signaling, and stress adaptation. Their activities are controlled not only by co-chaperones, but also by dynamic post-translational modifications (PTMs). This review dissects phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and other PTMs of Hsp70 and Hsp90 across systems. These PTMs regulate the ATPase activity, localization, and interactions of the molecular chaperones with major implications in health and disease. The term “chaperone code” describes the PTM landscape that fine-tunes chaperone function. This code governs client fate, drug sensitivity, and stress responses. Importantly, combinatorial PTMs introduce regulatory complexity and flexibility, especially in cancer, neurodegeneration, and inflammation. The crosstalk between various PTMs and feedback loops add new regulatory layers to chaperone function. Additionally, these PTMs impact the function of the clients that are central in regulating specific cellular processes or pathways, such as transcription, autophagy, metabolism, and immune regulation. These pathways are usually affected in different maladies, such cancer, neurodegenerative, infectious and chronic diseases. Unlocking the chaperone code is essential for directing chaperone activity toward therapeutic benefit. This can be achieved by targeting enzymes that write, erase, or read the chaperone code, thereby offering new therapeutic strategies.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100118"},"PeriodicalIF":3.2,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1016/j.cstres.2025.100115
Caitlin M. Lange , Ryo Higuchi-Sanabria , Caroline Kumsta
Proteostasis (protein homeostasis), the balance of protein synthesis, folding, and degradation, is critical for cellular function and organismal health. Its disruption leads to the accumulation of misfolded and aggregated proteins, hallmarks of aging and age-related diseases, including neurodegeneration. Autophagy, a conserved lysosome-mediated degradation pathway, is central to proteostasis by clearing toxic proteins and damaged organelles. In Caenorhabditis elegans, studies across conserved longevity paradigms and models of neurodegenerative diseases have defined key mechanisms by which autophagy maintains proteostasis during aging and stress. Beyond its degradative functions, autophagy contributes to spatial quality control by promoting the formation of potentially protective protein inclusions and coordinating with the ubiquitin-proteasome system. Emerging evidence also points to noncanonical autophagy pathways, such as unconventional secretion and inter-tissue communication, that broaden its role in systemic proteostasis. Together, these advances underscore autophagy’s multifaceted contribution to protein quality control, with wide-ranging implications for aging, stress resistance, and neurodegenerative disease.
{"title":"Autophagy in proteostasis and aging in Caenorhabditis elegans","authors":"Caitlin M. Lange , Ryo Higuchi-Sanabria , Caroline Kumsta","doi":"10.1016/j.cstres.2025.100115","DOIUrl":"10.1016/j.cstres.2025.100115","url":null,"abstract":"<div><div>Proteostasis (protein homeostasis), the balance of protein synthesis, folding, and degradation, is critical for cellular function and organismal health. Its disruption leads to the accumulation of misfolded and aggregated proteins, hallmarks of aging and age-related diseases, including neurodegeneration. Autophagy, a conserved lysosome-mediated degradation pathway, is central to proteostasis by clearing toxic proteins and damaged organelles. In <em>Caenorhabditis elegans</em>, studies across conserved longevity paradigms and models of neurodegenerative diseases have defined key mechanisms by which autophagy maintains proteostasis during aging and stress. Beyond its degradative functions, autophagy contributes to spatial quality control by promoting the formation of potentially protective protein inclusions and coordinating with the ubiquitin-proteasome system. Emerging evidence also points to noncanonical autophagy pathways, such as unconventional secretion and inter-tissue communication, that broaden its role in systemic proteostasis. Together, these advances underscore autophagy’s multifaceted contribution to protein quality control, with wide-ranging implications for aging, stress resistance, and neurodegenerative disease.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100115"},"PeriodicalIF":3.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-17DOI: 10.1016/j.cstres.2025.100112
Weihua Kong , Pei Jiang , Xinglu Miao , Ben Sang , Shunxin Hu , Lei Feng
Glucocorticoids (GCs), as commonly used anti-inflammatory and immunosuppressive drugs, may induce neurotoxicity with long-term use, although the specific mechanisms remain unclear. This study utilized zebrafish as a model to investigate the mechanisms and potential intervention targets of hydrocortisone (HC)-induced neurotoxicity. Transcriptome analysis revealed that HC exposure significantly downregulated the expression of Atp2a2 (encoding the endoplasmic reticulum calcium pump SERCA2). Functional experiments confirmed that HC disrupts cellular calcium homeostasis: endoplasmic reticulum Ca²⁺ levels decreased, mitochondrial Ca²⁺ accumulation occurred, accompanied by mitochondrial membrane potential depolarization, increased reactive oxygen species (ROS) generation, and cell apoptosis. Additionally, fluorescent signals in brain and spinal cord neurons were weakened, and significant decreases in movement distance, time, and average speed were observed. Intervention experiments with the GR antagonist RU486 and the SERCA2 activator demonstrated that both could partially restore calcium homeostasis, reduce ROS and apoptosis, and improve motor behavior. The findings revealed that HC disrupted calcium homeostasis by downregulating Atp2a2, activating endoplasmic reticulum stress, and triggering mitochondrial dysfunction, ultimately leading to neuronal damage and behavioral abnormalities. SERCA2 may serve as a potential target for alleviating GC-associated neurotoxicity, and this study provides experimental evidence for elucidating its mechanisms.
{"title":"The role of Atp2a2-mediated calcium imbalance and endoplasmic reticulum stress in hydrocortisone-induced neurotoxicity","authors":"Weihua Kong , Pei Jiang , Xinglu Miao , Ben Sang , Shunxin Hu , Lei Feng","doi":"10.1016/j.cstres.2025.100112","DOIUrl":"10.1016/j.cstres.2025.100112","url":null,"abstract":"<div><div>Glucocorticoids (GCs), as commonly used anti-inflammatory and immunosuppressive drugs, may induce neurotoxicity with long-term use, although the specific mechanisms remain unclear. This study utilized zebrafish as a model to investigate the mechanisms and potential intervention targets of hydrocortisone (HC)-induced neurotoxicity. Transcriptome analysis revealed that HC exposure significantly downregulated the expression of <em>Atp2a2</em> (encoding the endoplasmic reticulum calcium pump SERCA2). Functional experiments confirmed that HC disrupts cellular calcium homeostasis: endoplasmic reticulum Ca²⁺ levels decreased, mitochondrial Ca²⁺ accumulation occurred, accompanied by mitochondrial membrane potential depolarization, increased reactive oxygen species (ROS) generation, and cell apoptosis. Additionally, fluorescent signals in brain and spinal cord neurons were weakened, and significant decreases in movement distance, time, and average speed were observed. Intervention experiments with the GR antagonist RU486 and the SERCA2 activator demonstrated that both could partially restore calcium homeostasis, reduce ROS and apoptosis, and improve motor behavior. The findings revealed that HC disrupted calcium homeostasis by downregulating <em>Atp2a2</em>, activating endoplasmic reticulum stress, and triggering mitochondrial dysfunction, ultimately leading to neuronal damage and behavioral abnormalities. SERCA2 may serve as a potential target for alleviating GC-associated neurotoxicity, and this study provides experimental evidence for elucidating its mechanisms.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100112"},"PeriodicalIF":3.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The nucleus pulposus (NP) of the intervertebral disc is an immune-privileged tissue. During intervertebral disc degeneration (IDD), this immune privilege is compromised, resulting in the exposure of NP components to the peripheral immune system, which in turn activates monocytes and elicits an immune response. In this study, we demonstrate that monocytes respond to NP immunogenicity by activating damage-associated molecular patterns (DAMPs), thereby initiating a sustained NF-κB–mediated inflammatory response in NP tissue and ultimately driving a vicious cycle of inflammation and oxidative stress within NP cells. Mechanistically, NP-derived immunogenic stimulation induces monocyte activation, accompanied by increased expression and nuclear translocation of the deubiquitinase USP7. USP7 promotes the accumulation and nuclear translocation of the NF-κB subunit p65 via a deubiquitination-dependent mechanism, leading to enhanced transcription of TNF-α, HMGB1, and IL-1β. These DAMP-associated cytokines further stimulate NP cells, resulting in upregulation of HMGB1, TNF-α, COX-2, IL-1β, and reactive oxygen species (ROS), along with a concomitant decrease in the antioxidant enzyme SOD2—collectively amplifying inflammation and oxidative stress within the NP microenvironment. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP)-qPCR demonstrated that knockdown of USP7 in monocytes significantly reduced p65 binding to the promoter regions of TNF-α, HMGB1, and IL-1β, thereby attenuating the downstream inflammatory and oxidative stress responses in NP cells. Together, these findings uncover a novel immune-inflammatory mechanism underlying IDD and highlight the USP7-mediated pathway in monocytes as a potential therapeutic target for modulating disc degeneration.
{"title":"Monocyte USP7-p65 axis mediates immune responses to the immunogenicity of nucleus pulposus","authors":"Peng Feng , Xuelei Chu , Ying Che , Jinghua Gao , Chunyu Gao , Ting Zhang","doi":"10.1016/j.cstres.2025.100114","DOIUrl":"10.1016/j.cstres.2025.100114","url":null,"abstract":"<div><div>The nucleus pulposus (NP) of the intervertebral disc is an immune-privileged tissue. During intervertebral disc degeneration (IDD), this immune privilege is compromised, resulting in the exposure of NP components to the peripheral immune system, which in turn activates monocytes and elicits an immune response. In this study, we demonstrate that monocytes respond to NP immunogenicity by activating damage-associated molecular patterns (DAMPs), thereby initiating a sustained NF-κB–mediated inflammatory response in NP tissue and ultimately driving a vicious cycle of inflammation and oxidative stress within NP cells. Mechanistically, NP-derived immunogenic stimulation induces monocyte activation, accompanied by increased expression and nuclear translocation of the deubiquitinase USP7. USP7 promotes the accumulation and nuclear translocation of the NF-κB subunit p65 via a deubiquitination-dependent mechanism, leading to enhanced transcription of TNF-α, HMGB1, and IL-1β. These DAMP-associated cytokines further stimulate NP cells, resulting in upregulation of HMGB1, TNF-α, COX-2, IL-1β, and reactive oxygen species (ROS), along with a concomitant decrease in the antioxidant enzyme SOD2—collectively amplifying inflammation and oxidative stress within the NP microenvironment. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP)-qPCR demonstrated that knockdown of USP7 in monocytes significantly reduced p65 binding to the promoter regions of TNF-α, HMGB1, and IL-1β, thereby attenuating the downstream inflammatory and oxidative stress responses in NP cells. Together, these findings uncover a novel immune-inflammatory mechanism underlying IDD and highlight the USP7-mediated pathway in monocytes as a potential therapeutic target for modulating disc degeneration.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100114"},"PeriodicalIF":3.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-09DOI: 10.1016/j.cstres.2025.100113
Guoqin Wang , Chaojiang Fu , Changling Tu , Zhuangqing Yang , Wei Shi , Lijuan Zhang , Shufen Tan , Youguang Huang
Tumor stemness maintenance and endoplasmic reticulum (ER) stress response have been strongly correlated with the progression of lung cancer (LC). Nevertheless, the role of long non-coding RNAs (lncRNAs) in these processes remains incompletely understood. We screened LC-associated lncRNAs from the GEO database and validated the expression of TBX5-AS1 in clinical samples. Functional experiments were conducted to assess the biological effects of TBX5-AS1, and western blot was used to detect ER stress marker proteins. The interaction mechanism of the TBX5-AS1/miR-494–3p/ATF6 axis was elucidated through dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and pull-down experiments. Rescue experiments and a nude mouse xenograft model were employed to validate the functional outcomes. TBX5-AS1 was significantly downregulated in LC tissues and cell lines, and its low expression was associated with advanced tumor stages and poor patient prognosis. Overexpression of TBX5-AS1 markedly suppressed LC cell proliferation, migration, invasion, and self-renewal while promoting the activation of the ER stress pathway. Mechanistically, TBX5-AS1 competitively binds to miR-494–3p, thereby relieving its transcriptional repression of Activating transcription factor 6 (ATF6). Rescue experiments demonstrated that miR-494–3p overexpression reversed the regulatory effects of TBX5-AS1 on tumor malignant phenotype and ER stress. In vivo experiments further confirmed that TBX5-AS1 overexpression significantly inhibited tumor growth, accompanied by upregulation of ATF6 and ER stress-related proteins. TBX5-AS1 functioned as a tumor-suppressive lncRNA by activating ER stress signaling through the miR-494–3p/ATF6 axis, thereby inhibiting LC growth and tumor stemness.
{"title":"TBX5-AS1 induces ER stress and suppresses lung cancer growth and tumor stemness via the miR-494-3p/ATF6 axis","authors":"Guoqin Wang , Chaojiang Fu , Changling Tu , Zhuangqing Yang , Wei Shi , Lijuan Zhang , Shufen Tan , Youguang Huang","doi":"10.1016/j.cstres.2025.100113","DOIUrl":"10.1016/j.cstres.2025.100113","url":null,"abstract":"<div><div>Tumor stemness maintenance and endoplasmic reticulum (ER) stress response have been strongly correlated with the progression of lung cancer (LC). Nevertheless, the role of long non-coding RNAs (lncRNAs) in these processes remains incompletely understood. We screened LC-associated lncRNAs from the GEO database and validated the expression of TBX5-AS1 in clinical samples. Functional experiments were conducted to assess the biological effects of TBX5-AS1, and western blot was used to detect ER stress marker proteins. The interaction mechanism of the TBX5-AS1/miR-494–3p/ATF6 axis was elucidated through dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and pull-down experiments. Rescue experiments and a nude mouse xenograft model were employed to validate the functional outcomes. TBX5-AS1 was significantly downregulated in LC tissues and cell lines, and its low expression was associated with advanced tumor stages and poor patient prognosis. Overexpression of TBX5-AS1 markedly suppressed LC cell proliferation, migration, invasion, and self-renewal while promoting the activation of the ER stress pathway. Mechanistically, TBX5-AS1 competitively binds to miR-494–3p, thereby relieving its transcriptional repression of Activating transcription factor 6 (ATF6). Rescue experiments demonstrated that miR-494–3p overexpression reversed the regulatory effects of TBX5-AS1 on tumor malignant phenotype and ER stress. In vivo experiments further confirmed that TBX5-AS1 overexpression significantly inhibited tumor growth, accompanied by upregulation of ATF6 and ER stress-related proteins. TBX5-AS1 functioned as a tumor-suppressive lncRNA by activating ER stress signaling through the miR-494–3p/ATF6 axis, thereby inhibiting LC growth and tumor stemness.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100113"},"PeriodicalIF":3.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.cstres.2025.100111
Adelino S.R. da Silva , Caroline M. da Luz , Bruno B. Marafon , Maria Eduarda A. Tavares , Ivo Vieira de.S. Neto , Ruither O. Gomes Carolino , Driele C. da Silva Ferreira , Julia T. Marinho , Giovana R. Teixeira , Dennys E. Cintra , José R. Pauli , Eduardo R. Ropelle , Ellen C. de Freitas , Ana P. Pinto
Endoplasmic Reticulum (ER) homeostasis is closely regulated by an adaptive signaling network identified as the unfolded protein response (UPR), which is tightly related to the inflammatory pathway. However, physical exercise increases plasma concentrations of interleukin-6 (IL-6), which exhibits both pro- and anti-inflammatory properties that mediate ER function and mitochondrial metabolism, making its investigation relevant in physiological and pathological contexts. In kidney diseases, the IL-6 levels are effective in predicting mortality risk. To elucidate the relationship between exercise-induced IL-6 elevation, ER stress, and renal physiology, we explored the impact of an acute exhaustive exercise on the ER stress-related proteins and mitochondrial respiratory chain targets in the kidneys of IL-6 knockout (KO) mice. WT and IL-6 KO mice were divided into two subgroups for each phenotype: sedentary (Sed) and 1 h (after 1 h of acute exercise; Ex-1h). The kidneys were removed and prepared for histological, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunoblotting analysis. In summary, IL-6 KO mice had lower degranulated mast cells in the kidney. IL-6 KO mice exhibited reduced exercise performance. The Hspa5 mRNA levels were significantly increased in response to acute exhaustive exercise in both WT and KO groups, but Il-10 increased only in response to exercise in the KO group. Additionally, Ddit3 expression was significantly lower in IL-6 KO mice post-exercise, suggesting a blunted ER stress response without IL-6. At the protein levels, ATF6α expression was notably elevated in IL-6 KO mice following exercise. Regarding mitochondrial protein complexes, we observed lower protein levels of mitochondrial complex IV and CII in the WT Ex-1h group than in the WT Sed. At the same time, the absence of IL-6 did not seem to modify the expression of most mitochondrial complexes in response to acute exercise. Also, publicly available gene expression datasets in humans support our findings, indicating the upregulation of IL-6 signaling and heat shock proteins (HSPs), while decreasing mitochondrial respiratory complex mRNA levels in white blood cells of humans following acute exhaustive exercise. The findings indicate that IL-6 may modulate specific components of ER stress and cytokine responses in the kidney after acute exercise.
{"title":"Interleukin-6 modulates endoplasmic reticulum stress signaling and mitochondrial protein complexes in the kidney following acute exhaustive exercise","authors":"Adelino S.R. da Silva , Caroline M. da Luz , Bruno B. Marafon , Maria Eduarda A. Tavares , Ivo Vieira de.S. Neto , Ruither O. Gomes Carolino , Driele C. da Silva Ferreira , Julia T. Marinho , Giovana R. Teixeira , Dennys E. Cintra , José R. Pauli , Eduardo R. Ropelle , Ellen C. de Freitas , Ana P. Pinto","doi":"10.1016/j.cstres.2025.100111","DOIUrl":"10.1016/j.cstres.2025.100111","url":null,"abstract":"<div><div>Endoplasmic Reticulum (ER) homeostasis is closely regulated by an adaptive signaling network identified as the unfolded protein response (UPR), which is tightly related to the inflammatory pathway. However, physical exercise increases plasma concentrations of interleukin-6 (IL-6), which exhibits both pro- and anti-inflammatory properties that mediate ER function and mitochondrial metabolism, making its investigation relevant in physiological and pathological contexts. In kidney diseases, the IL-6 levels are effective in predicting mortality risk. To elucidate the relationship between exercise-induced IL-6 elevation, ER stress, and renal physiology, we explored the impact of an acute exhaustive exercise on the ER stress-related proteins and mitochondrial respiratory chain targets in the kidneys of IL-6 knockout (KO) mice. WT and IL-6 KO mice were divided into two subgroups for each phenotype: sedentary (Sed) and 1 h (after 1 h of acute exercise; Ex-1h). The kidneys were removed and prepared for histological, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunoblotting analysis. In summary, IL-6 KO mice had lower degranulated mast cells in the kidney. IL-6 KO mice exhibited reduced exercise performance. The <em>Hspa5</em> mRNA levels were significantly increased in response to acute exhaustive exercise in both WT and KO groups, but <em>Il-10</em> increased only in response to exercise in the KO group. Additionally, <em>Ddit3</em> expression was significantly lower in IL-6 KO mice post-exercise, suggesting a blunted ER stress response without IL-6. At the protein levels, ATF6α expression was notably elevated in IL-6 KO mice following exercise. Regarding mitochondrial protein complexes, we observed lower protein levels of mitochondrial complex IV and CII in the WT Ex-1h group than in the WT Sed. At the same time, the absence of IL-6 did not seem to modify the expression of most mitochondrial complexes in response to acute exercise. Also, publicly available gene expression datasets in humans support our findings, indicating the upregulation of IL-6 signaling and heat shock proteins (HSPs), while decreasing mitochondrial respiratory complex mRNA levels in white blood cells of humans following acute exhaustive exercise. The findings indicate that IL-6 may modulate specific components of ER stress and cytokine responses in the kidney after acute exercise.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 5","pages":"Article 100111"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2025-07-31DOI: 10.1016/j.cstres.2025.100106
Michele Maltz-Matyschsyk, Clare K Melchiorre, Kristen Dostie-Laprise, Michael A Lynes
Metallothionein (MT) is a highly conserved, low-molecular-weight (∼7 kDa), cysteine-thiol-rich, stress response protein essential to cellular homeostasis. Elevated MT levels can be induced in cells during response to oxidative stress, glucocorticoids, essential divalent cationic metals, toxic heavy metal cations, acute-phase cytokines, interferon-γ, and/or endotoxin exposure. MT isoforms 1 and 2 are expressed across most tissues/cells and are localized in cytosolic, nuclear, and extracellular environments, despite the absence of a signal peptide. Extracellular MT (eMT) plays a significant role in inflammatory disease by acting as a signal that modifies the functional profile of inflammatory cells. Treatment with anti-MT monoclonal antibody (UC1MT), which presumably targets the eMT, in various mouse models of inflammatory disease significantly reduces disease severity. This study examines the effects of eMT on T lymphocyte gene expression at exposure times of 5-90 min in vitro. Jurkat T-cells were treated with eMT alone or in combination with UC1MT, revealing distinct gene expression changes at all time points, with the most substantial effects observed at 90 min. The results demonstrated eMT's influence on G-protein-coupled receptor (GPCR) gene expression and cell proliferation, confirmed through calcium flux and Carboxyfluorescein Succinimdiyl Ester (CFSE) proliferation assays. An analysis at the 90-min time point identified a positive feedback loop wherein eMT induces additional MT messenger ribonucleic acid (mRNA) expression. Using an MT-GFP fusion vector, transfected Jurkat T-cells verified that eMT stimulates both MT transcript and protein expression. This study underscores eMT's role as an alarmin and its capacity to potentiate inflammatory disease by modulating gene and protein expression in T lymphocytes.
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