Pub Date : 2024-08-29DOI: 10.1016/j.freeradbiomed.2024.08.039
Ferroptosis, a recently discovered form of regulated cell death, has been implicated in the development of ulcerative colitis (UC). While Piezo1's role in inducing ferroptosis in chondrocytes and pulmonary endothelial cells is documented, its regulatory function in ferroptosis and intestinal epithelial cells in UC remains unclear. To address this, colonic tissue samples from patients with UC were examined, and specific intestinal epithelial Piezo1-deficient (Piezo1ΔIEC) mice were created to investigate Piezo1's role in UC pathogenesis. Elevated epithelial Piezo1 levels were observed in patients with UC, correlating with increased ferroptosis and tight junction (TJ) disruption. In dextran sulfate sodium (DSS)-induced colitis, Piezo1ΔIEC mice exhibited significantly reduced intestinal inflammation and improved gut barrier function compared to wild-type (WT) mice. Moreover, Piezo1 deficiency in colitis mice and lipopolysaccharide (LPS)-stimulated Caco-2 cells led to higher TJ protein levels, reduced lipid peroxidation, enhanced mitochondrial function, and altered expression of ferroptosis-associated proteins. Additionally, erastin, a ferroptosis activator, reversed the protective effect of Piezo1 silencing against LPS-induced ferroptosis in Caco-2 cells. Mechanistically, Piezo1 was found to regulate ferroptosis via the AMPK/mTOR signaling pathway. These findings highlight a novel role for Piezo1 deletion in mitigating ferroptosis in intestinal epithelial cells, suggesting Piezo1 as a potential therapeutic target for UC treatment.
{"title":"Epithelial Piezo1 deletion ameliorates intestinal barrier damage by regulating ferroptosis in ulcerative colitis","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.039","DOIUrl":"10.1016/j.freeradbiomed.2024.08.039","url":null,"abstract":"<div><p>Ferroptosis, a recently discovered form of regulated cell death, has been implicated in the development of ulcerative colitis (UC). While Piezo1's role in inducing ferroptosis in chondrocytes and pulmonary endothelial cells is documented, its regulatory function in ferroptosis and intestinal epithelial cells in UC remains unclear. To address this, colonic tissue samples from patients with UC were examined, and specific intestinal epithelial Piezo1-deficient (Piezo1<sup>ΔIEC</sup>) mice were created to investigate Piezo1's role in UC pathogenesis. Elevated epithelial Piezo1 levels were observed in patients with UC, correlating with increased ferroptosis and tight junction (TJ) disruption. In dextran sulfate sodium (DSS)-induced colitis, Piezo1<sup>ΔIEC</sup> mice exhibited significantly reduced intestinal inflammation and improved gut barrier function compared to wild-type (WT) mice. Moreover, Piezo1 deficiency in colitis mice and lipopolysaccharide (LPS)-stimulated Caco-2 cells led to higher TJ protein levels, reduced lipid peroxidation, enhanced mitochondrial function, and altered expression of ferroptosis-associated proteins. Additionally, erastin, a ferroptosis activator, reversed the protective effect of Piezo1 silencing against LPS-induced ferroptosis in Caco-2 cells. Mechanistically, Piezo1 was found to regulate ferroptosis <em>via</em> the AMPK/mTOR signaling pathway. These findings highlight a novel role for Piezo1 deletion in mitigating ferroptosis in intestinal epithelial cells, suggesting Piezo1 as a potential therapeutic target for UC treatment.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.freeradbiomed.2024.08.038
Metabolic-associated steatotic liver disease (MASLD), known as non-alcoholic fatty liver disease (NAFLD) in the past, encompasses a range of liver pathological conditions marked by the excessive lipid accumulation. Consumption of coffee is closely associated with the reduced risk of MASLD. Caffeic acid (CA), a key active ingredient in coffee, exhibits notable hepatoprotective properties. This study aims to investigate the improvement of CA on MASLD and the engaged mechanism. Mice underwent a 12-week high-fat diet (HFD) regimen to induce MASLD, and liver pathology was assessed using hematoxylin-eosin (H&E) and oil red O (ORO) staining. Hepatic inflammation was evaluated by F4/80 and Ly6G immunohistochemistry (IHC) and myeloperoxidase (MPO) measurement. Pathways and transcription factors relevant to MASLD were analyzed by using microarray data from patients' livers. Oxidative damage was evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). Co-immunoprecipitation (CoIP), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were used to validate the binding between CA and its target protein. CA significantly alleviated liver damage, steatosis and inflammatory injury, and reduced the elevated NAFLD activity score (NAS) in HFD-fed mice. Clinical data indicate that fatty acid metabolism and ROS generation are pivotal in MASLD progression. CA increased the expression of fibroblast growth factor 21 (FGF21), FGF receptor 1 (FGFR1) and β-Klotho (KLB), and promoted fatty acid consumption. Additionally, CA mitigated oxidative stress injury and activated nuclear factor erythroid 2-related factor-2 (Nrf2). In primary hepatocytes isolated from Nrf2 knockout mice, CA's promotion on FGF21 release and inhibition on oxidative stress and lipotoxicity was disappeared. CA could directly bind to kelch-like ECH-associated protein 1 (Keap1) that is an Nrf2 inhibitor protein. This study suggests that CA alleviates MASLD by reducing hepatic lipid accumulation, lipotoxicity and oxidative damage through activating Nrf2 via binding to Keap1.
{"title":"Caffeic acid ameliorates metabolic dysfunction-associated steatotic liver disease via alleviating oxidative damage and lipid accumulation in hepatocytes through activating Nrf2 via targeting Keap1","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.038","DOIUrl":"10.1016/j.freeradbiomed.2024.08.038","url":null,"abstract":"<div><p>Metabolic-associated steatotic liver disease (MASLD), known as non-alcoholic fatty liver disease (NAFLD) in the past, encompasses a range of liver pathological conditions marked by the excessive lipid accumulation. Consumption of coffee is closely associated with the reduced risk of MASLD. Caffeic acid (CA), a key active ingredient in coffee, exhibits notable hepatoprotective properties. This study aims to investigate the improvement of CA on MASLD and the engaged mechanism. Mice underwent a 12-week high-fat diet (HFD) regimen to induce MASLD, and liver pathology was assessed using hematoxylin-eosin (H&E) and oil red O (ORO) staining. Hepatic inflammation was evaluated by F4/80 and Ly6G immunohistochemistry (IHC) and myeloperoxidase (MPO) measurement. Pathways and transcription factors relevant to MASLD were analyzed by using microarray data from patients' livers. Oxidative damage was evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). Co-immunoprecipitation (CoIP), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were used to validate the binding between CA and its target protein. CA significantly alleviated liver damage, steatosis and inflammatory injury, and reduced the elevated NAFLD activity score (NAS) in HFD-fed mice. Clinical data indicate that fatty acid metabolism and ROS generation are pivotal in MASLD progression. CA increased the expression of fibroblast growth factor 21 (FGF21), FGF receptor 1 (FGFR1) and <em>β</em>-Klotho (KLB), and promoted fatty acid consumption. Additionally, CA mitigated oxidative stress injury and activated nuclear factor erythroid 2-related factor-2 (Nrf2). In primary hepatocytes isolated from Nrf2 knockout mice, CA's promotion on FGF21 release and inhibition on oxidative stress and lipotoxicity was disappeared. CA could directly bind to kelch-like ECH-associated protein 1 (Keap1) that is an Nrf2 inhibitor protein. This study suggests that CA alleviates MASLD by reducing hepatic lipid accumulation, lipotoxicity and oxidative damage through activating Nrf2 via binding to Keap1.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.freeradbiomed.2024.08.029
Hantavirus causes two types of acute diseases: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. It is a major health concern due to its high mortality and lack of effective treatment. Type I interferon treatment has been suggested to be effective against hantavirus when treated in advance. Interferons induce multiple interferon-stimulated genes (ISGs), whose products are highly effective at resisting and controlling viruses. A product of ISGs, the enzyme cholesterol 25-hydroxylase (CH25H), catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25HC). 25HC can inhibit multiple enveloped-virus infections, but the mechanism is largely unknown, and whether 25HC plays an important role in regulating hantavirus remains unexplored. In this study, we show that Hantaan virus (HTNV), the prototype hantavirus, induced CH25H gene in infected cells. Overexpression of CH25H and treatment with 25HC, inhibited HTNV infection, possibly by lowering 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase, HMGCR), which inhibits cholesterol biosynthesis. In addition, cholesterol-lowering drugs such as HMGCR-targeting statins have potent hantavirus inhibitory effects. Our results indicate that 25HC and some statins are potential antiviral agents effective against hantavirus infections. This study provides evidence that targeting cholesterol metabolism is promising in developing specific hantavirus antivirals and indicates the possibility of repurposing FDA-approved cholesterol-lowering drug, statins for treating hantavirus infection.
{"title":"25-Hydroxycholesterol inhibits Hantavirus infection by reprogramming cholesterol metabolism","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.029","DOIUrl":"10.1016/j.freeradbiomed.2024.08.029","url":null,"abstract":"<div><p>Hantavirus causes two types of acute diseases: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. It is a major health concern due to its high mortality and lack of effective treatment. Type I interferon treatment has been suggested to be effective against hantavirus when treated in advance. Interferons induce multiple interferon-stimulated genes (ISGs), whose products are highly effective at resisting and controlling viruses. A product of ISGs, the enzyme cholesterol 25-hydroxylase (CH25H), catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25HC). 25HC can inhibit multiple enveloped-virus infections, but the mechanism is largely unknown, and whether 25HC plays an important role in regulating hantavirus remains unexplored. In this study, we show that Hantaan virus (HTNV), the prototype hantavirus, induced CH25H gene in infected cells. Overexpression of CH25H and treatment with 25HC, inhibited HTNV infection, possibly by lowering 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase, HMGCR), which inhibits cholesterol biosynthesis. In addition, cholesterol-lowering drugs such as HMGCR-targeting statins have potent hantavirus inhibitory effects. Our results indicate that 25HC and some statins are potential antiviral agents effective against hantavirus infections. This study provides evidence that targeting cholesterol metabolism is promising in developing specific hantavirus antivirals and indicates the possibility of repurposing FDA-approved cholesterol-lowering drug, statins for treating hantavirus infection.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.freeradbiomed.2024.08.027
Cellular senescence is a natural barrier of the transition from premalignant cells to invasive cancer. Pharmacological induction of senescence has been proposed as a possible anticancer strategy. In this study, we found that deoxyarbutin inhibited the growth of glioblastoma (GBM) cells by inducing cellular senescence, independent of tyrosinase expression. Instead, deoxyarbutin induced mitochondrial oxidative stress and damage. These aberrant mitochondria were key to the p53-dependent senescence of GBM cells. Facilitating autophagy or mitigating mitochondrial oxidative stress both suppressed p53 expression and alleviated cellular senescence induced by deoxyarbutin. Thus, our study reveals that deoxyarbutin induces mitochondrial oxidative stress to trigger the p53-dependent senescence of GBM cells. Importantly, deoxyarbutin treatment resulted in accumulation of p53, induction of cellular senescence, and inhibition of tumor growth in a subcutaneous tumor model of mouse. In conclusion, our study reveals that deoxyarbutin has therapeutic potential for GBM by inducing mitochondrial oxidative stress for p53-dependent senescence of GBM cells.
{"title":"Deoxyarbutin targets mitochondria to trigger p53-dependent senescence of glioblastoma cells","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.027","DOIUrl":"10.1016/j.freeradbiomed.2024.08.027","url":null,"abstract":"<div><p>Cellular senescence is a natural barrier of the transition from premalignant cells to invasive cancer. Pharmacological induction of senescence has been proposed as a possible anticancer strategy. In this study, we found that deoxyarbutin inhibited the growth of glioblastoma (GBM) cells by inducing cellular senescence, independent of tyrosinase expression. Instead, deoxyarbutin induced mitochondrial oxidative stress and damage. These aberrant mitochondria were key to the p53-dependent senescence of GBM cells. Facilitating autophagy or mitigating mitochondrial oxidative stress both suppressed p53 expression and alleviated cellular senescence induced by deoxyarbutin. Thus, our study reveals that deoxyarbutin induces mitochondrial oxidative stress to trigger the p53-dependent senescence of GBM cells. Importantly, deoxyarbutin treatment resulted in accumulation of p53, induction of cellular senescence, and inhibition of tumor growth in a subcutaneous tumor model of mouse. In conclusion, our study reveals that deoxyarbutin has therapeutic potential for GBM by inducing mitochondrial oxidative stress for p53-dependent senescence of GBM cells.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Airway remodeling is an important pathological of airflow limitation in chronic obstructive pulmonary disease (COPD).However,its mechanism still needs to be further clarify.
Methods: Animals:Healthy male C57BL/6 mice aged 4-6 weeks were randomly divided into control group and cigarette smoke(CS)group. Mice in the CS group were placed in a homemade glass fumigator, 5 cigarettes/time, 40 min/time, 4 times/day, 5 days/week, for 24 weeks. Mice in the control group were placed in a normal air environment.Cells:BEAS-2B cells were stimulated with 0.1%cigarette smoke extract(CSE).HE staining,immunohistochemical staining and Masson staining were used to observe the pathological of lung tissues,transmission electron microscopy was used to observe the structural of mitochondria in bronchial epithelial cells.Western blotting was used to detect the expression of STAT3,transforming growth factor-β1(TGF-β1),microtubule-associated protein 1A/1B-light chain3(LC3),PINK1,Parkin,E-cadherin,zonula occludens1(ZO-1),vimentin and snail family transcriptional inhibitor1 (Snail1),and MitoSOX Red was used to detect mitochondrial reactive oxygen species(mtROS).
Results: CS exposure causes lung parenchymal destruction and airway remodeling in mice.Compared to the control group,the expression of p-STAT3,TGF-β1 and EMT in the whole lung homogenate of the CS group was increased.Mitochondrial architecture disruption in bronchial epithelial cells of CS mice,with impaired PINK1-Parkin-dependent mitophagy.In vitro experiments showed that CSE exposure led to STAT3 activation,increased TGF-β1,EMT and enhanced PINK1-Parkin-mediated mitophagy.STAT3 inhibition reversed TGF-β1 upregulation induced by CSE and improved CSE-induced EMT and mitophagy.Inhibition of mitophagy improves EMT induced by CSE. Inhibition of mitophagy reduces STAT3-induced EMT.
Conclusion: CS activates the STAT3,and activated STAT3 promotes EMT in bronchial epithelial cells by enhancing PINK1-Parkin-mediated mitophagy and TGF-β1 signaling.Moreover,activated STAT3 can promote EMT directly.This may be one of the mechanisms by which CS causes small airway remodeling in COPD.
{"title":"Mechanism of cigarette smoke in promoting small airway remodeling in mice via STAT 3 / PINK 1-Parkin / EMT.","authors":"Yunjie Wei, Qiqi Li, Kaiye He, Guopeng Liao, Lingyun Cheng, Meihua Li, Zhiyi He","doi":"10.1016/j.freeradbiomed.2024.08.036","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2024.08.036","url":null,"abstract":"<p><strong>Background: </strong>Airway remodeling is an important pathological of airflow limitation in chronic obstructive pulmonary disease (COPD).However,its mechanism still needs to be further clarify.</p><p><strong>Methods: </strong>Animals:Healthy male C57BL/6 mice aged 4-6 weeks were randomly divided into control group and cigarette smoke(CS)group. Mice in the CS group were placed in a homemade glass fumigator, 5 cigarettes/time, 40 min/time, 4 times/day, 5 days/week, for 24 weeks. Mice in the control group were placed in a normal air environment.Cells:BEAS-2B cells were stimulated with 0.1%cigarette smoke extract(CSE).HE staining,immunohistochemical staining and Masson staining were used to observe the pathological of lung tissues,transmission electron microscopy was used to observe the structural of mitochondria in bronchial epithelial cells.Western blotting was used to detect the expression of STAT3,transforming growth factor-β1(TGF-β1),microtubule-associated protein 1A/1B-light chain3(LC3),PINK1,Parkin,E-cadherin,zonula occludens1(ZO-1),vimentin and snail family transcriptional inhibitor1 (Snail1),and MitoSOX Red was used to detect mitochondrial reactive oxygen species(mtROS).</p><p><strong>Results: </strong>CS exposure causes lung parenchymal destruction and airway remodeling in mice.Compared to the control group,the expression of p-STAT3,TGF-β1 and EMT in the whole lung homogenate of the CS group was increased.Mitochondrial architecture disruption in bronchial epithelial cells of CS mice,with impaired PINK1-Parkin-dependent mitophagy.In vitro experiments showed that CSE exposure led to STAT3 activation,increased TGF-β1,EMT and enhanced PINK1-Parkin-mediated mitophagy.STAT3 inhibition reversed TGF-β1 upregulation induced by CSE and improved CSE-induced EMT and mitophagy.Inhibition of mitophagy improves EMT induced by CSE. Inhibition of mitophagy reduces STAT3-induced EMT.</p><p><strong>Conclusion: </strong>CS activates the STAT3,and activated STAT3 promotes EMT in bronchial epithelial cells by enhancing PINK1-Parkin-mediated mitophagy and TGF-β1 signaling.Moreover,activated STAT3 can promote EMT directly.This may be one of the mechanisms by which CS causes small airway remodeling in COPD.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.freeradbiomed.2024.08.037
Vitamin D deficiency (VDD) has been found among alcoholics. However, little is known about the effect of VDD on alcoholic liver disease and the molecular mechanisms remain unclear. The aim of the current study was to evaluate whether vitamin D was deficient among patients with alcoholic fatty liver disease (AFLD) and the effect of VDD on chronic alcoholic liver injury and possible molecular mechanisms in mice. Our results found that lower 25-hydroxyvitamin D [25(OH)D] concentrations in patients with AFLD. And further analysis found that 25(OH)D is a protective factor in patients with AFLD. Mice experiments indicated that VDD can alter the composition of gut microbiota, down-regulate the protein levels of intestinal tight junction protein Occludin and E-cadherin, up-regulate the expression of inflammatory cytokines (tnf-α, il-1β, il-6, il-8, ccl2, il-10) in liver and colon tissue. And further exacerbated the protein levels of p65,P-IκB,P-p65 in alcoholic liver injury mice. In conclusion, VDD aggravates chronic alcoholic liver injury by activating NF-κB signaling pathway.
在酗酒者中发现了维生素 D 缺乏症(VDD)。然而,人们对维生素 D 缺乏对酒精性肝病的影响知之甚少,其分子机制也仍不清楚。本研究旨在评估酒精性脂肪肝(AFLD)患者是否缺乏维生素D,以及维生素DD对小鼠慢性酒精性肝损伤的影响和可能的分子机制。我们的研究结果发现,酒精性脂肪肝患者体内的 25- 羟维生素 D [25(OH)D] 浓度较低。进一步分析发现,25(OH)D 是 AFLD 患者的保护因子。小鼠实验表明,VDD 可改变肠道微生物群的组成,下调肠道紧密连接蛋白 Occludin 和 E-cadherin 的蛋白水平,上调肝脏和结肠组织中炎症细胞因子(tnf-α、il-1β、il-6、il-8、cl2、il-10)的表达。酒精性肝损伤小鼠的 p65、P-IκB、P-p65 蛋白水平进一步升高。总之,VDD 通过激活 NF-κB 信号通路加重慢性酒精性肝损伤。
{"title":"Effects of vitamin D deficiency on chronic alcoholic liver injury","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.037","DOIUrl":"10.1016/j.freeradbiomed.2024.08.037","url":null,"abstract":"<div><p>Vitamin D deficiency (VDD) has been found among alcoholics. However, little is known about the effect of VDD on alcoholic liver disease and the molecular mechanisms remain unclear. The aim of the current study was to evaluate whether vitamin D was deficient among patients with alcoholic fatty liver disease (AFLD) and the effect of VDD on chronic alcoholic liver injury and possible molecular mechanisms in mice. Our results found that lower 25-hydroxyvitamin D [25(OH)D] concentrations in patients with AFLD. And further analysis found that 25(OH)D is a protective factor in patients with AFLD. Mice experiments indicated that VDD can alter the composition of gut microbiota, down-regulate the protein levels of intestinal tight junction protein Occludin and E-cadherin, up-regulate the expression of inflammatory cytokines (<em>tnf-α</em>, <em>il-1β</em>, <em>il-6</em>, <em>il-8</em>, <em>ccl2</em>, <em>il-10</em>) in liver and colon tissue. And further exacerbated the protein levels of <em>p65</em>,<em>P-IκB</em>,<em>P-p65</em> in alcoholic liver injury mice. In conclusion, VDD aggravates chronic alcoholic liver injury by activating NF-κB signaling pathway.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.freeradbiomed.2024.08.032
Glutathione transferase omega-1-1 (GSTO1-1) is a member of the glutathione transferase superfamily (GSTs) involved in the modulation of cell survival, proliferation and metabolism. Increased levels of GSTO1-1 have been associated with cancer progression and chemoresistance in different types of cancer cells, possibly supported by the post-traslational regulation of some major prosurvival pathways regulated by the enzyme. Our data demonstrate for the first time that GSTO1-1 can be released by cancer cells through the exosomal route and transferred to GSTO1-1 knock-out cells, this resulting in an increased resistance against cisplatin toxicity in recipient cells. The use of the exosomal route to transfer the regulatory competences of GSTO1-1 could be a further element supporting its role in neoplastic progression.
{"title":"Glutathione transferase omega 1-1 (GSTO1-1) can effect the inter-cell transfer of cisplatin resistance through the exosomal route","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.032","DOIUrl":"10.1016/j.freeradbiomed.2024.08.032","url":null,"abstract":"<div><p>Glutathione transferase omega-1-1 (GSTO1-1) is a member of the glutathione transferase superfamily (GSTs) involved in the modulation of cell survival, proliferation and metabolism. Increased levels of GSTO1-1 have been associated with cancer progression and chemoresistance in different types of cancer cells, possibly supported by the post-traslational regulation of some major prosurvival pathways regulated by the enzyme. Our data demonstrate for the first time that GSTO1-1 can be released by cancer cells through the exosomal route and transferred to GSTO1-1 knock-out cells, this resulting in an increased resistance against cisplatin toxicity in recipient cells. The use of the exosomal route to transfer the regulatory competences of GSTO1-1 could be a further element supporting its role in neoplastic progression.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.freeradbiomed.2024.08.034
Cisplatin-induced acute kidney injury (AKI) is characterized by mitochondrial damage and apoptosis, and safe and effective therapeutic agents are urgently needed. Renal tubular epithelial cells, the main site of AKI, are enriched with a large number of mitochondria, which are crucial for the progression of AKI with an impaired energy supply. Vincamine has anti-inflammatory and antioxidant effects in mouse AKI models. As a natural compound derived from Tabernaemontana pandacaqui, (+)-14, 15-Dehydrovincamine and Vincamine differ in structure by only one double bond, and the role and exact mechanism of (+)-14, 15-Dehydrovincamine remains to be elucidated in AKI. The present study demonstrated that (+)-14,15-Dehydrovincamine significantly ameliorated mitochondrial dysfunction and maintained mitochondrial homeostasis in a cisplatin-induced AKI model. Furthermore, (+)-14,15-Dehydrovincamine ameliorates cytochrome C-dependent apoptosis in renal tubular epithelial cells. c-Jun NH2-terminal kinase (JNK) was identified as a potential target protein of (+)-14,15-Dehydrovincamine attenuating AKI by network pharmacological analysis. (+)-14,15-Dehydrovincamine inhibited cisplatin-induced JNK activation, mitochondrial fission factor (Mff) phosphorylation, and dynamin-related protein 1 (Drp1) translocation to the mitochondria in renal tubular epithelial cells. Meanwhile, the JNK activator anisomycin restored Mff phosphorylation and Drp1 translocation, counteracting the protective effect of (+)-14,15-Dehydrovincamine on mitochondrial dysfunction in cisplatin-induced TECs injury. In conclusion, (+)-14,15-Dehydrovincamine reduced mitochondrial fission, maintained mitochondrial homeostasis, and attenuated apoptosis by inhibiting the JNK/Mff/Drp1 pathway, which in turn ameliorated cisplatin-induced AKI.
顺铂诱导的急性肾损伤(AKI)以线粒体损伤和凋亡为特征,急需安全有效的治疗药物。肾小管上皮细胞是 AKI 的主要部位,富含大量线粒体,这些线粒体对能量供应受损的 AKI 的进展至关重要。长春胺在小鼠 AKI 模型中具有抗炎和抗氧化作用。(+)-14、15-脱氢长春胺和长春胺作为一种从Tabernaemontana pandacaqui中提取的天然化合物,在结构上仅有一个双键不同,(+)-14、15-脱氢长春胺在AKI中的作用和确切机制仍有待阐明。本研究表明,在顺铂诱导的 AKI 模型中,(+)-14,15-去氢锌胺能显著改善线粒体功能障碍,维持线粒体平衡。此外,(+)-14,15-去氢锌胺还能改善肾小管上皮细胞中细胞色素 C 依赖性凋亡。通过网络药理学分析,发现 c-Jun NH2 端激酶(JNK)是(+)-14,15-去氢锌胺减轻 AKI 的潜在靶蛋白。(+)-14,15-去氢长春胺抑制了顺铂诱导的JNK活化、线粒体裂变因子(Mff)磷酸化以及肾小管上皮细胞中的动态相关蛋白1(Drp1)向线粒体的转位。同时,JNK 激活剂 anisomycin 恢复了 Mff 磷酸化和 Drp1 转位,抵消了 (+)-14,15-Dehydrovincamine 对顺铂诱导的 TECs 损伤线粒体功能障碍的保护作用。总之,(+)-14,15-去氢锌胺通过抑制JNK/Mff/Drp1通路,减少线粒体裂变,维持线粒体平衡,减轻细胞凋亡,从而改善顺铂诱导的AKI。
{"title":"Inhibition of mitochondrial over-division by (+)-14,15-Dehydrovincamine attenuates cisplatin-induced acute kidney injury via the JNK/Mff pathway","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.034","DOIUrl":"10.1016/j.freeradbiomed.2024.08.034","url":null,"abstract":"<div><p>Cisplatin-induced acute kidney injury (AKI) is characterized by mitochondrial damage and apoptosis, and safe and effective therapeutic agents are urgently needed. Renal tubular epithelial cells, the main site of AKI, are enriched with a large number of mitochondria, which are crucial for the progression of AKI with an impaired energy supply. Vincamine has anti-inflammatory and antioxidant effects in mouse AKI models. As a natural compound derived from <em>Tabernaemontana pandacaqui</em>, (+)-14, 15-Dehydrovincamine and Vincamine differ in structure by only one double bond, and the role and exact mechanism of (+)-14, 15-Dehydrovincamine remains to be elucidated in AKI. The present study demonstrated that (+)-14,15-Dehydrovincamine significantly ameliorated mitochondrial dysfunction and maintained mitochondrial homeostasis in a cisplatin-induced AKI model. Furthermore, (+)-14,15-Dehydrovincamine ameliorates cytochrome C-dependent apoptosis in renal tubular epithelial cells. c-Jun NH2-terminal kinase (JNK) was identified as a potential target protein of (+)-14,15-Dehydrovincamine attenuating AKI by network pharmacological analysis. (+)-14,15-Dehydrovincamine inhibited cisplatin-induced JNK activation, mitochondrial fission factor (Mff) phosphorylation, and dynamin-related protein 1 (Drp1) translocation to the mitochondria in renal tubular epithelial cells. Meanwhile, the JNK activator anisomycin restored Mff phosphorylation and Drp1 translocation, counteracting the protective effect of (+)-14,15-Dehydrovincamine on mitochondrial dysfunction in cisplatin-induced TECs injury. In conclusion, (+)-14,15-Dehydrovincamine reduced mitochondrial fission, maintained mitochondrial homeostasis, and attenuated apoptosis by inhibiting the JNK/Mff/Drp1 pathway, which in turn ameliorated cisplatin-induced AKI.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/j.freeradbiomed.2024.08.031
Background
Alzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood.
Aim
In this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects.
Methods
We pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, β-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin.
Results
Our data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection.
Conclusion
Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.
{"title":"Icariin targets p53 to protect against ceramide-induced neuronal senescence: Implication in Alzheimer's disease","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.031","DOIUrl":"10.1016/j.freeradbiomed.2024.08.031","url":null,"abstract":"<div><h3>Background</h3><p>Alzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood.</p></div><div><h3>Aim</h3><p>In this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects.</p></div><div><h3>Methods</h3><p>We pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, β-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin.</p></div><div><h3>Results</h3><p>Our data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection.</p></div><div><h3>Conclusion</h3><p>Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/j.freeradbiomed.2024.08.033
Fibronectin type III domain containing 4 (FNDC4) is highly homologous with FNDC5, which possesses various cardiometabolic protective functions. Emerging evidence suggests a noteworthy involvement of FNDC4 in fat metabolism and inflammatory processes. This study aimed to characterize the role of FNDC4 in myocardial ischemia/reperfusion (MI/R) injury and decrypt its underlying mechanisms. MI/R models of mice were established to investigate the alteration of FNDC4 in plasma and myocardium. We observed that plasma FNDC4 in MI/R-injury mice and patients experiencing acute myocardial infarction were both significantly reduced as opposed to their respective controls. Likewise, FNDC4 expression of myocardium decreased markedly in MI/R mice compared to the sham-operated group. Mice of FNDC4 knockout and myocardial overexpression were further introduced to elucidate the role of FNDC4 in MI/R injury by detecting cardiomyocyte apoptosis, myocardial infarct size, and cardiac function. Ablation of FNDC4 exacerbated cardiac dysfunction, increased myocardial infarction area and cardiomyocyte apoptosis when matched with wild-type mice post-MI/R. In contrast, FNDC4 overexpression through intramyocardial injection of rAAV9-Fndc4 significantly ameliorated cardiac function, reduced myocardial infarction area and cardiomyocyte apoptosis compared to sham group. Additionally, hypoxia-reoxygenation (H/R) was used to induce cardiomyocyte apoptosis, and to further elucidate the direct effects of FNDC4 on cardiomyocytes in vitro, and the results demonstrated that neonatal rat ventricular cardiomyocytes overexpressing FNDC4 showed less H/R-induced apoptosis, as evidenced by cleaved caspase 3 expression, TUNEL staining and flow cytometry. By performing RNA-seq analysis followed by cause-effect analysis, ERK1/2-Nrf2 pathway-mediated antioxidative effects were responsible for the protective roles of FNDC4 on cardiomyocytes. In summary, FNDC4 exerts cardioprotection against MI/R injury predominantly through mitigating oxidative stress responses and reducing cardiomyocyte apoptosis. These insights solidify the proposition of FNDC4 as a potential therapeutic aim for tackling MI/R damage.
{"title":"Fibronectin type III domain containing 4 alleviates myocardial ischemia/reperfusion injury via the Nrf2-dependent antioxidant pathway","authors":"","doi":"10.1016/j.freeradbiomed.2024.08.033","DOIUrl":"10.1016/j.freeradbiomed.2024.08.033","url":null,"abstract":"<div><p>Fibronectin type III domain containing 4 (FNDC4) is highly homologous with FNDC5, which possesses various cardiometabolic protective functions. Emerging evidence suggests a noteworthy involvement of FNDC4 in fat metabolism and inflammatory processes. This study aimed to characterize the role of FNDC4 in myocardial ischemia/reperfusion (MI/R) injury and decrypt its underlying mechanisms. MI/R models of mice were established to investigate the alteration of FNDC4 in plasma and myocardium. We observed that plasma FNDC4 in MI/R-injury mice and patients experiencing acute myocardial infarction were both significantly reduced as opposed to their respective controls. Likewise, FNDC4 expression of myocardium decreased markedly in MI/R mice compared to the sham-operated group. Mice of FNDC4 knockout and myocardial overexpression were further introduced to elucidate the role of FNDC4 in MI/R injury by detecting cardiomyocyte apoptosis, myocardial infarct size, and cardiac function. Ablation of FNDC4 exacerbated cardiac dysfunction, increased myocardial infarction area and cardiomyocyte apoptosis when matched with wild-type mice post-MI/R. In contrast, FNDC4 overexpression through intramyocardial injection of rAAV9-Fndc4 significantly ameliorated cardiac function, reduced myocardial infarction area and cardiomyocyte apoptosis compared to sham group. Additionally, hypoxia-reoxygenation (H/R) was used to induce cardiomyocyte apoptosis, and to further elucidate the direct effects of FNDC4 on cardiomyocytes <em>in vitro</em>, and the results demonstrated that neonatal rat ventricular cardiomyocytes overexpressing FNDC4 showed less H/R-induced apoptosis, as evidenced by cleaved caspase 3 expression, TUNEL staining and flow cytometry. By performing RNA-seq analysis followed by cause-effect analysis, ERK1/2-Nrf2 pathway-mediated antioxidative effects were responsible for the protective roles of FNDC4 on cardiomyocytes. In summary, FNDC4 exerts cardioprotection against MI/R injury predominantly through mitigating oxidative stress responses and reducing cardiomyocyte apoptosis. These insights solidify the proposition of FNDC4 as a potential therapeutic aim for tackling MI/R damage.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}