Pub Date : 2024-11-18DOI: 10.1016/j.redox.2024.103431
O Zatsepina, D Karpov, L Chuvakova, A Rezvykh, S Funikov, S Sorokina, A Zakluta, D Garbuz, V Shilova, M Evgen'ev
{"title":"Corrigendum to \"Genome-wide transcriptional effects of deletions of sulphur metabolism genes in Drosophila melanogaster\" [Redox Biol. 36 (2020) 101654].","authors":"O Zatsepina, D Karpov, L Chuvakova, A Rezvykh, S Funikov, S Sorokina, A Zakluta, D Garbuz, V Shilova, M Evgen'ev","doi":"10.1016/j.redox.2024.103431","DOIUrl":"https://doi.org/10.1016/j.redox.2024.103431","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":" ","pages":"103431"},"PeriodicalIF":10.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.redox.2024.103428
Rui-xia Dou , Ya-min Zhang , Xiao-juan Hu , Fu-Lin Gao , Lu-Lu Zhang , Yun-hua Liang , Yin-ying Zhang , Yu-ping Yao , Li Yin , Yi Zhang , Cheng Gu
Alzheimer's disease (AD) is one of the most common age-related neurodegenerative diseases and the most devastating form of senile dementia. It has a complex mechanism and no effective treatment. Exploring the pathogenesis of AD and providing ideas for treatment can effectively improve the prognosis of AD. Microglia were incubated with β-amyloid protein 1-42 (Aβ1-42) to construct an AD cell model. After microglia were activated, cell morphology changed, the expression level of inflammatory factors increased, cell apoptosis was promoted, and the expression of microtubule-associated protein (Tau protein) and related proteins increased. By up-regulating and down-regulating Toll-like receptor 4 (TLR4), the cells were divided into TLR4 knockdown negative control group(Lv-NC group), TLR4 knockdown group(Lv-TLR4 group), TLR4 overexpression negative control group(Sh-NC group), and TLR4 overexpression group(Sh-TLR4 group). The expression of inflammatory factors was detected again. It was found that compared with the Lv-NC group, the expression of various inflammatory factors in the Lv-TLR4 group decreased, cell apoptosis was inhibited, and the expression of Tau protein and related proteins decreased. Compared with the Sh-NC group, the expression of inflammatory factors in the Sh-TLR4 group increased, cell apoptosis was promoted, and the expression of Tau protein and related proteins increased. These results indicate that Aβ1-42 may promote microglial activation and apoptosis by binding to TLR4. Reducing the expression of TLR4 can reduce the occurrence of inflammatory response in AD cells and slow down cell apoptosis. Therefore, TLR4 is expected to become a new target for the prevention and treatment of AD.
{"title":"Aβ1-42 promotes microglial activation and apoptosis in the progression of AD by binding to TLR4","authors":"Rui-xia Dou , Ya-min Zhang , Xiao-juan Hu , Fu-Lin Gao , Lu-Lu Zhang , Yun-hua Liang , Yin-ying Zhang , Yu-ping Yao , Li Yin , Yi Zhang , Cheng Gu","doi":"10.1016/j.redox.2024.103428","DOIUrl":"10.1016/j.redox.2024.103428","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is one of the most common age-related neurodegenerative diseases and the most devastating form of senile dementia. It has a complex mechanism and no effective treatment. Exploring the pathogenesis of AD and providing ideas for treatment can effectively improve the prognosis of AD. Microglia were incubated with β-amyloid protein 1-42 (Aβ<sub>1-42</sub>) to construct an AD cell model. After microglia were activated, cell morphology changed, the expression level of inflammatory factors increased, cell apoptosis was promoted, and the expression of microtubule-associated protein (Tau protein) and related proteins increased. By up-regulating and down-regulating Toll-like receptor 4 (TLR4), the cells were divided into TLR4 knockdown negative control group(Lv-NC group), TLR4 knockdown group(Lv-TLR4 group), TLR4 overexpression negative control group(Sh-NC group), and TLR4 overexpression group(Sh-TLR4 group). The expression of inflammatory factors was detected again. It was found that compared with the Lv-NC group, the expression of various inflammatory factors in the Lv-TLR4 group decreased, cell apoptosis was inhibited, and the expression of Tau protein and related proteins decreased. Compared with the Sh-NC group, the expression of inflammatory factors in the Sh-TLR4 group increased, cell apoptosis was promoted, and the expression of Tau protein and related proteins increased. These results indicate that Aβ<sub>1-42</sub> may promote microglial activation and apoptosis by binding to TLR4. Reducing the expression of TLR4 can reduce the occurrence of inflammatory response in AD cells and slow down cell apoptosis. Therefore, TLR4 is expected to become a new target for the prevention and treatment of AD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103428"},"PeriodicalIF":10.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09DOI: 10.1016/j.redox.2024.103422
Yiran Chen, Xi Li, Ming Yang, Chen Jia, Zhenghao He, Suqing Zhou, Pinglang Ruan, Yikun Wang, Congli Tang, Wenjing Pan, Hai Long, Ming Zhao, Liwei Lu, Weijun Peng, Arne Akbar, Irene Xy Wu, Song Li, Haijing Wu, Qianjin Lu
Time-restricted eating (TRE) has been shown to extent lifespans in drosophila and mouse models by affecting metabolic and anti-inflammatory activities. However, the effect of TRE on the human immune system, especially on immunosenescence, intestinal microbiome, and metabolism remains unclear. We conducted a 30-day 16:8 TRE single-arm clinical trial with 49 participants. Participants consumed daily meals from 9 a.m. to 5 p.m., provided by a nutrition canteen with a balanced, calorie-appropriate nutrition, which is designed by clinical nutritionists (ChiCTR2200058137). We monitored weight changes and weight-related parameters and focused on changes in the frequency of CD4+ senescent T cells, immune repertoire from peripheral blood, as well as serum metabolites and gut microbiota. We found that up to 95.9 % of subjects experienced sustained weight loss after TRE. The frequency of circulating senescent CD4+ T cells was decreased, while the frequency of Th1, Treg, Tfh-like, and B cells was increased. Regarding the immune repertoire, the proportions of T cell receptor alpha and beta chains were increased, whereas B cell receptor kappa and lambda chains were reduced. In addition, a reduced class switch recombination from immunoglobulin M (IgM) to immunoglobulin A (IgA) was observed. TRE upregulated the levels of anti-inflammatory and anti-aging serum metabolites named sphingosine-1-phosphate and prostaglandin-1. Additionally, several anti-inflammatory bacteria and probiotics were increased, such as Akkermansia and Rikenellaceae, and the composition of the gut microbiota tended to be "younger". Overall, TRE showed multiple anti-aging effects, which may help humans maintain a healthy lifestyle to stay "young". Clinical Trial Registration URL: https://www.chictr.org.cn/showproj.html?proj=159876.
限时进食（TRE）通过影响新陈代谢和抗炎活动，延长了果蝇和小鼠模型的寿命。然而，限时进食对人体免疫系统的影响，尤其是对免疫衰老、肠道微生物组和新陈代谢的影响仍不清楚。我们对 49 名参与者进行了为期 30 天的 16:8 TRE 单臂临床试验。参与者每天从上午 9 点到下午 5 点进餐，由临床营养师设计的营养食堂提供均衡、热量适宜的营养（ChiCTR2200058137）。我们监测了体重变化和与体重相关的参数，并重点研究了 CD4+ 衰老 T 细胞频率、外周血免疫细胞群以及血清代谢物和肠道微生物群的变化。我们发现，多达 95.9% 的受试者在服用 TRE 后体重持续下降。循环中衰老的 CD4+ T 细胞的数量减少了，而 Th1、Treg、Tfh 样细胞和 B 细胞的数量增加了。在免疫序列方面，T细胞受体α链和β链的比例增加，而B细胞受体卡帕链和λ链的比例减少。此外，还观察到从免疫球蛋白 M（IgM）到免疫球蛋白 A（IgA）的类别转换重组减少。TRE 提高了抗炎和抗衰老血清代谢物（鞘氨醇-1-磷酸酯和前列腺素-1）的水平。此外，一些抗炎细菌和益生菌也有所增加，如 Akkermansia 和 Rikenellaceae，肠道微生物群的组成也趋于 "年轻化"。总之，TRE显示出多种抗衰老作用，可帮助人类保持健康的生活方式，从而保持 "年轻"。临床试验注册网址：https://www.chictr.org.cn/showproj.html?proj=159876。
{"title":"Time-restricted eating reveals a \"younger\" immune system and reshapes the intestinal microbiome in human.","authors":"Yiran Chen, Xi Li, Ming Yang, Chen Jia, Zhenghao He, Suqing Zhou, Pinglang Ruan, Yikun Wang, Congli Tang, Wenjing Pan, Hai Long, Ming Zhao, Liwei Lu, Weijun Peng, Arne Akbar, Irene Xy Wu, Song Li, Haijing Wu, Qianjin Lu","doi":"10.1016/j.redox.2024.103422","DOIUrl":"https://doi.org/10.1016/j.redox.2024.103422","url":null,"abstract":"<p><p>Time-restricted eating (TRE) has been shown to extent lifespans in drosophila and mouse models by affecting metabolic and anti-inflammatory activities. However, the effect of TRE on the human immune system, especially on immunosenescence, intestinal microbiome, and metabolism remains unclear. We conducted a 30-day 16:8 TRE single-arm clinical trial with 49 participants. Participants consumed daily meals from 9 a.m. to 5 p.m., provided by a nutrition canteen with a balanced, calorie-appropriate nutrition, which is designed by clinical nutritionists (ChiCTR2200058137). We monitored weight changes and weight-related parameters and focused on changes in the frequency of CD4<sup>+</sup> senescent T cells, immune repertoire from peripheral blood, as well as serum metabolites and gut microbiota. We found that up to 95.9 % of subjects experienced sustained weight loss after TRE. The frequency of circulating senescent CD4<sup>+</sup> T cells was decreased, while the frequency of Th1, Treg, Tfh-like, and B cells was increased. Regarding the immune repertoire, the proportions of T cell receptor alpha and beta chains were increased, whereas B cell receptor kappa and lambda chains were reduced. In addition, a reduced class switch recombination from immunoglobulin M (IgM) to immunoglobulin A (IgA) was observed. TRE upregulated the levels of anti-inflammatory and anti-aging serum metabolites named sphingosine-1-phosphate and prostaglandin-1. Additionally, several anti-inflammatory bacteria and probiotics were increased, such as Akkermansia and Rikenellaceae, and the composition of the gut microbiota tended to be \"younger\". Overall, TRE showed multiple anti-aging effects, which may help humans maintain a healthy lifestyle to stay \"young\". Clinical Trial Registration URL: https://www.chictr.org.cn/showproj.html?proj=159876.</p>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"103422"},"PeriodicalIF":10.7,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1016/j.redox.2024.103418
Brian Pak Shing Pang , Elsie Chit Yu Iu , Miaojia Hang , Wing Suen Chan , Margaret Chui Ling Tse , Connie Tsz Ying Yeung , Mingfu Wang , Parco Ming Fai Siu , Chi Wai Lee , Keqiang Ye , Ho So , Chi Bun Chan
Idiopathic inflammatory myopathy (commonly known as myositis) is a group of immune-related diseases characterized by muscle damage, weakness, and fatigue with unknown causes. Although overactivated innate immunity is a widely believed cause of myositis onset, the mechanism that provokes and maintains a high immune response in myositis patients is still unclear. This study aims to test if brain-derived neurotrophic factor (BDNF) deficiency per se is sufficient to cause myositis and determine its underlying mechanism. We found that ablating BDNF production in skeletal muscle is sufficient to trigger myositis development in mice. Muscle-specific Bdnf knockout (MBKO) mice displayed extensive myocyte necrosis, mononuclear cell infiltration, and myophagocytosis. In association with these damages, elevated production of pro-inflammatory cytokines such as interleukin (IL) 23, IL-1β, IL-18, and tumor necrosis factor α (TNFα) was found in the muscle of MBKO mice. Disruption of sarcolemma integrity was also detected in MBKO mice, which is a result of necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) and pyroptosis executioner Gasdermin D (GSDMD) activation. Mechanistically, diminishing BDNF synthesis in myotubes enhances the accumulation of mitochondrial reactive oxygen species (mtROS), which sensitizes the cells towards TNFα-induced receptor-interacting protein kinase (RIPs) activation and promotes the formation of NLR family pyrin domain containing 3 (NLRP3)-containing inflammasome. BDNF deficiency-induced cell death could be alleviated by scavenging mtROS, suppressing the activity of GSDMD, or inhibiting receptor-interacting kinase 3 (RIP3). Similarly, supplementation of BDNF mimetics, suppression of RIP3 activity, increasing the intramyocellular antioxidant, or enhancing mitophagy ameliorated the myopathies of MBKO mice and improved their muscle strength. Together, our study demonstrates that insufficient BDNF production in mouse muscle causes the development of pathological features of myositis via enhancing oxidative stress, necroptosis, and pyroptosis in myofibers.
{"title":"Deficiency of muscle-generated brain-derived neurotrophic factor causes inflammatory myopathy through reactive oxygen species-mediated necroptosis and pyroptosis","authors":"Brian Pak Shing Pang , Elsie Chit Yu Iu , Miaojia Hang , Wing Suen Chan , Margaret Chui Ling Tse , Connie Tsz Ying Yeung , Mingfu Wang , Parco Ming Fai Siu , Chi Wai Lee , Keqiang Ye , Ho So , Chi Bun Chan","doi":"10.1016/j.redox.2024.103418","DOIUrl":"10.1016/j.redox.2024.103418","url":null,"abstract":"<div><div>Idiopathic inflammatory myopathy (commonly known as myositis) is a group of immune-related diseases characterized by muscle damage, weakness, and fatigue with unknown causes. Although overactivated innate immunity is a widely believed cause of myositis onset, the mechanism that provokes and maintains a high immune response in myositis patients is still unclear. This study aims to test if brain-derived neurotrophic factor (BDNF) deficiency <em>per se</em> is sufficient to cause myositis and determine its underlying mechanism. We found that ablating BDNF production in skeletal muscle is sufficient to trigger myositis development in mice. Muscle-specific <em>Bdnf</em> knockout (MBKO) mice displayed extensive myocyte necrosis, mononuclear cell infiltration, and myophagocytosis. In association with these damages, elevated production of pro-inflammatory cytokines such as interleukin (IL) 23, IL-1β, IL-18, and tumor necrosis factor α (TNFα) was found in the muscle of MBKO mice. Disruption of sarcolemma integrity was also detected in MBKO mice, which is a result of necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) and pyroptosis executioner Gasdermin D (GSDMD) activation. Mechanistically, diminishing BDNF synthesis in myotubes enhances the accumulation of mitochondrial reactive oxygen species (mtROS), which sensitizes the cells towards TNFα-induced receptor-interacting protein kinase (RIPs) activation and promotes the formation of NLR family pyrin domain containing 3 (NLRP3)-containing inflammasome. BDNF deficiency-induced cell death could be alleviated by scavenging mtROS, suppressing the activity of GSDMD, or inhibiting receptor-interacting kinase 3 (RIP3). Similarly, supplementation of BDNF mimetics, suppression of RIP3 activity, increasing the intramyocellular antioxidant, or enhancing mitophagy ameliorated the myopathies of MBKO mice and improved their muscle strength. Together, our study demonstrates that insufficient BDNF production in mouse muscle causes the development of pathological features of myositis via enhancing oxidative stress, necroptosis, and pyroptosis in myofibers.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103418"},"PeriodicalIF":10.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute kidney injury (AKI) constitutes a significant public health issue. Sepsis accounts for over 50 % of AKI cases in the ICU. Recent findings from our research indicated that the PRD1-BF1-RIZ1 homeodomain protein 16 (PRDM16) inhibited the progression of diabetic kidney disease (DKD). However, its precise role and regulatory mechanism in sepsis-induced AKI remain obscure. This study reveals that lipopolysaccharide (LPS) and cecum ligation and puncture (CLP) instigated PRDM16 expression in Boston University mouse proximal tubule (BUMPT) cells and mouse kidneys, respectively. Functionally, PRDM16 curtailed LPS-induced ferroptosis. Mechanistically, PRDM16 associates with the promoter regions of nuclear factor-erythroid 2-related factor-2 (NRF2) and augments its expression, subsequently enhancing glutathione peroxidase 4 (GPX4) expression. Additionally, PRDM16 directly engages with the promoter regions of GPX4, stimulating its expression. Notably, these observations were corroborated in human renal tubular epithelial (HK-2) cells. Furthermore, the ablation of PRDM16 from kidney proximal tubules in mice inhibited NRF2 and GPX4 expression, leading to decreased glutathione (GSH)/oxidized glutathione (GSSG) ratio, increased Fe2+ and reactive oxygen species (ROS) production, exacerbated ferroptosis, and AKI progression. Conversely, PRDM16 knock-in exhibited the opposite effects. Ultimately, adenovirus (ADV)-PRDM16 plasmid or poly (lactide-glycolide acid) (PLGA)-encapsulated formononetin not only mitigated sepsis-induced AKI but also alleviated liver, cardiac, and lung injury. In summary, PRDM16 inhibits ferroptosis via the NRF2/GPX4 axis or GPX4 to prevent sepsis-induced multi-organ injury, including AKI. PLGA-encapsulated formononetin presents a promising therapeutic approach.
{"title":"PRDM16 suppresses ferroptosis to protect against sepsis-associated acute kidney injury by targeting the NRF2/GPX4 axis","authors":"Qiang Zheng , Jihong Xing , Xiaozhou Li , Xianming Tang , Dongshan Zhang","doi":"10.1016/j.redox.2024.103417","DOIUrl":"10.1016/j.redox.2024.103417","url":null,"abstract":"<div><div>Acute kidney injury (AKI) constitutes a significant public health issue. Sepsis accounts for over 50 % of AKI cases in the ICU. Recent findings from our research indicated that the PRD1-BF1-RIZ1 homeodomain protein 16 (PRDM16) inhibited the progression of diabetic kidney disease (DKD). However, its precise role and regulatory mechanism in sepsis-induced AKI remain obscure. This study reveals that lipopolysaccharide (LPS) and cecum ligation and puncture (CLP) instigated PRDM16 expression in Boston University mouse proximal tubule (BUMPT) cells and mouse kidneys, respectively. Functionally, PRDM16 curtailed LPS-induced ferroptosis. Mechanistically, PRDM16 associates with the promoter regions of nuclear factor-erythroid 2-related factor-2 (NRF2) and augments its expression, subsequently enhancing glutathione peroxidase 4 (GPX4) expression. Additionally, PRDM16 directly engages with the promoter regions of GPX4, stimulating its expression. Notably, these observations were corroborated in human renal tubular epithelial (HK-2) cells. Furthermore, the ablation of PRDM16 from kidney proximal tubules in mice inhibited NRF2 and GPX4 expression, leading to decreased glutathione (GSH)/oxidized glutathione (GSSG) ratio, increased Fe<sup>2+</sup> and reactive oxygen species (ROS) production, exacerbated ferroptosis, and AKI progression. Conversely, PRDM16 knock-in exhibited the opposite effects. Ultimately, adenovirus (ADV)-PRDM16 plasmid or poly (lactide-glycolide acid) (PLGA)-encapsulated formononetin not only mitigated sepsis-induced AKI but also alleviated liver, cardiac, and lung injury. In summary, PRDM16 inhibits ferroptosis via the NRF2/GPX4 axis or GPX4 to prevent sepsis-induced multi-organ injury, including AKI. PLGA-encapsulated formononetin presents a promising therapeutic approach.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103417"},"PeriodicalIF":10.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.redox.2024.103421
So-Won Pak , Woong-Il Kim , Se-Jin Lee , Sin-Hyang Park , Young-Kwon Cho , Joong-Sun Kim , Jong-Choon Kim , Sung-Hwan Kim , In-Sik Shin
Asian sand dust (ASD), a seasonal dust storm originating from the deserts of China and Mongolia, affects Korea and Japan during the spring, carrying soil particles and a variety of biochemical components. Exposure to ASD has been associated with the onset and exacerbation of respiratory disorders, although the underlying mechanisms remain unclear. This study investigates ASD-induced pulmonary toxicity and its mechanistic pathways, focusing on the role of thioredoxin-interacting protein (TXNIP). Using TXNIP knock-out (KO) mice and adeno-associated virus (AAV)-mediated TXNIP overexpression transgenic mice, we explored how TXNIP modulates ASD-induced pulmonary inflammation. Mice were exposed to ASD via intranasal administration on days 1, 3, and 5 to induce inflammation. ASD exposure led to significant pulmonary inflammation, evidenced by increased inflammatory cell counts and elevated cytokine levels in bronchoalveolar lavage fluid, as well as heightened protein expression of the TXNIP/NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. TXNIP KO mice exhibited attenuated airway inflammation and downregulation of the NLRP3 inflammasome compared to wild-type controls, while AAV-mediated TXNIP overexpression mice showed exacerbated inflammatory responses, including elevated NLRP3 inflammasome expression, compared to AAV-GFP controls. These findings suggest that TXNIP is a key regulator of ASD-induced pulmonary inflammation.
{"title":"TXNIP regulates pulmonary inflammation induced by Asian sand dust","authors":"So-Won Pak , Woong-Il Kim , Se-Jin Lee , Sin-Hyang Park , Young-Kwon Cho , Joong-Sun Kim , Jong-Choon Kim , Sung-Hwan Kim , In-Sik Shin","doi":"10.1016/j.redox.2024.103421","DOIUrl":"10.1016/j.redox.2024.103421","url":null,"abstract":"<div><div>Asian sand dust (ASD), a seasonal dust storm originating from the deserts of China and Mongolia, affects Korea and Japan during the spring, carrying soil particles and a variety of biochemical components. Exposure to ASD has been associated with the onset and exacerbation of respiratory disorders, although the underlying mechanisms remain unclear. This study investigates ASD-induced pulmonary toxicity and its mechanistic pathways, focusing on the role of thioredoxin-interacting protein (TXNIP). Using TXNIP knock-out (KO) mice and adeno-associated virus (AAV)-mediated TXNIP overexpression transgenic mice, we explored how TXNIP modulates ASD-induced pulmonary inflammation. Mice were exposed to ASD via intranasal administration on days 1, 3, and 5 to induce inflammation. ASD exposure led to significant pulmonary inflammation, evidenced by increased inflammatory cell counts and elevated cytokine levels in bronchoalveolar lavage fluid, as well as heightened protein expression of the TXNIP/NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. TXNIP KO mice exhibited attenuated airway inflammation and downregulation of the NLRP3 inflammasome compared to wild-type controls, while AAV-mediated TXNIP overexpression mice showed exacerbated inflammatory responses, including elevated NLRP3 inflammasome expression, compared to AAV-GFP controls. These findings suggest that TXNIP is a key regulator of ASD-induced pulmonary inflammation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103421"},"PeriodicalIF":10.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-05DOI: 10.1016/j.redox.2024.103419
Kai Wang , Xin Zhang , Yufei Fan , Liang Zhou , Yajun Duan , Su Li , Zhongkan Sun , Chunqian Zhang , Haoyu Yang , Wenxiu Yuan , Linyuan Peng , Xiaoyu Ma , Siliang Xiang , Tianzhi Wang , Mei Yang , Zhenyuan Zhang , Jiaxuan Wang , Zhongyuan Wang , Minxian Qian
The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.
{"title":"Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRASG12C inhibitor resistant tumors","authors":"Kai Wang , Xin Zhang , Yufei Fan , Liang Zhou , Yajun Duan , Su Li , Zhongkan Sun , Chunqian Zhang , Haoyu Yang , Wenxiu Yuan , Linyuan Peng , Xiaoyu Ma , Siliang Xiang , Tianzhi Wang , Mei Yang , Zhenyuan Zhang , Jiaxuan Wang , Zhongyuan Wang , Minxian Qian","doi":"10.1016/j.redox.2024.103419","DOIUrl":"10.1016/j.redox.2024.103419","url":null,"abstract":"<div><div>The clinical success of KRAS<sup>G12C</sup> inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRAS<sup>G12C</sup> mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRAS<sup>G12C</sup>-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103419"},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-05DOI: 10.1016/j.redox.2024.103415
Geli Li , Yuchen Ma , Sujie Zhang , Wen Lin , Xinyi Yao , Yating Zhou , Yanyong Zhao , Qi Rao , Yuchen Qu , Yuan Gao , Lianmin Chen , Yu Zhang , Feng Han , Meiling Sun , Chen Zhao
Ischemic stroke is a significant threat to human health. Currently, there is a lack of effective treatments for stroke, and progress in new neuron-centered drug target development is relatively slow. On the other hand, studies have demonstrated that brain microvascular endothelial cells (BMECs) are crucial components of the neurovascular unit and play pivotal roles in ischemic stroke progression. To better understand the complex multifaceted roles of BMECs in the regulation of ischemic stroke pathophysiology and facilitate BMEC-based drug target discovery, we utilized a transcriptomics-informed systems biology modeling approach and constructed a mechanism-based computational multipathway model to systematically investigate BMEC function and its modulatory potential. Extensive multilevel data regarding complex BMEC pathway signal transduction and biomarker expression under various pathophysiological conditions were used for quantitative model calibration and validation, and we generated dynamic BMEC phenotype maps in response to various stroke-related stimuli to identify potential determinants of BMEC fate under stress conditions. Through high-throughput model sensitivity analyses and virtual target perturbations in model-based single cells, our model predicted that targeting succinate could effectively reverse the detrimental cell phenotype of BMECs under oxygen and glucose deprivation/reoxygenation, a condition that mimics stroke pathogenesis, and we experimentally validated the utility of this new target in terms of regulating inflammatory factor production, free radical generation and tight junction protection in vitro and in vivo. Our work is the first that complementarily couples transcriptomic analysis with mechanistic systems-level pathway modeling in the study of BMEC function and endothelium-based therapeutic targets in ischemic stroke.
{"title":"A mechanistic systems biology model of brain microvascular endothelial cell signaling reveals dynamic pathway-based therapeutic targets for brain ischemia","authors":"Geli Li , Yuchen Ma , Sujie Zhang , Wen Lin , Xinyi Yao , Yating Zhou , Yanyong Zhao , Qi Rao , Yuchen Qu , Yuan Gao , Lianmin Chen , Yu Zhang , Feng Han , Meiling Sun , Chen Zhao","doi":"10.1016/j.redox.2024.103415","DOIUrl":"10.1016/j.redox.2024.103415","url":null,"abstract":"<div><div>Ischemic stroke is a significant threat to human health. Currently, there is a lack of effective treatments for stroke, and progress in new neuron-centered drug target development is relatively slow. On the other hand, studies have demonstrated that brain microvascular endothelial cells (BMECs) are crucial components of the neurovascular unit and play pivotal roles in ischemic stroke progression. To better understand the complex multifaceted roles of BMECs in the regulation of ischemic stroke pathophysiology and facilitate BMEC-based drug target discovery, we utilized a transcriptomics-informed systems biology modeling approach and constructed a mechanism-based computational multipathway model to systematically investigate BMEC function and its modulatory potential. Extensive multilevel data regarding complex BMEC pathway signal transduction and biomarker expression under various pathophysiological conditions were used for quantitative model calibration and validation, and we generated dynamic BMEC phenotype maps in response to various stroke-related stimuli to identify potential determinants of BMEC fate under stress conditions. Through high-throughput model sensitivity analyses and virtual target perturbations in model-based single cells, our model predicted that targeting succinate could effectively reverse the detrimental cell phenotype of BMECs under oxygen and glucose deprivation/reoxygenation, a condition that mimics stroke pathogenesis, and we experimentally validated the utility of this new target in terms of regulating inflammatory factor production, free radical generation and tight junction protection <em>in vitro</em> and <em>in vivo</em>. Our work is the first that complementarily couples transcriptomic analysis with mechanistic systems-level pathway modeling in the study of BMEC function and endothelium-based therapeutic targets in ischemic stroke.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103415"},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-02DOI: 10.1016/j.redox.2024.103416
Sarah Barakat , Şeyma Çimen , Seyed Mohammad Miri , Emre Vatandaşlar , Hayriye Ecem Yelkenci , Alejandro San Martín , Mustafa Çağlar Beker , Kıvanç Kök , Gürkan Öztürk , Emrah Eroglu
Fluorescent proteins (FPs) stand as pivotal tools extensively employed across diverse biological research endeavors in various model systems. However, long-standing concerns surround their use due to the numerous side effects associated with their expression. Recent investigations have brought to light the significance of hydrogen peroxide (H2O2) that is associated with the maturation process of green fluorescent protein (GFP) fluorophores. The structural and functional impairments associated with GFP expression are possibly linked to this amount of H2O2. In this study, we assess the impact of the GFP-based HyPer7 biosensor on cellular homeostasis and proteome changes, aiming to identify potential risks related to oxidative stress responses that potentially risks the application of such tools. Cells expressing genome-integrated HyPer7 demonstrated altered mitochondrial membrane potential (MMP), which was alleviated by the addition of antioxidants or culturing cells at physiological normoxia (5 kPa O2). Additionally, HyPer7-expressing cells also exhibited significant impairment in mitochondrial oxidative respiration, suggesting broader mitochondrial dysfunction. Through untargeted proteomics analysis, we identified 26 proteins exhibiting differential expression in HyPer7-expressing cells compared to respective control cells. Functional annotation analysis showed that the list of the delineated proteins is associated with cellular responses to stress and the regulation of antioxidant mechanisms. Our findings underscore the significance of caution and validation in ensuring a thorough comprehension of cellular responses when using fluorescent protein-based tools, thereby enhancing the reliability of the results.
{"title":"Bioenergetic shift and proteomic signature induced by lentiviral-transduction of GFP-based biosensors","authors":"Sarah Barakat , Şeyma Çimen , Seyed Mohammad Miri , Emre Vatandaşlar , Hayriye Ecem Yelkenci , Alejandro San Martín , Mustafa Çağlar Beker , Kıvanç Kök , Gürkan Öztürk , Emrah Eroglu","doi":"10.1016/j.redox.2024.103416","DOIUrl":"10.1016/j.redox.2024.103416","url":null,"abstract":"<div><div>Fluorescent proteins (FPs) stand as pivotal tools extensively employed across diverse biological research endeavors in various model systems. However, long-standing concerns surround their use due to the numerous side effects associated with their expression. Recent investigations have brought to light the significance of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) that is associated with the maturation process of green fluorescent protein (GFP) fluorophores. The structural and functional impairments associated with GFP expression are possibly linked to this amount of H<sub>2</sub>O<sub>2</sub>. In this study, we assess the impact of the GFP-based HyPer7 biosensor on cellular homeostasis and proteome changes, aiming to identify potential risks related to oxidative stress responses that potentially risks the application of such tools. Cells expressing genome-integrated HyPer7 demonstrated altered mitochondrial membrane potential (MMP), which was alleviated by the addition of antioxidants or culturing cells at physiological normoxia (5 kPa O<sub>2</sub>). Additionally, HyPer7-expressing cells also exhibited significant impairment in mitochondrial oxidative respiration, suggesting broader mitochondrial dysfunction. Through untargeted proteomics analysis, we identified 26 proteins exhibiting differential expression in HyPer7-expressing cells compared to respective control cells. Functional annotation analysis showed that the list of the delineated proteins is associated with cellular responses to stress and the regulation of antioxidant mechanisms. Our findings underscore the significance of caution and validation in ensuring a thorough comprehension of cellular responses when using fluorescent protein-based tools, thereby enhancing the reliability of the results.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"78 ","pages":"Article 103416"},"PeriodicalIF":10.7,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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