Life sciences最新文献_第7页

Ethanol exposure during differentiation of human induced pluripotent stem cells reduces cardiomyocyte generation and alters metabolism

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-30 DOI: 10.1016/j.lfs.2025.123434

Kun Man , Longping Fu , Alicia Lane , Frank Harris , Olivia Reid , Lawrence C. Armand , Parvin Forghani , Ronghu Wu , Victor Faundez , Lou Ann Brown , Chunhui Xu

Prenatal alcohol exposure increases the risk of congenital heart diseases (CHDs) by disrupting fetal development, yet the mechanisms underlying alcohol-induced cellular and molecular changes in human cardiogenesis remain unclear. This study investigates the effects of ethanol exposure on cardiomyocyte differentiation using human induced pluripotent stem cells (hiPSCs) as a model. Cardiomyocyte differentiation was induced using Wnt signaling molecules, and hiPSCs were treated with ethanol at concentrations of 17, 50, and 100 mM from day 0 to day 12. Ethanol treatment impaired cardiac differentiation efficiency in the early stage (days 5–7) and reduced cell proliferation in the late stage (days 12–13) in a dose-dependent manner, resulting in fewer cardiac progenitors and cardiomyocytes. Additionally, ethanol exposure caused mitochondrial defects, characterized by redox imbalance, reduced membrane potential, and decreased mitochondrial content and cellular respiration. Proteomic analysis revealed downregulation of proteins involved in calcium binding and fatty acid oxidation, a key metabolic pathway for cardiac development. These findings shed light on the mechanisms by which alcohol disrupts cardiomyocyte differentiation and may inform strategies to mitigate alcohol-induced CHD risk.

{"title":"Ethanol exposure during differentiation of human induced pluripotent stem cells reduces cardiomyocyte generation and alters metabolism","authors":"Kun Man , Longping Fu , Alicia Lane , Frank Harris , Olivia Reid , Lawrence C. Armand , Parvin Forghani , Ronghu Wu , Victor Faundez , Lou Ann Brown , Chunhui Xu","doi":"10.1016/j.lfs.2025.123434","DOIUrl":"10.1016/j.lfs.2025.123434","url":null,"abstract":"<div><div>Prenatal alcohol exposure increases the risk of congenital heart diseases (CHDs) by disrupting fetal development, yet the mechanisms underlying alcohol-induced cellular and molecular changes in human cardiogenesis remain unclear. This study investigates the effects of ethanol exposure on cardiomyocyte differentiation using human induced pluripotent stem cells (hiPSCs) as a model. Cardiomyocyte differentiation was induced using Wnt signaling molecules, and hiPSCs were treated with ethanol at concentrations of 17, 50, and 100 mM from day 0 to day 12. Ethanol treatment impaired cardiac differentiation efficiency in the early stage (days 5–7) and reduced cell proliferation in the late stage (days 12–13) in a dose-dependent manner, resulting in fewer cardiac progenitors and cardiomyocytes. Additionally, ethanol exposure caused mitochondrial defects, characterized by redox imbalance, reduced membrane potential, and decreased mitochondrial content and cellular respiration. Proteomic analysis revealed downregulation of proteins involved in calcium binding and fatty acid oxidation, a key metabolic pathway for cardiac development. These findings shed light on the mechanisms by which alcohol disrupts cardiomyocyte differentiation and may inform strategies to mitigate alcohol-induced CHD risk.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123434"},"PeriodicalIF":5.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-Endoglin monoclonal antibody prevents the progression of liver sinusoidal endothelial inflammation and fibrosis in MASH

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-29 DOI: 10.1016/j.lfs.2025.123428

Samira Eissazadeh , Petra Fikrova , Jana Urbankova Rathouska , Ivana Nemeckova , Katarina Tripska , Martina Vasinova , Radim Havelek , SeyedehNiloufar Mohammadi , Ivone Cristina Igreja Sa , Charles Theuer , Matthias König , Stanislav Micuda , Petr Nachtigal

Liver sinusoidal endothelial inflammation/dysfunction and fibrosis are a crucial part of Metabolic Dysfunction Associated Steatohepatitis (MASH) development. TRC105 and M1043 are anti-endoglin (ENG) monoclonal antibodies that bind ENG. In this study, we hypothesized that treatment with anti-ENG antibodies would prevent the progression of LSECs inflammation and fibrosis in vivo and in vitro.

MASH was induced in male C57BL/6 mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) for 4 or 8 weeks. In the rescue study, mice were divided into three groups: a control group (chow diet), a MASH group (CDAA-HFD + IgG), and a rescue group (CDAA-HFD + M1043). Later, two groups received rat IgG1 (10 mg/kg) and M1043 (10 mg/kg). In in vitro experiments, inflammation was induced in human LSECs by ox-LDL (50 μg/mL) and treated with TRC105 (300 μg/mL).

Liver sinusoidal endothelial inflammation/dysfunction in MASH animals was characterized by endothelial overexpression of ENG, VCAM-1, and ICAM-1 and reduced VE-cadherin and p-eNOS/eNOS expression. M1043 treatment prevented the overexpression of ENG, VCAM-1, and ICAM-1, the progression of liver fibrosis, and the increase of liver-to-body weight ratio. In vitro experiments with TRC105 confirmed the prevention of LSECs inflammation development by reduced ENG and VCAM-1 expression, as well as decreased THP-1 monocytic cell adhesion in ox-LDL activated LSECs.

In conclusion, we demonstrate that anti-ENG antibody treatment can prevent LSECs inflammation and fibrosis progression in a MASH animal model and LSECs inflammation in vitro. Thus, we propose directly targeted ENG may represent a promising pharmacological approach for addressing LSECs inflammation and liver fibrosis.

{"title":"Anti-Endoglin monoclonal antibody prevents the progression of liver sinusoidal endothelial inflammation and fibrosis in MASH","authors":"Samira Eissazadeh , Petra Fikrova , Jana Urbankova Rathouska , Ivana Nemeckova , Katarina Tripska , Martina Vasinova , Radim Havelek , SeyedehNiloufar Mohammadi , Ivone Cristina Igreja Sa , Charles Theuer , Matthias König , Stanislav Micuda , Petr Nachtigal","doi":"10.1016/j.lfs.2025.123428","DOIUrl":"10.1016/j.lfs.2025.123428","url":null,"abstract":"<div><div>Liver sinusoidal endothelial inflammation/dysfunction and fibrosis are a crucial part of Metabolic Dysfunction Associated Steatohepatitis (MASH) development. TRC105 and M1043 are anti-endoglin (ENG) monoclonal antibodies that bind ENG. In this study, we hypothesized that treatment with anti-ENG antibodies would prevent the progression of LSECs inflammation and fibrosis <em>in vivo</em> and <em>in vitro.</em></div><div>MASH was induced in male C57BL/6 mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) for 4 or 8 weeks. In the rescue study, mice were divided into three groups: a control group (chow diet), a MASH group (CDAA-HFD + IgG), and a rescue group (CDAA-HFD + M1043). Later, two groups received rat IgG1 (10 mg/kg) and M1043 (10 mg/kg). In <em>in vitro</em> experiments, inflammation was induced in human LSECs by ox-LDL (50 μg/mL) and treated with TRC105 (300 μg/mL).</div><div>Liver sinusoidal endothelial inflammation/dysfunction in MASH animals was characterized by endothelial overexpression of ENG, VCAM-1, and ICAM-1 and reduced VE-cadherin and p-eNOS/eNOS expression. M1043 treatment prevented the overexpression of ENG, VCAM-1, and ICAM-1, the progression of liver fibrosis, and the increase of liver-to-body weight ratio. <em>In vitro</em> experiments with TRC105 confirmed the prevention of LSECs inflammation development by reduced ENG and VCAM-1 expression, as well as decreased THP-1 monocytic cell adhesion in ox-LDL activated LSECs.</div><div>In conclusion, we demonstrate that anti-ENG antibody treatment can prevent LSECs inflammation and fibrosis progression in a MASH animal model and LSECs inflammation <em>in vitro</em>. Thus, we propose directly targeted ENG may represent a promising pharmacological approach for addressing LSECs inflammation and liver fibrosis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123428"},"PeriodicalIF":5.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MicroRNAs in vascular smooth muscle cells: Mechanisms, therapeutic potential, and advances in delivery systems

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-29 DOI: 10.1016/j.lfs.2025.123424

Boeun Jang , Dongfeng Zhang , Zhao Ma , Xueyao Yang , Libo Liu , Haoran Xing , Lanxin Feng , Jianqiao Song , Xin Zhao , Xiantao Song , Hongjia Zhang

Vascular smooth muscle cells (VSMCs) are essential players in a wide range of physiological processes, and their phenotypic transitions are critical in the development of vascular diseases such as atherosclerosis (AS), restenosis, aortic dissection/aneurysm (AAD), chronic kidney disease (CKD), and diabetes mellitus (DM). MicroRNAs (miRNAs), a class of short non-coding RNAs, regulates key cellular functions like proliferation, migration, and apoptosis by modulating gene expression. Numerous studies have shown that various miRNAs play pivotal roles in the pathophysiological processes of VSMCs, with VSMC phenotype switching being a key factor.

To harness miRNAs as therapeutic tools, researchers have focused on developing efficient delivery vectors, including exosomes, nanoparticles, and viral vectors. Recently, the exploration of miRNA characteristics and delivery mechanisms has led to the emergence of innovative systems, such as scaffold-based localized delivery methods, platelet-like fusion lipid nanoparticles(PLPs), liposome-exosome hybrid carriers, and stimulus-responsive delivery systems like miRNA micelles. These cutting-edge delivery systems not only enhance our understanding of miRNA's role in disease but also offer promising new strategies for gene therapy, paving the way for more precise and effective treatments in the future.

{"title":"MicroRNAs in vascular smooth muscle cells: Mechanisms, therapeutic potential, and advances in delivery systems","authors":"Boeun Jang , Dongfeng Zhang , Zhao Ma , Xueyao Yang , Libo Liu , Haoran Xing , Lanxin Feng , Jianqiao Song , Xin Zhao , Xiantao Song , Hongjia Zhang","doi":"10.1016/j.lfs.2025.123424","DOIUrl":"10.1016/j.lfs.2025.123424","url":null,"abstract":"<div><div>Vascular smooth muscle cells (VSMCs) are essential players in a wide range of physiological processes, and their phenotypic transitions are critical in the development of vascular diseases such as atherosclerosis (AS), restenosis, aortic dissection/aneurysm (AAD), chronic kidney disease (CKD), and diabetes mellitus (DM). MicroRNAs (miRNAs), a class of short non-coding RNAs, regulates key cellular functions like proliferation, migration, and apoptosis by modulating gene expression. Numerous studies have shown that various miRNAs play pivotal roles in the pathophysiological processes of VSMCs, with VSMC phenotype switching being a key factor.</div><div>To harness miRNAs as therapeutic tools, researchers have focused on developing efficient delivery vectors, including exosomes, nanoparticles, and viral vectors. Recently, the exploration of miRNA characteristics and delivery mechanisms has led to the emergence of innovative systems, such as scaffold-based localized delivery methods, platelet-like fusion lipid nanoparticles(PLPs), liposome-exosome hybrid carriers, and stimulus-responsive delivery systems like miRNA micelles. These cutting-edge delivery systems not only enhance our understanding of miRNA's role in disease but also offer promising new strategies for gene therapy, paving the way for more precise and effective treatments in the future.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123424"},"PeriodicalIF":5.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of NSUN6 protects against intermittent hypoxia-induced oxidative stress and inflammatory response in adipose tissue through suppressing macrophage ferroptosis and M1 polarization

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123433

Xinyu Wang , Linjing Gong , Chang Wei , Yuean Zhao , Longyi Ran , Peijun Li , Wenyu Gu , Xu Wu , Zongan Liang , Xinyuan Wang

Aims

Accumulating studies have demonstrated obstructive sleep apnea (OSA) is strongly associated with metabolic syndrome (MetS) and inflammatory response in adipose tissue. Chronic intermittent hypoxia (CIH) has been proved leading to M1 macrophage polarization that contributes to adipose tissue inflammation, but the molecular mechanism remains unclear. Epigenetic regulation of RNA has been found playing crucial roles in incremental diseases.

Main methods

Based on mining the GEO database, we constructed an IH (8 weeks) C57/6 J mice model to investigate the changes and interactions of key gene expression, M1 macrophage infiltration, and inflammatory markers in white adipose tissue. We also used an IH-treated (24 h) RAW 264.7 cells to further explore the mechanisms of hypoxia-induced M1 polarization, oxidative stress, and inflammatory response.

Key findings

According to the analysis of datasets, CIH increases the level of NSUN6 in adipose tissue and NSUN6 shows good diagnostic value of OSA. In the mice model, CIH exposure is also demonstrated to increases NSUN6 level and M1 macrophage infiltration in adipose tissue, which can be reversed by ferroptosis inhibitor. Studies show that CIH leads to ferroptosis and M1 macrophage polarization by promoting the expression of NSUN6 in vitro, thus resulting in inflammatory response.

Significance

Our findings provide a better understanding of the mechanisms of CIH-induced inflammation in adipose tissue. NSUN6 is firstly suggested to participate in macrophages ferroptosis and M1 polarization. Inhibition of NSUN6 in macrophages could protects against CIH-induce oxidative stress and inflammatory response in adipose tissue, thus becoming a potential therapeutic target to OSA-associated MetS.

{"title":"Inhibition of NSUN6 protects against intermittent hypoxia-induced oxidative stress and inflammatory response in adipose tissue through suppressing macrophage ferroptosis and M1 polarization","authors":"Xinyu Wang , Linjing Gong , Chang Wei , Yuean Zhao , Longyi Ran , Peijun Li , Wenyu Gu , Xu Wu , Zongan Liang , Xinyuan Wang","doi":"10.1016/j.lfs.2025.123433","DOIUrl":"10.1016/j.lfs.2025.123433","url":null,"abstract":"<div><h3>Aims</h3><div>Accumulating studies have demonstrated obstructive sleep apnea (OSA) is strongly associated with metabolic syndrome (MetS) and inflammatory response in adipose tissue. Chronic intermittent hypoxia (CIH) has been proved leading to M1 macrophage polarization that contributes to adipose tissue inflammation, but the molecular mechanism remains unclear. Epigenetic regulation of RNA has been found playing crucial roles in incremental diseases.</div></div><div><h3>Main methods</h3><div>Based on mining the GEO database, we constructed an IH (8 weeks) C57/6 J mice model to investigate the changes and interactions of key gene expression, M1 macrophage infiltration, and inflammatory markers in white adipose tissue. We also used an IH-treated (24 h) RAW 264.7 cells to further explore the mechanisms of hypoxia-induced M1 polarization, oxidative stress, and inflammatory response.</div></div><div><h3>Key findings</h3><div>According to the analysis of datasets, CIH increases the level of NSUN6 in adipose tissue and NSUN6 shows good diagnostic value of OSA. In the mice model, CIH exposure is also demonstrated to increases NSUN6 level and M1 macrophage infiltration in adipose tissue, which can be reversed by ferroptosis inhibitor. Studies show that CIH leads to ferroptosis and M1 macrophage polarization by promoting the expression of NSUN6 in vitro, thus resulting in inflammatory response.</div></div><div><h3>Significance</h3><div>Our findings provide a better understanding of the mechanisms of CIH-induced inflammation in adipose tissue. NSUN6 is firstly suggested to participate in macrophages ferroptosis and M1 polarization. Inhibition of NSUN6 in macrophages could protects against CIH-induce oxidative stress and inflammatory response in adipose tissue, thus becoming a potential therapeutic target to OSA-associated MetS.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123433"},"PeriodicalIF":5.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Arginine-derived carbon dots with antioxidant activity for treating aflatoxin B1-induced liver injury via Nrf2/Keap1 and NLRP3 pathways in mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123430

Xuejing Cao , Jiuxiang Cheng , Yongshou Yang , Jingmin Wang , Yongzhong Wang

Aflatoxin B1 (AFB1) is a prevalent contaminant in food and feed matrices, known for its hepatotoxic effects. Its metabolic breakdown generates reactive oxygen species (ROS), leading to oxidative stress and subsequent liver damage. Mitigating oxidative stress is, therefore, essential for ameliorating the hepatocellular damage and systemic toxicity caused by AFB1. Here, we synthesized arginine carbon dots (Arg-CDs) with robust antioxidant properties through a simple hydrothermal method using arginine and citric acid. Our investigation demonstrated that Arg-CDs effectively mitigate oxidative stress in nematodes. Furthermore, in murine models of AFB1-induced hepatic injury, Arg-CDs effectively restored liver function, as evidenced by the improvement in histopathological features and biochemical markers. Notably, Arg-CDs administration upregulated the transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2), along with its downstream antioxidant effectors and phase II detoxifying enzymes under AFB1 exposure. Moreover, Arg-CDs alleviated hepatic inflammatory injury by modulating the NLRP3/Caspase-1/GSDMD-mediated pyroptosis pathway. Arg-CDs also demonstrated therapeutic potential in enhancing intestinal barrier function in AFB1-exposed mice. Collectively, these findings highlight the potential of Arg-CDs as a novel and biocompatible therapeutic modality for alleviating AFB1-induced hepatic and intestinal damage.

{"title":"Arginine-derived carbon dots with antioxidant activity for treating aflatoxin B1-induced liver injury via Nrf2/Keap1 and NLRP3 pathways in mice","authors":"Xuejing Cao , Jiuxiang Cheng , Yongshou Yang , Jingmin Wang , Yongzhong Wang","doi":"10.1016/j.lfs.2025.123430","DOIUrl":"10.1016/j.lfs.2025.123430","url":null,"abstract":"<div><div>Aflatoxin B1 (AFB1) is a prevalent contaminant in food and feed matrices, known for its hepatotoxic effects. Its metabolic breakdown generates reactive oxygen species (ROS), leading to oxidative stress and subsequent liver damage. Mitigating oxidative stress is, therefore, essential for ameliorating the hepatocellular damage and systemic toxicity caused by AFB1. Here, we synthesized arginine carbon dots (Arg-CDs) with robust antioxidant properties through a simple hydrothermal method using arginine and citric acid. Our investigation demonstrated that Arg-CDs effectively mitigate oxidative stress in nematodes. Furthermore, in murine models of AFB1-induced hepatic injury, Arg-CDs effectively restored liver function, as evidenced by the improvement in histopathological features and biochemical markers. Notably, Arg-CDs administration upregulated the transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2), along with its downstream antioxidant effectors and phase II detoxifying enzymes under AFB1 exposure. Moreover, Arg-CDs alleviated hepatic inflammatory injury by modulating the NLRP3/Caspase-1/GSDMD-mediated pyroptosis pathway. Arg-CDs also demonstrated therapeutic potential in enhancing intestinal barrier function in AFB1-exposed mice. Collectively, these findings highlight the potential of Arg-CDs as a novel and biocompatible therapeutic modality for alleviating AFB1-induced hepatic and intestinal damage.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123430"},"PeriodicalIF":5.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular vesicles from mesenchymal stem cells improve liver injury in rats with mild liver damage. Underlying mechanisms and role of TGFβ

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123429

Gergana Mincheva , Victoria Moreno-Manzano , Vicente Felipo , Marta Llansola

Preventing the progression of liver damage to fibrosis would be beneficial for patients with steatotic liver disease (SLD). Mesenchymal stem cells (MSC) are a promising therapy for SLD and derived extracellular vesicles (EVs) could even improve the treatment's efficacy and safety. However, the mechanisms of MSC-EVs beneficial effects are not well known. It has been suggested that modifying the EVs cargo could improve their beneficial effects. The aims of this study were to assess if MSC-EVs reduce liver damage in a rat model of mild liver damage; to analyze the underlying mechanisms and to assess if silencing TGFβ enhances the beneficial effects of MSC-EVs. CCl₄ was injected three times per week during four weeks to induce mild liver damage. EVs from human adipocyte MSC and from TGFβ-depleted MSC (siTGFβ-MSC-EVs) were injected in the tail vein. Steatosis, fibrosis, liver inflammation, macrophage infiltration and liver content of fibrotic markers, DAMPs, cytokines and bile acids were analyzed. Normal MSC-EVs reduce the CCL2 increase in liver, macrophage infiltration and the increases in the fibrosis markers collagen I and α-SMA. Treatment with siTGFβ-MSC-EVs, in addition, reduces liver steatosis, the increase of bile acids (mainly TCA), and DAMP HMGB1 levels, inducing a larger reduction of collagen I in liver of CCl₄ rats.

Treatment with MSCs-EVs effectively reduces early liver damage. Silencing of TGFβ in MSCs enhances the beneficial effects by additional mechanisms. Early treatment with MSC-EVs, especially after silencing TGFβ, could improve liver damage in SLD patients.

{"title":"Extracellular vesicles from mesenchymal stem cells improve liver injury in rats with mild liver damage. Underlying mechanisms and role of TGFβ","authors":"Gergana Mincheva , Victoria Moreno-Manzano , Vicente Felipo , Marta Llansola","doi":"10.1016/j.lfs.2025.123429","DOIUrl":"10.1016/j.lfs.2025.123429","url":null,"abstract":"<div><div>Preventing the progression of liver damage to fibrosis would be beneficial for patients with steatotic liver disease (SLD). Mesenchymal stem cells (MSC) are a promising therapy for SLD and derived extracellular vesicles (EVs) could even improve the treatment's efficacy and safety. However, the mechanisms of MSC-EVs beneficial effects are not well known. It has been suggested that modifying the EVs cargo could improve their beneficial effects. The aims of this study were to assess if MSC-EVs reduce liver damage in a rat model of mild liver damage; to analyze the underlying mechanisms and to assess if silencing TGFβ enhances the beneficial effects of MSC-EVs. CCl<sub>4</sub> was injected three times per week during four weeks to induce mild liver damage. EVs from human adipocyte MSC and from TGFβ-depleted MSC (siTGFβ-MSC-EVs) were injected in the tail vein. Steatosis, fibrosis, liver inflammation, macrophage infiltration and liver content of fibrotic markers, DAMPs, cytokines and bile acids were analyzed. Normal MSC-EVs reduce the CCL2 increase in liver, macrophage infiltration and the increases in the fibrosis markers collagen I and α-SMA. Treatment with siTGFβ-MSC-EVs, in addition, reduces liver steatosis, the increase of bile acids (mainly TCA), and DAMP HMGB1 levels, inducing a larger reduction of collagen I in liver of CCl<sub>4</sub> rats.</div><div>Treatment with MSCs-EVs effectively reduces early liver damage. Silencing of TGFβ in MSCs enhances the beneficial effects by additional mechanisms. Early treatment with MSC-EVs, especially after silencing TGFβ, could improve liver damage in SLD patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123429"},"PeriodicalIF":5.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of megakaryocytic leukemia 1 in endothelial cells contributes to diabetic retinopathy in mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123425

Yuwen Zhu , Xiaofen Feng , Fei Wang , Yuhua Ding

Aims

Diabetic retinopathy (DR) represents one of the most devastating sequences in patients with diabetes. Endothelial dysfunction is a key pathological feature of and contributing factor to DR. In the present study we investigated the role of megakaryocytic leukemia 1 (MKL1) in DR pathogenesis.

Methods and materials

DR was induced in mice by feeding with a high-fat diet (HFD). The Mkl1-Rosa26-KI mice were crossed to the Cdh5-Cre^ERT2 mice to generate endothelial-specific MKL1 knock-in mice (MKL1^EC-KI).

Key findings

In cultured human primary retinal endothelial cells exposure to high glucose promoted nuclear translocation of MKL1 without altering its mRNA or protein expression. MKL1 knockdown ameliorated whereas MKL1 over-expression exacerbated high glucose induced impairment of endothelial barrier function. Compared to wild type littermates, MKL1^EC-KI mice fed on HFD displayed worsened insulin resistance and accelerated DR pathogenesis. Consistently, administration of an MKL1 inhibitor CCG-1423 protected the mice from HFD feeding induced metabolic disorders and DR pathogenesis.

Significance

Our data demonstrate that MKL1 may contribute to diabetic retinopathy by regulating endothelial behavior. Targeting MKL1 with small-molecule inhibitors can be considered as a therapeutic solution for the treatment of diabetic retinopathy.

{"title":"Activation of megakaryocytic leukemia 1 in endothelial cells contributes to diabetic retinopathy in mice","authors":"Yuwen Zhu , Xiaofen Feng , Fei Wang , Yuhua Ding","doi":"10.1016/j.lfs.2025.123425","DOIUrl":"10.1016/j.lfs.2025.123425","url":null,"abstract":"<div><h3>Aims</h3><div>Diabetic retinopathy (DR) represents one of the most devastating sequences in patients with diabetes. Endothelial dysfunction is a key pathological feature of and contributing factor to DR. In the present study we investigated the role of megakaryocytic leukemia 1 (MKL1) in DR pathogenesis.</div></div><div><h3>Methods and materials</h3><div>DR was induced in mice by feeding with a high-fat diet (HFD). The <em>Mkl1</em>-Rosa26-KI mice were crossed to the <em>Cdh5</em>-Cre<sup>ERT2</sup> mice to generate endothelial-specific MKL1 knock-in mice (MKL1<sup>EC-KI</sup>).</div></div><div><h3>Key findings</h3><div>In cultured human primary retinal endothelial cells exposure to high glucose promoted nuclear translocation of MKL1 without altering its mRNA or protein expression. MKL1 knockdown ameliorated whereas MKL1 over-expression exacerbated high glucose induced impairment of endothelial barrier function. Compared to wild type littermates, MKL1<sup>EC-KI</sup> mice fed on HFD displayed worsened insulin resistance and accelerated DR pathogenesis. Consistently, administration of an MKL1 inhibitor CCG-1423 protected the mice from HFD feeding induced metabolic disorders and DR pathogenesis.</div></div><div><h3>Significance</h3><div>Our data demonstrate that MKL1 may contribute to diabetic retinopathy by regulating endothelial behavior. Targeting MKL1 with small-molecule inhibitors can be considered as a therapeutic solution for the treatment of diabetic retinopathy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123425"},"PeriodicalIF":5.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cold and longevity: Can cold exposure counteract aging?

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123431

Ayoub Boulares, Hela Jdidi, Wafa Douzi

Aging is a multifaceted biological process characterized by a progressive decline in physiological functions and heightened vulnerability to diseases, shaped by genetic, environmental, and lifestyle factors. Among these, cold exposure has garnered interest for its potential anti-aging benefits. This review examines the impact of cold exposure on aging, focusing on key physiological processes such as inflammation, oxidative stress, metabolic regulation, and cardiovascular health. Cold exposure has been shown to reduce chronic inflammation, enhance antioxidant defenses, and improve metabolic health by activating brown adipose tissue. Furthermore, findings from hibernating mammals and model organisms suggest a connection between lower environmental temperatures and increased longevity. However, the potential long-term health risks of extended cold exposure, particularly in older adults, remain a significant concern. Epidemiological studies reveal increased rates of mortality and morbidity in populations living in cold climates, emphasizing the complexity of the relationship between cold exposure and aging. This review underscores the need for further research to elucidate the long-term effects of cold exposure on aging and to establish guidelines for leveraging its benefits while mitigating cold-induced risks.

{"title":"Cold and longevity: Can cold exposure counteract aging?","authors":"Ayoub Boulares, Hela Jdidi, Wafa Douzi","doi":"10.1016/j.lfs.2025.123431","DOIUrl":"10.1016/j.lfs.2025.123431","url":null,"abstract":"<div><div>Aging is a multifaceted biological process characterized by a progressive decline in physiological functions and heightened vulnerability to diseases, shaped by genetic, environmental, and lifestyle factors. Among these, cold exposure has garnered interest for its potential anti-aging benefits. This review examines the impact of cold exposure on aging, focusing on key physiological processes such as inflammation, oxidative stress, metabolic regulation, and cardiovascular health. Cold exposure has been shown to reduce chronic inflammation, enhance antioxidant defenses, and improve metabolic health by activating brown adipose tissue. Furthermore, findings from hibernating mammals and model organisms suggest a connection between lower environmental temperatures and increased longevity. However, the potential long-term health risks of extended cold exposure, particularly in older adults, remain a significant concern. Epidemiological studies reveal increased rates of mortality and morbidity in populations living in cold climates, emphasizing the complexity of the relationship between cold exposure and aging. This review underscores the need for further research to elucidate the long-term effects of cold exposure on aging and to establish guidelines for leveraging its benefits while mitigating cold-induced risks.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123431"},"PeriodicalIF":5.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Radiation exposure in neurosurgical intensive care unit patients: Balancing diagnostic benefits and long-term risks

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123426

A. Grote , M. Bopp , F. Stelten , A. Kemmling , B. Carl , Ch. Nimsky

Background

X-ray, computed tomography (CT), and digital subtraction angiography (DSA) techniques are indispensable in managing critically ill neurosurgical patients. However, repeated diagnostic imaging leads to cumulative radiation exposure, raising concerns about long-term risks such as malignancies. This study evaluates the frequency, dosage, and implications of radiation exposure in a neurosurgical intensive care unit (NICU) patient cohort.

Methods

A retrospective analysis was conducted on 589 patients admitted to the NICU between 2013 and 2018 with the diagnosis of traumatic brain injury (TBI), intracerebral hemorrhage (ICH), subarachnoidal hemorrhage (SAH), and stroke with >24 h of mechanical ventilation time. The cumulative radiation dose per patient from X-ray, CT, and DSA imaging was calculated and stratified by diagnostic indication, patient condition, and clinical course. To contextualize the findings, international benchmarks were compared.

Results

The cohort's median cumulative effective dose (ED) was 17.8 mSv (range: 1.7–194.3 mSv). CT scans accounted for 81.95 % of the total radiation exposure, with head and thorax imaging being the most frequently performed studies. Younger age and a shorter ventilation time revealed a significant increase in the calculated lifetime attributable risk (LAR) of radiation-induced cancer in multivariate testing. Comparisons with international data revealed a comparable level of radiation exposure in this cohort. Despite the high radiation burden, imaging was deemed clinically essential, with direct implications for patient outcomes.

Conclusion

While radiation exposure in NICU patients is substantial, the benefits of timely and accurate diagnostic information outweigh the potential long-term risks. In critical care settings, where patients face life-threatening conditions, the judicious use of diagnostic imaging is essential. Future efforts should focus on optimizing imaging protocols to minimize radiation exposure without compromising diagnostic quality.

{"title":"Radiation exposure in neurosurgical intensive care unit patients: Balancing diagnostic benefits and long-term risks","authors":"A. Grote , M. Bopp , F. Stelten , A. Kemmling , B. Carl , Ch. Nimsky","doi":"10.1016/j.lfs.2025.123426","DOIUrl":"10.1016/j.lfs.2025.123426","url":null,"abstract":"<div><h3>Background</h3><div>X-ray, computed tomography (CT), and digital subtraction angiography (DSA) techniques are indispensable in managing critically ill neurosurgical patients. However, repeated diagnostic imaging leads to cumulative radiation exposure, raising concerns about long-term risks such as malignancies. This study evaluates the frequency, dosage, and implications of radiation exposure in a neurosurgical intensive care unit (NICU) patient cohort.</div></div><div><h3>Methods</h3><div>A retrospective analysis was conducted on 589 patients admitted to the NICU between 2013 and 2018 with the diagnosis of traumatic brain injury (TBI), intracerebral hemorrhage (ICH), subarachnoidal hemorrhage (SAH), and stroke with >24 h of mechanical ventilation time. The cumulative radiation dose per patient from X-ray, CT, and DSA imaging was calculated and stratified by diagnostic indication, patient condition, and clinical course. To contextualize the findings, international benchmarks were compared.</div></div><div><h3>Results</h3><div>The cohort's median cumulative effective dose (ED) was 17.8 mSv (range: 1.7–194.3 mSv). CT scans accounted for 81.95 % of the total radiation exposure, with head and thorax imaging being the most frequently performed studies. Younger age and a shorter ventilation time revealed a significant increase in the calculated lifetime attributable risk (LAR) of radiation-induced cancer in multivariate testing. Comparisons with international data revealed a comparable level of radiation exposure in this cohort. Despite the high radiation burden, imaging was deemed clinically essential, with direct implications for patient outcomes.</div></div><div><h3>Conclusion</h3><div>While radiation exposure in NICU patients is substantial, the benefits of timely and accurate diagnostic information outweigh the potential long-term risks. In critical care settings, where patients face life-threatening conditions, the judicious use of diagnostic imaging is essential. Future efforts should focus on optimizing imaging protocols to minimize radiation exposure without compromising diagnostic quality.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123426"},"PeriodicalIF":5.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of a novel fibroblast growth factor receptor-agonistic peptide and its effect on diabetic wound healing

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123432

Mariya Farooq , Moonjung Hwang , Abdul Waheed Khan , Maria Batool , Bilal Ahmad , Wook Kim , Moon Suk Kim , Sangdun Choi

Aims

Fibroblast growth factor (FGF) is a broad class of secretory chemicals that act via FGF receptors (FGFR). The study aims to explore the role of a novel peptide, FAP1 (FGFR-agonistic peptide 1), in tissue regeneration and repair. It investigates whether FAP1 mimics basic fibroblast growth factor (bFGF) and accelerates wound healing both in vitro and in vivo.

Main methods

In this study, a novel peptide was designed and its ability to mimic bFGF was assessed through different in vitro experiments including its effect on cell proliferation, wound healing, cell signaling including FGFR1 phosphorylation and activation of mitogen-activated protein kinases (MAPKs). Specificity was confirmed through surface plasmon resonance (SPR) analysis and co-treatment with FGFR inhibitor, erdafitinib. In vivo, the effect of FAP1 on diabetic wound healing was tested in a mouse model, examining collagen production and the migration and proliferation of keratinocytes and fibroblasts.

Key findings

FAP1 specifically phosphorylated FGFR and activated MAPKs similar to bFGF. In vitro, it induced cell proliferation and accelerated wound healing. In vivo, FAP1 improved diabetic wound healing by increasing collagen production and promoting keratinocyte and fibroblast migration and proliferation. The specificity of FAP1 was confirmed through SPR.

Significance

FAP1 shows potential as a novel pharmacological alternative to natural bFGF for skin tissue regeneration and repair. Its ability to accelerate wound healing and its specificity for FGFR suggest that FAP1 could serve as a cost-effective substitute for bFGF protein in therapeutic applications.

{"title":"Identification of a novel fibroblast growth factor receptor-agonistic peptide and its effect on diabetic wound healing","authors":"Mariya Farooq , Moonjung Hwang , Abdul Waheed Khan , Maria Batool , Bilal Ahmad , Wook Kim , Moon Suk Kim , Sangdun Choi","doi":"10.1016/j.lfs.2025.123432","DOIUrl":"10.1016/j.lfs.2025.123432","url":null,"abstract":"<div><h3>Aims</h3><div>Fibroblast growth factor (FGF) is a broad class of secretory chemicals that act <em>via</em> FGF receptors (FGFR). The study aims to explore the role of a novel peptide, FAP1 (FGFR-agonistic peptide 1), in tissue regeneration and repair. It investigates whether FAP1 mimics basic fibroblast growth factor (bFGF) and accelerates wound healing both <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Main methods</h3><div>In this study, a novel peptide was designed and its ability to mimic bFGF was assessed through different <em>in vitro</em> experiments including its effect on cell proliferation, wound healing, cell signaling including FGFR1 phosphorylation and activation of mitogen-activated protein kinases (MAPKs). Specificity was confirmed through surface plasmon resonance (SPR) analysis and co-treatment with FGFR inhibitor, erdafitinib. <em>In vivo</em>, the effect of FAP1 on diabetic wound healing was tested in a mouse model, examining collagen production and the migration and proliferation of keratinocytes and fibroblasts.</div></div><div><h3>Key findings</h3><div>FAP1 specifically phosphorylated FGFR and activated MAPKs similar to bFGF. <em>In vitro</em>, it induced cell proliferation and accelerated wound healing. <em>In vivo</em>, FAP1 improved diabetic wound healing by increasing collagen production and promoting keratinocyte and fibroblast migration and proliferation. The specificity of FAP1 was confirmed through SPR.</div></div><div><h3>Significance</h3><div>FAP1 shows potential as a novel pharmacological alternative to natural bFGF for skin tissue regeneration and repair. Its ability to accelerate wound healing and its specificity for FGFR suggest that FAP1 could serve as a cost-effective substitute for bFGF protein in therapeutic applications.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123432"},"PeriodicalIF":5.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0