Pub Date : 2025-03-07DOI: 10.1016/j.lfs.2025.123547
Chengzhi Liu , Xinyu Wang , Shengnan Xu , Mingyue Liu , Xusheng Cao
Autophagy is a “self-eating” biological process that degrades cytoplasmic contents to ensure cellular homeostasis. Its response to stimuli occurs in two stages: Within a few to several hours of exposure to a stress condition, autophagic flow rapidly increases, which is mediated by post-translational modification (PTM). Subsequently, the transcriptional program is activated and mediates the persistent autophagic response. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is an inducible and dynamically cycling PTM; mounting evidence suggests that O-GlcNAc modification participates in the total autophagic process, including autophagy initiation, autophagosome formation, autophagosome-lysosome fusion, and transcriptional process. In this review, we summarize the current knowledge on the emerging role of O-GlcNAc modification in regulating autophagy-associated proteins and explain the different regulatory effects on autophagy exerted by O-GlcNAc modification.
{"title":"Regulation of autophagy: Insights into O-GlcNAc modification mechanisms","authors":"Chengzhi Liu , Xinyu Wang , Shengnan Xu , Mingyue Liu , Xusheng Cao","doi":"10.1016/j.lfs.2025.123547","DOIUrl":"10.1016/j.lfs.2025.123547","url":null,"abstract":"<div><div>Autophagy is a “self-eating” biological process that degrades cytoplasmic contents to ensure cellular homeostasis. Its response to stimuli occurs in two stages: Within a few to several hours of exposure to a stress condition, autophagic flow rapidly increases, which is mediated by post-translational modification (PTM). Subsequently, the transcriptional program is activated and mediates the persistent autophagic response. O-linked β-<em>N</em>-acetylglucosamine (O-GlcNAc) modification is an inducible and dynamically cycling PTM; mounting evidence suggests that O-GlcNAc modification participates in the total autophagic process, including autophagy initiation, autophagosome formation, autophagosome-lysosome fusion, and transcriptional process. In this review, we summarize the current knowledge on the emerging role of O-GlcNAc modification in regulating autophagy-associated proteins and explain the different regulatory effects on autophagy exerted by O-GlcNAc modification.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123547"},"PeriodicalIF":5.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578673","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}
Tuberculosis (TB) is one of the leading infectious disease causing mortality in the world and the rise of drug resistance; multi-drug resistance (MDR) and extensive-drug resistance (XDR) has added to extra complicacy of the disease. In this scenario, phage therapy has emerged as a potential treatment option against drug-sensitive/-resistant strains.
Materials and methods
The mycobacteriophage Kashi-SSH1 (KSSH1) was isolated from soil sample and was genomically, phenotypically, and functionally characterized. It includes genome assembly/annotation, transmission electron microscopy, multiplicity of infection (MOI), one-step growth curve, temperature/pH stability, confocal microscopy, host range determination and host growth reduction assays.
Key findings
KSSH1 is a novel polyvalent virulent mycobacteriophage from the Myoviridae family, classified under cluster C1 with a 155,659 bp genome carrying key lysis genes—Holliday junction resolvase, Holin, Lysin A, and Lysin B, has an optimal MOI of 0.01, a 60-min latent period, and a burst size of 200 phages/bacterial cell. It remains stable up to 55 °C and within pH 7–10, exhibiting broad-spectrum activity against Mycobacterium species, like M. fortuitum (opportunistic pathogen), M. tuberculosis H37Ra (attenuated pathogen), and M. smegmatis, but not non-mycobacterial hosts. KSSH1 exhibits comparable growth inhibition of M. smegmatis like the antibiotics isoniazid and rifampicin as compared to the control, in liquid cultures for over 50 h without regrowth.
Significance
KSSH1 exhibits strong lytic activity against various Mycobacterium species, lacks lysogeny-associated genes like integrases/transcriptional repressors, antibiotic resistance and virulence genes and remains stable from 4 °C to 37 °C and pH 8–10 ensuring safety/stability making it an ideal candidate for therapeutic use.
{"title":"Characterization of a novel virulent mycobacteriophage Kashi-SSH1 (KSSH1) depicting genus-specific broad-spectrum anti-mycobacterial activity","authors":"Tanmayee Nayak , Anuja Kakkar , Lav Kumar Jaiswal , Garima Kandwal , Anand Kumar Singh , Louise Temple , Ankush Gupta","doi":"10.1016/j.lfs.2025.123546","DOIUrl":"10.1016/j.lfs.2025.123546","url":null,"abstract":"<div><h3>Aim</h3><div>Tuberculosis (TB) is one of the leading infectious disease causing mortality in the world and the rise of drug resistance; multi-drug resistance (MDR) and extensive-drug resistance (XDR) has added to extra complicacy of the disease. In this scenario, phage therapy has emerged as a potential treatment option against drug-sensitive/-resistant strains.</div></div><div><h3>Materials and methods</h3><div>The mycobacteriophage Kashi-SSH1 (KSSH1) was isolated from soil sample and was genomically, phenotypically, and functionally characterized. It includes genome assembly/annotation, transmission electron microscopy, multiplicity of infection (MOI), one-step growth curve, temperature/pH stability, confocal microscopy, host range determination and host growth reduction assays.</div></div><div><h3>Key findings</h3><div>KSSH1 is a novel polyvalent virulent mycobacteriophage from the <em>Myoviridae</em> family, classified under cluster C1 with a 155,659 bp genome carrying key lysis genes—Holliday junction resolvase, Holin, Lysin A, and Lysin B, has an optimal MOI of 0.01, a 60-min latent period, and a burst size of 200 phages/bacterial cell. It remains stable up to 55 °C and within pH 7–10, exhibiting broad-spectrum activity against <em>Mycobacterium</em> species, like <em>M. fortuitum</em> (opportunistic pathogen), <em>M. tuberculosis</em> H37Ra (attenuated pathogen), and <em>M. smegmatis</em>, but not non-mycobacterial hosts. KSSH1 exhibits comparable growth inhibition of <em>M. smegmatis</em> like the antibiotics isoniazid and rifampicin as compared to the control, in liquid cultures for over 50 h without regrowth.</div></div><div><h3>Significance</h3><div>KSSH1 exhibits strong lytic activity against various <em>Mycobacterium</em> species, lacks lysogeny-associated genes like integrases/transcriptional repressors, antibiotic resistance and virulence genes and remains stable from 4 °C to 37 °C and pH 8–10 ensuring safety/stability making it an ideal candidate for therapeutic use.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123546"},"PeriodicalIF":5.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586196","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}
Pub Date : 2025-03-06DOI: 10.1016/j.lfs.2025.123530
Chun Feng , Jing Tang , Ke Wu , Lin Cheng , Lei Zhao , Wentao Zhu , Yuanzhen Zhang , Xingzhong Zhao , Bo Cai , Rongxiang He
Traditional prenatal diagnosis detects fetal disorders through invading uterus to access fetal cells, which may cause maternal complications, fetal injury, or even miscarriage. Safe and convenient non-invasive prenatal testing (NIPT) by analyzing fetal materials (cell-free DNA/RNA, cells, and extracellular vesicles) that circulate in maternal peripheral blood attracts great attention and has been applied in risk evaluation of several fetal disorders. Among those fetal analytes, fetal nucleated red blood cells (fNRBCs) comprise entire fetal genome, possess distinct membrane antigens, and have a lifespan limited in every single gestation. They were once expected to be an ideal biomarker for NIPT and even definitive prenatal diagnosis. However, recent advances of fNRBC-based NIPT are limited and their applications toward clinical practices are still challenging. Herein, we comprehensively overview research on fNRBCs in maternal peripheral blood, trying to dissect current predicament and inspire potential solutions. The source and lineage of fNRBCs, their entrance into maternal peripheral blood, and their physiochemical characteristics are discussed, and various strategies of label-free or immuno-affinitive isolation and subsequential identification of fNRBCs from maternal blood cells are summarized. Although proof-of-concept analyses toward detecting a few fetal disorders are demonstrated, current fNRBC-based NIPT still suffers many challenges when applied to clinical practices. Nevertheless, via thorough investigation and new analytical technologies, it is believed fNRBC-based NIPT will provide a promising platform to supplement the insufficiency of current strategies.
{"title":"The path winds along isolation and analyses of fetal nucleated red blood cells in maternal peripheral blood: Past, present, and future toward non-invasive prenatal diagnosis","authors":"Chun Feng , Jing Tang , Ke Wu , Lin Cheng , Lei Zhao , Wentao Zhu , Yuanzhen Zhang , Xingzhong Zhao , Bo Cai , Rongxiang He","doi":"10.1016/j.lfs.2025.123530","DOIUrl":"10.1016/j.lfs.2025.123530","url":null,"abstract":"<div><div>Traditional prenatal diagnosis detects fetal disorders through invading uterus to access fetal cells, which may cause maternal complications, fetal injury, or even miscarriage. Safe and convenient non-invasive prenatal testing (NIPT) by analyzing fetal materials (cell-free DNA/RNA, cells, and extracellular vesicles) that circulate in maternal peripheral blood attracts great attention and has been applied in risk evaluation of several fetal disorders. Among those fetal analytes, fetal nucleated red blood cells (fNRBCs) comprise entire fetal genome, possess distinct membrane antigens, and have a lifespan limited in every single gestation. They were once expected to be an ideal biomarker for NIPT and even definitive prenatal diagnosis. However, recent advances of fNRBC-based NIPT are limited and their applications toward clinical practices are still challenging. Herein, we comprehensively overview research on fNRBCs in maternal peripheral blood, trying to dissect current predicament and inspire potential solutions. The source and lineage of fNRBCs, their entrance into maternal peripheral blood, and their physiochemical characteristics are discussed, and various strategies of label-free or immuno-affinitive isolation and subsequential identification of fNRBCs from maternal blood cells are summarized. Although proof-of-concept analyses toward detecting a few fetal disorders are demonstrated, current fNRBC-based NIPT still suffers many challenges when applied to clinical practices. Nevertheless, <em>via</em> thorough investigation and new analytical technologies, it is believed fNRBC-based NIPT will provide a promising platform to supplement the insufficiency of current strategies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123530"},"PeriodicalIF":5.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578670","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}
Pub Date : 2025-03-06DOI: 10.1016/j.lfs.2025.123532
Chenchen Geng , Xiaohan Li , Lingfeng Dan , Liyan Xie , Min Zhou , Kaile Guan , Qi Chen , Yan Xu , Rong Ding , Jiaqi Li , Yue Zhang , Mohammad Sharifzadeh , Rui Liu , Wenting Li , Huimin Lu
Aims
While emerging evidence implicates an abnormal stearic-to-palmitic acid ratio in saturated fats in beta-cell dysfunction, their gestational/lactational impacts remain underexplored. This study evaluates the differential transient and long-lasting effects of high-fat diets with contrasting stearic-to-palmitic acid ratios on maternal beta-cell function.
Materials and methods
Female mice were fed high-fat diets with high/low stearic-to-palmitic acid ratios during gestation/lactation, followed by a recovery period and subsequent exposure to an obesogenic diet. Beta-cell function was assessed using ex-vivo glucose-stimulated insulin secretion (GSIS) and immunohistochemistry. Islets mRNA profiling was performed using RNA-sequencing.
Key findings
Both high- and low-ratio groups showed impaired GSIS post-lactation. High-ratio-fed dams exhibited pronounced compensatory responses, including increased islet size, number, and elevated Stx1a, Stx4, Pdx1, Mafa expression. Following metabolic re-challenge, high-ratio group demonstrated more severely impaired ex vivo insulin release. No significant differences in islet apoptosis and senescence were observed between the two groups. Transcriptomic profiling, however, revealed distinct mechanistic pathways: the high-ratio diet was likely to disrupt beta-cell organelles ultrastructure, while the low-ratio diet predominantly dysregulated chemokine-mediated immune signaling networks.
Significance
Gestational/lactational exposure to high-fat diets with both high and low ratios of stearic-to-palmitic acid exerts pronounced transient impacts on beta-cell function, with the high-ratio diet inducing more severe and persistent detrimental effects. These findings highlight the critical influence and importance of dietary saturated fatty acid composition in maternal metabolic programming and beta-cell vulnerability.
{"title":"Female mice exposed to varying ratios of stearic to palmitic acid in a high-fat diet during gestation and lactation shows differential impairments of beta-cell function","authors":"Chenchen Geng , Xiaohan Li , Lingfeng Dan , Liyan Xie , Min Zhou , Kaile Guan , Qi Chen , Yan Xu , Rong Ding , Jiaqi Li , Yue Zhang , Mohammad Sharifzadeh , Rui Liu , Wenting Li , Huimin Lu","doi":"10.1016/j.lfs.2025.123532","DOIUrl":"10.1016/j.lfs.2025.123532","url":null,"abstract":"<div><h3>Aims</h3><div>While emerging evidence implicates an abnormal stearic-to-palmitic acid ratio in saturated fats in beta-cell dysfunction, their gestational/lactational impacts remain underexplored. This study evaluates the differential transient and long-lasting effects of high-fat diets with contrasting stearic-to-palmitic acid ratios on maternal beta-cell function.</div></div><div><h3>Materials and methods</h3><div>Female mice were fed high-fat diets with high/low stearic-to-palmitic acid ratios during gestation/lactation, followed by a recovery period and subsequent exposure to an obesogenic diet. Beta-cell function was assessed using <em>ex-vivo</em> glucose-stimulated insulin secretion (GSIS) and immunohistochemistry. Islets mRNA profiling was performed using RNA-sequencing.</div></div><div><h3>Key findings</h3><div>Both high- and low-ratio groups showed impaired GSIS post-lactation. High-ratio-fed dams exhibited pronounced compensatory responses, including increased islet size, number, and elevated <em>Stx1a</em>, <em>Stx4</em>, <em>Pdx1</em>, <em>Mafa</em> expression. Following metabolic re-challenge, high-ratio group demonstrated more severely impaired <em>ex vivo</em> insulin release. No significant differences in islet apoptosis and senescence were observed between the two groups. Transcriptomic profiling, however, revealed distinct mechanistic pathways: the high-ratio diet was likely to disrupt beta-cell organelles ultrastructure, while the low-ratio diet predominantly dysregulated chemokine-mediated immune signaling networks.</div></div><div><h3>Significance</h3><div>Gestational/lactational exposure to high-fat diets with both high and low ratios of stearic-to-palmitic acid exerts pronounced transient impacts on beta-cell function, with the high-ratio diet inducing more severe and persistent detrimental effects. These findings highlight the critical influence and importance of dietary saturated fatty acid composition in maternal metabolic programming and beta-cell vulnerability.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123532"},"PeriodicalIF":5.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578675","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}
Sickle cell disease (SCD) is one of the most prevalent hereditary blood disorders characterized by aberrant hemoglobin synthesis that causes red blood cells (RBCs) to sickle and result in vaso-occlusion. The complex pathophysiological mechanisms that underlie SCD are explored in this study, including hemoglobin polymerization, the formation of fetal hemoglobin (HbF), and hemoglobin switching regulation. Notably, pharmaceutical approaches like hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, in addition to therapeutic techniques like gene therapies like Casgevy and Lyfgenia, signify noteworthy advancements in the management of issues connected to SCD. Furthermore, the deciphering of the molecular mechanisms that dictate hemoglobin switching has revealed several potentially therapeutic targets, including key transcriptional repressors such as β-cell lymphoma/leukemia 11A (BCL11A), Zinc finger and BTB domain-containing 7A (ZBTB7A), Nuclear Factor IX (NFIX), and Nuclear Factor IA (NFIA), which play crucial roles in γ-globin silencing. Additionally, transcriptional activators such as Nuclear Factor Y (NF-Y), and Hypoxia-inducible factor 1α (HIF1α) have emerged as promising regulators that can disrupt repression and enhance HbF synthesis. Other epigenetic regulators, such as lysine-specific histone demethylase 1 (LSD1), euchromatic histone methyltransferases 1/2 (EHMT1/2), histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and protein arginine methyltransferases (PRMTs). It has been demonstrated that inhibiting these targets can prevent the silencing of the gene encoding for the formation of γ-chains and, in turn, increase the synthesis of HbF, providing a possible treatment option for SCD symptoms. These approaches could pave the way for innovative, mechanism-driven therapies that address the unmet medical needs of SCD patients.
{"title":"A critique review of fetal hemoglobin modulators through targeting epigenetic regulators for the treatment of sickle cell disease","authors":"Chandu Ala , Sivaprakash Ramalingam , Chandra Sekhar Kondapalli Venkata Gowri , Murugesan Sankaranarayanan","doi":"10.1016/j.lfs.2025.123536","DOIUrl":"10.1016/j.lfs.2025.123536","url":null,"abstract":"<div><div>Sickle cell disease (SCD) is one of the most prevalent hereditary blood disorders characterized by aberrant hemoglobin synthesis that causes red blood cells (RBCs) to sickle and result in vaso-occlusion. The complex pathophysiological mechanisms that underlie SCD are explored in this study, including hemoglobin polymerization, the formation of fetal hemoglobin (HbF), and hemoglobin switching regulation. Notably, pharmaceutical approaches like hydroxyurea, <span>l</span>-glutamine, voxelotor, and crizanlizumab, in addition to therapeutic techniques like gene therapies like Casgevy and Lyfgenia, signify noteworthy advancements in the management of issues connected to SCD. Furthermore, the deciphering of the molecular mechanisms that dictate hemoglobin switching has revealed several potentially therapeutic targets, including key transcriptional repressors such as β-cell lymphoma/leukemia 11A (BCL11A), Zinc finger and BTB domain-containing 7A (ZBTB7A), Nuclear Factor IX (NFIX), and Nuclear Factor IA (NFIA), which play crucial roles in γ-globin silencing. Additionally, transcriptional activators such as Nuclear Factor Y (NF-Y), and Hypoxia-inducible factor 1α (HIF1α) have emerged as promising regulators that can disrupt repression and enhance HbF synthesis. Other epigenetic regulators, such as lysine-specific histone demethylase 1 (LSD1), euchromatic histone methyltransferases 1/2 (EHMT1/2), histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and protein arginine methyltransferases (PRMTs). It has been demonstrated that inhibiting these targets can prevent the silencing of the gene encoding for the formation of γ-chains and, in turn, increase the synthesis of HbF, providing a possible treatment option for SCD symptoms. These approaches could pave the way for innovative, mechanism-driven therapies that address the unmet medical needs of SCD patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123536"},"PeriodicalIF":5.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578672","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}
Pub Date : 2025-03-05DOI: 10.1016/j.lfs.2025.123537
Shengyu Chen , Rongrong Chen , Mengxian Luo , Yijun Luo , Xiao Ma , Huawei Zhao , Zhenghao Xu
Aims
Numerous clinical studies have revealed a positive correlation between rheumatoid arthritis (RA) and an elevated risk of epilepsy. This study aimed to investigate the seizure susceptibility in the collagen-induced arthritis (CIA) mice model.
Main methods
The classic CIA model was used to mimic RA pathogenesis in mice. The pentylenetetrazole (PTZ)-induced seizure model and audiogenic seizure model were used to evaluate seizure susceptibility. Neuroinflammation was assessed through ELISA, Western blot, and immunofluorescence staining. Additionally, electrophysiological techniques were applied to investigate the excitation/inhibition (E/I) balance.
Key findings
CIA modeling raised the level of IL-1β, induced E/I imbalance in the dentate gyrus (DG) region, and enhanced seizure susceptibility to PTZ in C57BL/6 mice. However, knockout (KO) of IL-1β attenuated peripheral inflammatory symptoms and blocked the increase in seizure susceptibility in CIA-modeled mice. Additionally, conditional IL-1R1 KO in CaMKIIα-positive neurons did not affect the peripheral inflammatory symptoms but rescued both the increased seizure susceptibility and E/I imbalance in CIA-modeled mice. Furthermore, increased susceptibility to audiogenic seizure susceptibility was also observed in CIA-modeled BDA/1 mice, accompanied by the elevated IL-1β levels and neuronal IL-1R1-related Akt phosphorylation in the hippocampus.
Significance
Increased seizure susceptibility in the CIA mouse model depends on IL-1β and neuronal IL-1R1. These data indicated that IL-1β and neuronal IL-1R1 may be the key targets for its intervention.
{"title":"Increased seizure susceptibility in the collagen-induced arthritis mouse model depends on neuronal IL-1R1","authors":"Shengyu Chen , Rongrong Chen , Mengxian Luo , Yijun Luo , Xiao Ma , Huawei Zhao , Zhenghao Xu","doi":"10.1016/j.lfs.2025.123537","DOIUrl":"10.1016/j.lfs.2025.123537","url":null,"abstract":"<div><h3>Aims</h3><div>Numerous clinical studies have revealed a positive correlation between rheumatoid arthritis (RA) and an elevated risk of epilepsy. This study aimed to investigate the seizure susceptibility in the collagen-induced arthritis (CIA) mice model.</div></div><div><h3>Main methods</h3><div>The classic CIA model was used to mimic RA pathogenesis in mice. The pentylenetetrazole (PTZ)-induced seizure model and audiogenic seizure model were used to evaluate seizure susceptibility. Neuroinflammation was assessed through ELISA, Western blot, and immunofluorescence staining. Additionally, electrophysiological techniques were applied to investigate the excitation/inhibition (E/I) balance.</div></div><div><h3>Key findings</h3><div>CIA modeling raised the level of IL-1β, induced E/I imbalance in the dentate gyrus (DG) region, and enhanced seizure susceptibility to PTZ in C57BL/6 mice. However, knockout (KO) of IL-1β attenuated peripheral inflammatory symptoms and blocked the increase in seizure susceptibility in CIA-modeled mice. Additionally, conditional IL-1R1 KO in CaMKIIα-positive neurons did not affect the peripheral inflammatory symptoms but rescued both the increased seizure susceptibility and E/I imbalance in CIA-modeled mice. Furthermore, increased susceptibility to audiogenic seizure susceptibility was also observed in CIA-modeled BDA/1 mice, accompanied by the elevated IL-1β levels and neuronal IL-1R1-related Akt phosphorylation in the hippocampus.</div></div><div><h3>Significance</h3><div>Increased seizure susceptibility in the CIA mouse model depends on IL-1β and neuronal IL-1R1. These data indicated that IL-1β and neuronal IL-1R1 may be the key targets for its intervention.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123537"},"PeriodicalIF":5.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578674","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}
Pub Date : 2025-03-05DOI: 10.1016/j.lfs.2025.123535
Min Li, Yanqiu Peng, Yuke Shi, Yunfei Liu, Jian Zhang
DLK1, as a membrane-bound protein, has been extensively studied in the field of cancer research. As a ligand downstream of the Notch pathway, it broadly influences developmental and metabolic processes in the body. With deeper research, it has been found that DLK1 can induce the synthesis and secretion of insulin through the ERK and AKT pathways, playing a crucial role in the development of metabolic diseases. Diabetes mellitus (DM) is a chronic metabolic disorder characterized by insufficient insulin production by the pancreas or inadequate utilization of insulin by the body. This article aims to review the relationship between DLK1 and diabetes, recent research advancements, and to discuss future research directions and challenges.
{"title":"Advancements in the study of DLK1 in the pathogenesis of diabetes","authors":"Min Li, Yanqiu Peng, Yuke Shi, Yunfei Liu, Jian Zhang","doi":"10.1016/j.lfs.2025.123535","DOIUrl":"10.1016/j.lfs.2025.123535","url":null,"abstract":"<div><div>DLK1, as a membrane-bound protein, has been extensively studied in the field of cancer research. As a ligand downstream of the Notch pathway, it broadly influences developmental and metabolic processes in the body. With deeper research, it has been found that DLK1 can induce the synthesis and secretion of insulin through the ERK and AKT pathways, playing a crucial role in the development of metabolic diseases. Diabetes mellitus (DM) is a chronic metabolic disorder characterized by insufficient insulin production by the pancreas or inadequate utilization of insulin by the body. This article aims to review the relationship between DLK1 and diabetes, recent research advancements, and to discuss future research directions and challenges.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123535"},"PeriodicalIF":5.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578671","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}
Pub Date : 2025-03-05DOI: 10.1016/j.lfs.2025.123531
Yutong Liu , Yaqi Sun , Anjie Chen , Jiaqi Chen , Tikang Zhu , Shuting Wang , Wanying Qiao , Ding Zhou , Xirui Zhang , Shuangshuang Chen , Yaxin Shi , Yuan Yang , Jia Wang , Lijie Wu , Lili Fan
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder, with oxidative stress recognized as a key pathogenic mechanisms. Oxidative stress disrupts intracellular dynamic- thiol/disulfide homeostasis (DTDH), potentially leading to disulfidptosis, a newly identified cell death mechanism. While studies suggest a link between DTDH and ASD, direct evidence implicating disulfidptosis in ASD pathogenesis remains limited. In this study, Mendelian randomization analysis revealed a significant causal association between disulfidptosis-related sulfhydryl oxidase 1 and 2 and ASD (OR1 = 0.883, OR2 = 0.924, p < 0.05). A positive correlation between protein disulfide-isomerase and cognitive performance (OR = 1.021, p < 0.01) further supported the role of disulfidptosis in ASD. Seven disulfidptosis-related genes (TIMP1, STAT3, VWA1, ADA, IL5, PF4, and TXNDC12) were identified and linked to immune cell alterations. A TF-miRNA-mRNA regulatory network and a predictive model (AUC = 0.759) were constructed and external validation datasets (AUC = 0.811). Immune infiltration analysis demonstrated altered expression of naive B cells and three other types of immune cells in ASD children. Animal experiments further validated the differential expression of key genes, highlighting their relevance to ASD pathogenesis. Animal experiments found that BTBR mice exhibit glucose starvation and NADPH depletion, with the specific indicator Slc7a11 being highly expressed. Silencing Slc7a11 can improve core ASD impairments in BTBR mice.
Conclusion
This study establishes the first mechanistic link between disulfidptosis and ASD, identifies seven key genes and their regulatory network, and develops a predictive model with clinical utility. Animal experiments further confirmed the strong association between disulfidpotosis and ASD phenotypes. These findings offer novel therapeutic targets for modulating oxidative stress in ASD.
{"title":"Involvement of disulfidptosis in the pathophysiology of autism spectrum disorder","authors":"Yutong Liu , Yaqi Sun , Anjie Chen , Jiaqi Chen , Tikang Zhu , Shuting Wang , Wanying Qiao , Ding Zhou , Xirui Zhang , Shuangshuang Chen , Yaxin Shi , Yuan Yang , Jia Wang , Lijie Wu , Lili Fan","doi":"10.1016/j.lfs.2025.123531","DOIUrl":"10.1016/j.lfs.2025.123531","url":null,"abstract":"<div><div>Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder, with oxidative stress recognized as a key pathogenic mechanisms. Oxidative stress disrupts intracellular dynamic- thiol/disulfide homeostasis (DTDH), potentially leading to disulfidptosis, a newly identified cell death mechanism. While studies suggest a link between DTDH and ASD, direct evidence implicating disulfidptosis in ASD pathogenesis remains limited. In this study, Mendelian randomization analysis revealed a significant causal association between disulfidptosis-related sulfhydryl oxidase 1 and 2 and ASD (OR1 = 0.883, OR2 = 0.924, <em>p</em> < 0.05). A positive correlation between protein disulfide-isomerase and cognitive performance (OR = 1.021, <em>p</em> < 0.01) further supported the role of disulfidptosis in ASD. Seven disulfidptosis-related genes (<em>TIMP1, STAT3, VWA1, ADA, IL5, PF4,</em> and <em>TXNDC12</em>) were identified and linked to immune cell alterations. A TF-miRNA-mRNA regulatory network and a predictive model (AUC = 0.759) were constructed and external validation datasets (AUC = 0.811). Immune infiltration analysis demonstrated altered expression of naive B cells and three other types of immune cells in ASD children. Animal experiments further validated the differential expression of key genes, highlighting their relevance to ASD pathogenesis. Animal experiments found that BTBR mice exhibit glucose starvation and NADPH depletion, with the specific indicator Slc7a11 being highly expressed. Silencing Slc7a11 can improve core ASD impairments in BTBR mice.</div></div><div><h3>Conclusion</h3><div>This study establishes the first mechanistic link between disulfidptosis and ASD, identifies seven key genes and their regulatory network, and develops a predictive model with clinical utility. Animal experiments further confirmed the strong association between disulfidpotosis and ASD phenotypes. These findings offer novel therapeutic targets for modulating oxidative stress in ASD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123531"},"PeriodicalIF":5.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562197","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}
Pub Date : 2025-03-05DOI: 10.1016/j.lfs.2025.123525
Xi Wang , Houda Gui , Chenghang Liu , Fenglei Huo , Weipeng Lan , Xingyan Zhu , Wenhao Wang , Anquan Ma , Jing Lan
Aims
Periodontitis is a chronic inflammatory disorder arising from an imbalance between oral microbiota and the host's immune response, with macrophages as pivotal targets for prevention and treatment. Endosome-associated Trafficking Regulator 1 (ENTR1) is indispensable for protein trafficking and implant osseointegration. However, its specific role in periodontitis has yet to be clarified. This research seeks to explore the effects of ENTR1 on macrophage polarization, elucidate its mechanisms, and evaluate its regulatory functions in the regeneration of periodontal tissues.
Materials and methods
A ligature-induced periodontitis mouse model was established to investigate the correlation between macrophage polarization markers and ENTR1 expression. Techniques including qRT-PCR, Western blot, ELISA, flow cytometry, and immunofluorescence staining were utilized to evaluate the impact of ENTR1 on macrophage polarization under inflammatory stimuli. Micro-CT and histological staining were applied to assess periodontal bone resorption. The interaction between ENTR1 and AMP-activated protein kinase (AMPK) was explored through Western blot and co-immunoprecipitation, further validated by applying the AMPK inhibitor Compound C (CpC).
Key findings
ENTR1 expression was down-regulated in the mice with periodontitis relative to healthy controls. Overexpressing ENTR1 suppressed macrophage M1 polarization and mitigated bone loss in periodontitis, while knocking down ENTR1 exacerbated these effects. ENTR1 directly interacted with AMPK, enhancing its phosphorylation. Furthermore, the inhibitory impact of ENTR1 on macrophage M1 polarization and inflammation-induced alveolar bone resorption were partially attenuated by CpC treatment.
Significance
ENTR1 regulates periodontitis by suppressing macrophage M1 polarization through enhancing AMPK phosphorylation, presenting a promising therapeutic target for its prevention and management.
{"title":"ENTR1 regulates periodontitis by modulating macrophage M1 polarization via AMPK activation","authors":"Xi Wang , Houda Gui , Chenghang Liu , Fenglei Huo , Weipeng Lan , Xingyan Zhu , Wenhao Wang , Anquan Ma , Jing Lan","doi":"10.1016/j.lfs.2025.123525","DOIUrl":"10.1016/j.lfs.2025.123525","url":null,"abstract":"<div><h3>Aims</h3><div>Periodontitis is a chronic inflammatory disorder arising from an imbalance between oral microbiota and the host's immune response, with macrophages as pivotal targets for prevention and treatment. Endosome-associated Trafficking Regulator 1 (ENTR1) is indispensable for protein trafficking and implant osseointegration. However, its specific role in periodontitis has yet to be clarified. This research seeks to explore the effects of ENTR1 on macrophage polarization, elucidate its mechanisms, and evaluate its regulatory functions in the regeneration of periodontal tissues.</div></div><div><h3>Materials and methods</h3><div>A ligature-induced periodontitis mouse model was established to investigate the correlation between macrophage polarization markers and ENTR1 expression. Techniques including qRT-PCR, Western blot, ELISA, flow cytometry, and immunofluorescence staining were utilized to evaluate the impact of ENTR1 on macrophage polarization under inflammatory stimuli. Micro-CT and histological staining were applied to assess periodontal bone resorption. The interaction between ENTR1 and AMP-activated protein kinase (AMPK) was explored through Western blot and co-immunoprecipitation, further validated by applying the AMPK inhibitor Compound C (CpC).</div></div><div><h3>Key findings</h3><div>ENTR1 expression was down-regulated in the mice with periodontitis relative to healthy controls. Overexpressing ENTR1 suppressed macrophage M1 polarization and mitigated bone loss in periodontitis, while knocking down ENTR1 exacerbated these effects. ENTR1 directly interacted with AMPK, enhancing its phosphorylation. Furthermore, the inhibitory impact of ENTR1 on macrophage M1 polarization and inflammation-induced alveolar bone resorption were partially attenuated by CpC treatment.</div></div><div><h3>Significance</h3><div>ENTR1 regulates periodontitis by suppressing macrophage M1 polarization through enhancing AMPK phosphorylation, presenting a promising therapeutic target for its prevention and management.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123525"},"PeriodicalIF":5.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562198","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}
Pub Date : 2025-03-04DOI: 10.1016/j.lfs.2025.123533
Songwen Li , Gang Liu , Shuo Cheng , Xin Li , Xinyu Weng , Jing Yang
Aims
Aortic aneurysm and dissection (AAD) involves complex immune responses, with macrophages playing a central role in vascular inflammation and AAD progression. The aim of this study was to determine the role of Bruton's tyrosine kinase (BTK) in macrophage-mediated inflammation and its impact on AAD progression.
Main methods
We employed pharmacological and genetic approaches to inhibit BTK in AAD models induced by β-aminopropionitrile (BAPN) and angiotensin II (Ang II). Histological analysis, RNA sequencing, and molecular assays were used to assess macrophage polarization, inflammatory responses and progression of AAD.
Key findings
BTK was upregulated in both aortic tissue from patients undergoing surgery for aortic dissection and AAD mice model. BTK inhibition significantly reduced macrophage infiltration, modulated macrophage polarization, and attenuated AAD progression by limiting vascular inflammation.
Significance
These findings establish BTK as a key regulator of macrophage-driven vascular inflammation and a promising therapeutic target for AAD.
{"title":"Pharmacological and genetic inhibition of BTK ameliorates vascular degeneration, dissection, and rupture","authors":"Songwen Li , Gang Liu , Shuo Cheng , Xin Li , Xinyu Weng , Jing Yang","doi":"10.1016/j.lfs.2025.123533","DOIUrl":"10.1016/j.lfs.2025.123533","url":null,"abstract":"<div><h3>Aims</h3><div>Aortic aneurysm and dissection (AAD) involves complex immune responses, with macrophages playing a central role in vascular inflammation and AAD progression. The aim of this study was to determine the role of Bruton's tyrosine kinase (BTK) in macrophage-mediated inflammation and its impact on AAD progression.</div></div><div><h3>Main methods</h3><div>We employed pharmacological and genetic approaches to inhibit BTK in AAD models induced by β-aminopropionitrile (BAPN) and angiotensin II (Ang II). Histological analysis, RNA sequencing, and molecular assays were used to assess macrophage polarization, inflammatory responses and progression of AAD.</div></div><div><h3>Key findings</h3><div>BTK was upregulated in both aortic tissue from patients undergoing surgery for aortic dissection and AAD mice model. BTK inhibition significantly reduced macrophage infiltration, modulated macrophage polarization, and attenuated AAD progression by limiting vascular inflammation.</div></div><div><h3>Significance</h3><div>These findings establish BTK as a key regulator of macrophage-driven vascular inflammation and a promising therapeutic target for AAD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123533"},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552154","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}
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