Pub Date : 2025-02-04DOI: 10.1016/j.lfs.2025.123445
Jinchao Song , Jiankui Du , Qian Zhao , Yuan Gao , Xing Tan , Binhai Cong
Aims
Tissue kallikrein-related peptidase 8 (KLK8) plays a significant role in the regulation of cardiac remodeling following myocardial infarction (MI). However, the impact of KLK8 on macrophage (MΦ) function in the context of MI remains to be elucidated.
Materials and methods
MI was induced through the ligation of the left anterior descending coronary artery for a duration of 1 h, followed by reperfusion. The morphological and molecular alterations in the heart were assessed at 24 h and 14 days post-ischemic injury. Adult rat cardiac fibroblasts and bone marrow-derived macrophages were employed to explore the underlying molecular mechanisms in vitro.
Key findings
In the acute phase of MI (24 h post-MI), KLK8 was observed to diminish the inflammatory response and mitigate tissue damage within the ischemic ventricle. Conversely, during the reparative phase of MI (14 days post-MI), KLK8 was found to enhance the accumulation of the M2 MΦs, elevate pro-fibrotic factors, and intensify cardiac fibrosis. The in vitro analysis revealed that KLK8 did not exert a direct effect on MΦs; rather, it facilitated the paracrine secretion of epidermal growth factor (EGF) from the cardiac fibroblasts. This EGF may play a role in inhibiting the pro-inflammatory activation of the MΦs and promoting their polarization towards the M2 phenotype under conditions of inflammatory stress.
Significance
In summary, KLK8 modulates MΦ function through the paracrine of EGF derived from cardiac fibroblasts, which may have implications for cardiac injury and remodeling following MI.
{"title":"KLK8 modulates macrophage function following myocardial infarction by promoting the paracrine of epidermal growth factor from cardiac fibroblasts","authors":"Jinchao Song , Jiankui Du , Qian Zhao , Yuan Gao , Xing Tan , Binhai Cong","doi":"10.1016/j.lfs.2025.123445","DOIUrl":"10.1016/j.lfs.2025.123445","url":null,"abstract":"<div><h3>Aims</h3><div>Tissue kallikrein-related peptidase 8 (KLK8) plays a significant role in the regulation of cardiac remodeling following myocardial infarction (MI). However, the impact of KLK8 on macrophage (MΦ) function in the context of MI remains to be elucidated.</div></div><div><h3>Materials and methods</h3><div>MI was induced through the ligation of the left anterior descending coronary artery for a duration of 1 h, followed by reperfusion. The morphological and molecular alterations in the heart were assessed at 24 h and 14 days post-ischemic injury. Adult rat cardiac fibroblasts and bone marrow-derived macrophages were employed to explore the underlying molecular mechanisms <em>in vitro</em>.</div></div><div><h3>Key findings</h3><div>In the acute phase of MI (24 h post-MI), KLK8 was observed to diminish the inflammatory response and mitigate tissue damage within the ischemic ventricle. Conversely, during the reparative phase of MI (14 days post-MI), KLK8 was found to enhance the accumulation of the M2 MΦs, elevate pro-fibrotic factors, and intensify cardiac fibrosis. The <em>in vitro</em> analysis revealed that KLK8 did not exert a direct effect on MΦs; rather, it facilitated the paracrine secretion of epidermal growth factor (EGF) from the cardiac fibroblasts. This EGF may play a role in inhibiting the pro-inflammatory activation of the MΦs and promoting their polarization towards the M2 phenotype under conditions of inflammatory stress.</div></div><div><h3>Significance</h3><div>In summary, KLK8 modulates MΦ function through the paracrine of EGF derived from cardiac fibroblasts, which may have implications for cardiac injury and remodeling following MI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123445"},"PeriodicalIF":5.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143102175","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 : 2025-02-04DOI: 10.1016/j.lfs.2025.123444
Seungheon Shin , Steve K. Cho
CRBN (Cereblon), a substrate receptor of the CRL4 (Cullin4-RING E3 ubiquitin ligase) complex, has emerged as a key player in cancer metabolism. While its role in influencing metabolic phenotypes has been suggested, the precise functions of CRBN in cellular metabolism and cancer progression remain underexplored. This study investigates the impact of CRBN downregulation in lung cancer, focusing on mitochondrial metabolism and cellular functions. Data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) revealed significant reductions in CRBN expression at both mRNA and protein levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This downregulation was further confirmed in most lung cancer cell lines examined. Functional analyses of CRBN knockout (KO) cells revealed substantial alterations in mitochondrial metabolism, including enhanced oxidative phosphorylation, increased mitochondrial membrane potential (ΔΨm), and elevated production of mitochondrial reactive oxygen species (mROS). CRBN deficiency also accelerated tricarboxylic acid (TCA) cycle flux and increased mitochondrial calcium accumulation, contributing to elevated ΔΨm and potentially compromised mitochondrial integrity. Additionally, CRBN KO cells demonstrated increased cell migration, which could be mitigated by inhibiting mitochondrial calcium import. These findings suggest that CRBN plays a pivotal role in regulating mitochondrial function and metabolic activity in non-small cell lung cancer. The loss of CRBN enhances mitochondrial metabolism and contributes to increased cancer cell migration, providing new insights into the metabolic adaptations associated with CRBN deficiency in cancer progression.
{"title":"CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer","authors":"Seungheon Shin , Steve K. Cho","doi":"10.1016/j.lfs.2025.123444","DOIUrl":"10.1016/j.lfs.2025.123444","url":null,"abstract":"<div><div>CRBN (Cereblon), a substrate receptor of the CRL4 (Cullin4-RING E3 ubiquitin ligase) complex, has emerged as a key player in cancer metabolism. While its role in influencing metabolic phenotypes has been suggested, the precise functions of CRBN in cellular metabolism and cancer progression remain underexplored. This study investigates the impact of CRBN downregulation in lung cancer, focusing on mitochondrial metabolism and cellular functions. Data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) revealed significant reductions in CRBN expression at both mRNA and protein levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This downregulation was further confirmed in most lung cancer cell lines examined. Functional analyses of CRBN knockout (KO) cells revealed substantial alterations in mitochondrial metabolism, including enhanced oxidative phosphorylation, increased mitochondrial membrane potential (ΔΨm), and elevated production of mitochondrial reactive oxygen species (mROS). CRBN deficiency also accelerated tricarboxylic acid (TCA) cycle flux and increased mitochondrial calcium accumulation, contributing to elevated ΔΨm and potentially compromised mitochondrial integrity. Additionally, CRBN KO cells demonstrated increased cell migration, which could be mitigated by inhibiting mitochondrial calcium import. These findings suggest that CRBN plays a pivotal role in regulating mitochondrial function and metabolic activity in non-small cell lung cancer. The loss of CRBN enhances mitochondrial metabolism and contributes to increased cancer cell migration, providing new insights into the metabolic adaptations associated with CRBN deficiency in cancer progression.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123444"},"PeriodicalIF":5.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143102576","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 : 2025-02-03DOI: 10.1016/j.lfs.2025.123441
Mi Li , Tao Zhang , Pengfei Li , Zhiwei Luan , Jingsong Liu , Yangyang Wang , Yubo Zhang , Yishu Liu , Yansong Wang
Spinal cord injury (SCI) represents a significant neurological disorder that profoundly impacts human life. Transplantation of extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) has emerged as a promising therapeutic strategy. microRNA (miRNA) containing EVs serve as crucial mediators of intercellular communication, playing vital roles in physiological and pathological processes. Research indicates that EVs from hUC-MSCs could attenuate inflammation and facilitate recovery from SCI. Nevertheless, their application in clinical treatment necessitates further investigation. We are actively pursuing an effective approach to modulate the intensity of the inflammatory response, thereby addressing secondary SCI. Initially, we activated hUC-MSCs with interleukin-4 (IL-4) and subsequently harvested their EVs. We investigated the influences of A-hUC-MSCs-EVs compared to routinely acquired EVs on macrophage polarization phenotypes both in vitro and in vivo. Our results show that EVs originating from A-hUC-MSCs are more effective at promoting macrophage polarization from the M1 phenotype to the M2 phenotype than those derived from hUC-MSCs. Notably, we found that A-hUC-MSCs-derived EVs had a superior impact on motor function recovery in mice with SCI. Importantly, we observed that IL-4 activation significantly upregulated the expression of miR-21-5p within these EVs. More specifically, our data demonstrate that A-hUC-MSCs-EVs depend on miR-21-5p to inhibit the effects of PDCD4 on macrophage polarization. This mechanism regulates inflammatory responses while simultaneously reducing apoptosis. In summary, EVs derived from IL-4 primed hUC-MSCs are enriched with miR-21-5p, which exerts a pivotal influence in shifting macrophage polarization, alleviating inflammatory responses following SCI, and facilitating recovery.
{"title":"IL-4-primed human umbilical cord mesenchymal stem cells-derived extracellular vesicles facilitate recovery in spinal cord injury via the miR-21-5p/PDCD4-mediated shifting of macrophage M1/M2 polarization","authors":"Mi Li , Tao Zhang , Pengfei Li , Zhiwei Luan , Jingsong Liu , Yangyang Wang , Yubo Zhang , Yishu Liu , Yansong Wang","doi":"10.1016/j.lfs.2025.123441","DOIUrl":"10.1016/j.lfs.2025.123441","url":null,"abstract":"<div><div>Spinal cord injury (SCI) represents a significant neurological disorder that profoundly impacts human life. Transplantation of extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) has emerged as a promising therapeutic strategy. microRNA (miRNA) containing EVs serve as crucial mediators of intercellular communication, playing vital roles in physiological and pathological processes. Research indicates that EVs from hUC-MSCs could attenuate inflammation and facilitate recovery from SCI. Nevertheless, their application in clinical treatment necessitates further investigation. We are actively pursuing an effective approach to modulate the intensity of the inflammatory response, thereby addressing secondary SCI. Initially, we activated hUC-MSCs with interleukin-4 (IL-4) and subsequently harvested their EVs. We investigated the influences of A-hUC-MSCs-EVs compared to routinely acquired EVs on macrophage polarization phenotypes both in vitro and in vivo. Our results show that EVs originating from A-hUC-MSCs are more effective at promoting macrophage polarization from the M1 phenotype to the M2 phenotype than those derived from hUC-MSCs. Notably, we found that A-hUC-MSCs-derived EVs had a superior impact on motor function recovery in mice with SCI. Importantly, we observed that IL-4 activation significantly upregulated the expression of miR-21-5p within these EVs. More specifically, our data demonstrate that A-hUC-MSCs-EVs depend on miR-21-5p to inhibit the effects of PDCD4 on macrophage polarization. This mechanism regulates inflammatory responses while simultaneously reducing apoptosis. In summary, EVs derived from IL-4 primed hUC-MSCs are enriched with miR-21-5p, which exerts a pivotal influence in shifting macrophage polarization, alleviating inflammatory responses following SCI, and facilitating recovery.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123441"},"PeriodicalIF":5.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255782","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 : 2025-02-01DOI: 10.1016/j.lfs.2024.123337
Juan Du, Kaiyi Zhang, Jiakun Miao, Yu Yang, Yuying Tian, Tianwen Wu, Cong Tao, Yanfang Wang, Shulin Yang
Aims
This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis.
Materials and methods
The triple-transgenic (PNPLA3I148M-GIPRdn-hIAPP) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials. The transcriptome, metabolome, and lipidome were used to investigate the molecular mechanisms of the liver in pigs.
Key findings
The TG2 pigs presented mild metaflammation and insulin resistance (IR) which was similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as ETNPPL, GABBR2, and BMP8B might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury.
Significance
ETNPPL, GABBR2, and BMP8B might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases.
{"title":"Molecular pathological characteristics and mechanisms of the liver in metabolic disease-susceptible transgenic pigs","authors":"Juan Du, Kaiyi Zhang, Jiakun Miao, Yu Yang, Yuying Tian, Tianwen Wu, Cong Tao, Yanfang Wang, Shulin Yang","doi":"10.1016/j.lfs.2024.123337","DOIUrl":"10.1016/j.lfs.2024.123337","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis.</div></div><div><h3>Materials and methods</h3><div>The triple-transgenic (<em>PNPLA3</em><sup><em>I148M</em></sup><em>-GIPR</em><sup><em>dn</em></sup><em>-hIAPP</em>) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials. The transcriptome, metabolome, and lipidome were used to investigate the molecular mechanisms of the liver in pigs.</div></div><div><h3>Key findings</h3><div>The TG2 pigs presented mild metaflammation and insulin resistance (IR) which was similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as <em>ETNPPL</em>, <em>GABBR2</em>, and <em>BMP8B</em> might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury.</div></div><div><h3>Significance</h3><div><em>ETNPPL</em>, <em>GABBR2</em>, and <em>BMP8B</em> might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123337"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903343","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 : 2025-02-01DOI: 10.1016/j.lfs.2024.123344
Sen-lin Lu , Zhi-hao Pan , Zhi Cui , Ji-li Wang , Jian-lin Yang , Ya-feng Lv , Chun-yu Cao , Xiao-fei Huang
Background
Fibroblast Growth Factor 21 (FGF21) is a naturally occurring peptide hormone involved in the regulation of glycolipid metabolism, and it shows promise as a potential treatment for type 2 diabetes mellitus (T2DM). However, the short half-life and poor pharmacokinetics of native FGF21 limit its efficacy in reducing hyperglycemia in vivo. Therefore, maintaining stable and sustained blood concentrations of FGF21 is crucial for its role as an effective regulator of glycolipid metabolism in vivo. In this study, we developed an AAV2-mediated gene delivery system incorporating an Albumin-binding domain (ABD) fused to FGF21, and we evaluated its effects in a type 2 diabetic mouse model.
Methods
The plasmids pAAV-FGF21-Luciferase, pHelper, and the capsid plasmid were transfected into HEK293T cells to generate recombinant AAV (rAAV) virus. A type 2 diabetes mellitus (T2DM) mouse model was established for evaluation. The rAAV was administered via tail vein injection into the mice. The effects of rAAV injection on various parameters were assessed using commercial kits. Histological changes in the liver and adipose tissue of T2DM mice were examined using hematoxylin and eosin (H&E) staining.
Results
The data showed that the inclusion of ABD significantly prolonged the half-life of FGF21 in the serum of mice. Additionally, AAV2-mediated delivery of ABD-FGF21 to the liver resulted in sustained gene expression and a significant increase in circulating FGF21 levels in mice. Treatment with AAV2-ABD-FGF21 led to several benefits, including reduced fasting glucose, improved insulin sensitivity, decreased triglyceride and total cholesterol levels, and improved body weight in T2DM mice. Furthermore, serum analysis and histological examination showed no significant liver damage at the study endpoint after seven weeks.
Conclusion
In conclusion, we have developed a novel strategy for producing long-acting FGF21 using the AAV vector, and AAV2-ABD-FGF21 shows promise as a therapeutic approach for type 2 diabetes mellitus and other glycolipid metabolic disorders.
{"title":"AAV2-mediated ABD-FGF21 gene delivery produces a sustained anti-hyperglycemic effect in type 2 diabetic mouse","authors":"Sen-lin Lu , Zhi-hao Pan , Zhi Cui , Ji-li Wang , Jian-lin Yang , Ya-feng Lv , Chun-yu Cao , Xiao-fei Huang","doi":"10.1016/j.lfs.2024.123344","DOIUrl":"10.1016/j.lfs.2024.123344","url":null,"abstract":"<div><h3>Background</h3><div>Fibroblast Growth Factor 21 (FGF21) is a naturally occurring peptide hormone involved in the regulation of glycolipid metabolism, and it shows promise as a potential treatment for type 2 diabetes mellitus (T2DM). However, the short half-life and poor pharmacokinetics of native FGF21 limit its efficacy in reducing hyperglycemia in vivo. Therefore, maintaining stable and sustained blood concentrations of FGF21 is crucial for its role as an effective regulator of glycolipid metabolism in vivo. In this study, we developed an AAV2-mediated gene delivery system incorporating an Albumin-binding domain (ABD) fused to FGF21, and we evaluated its effects in a type 2 diabetic mouse model.</div></div><div><h3>Methods</h3><div>The plasmids pAAV-FGF21-Luciferase, pHelper, and the capsid plasmid were transfected into HEK293T cells to generate recombinant AAV (rAAV) virus. A type 2 diabetes mellitus (T2DM) mouse model was established for evaluation. The rAAV was administered via tail vein injection into the mice. The effects of rAAV injection on various parameters were assessed using commercial kits. Histological changes in the liver and adipose tissue of T2DM mice were examined using hematoxylin and eosin (H&E) staining.</div></div><div><h3>Results</h3><div>The data showed that the inclusion of ABD significantly prolonged the half-life of FGF21 in the serum of mice. Additionally, AAV2-mediated delivery of ABD-FGF21 to the liver resulted in sustained gene expression and a significant increase in circulating FGF21 levels in mice. Treatment with AAV2-ABD-FGF21 led to several benefits, including reduced fasting glucose, improved insulin sensitivity, decreased triglyceride and total cholesterol levels, and improved body weight in T2DM mice. Furthermore, serum analysis and histological examination showed no significant liver damage at the study endpoint after seven weeks.</div></div><div><h3>Conclusion</h3><div>In conclusion, we have developed a novel strategy for producing long-acting FGF21 using the AAV vector, and AAV2-ABD-FGF21 shows promise as a therapeutic approach for type 2 diabetes mellitus and other glycolipid metabolic disorders.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123344"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906559","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 : 2025-02-01DOI: 10.1016/j.lfs.2024.123360
Chang Wu , Qingmei Wang , Wenmi Li , Mingxuan Han , Huawei Zhao , Zhenghao Xu
Febrile seizures (FSs) are the most common pediatric neurological disorder, affecting approximately 5 % of children aged 6 months to 5 years. While most FSs are self-limiting and benign, about 20–30 % present as complex FSs (CFSs), which pose a risk of acute brain injury and the development of temporal lobe epilepsy. Various factors, including age, geographical distribution, and type of infection influence the occurrence of FS. Infection is the primary external trigger for FS, while the underlying intrinsic factors are linked to the immature and incomplete myelination of the brain during specific developmental stages. Although the precise pathogenesis of FS is not yet fully understood, it is likely caused by the interaction of immature brain development, fever, neuroinflammation, and genetic susceptibility. This review discussed the pathogenesis of febrile seizures, focusing on factors such as age, fever, neuroinflammation, genetics, and intestinal microbiota, and summarized existing therapeutic approaches. Our review may facilitate the identification of new targets for mechanistic studies and clinical treatment of febrile seizures.
{"title":"Research progress on pathogenesis and treatment of febrile seizures","authors":"Chang Wu , Qingmei Wang , Wenmi Li , Mingxuan Han , Huawei Zhao , Zhenghao Xu","doi":"10.1016/j.lfs.2024.123360","DOIUrl":"10.1016/j.lfs.2024.123360","url":null,"abstract":"<div><div>Febrile seizures (FSs) are the most common pediatric neurological disorder, affecting approximately 5 % of children aged 6 months to 5 years. While most FSs are self-limiting and benign, about 20–30 % present as complex FSs (CFSs), which pose a risk of acute brain injury and the development of temporal lobe epilepsy. Various factors, including age, geographical distribution, and type of infection influence the occurrence of FS. Infection is the primary external trigger for FS, while the underlying intrinsic factors are linked to the immature and incomplete myelination of the brain during specific developmental stages. Although the precise pathogenesis of FS is not yet fully understood, it is likely caused by the interaction of immature brain development, fever, neuroinflammation, and genetic susceptibility. This review discussed the pathogenesis of febrile seizures, focusing on factors such as age, fever, neuroinflammation, genetics, and intestinal microbiota, and summarized existing therapeutic approaches. Our review may facilitate the identification of new targets for mechanistic studies and clinical treatment of febrile seizures.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123360"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921622","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}
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and grave malignancies with confined and ineffective therapeutic options. XPO1 is a critical regulator of nuclear export and activation of tumor suppressor proteins. The present study evaluated the therapeutic potential and molecular mechanisms of XPO1 inhibition against PDAC. Firstly, we observed significant overexpression of XPO1 transcript in 179 PDAC patients than 171 normal pancreatic tissues in TCGA transcriptomic dataset. Higher XPO1 transcript levels displayed worse overall and disease-free survival. Further, we confirmed significant upregulation of XPO1 in a panel of PDAC cells. Eltanexor treatment resulted in significant inhibition of cell viability, clonogenic growth, migration, and epithelial-mesenchymal transition (EMT), along with the induction of cell cycle arrest. Mechanistically, eltanexor modulated the expression of key proteins including p21, p27, p53, cyclin B1, cyclin D1, c-Myc, N-cadherin, vimentin, E-cadherin associated with the cell viability, growth, cell cycle and EMT. Additionally, the eltanexor treatment resulted in marked increase in expression of γH2AX, and cleaved PARP, cleaved caspase-9 leading to induction of DNA damage and apoptosis of PDAC cells, respectively. Moreover, eltanexor treatment regulated the expression of key non-coding RNAs including miR193b, DINO, MALAT-1, H19, and SOX21-AS1 linked with tumorigenesis. Our results revealed a correlation among miR193b/KRAS/LAMC2, XPO1/KRAS, and LAMC2/KRAS. The findings also revealed that eltanexor treatment rescued the expression of miR193b which acts as a sponge for LAMC2 and KRAS resulting in the suppression of AKT/ERK downstream signaling cascade in PDAC. Interestingly, the combination of eltanexor with gemcitabine showed significant anticancer activity in PDAC cells. Altogether, our findings revealed the crucial role of XPO1 in modulating the expression of oncogenic proteins, ncRNAs, and DNA damage during PDAC progression as well as identified novel therapeutic miR-193b/KRAS/LAMC2/ERK/AKT axis.
{"title":"Anticancer and therapeutic efficacy of XPO1 inhibition in pancreatic ductal adenocarcinoma through DNA damage and modulation of miR-193b/KRAS/LAMC2/ERK/AKT signaling cascade","authors":"Anuradha Kirtonia , Gouri Pandya , Aishwarya Singh , Rachana Kumari , Bhavana Singh , Sonia Kapoor , Ekta Khattar , Amit Kumar Pandey , Manoj Garg","doi":"10.1016/j.lfs.2024.123364","DOIUrl":"10.1016/j.lfs.2024.123364","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and grave malignancies with confined and ineffective therapeutic options. XPO1 is a critical regulator of nuclear export and activation of tumor suppressor proteins. The present study evaluated the therapeutic potential and molecular mechanisms of XPO1 inhibition against PDAC. Firstly, we observed significant overexpression of <em>XPO1</em> transcript in 179 PDAC patients than 171 normal pancreatic tissues in TCGA transcriptomic dataset. Higher <em>XPO1</em> transcript levels displayed worse overall and disease-free survival. Further, we confirmed significant upregulation of XPO1 in a panel of PDAC cells. Eltanexor treatment resulted in significant inhibition of cell viability, clonogenic growth, migration, and epithelial-mesenchymal transition (EMT), along with the induction of cell cycle arrest. Mechanistically, eltanexor modulated the expression of key proteins including p21, p27, p53, cyclin B1, cyclin D1, c-Myc, N-cadherin, vimentin, E-cadherin associated with the cell viability, growth, cell cycle and EMT. Additionally, the eltanexor treatment resulted in marked increase in expression of γH2AX, and cleaved PARP, cleaved caspase-9 leading to induction of DNA damage and apoptosis of PDAC cells, respectively. Moreover, eltanexor treatment regulated the expression of key non-coding RNAs including miR193b, DINO, MALAT-1, H19, and SOX21-AS1 linked with tumorigenesis. Our results revealed a correlation among miR193b/KRAS/LAMC2, XPO1/KRAS, and LAMC2/KRAS. The findings also revealed that eltanexor treatment rescued the expression of miR193b which acts as a sponge for LAMC2 and KRAS resulting in the suppression of AKT/ERK downstream signaling cascade in PDAC. Interestingly, the combination of eltanexor with gemcitabine showed significant anticancer activity in PDAC cells. Altogether, our findings revealed the crucial role of XPO1 in modulating the expression of oncogenic proteins, ncRNAs, and DNA damage during PDAC progression as well as identified novel therapeutic miR-193b/KRAS/LAMC2/ERK/AKT axis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123364"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950976","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 : 2025-02-01DOI: 10.1016/j.lfs.2024.123345
Ioanna Ploumaki , Valeria I. Macri , James H. Segars , Md Soriful Islam
Progesterone (P4) is a vital female sex hormone involved in various physiological processes, including the maintenance of the endometrium, mammary gland development, and bone health. Beyond its reproductive roles, P4 is implicated in the pathogenesis of hormone-dependent conditions like uterine fibroids, the most common benign tumors in women, which can severely affect quality of life and fertility. Traditionally, estrogen was considered the primary driver of fibroid growth, but recent research highlights the significant role of P4 in fibroid growth. P4 interacts with progesterone receptors (PRs) and non-genomic membrane receptors (mPRs and PGRMCs) to activate signaling pathways that enhance tumor growth and survival. P4 promotes vascular changes that improve the blood supply to fibroids and modifies the extracellular matrix, a key component of fibroid structure. This understanding has led to the investigation of selective progesterone receptor modulators (SPRMs) as potential therapies for fibroids. Clinical trials have demonstrated the effectiveness of SPRMs like mifepristone, asoprisnil, and ulipristal acetate in reducing fibroid size and symptoms, though concerns about safety, particularly with long-term use, remain. Newer SPRMs, such as vilaprisan, show promise, but further research is necessary to assess the long-term safety and effectiveness. This review discusses the mechanisms by which progesterone contributes to fibroid growth and examines clinical effectiveness of SPRMs as potential treatments for uterine fibroids.
{"title":"Progesterone signaling in uterine fibroids: Molecular mechanisms and therapeutic opportunities","authors":"Ioanna Ploumaki , Valeria I. Macri , James H. Segars , Md Soriful Islam","doi":"10.1016/j.lfs.2024.123345","DOIUrl":"10.1016/j.lfs.2024.123345","url":null,"abstract":"<div><div>Progesterone (P4) is a vital female sex hormone involved in various physiological processes, including the maintenance of the endometrium, mammary gland development, and bone health. Beyond its reproductive roles, P4 is implicated in the pathogenesis of hormone-dependent conditions like uterine fibroids, the most common benign tumors in women, which can severely affect quality of life and fertility. Traditionally, estrogen was considered the primary driver of fibroid growth, but recent research highlights the significant role of P4 in fibroid growth. P4 interacts with progesterone receptors (PRs) and non-genomic membrane receptors (mPRs and PGRMCs) to activate signaling pathways that enhance tumor growth and survival. P4 promotes vascular changes that improve the blood supply to fibroids and modifies the extracellular matrix, a key component of fibroid structure. This understanding has led to the investigation of selective progesterone receptor modulators (SPRMs) as potential therapies for fibroids. Clinical trials have demonstrated the effectiveness of SPRMs like mifepristone, asoprisnil, and ulipristal acetate in reducing fibroid size and symptoms, though concerns about safety, particularly with long-term use, remain. Newer SPRMs, such as vilaprisan, show promise, but further research is necessary to assess the long-term safety and effectiveness. This review discusses the mechanisms by which progesterone contributes to fibroid growth and examines clinical effectiveness of SPRMs as potential treatments for uterine fibroids.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123345"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909777","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 : 2025-02-01DOI: 10.1016/j.lfs.2024.123357
Jing Zhao , Yimeng Fang , Junying Qu , Jiaxuan He , Jia Yi , Rongbing Chen , Qinsi Yang , Kun Zhang , Wei Wu , Da Sun , Bin Fang
Skeletal muscle atrophy, resulting from an imbalance in muscle protein synthesis and degradation, compromises muscle quality and function, imposing significant burdens on movement and metabolic stability. Animal models are crucial for understanding the mechanisms of skeletal muscle atrophy and developing clinical prevention and treatment strategies. Zebrafish, as small aquatic vertebrates, exhibit high genetic homology with humans and offer advantages such as rapid reproduction, development, and transparent embryos. Their physiological and anatomical similarities to mammals, including a substantial proportion of skeletal muscle and observable swimming behavior reflecting body dysfunction, make zebrafish an ideal model for studying skeletal muscle-related diseases. This review outlines the development of zebrafish skeletal muscle and highlights key pathways regulating muscle proteins, emphasizing their anatomical and genetic consistency with humans. Various zebrafish models of skeletal muscle atrophy created through physical, chemical, and gene-editing methods are systematically summarized. Current challenges and proposed improvement strategies are also discussed to enhance the reliability and applicability of zebrafish models, providing a comprehensive reference for advancing research on skeletal muscle atrophy.
{"title":"Utilizing zebrafish models to elucidate mechanisms and develop therapies for skeletal muscle atrophy","authors":"Jing Zhao , Yimeng Fang , Junying Qu , Jiaxuan He , Jia Yi , Rongbing Chen , Qinsi Yang , Kun Zhang , Wei Wu , Da Sun , Bin Fang","doi":"10.1016/j.lfs.2024.123357","DOIUrl":"10.1016/j.lfs.2024.123357","url":null,"abstract":"<div><div>Skeletal muscle atrophy, resulting from an imbalance in muscle protein synthesis and degradation, compromises muscle quality and function, imposing significant burdens on movement and metabolic stability. Animal models are crucial for understanding the mechanisms of skeletal muscle atrophy and developing clinical prevention and treatment strategies. Zebrafish, as small aquatic vertebrates, exhibit high genetic homology with humans and offer advantages such as rapid reproduction, development, and transparent embryos. Their physiological and anatomical similarities to mammals, including a substantial proportion of skeletal muscle and observable swimming behavior reflecting body dysfunction, make zebrafish an ideal model for studying skeletal muscle-related diseases. This review outlines the development of zebrafish skeletal muscle and highlights key pathways regulating muscle proteins, emphasizing their anatomical and genetic consistency with humans. Various zebrafish models of skeletal muscle atrophy created through physical, chemical, and gene-editing methods are systematically summarized. Current challenges and proposed improvement strategies are also discussed to enhance the reliability and applicability of zebrafish models, providing a comprehensive reference for advancing research on skeletal muscle atrophy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123357"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931449","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 : 2025-02-01DOI: 10.1016/j.lfs.2024.123366
Catarina S. Silva , Marta R. Casanova , Pedro Ferreirinha , Alain da Silva Morais , Hugo Osório , Ana C. Lima , Joana F. Fangueiro , Mariana T. Cerqueira , Rui L. Reis , Nuno L. Alves , Albino Martins , Nuno M. Neves
Aims
The development and selection of T cells occur within the thymus. This organ involutes throughout life, compromising the generation of T cells and, consequently, the efficacy of the immune system. Mesenchymal stem cells (MSC) have beneficial effects on the immune system. Therefore, MSC have been applied in different pathologies related with thymic function. However, there is a lack of knowledge on the potential role of MSC-derived secretome on thymus involution. This work aims at studying the effect of human amniotic membrane-derived MSC conditioned media (hAMMSC CM) on aged thymus.
Materials and methods
The proteomic profile of hAMMSC CM was determined by liquid chromatography-tandem mass spectrometry. The CM was then intravenously injected in 12 months old mice, and the thymic stromal compartment and the different T cell populations characterized by flow cytometry.
Key findings
The hAMMSC CM is mostly enriched in proteins involved in extracellular matrix interaction, composition and organization, endodermal cell differentiation and angiogenesis. Its intravenous administration tends to increase the total thymic cellularity. A positive effect on the thymic epithelial cell (TEC) compartment was observed, with an increase of all TEC subsets. The hAMMSC CM also induced an increase in the thymocyte populations, accompanied by a confirmed positive selection. Mature single positive thymocytes expressed high levels of CD62L and low levels of CD24, indicating their ability to egress the thymus into the periphery.
Significance
Experimental findings support the potential role of hAMMSC CM as a cell-free therapeutic strategy for thymus involution.
{"title":"The effect of conditioned medium from human amniotic membrane-derived mesenchymal stem cells on thymus involution","authors":"Catarina S. Silva , Marta R. Casanova , Pedro Ferreirinha , Alain da Silva Morais , Hugo Osório , Ana C. Lima , Joana F. Fangueiro , Mariana T. Cerqueira , Rui L. Reis , Nuno L. Alves , Albino Martins , Nuno M. Neves","doi":"10.1016/j.lfs.2024.123366","DOIUrl":"10.1016/j.lfs.2024.123366","url":null,"abstract":"<div><h3>Aims</h3><div>The development and selection of T cells occur within the thymus. This organ involutes throughout life, compromising the generation of T cells and, consequently, the efficacy of the immune system. Mesenchymal stem cells (MSC) have beneficial effects on the immune system. Therefore, MSC have been applied in different pathologies related with thymic function. However, there is a lack of knowledge on the potential role of MSC-derived secretome on thymus involution. This work aims at studying the effect of human amniotic membrane-derived MSC conditioned media (hAMMSC CM) on aged thymus.</div></div><div><h3>Materials and methods</h3><div>The proteomic profile of hAMMSC CM was determined by liquid chromatography-tandem mass spectrometry. The CM was then intravenously injected in 12 months old mice, and the thymic stromal compartment and the different T cell populations characterized by flow cytometry.</div></div><div><h3>Key findings</h3><div>The hAMMSC CM is mostly enriched in proteins involved in extracellular matrix interaction, composition and organization, endodermal cell differentiation and angiogenesis. Its intravenous administration tends to increase the total thymic cellularity. A positive effect on the thymic epithelial cell (TEC) compartment was observed, with an increase of all TEC subsets. The hAMMSC CM also induced an increase in the thymocyte populations, accompanied by a confirmed positive selection. Mature single positive thymocytes expressed high levels of CD62L and low levels of CD24, indicating their ability to egress the thymus into the periphery.</div></div><div><h3>Significance</h3><div>Experimental findings support the potential role of hAMMSC CM as a cell-free therapeutic strategy for thymus involution.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123366"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950795","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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