Pub Date : 2025-02-06DOI: 10.1016/j.bbadis.2025.167707
Simona Rossi , Martina Milani , Ilaria Della Valle , Savina Apolloni
•
ALS is a neurodegenerative disease marked by the loss of motor neurons.
•
Damaged neurons are not regenerated but attract immune cells, fibroblasts, and astrocytes.
•
Research suggests fibrosis and inflammation contribute to ALS progression.
•
This study profiled spinal cord tissues from SOD1-G93A male mice at different disease stages using RNA sequencing.
•
We identified differentially expressed genes and pathways linked to disease progression.
•
We highlighted notable changes in ECM-related genes: Fmod, S100a4, S100a6 and Col1a1.
•
These findings provide insights into ALS pathology and potential therapeutic targets.
{"title":"Transcriptomic profiling of symptomatic and end-stage SOD1-G93A transgenic mice reveals extracellular matrix components as key players in ALS pathogenesis","authors":"Simona Rossi , Martina Milani , Ilaria Della Valle , Savina Apolloni","doi":"10.1016/j.bbadis.2025.167707","DOIUrl":"10.1016/j.bbadis.2025.167707","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>ALS is a neurodegenerative disease marked by the loss of motor neurons.</div></span></li><li><span>•</span><span><div>Damaged neurons are not regenerated but attract immune cells, fibroblasts, and astrocytes.</div></span></li><li><span>•</span><span><div>Research suggests fibrosis and inflammation contribute to ALS progression.</div></span></li><li><span>•</span><span><div>This study profiled spinal cord tissues from SOD1-G93A male mice at different disease stages using RNA sequencing.</div></span></li><li><span>•</span><span><div>We identified differentially expressed genes and pathways linked to disease progression.</div></span></li><li><span>•</span><span><div>We highlighted notable changes in ECM-related genes: <em>Fmod, S100a4, S100a6</em> and <em>Col1a1</em>.</div></span></li><li><span>•</span><span><div>These findings provide insights into ALS pathology and potential therapeutic targets.</div></span></li></ul></div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167707"},"PeriodicalIF":4.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1016/j.bbadis.2025.167700
Muxin Yu , Chuwei Zheng , Xiaowen Li , Xia Ji , Xiaolan Hu , Xiaoguang Wang , Jinming Zhang
Background
Neutrophil extracellular traps (NETs) and NOD-like receptor protein 3 (NLRP3) inflammation are key contributors to cholestatic liver disease (CLD). However, the relationship between NETs release and inflammasome activation, as well as its contribution to intrahepatic coagulation in CLD, remains unexplored. This study explores NETs-induced liver sinusoidal endothelial cells (LSECs) pyroptosis on intrahepatic coagulation in CLD.
Methods
Wild-type (WT) and PAD4−/− mice underwent bile duct ligation (BDL) or sham surgery for 7 or 14 days. The liver analysis assessed intrahepatic coagulation, inflammation, fibrosis, NETs release, and NLRP3 activation. Primary LSECs were exposed to NETs with or without MCC950. Pyroptosis and LSECs procoagulant activity were quantified.
Results
BDL mice exhibited significantly increased inflammation, tissue factor (TF), and fibrin deposition compared with controls. NETs release in the liver was increased significantly in WT BDL mice and was responsible for intrahepatic coagulation. PAD4 deficiency reduced TF and fibrin expression, improving hepatic sinusoid function. RNA-seq revealed BDL-induced enrichment of coagulation, neutrophil activation, and pyroptosis pathways. In vivo, NETs increased intrahepatic NLRP3 and IL-1β expression in BDL mice. However, NLRP3 inhibition (MCC950) or activation (BMS-986299) did not alter NETs release. Furthermore, NETs-induced NLRP3 activation increased intrahepatic coagulation, inflammation, and fibrosis. Finally, we demonstrated that NETs triggered LSECs dysfunction and pyroptosis, upregulating TF and phosphatidylserine production and enhancing procoagulant activity.
Conclusions
NETs-induced LSECs pyroptosis exacerbates intrahepatic coagulation in cholestasis. Targeting NETs and LSECs pyroptosis holds promise for treating chronic liver injury in CLD.
{"title":"Neutrophil extracellular traps-induced pyroptosis of liver sinusoidal endothelial cells exacerbates intrahepatic coagulation in cholestatic mice","authors":"Muxin Yu , Chuwei Zheng , Xiaowen Li , Xia Ji , Xiaolan Hu , Xiaoguang Wang , Jinming Zhang","doi":"10.1016/j.bbadis.2025.167700","DOIUrl":"10.1016/j.bbadis.2025.167700","url":null,"abstract":"<div><h3>Background</h3><div>Neutrophil extracellular traps (NETs) and NOD-like receptor protein 3 (NLRP3) inflammation are key contributors to cholestatic liver disease (CLD). However, the relationship between NETs release and inflammasome activation, as well as its contribution to intrahepatic coagulation in CLD, remains unexplored. This study explores NETs-induced liver sinusoidal endothelial cells (LSECs) pyroptosis on intrahepatic coagulation in CLD.</div></div><div><h3>Methods</h3><div>Wild-type (WT) and <em>PAD4</em><sup><em>−/−</em></sup> mice underwent bile duct ligation (BDL) or sham surgery for 7 or 14 days. The liver analysis assessed intrahepatic coagulation, inflammation, fibrosis, NETs release, and NLRP3 activation. Primary LSECs were exposed to NETs with or without MCC950. Pyroptosis and LSECs procoagulant activity were quantified.</div></div><div><h3>Results</h3><div>BDL mice exhibited significantly increased inflammation, tissue factor (TF), and fibrin deposition compared with controls. NETs release in the liver was increased significantly in WT BDL mice and was responsible for intrahepatic coagulation. <em>PAD4</em> deficiency reduced TF and fibrin expression, improving hepatic sinusoid function. RNA-seq revealed BDL-induced enrichment of coagulation, neutrophil activation, and pyroptosis pathways. In vivo, NETs increased intrahepatic NLRP3 and IL-1β expression in BDL mice. However, NLRP3 inhibition (MCC950) or activation (BMS-986299) did not alter NETs release. Furthermore, NETs-induced NLRP3 activation increased intrahepatic coagulation, inflammation, and fibrosis. Finally, we demonstrated that NETs triggered LSECs dysfunction and pyroptosis, upregulating TF and phosphatidylserine production and enhancing procoagulant activity.</div></div><div><h3>Conclusions</h3><div>NETs-induced LSECs pyroptosis exacerbates intrahepatic coagulation in cholestasis. Targeting NETs and LSECs pyroptosis holds promise for treating chronic liver injury in CLD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167700"},"PeriodicalIF":4.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143162289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-04DOI: 10.1016/j.bbadis.2025.167701
Yiding Yu , Xiujuan Liu , Wenwen Liu , Huajing Yuan , Quancheng Han , Jingle Shi , Yitao Xue , Yan Li
Background
Despite maximal pharmacological treatment guided by clinical guidelines, the prognosis of heart failure (HF) remains poor, posing a significant public health burden. This necessitates uncovering novel pathological and cardioprotective pathways. Targeting cytokines presents a promising therapeutic strategy for HF, yet their intricate mechanisms in HF progression remain obscure.
Methods
HF datasets were obtained from the GEO database. Cytokine-related genes were identified through WGCNA and the CytReg database. GO and KEGG enrichment analyses were conducted using the clusterProfiler package. Reactome pathway enrichment analysis and Bayesian regulatory network construction were performed using the CBNplot package. Key genes were identified via LASSO regression and RF algorithms, with diagnostic accuracy evaluated by ROC curves. Potential therapeutic drugs were predicted using the DSigDB database, and immune cell infiltration was assessed with the CIBERSORT package.
Results
We identified 13 cytokine-related genes associated with HF. Enrichment analyses indicated these genes mediate inflammatory responses and immune cell recruitment. Bayesian network analysis revealed two cytokine regulatory chains: IL34-CCL5-CCL4 and IL34-CCL5-CXCL12. Machine learning algorithms identified five key cytokine genes: CCL4, CCL5, CXCL12, CXCL14, and IL34. The DSigDB database predicted 47 potential therapeutic drugs, including Proscillaridin. Immune infiltration analysis showed significant differences in seven immune cell types between HF and healthy samples.
Conclusion
Our study provides insights into cytokines' molecular mechanisms in HF pathophysiology and highlights potential immunomodulatory strategies, gene therapies, and candidate drugs. Future research should validate these findings in clinical settings to develop effective HF therapies.
{"title":"Decoding the cytokine code for heart failure based on bioinformatics, machine learning and Bayesian networks","authors":"Yiding Yu , Xiujuan Liu , Wenwen Liu , Huajing Yuan , Quancheng Han , Jingle Shi , Yitao Xue , Yan Li","doi":"10.1016/j.bbadis.2025.167701","DOIUrl":"10.1016/j.bbadis.2025.167701","url":null,"abstract":"<div><h3>Background</h3><div>Despite maximal pharmacological treatment guided by clinical guidelines, the prognosis of heart failure (HF) remains poor, posing a significant public health burden. This necessitates uncovering novel pathological and cardioprotective pathways. Targeting cytokines presents a promising therapeutic strategy for HF, yet their intricate mechanisms in HF progression remain obscure.</div></div><div><h3>Methods</h3><div>HF datasets were obtained from the GEO database. Cytokine-related genes were identified through WGCNA and the CytReg database. GO and KEGG enrichment analyses were conducted using the clusterProfiler package. Reactome pathway enrichment analysis and Bayesian regulatory network construction were performed using the CBNplot package. Key genes were identified via LASSO regression and RF algorithms, with diagnostic accuracy evaluated by ROC curves. Potential therapeutic drugs were predicted using the DSigDB database, and immune cell infiltration was assessed with the CIBERSORT package.</div></div><div><h3>Results</h3><div>We identified 13 cytokine-related genes associated with HF. Enrichment analyses indicated these genes mediate inflammatory responses and immune cell recruitment. Bayesian network analysis revealed two cytokine regulatory chains: IL34-CCL5-CCL4 and IL34-CCL5-CXCL12. Machine learning algorithms identified five key cytokine genes: CCL4, CCL5, CXCL12, CXCL14, and IL34. The DSigDB database predicted 47 potential therapeutic drugs, including Proscillaridin. Immune infiltration analysis showed significant differences in seven immune cell types between HF and healthy samples.</div></div><div><h3>Conclusion</h3><div>Our study provides insights into cytokines' molecular mechanisms in HF pathophysiology and highlights potential immunomodulatory strategies, gene therapies, and candidate drugs. Future research should validate these findings in clinical settings to develop effective HF therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167701"},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-04DOI: 10.1016/j.bbadis.2025.167704
Linshan Yang , Leyu Lyu , Jie Ming , Chengye Che
Purpose
To evaluate the effects of co-treatment with Disulfiram and Resatorvid on sepsis.
Methods
Monocytes were isolated from the peripheral blood of sepsis patients with Staphylococcus aureus (S. aureus)-induced infective endocarditis and healthy controls. The expression of Gasdermin D (GSDMD) was analyzed using quantitative polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence. An in vitro cellular model of sepsis was established by stimulating monocytes with heat-killed Staphylococcus aureus (HK S. aureus). Cells were pre-treated with Disulfiram and/or Resatorvid. Caspase-1, GSDMD, and interleukin-1 beta (IL-1β) expression were measured by qRT-PCR and Western blotting. A cecal ligation and puncture (CLP) mouse model was used to study in vivo sepsis. Outcomes assessed included survival rate, sickness behavior score, lung wet-to-dry weight ratio, and neutrophil count in the lung.
Results
Compared to healthy controls, GSDMD expression was elevated in monocytes from sepsis patients. Cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β increased in monocytes were stimulated with HK S. aureus over time. Disulfiram pre-treatment reduced the secretion of IL-1β in HK S. aureus-stimulated monocytes. Resatorvid pre-treatment decreased levels of cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β. Co-treatment with Disulfiram and Resatorvid resulted in greater reductions in cleaved Caspase-1, N-terminal GSDMD fragments, and IL-1β, and improved outcomes in the CLP mouse model, including higher survival rates, lower sickness behavior scores, reduced lung wet-to-dry weight ratios, and fewer neutrophils in the lung.
Conclusion
These findings indicated that pyroptosis of monocytes was activated in sepsis. Disulfiram and Resatorvid pre-treatment effectively suppressed the pyroptosis of monocytes through the Caspase-1/GSDMD/IL-1β signaling pathway. The combination of Disulfiram and Resatorvid showed potential as a therapeutic strategy to mitigate sepsis severity.
{"title":"Effect of co-treatment with disulfiram and resatorvid on the pyroptosis of monocytes in sepsis","authors":"Linshan Yang , Leyu Lyu , Jie Ming , Chengye Che","doi":"10.1016/j.bbadis.2025.167704","DOIUrl":"10.1016/j.bbadis.2025.167704","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate the effects of co-treatment with Disulfiram and Resatorvid on sepsis.</div></div><div><h3>Methods</h3><div>Monocytes were isolated from the peripheral blood of sepsis patients with <em>Staphylococcus aureus</em> (<em>S. aureus</em>)-induced infective endocarditis and healthy controls. The expression of Gasdermin D (GSDMD) was analyzed using quantitative polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence. An <em>in vitro</em> cellular model of sepsis was established by stimulating monocytes with heat-killed <em>Staphylococcus aureus</em> (HK <em>S. aureus</em>). Cells were pre-treated with Disulfiram and/or Resatorvid. Caspase-1, GSDMD, and interleukin-1 beta (IL-1β) expression were measured by qRT-PCR and Western blotting. A cecal ligation and puncture (CLP) mouse model was used to study <em>in vivo</em> sepsis. Outcomes assessed included survival rate, sickness behavior score, lung wet-to-dry weight ratio, and neutrophil count in the lung.</div></div><div><h3>Results</h3><div>Compared to healthy controls, GSDMD expression was elevated in monocytes from sepsis patients. Cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β increased in monocytes were stimulated with HK <em>S. aureus</em> over time. Disulfiram pre-treatment reduced the secretion of IL-1β in HK <em>S. aureus</em>-stimulated monocytes. Resatorvid pre-treatment decreased levels of cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β. Co-treatment with Disulfiram and Resatorvid resulted in greater reductions in cleaved Caspase-1, N-terminal GSDMD fragments, and IL-1β, and improved outcomes in the CLP mouse model, including higher survival rates, lower sickness behavior scores, reduced lung wet-to-dry weight ratios, and fewer neutrophils in the lung.</div></div><div><h3>Conclusion</h3><div>These findings indicated that pyroptosis of monocytes was activated in sepsis. Disulfiram and Resatorvid pre-treatment effectively suppressed the pyroptosis of monocytes through the Caspase-1/GSDMD/IL-1β signaling pathway. The combination of Disulfiram and Resatorvid showed potential as a therapeutic strategy to mitigate sepsis severity.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167704"},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143285103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by the progressive degeneration of retinal ganglion cells (RGCs). While elevated intraocular pressure (IOP) significantly contributes to disease progression, managing IOP alone does not completely halt it. The mechanisms underlying RGCs loss in glaucoma remain unclear, but ferroptosis—an iron-dependent form of oxidative cell death—has been implicated, particularly in IOP-induced RGCs loss. There is an urgent need for neuroprotective treatments. Our previous research showed that hydrogen sulfide (H2S) protects RGCs against glaucomatous injury. This study aims to investigate the interplay between elevated pressure, mitochondrial dysfunction, iron homeostasis, and ferroptosis in RGCs death, focusing on how H2S may mitigate pressure-induced ferroptosis and protect RGCs. We demonstrate alterations in iron metabolism and mitochondrial function in a subacute IOP elevation model in vivo. In vitro, we confirm that elevated pressure, iron overload, and mitochondrial dysfunction lead to RGCs loss, increased retinal ferrous iron and total iron content, and heightened reactive oxygen species (ROS). Notably, pressure increases NADPH oxidase 2 (NOX2) and decreases glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. NOX2 deletion or inhibition by H2S prevents pressure-induced RGCs loss and ferroptosis. Our findings reveal that H2S chelates iron, regulates iron metabolism, reduces oxidative stress, and mitigates ferroptosis, positioning slow-releasing H2S donors are positioning as a promising multi-target therapy for glaucoma, with NOX2 emerging as a key regulator of ferroptosis.
{"title":"Exogenous hydrogen sulfide and NOX2 inhibition mitigate ferroptosis in pressure-induced retinal ganglion cell damage","authors":"Yuan Feng, Xiaosha Wang, Panpan Li, Xin Shi, Verena Prokosch, Hanhan Liu","doi":"10.1016/j.bbadis.2025.167705","DOIUrl":"10.1016/j.bbadis.2025.167705","url":null,"abstract":"<div><div>Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by the progressive degeneration of retinal ganglion cells (RGCs). While elevated intraocular pressure (IOP) significantly contributes to disease progression, managing IOP alone does not completely halt it. The mechanisms underlying RGCs loss in glaucoma remain unclear, but ferroptosis—an iron-dependent form of oxidative cell death—has been implicated, particularly in IOP-induced RGCs loss. There is an urgent need for neuroprotective treatments. Our previous research showed that hydrogen sulfide (H<sub>2</sub>S) protects RGCs against glaucomatous injury. This study aims to investigate the interplay between elevated pressure, mitochondrial dysfunction, iron homeostasis, and ferroptosis in RGCs death, focusing on how H<sub>2</sub>S may mitigate pressure-induced ferroptosis and protect RGCs. We demonstrate alterations in iron metabolism and mitochondrial function in a subacute IOP elevation model in vivo. In vitro, we confirm that elevated pressure, iron overload, and mitochondrial dysfunction lead to RGCs loss, increased retinal ferrous iron and total iron content, and heightened reactive oxygen species (ROS). Notably, pressure increases NADPH oxidase 2 (NOX2) and decreases glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. NOX2 deletion or inhibition by H<sub>2</sub>S prevents pressure-induced RGCs loss and ferroptosis. Our findings reveal that H<sub>2</sub>S chelates iron, regulates iron metabolism, reduces oxidative stress, and mitigates ferroptosis, positioning slow-releasing H<sub>2</sub>S donors are positioning as a promising multi-target therapy for glaucoma, with NOX2 emerging as a key regulator of ferroptosis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167705"},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143285101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-02DOI: 10.1016/j.bbadis.2025.167689
Yingyu Liu, Beibei Fu, Quanrun He, Xuesong Bai, Ying Fan
We have previously reported that inactivation of c-kit and stem cell factor (SCF) might reduce interstitial Cajal-like cells (ICLCs) density, leading to gallbladder motility impairment and cholesterol gallstone (CG) formation. Based on bioinformatics prediction, this study explores the possible role of POU class 5 homeobox 1 (POU5F1) in c-kit/SCF regulation and investigates their function in ICLC activity and CG development. POU5F1 was identified as a transcription factor targeting both c-kit and SCF for transcription activation. They were poorly expressed in mice fed a lithogenic diet (LD) and mouse ICLCs treated with cholesterol. Upregulation of POU5F1 alleviated ICLC apoptosis, contraction dysfunction, and CG formation in the gallbladder wall of mice. Similarly, the POU5F1 upregulation enhanced the viability of ICLCs in vitro while reducing cell apoptosis. However, these effects were blocked by either c-kit or SCF knockdown. Furthermore, DNA methyltransferase 1 (DNMT1) and DNMT3B were identified as two important regulators suppressing POU5F1 transcription through DNA methylation. Knockdown of either DNMT1 or DNMT3B restored POU5F1 and c-kit/SCF levels, therefore reducing ICLC apoptosis and CG formation. In conclusion, this study demonstrates that DNMT1/DNMT3B-mediated DNA methylation of POU5F1 induces c-kit/SCF downregulation, thus promoting apoptosis of ICLCs and CG formation.
{"title":"DNA methylation of POU5F1 by DNMT1 and DNMT3B triggers apoptosis in interstitial Cajal-like cells via c-kit/SCF inhibition during cholesterol gallstone formation","authors":"Yingyu Liu, Beibei Fu, Quanrun He, Xuesong Bai, Ying Fan","doi":"10.1016/j.bbadis.2025.167689","DOIUrl":"10.1016/j.bbadis.2025.167689","url":null,"abstract":"<div><div>We have previously reported that inactivation of c-kit and stem cell factor (SCF) might reduce interstitial Cajal-like cells (ICLCs) density, leading to gallbladder motility impairment and cholesterol gallstone (CG) formation. Based on bioinformatics prediction, this study explores the possible role of POU class 5 homeobox 1 (POU5F1) in c-kit/SCF regulation and investigates their function in ICLC activity and CG development. POU5F1 was identified as a transcription factor targeting both c-kit and SCF for transcription activation. They were poorly expressed in mice fed a lithogenic diet (LD) and mouse ICLCs treated with cholesterol. Upregulation of POU5F1 alleviated ICLC apoptosis, contraction dysfunction, and CG formation in the gallbladder wall of mice. Similarly, the POU5F1 upregulation enhanced the viability of ICLCs <em>in vitro</em> while reducing cell apoptosis. However, these effects were blocked by either c-kit or SCF knockdown. Furthermore, DNA methyltransferase 1 (DNMT1) and DNMT3B were identified as two important regulators suppressing POU5F1 transcription through DNA methylation. Knockdown of either DNMT1 or DNMT3B restored POU5F1 and c-kit/SCF levels, therefore reducing ICLC apoptosis and CG formation. In conclusion, this study demonstrates that DNMT1/DNMT3B-mediated DNA methylation of POU5F1 induces c-kit/SCF downregulation, thus promoting apoptosis of ICLCs and CG formation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167689"},"PeriodicalIF":4.2,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.bbadis.2025.167702
Zimu Li , Shun Xi , Ziqi Zhang , Xugang Kan , Yang Zhang , Miaomiao Wang , Yudong Wang , Yefeng Shi , Haoyue Xu , Baole Zhang
Elevated levels of glial cell line-derived neurotrophic factor (GDNF) are implicated in the transformation of astrocytes into astrogliomas, but the underlying mechanisms are not fully understood. In this study, we found that hypoxia led to a significant increase in GDNF expression in primary rat astrocytes from various brain regions, including the cortex, hippocampus, and corpus callosum. This was accompanied by the activation of astrocytes, particularly those of the A2 subtype, and a concurrent increase in hypoxia-inducible factor 1-alpha (HIF-1α) expression. The elevated levels of HIF-1α enhanced its binding to the GDNF promoter, resulting in increased GDNF expression. Interestingly, this process formed a positive feedback loop, as elevated GDNF further activated HIF-1α in primary rat and human astrocytes. Furthermore, lysyl oxidase-like protein 2 (LOXL2), a novel downstream oncogene of GDNF, showed a significant increase following hypoxia treatment and exhibited a positive correlation with GDNF expression. Inhibiting GDNF signaling effectively suppressed this expression. Hypoxia-induced GDNF also increased the phosphorylation of ERK, P38, and CREB through the classical GDNF receptors, GFRα1 and RET. This led to increased binding of phosphorylated CREB to the LOXL2 promoter, resulting in enhanced LOXL2 expression. Consequently, rat astrocytes under hypoxic stress exhibited increased cell viability, migration, and epithelial-mesenchymal transition, which were mitigated by inhibiting GDNF signaling or silencing LOXL2. This phenomenon was also observed in C6 cells. Our findings suggest that hypoxia induces astrocyte activation and upregulates LOXL2 expression through the HIF-1α/GDNF/P-CREB signaling axis, facilitating the infiltration-like growth of astrocytes and the infiltrative growth of C6 astroglioma cells.
{"title":"Hypoxic stress promotes astrocyte infiltration-like growth via HIF-1α/GDNF/LOXL2 axis","authors":"Zimu Li , Shun Xi , Ziqi Zhang , Xugang Kan , Yang Zhang , Miaomiao Wang , Yudong Wang , Yefeng Shi , Haoyue Xu , Baole Zhang","doi":"10.1016/j.bbadis.2025.167702","DOIUrl":"10.1016/j.bbadis.2025.167702","url":null,"abstract":"<div><div>Elevated levels of glial cell line-derived neurotrophic factor (GDNF) are implicated in the transformation of astrocytes into astrogliomas, but the underlying mechanisms are not fully understood. In this study, we found that hypoxia led to a significant increase in GDNF expression in primary rat astrocytes from various brain regions, including the cortex, hippocampus, and corpus callosum. This was accompanied by the activation of astrocytes, particularly those of the A2 subtype, and a concurrent increase in hypoxia-inducible factor 1-alpha (HIF-1α) expression. The elevated levels of HIF-1α enhanced its binding to the GDNF promoter, resulting in increased GDNF expression. Interestingly, this process formed a positive feedback loop, as elevated GDNF further activated HIF-1α in primary rat and human astrocytes. Furthermore, lysyl oxidase-like protein 2 (LOXL2), a novel downstream oncogene of GDNF, showed a significant increase following hypoxia treatment and exhibited a positive correlation with GDNF expression. Inhibiting GDNF signaling effectively suppressed this expression. Hypoxia-induced GDNF also increased the phosphorylation of ERK, P38, and CREB through the classical GDNF receptors, GFRα1 and RET. This led to increased binding of phosphorylated CREB to the LOXL2 promoter, resulting in enhanced LOXL2 expression. Consequently, rat astrocytes under hypoxic stress exhibited increased cell viability, migration, and epithelial-mesenchymal transition, which were mitigated by inhibiting GDNF signaling or silencing LOXL2. This phenomenon was also observed in C6 cells. Our findings suggest that hypoxia induces astrocyte activation and upregulates LOXL2 expression through the HIF-1α/GDNF/P-CREB signaling axis, facilitating the infiltration-like growth of astrocytes and the infiltrative growth of C6 astroglioma cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167702"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.bbadis.2025.167703
Prachi Umbarkar, Sultan Tousif, Ashish Jaiswal, Arvind Singh Bhati, Angelica Toro Cora, Rohan Sethi, Qinkun Zhang, Hind Lal
Background
Excessive fibrosis and chronic inflammation are vital to adverse cardiac remodeling of the MI heart. The crosstalk of fibroblasts (FBs) (primary drivers of fibrosis) and immune cells (that govern inflammation) is critical for the repair and remodeling of the injured heart. However, the molecular mechanisms through which FBs communicate with immune cells are poorly understood. In the MI heart, substantial cardiac cell damage releases alarmins, which trigger an immune response through the TLR/MyD88 pathway. The role of MyD88-dependent signaling is well characterized in immune cell biology. However, the role of FB-derived MyD88 signaling in MI heart injury is unknown.
Objective
To define the role of FB-MyD88 in MI pathology.
Methods and results
MyD88 was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn- promoter-driven Cre recombinase. Control and MyD88 KO mice were subjected to permanent LAD ligation (MI injury), and cardiac parameters were evaluated. Additionally, co-culture experiments and chemokine profiling were conducted to identify mechanisms facilitating FB-immune cell crosstalk. FB-specific MyD88 deletion restricted MI-induced adverse cardiac remodeling and cardiac dysfunction. Surprisingly, FB-specific MyD88 deletion reduced myeloid cell recruitment and molecular markers of chronic inflammation in the KO heart. The mechanistic studies confirmed that MyD88 is required for the activation of NF-κB in FBs. Additionally, co-culture experiments demonstrated that FB-MyD88 facilitates immune cell crosstalk through chemokines and promotes an inflammatory gene program.
Conclusion
These findings suggest that FB-MyD88 promotes MI-induced chronic inflammation and cardiac dysfunction. Therefore, targeting MyD88 could serve as a potential therapeutic strategy.
{"title":"Fibroblast-specific MyD88-dependent signaling aggravates inflammation and cardiac dysfunction in the MI heart","authors":"Prachi Umbarkar, Sultan Tousif, Ashish Jaiswal, Arvind Singh Bhati, Angelica Toro Cora, Rohan Sethi, Qinkun Zhang, Hind Lal","doi":"10.1016/j.bbadis.2025.167703","DOIUrl":"10.1016/j.bbadis.2025.167703","url":null,"abstract":"<div><h3>Background</h3><div>Excessive fibrosis and chronic inflammation are vital to adverse cardiac remodeling of the MI heart. The crosstalk of fibroblasts (FBs) (primary drivers of fibrosis) and immune cells (that govern inflammation) is critical for the repair and remodeling of the injured heart. However, the molecular mechanisms through which FBs communicate with immune cells are poorly understood. In the MI heart, substantial cardiac cell damage releases alarmins, which trigger an immune response through the TLR/MyD88 pathway. The role of MyD88-dependent signaling is well characterized in immune cell biology. However, the role of FB-derived MyD88 signaling in MI heart injury is unknown.</div></div><div><h3>Objective</h3><div>To define the role of FB-MyD88 in MI pathology.</div></div><div><h3>Methods and results</h3><div>MyD88 was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn- promoter-driven Cre recombinase. Control and MyD88 KO mice were subjected to permanent LAD ligation (MI injury), and cardiac parameters were evaluated. Additionally, co-culture experiments and chemokine profiling were conducted to identify mechanisms facilitating FB-immune cell crosstalk. FB-specific MyD88 deletion restricted MI-induced adverse cardiac remodeling and cardiac dysfunction. Surprisingly, FB-specific MyD88 deletion reduced myeloid cell recruitment and molecular markers of chronic inflammation in the KO heart. The mechanistic studies confirmed that MyD88 is required for the activation of NF-κB in FBs. Additionally, co-culture experiments demonstrated that FB-MyD88 facilitates immune cell crosstalk through chemokines and promotes an inflammatory gene program.</div></div><div><h3>Conclusion</h3><div>These findings suggest that FB-MyD88 promotes MI-induced chronic inflammation and cardiac dysfunction. Therefore, targeting MyD88 could serve as a potential therapeutic strategy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167703"},"PeriodicalIF":4.2,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.bbadis.2025.167699
S. Iglesias-Fortes , A.C. Lockwood , C. González-Blanco , D. Lozano , A. García-Aguilar , O. Palomino , G. García , E. Fernández-Millán , M. Benito , C. Guillén
Type 2 diabetes mellitus is a disease which initiates with insulin resistance. Then, pancreatic β cells start to counteract this situation by increasing insulin secretion, which is known as pre-diabetic state. Amylin protein or islet amyloid polypeptide (IAPP), has multiple physiological roles such as the regulation of satiety and avoiding gastric emptying. However, amylin is able to aggregate, forming insoluble structures that affects pancreatic β cell survival. Interestingly, not all the amylin from the different species has this aggregate-prone capacity. There are species, which possesses non-amyloidogenic capacity and does not aggregate such as the rodents. However, there are versions of the protein, for instance from humans and primates, which can aggregate. Previously, we observed that small oligomers could be found in extracellular vesicles (EVs). Now, we have used a pancreatic β cell which overexpresses human amylin (hIAPP) (INS1E-hIAPP) and we have explored the capacity of amylin to be incorporated into EVs and how amylin could affect to different essential signaling pathways such as the mammalian target of rapamycin complex 1, endoplasmic-reticulum stress and senescence. Here, we report that amylin can be incorporated into EVs in an endosomal sorting complexes required for transport (ESCRT)-dependent manner. When we treated the cells with the neutral sphingomyelinase inhibitor, GW4869, one of the pathways for EV biogenesis and under high glucose conditions, there was an increased incorporation of soluble amylin into vesicles. Interestingly in this condition, when we isolated the EVs, we clearly observed that the size of the vesicles was higher, compatible with microvesicles (MVs). Resveratrol increased a pro-senescent phenotype but, it was able to revert either the high glucose or GW4869-associated senescent. In summary, these results indicate that amylin can be recruited in an ESCRT-dependent manner into EVs and, resveratrol presents an important role in inducing senescence in INS1E-hIAPP pancreatic β cells.
{"title":"Amylin is incorporated into extracellular vesicles in an ESCRT-dependent manner and regulates senescence","authors":"S. Iglesias-Fortes , A.C. Lockwood , C. González-Blanco , D. Lozano , A. García-Aguilar , O. Palomino , G. García , E. Fernández-Millán , M. Benito , C. Guillén","doi":"10.1016/j.bbadis.2025.167699","DOIUrl":"10.1016/j.bbadis.2025.167699","url":null,"abstract":"<div><div>Type 2 diabetes mellitus is a disease which initiates with insulin resistance. Then, pancreatic β cells start to counteract this situation by increasing insulin secretion, which is known as pre-diabetic state. Amylin protein or islet amyloid polypeptide (IAPP), has multiple physiological roles such as the regulation of satiety and avoiding gastric emptying. However, amylin is able to aggregate, forming insoluble structures that affects pancreatic β cell survival. Interestingly, not all the amylin from the different species has this aggregate-prone capacity. There are species, which possesses non-amyloidogenic capacity and does not aggregate such as the rodents. However, there are versions of the protein, for instance from humans and primates, which can aggregate. Previously, we observed that small oligomers could be found in extracellular vesicles (EVs). Now, we have used a pancreatic β cell which overexpresses human amylin (hIAPP) (INS1E-hIAPP) and we have explored the capacity of amylin to be incorporated into EVs and how amylin could affect to different essential signaling pathways such as the mammalian target of rapamycin complex 1, endoplasmic-reticulum stress and senescence. Here, we report that amylin can be incorporated into EVs in an endosomal sorting complexes required for transport (ESCRT)-dependent manner. When we treated the cells with the neutral sphingomyelinase inhibitor, GW4869, one of the pathways for EV biogenesis and under high glucose conditions, there was an increased incorporation of soluble amylin into vesicles. Interestingly in this condition, when we isolated the EVs, we clearly observed that the size of the vesicles was higher, compatible with microvesicles (MVs). Resveratrol increased a pro-senescent phenotype but, it was able to revert either the high glucose or GW4869-associated senescent. In summary, these results indicate that amylin can be recruited in an ESCRT-dependent manner into EVs and, resveratrol presents an important role in inducing senescence in INS1E-hIAPP pancreatic β cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167699"},"PeriodicalIF":4.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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