Biochimica et biophysica acta. Molecular basis of disease最新文献

Matrisome analysis of NSCLC unveils clinically-important cancer-associated extracellular matrix changes

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-11 DOI: 10.1016/j.bbadis.2025.167709

Camila Machado Baldavira , Tabatha Gutierrez Prieto , Maria Luiza Fernezlian de Souza , Aline Nery Qualiotto , Ana Paula Pereira Velosa , Walcy Rosolia Teodoro , Teresa Takagaki , Alexandre Ab'Saber , Vera Luiza Capelozzi

Introduction

Non-small cell lung carcinoma (NSCLC), comprising adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), is characterized by an active desmoplastic stroma with an accumulation of extracellular matrix (ECM) proteins. ECM remodeling is a key feature of cancer progression, but the identification of specific therapeutic targets within this compartment remains challenging. Recent studies suggest a link between increased desmoplastic stroma and malignancy in NSCLC, the role of ECM proteins in disease pathogenesis remains unclear.

Methods

We analyzed an exploratory cohort of Pan-Cancer Atlas and a study cohort to identify differentially expressed ECM proteins. Our focus was on fibrillar components (elastin, fibrillin, collagens), glycosaminoglycans (chondroitin sulfate and heparan sulfate), and matricellular proteins (SPARC). Bioinformatics analysis highlighted matrix proteins that modulate ECM functionality and structure, potentially serving as biomarkers and/or therapeutic targets.

Results

Adenocarcinomas exhibited an ECM enriched with abnormal elastin, chondroitin sulfate, and SPARC. Collagen IV expression in the basement membrane was reduced, while collagen III and V were prominent around tumors. LUSC showed more fibrotic ECM, leading to a stiffer microenvironment. While LUSC's basement membrane may be fragmented, it often retains more intact collagen IV compared to LUAD. High elastin expression in LUAD correlated with smaller tumors (P = 0.022), while fibrillin-2 expression was linked to T1 stage (P = 0.035) and pathological stage I (P = 0.014). In LUSC, elastin expression correlated with negative lymph nodes (P = 0.037). SPARC was an independent factor for overall survival for both subtypes (P < 0.05).

Conclusion

This study provides insights into matrix changes in NSCLC and identifies promising candidates for targeted therapies.

{"title":"Matrisome analysis of NSCLC unveils clinically-important cancer-associated extracellular matrix changes","authors":"Camila Machado Baldavira , Tabatha Gutierrez Prieto , Maria Luiza Fernezlian de Souza , Aline Nery Qualiotto , Ana Paula Pereira Velosa , Walcy Rosolia Teodoro , Teresa Takagaki , Alexandre Ab'Saber , Vera Luiza Capelozzi","doi":"10.1016/j.bbadis.2025.167709","DOIUrl":"10.1016/j.bbadis.2025.167709","url":null,"abstract":"<div><h3>Introduction</h3><div>Non-small cell lung carcinoma (NSCLC), comprising adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), is characterized by an active desmoplastic stroma with an accumulation of extracellular matrix (ECM) proteins. ECM remodeling is a key feature of cancer progression, but the identification of specific therapeutic targets within this compartment remains challenging. Recent studies suggest a link between increased desmoplastic stroma and malignancy in NSCLC, the role of ECM proteins in disease pathogenesis remains unclear.</div></div><div><h3>Methods</h3><div>We analyzed an exploratory cohort of Pan-Cancer Atlas and a study cohort to identify differentially expressed ECM proteins. Our focus was on fibrillar components (elastin, fibrillin, collagens), glycosaminoglycans (chondroitin sulfate and heparan sulfate), and matricellular proteins (SPARC). Bioinformatics analysis highlighted matrix proteins that modulate ECM functionality and structure, potentially serving as biomarkers and/or therapeutic targets.</div></div><div><h3>Results</h3><div>Adenocarcinomas exhibited an ECM enriched with abnormal elastin, chondroitin sulfate, and SPARC. Collagen IV expression in the basement membrane was reduced, while collagen III and V were prominent around tumors. LUSC showed more fibrotic ECM, leading to a stiffer microenvironment. While LUSC's basement membrane may be fragmented, it often retains more intact collagen IV compared to LUAD. High elastin expression in LUAD correlated with smaller tumors (<em>P</em> = 0.022), while fibrillin-2 expression was linked to T1 stage (<em>P</em> = 0.035) and pathological stage I (<em>P</em> = 0.014). In LUSC, elastin expression correlated with negative lymph nodes (<em>P</em> = 0.037). SPARC was an independent factor for overall survival for both subtypes (<em>P</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>This study provides insights into matrix changes in NSCLC and identifies promising candidates for targeted therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167709"},"PeriodicalIF":4.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387801","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}

引用次数: 0

Ncl liquid-liquid phase separation and SUMOylation mediate the stabilization of HIF-1α expression and promote pyroptosis in ischemic hindlimb

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-10 DOI: 10.1016/j.bbadis.2025.167706

Yanli Wang , Weiliang Wu , Yan Xu , Chengjie Wu , Qingfang Han , Tonggan Lu , Huiling Zhang , Lijuan Jiao , Yu Zhang , Bin Liu , Xi-yong Yu , Yangxin Li

Liquid-liquid phase separation (LLPS) has emerged as a flexible intracellular compartment that modulates various pathological processes. Hypoxia-inducible factor-1α (HIF-1α) has been shown to play an essential role in inflammation after ischemic injury. However, the mechanisms underlying HIF-1α-induced inflammation in ischemic diseases have not been defined. This study found that HIF-1α mediated the progression of ischemia-induced muscle injury. After ischemic injury, SUMO1 is upregulated and rapidly activates NLRP3 inflammasome through the upregulation of HIF-1α, leading to enhanced inflammation and pyroptosis. Co-IP revealed an interaction between SUMO1 and HIF-1α and SUMOylation of HIF-1α at K477. Moreover, we demonstrated the important role of dynamic phase separation of Nucleolin (Ncl) in regulating HIF-1α mRNA stability through fluorescence recovery after photobleach (FRAP) analysis. The stability of HIF-1α is regulated by Ncl liquid-liquid phase separation and SUMOylation in ischemia-induced hindlimb injury. HIF-1α can promote the expression of NLRP3 and other inflammation-related molecules, leading to pyroptosis, suggesting that Ncl/LLPS/HIF-1α or SUMO1/HIF-1α pathway may be a new target for the treatment of inflammation in ischemic diseases. Although previous studies have found that HIF-1α is able to promote the expression of target genes after hypoxia, and these genes are used to maintain the stability of the intracellular environment to adapt to hypoxia. We found that HIF-1α is involved in the activation process of NLRP3 inflammasomes after hind limb ischemia, which enriches our understanding of the biological role of HIF-1α.

{"title":"Ncl liquid-liquid phase separation and SUMOylation mediate the stabilization of HIF-1α expression and promote pyroptosis in ischemic hindlimb","authors":"Yanli Wang , Weiliang Wu , Yan Xu , Chengjie Wu , Qingfang Han , Tonggan Lu , Huiling Zhang , Lijuan Jiao , Yu Zhang , Bin Liu , Xi-yong Yu , Yangxin Li","doi":"10.1016/j.bbadis.2025.167706","DOIUrl":"10.1016/j.bbadis.2025.167706","url":null,"abstract":"<div><div>Liquid-liquid phase separation (LLPS) has emerged as a flexible intracellular compartment that modulates various pathological processes. Hypoxia-inducible factor-1α (HIF-1α) has been shown to play an essential role in inflammation after ischemic injury. However, the mechanisms underlying HIF-1α-induced inflammation in ischemic diseases have not been defined. This study found that HIF-1α mediated the progression of ischemia-induced muscle injury. After ischemic injury, SUMO1 is upregulated and rapidly activates NLRP3 inflammasome through the upregulation of HIF-1α, leading to enhanced inflammation and pyroptosis. Co-IP revealed an interaction between SUMO1 and HIF-1α and SUMOylation of HIF-1α at K477. Moreover, we demonstrated the important role of dynamic phase separation of Nucleolin (Ncl) in regulating HIF-1α mRNA stability through fluorescence recovery after photobleach (FRAP) analysis. The stability of HIF-1α is regulated by Ncl liquid-liquid phase separation and SUMOylation in ischemia-induced hindlimb injury. HIF-1α can promote the expression of NLRP3 and other inflammation-related molecules, leading to pyroptosis, suggesting that Ncl/LLPS/HIF-1α or SUMO1/HIF-1α pathway may be a new target for the treatment of inflammation in ischemic diseases. Although previous studies have found that HIF-1α is able to promote the expression of target genes after hypoxia, and these genes are used to maintain the stability of the intracellular environment to adapt to hypoxia. We found that HIF-1α is involved in the activation process of NLRP3 inflammasomes after hind limb ischemia, which enriches our understanding of the biological role of HIF-1α.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167706"},"PeriodicalIF":4.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379352","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}

引用次数: 0

RGS1 can serve as a long-term prognostic marker in gastric cancer by promoting the infiltration and polarization of macrophages

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-09 DOI: 10.1016/j.bbadis.2025.167711

Yuzheng Zhang , Zhifang Jia , Donghui Cao , Yanping Zhong , Yanhua Wu , Yingli Fu , Yingnan Cui , Xinyi Yu , Yu Liu , Jing Jiang

Gastric cancer (GC) remains a prevalent and aggressive malignancy worldwide, characterized by significant morbidity and mortality. The regulator of G-protein signaling 1 (RGS1) plays an oncogenic role in various cancers, including GC, but its clinical relevance and mechanisms remain underexplored. In this pilot study, we investigated RGS1 expression in GC tissues and its potential as a prognostic marker, laying the groundwork for future research. Our analysis of patient data from the TCGA data and our cohort of 375 surgically resected GC patients revealed that RGS1 was upregulated in GC tissues and had prognostic significance (TCGA: adjusted HR:1.49, 95%CI: 1.02–2.18; GC cohort: adjusted HR: 1.38, 95%CI: 1.02–1.85). GO function and KEGG enrichment analyses suggest that RGS1 is involved in macrophage-mediated immune responses in GC. We observed a positive correlation between RGS1 expression and M2 macrophage infiltration. Furthermore, co-occurrence of elevated RGS1 expression and M2 macrophage infiltration predicts a worse prognosis (adjusted HR: 1.73, 95%CI: 1.24–2.42 in our cohort). In vitro, RGS1 upregulation and the presence of M2 macrophages enhanced malignant phenotypes of GC cells. Additionally, we confirmed that RGS1 promoted macrophage recruitment and M2 polarization via upregulation of CCL4 expression in vivo. In conclusion, this study suggests that RGS1 could serve as a promising prognostic marker for GC and a potential target for immunotherapy. However, further investigation with more advanced experimental models is needed to confirm these preliminary findings.

{"title":"RGS1 can serve as a long-term prognostic marker in gastric cancer by promoting the infiltration and polarization of macrophages","authors":"Yuzheng Zhang , Zhifang Jia , Donghui Cao , Yanping Zhong , Yanhua Wu , Yingli Fu , Yingnan Cui , Xinyi Yu , Yu Liu , Jing Jiang","doi":"10.1016/j.bbadis.2025.167711","DOIUrl":"10.1016/j.bbadis.2025.167711","url":null,"abstract":"<div><div>Gastric cancer (GC) remains a prevalent and aggressive malignancy worldwide, characterized by significant morbidity and mortality. The regulator of G-protein signaling 1 (RGS1) plays an oncogenic role in various cancers, including GC, but its clinical relevance and mechanisms remain underexplored. In this pilot study, we investigated RGS1 expression in GC tissues and its potential as a prognostic marker, laying the groundwork for future research. Our analysis of patient data from the TCGA data and our cohort of 375 surgically resected GC patients revealed that RGS1 was upregulated in GC tissues and had prognostic significance (TCGA: adjusted HR:1.49, 95%CI: 1.02–2.18; GC cohort: adjusted HR: 1.38, 95%CI: 1.02–1.85). GO function and KEGG enrichment analyses suggest that RGS1 is involved in macrophage-mediated immune responses in GC. We observed a positive correlation between RGS1 expression and M2 macrophage infiltration. Furthermore, co-occurrence of elevated RGS1 expression and M2 macrophage infiltration predicts a worse prognosis (adjusted HR: 1.73, 95%CI: 1.24–2.42 in our cohort). In vitro, RGS1 upregulation and the presence of M2 macrophages enhanced malignant phenotypes of GC cells. Additionally, we confirmed that RGS1 promoted macrophage recruitment and M2 polarization via upregulation of CCL4 expression in vivo. In conclusion, this study suggests that RGS1 could serve as a promising prognostic marker for GC and a potential target for immunotherapy. However, further investigation with more advanced experimental models is needed to confirm these preliminary findings.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167711"},"PeriodicalIF":4.2,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143395605","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}

引用次数: 0

Pinocembrin reduces pyroptosis to improve flap survival by modulating the TLR4/NF-κB/NLRP3 signaling pathway

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-08 DOI: 10.1016/j.bbadis.2025.167710

Kaitao Wang, Jialong Yang, Jiapeng Deng, An Wang, Guodong Chen, Dingsheng Lin

Background

Pinocembrin has been widely utilized in clinical settings as a topical treatment for detoxification, inflammation reduction, and healing dermal conditions such as cracked skin and burns.

Methods

In this study, pinocembrin was administered to hypoxia-reoxygenation model in human umbilical vein endothelial cells and 36 rats for 7 days using the McFarlane flap model. Neovascularization was then assessed using Doppler and lead oxide gelatin angiography. Neutrophil infiltration and mean microvessel density were assessed through hematoxylin and eosin staining. Immunofluorescence was employed to assess neovascularization and inflammation by detecting vascular endothelial growth factor, interleukin-1β, interleukin-6, and tumor necrosis factor-α. Pyroptosis was evaluated using western blot analysis.

Results

Compared with the control group, the experimental groups exhibited a significant increase in flap survival area with the promotion of neovascularization, mitigation of oxidative stress, and suppression of pyroptosis and inflammation.

Conclusion

Pinocembrin enhanced flap survival, promoted neovascularization, mitigated oxidative stress, and suppressed pyroptosis and inflammation by downregulating the TLR4/NF-κB/NLRP3 signaling pathway.

{"title":"Pinocembrin reduces pyroptosis to improve flap survival by modulating the TLR4/NF-κB/NLRP3 signaling pathway","authors":"Kaitao Wang, Jialong Yang, Jiapeng Deng, An Wang, Guodong Chen, Dingsheng Lin","doi":"10.1016/j.bbadis.2025.167710","DOIUrl":"10.1016/j.bbadis.2025.167710","url":null,"abstract":"<div><h3>Background</h3><div>Pinocembrin has been widely utilized in clinical settings as a topical treatment for detoxification, inflammation reduction, and healing dermal conditions such as cracked skin and burns.</div></div><div><h3>Methods</h3><div>In this study, pinocembrin was administered to hypoxia-reoxygenation model in human umbilical vein endothelial cells and 36 rats for 7 days using the McFarlane flap model. Neovascularization was then assessed using Doppler and lead oxide gelatin angiography. Neutrophil infiltration and mean microvessel density were assessed through hematoxylin and eosin staining. Immunofluorescence was employed to assess neovascularization and inflammation by detecting vascular endothelial growth factor, interleukin-1β, interleukin-6, and tumor necrosis factor-α. Pyroptosis was evaluated using western blot analysis.</div></div><div><h3>Results</h3><div>Compared with the control group, the experimental groups exhibited a significant increase in flap survival area with the promotion of neovascularization, mitigation of oxidative stress, and suppression of pyroptosis and inflammation.</div></div><div><h3>Conclusion</h3><div>Pinocembrin enhanced flap survival, promoted neovascularization, mitigated oxidative stress, and suppressed pyroptosis and inflammation by downregulating the TLR4/NF-κB/NLRP3 signaling pathway.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167710"},"PeriodicalIF":4.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349415","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}

引用次数: 0

Free fatty acid receptors type 2 and 4 mediate the anticancer effects of fatty acids in colorectal cancer - in vitro and in vivo studies

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-06 DOI: 10.1016/j.bbadis.2025.167708

Agata Binienda, Weronika Machelak, Marta Zielińska, Jakub Fichna

High incidence of colorectal cancer (CRC) is influenced by diet low in fiber (source of short chain fatty acids, SCFAs, natural agonists for free fatty acid receptor type 2 (FFAR2)) and high in fat (main source of long chain fatty acids, LCFAs, FFAR4 agonists). FFAR2 and FFAR4 are downregulated in CRC. In this study, we characterized whether the anticancer effects of SCFAs and LCFAs are FFAR-dependent in in vitro and in vivo models of CRC. In vitro, SW-480 cell growth was determined after incubation with FFARs ligands (SCFAs: acetate, butyrate; LCFAs: palmitate, stearate) using MTT assay. Cell migration and invasion were investigated by wound healing and transwell-based invasion assays. In vivo, SCFAs and LCFAs were administered to azoxymethane/dextran sodium sulfate-treated mice. Real-time qPCR and Western blot were used to determine FFARs expression. SCFAs and LCFAs significantly decreased SW-480 cell growth, migration and invasion capacities. Combination of SCFAs and LCFAs induced synergistic inhibitory effects on CRC cell growth and motility. FFAR2 and FFAR4 expression were elevated in CRC cells treated with butyrate as well as with butyrate+acetate, and butyrate+palmitate+stearate. Concurrently, only FFAR4 expression was increased in CRC cells incubated with LCFAs. In vivo, treatment with LCFAs, but not SCFAs increased ffar2 and Ffar4 expression. Our findings showed that SCFAs and LCFAs inhibit cancer cell growth and their migration and invasion capabilities. Our study evidenced that the anticancer effects of SCFAs- and LCFAs are mediated by FFAR2 and FFAR4.

{"title":"Free fatty acid receptors type 2 and 4 mediate the anticancer effects of fatty acids in colorectal cancer - in vitro and in vivo studies","authors":"Agata Binienda, Weronika Machelak, Marta Zielińska, Jakub Fichna","doi":"10.1016/j.bbadis.2025.167708","DOIUrl":"10.1016/j.bbadis.2025.167708","url":null,"abstract":"<div><div>High incidence of colorectal cancer (CRC) is influenced by diet low in fiber (source of short chain fatty acids, SCFAs, natural agonists for free fatty acid receptor type 2 (FFAR2)) and high in fat (main source of long chain fatty acids, LCFAs, FFAR4 agonists). FFAR2 and FFAR4 are downregulated in CRC. In this study, we characterized whether the anticancer effects of SCFAs and LCFAs are FFAR-dependent in <em>in vitro</em> and <em>in vivo</em> models of CRC. <em>In vitro</em>, SW-480 cell growth was determined after incubation with FFARs ligands (SCFAs: acetate, butyrate; LCFAs: palmitate, stearate) using MTT assay. Cell migration and invasion were investigated by wound healing and transwell-based invasion assays. <em>In vivo</em>, SCFAs and LCFAs were administered to azoxymethane/dextran sodium sulfate-treated mice. Real-time qPCR and Western blot were used to determine FFARs expression. SCFAs and LCFAs significantly decreased SW-480 cell growth, migration and invasion capacities. Combination of SCFAs and LCFAs induced synergistic inhibitory effects on CRC cell growth and motility. <em>FFAR2</em> and <em>FFAR4</em> expression were elevated in CRC cells treated with butyrate as well as with butyrate+acetate, and butyrate+palmitate+stearate. Concurrently, only FFAR4 expression was increased in CRC cells incubated with LCFAs. <em>In vivo</em>, treatment with LCFAs, but not SCFAs increased <em>ffar2</em> and Ffar4 expression. Our findings showed that SCFAs and LCFAs inhibit cancer cell growth and their migration and invasion capabilities. Our study evidenced that the anticancer effects of SCFAs- and LCFAs are mediated by FFAR2 and FFAR4.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167708"},"PeriodicalIF":4.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374976","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}

引用次数: 0

Neutrophil extracellular traps-induced pyroptosis of liver sinusoidal endothelial cells exacerbates intrahepatic coagulation in cholestatic mice

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-05 DOI: 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}

引用次数: 0

Decoding the cytokine code for heart failure based on bioinformatics, machine learning and Bayesian networks

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-04 DOI: 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}

引用次数: 0

Effect of co-treatment with disulfiram and resatorvid on the pyroptosis of monocytes in sepsis

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-04 DOI: 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}

引用次数: 0

Exogenous hydrogen sulfide and NOX2 inhibition mitigate ferroptosis in pressure-induced retinal ganglion cell damage

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-04 DOI: 10.1016/j.bbadis.2025.167705

Yuan Feng, Xiaosha Wang, Panpan Li, Xin Shi, Verena Prokosch, Hanhan Liu

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}

引用次数: 0

DNA methylation of POU5F1 by DNMT1 and DNMT3B triggers apoptosis in interstitial Cajal-like cells via c-kit/SCF inhibition during cholesterol gallstone formation 在胆固醇胆石形成过程中，DNMT1 和 DNMT3B 对 POU5F1 的 DNA 甲基化会通过 c-kit/SCF 抑制作用引发卡贾尔间质样细胞凋亡。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-02-02 DOI: 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}

引用次数: 0