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

{"title":"Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway","authors":"Roman A. Blaheta ,&nbsp;Jiaoyan Han ,&nbsp;Elsie Oppermann ,&nbsp;Wolf Otto Bechstein ,&nbsp;Katrin Burkhard ,&nbsp;Axel Haferkamp ,&nbsp;Michael A. Rieger ,&nbsp;Patrizia Malkomes","doi":"10.1016/j.bbadis.2024.167538","DOIUrl":"10.1016/j.bbadis.2024.167538","url":null,"abstract":"<div><div>Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells.</div><div>TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling.</div><div>TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7.</div><div>TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167538"},"PeriodicalIF":4.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402318","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}

{"title":"Maternal heart exhibits metabolic and redox adaptations post-uncomplicated pregnancy","authors":"Carolina Tocantins ,&nbsp;João D. Martins ,&nbsp;Óscar M. Rodrigues ,&nbsp;Luís F. Grilo ,&nbsp;Mariana S. Diniz ,&nbsp;Jelena Stevanovic-Silva ,&nbsp;Jorge Beleza ,&nbsp;Pedro Coxito ,&nbsp;David Rizo-Roca ,&nbsp;Estela Santos-Alves ,&nbsp;António J. Moreno ,&nbsp;António Ascensão ,&nbsp;José Magalhães ,&nbsp;Paulo J. Oliveira ,&nbsp;Susana P. Pereira","doi":"10.1016/j.bbadis.2024.167539","DOIUrl":"10.1016/j.bbadis.2024.167539","url":null,"abstract":"<div><div>Pregnancy may be a challenging period for the maternal systems and has been regarded as a stress test, as imperceptible/mild dysfunctions eventually present may be exacerbated during this period. The cardiovascular system is no exception, and several morphological and functional adaptations accompanying pregnancy have been described. However, long-term pregnancy-induced cardiac molecular alterations remain highly unexplored. The postpartum is marked by reverse remodeling of the pregnancy-induced cardiovascular adaptations, representing a possible critical period for assessing future maternal cardiovascular health. The current study explored the molecular and metabolic alterations in the cardiac tissue eight weeks after a physiological uncomplicated pregnancy. Female Sprague-Dawley rats were fed a chow diet through pregnancy, lactation, and weaning and compared to their non-pregnant counterparts. Eight weeks postpartum, increased levels of the phosphorylated form of AMPKα (Thr172) and its ratio to total AMPKα indicated possible alterations in cardiac metabolic flexibility, accompanied by increased <em>Ppar</em>α and <em>Hif</em>1α transcripts levels. Additionally, postpartum hearts exhibited higher mitochondrial ATP and NADH levels without major changes in mitochondrial respiratory function. Elevated Nrf2 levels in the cardiac tissue suggested potential implications for cardiac redox balance, further supported by increased levels or activity of proteins directly regulated by Nrf2. The findings herein reported suggest that at eight weeks postpartum, molecular alterations induced by pregnancy, especially regarding redox balance, are still observed in the mothers' heart. These alterations present at late postpartum may open new avenues to understand the different risk for cardiovascular complications development after normal pregnancies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167539"},"PeriodicalIF":4.2,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395894","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}

{"title":"VEGFB promotes adipose tissue thermogenesis by inhibiting norepinephrine clearance in macrophages","authors":"Lei Wang ,&nbsp;Jing Jin ,&nbsp;Nuo Zhang ,&nbsp;Yan Dai ,&nbsp;Xueya Bai ,&nbsp;Jinhao Li ,&nbsp;Yueqi Yu ,&nbsp;Xiaoling Shi ,&nbsp;Hui Bai ,&nbsp;Qing Yang ,&nbsp;Bin Jiang ,&nbsp;Jingjing Ben ,&nbsp;Hanwen Zhang ,&nbsp;Xiaoyu Li ,&nbsp;Qi Chen ,&nbsp;Xudong Zhu","doi":"10.1016/j.bbadis.2024.167536","DOIUrl":"10.1016/j.bbadis.2024.167536","url":null,"abstract":"<div><div>Adipokines play key roles in adaptive thermogenesis of beige adipocytes, though its detailed regulatory mechanisms are not fully understood. In the present study, we identify a critical function of vascular endothelial growth factor B (VEGFB)/vascular endothelial growth factor receptor 1 (VEGFR1) signaling in improving thermogenesis in white adipose tissue (WAT). In mouse subcutaneous WAT (scWAT), thermogenesis activation leads to the up-regulation of VEGFB in adipocytes and its receptor VEGFR1 in macrophages. Ablation of adipocyte VEGFB results in deficiency in murine WAT browning. Meanwhile, supplementation of VEGFB promotes WAT thermogenesis, but this effect is blocked by knockout of macrophage VEGFR1. Mechanistic studies show that the VEGFB-activated VEGFR1 inhibits p38 MAPK signaling through its dissociation with receptor for activated C kinase 1, thereby preventing norepinephrine transporter (solute carrier family 6 member 2) and norepinephrine-degrative monoamine oxidase a mediated norepinephrine clearance in macrophages. Our findings demonstrate that VEGFB/VEGFR1 circuit contributes to the WAT thermogenesis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167536"},"PeriodicalIF":4.2,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395897","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}

{"title":"Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells","authors":"Chotirat Rattanasinchai ,&nbsp;Panida Navasumrit ,&nbsp;Chidchanok Chornkrathok ,&nbsp;Mathuros Ruchirawat","doi":"10.1016/j.bbadis.2024.167521","DOIUrl":"10.1016/j.bbadis.2024.167521","url":null,"abstract":"<div><h3>Background</h3><div>Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive.</div></div><div><h3>Methods</h3><div>The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated.</div></div><div><h3>Results</h3><div>Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top ‘hit’ inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations.</div></div><div><h3>Conclusions</h3><div>IGF-1R plays a critical role in maintaining iCCA-stem like cell populations.</div></div><div><h3>General significance</h3><div>Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167521"},"PeriodicalIF":4.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382733","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}

{"title":"Bulk integrated single-cell-spatial transcriptomics reveals the impact of preoperative chemotherapy on cancer-associated fibroblasts and tumor cells in colorectal cancer, and construction of related predictive models using machine learning","authors":"Shangshang Hu ,&nbsp;Jian Qin ,&nbsp;Muzi Ding ,&nbsp;Rui Gao ,&nbsp;QianNi Xiao ,&nbsp;Jinwei Lou ,&nbsp;Yuhan Chen ,&nbsp;Shukui Wang ,&nbsp;Yuqin Pan","doi":"10.1016/j.bbadis.2024.167535","DOIUrl":"10.1016/j.bbadis.2024.167535","url":null,"abstract":"<div><h3>Background</h3><div>Preoperative chemotherapy (PC) is an important component of Colorectal cancer (CRC) treatment, but its effects on the biological functions of fibroblasts and epithelial cells in CRC are unclear.</div></div><div><h3>Methods</h3><div>This study utilized bulk, single-cell, and spatial transcriptomic sequencing data from 22 independent cohorts of CRC. Through bioinformatics analysis and in vitro experiments, the research investigated the impact of PC on fibroblast and epithelial cells in CRC. Subpopulations associated with PC and CRC prognosis were identified, and a predictive model was constructed using machine learning.</div></div><div><h3>Results</h3><div>PC significantly attenuated the pathways related to tumor progression in fibroblasts and epithelial cells. NOTCH3 + Fibroblast (NOTCH3 + Fib), TNNT1 + Epithelial (TNNT1 + Epi), and HSPA1A + Epithelial (HSPA1A + Epi) subpopulations were identified in the adjacent spatial region and were associated with poor prognosis in CRC. PC effectively diminished the presence of these subpopulations, concurrently inhibiting pathway activity and intercellular crosstalk. A risk signature model, named the Preoperative Chemotherapy Risk Signature Model (PCRSM), was constructed using machine learning. PCRSM emerged as an independent prognostic indicator for CRC, impacting both overall survival (OS) and recurrence-free survival (RFS), surpassing the performance of 89 previously published CRC risk signatures. Additionally, patients with a high PCRSM risk score showed sensitivity to fluorouracil-based adjuvant chemotherapy (FOLFOX) but resistance to single chemotherapy drugs (such as Bevacizumab and Oxaliplatin). Furthermore, this study predicted that patients with high PCRSM were resistant to anti-PD1therapy.</div></div><div><h3>Conclusion</h3><div>In conclusion, this study identified three cell subpopulations (NOTCH3 + Fib, TNNT1 + Epi, and HSPA1A + Epi) associated with PC, which can be targeted to improve the prognosis of CRC patients. The PCRSM model shows promise in enhancing the survival and treatment of CRC patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167535"},"PeriodicalIF":4.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395895","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}

{"title":"Trim21 modulates endoplasmic reticulum-associated degradation and sensitizes cancer cells to ER stress-induced apoptosis by inhibiting VCP/Npl4/UFD1 assembly","authors":"Chao Yuan ,&nbsp;Yanli Liao ,&nbsp;WenXia Si ,&nbsp;Mi Huang ,&nbsp;Duanzhuo Li ,&nbsp;Fuqing Wang ,&nbsp;Yi Quan ,&nbsp;Xin Yu ,&nbsp;Shengjie Liao","doi":"10.1016/j.bbadis.2024.167533","DOIUrl":"10.1016/j.bbadis.2024.167533","url":null,"abstract":"<div><div>Endoplasmic reticulum-associated degradation (ERAD) serves as a crucial quality and quantity control system that removes misfolded or unassembled proteins from the Endoplasmic Reticulum (ER) through the cytoplasmic ubiquitin-proteasome system (UPS), which is critical for cell fate decision. ER stress arises when misfolded proteins accumulated within the ER lumen, potentially leading to cell death via proapoptotic unfolded protein response (UPR). UFD1 in associated with VCP-Npl4, is recognized as a key regulator of protein homeostasis in ERAD. However, the factors that control VCP complex assembly remain unclear. The study elucidates the function of Trim21, an E3 ubiquitin ligase, through its interaction with UFD1, facilitating K27-linkage ubiquitination of UFD1 and inhibiting its incorporation into the VCP complex. This results in the suppression of ERAD substrates degradation and the activation of a proapoptotic unfolded protein response in cancer cells. Additionally, Trim21 over-expression enhances ER stress response and promotes apoptosis upon expose to the ER inducer Tunicamycin. Notably, elevated Trim21 expression correlates with improved overall survival in various tumor types. Overall, the findings highlight the critical role of Trim21 in regulating ERAD progression and cell fate determination in cancer cells through modulation of VCP/Npl4/UFD1 complex assembly.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167533"},"PeriodicalIF":4.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378707","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}

{"title":"Tibolone treatment after traumatic brain injury exerts a sex-specific and Y chromosome-dependent regulation of methylation and demethylation enzymes and estrogen receptors in the cerebral cortex","authors":"Daniel Pinto-Benito ,&nbsp;Alvaro Bautista-Abad ,&nbsp;Natalia Lagunas ,&nbsp;Nebai Ontiveros ,&nbsp;Danny Ganchala ,&nbsp;Luis M. Garcia-Segura ,&nbsp;Maria-Angeles Arevalo ,&nbsp;Daniela Grassi","doi":"10.1016/j.bbadis.2024.167532","DOIUrl":"10.1016/j.bbadis.2024.167532","url":null,"abstract":"<div><div>Tibolone, a synthetic steroid used for the treatment of climacteric symptoms, displays sex-specific protective actions in experimental models of brain diseases. Previous in vitro findings suggest that tibolone reduces oxidative stress and neuroinflammation through the regulation of DNA methylation and the activation of estrogen receptors (ERs) α and β. In this study, we assessed whether tibolone regulates the expression of genes coding for DNA methylation and demethylation enzymes and ERs in the injured cerebral cortex of animals suffering a traumatic brain injury. The four-core genotype mouse model was used to determine whether the effect of tibolone on gene regulation was influenced by gonads or by cell-autonomous actions of sex chromosomes. Tibolone treatment resulted in sex-specific modification in the expression of genes coding for DNA methyl transferases (Dnmt) 3a, and 3b, for growth arrest and DNA-damage-inducible proteins (Gadd) 45β and 45γ, and for ERα and ERβ. In contrast, tibolone did not affect the expression of genes coding for Dnmt1, Gadd45α, and ten-eleven translocation methylcytosine dioxygenases 1–3. The sex-specific effect of tibolone on <em>Dnmt3a</em> expression depended on gonadal sex. In contrast, the presence or absence of the Y chromosome determined the effect of tibolone on <em>Dnmt3b</em>, <em>Gadd45β</em>, <em>Gadd45γ</em>, <em>ERα</em> and <em>ERβ</em> expression. These findings suggest that tibolone exerts a sex-specific regulation of DNA methylation and ER expression in the injured cerebral cortex that is determined by a combination of gonadal effects and cell-autonomous actions of sex chromosome genes.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167532"},"PeriodicalIF":4.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376436","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}

{"title":"Myeloid PGC1β attenuates high-fat-diet induced inflammation via mitochondrial fission/mtDNA/Nlrp3 pathway","authors":"En Li ,&nbsp;Jiajia Ji ,&nbsp;Gaoyang Zong ,&nbsp;Hao Liu ,&nbsp;Yue Sun ,&nbsp;Liangliang Wei ,&nbsp;Zhihao Xia ,&nbsp;Xiaoyu Yang ,&nbsp;Dageng Huang ,&nbsp;Yan Zhang","doi":"10.1016/j.bbadis.2024.167528","DOIUrl":"10.1016/j.bbadis.2024.167528","url":null,"abstract":"<div><div>Peroxisome proliferator-activated receptor gamma coactivators 1β (PGC1β) is essential in mitochondrial oxidative phosphorylation and alternative macrophages activation. To determine the contribution of PGC1β in obesity induced inflammation, <em>Ppargc1b</em> (PGC1β coding gene) myeloid conditional knockout mice (cKO) were fed with high fat diet (HFD) to examine the following effects. We found that HFD-fed cKO mice gained more fat with increased serum triglyceride (TG), low density lipoprotein (LDL), adiponectin, and leptin. Adipogenesis was stimulated while lipolysis was retarded in HFD-fed cKO mice adipose. Gluconeogenesis, lipogenesis, and fatty acid uptake were provoked while lipolysis was inhibited in HFD-fed cKO liver. Serum alanine transaminase (ALT) level, indicating fatty liver, also increased. Inflammatory cytokine including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 was elevated in cKO mice, accompanied with glucose intolerant and insulin resistance. Energy expenditure was decreased in HFD-fed cKO mice. Further evidence showed that cKO macrophages were prone to repolarize into M1 inflammatory type in vitro. In addition to mitochondrial biogenesis and oxidative respiration, PGC1β also modulated mitochondrial fission and cytosolic mitochondrial DNA (mtDNA) release, contributing to NLR family pyrin domain containing 3 (Nlrp3) inflammasome priming and activation. Treatment of mitochondrial fission inhibitor abolished the increased mRNA levels of Nlrp3 and IL-1β induced by PGC1β depletion. Nlrp3 knockdown restored the induced IL-1β mRNA expression by PGC1β deficiency. Myeloid PGC1β regulated adipocyte adipogenesis and lipolysis. PGC1β loss-of-function and mtDNA abundance correlated with obesity and diabetes. These observations uncovered the protective role of PGC1β against obesity induced systemic inflammation. Enhancing myeloid PGC1β function may be a potential strategy for the intervention of obesity and related diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167528"},"PeriodicalIF":4.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376434","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}

{"title":"Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway","authors":"Yuting Huang ,&nbsp;Jikai Zhao ,&nbsp;Zijun Zhou ,&nbsp;Xiaodong Guo ,&nbsp;Yinli Xu ,&nbsp;Tao Huang ,&nbsp;Shan Meng ,&nbsp;Zijun Cao ,&nbsp;Dengyue Xu ,&nbsp;Qiusheng Zhao ,&nbsp;Zongtao Yin ,&nbsp;Hui Jiang ,&nbsp;Liming Yu ,&nbsp;Huishan Wang","doi":"10.1016/j.bbadis.2024.167534","DOIUrl":"10.1016/j.bbadis.2024.167534","url":null,"abstract":"<div><div>Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice, with hypertension emerging as an independent risk factor. Previous literature has established associations between DNA damage response (DDR) and autophagy in relation to the pathogenesis of AF. The aim of this study was to evaluate the effect of atrial DNA damage response in persistent hypertension-induced atrial electrical and structural remodeling, and to further explore the potential therapeutic targets. Patient samples, spontaneous hypertensive rats (SHR) and angiotensin II (Ang II)-challenged HL-1 cells were employed to elucidate the detailed mechanisms. Bioinformatics analysis and investigation on human atrial samples revealed a critical role of DDR in the pathogenesis of AF. The markers of atrial DNA damage, DDR, autophagy, inflammation and fibrosis were detected by western blot, immunofluorescence, monodansyl cadaverine (MDC) assay and transmission electron microscopy. Compared with the control group, SHR exhibited significant atrial electrical and structural remodeling, abnormal increase of autophagy, inflammation, and fibrosis, which was accompanied by excessive activation of DDR mediated by the ATM/CHK2/p53 pathway. These detrimental changes were validated by in vitro experiments. Ang II-challenged HL-1 cells also exhibited significantly elevated γH2AX expression, and markers related to autophagy, inflammation as well as structural remodeling. Additionally, inhibition of ATM with KU55933 (a specific ATM inhibitor) significantly reversed these effects. Collectively, these data demonstrate that DNA damage and the subsequently overactivated ATM/CHK2/p53 pathway play critical roles in hypertension-induced atrial remodeling and the susceptibility to AF. Targeting ATM/CHK2/p53 signaling may serve as a potential therapeutic strategy against AF.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167534"},"PeriodicalIF":4.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376435","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}

{"title":"Upregulation of GRP78 is accompanied by decreased antioxidant response and mitophagy promotion in streptozotocin-induced type 1 diabetes in rats","authors":"O. Kaniuka ,&nbsp;A. Deregowska ,&nbsp;Yu. Bandura ,&nbsp;M. Sabadashka ,&nbsp;D. Chala ,&nbsp;O. Kulachkovskyi ,&nbsp;H. Kubis ,&nbsp;J. Adamczyk-Grochala ,&nbsp;N. Sybirna","doi":"10.1016/j.bbadis.2024.167531","DOIUrl":"10.1016/j.bbadis.2024.167531","url":null,"abstract":"<div><div>Endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction are interconnected processes involved in the pathogenesis of diabetes mellitus (DM). In the present study, we demonstrate a distinct unfolded protein response (UPR) signaling pathways in two mammalian models of DM: β-TC-6 cell line and streptozotocin-induced type 1 diabetes model in rats. However, a feature common to both systems was the upregulation of the GRP78 protein. Moreover, <em>in vivo</em> studies showed the disruption of the antioxidant system and an escalation of mitophagy against the background of a depletion of the level of ATP in pancreatic cells. In conclusion, we suggest that glucotoxic conditions induced GRP78 upregulation, and next cause depletion of the antioxidant pool and disruption of the functioning of antioxidant defense enzymes and in consequence promote mitophagy in pancreatic cells. Therefore, GRP78 may be considered as a potential therapeutic factor in patients with diabetes.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167531"},"PeriodicalIF":4.2,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367849","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}