Biochimica et biophysica acta. Molecular basis of disease最新文献_第10页

Doxorubicin-induced phosphorylation of lamin A/C enhances DNMT1 and activates cardiomyocyte death via suppressing GATA-4 and Bcl-xL in rat heart 多柔比星诱导的层粘连蛋白 A/C磷酸化可增强 DNMT1，并通过抑制大鼠心脏中的 GATA-4 和 Bcl-xL 激活心肌细胞死亡。

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-25 DOI: 10.1016/j.bbadis.2025.167692

Vikas Tiwari , Sanjay Salgar , Sachin B. Jorvekar , Bhagyashri Manoj Kumbhar , Sudheer K. Arava , Roshan M. Borkar , Sanjay K. Banerjee

{"title":"Doxorubicin-induced phosphorylation of lamin A/C enhances DNMT1 and activates cardiomyocyte death via suppressing GATA-4 and Bcl-xL in rat heart","authors":"Vikas Tiwari , Sanjay Salgar , Sachin B. Jorvekar , Bhagyashri Manoj Kumbhar , Sudheer K. Arava , Roshan M. Borkar , Sanjay K. Banerjee","doi":"10.1016/j.bbadis.2025.167692","DOIUrl":"10.1016/j.bbadis.2025.167692","url":null,"abstract":"<div><div>Cardiotoxic effect of Doxorubicin (Dox) limits its clinical application. Previously, we reported that Dox induces phosphorylation of lamin A/C (pS22 lamin A/C), increased nuclear size, damage to the nuclear membrane, and cell death. However, the activation of signalling pathway during this event remains elusive, and it is unclear whether increased phospho-lamin A/C activates the cell death pathway in heart. Here, we demonstrated that Dox-induced lamin A/C phosphorylation causes apoptotic cell death. Increased levels of reactive oxygen species (ROS), DNA methylation and apoptosis markers (Bax, Bid, caspase 3 and caspase 9) were observed in Dox-exposed H9c2 cells. Nuclear membrane damage due to increased pS22 lamin A/C causes increased DNMT1 and DNA methylation followed by reduced expression of GATA-4 and Bcl-xL in Dox-treated H9c2 cells and rat hearts. Further, increased mRNA expression of DNMT1 and reduced expression of GATA-4 and Bcl-xL was observed in H9c2 cells after knocking down of lamin A/C expression. Previously, we reported that <em>N</em>-acetylcysteine improves lamin A/C levels and maintain nuclear membrane integrity. Similarly, in this study Astaxanthin (Ast), a membrane-specific antioxidant, reduces the expression of DNMT1 and phospho-lamin A/C levels; increases mRNA expression of GATA-4 and Bcl-xL; reduces ROS levels and DNA leakage in Dox-treated H9c2 cells and rat hearts. Ast also improves the cardiac structure and function in Dox-treated rats. In conclusion, Dox exposure in cardiomyoblasts and hearts causes cell death by increasing the pS22 lamin A/C, DNA methylation and reducing the expression GATA-4 and Bcl-xL. This study provides a novel pathway for Dox-induced cardiotoxicity and a possible therapeutic approach to reduce it.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167692"},"PeriodicalIF":4.2,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049233","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

Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-24 DOI: 10.1016/j.bbadis.2025.167695

Tiantian Wang , Guoqing Xia , Xue Li, Mingxu Gong, Xiongwen Lv

{"title":"Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential","authors":"Tiantian Wang , Guoqing Xia , Xue Li, Mingxu Gong, Xiongwen Lv","doi":"10.1016/j.bbadis.2025.167695","DOIUrl":"10.1016/j.bbadis.2025.167695","url":null,"abstract":"<div><div>This paper reviews the important role of endoplasmic reticulum stress in the patho mechanism of liver fibrosis and its potential as a potential target for the treatment of liver fibrosis. Liver fibrosis is the result of sustained inflammation and injury to the liver due to a variety of factors, triggering excessive deposition of extracellular matrix and fibrous scar formation, which in turn leads to loss of liver function and a variety of related complications. Endoplasmic reticulum stress is one of the characteristics of chronic liver disease and is closely related to the pathological process of chronic liver disease, including alcohol-related liver disease, viral hepatitis, and liver fibrosis. The unfolded protein response is one of the important response mechanisms to endoplasmic reticulum stress. It is associated with several pathological aspects of liver fibrosis and the maintenance of endoplasmic reticulum homeostasis. Interventions targeting endoplasmic reticulum stress for the treatment of liver fibrosis have potential research and application value. An in-depth understanding of the biological basis of endoplasmic reticulum stress is also needed in the treatment of liver fibrosis, as well as the development of more effective drugs and interventions to accurately regulate the endoplasmic reticulum signaling network, to achieve the restoration and maintenance of endoplasmic reticulum homeostasis at the cellular and organ levels, and to further promote the reversal of the pathological process of liver fibrosis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167695"},"PeriodicalIF":4.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049144","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

NetSDR: Drug repurposing for cancers based on subtype-specific network modularization and perturbation analysis

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-23 DOI: 10.1016/j.bbadis.2025.167688

Bin Yang , Wanshi Li , Zhen Xu , Wei Li , Guang Hu

{"title":"NetSDR: Drug repurposing for cancers based on subtype-specific network modularization and perturbation analysis","authors":"Bin Yang , Wanshi Li , Zhen Xu , Wei Li , Guang Hu","doi":"10.1016/j.bbadis.2025.167688","DOIUrl":"10.1016/j.bbadis.2025.167688","url":null,"abstract":"<div><div>Cancer, a heterogeneous disease, presents significant challenges for drug development due to its complex etiology. Drug repurposing, particularly through network medicine approaches, offers a promising avenue for cancer treatment by analyzing how drugs influence cellular networks on a systemic scale. The advent of large-scale proteomics data provides new opportunities to elucidate regulatory mechanisms specific to cancer subtypes. Herein, we present NetSDR, a Network-based Subtype-specific Drug Repurposing framework for prioritizing repurposed drugs specific to certain cancer subtypes, guided by subtype-specific proteomic signatures and network perturbations. First, by integrating cancer subtype information into a network-based method, we developed a pipeline to recognize subtype-specific functional modules. Next, we conducted drug response analysis for each module to identify the “therapeutic module” and then used deep learning to construct weighted drug response network for the particular subtype. Finally, we employed a perturbation response scanning-based drug repurposing method, which incorporates dynamic information, to facilitate the prioritization of candidate drugs. Applying the framework to gastric cancer, we attested the significance of the extracellular matrix module in treatment strategies and discovered a promising potential drug target, LAMB2, as well as a series of possible repurposed drugs. This study demonstrates a systems biology framework for precise drug repurposing in cancer and other complex diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167688"},"PeriodicalIF":4.2,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043239","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

ALB inhibits tumor cell proliferation and invasion by regulating immune microenvironment and endoplasmic reticulum stress in clear cell renal cell carcinoma

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-23 DOI: 10.1016/j.bbadis.2025.167672

Jun-Ming Zhu , Shao-Hao Chen , Yi-Cheng Xu , Rui-Cheng Gao , Hai Cai , Qing-Shui Zheng , Xiong-Lin Sun , Xue-Yi Xue , Yong Wei , Ning Xu

{"title":"ALB inhibits tumor cell proliferation and invasion by regulating immune microenvironment and endoplasmic reticulum stress in clear cell renal cell carcinoma","authors":"Jun-Ming Zhu , Shao-Hao Chen , Yi-Cheng Xu , Rui-Cheng Gao , Hai Cai , Qing-Shui Zheng , Xiong-Lin Sun , Xue-Yi Xue , Yong Wei , Ning Xu","doi":"10.1016/j.bbadis.2025.167672","DOIUrl":"10.1016/j.bbadis.2025.167672","url":null,"abstract":"<div><h3>Objective</h3><div>The aim of this work is to identify putative hub genes for the advancement of clear cell renal cell carcinoma (ccRCC) and determine the fundamental mechanisms.</div></div><div><h3>Methods</h3><div>We employed multiple bioinformatics techniques to screen hub genes. Key hub gene expression levels in ccRCC were assessed. A plethora of functional experiments were carried out to explore the biological role of hub gene. Based on genome-wide association studies, a Mendelian randomization research was conducted to ascertain the causative relationship between albumin (ALB) and ccRCC.</div></div><div><h3>Results</h3><div>ALB was low expression in ccRCC tissues and cell lines. It was an independent predictor of progression-free survival following treatment and the overall survival of ccRCC patients. ALB overexpression exhibited the reverse effects of ALB knockdown, which increased cell proliferation, migration, and invasion while inhibiting cell death. Similarly, ALB overexpression inhibited the growth of ccRCC tumors in vivo. Consistent with functional enrichment analysis, ALB overexpression activates the endoplasmic reticulum stress (ERS) in vitro and vivo. The Mendelian randomization showed ALB was associated with the risk of ccRCC. Additionally, ALB was causally associated with γδT cells infiltrates in ccRCC.</div></div><div><h3>Conclusion</h3><div>ALB plays an important effect in ccRCC via activation of the ERS and regulating immune microenvironment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167672"},"PeriodicalIF":4.2,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042836","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

IKZF1 promotes pyroptosis and prevents M2 macrophage polarization by inhibiting JAK2/STAT5 pathway in colon cancer

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-23 DOI: 10.1016/j.bbadis.2025.167690

Guanglong Liu , Kaihua Huang , Bingheng Lin , Renyi Zhang , Yu Zhu , Xiaoyu Dong , Chaosong Wu , Huacong Zhu , Jiabao Lin , Ming Bao , Shenglong Li , Ruinian Zheng , Fangyan Jing

{"title":"IKZF1 promotes pyroptosis and prevents M2 macrophage polarization by inhibiting JAK2/STAT5 pathway in colon cancer","authors":"Guanglong Liu , Kaihua Huang , Bingheng Lin , Renyi Zhang , Yu Zhu , Xiaoyu Dong , Chaosong Wu , Huacong Zhu , Jiabao Lin , Ming Bao , Shenglong Li , Ruinian Zheng , Fangyan Jing","doi":"10.1016/j.bbadis.2025.167690","DOIUrl":"10.1016/j.bbadis.2025.167690","url":null,"abstract":"<div><div>Pyroptosis and macrophage pro-inflammatory activation play an important role in hepatocellular carcinoma (HCC) progression. However, the specific regulatory mechanisms remain unclear. We identified pyroptosis-related differentially expressed genes (DEGs) based on the GSE4183 and GSE44861 datasets as well as EVenn database. Expression levels of key genes were detected by qRT-PCR. IKZF1 was overexpressed in colon cancer cells and tumor-bearing mice, and its functions were assessed by various cell biology assays in vitro and in vivo. To investigate the interactions between IKZF1 and macrophages, a co-culture system was constructed. The activator RO8191 or inhibitor ruxolitinib of the JAK/STAT pathway was employed to confirm whether IKZF1 inhibited colon cancer development by regulating JAK2/STAT5 pathway. Pyroptosis-related hub genes RBBP7, HSP90AB1, and RBBP4 were highly expressed, while IKZF1, NLRP1, and PYCARD were lowly expressed. These hub genes had good performance in distinguishing colon cancer from controls. Furthermore, overexpression of IKZF1 inhibited tumor growth and promoted pyroptosis. Overexpression of IKZF1 suppressed cell proliferation, metastasis, and inactivated JAK2/STAT5 signaling pathway in colon cancer cells. Furthermore, upregulation of IKZF1 promoted M1 macrophage polarization while inhibiting M2 macrophage polarization in vivo and in vitro by inhibiting the JAK2/STAT5 signaling pathway. This study identifies IKZF1 as a potential biomarker inactivating JAK2/STAT5 pathway for colon cancer.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167690"},"PeriodicalIF":4.2,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042843","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

Piplartine alleviates sepsis-induced acute kidney injury by inhibiting TSPO-mediated macrophage pyroptosis

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-23 DOI: 10.1016/j.bbadis.2025.167687

Rui Gong , Gangyu Long , Qian Wang , Xujuan Hu , Hong Luo , Dingyu Zhang , Jun Shang , Yang Han , Chaolin Huang , You Shang

{"title":"Piplartine alleviates sepsis-induced acute kidney injury by inhibiting TSPO-mediated macrophage pyroptosis","authors":"Rui Gong , Gangyu Long , Qian Wang , Xujuan Hu , Hong Luo , Dingyu Zhang , Jun Shang , Yang Han , Chaolin Huang , You Shang","doi":"10.1016/j.bbadis.2025.167687","DOIUrl":"10.1016/j.bbadis.2025.167687","url":null,"abstract":"<div><div>Sepsis-induced acute kidney injury (SI-AKI) is the most common organ dysfunction of sepsis, characterized with prolonged hospitalization periods and significantly elevated mortality rates. Piplartine (PLG), an alkaloid extracted from <em>Piper longum</em> within the Piperaceae family, has exhibited diverse pharmacological activities, including anti-inflammatory, anti-atherosclerotic, and anti-tumor effects. Herein, we investigated whether the PLG could reverse SI-AKI and explore its possible anti-inflammatory mechanisms. We constructed an SI-AKI model using cecal ligation and puncture (CLP) and systematically evaluated the protective effect of PLG administered by gavage in the SI-AKI mice. Subsequently, we performed proteomic sequencing of the kidney and integrated data from the GeneCards and SwissTargetPrediction databases to identify potential targets and mechanisms. Immunofluorescence and western blotting were used to examine the expression of relevant targets and pathways in vivo and in vitro. The influence of PLG on the predicted target and pathway was verified using an agonist of the target protein and a series of biochemical experiments. PLG exhibited significant efficacy against pathological damage, neutrophil and macrophage infiltration, and macrophage pyroptosis in kidneys at 30 mg/kg. An integrated analysis of proteomic data identified the translocator protein (TSPO) as a potential target for the renoprotective effects of PLG. Moreover, a TSPO agonist (RO5–4864) prominently reversed the protective effect of PLG in SI-AKI mice, as manifested by a deterioration in renal function, histopathological lesions and macrophage pyroptosis in the kidneys. Our results suggest that PLG may ameliorate SI-AKI, potentially through partial inhibition of the TSPO-macrophage pyroptosis pathway.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167687"},"PeriodicalIF":4.2,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043495","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

Molecular mechanism of mitochondrial autophagy mediating impaired energy metabolism leading to osteoporosis

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-20 DOI: 10.1016/j.bbadis.2025.167685

Yuheng He , Tao Liu , Xin Peng , Chaorui Yao , Daqian Zhou , Chao Song , Zhangchao Wei , Jinwen Chen , Zongchao Liu , Feng Jiang

{"title":"Molecular mechanism of mitochondrial autophagy mediating impaired energy metabolism leading to osteoporosis","authors":"Yuheng He , Tao Liu , Xin Peng , Chaorui Yao , Daqian Zhou , Chao Song , Zhangchao Wei , Jinwen Chen , Zongchao Liu , Feng Jiang","doi":"10.1016/j.bbadis.2025.167685","DOIUrl":"10.1016/j.bbadis.2025.167685","url":null,"abstract":"<div><div>Osteoporosis (OP) is a bone metabolic disease caused by decreased bone mass leading to destruction of bone microstructure. Treatment of OP is characterized by a lifelong nature, causing extreme financial and psychological burdens to patients. Hormonal abnormalities, cellular autophagy, Ferroptosis, and oxidative stress are all part of the intricate and varied pathophysiology of OP. Recent research has revealed that mitochondrial dysfunction is a significant factor in the onset and progression of OP. By regulating bone marrow mesenchymal stem cell differentiation through various signaling pathways and cytokines, abnormal mitochondrial energy metabolism brought on by oxidative stress processes impacts osteoblast and osteoclast proliferation and differentiation, causing an imbalance in bone metabolism that ultimately results in OP. Therefore, one possible method to prevent and manage OP may be to use mitochondria as a carrier to trigger osteogenic differentiation of bone marrow mesenchymal stem cells from mitochondrial energy consumption, oxidative stress, autophagy, and osteoclast death. In order to offer some theoretical references and therapeutic approaches for the clinical prevention and treatment of OP, we will examine the pathophysiology of OP from mitochondrial dysfunction in this work.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167685"},"PeriodicalIF":4.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026141","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

Gelsolin traps ribosomal protein SA (RPSA) within lipid nanodomains of the plasma membrane and modulates the level of protein synthesis in the submembranous region of human skin melanoma cells

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-20 DOI: 10.1016/j.bbadis.2025.167686

Ewa Mazurkiewicz-Stanek , Joanna Machnik , Iryna Kopernyk , Wojciech Wiertelak , Dorota Maszczak-Seneczko , Estera Jeruzalska , Agnieszka Biernatowska , Aleksandra Makowiecka , Michał Majkowski , Przemysław Biecek , Tomasz Trombik , Piotr Donizy , Antonina J. Mazur

{"title":"Gelsolin traps ribosomal protein SA (RPSA) within lipid nanodomains of the plasma membrane and modulates the level of protein synthesis in the submembranous region of human skin melanoma cells","authors":"Ewa Mazurkiewicz-Stanek , Joanna Machnik , Iryna Kopernyk , Wojciech Wiertelak , Dorota Maszczak-Seneczko , Estera Jeruzalska , Agnieszka Biernatowska , Aleksandra Makowiecka , Michał Majkowski , Przemysław Biecek , Tomasz Trombik , Piotr Donizy , Antonina J. Mazur","doi":"10.1016/j.bbadis.2025.167686","DOIUrl":"10.1016/j.bbadis.2025.167686","url":null,"abstract":"<div><div>The connection between the F-actin and ribosome docking to the PM has been reported, but the exact mechanism has remained unclear. Previously, we discovered that gelsolin (GSN) forms complexes with numerous ribosomal proteins, including ribosomal protein SA (RPSA). Now, we have unraveled the mechanism of ribosome recruitment to the lipid nanodomains of the PM, with GSN playing a pivotal role in this process. We demonstrate that GSN directly interacts with RPSA, and microscopic analyses reveal their colocalization in the cell's submembranous region. Through spot variation fluorescence correlation spectroscopy, we confirm that GSN is responsible for trapping RPSA within PM's lipid nanodomains, a process dependent on F-actin. Importantly, we establish a correlation between the GSN level and the level of protein synthesis in melanoma cells. Furthermore, we present compelling evidence that high levels of GSN and RPSA are associated with the progression of cutaneous melanoma and a poorer prognosis for patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167686"},"PeriodicalIF":4.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026137","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

Unlocking the therapeutic potential of canagliflozin in NAFLD: Insights into AMPK/SIRT1-mediated lipophagy 解锁卡格列净在NAFLD中的治疗潜力：对AMPK/ sirt1介导的脂肪吞噬的见解。

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-20 DOI: 10.1016/j.bbadis.2025.167666

Nahla E. El-Ashmawy , Ghada M. Al-Ashmawy , Asmaa A. Kamel , Eman G. Khedr

{"title":"Unlocking the therapeutic potential of canagliflozin in NAFLD: Insights into AMPK/SIRT1-mediated lipophagy","authors":"Nahla E. El-Ashmawy , Ghada M. Al-Ashmawy , Asmaa A. Kamel , Eman G. Khedr","doi":"10.1016/j.bbadis.2025.167666","DOIUrl":"10.1016/j.bbadis.2025.167666","url":null,"abstract":"<div><div>Nonalcoholic fatty liver disease (NAFLD) is a rising global health problem. The antidiabetic canagliflozin (CANA) has been proposed to ameliorate the metabolic abnormalities in NAFLD.</div></div><div><h3>Aim</h3><div>This study aimed to explore the possible anti-NAFLD effects of CANA in rats and HepG2 cells, focusing on AMPK/SIRT1-mediated lipophagy.</div></div><div><h3>Methods</h3><div>Wistar rats were assigned to four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+chloroquine (CQ) group, where CQ served as autophagy inhibitor. HepG2 cells were also divided into four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+compound C (Comp C) group, where Comp C served as AMPK inhibitor.</div></div><div><h3>Results</h3><div>The histopathological examination showed that CANA alleviated hepatic and intracellular lipid deposition in rats and HepG2 cells. CANA induced lipophagy by increasing LC3-II levels and lowering both p62 and perilipin 2 levels in rats and HepG2 cells, in addition to decreasing mTOR protein expression in rats' livers. These outcomes were associated with upregulation of the lipophagy regulator Rab7 and downregulation of the ER stress-related protein CHOP. CANA enhanced autophagic engulfment of lipid droplets while decreased ER stress and mitochondrial damage in rats' livers, as demonstrated by TEM. In rats, CANA improved hyperglycemia, hyperinsulinemia, dyslipidemia, and obesity. In HepG2 cells, CANA's effects were linked to increased phosphorylated AMPK level and enhanced SIRT1 level and expression. However, blocking lipophagy in rats and AMPK in HepG2 cells markedly weakened CANA's protective effects against NAFLD.</div></div><div><h3>Conclusion</h3><div>CANA ameliorated NAFLD <em>via</em> enhancing AMPK/SIRT1-mediated lipophagy, suggesting its potential as a therapeutic intervention for this metabolic disorder.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167666"},"PeriodicalIF":4.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018176","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

Mitochondrial regulation of obesity by POMC neurons POMC神经元对肥胖的线粒体调控。

IF 4.2 2区生物学

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-19 DOI: 10.1016/j.bbadis.2025.167682

Xing-dan Luo , Si Tang , Xiang-yun Luo , Luosang Quzhen , Ruo-han Xia , Xian-wang Wang

{"title":"Mitochondrial regulation of obesity by POMC neurons","authors":"Xing-dan Luo , Si Tang , Xiang-yun Luo , Luosang Quzhen , Ruo-han Xia , Xian-wang Wang","doi":"10.1016/j.bbadis.2025.167682","DOIUrl":"10.1016/j.bbadis.2025.167682","url":null,"abstract":"<div><div>Pro-opiomelanocortin (POMC) neurons, nestled in the hypothalamus, play a pivotal role in the intricate coordination of energy homeostasis and metabolic pathways. These neurons' mitochondria, often hailed as the cell's powerhouses, are crucial for maintaining cellular energy equilibrium and metabolic functionality. Recent research has illuminated the complex interplay between mitochondrial dynamics and POMC neuronal activity, underscoring their critical involvement in the pathogenesis of a spectrum of metabolic disorders, notably obesity and diabetes. This comprehensive review delves into the molecular mechanisms that underlie how mitochondrial function within POMC neurons modulates metabolic regulation. We dissect the impact of mitochondrial dynamics, encompassing fusion, fission, mitophagy, and biogenesis, on the regulation of POMC neuronal activity. Furthermore, we scrutinize the role of mitochondrial dysfunction in POMC neurons in the etiology of obesity, identifying key therapeutic targets within these pathways. We offer an in-depth perspective on the indispensable role of POMC neuronal mitochondria in metabolic regulation and chart future research directions to bridge the existing knowledge gaps in this field.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167682"},"PeriodicalIF":4.2,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018169","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