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

英文中文

Programmed cell death protein 5 inhibits hepatocellular carcinoma progression by inducing pyroptosis through regulation of TGF-β/Smad2/3/Snail pathway

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-28 DOI: 10.1016/j.bbadis.2025.167696

Yiqiao Wang , Shihao Huang , Yangbai Cai , Taicheng Wang , Hongyan Zhao , Xianke Lin , Xueguo Wang , Peng Li

Background

Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain unclear.

Methods

PDCD5-overexpressing cell and xenograft tumor models were developed. Cell Counting Kit-8, 5-Ethynyl-2′-deoxyuridine, wound healing, Transwell, flow cytometry, immunohistochemistry, and hematoxylin-eosin staining were employed to explore the effects of PDCD5 on HCC cell behaviors and tumor growth. The enzyme-linked immunosorbent assay and western blot were used to detect pyroptosis-related marker levels. The molecular mechanisms underlying PDCD5's role in HCC were investigated through transcriptome sequencing and coimmunoprecipitation. SRI-011381, a TGF-β signaling activator, was applied to evaluate the impact of PDCD5 in modulating the TGF-β/Smad2/3/Snail pathway.

Results

PDCD5 expression was reduced in HCC cells. Overexpression of PDCD5 inhibited HCC cell proliferation, migration, invasion, and xenograft tumor growth. Additionally, PDCD5 overexpression promoted apoptosis and pyroptosis, with corresponding increases in inflammatory factors and Caspase-1, GSDMD, and NLRP3 protein levels. Mechanistically, PDCD5 bound to receptor-regulated Smads (Smad2/3), inhibiting the TGF-β pathway. Treatment with the TGF-β pathway activator SRI-011381 significantly counteracted the inhibitory effects of PDCD5 overexpression on HCC progression.

Conclusion

Our findings suggest that PDCD5 impedes the progression of HCC by promoting pyroptosis via regulation of TGF-β/Smad2/3/Snail pathway, which could be a possible therapeutic target for HCC.

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引用次数: 0

The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll? 线粒体 sirtuin 在重构乳腺癌新陈代谢中的奇特作用：海德先生还是杰基尔博士？

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-27 DOI: 10.1016/j.bbadis.2025.167691

Jesline Shaji Tharayil , Amoolya Kandettu , Sanjiban Chakrabarty

Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.

{"title":"The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?","authors":"Jesline Shaji Tharayil , Amoolya Kandettu , Sanjiban Chakrabarty","doi":"10.1016/j.bbadis.2025.167691","DOIUrl":"10.1016/j.bbadis.2025.167691","url":null,"abstract":"<div><div>Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167691"},"PeriodicalIF":4.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049226","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

BRCC3 aggravates pulpitis by activating the NF-κB signaling pathway in dental pulp cells

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-27 DOI: 10.1016/j.bbadis.2025.167698

Xinye Zhang , Lu Zhang , Linfang Zhou , Huangheng Tao , Zhi Chen

BRCA1/BRCA2-containing complex subunit 3 (BRCC3) has been proved to exert pro-inflammatory effect in various inflammatory diseases through different mechanisms, but its involvement in pulpitis remains unclear. This study aims to investigate the regulatory role and mechanisms of BRCC3 in modulating dental pulp cell inflammation and pulpitis progression. The expression of BRCC3 was observed to be elevated in human/mouse pulpitis samples and lipopolysaccharide-stimulated human dental pulp cells (hDPCs). Manipulation of BRCC3 expression revealed that BRCC3 facilitated the expression of pro-inflammatory cytokines and apoptosis of hDPCs. RNA-sequencing and gene set enrichment analysis were utilized to explore the downstream signaling pathways related to BRCC3 functions. Dual luciferase reporter assay, western blot, and immunofluorescence staining were conducted for further validation. The results demonstrated that BRCC3 expedited IκBα phosphorylation and degradation, as well as p65 phosphorylation and nuclear translocation in hDPCs, ultimately activating the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, conditional knockout of Brcc3 in mouse dental pulp cells effectively impeded the expression of IL-6, recruitment of immune cells, and necrosis of inflamed pulp tissue after 1 day and 1 week of pulp exposure. The level of p-p65 in Brcc3 conditional knockout mice was lower than the control mice, indicating the inhibition of NF-κB. Taken together, BRCC3 promotes pulpitis by activating the NF-κB signaling pathway in dental pulp cells.

{"title":"BRCC3 aggravates pulpitis by activating the NF-κB signaling pathway in dental pulp cells","authors":"Xinye Zhang , Lu Zhang , Linfang Zhou , Huangheng Tao , Zhi Chen","doi":"10.1016/j.bbadis.2025.167698","DOIUrl":"10.1016/j.bbadis.2025.167698","url":null,"abstract":"<div><div>BRCA1/BRCA2-containing complex subunit 3 (BRCC3) has been proved to exert pro-inflammatory effect in various inflammatory diseases through different mechanisms, but its involvement in pulpitis remains unclear. This study aims to investigate the regulatory role and mechanisms of BRCC3 in modulating dental pulp cell inflammation and pulpitis progression. The expression of <em>BRCC3</em> was observed to be elevated in human/mouse pulpitis samples and lipopolysaccharide-stimulated human dental pulp cells (hDPCs). Manipulation of <em>BRCC3</em> expression revealed that BRCC3 facilitated the expression of pro-inflammatory cytokines and apoptosis of hDPCs. RNA-sequencing and gene set enrichment analysis were utilized to explore the downstream signaling pathways related to BRCC3 functions. Dual luciferase reporter assay, western blot, and immunofluorescence staining were conducted for further validation. The results demonstrated that BRCC3 expedited IκBα phosphorylation and degradation, as well as p65 phosphorylation and nuclear translocation in hDPCs, ultimately activating the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, conditional knockout of <em>Brcc3</em> in mouse dental pulp cells effectively impeded the expression of IL-6, recruitment of immune cells, and necrosis of inflamed pulp tissue after 1 day and 1 week of pulp exposure. The level of p-p65 in <em>Brcc3</em> conditional knockout mice was lower than the control mice, indicating the inhibition of NF-κB. Taken together, BRCC3 promotes pulpitis by activating the NF-κB signaling pathway in dental pulp cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167698"},"PeriodicalIF":4.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070223","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

Targeting GSK3 to attenuate spaceflight-induced SERCA dysfunction: Lessons from hindlimb-suspended mice 以 GSK3 为靶点减轻太空飞行诱发的 SERCA 功能障碍：后肢悬空小鼠的启示

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-27 DOI: 10.1016/j.bbadis.2025.167694

Amélie A.T. Marais, Ryan W. Baranowski, Jessica L. Braun, Briana L. Hockey, Val A. Fajardo

•
In the absence of gravity, muscles become unloaded, reducing their size, strength, and endurance.
•
Calcium (Ca²⁺) dysregulation due to impairments in sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) function may be one reason for the decline in muscle performance.
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Our previous work has shown that genetic reduction of glycogen synthase kinase 3 (GSK3) maintains soleus muscle mass and strength in mice after 7 days of hindlimb suspension.
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Here, we tested whether these benefits could be, in part, due to an improvement in SERCA activity.
•
We show that muscle-specific GSK3 knockdown enhances soleus maximal SERCA activity, SERCA1 protein content, soleus relaxation and soleus muscle endurance.

引用次数: 0

Single-cell RNA sequencing and machine learning provide candidate drugs against drug-tolerant persister cells in colorectal cancer

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-25 DOI: 10.1016/j.bbadis.2025.167693

Yosui Nojima , Ryoji Yao , Takashi Suzuki

Drug resistance often stems from drug-tolerant persister (DTP) cells in cancer. These cells arise from various lineages and exhibit complex dynamics. However, effectively targeting DTP cells remains challenging. We used single-cell RNA sequencing (scRNA-Seq) data and machine learning (ML) models to identify DTP cells in patient-derived organoids (PDOs) and computationally screened candidate drugs targeting these cells in familial adenomatous polyposis (FAP), associated with a high risk of colorectal cancer. Three PDOs (benign and malignant tumor organoids and a normal organoid) were evaluated using scRNA-Seq. ML models constructed based on public scRNA-Seq data classified DTP versus non-DTP cells. Candidate drugs for DTP cells in a malignant tumor organoid were identified from public drug sensitivity data. From FAP scRNA-Seq data, a specific TC1 cell cluster in tumor organoids was identified. The ML model identified up to 36 % of TC1 cells as DTP cells, a higher proportion than those for other clusters. A viability assay using a malignant tumor organoid demonstrated that YM-155 and THZ2 exert synergistic effects with trametinib. The constructed ML model is effective for DTP cell identification based on scRNA-Seq data for FAP and provides candidate treatments. This approach may improve DTP cell targeting in the treatment of colorectal and other cancers.

{"title":"Single-cell RNA sequencing and machine learning provide candidate drugs against drug-tolerant persister cells in colorectal cancer","authors":"Yosui Nojima , Ryoji Yao , Takashi Suzuki","doi":"10.1016/j.bbadis.2025.167693","DOIUrl":"10.1016/j.bbadis.2025.167693","url":null,"abstract":"<div><div>Drug resistance often stems from drug-tolerant persister (DTP) cells in cancer. These cells arise from various lineages and exhibit complex dynamics. However, effectively targeting DTP cells remains challenging. We used single-cell RNA sequencing (scRNA-Seq) data and machine learning (ML) models to identify DTP cells in patient-derived organoids (PDOs) and computationally screened candidate drugs targeting these cells in familial adenomatous polyposis (FAP), associated with a high risk of colorectal cancer. Three PDOs (benign and malignant tumor organoids and a normal organoid) were evaluated using scRNA-Seq. ML models constructed based on public scRNA-Seq data classified DTP versus non-DTP cells. Candidate drugs for DTP cells in a malignant tumor organoid were identified from public drug sensitivity data. From FAP scRNA-Seq data, a specific TC1 cell cluster in tumor organoids was identified. The ML model identified up to 36 % of TC1 cells as DTP cells, a higher proportion than those for other clusters. A viability assay using a malignant tumor organoid demonstrated that YM-155 and THZ2 exert synergistic effects with trametinib. The constructed ML model is effective for DTP cell identification based on scRNA-Seq data for FAP and provides candidate treatments. This approach may improve DTP cell targeting in the treatment of colorectal and other cancers.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167693"},"PeriodicalIF":4.2,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054501","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

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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

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 N-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.

{"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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

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.

{"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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

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.

{"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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

Objective

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.

Methods

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.

Results

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.

Conclusion

ALB plays an important effect in ccRCC via activation of the ERS and regulating immune microenvironment.

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

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.

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引用次数: 0

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