Pub Date : 2025-04-24DOI: 10.1016/j.bbadis.2025.167848
Shengxia Yin , Minxin Mao , Linyan Gong , Yijia Zhu , Yawen Wan , Xin Tong , Jian Wang , Guiyang Wang , Yong Liu , Chao Wu , Rui Huang , Yuxin Chen
Restoring B cell defects is crucial to achieve the functional cure of chronic hepatitis B virus (CHB) infection, yet the specific targets remain largely unexplored. Our study identified that CTLA4 was highly upregulated in both peripheral and hepatic HBsAg-specific B cells from CHB patients, while effective peginterferon-α treatment could reduce the frequency of CTLA4+HBsAg+ B cells. Single-cell RNA-seq analysis revealed that the diminished IL-6 JAK/STAT3 and IL-2/STAT5 signaling pathways in memory B cells from CHB patients,which might contribute to the incapability of HBsAb antibody secretion. CTLA4+ B cells, especially from CHB patients, consistently showed defective responses in B cell receptor signaling and inflammatory responses compared to CTLA4− B cells. Notably, CTLA4 depletion partially restored the secretion of HBsAb in vitro from peripheral B cells from CHB patients, but also could restore anti-HBs humoral responses and potentiate viral clearance in HBV mouse model. Mechanistic analysis revealed that CTLA4 is directly bound to SHP-1, resulting in the impaired Jak-STAT and B cell receptor signaling pathway. Collectively, our data highlights an unappreciated role of CTLA4 on B cell responses. Targeting CTLA4 on B cells holds promise to achieve the functional cure of CHB patients.
{"title":"CTLA4 modulates B cell receptor signals to inhibit HBsAb secretion in chronic hepatitis B patients","authors":"Shengxia Yin , Minxin Mao , Linyan Gong , Yijia Zhu , Yawen Wan , Xin Tong , Jian Wang , Guiyang Wang , Yong Liu , Chao Wu , Rui Huang , Yuxin Chen","doi":"10.1016/j.bbadis.2025.167848","DOIUrl":"10.1016/j.bbadis.2025.167848","url":null,"abstract":"<div><div>Restoring B cell defects is crucial to achieve the functional cure of chronic hepatitis B virus (CHB) infection, yet the specific targets remain largely unexplored. Our study identified that CTLA4 was highly upregulated in both peripheral and hepatic HBsAg-specific B cells from CHB patients, while effective peginterferon-α treatment could reduce the frequency of CTLA4<sup>+</sup>HBsAg<sup>+</sup> B cells. Single-cell RNA-seq analysis revealed that the diminished IL-6 JAK/STAT3 and IL-2/STAT5 signaling pathways in memory B cells from CHB patients,which might contribute to the incapability of HBsAb antibody secretion. CTLA4<sup>+</sup> B cells, especially from CHB patients, consistently showed defective responses in B cell receptor signaling and inflammatory responses compared to CTLA4<sup>−</sup> B cells. Notably, CTLA4 depletion partially restored the secretion of HBsAb in vitro from peripheral B cells from CHB patients, but also could restore anti-HBs humoral responses and potentiate viral clearance in HBV mouse model. Mechanistic analysis revealed that CTLA4 is directly bound to SHP-1, resulting in the impaired Jak-STAT and B cell receptor signaling pathway. Collectively, our data highlights an unappreciated role of CTLA4 on B cell responses. Targeting CTLA4 on B cells holds promise to achieve the functional cure of CHB patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167848"},"PeriodicalIF":4.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-21DOI: 10.1016/j.bbadis.2025.167857
Sheng-Li Liu , Peng Zhao , Yan-Man Zhou , Zhi-Guo Peng , Ning Guo , Huai-Bin Sun , Xian-Quan Cui
The cause of acute T cell-mediated rejection (aTCMR) is believed to be immune hyperfunction of T cells after kidney transplantation. Nowadays, calcineurin inhibitors are widely used to inhibit the proliferation of T cells when aTCMR occurs. However, the therapeutic dose window of these drugs is relatively narrow and long time use of these drugs may lead to serious side effects. Besides, whether IL-10, a new immune tolerance mediator, playing a therapeutic role on aTCMR remains unclear. The level of IL-10 decreased in patients with aTCMR, suggesting that IL-10 may be involved in the progression of aTCMR. IL-10 could inhibit the proliferation and metabolism of T cells in vitro and in vivo, accompanied by reducing the levels of IL-2, IFN-γ, and TNF-α. Moreover, we confirmed that IL-10 exerts immunosuppressive effects by inhibiting the NFATc1 signaling pathway of T cells. This viewpoint may provide a new therapeutic idea for clinical application.
{"title":"IL-10 alleviates aTCMR by inhibiting NFATc1 signaling pathway of T cells after kidney transplantation","authors":"Sheng-Li Liu , Peng Zhao , Yan-Man Zhou , Zhi-Guo Peng , Ning Guo , Huai-Bin Sun , Xian-Quan Cui","doi":"10.1016/j.bbadis.2025.167857","DOIUrl":"10.1016/j.bbadis.2025.167857","url":null,"abstract":"<div><div>The cause of acute T cell-mediated rejection (aTCMR) is believed to be immune hyperfunction of T cells after kidney transplantation. Nowadays, calcineurin inhibitors are widely used to inhibit the proliferation of T cells when aTCMR occurs. However, the therapeutic dose window of these drugs is relatively narrow and long time use of these drugs may lead to serious side effects. Besides, whether IL-10, a new immune tolerance mediator, playing a therapeutic role on aTCMR remains unclear. The level of IL-10 decreased in patients with aTCMR, suggesting that IL-10 may be involved in the progression of aTCMR. IL-10 could inhibit the proliferation and metabolism of T cells in vitro and in vivo, accompanied by reducing the levels of IL-2, IFN-γ, and TNF-α. Moreover, we confirmed that IL-10 exerts immunosuppressive effects by inhibiting the NFATc1 signaling pathway of T cells. This viewpoint may provide a new therapeutic idea for clinical application.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167857"},"PeriodicalIF":4.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-18DOI: 10.1016/j.bbadis.2025.167861
Irene Bissoli , Francesco Alabiso , Cristina Cosentino , Aleksandra Seragnoli Chystyakova , Fabrizio Ferré , Francesco Alviano , Pasquale Marrazzo , Carla Pignatti , Giulio Agnetti , Romano Regazzi , Flavio Flamigni , Stefania D’Adamo , Silvia Cetrullo
Cardiac organoids offer significant advantages for in vitro studies, as their 3D structure and cellular composition more closely replicate tissue complexity compared to 2D models. This is particularly relevant for studying complex diseases like heart failure (HF), which involve multiple cell types and cardiac structures. Thus, the primary aim of this study was to produce self-assembled, scaffold-free cardiac organoids from induced pluripotent stem cells (iPSCs), capable of simulating key aspects of HF in vitro. Gene expression analysis confirmed a transition from stemness markers (OCT4, NANOG) to cardiac markers (TNNT2, DES), validating their cardiac phenotype. To induce hallmark HF features, endothelin-1 (ET-1) treatment was applied.
Key findings indicate that this experimental model successfully reproduced HF pathological markers, including the upregulation of genes encoding atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and the cytoskeletal protein α-skeletal actin (ACTA1), along with changes in microRNA (miR) expression profiles. Functionally, ET-1 treatment reduced organoid contractility, indicating a decline in contractile function—a hallmark of HF. Furthermore, histological analyses by Thioflavin T (ThT) staining, ThT fluorescence assay and filter trap assay on protein extracts demonstrated protein aggregation following ET-1 treatment. Co-administration of various nutraceuticals was shown to mitigate these effects. These findings underscore the value of this ET-1-stimulated cardiac organoid model as a powerful platform for studying HF mechanisms and evaluating novel therapeutic approaches.
{"title":"Modeling heart failure by induced pluripotent stem cell-derived organoids.","authors":"Irene Bissoli , Francesco Alabiso , Cristina Cosentino , Aleksandra Seragnoli Chystyakova , Fabrizio Ferré , Francesco Alviano , Pasquale Marrazzo , Carla Pignatti , Giulio Agnetti , Romano Regazzi , Flavio Flamigni , Stefania D’Adamo , Silvia Cetrullo","doi":"10.1016/j.bbadis.2025.167861","DOIUrl":"10.1016/j.bbadis.2025.167861","url":null,"abstract":"<div><div>Cardiac organoids offer significant advantages for in vitro studies, as their 3D structure and cellular composition more closely replicate tissue complexity compared to 2D models. This is particularly relevant for studying complex diseases like heart failure (HF), which involve multiple cell types and cardiac structures. Thus, the primary aim of this study was to produce self-assembled, scaffold-free cardiac organoids from induced pluripotent stem cells (iPSCs), capable of simulating key aspects of HF in vitro. Gene expression analysis confirmed a transition from stemness markers (OCT4, NANOG) to cardiac markers (TNNT2, DES), validating their cardiac phenotype. To induce hallmark HF features, endothelin-1 (ET-1) treatment was applied.</div><div>Key findings indicate that this experimental model successfully reproduced HF pathological markers, including the upregulation of genes encoding atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and the cytoskeletal protein α-skeletal actin (ACTA1), along with changes in microRNA (miR) expression profiles. Functionally, ET-1 treatment reduced organoid contractility, indicating a decline in contractile function—a hallmark of HF. Furthermore, histological analyses by Thioflavin T (ThT) staining, ThT fluorescence assay and filter trap assay on protein extracts demonstrated protein aggregation following ET-1 treatment. Co-administration of various nutraceuticals was shown to mitigate these effects. These findings underscore the value of this ET-1-stimulated cardiac organoid model as a powerful platform for studying HF mechanisms and evaluating novel therapeutic approaches.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167861"},"PeriodicalIF":4.2,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-18DOI: 10.1016/j.bbadis.2025.167854
Shuang-Hao Yang , Jiatong Liu , Yuan Quan , Guangyu Lin , Xiaohua Zhou , Hua He , Xianfeng Gan , Tuanfeng Yang , Ming-Yang Cui , Xilong Du , Xiaofang Quan , Weiyue Gu , Hong-Yu Zhang , Hua Wang , WenZheng Guan
Despite traditional panel and Whole Exome Sequencing (WES) assays, the causative factors for 60 % of epilepsy cases remain elusive, mainly due to incomplete detection of variant spectrums, and limited ability to interpret variants. Our research developed the multi-omics method of a comprehensive sequential testing methodology, to enhance the diagnostic yield for the etiology. In this study, we performed sequential multi-omics analyses on a cohort of 236 Chinese patients exhibiting recurrent seizures along with developmental delay or intellectual disability. Our study had devised a comprehensive multi-omics variant analysis methodology in a sequential mode. The initial analytical strategy included WES, CNV-seq and in-house cases evidence. If no pathogenic cause was identified, the subsequent analytical approach in the sequential mode included the analysis of WGS SVs, mitochondrial variations, dynamic mutations, and abnormalities in RNA-seq. Our results revealed that the initial step achieved a diagnostic detection rate of 44.1 % (104 cases). Subsequently, WGS and RNA-seq testing were performed, with 33 familial diagnoses tested positive, representing a 14 % increase. Meanwhile our pipeline has elucidated the pathogenicity classification of 72 variants which are either not yet recorded in the ClinVar database or are classified as VUS. Our study achieved an overall positive diagnostic rate of 58.1 % (137/236). In summary, our pipeline can detect comprehensive variant spectrums and provide a clear interpretation of variations with unclear clinical significance, the multi-omics sequential testing approach significantly improves the rate of genetic diagnosis for epileptic disorders.
{"title":"The improvement in diagnostic yield of developmental and epileptic encephalopathy by the multi-omics sequential testing method","authors":"Shuang-Hao Yang , Jiatong Liu , Yuan Quan , Guangyu Lin , Xiaohua Zhou , Hua He , Xianfeng Gan , Tuanfeng Yang , Ming-Yang Cui , Xilong Du , Xiaofang Quan , Weiyue Gu , Hong-Yu Zhang , Hua Wang , WenZheng Guan","doi":"10.1016/j.bbadis.2025.167854","DOIUrl":"10.1016/j.bbadis.2025.167854","url":null,"abstract":"<div><div>Despite traditional panel and Whole Exome Sequencing (WES) assays, the causative factors for 60 % of epilepsy cases remain elusive, mainly due to incomplete detection of variant spectrums, and limited ability to interpret variants. Our research developed the multi-omics method of a comprehensive sequential testing methodology, to enhance the diagnostic yield for the etiology. In this study, we performed sequential multi-omics analyses on a cohort of 236 Chinese patients exhibiting recurrent seizures along with developmental delay or intellectual disability. Our study had devised a comprehensive multi-omics variant analysis methodology in a sequential mode. The initial analytical strategy included WES, CNV-seq and in-house cases evidence. If no pathogenic cause was identified, the subsequent analytical approach in the sequential mode included the analysis of WGS SVs, mitochondrial variations, dynamic mutations, and abnormalities in RNA-seq. Our results revealed that the initial step achieved a diagnostic detection rate of 44.1 % (104 cases). Subsequently, WGS and RNA-seq testing were performed, with 33 familial diagnoses tested positive, representing a 14 % increase. Meanwhile our pipeline has elucidated the pathogenicity classification of 72 variants which are either not yet recorded in the ClinVar database or are classified as VUS. Our study achieved an overall positive diagnostic rate of 58.1 % (137/236). In summary, our pipeline can detect comprehensive variant spectrums and provide a clear interpretation of variations with unclear clinical significance, the multi-omics sequential testing approach significantly improves the rate of genetic diagnosis for epileptic disorders.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167854"},"PeriodicalIF":4.2,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-18DOI: 10.1016/j.bbadis.2025.167862
Fatemeh Mirab , Mitra Pirhaghi , Daniel E. Otzen , Ali Akbar Saboury
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal accumulation of alpha-synuclein (α-Syn). Recent research emphasizes the significant role of the gut microbiota, the diverse community of microbes living in the intestines, in modulating α-Syn pathology. This review explores the bi-directional communication along the microbiota-gut-brain axis, highlighting the paradoxical impact of two gut microbiota metabolites—functional bacterial amyloids (FuBA) and vitamins—on neurodegenerative diseases, particularly PD. FuBA contributes to PD pathogenesis by promoting α-Syn aggregation, while vitamins offer neuroprotection through their anti-amyloidogenic, antioxidant, and anti-inflammatory properties. Understanding these processes could lead to precision clinical approaches and novel strategies for managing and preventing PD.
{"title":"Parkinson's disease and gut microbiota metabolites: The dual impact of vitamins and functional amyloids","authors":"Fatemeh Mirab , Mitra Pirhaghi , Daniel E. Otzen , Ali Akbar Saboury","doi":"10.1016/j.bbadis.2025.167862","DOIUrl":"10.1016/j.bbadis.2025.167862","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal accumulation of alpha-synuclein (α-Syn). Recent research emphasizes the significant role of the gut microbiota, the diverse community of microbes living in the intestines, in modulating α-Syn pathology. This review explores the bi-directional communication along the microbiota-gut-brain axis, highlighting the paradoxical impact of two gut microbiota metabolites—functional bacterial amyloids (FuBA) and vitamins—on neurodegenerative diseases, particularly PD. FuBA contributes to PD pathogenesis by promoting α-Syn aggregation, while vitamins offer neuroprotection through their anti-amyloidogenic, antioxidant, and anti-inflammatory properties. Understanding these processes could lead to precision clinical approaches and novel strategies for managing and preventing PD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167862"},"PeriodicalIF":4.2,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-17DOI: 10.1016/j.bbadis.2025.167853
He Yingli , Yang Ping , Yan Jun , Zhu Xingwang
Colorectal cancer (CRC) is a leading contributor to global cancer-related morbidity and mortality. Glycosylation is a common post-translational protein modification. Aberrant protein glycosylation is a hallmark of cancer, affecting biological processes and driving malignant CRC phenotypes. Specifically, abnormal N-glycosylation manifests as structural alterations in high mannose, sialylated, and fucosylated structures, collectively promoting cancer stemness and invasiveness. Concurrently, O-GlcNAcylation facilitates tumorigenesis through metabolic reprogramming and oncogene activation. Dysregulated mucin-type O-glycans (e.g., Core-1/Core-3 imbalance) and elevated SLex/SLea antigen expression are significantly correlated with tumor adhesion, metastatic dissemination, and adverse clinical outcomes. Furthermore, protein glycosylation contributes to chemoresistance through anti-apoptotic mechanisms, aberrant signaling activation, and pro-angiogenic pathways. This review systematically examines the dynamic evolution of protein glycosylation during CRC progression from normal mucosa to adenoma to adenocarcinoma. It also evaluates the CRC diagnostic and therapeutic implications of glycoproteins and glycans. This review can provide a molecular understanding for advancing CRC diagnostics and treatment.
{"title":"Aberrant protein glycosylation in the colon adenoma-cancer sequence: Colorectal cancer mechanisms and clinical implications","authors":"He Yingli , Yang Ping , Yan Jun , Zhu Xingwang","doi":"10.1016/j.bbadis.2025.167853","DOIUrl":"10.1016/j.bbadis.2025.167853","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a leading contributor to global cancer-related morbidity and mortality. Glycosylation is a common post-translational protein modification. Aberrant protein glycosylation is a hallmark of cancer, affecting biological processes and driving malignant CRC phenotypes. Specifically, abnormal N-glycosylation manifests as structural alterations in high mannose, sialylated, and fucosylated structures, collectively promoting cancer stemness and invasiveness. Concurrently, O-GlcNAcylation facilitates tumorigenesis through metabolic reprogramming and oncogene activation. Dysregulated mucin-type O-glycans (e.g., Core-1/Core-3 imbalance) and elevated SLex/SLea antigen expression are significantly correlated with tumor adhesion, metastatic dissemination, and adverse clinical outcomes. Furthermore, protein glycosylation contributes to chemoresistance through anti-apoptotic mechanisms, aberrant signaling activation, and pro-angiogenic pathways. This review systematically examines the dynamic evolution of protein glycosylation during CRC progression from normal mucosa to adenoma to adenocarcinoma. It also evaluates the CRC diagnostic and therapeutic implications of glycoproteins and glycans. This review can provide a molecular understanding for advancing CRC diagnostics and treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167853"},"PeriodicalIF":4.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-16DOI: 10.1016/j.bbadis.2025.167856
Fei-Fei Wu , Bo-Zhi Liu , Yun-Qiang Huang , Chang-Lei Zhu , Yu-Lu Xia , Kun-Long Zhang , Shu-Jiao Li , Yan-Ling Yang , Ya-Yun Wang
The stability of membrane contact sites is critically dependent on Endoplasmic Reticulum mitochondria contact tethering complexes (EMCTCs), and dysregulation of these sites has been implicated in neuropathic diseases. In this study, we examined the role of Annexin A10 (Anxa10), a calcium-dependent protein, in neuropathic pain by investigating its influence on EMCTCs dysregulation. Using RNA sequencing, western blotting, and behavioral assays, we observed that spared nerve injury (SNI)-induced neuropathic pain significantly increased Anxa10 expression levels within the spinal dorsal horn (SDH) of mice. By employing cell-specific gene regulation via the Cre/loxp system, we utilized loxp-modified adeno-associated virus vectors to modulate Anxa10 expression in GAD2-Cre (inhibitory neurons), vGlut2-Cre (excitatory neurons), and Fos-Cre (activity-induced neurons) transgenic mice. Our results demonstrated that specific down-regulation of Anxa10 in excitatory neurons within the SDH alleviated neuropathic pain, whereas up-regulation of Anxa10, regardless of cell type, induced spontaneous pain in mice. Ultrastructural analysis of the endoplasmic reticulum (ER) and mitochondria, as well as double immunofluorescence staining, revealed that downregulation of Anxa10 mitigated the SNI-induced reduction in ER-mitochondrial distance. Additionally, it attenuated the SNI-induced upregulation of key components of EMCTCs, including IP3R, GRP75, and VDAC1, while preventing the SNI-induced downregulation of NCX3 expression. Furthermore, we formulated and validated the hypothesis that SGK1 and PI3K are positioned downstream of Anxa10. The up-regulation of Anxa10 compromised mitochondrial integrity and disrupted mitochondrial networks, ultimately leading to elevated oxidative stress. Collectively, these findings suggest that Anxa10 represents a promising therapeutic target for correcting EMCTCs dysregulation and mitigating neuropathic pain.
{"title":"Anxa10 and neuropathic pain: Insights into dysregulation of endoplasmic reticulum-mitochondria contact tethering complex and therapeutic potential","authors":"Fei-Fei Wu , Bo-Zhi Liu , Yun-Qiang Huang , Chang-Lei Zhu , Yu-Lu Xia , Kun-Long Zhang , Shu-Jiao Li , Yan-Ling Yang , Ya-Yun Wang","doi":"10.1016/j.bbadis.2025.167856","DOIUrl":"10.1016/j.bbadis.2025.167856","url":null,"abstract":"<div><div>The stability of membrane contact sites is critically dependent on Endoplasmic Reticulum mitochondria contact tethering complexes (EMCTCs), and dysregulation of these sites has been implicated in neuropathic diseases. In this study, we examined the role of Annexin A10 (Anxa10), a calcium-dependent protein, in neuropathic pain by investigating its influence on EMCTCs dysregulation. Using RNA sequencing, western blotting, and behavioral assays, we observed that spared nerve injury (SNI)-induced neuropathic pain significantly increased Anxa10 expression levels within the spinal dorsal horn (SDH) of mice. By employing cell-specific gene regulation via the Cre/loxp system, we utilized loxp-modified adeno-associated virus vectors to modulate Anxa10 expression in GAD2-Cre (inhibitory neurons), vGlut2-Cre (excitatory neurons), and Fos-Cre (activity-induced neurons) transgenic mice. Our results demonstrated that specific down-regulation of Anxa10 in excitatory neurons within the SDH alleviated neuropathic pain, whereas up-regulation of Anxa10, regardless of cell type, induced spontaneous pain in mice. Ultrastructural analysis of the endoplasmic reticulum (ER) and mitochondria, as well as double immunofluorescence staining, revealed that downregulation of Anxa10 mitigated the SNI-induced reduction in ER-mitochondrial distance. Additionally, it attenuated the SNI-induced upregulation of key components of EMCTCs, including IP3R, GRP75, and VDAC1, while preventing the SNI-induced downregulation of NCX3 expression. Furthermore, we formulated and validated the hypothesis that SGK1 and PI3K are positioned downstream of Anxa10. The up-regulation of Anxa10 compromised mitochondrial integrity and disrupted mitochondrial networks, ultimately leading to elevated oxidative stress. Collectively, these findings suggest that Anxa10 represents a promising therapeutic target for correcting EMCTCs dysregulation and mitigating neuropathic pain.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167856"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-16DOI: 10.1016/j.bbadis.2025.167859
Wenying Shan , Shao-Lin Zhang , Yehuda G. Assaraf , Kin Yip Tam
KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation in vitro, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.
{"title":"Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation","authors":"Wenying Shan , Shao-Lin Zhang , Yehuda G. Assaraf , Kin Yip Tam","doi":"10.1016/j.bbadis.2025.167859","DOIUrl":"10.1016/j.bbadis.2025.167859","url":null,"abstract":"<div><div>KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the <em>in vitro</em> and <em>in vivo</em> efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation <em>in vitro</em>, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167859"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-16DOI: 10.1016/j.bbadis.2025.167855
Alicja Rabiasz , Zuzanna Bukowy-Bieryłło , Patrycja Kaźmierczak , Hanna Przystałowska-Macioła , Marcin Mikoś , Irena Wojsyk-Banaszak , Ewa Ziętkiewicz
Primary ciliary dyskinesia (PCD) is a heritable disease caused by the dysfunction of motile cilia, with a highly heterogeneous genetic background. CFAP221 (Cilia and Flagella Associated Protein 221) is one of the genes, whose role in the PCD pathogenesis requires further evidence.
Using whole-exome sequencing we found a novel, homozygous protein-truncating variant in CFAP221 in a Polish PCD patient. To better understand the effect of the identified pathogenic variant on motile cilia structure and function, the proband's nasal epithelium was examined using immunofluorescence, high-speed videomicroscopy, and mucociliary transport assay. Subtle abnormalities in the protein composition of the ciliary central apparatus were consistent with the asynchronous, circular motion of cilia and reduced ciliary beat frequency in the proband; importantly, the motility of proband's sperm cells was within the normal range. To independently confirm the role of CFAP221, the impact of RNA interference (RNAi)-mediated knockdown of CFAP221 homolog on motile cilia function in a ciliated flatworm, Schmidtea mediterranea, was analyzed. Knockdown of CFAP221 homolog impaired motile cilia function and led to a visible change in the speed of worms' locomotion.
Taken together, our study provided an independent confirmation of the involvement of CFAP221 in the PCD pathogenesis. The subtle effect of Smed-cfap221 knockdown in worms was consistent with the mild course of PCD in the proband.
{"title":"A novel pathogenic variant of CFAP221 is a cause of a mild form of primary ciliary dyskinesia","authors":"Alicja Rabiasz , Zuzanna Bukowy-Bieryłło , Patrycja Kaźmierczak , Hanna Przystałowska-Macioła , Marcin Mikoś , Irena Wojsyk-Banaszak , Ewa Ziętkiewicz","doi":"10.1016/j.bbadis.2025.167855","DOIUrl":"10.1016/j.bbadis.2025.167855","url":null,"abstract":"<div><div>Primary ciliary dyskinesia (PCD) is a heritable disease caused by the dysfunction of motile cilia, with a highly heterogeneous genetic background. <em>CFAP221</em> (Cilia and Flagella Associated Protein 221) is one of the genes, whose role in the PCD pathogenesis requires further evidence.</div><div>Using whole-exome sequencing we found a novel, homozygous protein-truncating variant in <em>CFAP221</em> in a Polish PCD patient. To better understand the effect of the identified pathogenic variant on motile cilia structure and function, the proband's nasal epithelium was examined using immunofluorescence, high-speed videomicroscopy, and mucociliary transport assay. Subtle abnormalities in the protein composition of the ciliary central apparatus were consistent with the asynchronous, circular motion of cilia and reduced ciliary beat frequency in the proband; importantly, the motility of proband's sperm cells was within the normal range. To independently confirm the role of <em>CFAP221</em>, the impact of RNA interference (RNAi)-mediated knockdown of <em>CFAP221</em> homolog on motile cilia function in a ciliated flatworm, <em>Schmidtea mediterranea,</em> was analyzed<em>.</em> Knockdown of <em>CFAP221</em> homolog impaired motile cilia function and led to a visible change in the speed of worms' locomotion.</div><div>Taken together, our study provided an independent confirmation of the involvement of <em>CFAP221</em> in the PCD pathogenesis. The subtle effect of <em>Smed-cfap221</em> knockdown in worms was consistent with the mild course of PCD in the proband.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167855"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-12DOI: 10.1016/j.bbadis.2025.167851
Lei Zhou , Soroosh Mozaffaritabar , Erika Koltai , Smaragda Giannopoulou , Attila Kolonics , Yaodong Gu , Ricardo A. Pinho , Ildiko Miklossy , Istvan Boldogh , Zsolt Radák
<div><div>Mitochondrial dysfunction is a critical contributor to age-related functional declines in skeletal muscle and brain. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is essential for mitochondrial biogenesis and function during aging. While skeletal muscle-specific overexpression of PGC-1α is known to mimic exercise-induced benefits in young animals, its chronic systemic effects on aging tissues remain unclear. This study aimed to determine the lifelong impact of skeletal muscle-specific PGC-1α overexpression on mitochondrial health, oxidative stress, inflammation, and cognitive function in aged mice.</div><div>We established three experimental groups: young wild-type mice (3–4 months old), aged wild-type mice (25–27 months old), and aged mice with skeletal muscle-specific PGC-1α overexpression (24–27 months old). In skeletal muscle, aging led to significant reductions in mitochondrial biogenesis markers, including PGC-1α, FNDC5, and mtDNA content. PGC-1α overexpression reversed this decline, elevating the expression of PGC-1α, SIRT1, LONP1, SDHA, CS, TFAM, eNOS, and mtDNA levels, suggesting preserved mitochondrial biogenesis. However, FNDC5 and SIRT3 were paradoxically suppressed, indicating potential compensatory feedback mechanisms. PGC-1α overexpression also enhanced anabolic signaling, as evidenced by increased phosphorylation of mTOR and S6, and reduced FOXO1 expression, favoring a muscle growth-promoting environment. Moreover, aging impaired mitochondrial dynamics by downregulating MFN1, MFN2, OPA1, FIS1, and PINK1. While PGC-1α overexpression did not restore fusion-related proteins, it further reduced fission-related protein and enhanced mitophagy proteins, as evidenced by increased PINK1 phosphorylation. In contrast, in the hippocampus, muscle-specific PGC-1α overexpression exacerbated age-associated mitochondrial biogenesis decline. Expression levels of key mitochondrial markers, including PGC-1α, SIRT1, CS, FNDC5, Cytochrome C, and TFAM, were further reduced compared to aged wild-type controls. mTOR phosphorylation was also significantly suppressed, whereas cognition-related proteins (BDNF, VEGF, eNOS) and performance in behavioral tests remained unchanged. Importantly, skeletal muscle-specific PGC-1α overexpression triggered pronounced oxidative stress and inflammatory responses in both skeletal muscle and the hippocampus. In skeletal muscle, elevated levels of protein carbonyls, IκB-α, NF-κB, TNF-α, SOD2, and NRF2 were observed, accompanied by a reduction in the DNA repair enzyme OGG1. Notably, similar patterns were detected in the hippocampus, including increased expression of protein carbonyls, iNOS, NF-κB, TNF-α, SOD2, GPX1, and NRF2, alongside decreased OGG1 levels. These findings suggest that the overexpression of PGC-1α in skeletal muscle may have contributed to systemic oxidative stress and inflammation.</div><div>In conclusion, skeletal muscle-specific PGC-1α overexpression preserves mit
{"title":"Consecutive skeletal muscle PGC-1α overexpression: A double-edged sword for mitochondrial health in the aging brain","authors":"Lei Zhou , Soroosh Mozaffaritabar , Erika Koltai , Smaragda Giannopoulou , Attila Kolonics , Yaodong Gu , Ricardo A. Pinho , Ildiko Miklossy , Istvan Boldogh , Zsolt Radák","doi":"10.1016/j.bbadis.2025.167851","DOIUrl":"10.1016/j.bbadis.2025.167851","url":null,"abstract":"<div><div>Mitochondrial dysfunction is a critical contributor to age-related functional declines in skeletal muscle and brain. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is essential for mitochondrial biogenesis and function during aging. While skeletal muscle-specific overexpression of PGC-1α is known to mimic exercise-induced benefits in young animals, its chronic systemic effects on aging tissues remain unclear. This study aimed to determine the lifelong impact of skeletal muscle-specific PGC-1α overexpression on mitochondrial health, oxidative stress, inflammation, and cognitive function in aged mice.</div><div>We established three experimental groups: young wild-type mice (3–4 months old), aged wild-type mice (25–27 months old), and aged mice with skeletal muscle-specific PGC-1α overexpression (24–27 months old). In skeletal muscle, aging led to significant reductions in mitochondrial biogenesis markers, including PGC-1α, FNDC5, and mtDNA content. PGC-1α overexpression reversed this decline, elevating the expression of PGC-1α, SIRT1, LONP1, SDHA, CS, TFAM, eNOS, and mtDNA levels, suggesting preserved mitochondrial biogenesis. However, FNDC5 and SIRT3 were paradoxically suppressed, indicating potential compensatory feedback mechanisms. PGC-1α overexpression also enhanced anabolic signaling, as evidenced by increased phosphorylation of mTOR and S6, and reduced FOXO1 expression, favoring a muscle growth-promoting environment. Moreover, aging impaired mitochondrial dynamics by downregulating MFN1, MFN2, OPA1, FIS1, and PINK1. While PGC-1α overexpression did not restore fusion-related proteins, it further reduced fission-related protein and enhanced mitophagy proteins, as evidenced by increased PINK1 phosphorylation. In contrast, in the hippocampus, muscle-specific PGC-1α overexpression exacerbated age-associated mitochondrial biogenesis decline. Expression levels of key mitochondrial markers, including PGC-1α, SIRT1, CS, FNDC5, Cytochrome C, and TFAM, were further reduced compared to aged wild-type controls. mTOR phosphorylation was also significantly suppressed, whereas cognition-related proteins (BDNF, VEGF, eNOS) and performance in behavioral tests remained unchanged. Importantly, skeletal muscle-specific PGC-1α overexpression triggered pronounced oxidative stress and inflammatory responses in both skeletal muscle and the hippocampus. In skeletal muscle, elevated levels of protein carbonyls, IκB-α, NF-κB, TNF-α, SOD2, and NRF2 were observed, accompanied by a reduction in the DNA repair enzyme OGG1. Notably, similar patterns were detected in the hippocampus, including increased expression of protein carbonyls, iNOS, NF-κB, TNF-α, SOD2, GPX1, and NRF2, alongside decreased OGG1 levels. These findings suggest that the overexpression of PGC-1α in skeletal muscle may have contributed to systemic oxidative stress and inflammation.</div><div>In conclusion, skeletal muscle-specific PGC-1α overexpression preserves mit","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167851"},"PeriodicalIF":4.2,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834705","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}
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