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

{"title":"The IGF2BP2-circ-DAPK1 axis promotes high-glucose-induced ferroptosis of HUVECs by decreasing NQO1 expression","authors":"Chenyang Qiu ,&nbsp;Xiangtao Zheng ,&nbsp;Xiaoxiang Zhou ,&nbsp;Bing Wang ,&nbsp;Tianchi Chen ,&nbsp;Yiting Xu ,&nbsp;Xinyu Yu ,&nbsp;Wei Lu ,&nbsp;Ziheng Wu","doi":"10.1016/j.bbadis.2025.167797","DOIUrl":"10.1016/j.bbadis.2025.167797","url":null,"abstract":"<div><div>Circular RNAs (circRNAs) are non-coding RNAs with covalently closed loop structures that participate in various biological processes. However, the functions of many circRNAs remain unclear. Endothelial cell dysfunction, which involves abnormal ferroptosis, a unique form of regulated cell death, is a characteristic of various diseases. However, the mechanisms governing ferroptosis in endothelial cells are not fully understood. Here, we investigated the impact of a novel circRNA, circ-DAPK1, on ferroptosis in human umbilical vein endothelial cells (HUVECs) under high-glucose conditions. Our data showed that high-glucose conditions upregulate circ-DAPK1 expression in HUVECs. Overexpression of circ-DAPK1 induced ferroptosis in HUVECs, whereas depletion of circ-DAPK1 mitigated the ferroptosis triggered by high-glucose treatment. Inhibition of ferroptosis reversed the decrease in cell viability induced by high glucose or circ-DAPK1 overexpression. Using RNA immunoprecipitation analyses, we identified several ferroptosis-regulating proteins, including NAD(<em>P</em>)H dehydrogenase [quinone] 1 (NQO1) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Mechanistically, circ-DAPK1 interacts with NQO1, enhancing its ubiquitination and accelerating its degradation. NQO1 overexpression partially rescues HUVECs from high-glucose-induced ferroptosis. We also found that IGF2BP2 binds to the m⁶A site on circ-DAPK1. Depletion of IGF2BP2 in HUVECs reduced circ-DAPK1 expression and inhibited high-glucose-induced ferroptosis. These findings reveal the effects of the IGF2BP2-circ-DAPK1 axis in regulating ferroptosis in HUVECs under high-glucose conditions and extend our understanding of the mechanisms controlling ferroptosis in endothelial cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167797"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MBD2 promotes epithelial-to-mesenchymal transition (EMT) and ARDS-related pulmonary fibrosis by modulating FZD2","authors":"Yang Zhou ,&nbsp;Guifang Yang ,&nbsp;Jiqiang Liu ,&nbsp;Shuo Yao ,&nbsp;Jingsi Jia ,&nbsp;Xianming Tang ,&nbsp;Xun Gong ,&nbsp;Fang Wan ,&nbsp;Ren Wu ,&nbsp;Zhenyu Zhao ,&nbsp;Hengxing Liang ,&nbsp;Linxia Liu ,&nbsp;Qimi Liu ,&nbsp;Shanshan Xie ,&nbsp;Xian Long ,&nbsp;Xudong Xiang ,&nbsp;Guyi Wang ,&nbsp;Bing Xiao","doi":"10.1016/j.bbadis.2025.167798","DOIUrl":"10.1016/j.bbadis.2025.167798","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis.</div></div><div><h3>Methods</h3><div>Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell sequencing data and Human pulmonary fibrosis samples were analyzed.</div></div><div><h3>Results</h3><div>Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis.</div></div><div><h3>Conclusion</h3><div>Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167798"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AAV8-mediated silencing of Atad3 prevents the progression from simple steatosis to MASH in mice by reduced IL6 secretion","authors":"Liting Chen ,&nbsp;Yuchang Li ,&nbsp;Rahil Nitinkumar Patel ,&nbsp;Chantal Sottas ,&nbsp;Mahima Chandrakant Raul ,&nbsp;Nrupa Dinesh Patel ,&nbsp;Alexander Zambidis ,&nbsp;Meng Li ,&nbsp;Shefali Chopra ,&nbsp;Vassilios Papadopoulos","doi":"10.1016/j.bbadis.2025.167792","DOIUrl":"10.1016/j.bbadis.2025.167792","url":null,"abstract":"<div><div>ATAD3A deficiency in hepatocytes has been shown to promote simple steatosis (SS). ATAD3 is upregulated in MCD diet-induced MASH. Since the MCD diet is commonly used to induce liver fibrosis, which is related to HSCs activation, we are prompted to investigate the functions of ATAD3 in these two cell types and their mediated transition from SS to MASH. To investigate the role of ATAD3A in HSCs, human LX-2 cells were treated with TGFβ. The results showed that ATAD3A expression was linked to the fibrotic markers ACTA2 and COL1A1. Knockdown of <em>ATAD3A</em> reversed TGFβ-induced HSC activation by downregulating both canonical (SMAD2/3) and non-canonical (ERK1/2 and p38 MAPK) TGFβ signaling pathways. To examine the effect of ATAD3 on the transition from SS to MASH, MASH was induced in mice using the GAN diet for 24 weeks. After 12 weeks, AAV8-conjugated <em>Atad3</em> shRNA was administered to knock down <em>Atad3</em> in the liver. This intervention suppressed steatosis and fibrosis while enhancing insulin sensitivity. Further analysis using conditioned medium (CM) from WT and <em>ATAD3A KO</em> Huh7 cells treated with LPS and PA revealed that IL-6 secretion from Huh7 hepatocytes activated HSCs. However, IL-6 secretion was diminished in <em>ATAD3A KO</em> CM. CM from <em>ATAD3A KO</em> cells also suppressed expression of fibrotic markers ACTA2, P<img>P38, and P-SMAD3 compared to WT cells under MASH conditions. These data suggest that AAV8-mediated <em>Atad3</em> silencing in hepatocytes prevents the transition from SS to MASH, at least in part, by downregulating IL-6 secretion to suppress HSC activation in MASH.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167792"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircPICALM promotes neonatal acute kidney injury triggered by hypoxia/reoxygenation via sponging microRNA-204-5p","authors":"Yang Yang ,&nbsp;Jing-jing Pan ,&nbsp;Xiao-qing Chen ,&nbsp;Jia Shi ,&nbsp;Mu-zi Wang ,&nbsp;Tian-yu Liu ,&nbsp;Xiao-guang Zhou","doi":"10.1016/j.bbadis.2025.167795","DOIUrl":"10.1016/j.bbadis.2025.167795","url":null,"abstract":"<div><h3>Background</h3><div>Circular RNAs (circRNAs) have been documented to regulate neonatal acute kidney injury (AKI). Based on previous RNA-sequence findings, circPICALM exhibited significantly disparate expression between AKI newborns and Controls. This study aimed to provide further insights into the regulatory mechanism of circPICALM in neonatal AKI.</div></div><div><h3>Methods</h3><div>C57BL/6 mice born 7 days were divided into Control group and hypoxia groups (11%O₂ and 8%O₂ groups). Human tubule epithelial cells (HK-2) were stimulated with hypoxia/reoxygenation (H/R) to establish an AKI cell model. Through overexpression and knockdown techniques, the regulatory role of circPICALM in H/R-induced kidney injury was explored. Inflammatory cytokines, cell apoptosis, and oxidative stress were also detected to confirm the regulatory function of circPICALM in neonatal AKI.</div></div><div><h3>Results</h3><div>RT-qPCR confirmed that circPICALM was highly expressed in the serum of AKI newborns, neonatal I/R mice and H/R-treated HK-2 cells. Functionally, circPICALM exacerbated H/R-induced HK-2 cell injury by aggravating apoptosis and mitochondrial oxidative stress, increasing the expression of inflammatory factors, including IL-6, IL-1β, and TNF-α. Conversely, inhibition of circPICALM alleviated H/R injury in the HK-2 cell line. The interaction between circPICALM and miR-204-5p was validated through RNA immunoprecipitation and luciferase assay. Finally, circPICALM functioned as a molecular sponge of miR-204-5p and promoted the upregulation of downstream IL-1β expression.</div></div><div><h3>Conclusion</h3><div>CircPICALM plays a critical role in H/R-induced neonatal AKI by sponging miR-204-5p and then activating the downstream IL-1β signaling axis. The inhibition of circPICALM and subsequent suppression of pro-inflammatory factors could serve as a promising biomarker and therapeutic target for early intervention in neonatal AKI.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167795"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CNC-family transcription factor NRF3: A crucial therapeutic target for cancer treatment","authors":"Liangwen Yan ,&nbsp;Xinyan Li ,&nbsp;Jiayi Xu ,&nbsp;Shenkang Tang ,&nbsp;Gang Wang ,&nbsp;Mengjiao Shi ,&nbsp;Pengfei Liu","doi":"10.1016/j.bbadis.2025.167794","DOIUrl":"10.1016/j.bbadis.2025.167794","url":null,"abstract":"<div><div>The CNC-bZIP family member NRF3 (NFE2L3) has received limited attention since its discovery. However, recent research has gradually revealed its biological functions, such as involvement in the regulation of cell differentiation, lipid metabolism, and malignant cell proliferation. Under physiological conditions, NRF3 is anchored to the endoplasmic reticulum within the cytoplasm and is biologically inactive. Upon cellular exposure to microenvironmental stresses such as oxidative stress, NRF3 translocates to the nucleus, binds to DNA, and acts as a transcription factor by inducing or repressing the expression of various genes. In terms of tumor regulation, NRF3 exhibits a dual role. It can function as a tumor suppressor to prevent the malignant progression of tumor tissues, protecting the organism from harm. Conversely, current research indicates that NRF3 plays a tumor-promoting role in most tumor tissues. NRF3 enhances the proliferation, migration and invasion of tumor cells by regulating cell cycle-related proteins and enhancing proteasome assembly to degrade tumor suppressors. Studies correlating NRF3 expression with clinical tumor features have found that elevated NRF3 expression is often associated with poor prognoses in various cancers, with patients exhibiting higher NRF3 expression typically having lower survival rates. Several studies suggest that NRF3 could serve as a clinical diagnostic and prognostic marker for tumors. Finally, from the clinical perspective, exploring the feasibility of inhibiting NRF3 activity in tumor treatment provides new insights for the development of NRF3-targeted oncological therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167794"},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells","authors":"Congyu Wang ,&nbsp;Siwen Wang ,&nbsp;Guowei Zhang ,&nbsp;Haihong Shi,&nbsp;Pengfei Li,&nbsp;Sijie Bao,&nbsp;Lihua Kang,&nbsp;Min Ji,&nbsp;Huaijin Guan","doi":"10.1016/j.bbadis.2025.167796","DOIUrl":"10.1016/j.bbadis.2025.167796","url":null,"abstract":"<div><div>Mitochondrial dysfunction, resulting from a diminished oxidative damage repair capacity of mitochondrial DNA (mtDNA) in peripheral lens epithelial cells (LECs), is a key pathogenic mechanism in age-related cortical cataract (ARCC). This study aims to investigate the potential role of the E3 ligase HUWE1 and its ubiquitination substrate, the oxidative damage repair gene ATM, in the pathogenesis of ARCC. Our findings reveal that ATM protein expression is downregulated in human peripheral lens epithelial cells and the turbid cortex, correlating with increased expression of HUWE1. Overexpression of ATM is shown to repair damaged mtDNA, protect mitochondria in LECs from oxidative damage, inhibit mitochondrial fission, enhance mitochondrial biogenesis and mitophagy, and prevent LECs apoptosis. Conversely, overexpression of HUWE1 may negate the protective effects of ATM via the ubiquitination pathway, promote oxidative stress-induced mitochondrial damage, increase the expression of mitochondrial fission proteins Drp1/Fis1, lead to mitochondrial network fragmentation and LECs apoptosis. In a SD rat lens model ex vitro, the ATM inhibitor AZD0156 exacerbated lens opacity, whereas the mitochondrial fission inhibitor Mdivi-1 restored lens transparency. These results suggest that modulating key molecules involved in oxidative damage repair and mitochondrial fission pathways could enhance mitochondrial quality control, paving the way for the development of targeted molecular therapies for the prevention and treatment of ARCC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167796"},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modified expression of JAK-STAT pathway genes in an in vivo rheumatoid arthritis model: A preclinical study to explore genetic insights","authors":"Maham Ghouri ,&nbsp;Nadir Naveed Siddiqui ,&nbsp;Mehreen Lateef ,&nbsp;Lubna Avesi ,&nbsp;Rizma Khan ,&nbsp;Humaira Ghauri ,&nbsp;Ehtisham Asif ,&nbsp;Sitwat Zehra","doi":"10.1016/j.bbadis.2025.167780","DOIUrl":"10.1016/j.bbadis.2025.167780","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by inflammatory synovial tissue, joint deterioration, and effects on systems other than the joints. The biological process underlying the progression of the disease remains unknown, however cell-mediated immunity plays an important part in the onset of RA. The current study investigated the involvement of the JAK-STAT pathway genes (<em>JAK-1</em>, <em>IL-6</em>, and <em>SOCS-2</em>) in the pathogenesis of RA (Rheumatoid arthritis).</div></div><div><h3>Methodology</h3><div>The study was carried out on thirty male Albino Wistar rats categorised in to the three groups. The AIA (Adjuvant induced animal) model was utilised to study the disease pathogenesis. The haematoxylin and Eosin (H and E) was performed followed by ELISA and expression analyses by RT-q-PCR. The obtained data was analysed using one-way ANOVA (Analysis of Variance).</div></div><div><h3>Results</h3><div>Histopathology confirmed that diseased group appeared to be severely impaired, demonstrating manifestations of inflammation with chronic as well as cartilage degenerative changes. Furthermore, chronic inflammation was also noticed in the intertrabecular area. The significant increased levels of JAK1, IL-6 and TYK-2 were recorded among RA group. The gene expression assessment indicated that higher expression of <em>JAK-1</em> and <em>IL-6</em> was linked to the further development of RA in the disease group. The <em>SOSC2</em> (a negative regulator of the JAK-STAT pathway) was significantly (<em>p</em> &lt; 0.01) downregulated. Moreover, <em>SOCS2</em> may be unable to suppress the transcription of the related JAKs (<em>IL-6</em> and <em>JAK-1</em>), resulting in the constant release of immune mediators and contributing to the pathophysiology of RA.</div></div><div><h3>Conclusions</h3><div>The JAK-STAT pathway may serve as the target for diagnosing and treating inflammatory and autoimmune disorders (RA). The findings may enhance therapeutic possibilities by investigating the possible implications of JAK-STAT pathway genes as candidates for progressive rheumatoid arthritis therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167780"},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of LMOD1 induces oxidative stress and enhances cell apoptosis of melanoma through the RIG-I like receptor pathway","authors":"Hua Lei ,&nbsp;Linxue Huang ,&nbsp;Huiying Wan,&nbsp;Mingyi Chen","doi":"10.1016/j.bbadis.2025.167762","DOIUrl":"10.1016/j.bbadis.2025.167762","url":null,"abstract":"<div><h3>Background</h3><div>Oxidative stress is crucial in the development of cutaneous melanoma, but its role in melanoma is controversial. We aimed to identify melanoma-associated targets and understand the underlying mechanism.</div></div><div><h3>Methods</h3><div>Differential expressed genes (DEGs) were discovered between control and melanoma samples, and a protein-protein interaction (PPI) network was constructed to find key genes. The prediction accuracy of LMOD1 was assessed by receiver operating characteristic (ROC) curves, and pan-cancer analysis was also performed for LMOD1 expression and immune characteristics. The downstream pathway of LMOD1 was found via KEGG analysis. The effects of LMOD1 on oxidative stress, apoptosis, CD4 + T cells and the downstream pathway were evaluated in melanoma cells and mice.</div></div><div><h3>Results</h3><div>We identified ACTG2, CNN1, LMOD1, MYH11, MYL9, MYLK, TAGLN, TPM1 and TPM2 as melanoma-related DEGs, which could separate control and melanoma samples. The area under curve (AUC) of LMOD1 was &gt; 0.89, indicating high prediction accuracy. LMOD1 expression was decreased in melanoma, and LMOD1 notably correlated with B cells, CD4 T cells, neutrophils, macrophages and dendritic cells (DCs). Overexpression of LMOD1 promoted apoptosis, enhanced migration and invasion, and activated oxidative stress in melanoma cells. LMOD1 promoted apoptosis via activating oxidative stress. The RIG-I-like receptor signaling (RLR) was a downstream pathway of LMOD1. Overexpression of LMOD1 activated oxidative stress, increased apoptosis and CD4 + T cells, and elevated RIG-I and MDA5, while Cyclo (Phe-Pro) (cFP) reversed the results.</div></div><div><h3>Conclusion</h3><div>LMOD1 triggers oxidative stress-mediated apoptosis in melanoma via activating the RLR pathway, which provides promising targets and regulatory pathway for melanoma.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167762"},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DDR2 alleviates retinal vaso-obliteration and pathological neovascularization by modulating microglia M1/M2 phenotypic polarization in a mouse model of proliferative retinopathy","authors":"Qinjin Dai ,&nbsp;Wenqi Su ,&nbsp;Zhongcheng Zhou ,&nbsp;Jiaguo Yuan ,&nbsp;Xinru Wei ,&nbsp;Jin Su ,&nbsp;Jie Zhu","doi":"10.1016/j.bbadis.2025.167787","DOIUrl":"10.1016/j.bbadis.2025.167787","url":null,"abstract":"<div><div>Retinopathy of prematurity (ROP), a leading cause of blindness in premature infants, is characterized by retinal vaso-obliteration during hyperoxia and pathological neovascularization (NV) in relative hypoxia phase. Current treatments, which focus on the late stages of pathological neovascularization, are associated with numerous side effects. Studies demonstrated that discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase, inhibits the experimental choroidal neovascularization and participates in tumor angiogenesis. However, the role of DDR2 in ROP and underlying mechanisms is unclear. In this study, we initially found that DDR2 expressed during mouse physiological retinal vascular development and significantly decreased in vaso-obliteration phase followed by increase during pathological neovascularization phase in mouse oxygen-induced retinopathy (OIR) model. Early upregulation of DDR2 before hyperoxia attenuates oxygen-induced vaso-obliteration, reduces pathological neovascularization, and promotes retinal vascular maturation. Additionally, DDR2 upregulation increased the number of microglia around retinal blood vessels and induced anti-inflammatory M2 polarization. Furthermore, the STAT6/TGF-β signaling pathway suppressed during hyperoxia was activated after DDR2 upregulation. In conclusion, DDR2 attenuated vaso-obliteration and inhibited pathological neovascularization by switching the microglia polarization from M1 to M2 phenotype via the STAT6/TGF-β signaling pathway in OIR. This suggests that DDR2 could be a novel target for the early treatment of ROP.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167787"},"PeriodicalIF":4.2,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new strategy to HER2-specific antibody discovery through artificial intelligence-powered phage display screening based on the Trastuzumab framework","authors":"Mancang Zhang ,&nbsp;Qiangzhen Yang ,&nbsp;Jiangrong Lou ,&nbsp;Yang Hu ,&nbsp;Yongyong Shi","doi":"10.1016/j.bbadis.2025.167772","DOIUrl":"10.1016/j.bbadis.2025.167772","url":null,"abstract":"<div><div>Human epidermal growth factor receptor 2 (HER2) is a recognized drug target, and it serves as a critical target for various cancer treatments, necessitating the discovery of more antibodies for therapeutic and detection purposes. Here, we have developed an innovative workflow for antibody generation through Artificial Intelligence-powered Phage Display Screening (AIPDS). This workflow integrates artificial intelligence-driven antibody CDRH3 sequence design, high-throughput DNA synthesis and phage display screening. We applied AIPDS workflow to generate promising antibodies against the human epidermal growth factor receptor 2 (HER2), offering a template for streamlined antibody generation. Seven novel antibodies stood out, demonstrating promising efficacy in various functional assays. Notably, DYHER2–02 demonstrates strong performance across all experimental tests. In summary, our study introduces a novel methodology to generate new antibody variants of an existing antibody using an AI-assisted phage display approach. These new antibody variants hold potential applications in research, diagnosis, and therapeutic applications.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167772"},"PeriodicalIF":4.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562261","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}