Life sciences最新文献

{"title":"Regional uterine contractility differences during pregnancy: The role of hypoxia and ferroptosis in vitro","authors":"Ruixian Tian ,&nbsp;Xuan Li ,&nbsp;Jingjing Su ,&nbsp;Huihui Yu ,&nbsp;Jiajia Fei ,&nbsp;Chenyi Xu ,&nbsp;Xue Du ,&nbsp;Biao Yu ,&nbsp;Yunxia Cao ,&nbsp;Zongzhi Yin","doi":"10.1016/j.lfs.2025.123603","DOIUrl":"10.1016/j.lfs.2025.123603","url":null,"abstract":"<div><div>Regional variations in uterine contractility during pregnancy have been well-documented. However, the molecular mechanisms underlying these differences remain unclear. To address this, isotonic contraction experiments were conducted on pregnant rat uteri, revealing significantly lower contractility on the placenta-attached side compared to the non-attached side. Interestingly, lactic acid accumulation was higher in the placenta-attached tissue, suggesting metabolic differences between these regions. Muscle contraction requires substantial energy, with adenosine triphosphate (ATP) serving as the direct source of energy, which is predominantly supplied by mitochondria, the cellular energy production centers. Mitochondrial energy generation relies heavily on oxygen availability. To explore the impact of oxygen conditions on uterine smooth muscle cell (USMC) contraction, we cultured these cells under hypoxic conditions. Hypoxia was found to reduce cell contraction and disrupt mitochondrial integrity. Specifically, mitochondria exhibited shrinkage and deformation, characterized by reduced cristae and a collapse of the mitochondrial membrane potential. These structural and functional changes align with hallmarks of ferroptosis. Furthermore, hypoxia stimulated the translocation of dynamic related protein 1 (Drp1) to mitochondria, a process linked to mitochondrial fragmentation. Ferroptosis was downregulated when Drp1 activity was inhibited, highlighting its regulatory role in this process. Collectively, these findings demonstrate that hypoxia induced-ferroptosis impairs mitochondria, leading to reduced energy production and cell viability. This ultimately decreases the contractility of pregnant USMC, providing new insights into the molecular mechanisms underlying regional differences in uterine contractility during pregnancy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123603"},"PeriodicalIF":5.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The crosstalk between lung adenocarcinoma cells and M2 macrophages promotes cancer cell development via the SFRS1/miR-708-5p/PD-L1 axis","authors":"Li Xu ,&nbsp;Kang Li ,&nbsp;Jia Li,&nbsp;Fang Xu,&nbsp;Shuzhi Liang,&nbsp;Yi Kong,&nbsp;Bolin Chen","doi":"10.1016/j.lfs.2025.123599","DOIUrl":"10.1016/j.lfs.2025.123599","url":null,"abstract":"<div><div>This study aimed to elucidate the underlying mechanisms regarding microRNA-708-5p (miR-708-5p) in lung adenocarcinoma (LUAD). Here, the co-culture system of LUAD cells and macrophages, as well as a xenograft mouse model, were established. High levels of <em>miR-708-5p</em> were observed in LUAD. Exosomal miR-708-5p facilitated M2-like phenotype polarization, whereas miR-708-5p inhibition blocked the polarization. Exosomal miR-708-5p was identified as a pivotal signaling molecule for macrophages to mediate tumor cell proliferation, invasion, migration and IFN-γ production in T cells. In addition, miR708-5p was observed to induce PD-L1 expression, and PD-L1 silencing inhibited macrophage-induced tumor cell growth behavior and regulated CD8 T cell activity. In xenograft models, miR-708-5p inhibition and PD-L1 silencing attenuated macrophage-induced tumor growth, induced IFN-γ secretion and CD8 expression, and modulated the PTEN/AKT/mTOR pathway. In LUAD patients, there was an upregulation of both <em>miR-708-5p</em> and PD-L1 expression, accompanied by the activation of PTEN/AKT/mTOR. In conclusion, this study demonstrated the induction of M2 macrophage polarization and PD-L1 expression by exosomal miR-708-5p. We observed that exosomal miR-708-5p mediated the PTEN/AKT/mTOR pathway, diminished CD8 T cell activity and accelerated LUAD progression. The inhibition of specific exosomal miRNA secretion and anti-PD-L1 in the LUAD microenvironment may represent a promising avenue for LUAD immunotherapy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123599"},"PeriodicalIF":5.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicenter experience with Efgartigimod in the treatment of anti-NMDAR encephalitis compared with IVIG and SPA-IA during acute attacks","authors":"Jia Liu ,&nbsp;Min Li ,&nbsp;Junyu Liu ,&nbsp;Dong Zheng ,&nbsp;Yanxia Zhou ,&nbsp;Yi Li ,&nbsp;Xialing Chen ,&nbsp;Yanni Lin ,&nbsp;Lu Yang ,&nbsp;Xiaofeng Xu ,&nbsp;Ying Jiang ,&nbsp;Fuhua Peng","doi":"10.1016/j.lfs.2025.123597","DOIUrl":"10.1016/j.lfs.2025.123597","url":null,"abstract":"<div><h3>Objectives</h3><div>The purpose of this study was to evaluate the efficacy of Efgartigimod (EFG) in anti-<em>N</em>-methyl-<span>d</span>-aspartate receptor (anti-NMDAR) encephalitis patients during acute attacks.</div></div><div><h3>Methods</h3><div>A case-control study was designed to compare 26 anti-NMDAR encephalitis patients who were treated with EFG, and 15 patients with intravenous immunoglobulin (IVIG), and 23 patients with immunoadsorption with staphylococcal protein A column (SPA-IA) treatment.</div></div><div><h3>Results</h3><div>At baseline, no significant differences in mRS scores were observed among the EFG, IVIG, and SPA-IA groups of anti-NMDAR encephalitis patients. When compared with the IVIG group, patients treated with EFG had significantly decreased serum IgG levels. Compared with the SPA-IA group, EFG-treated patients had lower CSF anti-NMDAR antibody titers at admission (<em>p</em> = 0.039) and higher post-treatment IgG levels (<em>p</em> = 0.002). When compared with the IVIG group, SPA-IA patients had higher CASE scores (<em>p</em> = 0.022) and baseline IgG levels (<em>p</em> = 0.023). All groups improved the symptoms of anti-NMDAR encephalitis patients after treatment during acute attacks, with significant decreases in mRS and CASE scores from admission to discharge (<em>p</em> &lt; 0.01). In the EFG and SPA-IA groups, there was a significant reduction in anti-NMDAR antibody titers in both CSF and serum (<em>p</em> &lt; 0.01), while no remarkable decrease was found in the IVIG group. Additionally, serum IgG levels significantly decreased in both the EFG and SPA-IA groups post treatment and during the 1-month follow-up. By the 3-month of follow-up, IgG levels in the blood of both groups remained below the baseline levels.</div></div><div><h3>Conclusion</h3><div>EFG could be an elegant alternative to both IVIG and SPA-IA therapies for anti-NMDAR encephalitis during acute attacks. It has a better effect on reducing antibody titers than IVIG and is comparable to SPA-IA therapy, and no serious adverse events were observed during infusion.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123597"},"PeriodicalIF":5.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of exosomes derived from activated corneal stromal keratocytes on the inflammation, proliferation, neuroprotection and epithelial-mesenchymal transition in retinal pigment epithelium cells","authors":"Fatemeh Sanie-Jahromi ,&nbsp;Niloofar Sadeghi ,&nbsp;Zahra Moayedfard ,&nbsp;Zahra Gharegezloo ,&nbsp;Mahmood Nejabat ,&nbsp;M. Hossein Nowroozzadeh","doi":"10.1016/j.lfs.2025.123592","DOIUrl":"10.1016/j.lfs.2025.123592","url":null,"abstract":"<div><h3>Aims</h3><div>This study investigated the effects of activated keratocyte-derived exosomes (aKExo) on retinal pigment epithelial (RPE) cells <em>in-vitro</em>, focusing on cell viability, inflammatory cytokine expression, and neuroprotective properties.</div></div><div><h3>Materials and methods</h3><div>Keratocytes were cultured, and exosomes were extracted and characterized using transmission electron microscopy (TEM), scanning electron microscopy (SEM), flow cytometry, and dynamic light scattering (DLS). RPE cells, isolated from a human donor, were confirmed <em>via</em> RPE65 expression. aKExo effects on RPE cells were assessed using MTT assay at concentrations from 10⁻¹ (35 μg/mL) to 10⁻⁵ (3.5 × 10⁻³ μg/mL). The optimal aKExo concentration (10⁻⁵) enhanced cell viability and exhibited the highest proliferative potential compared to the control group, making it the optimal dose for subsequent experiments including gene expression analysis, and ELISA.</div></div><div><h3>Key findings</h3><div>aKExo downregulated IL-6 mRNA (0.70 ± 0.06, <em>p</em> = 0.0009) and marginally reduced TGF-β mRNA (0.75 ± 0.16, <em>p</em> = 0.0575). ELISA confirmed a reduction in IL-6 (31.33 ± 5.77 pg/mL <em>vs.</em> 50.22 ± 13.47 pg/mL, <em>p</em> = 0.0894) and TGF-β (8.91 ± 0.16 pg/mL <em>vs.</em> 11.39 ± 1.49 pg/mL, <em>p</em> = 0.0460). No significant changes were observed for IL-1β expression or other epithelial-mesenchymal transition (EMT)-related genes (α-SMA, ZEB-1, β-catenin). Neuroprotective genes NGF (4.34 ± 1.05, <em>p</em> = 0.0053) and CD90 (1.55 ± 0.25, <em>p</em> = 0.0184) were significantly upregulated, while VEGF-A was elevated (1.65 ± 0.15, <em>p</em> = 0.0018).</div></div><div><h3>Significance</h3><div>These findings highlight aKExo's immunomodulatory, neuroprotective, and anti-EMT effects, suggesting potential therapeutic applications for retinal disorders, while noting that VEGF-A upregulation requires further investigation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123592"},"PeriodicalIF":5.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes in treating Eye Diseases: Targeting strategies","authors":"Pengfei Ge,&nbsp;Jingfan Wang,&nbsp;Ping Xie,&nbsp;Zizhong Hu","doi":"10.1016/j.lfs.2025.123598","DOIUrl":"10.1016/j.lfs.2025.123598","url":null,"abstract":"<div><div>Exosomes are lipid-based vesicles carrying bioactive molecules (nucleic acids, proteins, lipids) that mediate intercellular communication. Emerging research explores their potential as therapeutic delivery systems, with bioengineering approaches enhancing stability and efficacy for clinical translation. This review focuses on exosome applications in ocular diseases, particularly engineered targeting strategies, while addressing current limitations and future clinical prospects.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123598"},"PeriodicalIF":5.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of mannose receptor C type 1 in macrophages improves renal fibrosis through mediating fibronectin endocytosis","authors":"Luosha Long ,&nbsp;Meng Li ,&nbsp;Minghui Wang ,&nbsp;Baien Liang ,&nbsp;Meiying Huang ,&nbsp;Xi Yuan ,&nbsp;Xinyan Wu ,&nbsp;Xiangdong Guo ,&nbsp;Suchun Li ,&nbsp;Zhende Liu ,&nbsp;Weizhi Liu ,&nbsp;Wei Chen ,&nbsp;Weidong Wang ,&nbsp;Qianqian Lyu ,&nbsp;Chunling Li","doi":"10.1016/j.lfs.2025.123593","DOIUrl":"10.1016/j.lfs.2025.123593","url":null,"abstract":"<div><h3>Aims</h3><div>Excess extracellular matrix (ECM) deposition is the characteristic of renal fibrosis, owing to the imbalance between synthesis and degradation. Fibronectin could regulate the deposition of other ECM, thus plays a crucial role in the progression of renal fibrosis. Mannose receptor C type 1 (MRC1), largely expressed on macrophages, owns an extracellular fibronectin type II domain that binds to and internalizes collagen and thus involves in fibrosis modulation. The purpose of the present study was to investigate whether MRC1 participates in the internalization of fibronectin and whether alginate oligosaccharides (AOSC), a degradation product of alginate, has beneficial effects in the resolution of renal fibrosis via MRC1.</div></div><div><h3>Materials and methods</h3><div>Renal fibrosis models were constructed by unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) in MRC1-WT and MRC1-KO mice. RAW264.7 cells were treated with TGF-β1 to induce pro-fibrotic responses. Expression of fibrotic markers and fibronectin endocytosis were examined.</div></div><div><h3>Key findings</h3><div>MRC1 gene knockout aggravated renal fibrosis in UUO and UIRI models. Inhibition of MRC1 exacerbated TGF-β1-induced pro-fibrotic responses in RAW264.7 cells. MRC1 regulated integrin β1-mediated fibronectin endocytosis through Arp2/3-Kindlin-2 signaling pathway. AOSC improved renal fibrosis by increasing MRC1 expression and endocytosis of fibronectin.</div></div><div><h3>Significance</h3><div>Our findings highlight the importance of MRC1 and fibronectin endocytosis in the development of renal fibrosis, suggesting that activation of MRC1 by AOSC is probably a therapeutic option to delay the progress of kidney fibrosis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123593"},"PeriodicalIF":5.2,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esketamine mitigates systemic inflammation via modulating phenotypic transformation of monocytes in patients undergoing thoracic surgery","authors":"Weiyun Shen ,&nbsp;Yan Yan ,&nbsp;Wenjuan Zhang ,&nbsp;Junmei Xu ,&nbsp;Zhijian Li ,&nbsp;Lin Yang","doi":"10.1016/j.lfs.2025.123594","DOIUrl":"10.1016/j.lfs.2025.123594","url":null,"abstract":"<div><h3>Aim</h3><div>To assess esketamine's anti-inflammatory effects during thoracic surgery and its modulation of immune responses.</div></div><div><h3>Material and methods</h3><div>In a randomized trial, 64 of 73 patients undergoing thoracic surgery were allocated into the Control (not receiving esketamine) or the ES-KTM group (intraoperative esketamine infusion). Blood routine tests were conducted one day before (T0) and one day after the surgery (T3). Plasma levels of tumor necrosis factor-α (TNF-α) and interleukine-10 (IL-10) were analyzed by ELISA, and cell surface markers including CD14, CD16, CD163, CD40, CX3CR1, CD206 were tested by cytometry at the entry to the surgical room (T1) and the skin closure (T2). For the in vitro study, esketamine at 10 μM was employed to treat the lipopolysaccharide (LPS) stimulated macrophage cell line-Raw264.7, and its effects were tested by cytometry and RNA sequencing analysis.</div></div><div><h3>Key findings</h3><div>Esketamine application reduces the count of neutrophils and monocytes, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and systemic inflammatory index (SII), and enhances the lymphocyte counting and lymphocyte to monocyte ratio (LMR). Then, esketamine application decreases the plasma TNF-α levels, while maintaining the IL-10 level in comparison with the Control group. Additionally, esketamine reduced the proportion of intermediate monocytes, downregulates the expressions of CD16, CD40 and CX3CR1, while upregulates the CD206 expression. Finally, in the in-vitro study, esketamine inhibits the M1 pro-inflammatory markers in LPS-challenged macrophages, and downregulates multiple immune-related pathways.</div></div><div><h3>Significance</h3><div>Esketamine mitigates surgery-triggered inflammation by suppressing monocyte/macrophage proinflammatory activity and TNF-α release, offering dual anesthetic and immunomodulatory benefits.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123594"},"PeriodicalIF":5.2,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Akt mitigates ER stress-instigated cardiac dysfunction via regulation of ferroptosis and mitochondrial integrity in a DHODH-dependent manner","authors":"Na Zhou ,&nbsp;Li Ma ,&nbsp;Wanting Shi ,&nbsp;Russel J. Reiter ,&nbsp;Jie Lin ,&nbsp;Yingmei Zhang ,&nbsp;Dandan Hu ,&nbsp;Jun Ren ,&nbsp;Kaishou Xu","doi":"10.1016/j.lfs.2025.123591","DOIUrl":"10.1016/j.lfs.2025.123591","url":null,"abstract":"<div><div>ER stress evokes various types of cell death and myocardial dysfunction. This study aimed to discern the involvement of ferroptosis in chronic Akt activation-offered benefit, if any, against ER stress-triggered cardiac remodeling and contractile anomalies. Cardiac-selective expression of active mutant of Akt (AktOE) and wild-type (WT) mice were challenged with the ER stress instigator tunicamycin (1 mg/kg, 48 h) prior to assessment of cardiac morphology and function. Tunicamycin insult prompted cardiac remodeling (interstitial fibrosis), deranged echocardiographic (higher LVESD, dropped ejection fraction and fractional shortening), cardiomyocyte mechanical and intracellular Ca²⁺ features alongside mitochondrial injury (collapsed mitochondrial membrane potential and ultrastructural change), oxidative stress, compromised Akt-GSK3β signaling, ER stress (upregulated GRP78 and <em>Gadd</em>153), carbonyl formation, apoptosis and ferroptosis (decreased GPX4, SLC7A11). Intriguingly, tunicamycin-evoked anomalies (except GRP78 and Gadd153) were abrogated by Akt activation. Chronic Akt activation negated tunicamycin-induced downregulation of ferric flavin enzyme dihydroorotate dehydrogenase (DHODH), which catalyzes the fourth step of pyrimidine <em>ab initio</em> biosynthesis, and conversion of dihydroorotic acid to orotate. ER stress-induced myocardial anomalies were reversed by the newly identified PI3K activator triptolide, DHODH activator menaquinone-4 and pyrimidine booster coenzyme Q. <em>In vitro</em> experiment revealed that Akt activation- or triptolide-evoked beneficial responses against tunicamycin-induced cardiomyocyte anomalies were cancelled off by DHODH inhibitor BAY2402234 or ferroptosis inducer erastin. These findings support that chronic Akt activation rescues ER stress-evoked myocardial derangements through DHODH-dependent control of ferroptosis and mitochondrial homeostasis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123591"},"PeriodicalIF":5.2,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Different GJA8 missense variants reveal distinct pathogenic mechanisms in congenital cataract","authors":"Zexuan Li ,&nbsp;Xinyue Deng ,&nbsp;Yanna Cao ,&nbsp;Hongbo Xu ,&nbsp;Jiangang Wang ,&nbsp;Lamei Yuan ,&nbsp;Hao Deng","doi":"10.1016/j.lfs.2025.123596","DOIUrl":"10.1016/j.lfs.2025.123596","url":null,"abstract":"<div><h3>Aim</h3><div>Congenital cataract, a lenticular opacity diagnosed at birth or early in the postnatal period, often causes visual impairment. The pathogenic mechanisms of various cataract-associated variants are complex and diverse, and current knowledge is insufficient. This study aimed to determine the molecular etiology of congenital nuclear cataract in a Han-Chinese family and to reveal the pathogenic mechanisms of common cataract-associated variants with unclear mechanisms.</div></div><div><h3>Methods</h3><div>Genetic analysis including whole exome sequencing and bioinformatics analysis were conducted in the family. Functional analysis was performed to elucidate the changes in protein cellular distribution, degradation, and function induced by the variants.</div></div><div><h3>Results</h3><div>A heterozygous c.773C&gt;T transition (p.S258F) in the gap junction protein alpha 8 gene (<em>GJA8</em>), encoding connexin 50 (Cx50), was identified in a family with congenital nuclear cataract. Functional analysis of this variant and two other <em>GJA8</em> variants with unclear pathogenic mechanisms showed that the Cx50V44M mutant correctly trafficked to the plasma membrane, whereas the Cx50R76C mutant and Cx50S258F mutant exhibited trafficking defects resulting from delayed degradation and accelerated degradation, respectively. All three mutants exhibited increased autophagic activity, while only the Cx50V44M mutant and Cx50S258F mutant underwent autophagy-mediated Cx50 degradation. All mutants failed to form functional hemichannels and gap junction channels.</div></div><div><h3>Significance</h3><div>This study identified a heterozygous <em>GJA8</em> missense variant c.773C&gt;T (p.S258F) responsible for congenital nuclear cataract, and revealed three distinct pathogenic mechanisms of three cataract-associated <em>GJA8</em> variants, particularly emphasizing dysregulated autophagy involving in aberrant Cx50 degradation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123596"},"PeriodicalIF":5.2,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity","authors":"Neha Saroj ,&nbsp;Pankaj Singh Dholaniya ,&nbsp;Syed Baseeruddin Alvi ,&nbsp;Divya Sridharan ,&nbsp;Navisha Soni ,&nbsp;Syed Abdullah Ashraf ,&nbsp;Ayza Choudhry ,&nbsp;Yusuf Ali Ashraf ,&nbsp;Sarah Kathleen Mikula ,&nbsp;Dinender Kumar Singla ,&nbsp;Mahmood Khan","doi":"10.1016/j.lfs.2025.123595","DOIUrl":"10.1016/j.lfs.2025.123595","url":null,"abstract":"<div><h3>Aims</h3><div>Doxorubicin (Dox) is a potent chemotherapeutic agent, but its use is limited by cardiotoxicity, primarily due to the disruption of Topoisomerase-2 beta (TOP2B) activity. Dexrazoxane (Dex), an FDA-approved cardioprotective drug, alleviates Dox-induced toxicity but lacks heart-specific targeting. This study investigates siRNA-mediated TOP2B knockdown as a more targeted strategy to protect cardiomyocytes from Dox-induced damage.</div></div><div><h3>Materials and methods</h3><div>Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with siRNA to knock down TOP2B and were then exposed to Dox. We compared the cardioprotective effects of siRNA-mediated knockdown to Dex treatment using cell viability, cell toxicity assay and electrophysiological evaluation was performed using a multielectrode array (MEA).</div></div><div><h3>Key findings</h3><div>Our results demonstrate that TOP2B silencing significantly decreases apoptosis and improved cell viability, as compared to the Dex treatment. Additionally, electrophysiological assays using a Multielectrode Array (MEA) demonstrated enhanced contractility and conductivity in siRNA-treated hiPSC-CMs. Furthermore, transmission electron microscopy (TEM) data revealed that TOP2B knockdown preserves mitochondrial morphology and sarcomere structure, compared to Dox and Dex-treated groups.</div></div><div><h3>Significance</h3><div>These findings suggest that siRNA-mediated TOP2B inhibition could provide a safer, more specific approach to mitigate Dox-induced cardiotoxicity.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123595"},"PeriodicalIF":5.2,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}