Cellular and Molecular Life Sciences最新文献

{"title":"Temporal and protein-specific S-palmitoylation supports synaptic and neural network plasticity.","authors":"Agata Pytyś, Rabia Ijaz, Anna Buszka, Jacek Miłek, Izabela Figiel, Patrycja Wardaszka-Pianka, Matylda Roszkowska, Natalia Mierzwa, Adam Wojtas, Eli Kerstein, Remigiusz Serwa, Katarzyna Kalita, Rhonda Dzakpasu, Magdalena Dziembowska, Jakub Włodarczyk, Tomasz Wójtowicz","doi":"10.1007/s00018-025-05893-5","DOIUrl":"10.1007/s00018-025-05893-5","url":null,"abstract":"<p><strong>Background: </strong>Synaptic plasticity, a fundamental process underlying learning and memory, depends on activity-driven changes in neural connectivity. S-palmitoylation, a reversible post-translational lipid modification, modulates synaptic protein function by influencing protein conformation, localization, trafficking, and molecular interactions. Despite its known significance in neuronal function, the temporal and protein-specific dynamics of S-palmitoylation during synaptic plasticity remain poorly understood.</p><p><strong>Methodology & principal findings: </strong>Using electrophysiological methods, molecular biology, proteomics, and imaging across various models (neuronal cultures, hippocampal slices, and synaptoneurosomes), we investigated S-palmitoylation during synaptic activity. Induction of long-term potentiation (LTP) resulted in protein-specific palmitoylation changes without altering global levels. In hippocampal slices, synaptophysin and PSD95 displayed distinct temporal patterns of palmitoylation, influenced by LTP. Deacylation experiments using N-(tert-butyl)hydroxylamine (NtBuHA) demonstrated that protein S-palmitoylation is crucial for organizing neuronal spiking and enabling LTP, particularly in the stratum radiatum. Mass spectrometry of synaptoneurosomes revealed a palmitoylome including over 700 proteins, with stimulation-induced predominant depalmitoylation. Differentially palmitoylated proteins were associated with synaptic vesicle cycling, cytoskeletal dynamics, and neurotransmitter release. What is interesting is that synaptoneurosomes contained active palmitoylation machinery, supporting rapid, target-specific responses to NMDA receptor activation.</p><p><strong>Conclusions: </strong>Temporal and protein-specific S-palmitoylation emerges as a vital mechanism for synaptic plasticity, contributing to neuronal network function and memory formation. These findings elucidate how palmitoylation acts as a dynamic regulator of synaptic activity and offer insights into its regulation. The study highlights the potential of targeting palmitoylation pathways for enhancing neuronal function.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"355"},"PeriodicalIF":6.2,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273969","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":"Enhancing anti-tumor immunity by targeting BATF and the STAT1/PD-L1 pathway in cervical carcinoma.","authors":"Xing Peng, Yuanyuan Zhu, Yaqing Han, Chunyan Cai","doi":"10.1007/s00018-025-05792-9","DOIUrl":"10.1007/s00018-025-05792-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cervical carcinoma remains a leading cause of cancer-related mortality in women worldwide, with poor prognosis often linked to immune evasion mechanisms. The Basic Leucine Zipper Activating Transcription Factor (BATF) has emerged as a critical regulator of T-cell functionality, yet its role in cervical cancer progression and immune modulation remains poorly understood. This study investigates the role of BATF in cervical carcinoma, focusing on its effects on tumor progression, immune modulation, and immune checkpoint regulation, to identify BATF as a therapeutic target to enhance anti-tumor immunity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;BATF expression was analyzed in cervical cancer tissues and cell lines. Functional assays, including cell proliferation, migration, and invasion, were performed following BATF knockdown. In vivo studies assessed tumor growth and metastasis in xenograft models. Immune cell populations, cytokine production, and immune checkpoint expression were analyzed using flow cytometry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and immunohistochemistry. Mechanistic studies evaluated BATF regulation of programmed cell death-ligand 1 (PD-L1) through the signal transducer and activator of transcription 1 (STAT1) signaling pathway. Finally, the therapeutic potential of BATF knockdown in combination with PD-L1 blockade was evaluated in vivo.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Analysis of patient-derived samples and cell lines revealed that BATF is overexpressed in cervical cancer and correlates with poor prognosis. Functional studies demonstrated that BATF promotes tumor proliferation, epithelial-to-mesenchymal transition (EMT), migration, and invasion. In vivo, BATF knockdown significantly suppressed tumor growth and metastasis in xenograft models. Immune profiling revealed that BATF deficiency enhanced antitumor immunity by increasing CD8⁺ and CD4⁺ T-cell infiltration, increasing the production of CD8⁺ cytotoxic molecules such as granzyme B and IFN-γ while reducing tumor-associated macrophages and immune checkpoint expression, including Programmed death 1 (PD-1), T cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and Lymphocyte activation gene-3 (LAG-3.) Mechanistically, BATF regulated PD-L1 expression via the STAT1 signaling pathway, promoting immune evasion. Combination therapy with BATF knockdown and anti-PD-L1 antibodies significantly enhanced anti-tumor immunity and inhibited tumor growth compared to monotherapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;BATF plays a pivotal role in cervical cancer progression and immune evasion by regulating the STAT1/PD-L1 axis and modulating the tumor immune microenvironment. Targeting BATF, alone or in combination with immune checkpoint inhibitors (PD-L1), represents a promising therapeutic strategy to improve outcomes in cervical cancer patients. Further research is warranted to translate these findings into clinical applications.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"353"},"PeriodicalIF":6.2,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273978","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":"Cell therapy for Duchenne muscular dystrophy: promises, challenges, and controversies.","authors":"Agnieszka Łoboda, Józef Dulak","doi":"10.1007/s00018-025-05904-5","DOIUrl":"10.1007/s00018-025-05904-5","url":null,"abstract":"<p><p>Despite extensive studies, Duchenne muscular dystrophy, a neuromuscular disorder caused by the lack of dystrophin, a key muscle structural protein, remains an incurable disease. One of the potential treatment options currently being investigated is cell therapy, although it has not yet been clinically established. Several strategies, including muscle satellite cells, mesoangioblasts (vessel-associated multipotent stem cells), and induced pluripotent stem cell (iPSC)-derived muscle cells, have emerged as tools for restoring dystrophin expression and regenerating damaged muscle tissue. Nevertheless, each of these approaches faces significant limitations, including poor cell engraftment, low delivery efficiency, and the risk of immune rejection. Furthermore, long-term safety, the possibility of tumorigenicity, and off-target effects must be rigorously evaluated. Importantly, the latter technology, utilizing cardiomyocytes differentiated from iPSC, holds the potential for addressing cardiomyopathy, the major cause of death of DMD patients. At the same time, several interventions using cells with claimed stem cell potential have emerged, raising both scientific and ethical concerns. This review summarizes recent advancements in the development of cell therapies for DMD, highlighting promising progress while critically analysing questionable approaches.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"356"},"PeriodicalIF":6.2,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273816","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":"Microbial dysbiosis in oral cavity determines obesity status in adolescents.","authors":"Md Zubbair Malik, Rasheeba Nizam, Sindhu Jacob, Hend Al Alqaderi, Fahd Al-Mulla, Hend Alqaderi","doi":"10.1007/s00018-025-05889-1","DOIUrl":"10.1007/s00018-025-05889-1","url":null,"abstract":"<p><p>The prevalence of obesity is rapidly increasing among adolescents in Kuwait. The ecological and dynamic changes within the oral microbiota during this developmental stage remain elusive. This study aimed to investigate the impact of body mass index (BMI) on salivary microbiome diversity and composition in Kuwaiti adolescents by utilizing next-generation sequencing technologies. DNA was extracted from saliva samples of 62 Kuwaiti adolescents enrolled in the nationwide Kuwait Healthy Lifestyle Study, categorized as underweight, normal weight, overweight, and obese based on their BMI percentiles. The 16 S metagenomic profiling was performed to identify the key oral lineages and genera associated with obesity through comprehensive analysis involving taxonomic composition, co-occurrence networks, and key metabolic profiles. Our study reveals an inverse relationship between oral bacterial diversity and obesity status in Kuwaiti adolescents. The obese and overweight groups showed comparatively low microbial taxa compared to those of normal weight. We identified three potential microbial biomarkers linked to obesity and overweight: Prevotella melaninogenica, Veillonella dispar, and Veillonella parvula. The abundance of Neisseria subflava and Rothia mucilaginosa in normal weight adolescents indicates their role in weight homeostasis. In- silico analysis of differentially expressed microbiota revealed increased activity of major metabolic enzymes such as glucose- 6- phosphate dehydrogenase, pyruvate oxidase, and glycogen phosphorylase, along with oxidative stress- related enzymes including superoxide reductase and glutathione peroxidase in obese and over-weight adolescents. Conversely, normal weight adolescents exhibited heightened activity of pyruvate synthase and tRNA- methyltransferase, which are linked to antioxidative pathways and balanced energy metabolism. Our study highlights taxonomic and functional shifts in the oral microbiota of Kuwaiti adolescents across varying BMI categories, signifying key microbial markers that could pave the way for future research focused on microbiome- targeted interventions in obesity management.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"354"},"PeriodicalIF":6.2,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273909","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":"miRNA-130b-3p upregulation impairs osteogenic differentiation in AIS patients by inhibiting the IGF1/ERK pathway.","authors":"Gang Xiang, Jiang Xie, Yunjia Wang, Zhongjing Jiang, Sihan He, Jiong Li, Hongqi Zhang","doi":"10.1007/s00018-025-05885-5","DOIUrl":"10.1007/s00018-025-05885-5","url":null,"abstract":"<p><p>Adolescents with idiopathic scoliosis (AIS) often exhibit a slender body shape and reduced bone mass, even in the absence of evident vertebral deformities. Although prior studies have implicated microRNAs (miRNAs) in the development and progression of AIS, the precise mechanisms remain poorly understood. Therefore, primary osteoblasts and plasma samples from AIS patients and controls were isolated and associated mechanism was investigated in this study. We observed impaired osteogenic capacity of AIS-osteoblasts, and further identified a significant elevation of miRNA-130b-3p in AIS patients compared to controls through RNA sequencing of plasma samples. The expression levels of miR-130b-3p were validated in an independent cohort of 40 individuals using qPCR. Dual-energy X-ray absorptiometry showed reduced bone mineral density (BMD) in AIS patients. And the correlation analysis revealed a significant negative relationship between miR-130b-3p levels and BMD. Additionally, transcriptomic analysis and dual-luciferase assays confirmed that overexpression of miR-130b-3p in primary osteoblasts inhibited the activation of the ERK1/2 signaling pathway by targeting IGF1, thereby disrupting bone metabolism. Meanwhile, knockdown of miR-130b-3p in AIS-derived osteoblasts improved osteogenic function. In zebrafish, miR-130b-3p overexpression delayed vertebral development and induced spinal deformities. In summary, this study identifies a significant increase of miR-130b-3p in AIS patients and demonstrates its role in impairing osteogenic function through suppression of the IGF1/ERK signaling pathway.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"350"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238358","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":"Mechanistic insights into miR-584-5p-mediated Inhibition of PDLSCs osteogenic differentiation through H2AFZ upregulation and RUNX2 suppression.","authors":"Chengze Wang, Xiaoyan Miao, Yongzheng Li, Lingfei Ren, Bo Zheng, Zhiwei Jiang, Ying Wang, Guoli Yang","doi":"10.1007/s00018-025-05887-3","DOIUrl":"10.1007/s00018-025-05887-3","url":null,"abstract":"<p><p>Periodontal ligament stem cells (PDLSCs) hold promise for bone regeneration, but their osteogenic differentiation is tightly regulated by various molecular mechanisms. MicroRNAs are key regulators of this process, and miR-584-5p has been identified as a potential modulator of osteogenesis. In this study, we investigated the role of miR-584-5p in the osteogenic differentiation of PDLSCs. Our findings show that overexpression of miR-584-5p inhibits osteogenic differentiation in vitro, as evidenced by reduced alkaline phosphatase activity, diminished mineralized nodule formation, and decreased expression of osteogenic markers, including ALPL, SP7, and RUNX2. In animal models, suppression of miR-584-5p enhances bone formation in both ectopic bone formation and rat calvarial defect models. Mechanistically, we demonstrate that miR-584-5p upregulates the histone variant H2AFZ, leading to its increased nuclear localization and binding to osteogenic gene promoters, including ALPL, SP7, and RUNX2, thereby repressing their expression. Furthermore, miR-584-5p directly targets RUNX2 mRNA, further suppressing its expression. Rescue experiments confirmed that knockdown of H2AFZ or overexpression of RUNX2 mitigates the suppressive effects of miR-584-5p on osteogenesis. Our study reveals that miR-584-5p inhibits osteogenic differentiation of PDLSCs through dual mechanisms: H2AFZ upregulation and RUNX2 suppression, offering novel insights into the epigenetic regulation of bone formation and potential therapeutic strategies for bone regeneration.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"351"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238322","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":"The E3 ubiquitin ligase MARCH9 alleviates pyroptosis by regulating NLPR3 ubiquitination following myocardial ischemia reperfusion.","authors":"Hongquan Lu, Gang Ma, Cong Ding, Ping Wang, Qiuyue Ruan, Yun Zeng, Lingkun Ma, Min Lu, Yilin Li, Wenjing Sun","doi":"10.1007/s00018-025-05861-z","DOIUrl":"10.1007/s00018-025-05861-z","url":null,"abstract":"<p><p>NLRP3, a member of the NOD-like receptor family, mediates pyroptosis via inflammasome activation, contributing significantly to myocardial ischemia-reperfusion (MI/R) injury. However, the molecular mechanisms remain unclear. This study aimed to elucidate the mechanisms underlying NLRP3 inflammasome activation and its role in pyroptotic myocyte death following MI/R injury, with a particular focus on the effects of MARCH9, an E3 ubiquitin ligase that encodes a RING finger domain. In our in vivo experiments, we established an MI/R injury model by ligating the anterior descending branch of the coronary artery in mice. Cardiac tissues were analyzed using various methods, including proteomic analysis, TTC and Evan's blue dual-dye staining, immunohistochemical staining (F4/80, CD11b and Ly6G), and immunofluorescent staining (GSDMD-N). Western blotting was also performed to assess the expression of key pyroptosis-related proteins, such as MARCH9, NLRP3, caspase-1, GSDMD-N, and AIM2. In vitro studies in H9C2 and HEK293 cell lines involved western blotting, co-immunoprecipitation, and immunofluorescent staining to examine protein interactions and functional domains. Our findings reveal that MARCH9 plays a key regulatory role in NLRP3 inflammasome activation and pyroptosis during MI/R injury. MARCH9 was identified as an E3 ubiquitin ligase that interacts with NLRP3, promoting its K48-linked polyubiquitination and subsequent proteasomal degradation. This process inhibits NLRP3 activation, thereby mitigating pyroptosis and reducing myocardial injury. In conclusion, MARCH9 suppresses pyroptosis by modulating NLRP3 ubiquitination in response to MI/R injury, highlighting its potential as a novel cardioprotective target for therapeutic intervention.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"348"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238406","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":"Reduced ALDH1A1 expression in multiple myeloma cells increases resistance to daratumumab via downregulation of retinoic acid.","authors":"Sujie Zheng, Jing He, Xiaolu Song, Ye Peng, Wufeng Yuan, Xiangmin Tong","doi":"10.1007/s00018-025-05891-7","DOIUrl":"10.1007/s00018-025-05891-7","url":null,"abstract":"<p><p>Multiple myeloma (MM) remains challenging in relapsed/refractory cases due to resistance to therapies like the proteosome inhibitors or anti-CD38 antibody daratumumab (Dara). This study investigates the dual role of ALDH1A1, an aldehyde dehydrogenase implicated in drug resistance, especially in modulating daratumumab efficacy. Clinical samples from newly diagnosed multiple myeloma (NDMM) patients and in vitro studies demonstrated that ALDH1A1 expression increases consistently with the development of drug resistance to proteasome inhibitor-based chemotherapy. However, paradoxically, daratumumab-resistant non-responder relapsed/refractory MM (nrRRMM) patients showed lower ALDH1A1 expression compared to responder RRMM (rRRMM) patients. Mechanistically, ALDH1A1 enhanced CD38 expression by upregulating retinoic acid (RA), which activated the retinoid acid receptor (RAR) signaling pathway. Knockdown of ALDH1A1 in MM cell lines (H929, RPMI 8226) reduced CD38 levels, impaired daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC), and suppressed NK (natural killer) cell activity (perforin/granzyme B secretion). In contrast, RA supplement reversed declined CD38 expression caused by knocking down ALDH1A1, thereby restoring antibody-dependent cellular cytotoxicity (ADCC) efficacy. In vivo, ALDH1A1 inhibition diminished daratumumab's antitumor effects in xenograft models, while RA co-administration reversed this resistance. These findings highlight ALDH1A1 as a context-dependent regulator: promoting chemotherapy resistance but enhancing daratumumab sensitivity via RA-CD38 axis activation. This study identifies ALDH1A1 as a predictive biomarker and proposes therapeutic strategies combining RA or ALDH1A1 modulation to overcome daratumumab resistance in RRMM.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"352"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238416","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":"Ginkgolide a enhances the resistance to pathogen infection through mitochondrial unfolded protein response.","authors":"Yingwen Cui, Rujia Wang, Xie Li, Guohui Bai, Yi Xiao","doi":"10.1007/s00018-025-05869-5","DOIUrl":"10.1007/s00018-025-05869-5","url":null,"abstract":"<p><p>The normal function of mitochondria plays a key role in innate immunity. Normally, changes in the internal and external environment will lead to mitochondrial stress, and then the body will produce mitochondrial unfolded protein response (UPR^mt) to maintain mitochondrial homeostasis. Ginkgolide A (GA) is a diterpenoid isolated from Ginkgo, which has many important biological activities such as anti-inflammatory, anticancer, anxiolytic-like, anti-antherosclerosis and anti-atherombosis. However, whether GA affects innate immune responses and the underlying molecular mechanisms are still unknown. In the present study, we show that 100 µM GA enhances the resistance to Gram-negative pathogens Pseudomonas aeruginosa, Salmonella enterica and Gram-positive pathogens Staphylococcus aureus, Enterococcus faecalis in Caenorhabditis elegans by clearance intestinal bacterial loads. We also find that GA enhances innate immunity through a homeodomain transcriptional regulator DVE-1, which activates the UPR^mt. Because DVE-1 encodes a homeodomain transcription regulator that is homologous to the mammalian SATB2 transcription factor. Furthermore, we demonstrate that this function was conserved, because GA also manifested protective function in lung epithelial cell and mice during P. aeruginosa infection via the homeodomain transcription factor SATB2. Hence, our research suggests that GA has the potential therapeutic compound to protect patients from pathogen infection.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"349"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238302","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":"Altered venous flow drives endothelial to mesenchymal transition in varicose veins by suppressing PIEZO1-KLF2 signaling.","authors":"S Ahalya, C L Karthika, B J Sreelakshmi, S R Kalpana, S Sumi","doi":"10.1007/s00018-025-05854-y","DOIUrl":"10.1007/s00018-025-05854-y","url":null,"abstract":"<p><p>Varicose veins are characterized by disturbed hemodynamics due to blood reflux. We previously identified altered flow-driven endothelial-to-mesenchymal transition (EndMT) in varicose veins. Mechanosensors such as Piezo1 provide a molecular bridge between hemodynamic forces and cellular mechanoregulation in vasculature. We hence hypothesized that depletion of blood flow-sensing Piezo1 channels induces EndMT process during venous remodeling. Here, we analyzed 20 human varicose veins and 22 healthy saphenous veins for a comprehensive view of Piezo1 expression using qRT-PCR, western blot and immunohistostaining techniques. Our study reveals a significant loss of Piezo1 expression in varicose veins at both mRNA and protein levels. Our in vitro experiments using microfluidic flow channels showed that Piezo1 expression and calcium influx function are drastically affected in endothelial cells (ECs) exposed to oscillatory venous shear stress. Piezo1 depletion reduces KLF2, which triggers the EndMT program in venous ECs. Kinase inhibitor assays indicated that Piezo1-based calcium influx promotes CAMKII autophosphorylation and induces KLF2 expression via both MEK5/ERK5 and PI3K-AKT-FOXO pathways in venous flow. Piezo1 agonist Yoda1, at low doses mimicking venous flow, augmented KLF2 expression and prevented aberrant molecular EndMT reprogramming in cells exposed to oscillatory shear stress. Yoda1 was also effective in restoring calcium influx and stimulating angiogenesis by promoting endothelial tube formation hindered by Piezo1 depletion. Taken together, the endothelial-protective role of Piezo1 ion channels due to uniform hemodynamic flow is coupled to KLF2, a downstream mediator in the venous circulation. The Piezo1-KLF2 pathway can be utilized for identifying targeted therapeutic options in patients with varicose veins.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"345"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238253","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}