Journal of Biomedical Science最新文献

{"title":"The ZBTB16/CUL3/ROC1 ubiquitin ligase drives the degradation of pathogenic pendrin (SLC26A4) protein variants.","authors":"Florian Huber, Emanuele Bernardinelli, Bassam G Haddad, Sophie Klaus, Lennart Weitgasser, Sebastian Roesch, Martin Jakab, Robert Konrat, Jan-Philipp Machtens, Dominique Eladari, Silvia Dossena","doi":"10.1186/s12929-026-01283-6","DOIUrl":"10.1186/s12929-026-01283-6","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic sequence alterations in the SLC26A4 gene, which encodes the solute carrier SLC26A4/pendrin, lead to Pendred syndrome and non-syndromic autosomal recessive deafness type B4 (DFNB4), two of the most common forms of hearing loss worldwide. Many pathogenic SLC26A4 protein variants exhibit reduced cellular levels due to ubiquitin-proteasome system (UPS)-mediated degradation, and UPS inhibition rescues their plasma membrane expression and ion transport function. However, the underlying molecular mechanisms remain unclear and may involve interactions with novel molecular partners.</p><p><strong>Methods: </strong>A candidate SLC26A4 protein partner was found by a yeast two-hybrid screening. The biological significance of this interaction has been studied by immunohistochemistry and co-localization in the mouse inner ear and kidney, co-immunoprecipitation of endogenous and recombinant proteins, Liquid Chromatography-Tandem Mass Spectrometry, and Fluorescence Resonance Energy Transfer.</p><p><strong>Results: </strong>We identified the zinc finger and BTB domain-containing protein ZBTB16 as a novel SLC26A4-interacting partner. ZBTB16 co-localized with SLC26A4 in the outer sulcus and spiral prominence epithelial cells of the mouse cochlea and in the apical membrane of non-alpha non-beta intercalated cells of the distal nephron. ZBTB16 was found to be part of a ubiquitin-ligase complex comprising the scaffold protein Cullin 3 and the ubiquitin ligase RocI, and to bind with its C-terminal zinc finger region a unique amino acid sequence within the C-terminal Sulfate Transporter and Anti-Sigma factor Antagonist (STAS) domain of SLC26A4. This direct molecular interaction leads to increased site- and variant-specific ubiquitination and accelerated degradation of SLC26A4. Finally, using AI-based structure prediction, we provide an atomistic model of the complete SLC26A4/ZBTB16/Cullin 3/RocI complex in agreement with our experimental results.</p><p><strong>Conclusion: </strong>These findings describe a primary mechanism of SLC26A4 regulation in the inner ear and kidney and of SLC26A4 loss of function in Pendred syndrome and deafness DFNB4, and identify potential novel molecular targets for therapeutic intervention.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758408","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":"Smyca-FOXM1 ribonucleoprotein complex promotes homologous recombination and tumor immune evasion to define a therapeutic target of triple-negative breast cancer.","authors":"Han-Hsiun Chen, Keng-Hao Chang, Sin-Rong Lee, Chih-Hao Chiu, Bing-Yu Yao, Tera Carissa, Shih-Duo Hsu Hung, Wen-Ling Kuo, Lily Hui-Ching Wang, Chia-Wei Li, Che-Ming Hu, Hsin-Yi Chen, Ruey-Hwa Chen","doi":"10.1186/s12929-026-01279-2","DOIUrl":"10.1186/s12929-026-01279-2","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options. Although PARP inhibitor (PARPi) offers great promise in treating TNBC with deficiency in homologous recombination (HR), most TNBC patients are HR-proficient. Furthermore, acquired resistance to PARPi remains as a challenge. Thus, there is an unmet need to identify new therapeutic target for developing advanced TNBC treatment strategy.</p><p><strong>Methods: </strong>I-SceI reporter assay and alkaline comet assay were used to analyze the role of Smyca in HR repair. Ingenuity pathway analysis was used to identify upstream regulators of Smyca-regulated transcriptome. RNA immunoprecipitation and RNA pull down were used to examine Smyca-FOXM1 interaction. Chromatin immunoprecipitation followed by sequencing was performed to identify FOXM1 target genes that are regulated by Smyca. Chromatin isolation by RNA purification was used to determine Smyca loading onto the promoters of FOXM1 target genes. Patient-derived organoid and xenograft mouse models were performed to evaluate the effect of Smyca on chemoresistance. Nanoparticle-assisted gapmer antisense oligonucleotides delivery was used to target Smyca in vivo. Co-culture of CD3 + T cells with TNBC cells and syngeneic mouse model were used to examine the effect of Smyca-FOXM1 targeting on anti-tumor immunity.</p><p><strong>Results: </strong>The long non-coding RNA Smyca is highly expressed in TNBC. We show that Smyca is induced by genotoxic agents to enhance HR repair. Mechanistically, Smyca binds FOXM1 and promotes the recruitment of FOXM1 to the promoters of a set of HR and nucleotide metabolism genes, thereby promoting their expression. Smyca ablation induces BRCAness in HR-proficient TNBC, thereby sensitizing these tumors to platinum or PARPi. Furthermore, targeting Smyca-FOXM1 complex in combination with platinum or PARPi activates cGAS/STING pathway and tumor immunogenicity to enhance anti-tumor immune surveillance. Clinically, Smyca expression in breast cancer patients correlates positively with therapy resistance and negatively with HR deficiency, interferon signature, and infiltration of anti-tumor immune cells.</p><p><strong>Conclusions: </strong>Our study identifies an unprecedented role of Smyca in HR repair to promote TNBC survival and immune evasion in response to therapy and suggests Smyca as a potential target for sensitizing TNBC to chemotherapy, PARPi, or immunotherapy.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706858","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":"A population-specific genomic reference panel for Taiwan: NHRI-RP-1.","authors":"Kuang-Huan Cheng, Yi-Rong Chen, Ren-Hua Chung, Ming-Wei Lin, Hui-Ying Weng, Yuh-Ru Lin, Yung-Feng Lin, Jacob Shujui Hsu, Ralph Kirby, Shao-Yuan Chuang, Yu-Li Liu, Shiu-Feng Kathy Huang, Wei J Chen, Chih-Cheng Hsu, Wayne Huey-Herng Sheu, Shih-Feng Tsai","doi":"10.1186/s12929-026-01261-y","DOIUrl":"10.1186/s12929-026-01261-y","url":null,"abstract":"<p><strong>Background: </strong>To enhance the efficiency of identifying rare variants within the Taiwanese population and to support genome-wide association studies (GWAS) and imputation studies for genetic risk prediction in the Han population, we have developed the National Health Research Institutes (NHRI) reference panel (NHRI-RP-1).</p><p><strong>Methods: </strong>NHRI-RP-1 is based on 2,561 whole genome sequences taken from the in-house NHRI datasets. Our objective was to optimize conditions of sample sizes (0.5K, 1K, 1.5K, 2K, 2.5K), minor allele frequency (MAF) thresholds (MAF ≥ 0.05, 0.01, 0.001, 2 × 10^-4), and imputation quality (r² ≥ 0, 0.3, 0.5) to build an aggregated genome reference panel for genetic medicine by comparing with worldwide references. Clinical applications and GWAS were then evaluated to demonstrate the capability of the reference panel.</p><p><strong>Results: </strong>Among different combinations of relevant parameters, the NHRI-RP-1 (with a 2,500-sample size, MAF ≥ 2 × 10^-4, r² ≥ 0) demonstrated a superior F1 score on local match, genotype concordance and r-squared, as compared to those using worldwide reference genomes, particularly for rare MAFs. Furthermore, NHRI-RP-1 achieved over 95% accuracy for nine pathogenic variants present in the Taiwan Biobank and 93.49% and 92.9% accuracy for imputing two DRD1 variants.</p><p><strong>Conclusions: </strong>The use of different reference panels can influence the outcomes of GWAS. Our case studies demonstrate the utility of the NHRI-RP-1 for genetic medicine. Incorporating a population-specific panel such as NHRI-RP-1 can facilitate the development of prediction models using polygenic risk scores for diseases that are common in the Han population.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706861","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":"The current landscape of mRNA therapy and the strategies for mRNA purification and dsRNA removal.","authors":"Jin-He Liu, Jian Zang, Jing-Ru Xu, Xue-Bin Ran, Min Su, Wang-Ming Zhang, Zhang-Wen Ge, Qiao-Yang Sun, Ling-Wen Ding","doi":"10.1186/s12929-026-01277-4","DOIUrl":"10.1186/s12929-026-01277-4","url":null,"abstract":"<p><p>Messenger RNA (mRNA) technology has emerged as a cornerstone in vaccine development and therapeutic applications, offering key benefits such as high potency, rapid scalability, and cost-effectiveness. The success of COVID-19 mRNA vaccines has underscored their efficacy and safety. However, residual byproducts generated during mRNA synthesis, such as unincorporated caps, nucleoside triphosphates (NTPs), DNA templates, enzymes, abortive transcripts, and double-stranded RNA (dsRNA), pose significant challenges to the clinical application of the RNA therapy. Among these, dsRNA is particularly problematic as it can activate various innate immune responses, suppress mRNA translation and potentially compromise the therapeutic efficacy of mRNA. Therefore, effectively removing dsRNA from in vitro synthesized mRNA is essential before its used in preclinical or clinical settings. In this review article, we provide a comprehensive overview of current mRNA development pipelines and ongoing clinical trials, and recent advances in mRNA purification techniques. Specifically, we focus on strategies for dsRNA removal, which can be broadly categorized into two approaches: (1) separating or removing dsRNA from in vitro transcription (IVT) mRNA products using methods such as RP-HPLC chromatography and cellulose-based purification; and (2) minimizing dsRNA formation during IVT by employing engineered RNA polymerase mutants, chaotropic agents, and magnetic beads, as well as modifying/optimizing DNA templates or RNA molecules to reduce dsRNA generation. We also discuss the advantages and limitations of these purification methods, the factors influencing the selection of purification strategies, and explore potential future directions for improving dsRNA purification technologies and their applications in mRNA-based therapeutics.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148603472","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":"Correction: Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer.","authors":"Chun-Chia Cheng, Siao-Syun Guan, Hao-Jhih Yang, Chun-Chao Chang, Tsai-Yueh Luo, Jungshan Chang, Ai-Sheng Ho","doi":"10.1186/s12929-025-01175-1","DOIUrl":"10.1186/s12929-025-01175-1","url":null,"abstract":"","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148603474","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":"Hidden asymptomatic breakthrough infection in a proof-of-concept longitudinal study on SARS-CoV-2 vaccine recipients.","authors":"Chiaho Shih, You-Zhen Liao, Che-Yu Hsu, Ying-Chen Tsai, Ming-Yen Lin, Hsin-Ying Clair Chiou, Wen-Hui Kuan, Chih-Hsu Chang, An-Ting Liou, Yu-Chi Chou, Jih-Jin Tsai, Ping-Chang Lin, Ming-Lung Yu, Wan-Long Chuang, Jia-Jung Lee, Jer-Ming Chang, Shang-Jyh Hwang, Justin Shih, Wen-Chun Hung, Ming-Feng Hou, Inn-Wen Chong, Yuh-Jyh Jong, Jung-San Chang","doi":"10.1186/s12929-026-01276-5","DOIUrl":"10.1186/s12929-026-01276-5","url":null,"abstract":"<p><strong>Background: </strong>Individuals with asymptomatic SARS-CoV-2 infection can unknowingly transmit the virus, yet identifying such subclinical infections in post-vaccinated populations remains challenging.</p><p><strong>Methods: </strong>We conducted a longitudinal study of 129 infection-naïve vaccine recipients immunized with various combinations of SARS-CoV-2 spike (S) protein vaccine platforms. Sera were collected before the first dose (v1), at 2 weeks (v7) and 6 months (v8) after the third dose. Taiwan's first major COVID-19 outbreak occurred between v7 and v8. We measured anti-nucleocapsid (anti-N) and anti-S IgG antibody titers by ELISA and assessed virus-neutralizing activity using live virus and pseudovirus assays.</p><p><strong>Results: </strong>By developing an iterative serial screening method, we identified asymptomatic breakthrough (post-vaccination) infections among unconfirmed cases. Our v7-v8 paired cohort resolved into three distinct groups: confirmed cases (21%), asymptomatic breakthrough infections (17%), and uninfected subjects (62%). In normalized v8 sera, confirmed cases exhibited an anti-S⁺⁺⁺ (high) /anti-N⁺⁺⁺ (high) phenotype, while uninfected subjects showed an anti-S⁺ (low)/anti-N⁺(baseline) phenotype. Statistical analysis validated a distinct asymptomatic group characterized by an antibody profile anti-S⁺⁺ (intermediate) /anti-N⁺ (baseline).</p><p><strong>Conclusions: </strong>This approach may enable more accurate estimates of vaccine efficacy and infection prevalence. In a spike-vaccinated population, anti-N antibody is more a potential specific marker for COVID-19 symptomatic disease than an ideal marker for SARS-CoV-2 infection. To our knowledge, this is the first preliminary report of identification of asymptomatic breakthrough infection from a well-vaccinated population using self-matched longitudinal pairs of serum samples.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562058","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":"MPT0E028, a pan-HDAC inhibitor, ameliorates bleomycin-induced pulmonary fibrosis by promoting AT2-to-AT1 differentiation through the ATM/AMPK/FoxO1 pathway.","authors":"Chia-Hao Liu, Hong-Sheng Lee, Jing-Ping Liou, Wun-Hao Cheng, Hung-Sheng Hua, Bing-Chang Chen, Chien-Huang Lin","doi":"10.1186/s12929-026-01281-8","DOIUrl":"10.1186/s12929-026-01281-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Persistent injury and impaired regeneration of the alveolar epithelium are key contributors to the pathogenesis of pulmonary fibrosis. In idiopathic pulmonary fibrosis (IPF), type 2 alveolar epithelial (AT2) cells fail to fully differentiate into type 1 alveolar epithelial (AT1) cells, remaining instead in a transitional state. Histone deacetylase (HDAC) inhibitors are promising therapeutic agents for pulmonary fibrosis. Therefore, this study investigated whether MPT0E028, a pan-HDAC inhibitor, ameliorated bleomycin (BLM)-induced pulmonary fibrosis in a therapeutic model of mice by promoting AT2-to-AT1 cell differentiation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The effects of MPT0E028 on pulmonary fibrosis were assessed by evaluating the expression of fibrogenic proteins and cell markers of AT1 (T1α and aquaporin 5 [AQP5]), AT2 (surfactant protein C [SPC]) and alveolar epithelial transitional cells (Keratin 8 [KRT8]) in a therapeutic model of BLM-induced pulmonary fibrosis in mice. The role of the ataxia-telangiectasia mutated (ATM)/AMP-activated protein kinase (AMPK)/forkhead box O1 (FoxO1) signaling pathway in MPT0E028-induced T1α expression was examined in murine AT2 cells (MLE-12 cells).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Administration of MPT0E028 significantly reduced fibrosis scores; suppressed the expression of connective tissue growth factor, collagen I, fibronectin, and α-smooth muscle actin; and improved lung function in the therapeutic model of BLM-induced pulmonary fibrosis in mice. MPT0E028 enhanced the expression of T1α and AQP5 but reduced the expression of SPC and KRT8 in lung tissues from BLM-treated mice. In MLE-12 cells and primary human AT2 cells, MPT0E028 upregulated T1α and AQP5 expression in a time-dependent manner, with this accompanied by a decrease in SPC expression. AS1842856, an FoxO1 inhibitor, and FoxO1 siRNA transfection inhibited MPT0E028-stimulated T1α expression, whereas transfection with FoxO3 siRNA had no effect. FoxO1 siRNA transfection also inhibited MPT0E028-stimulated T1α-luciferase activity. MPT0E028 induced FoxO1 serine phosphorylation, increased FoxO1 recruitment to the T1α promoter, and enhanced FoxO1-luciferase activity. Compound C, an AMPK inhibitor, and AMPK siRNA transfection suppressed MPT0E028-stimulated T1α expression, and compound C also inhibited MPT0E028-promoted FoxO1 recruitment to the T1α promoter. MPT0E028 induced AMPK phosphorylation in a time-dependent manner and increased ATM acetylation and phosphorylation in MLE-12 cells. ATM siRNA transfection suppressed MPT0E028-induced T1α expression, AMPK and FoxO1 serine phosphorylation, FoxO1 recruitment to the T1α promoter, and FoxO1-luciferase activity. MPT0E028 induced FoxO1 phosphorylation in AT2 cells in the therapeutic model of BLM-induced pulmonary fibrosis in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;MPT0E028 is the first pan-HDAC inhibitor shown to activate ATM acetylation-mediated AMPK/FoxO1 signaling to induce ","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549222","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":"Emetine dihydrochloride inhibits Chikungunya virus nsP2 helicase and shows robust antiviral activity in cells and mice.","authors":"Anshula Sharma, Chandru Subramani, K A Shouri, Ghanshyam Sharma, Brohmomoy Basu, Abhay Deep Pandey, Archana Rout, Devendra Sharma, Deepti Jain, Sudhanshu Vrati","doi":"10.1186/s12929-026-01280-9","DOIUrl":"10.1186/s12929-026-01280-9","url":null,"abstract":"<p><strong>Background: </strong>Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes frequent global epidemics of chikungunya fever, characterized by severe joint pain and debilitating arthritis. With no specific antiviral therapies available, these outbreaks pose a major public health challenge, particularly in tropical regions. There is thus urgent need to develop novel antivirals. Drug repurposing is an attractive strategy to identify potential antivirals targeting CHIKV replication.</p><p><strong>Methods: </strong>The Spectrum collection of approved drugs was screened using high-content cell imaging to identify potential CHIKV replication inhibitors. Efficacy of these CHIKV inhibitors was evaluated in a C57BL/6 mouse model of chikungunya disease, monitoring viremia and clinical symptoms like joint swelling. The CHIKV inhibitor's effect on virus uptake, replication, RNA synthesis, and protein production was studied in ERMS cells. In silico molecular docking was used to study the inhibitor's binding to the CHIKV proteins. Binding was validated in vitro using microscale thermophoresis and isothermal titration calorimetry. CHIKV helicase, protease, and ATPase activities were measured in the presence of emetine dihydrochloride (ED) to determine its mechanism of action.</p><p><strong>Results: </strong>Out of the four CHIKV inhibitors identified by high content screening, ED potently inhibited CHIKV replication in the mouse model, yielding significantly lower viremia levels. Notably, CHIKV-infected mice treated with ED showed no clinical symptoms of joint swelling. In ERMS cells, ED blocked CHIKV uptake and early replication by suppressing viral RNA synthesis, which in turn prevented viral protein production. Computational modelling predicted ED's binding around the RNA-binding site of the CHIKV nsP2 helicase domain. In vitro validation confirmed dose-dependent ED binding with CHIKV nsP2. ED specifically inhibited helicase unwinding in a concentration-dependent manner without affecting ATPase or protease activity.</p><p><strong>Conclusions: </strong>This study demonstrates that ED inhibits CHIKV replication in cultured cells and a mouse model of infection through binding to CHIKV nsP2 and inhibition of its helicase activity. While this is a promising virus-targeted mechanism of ED's antiviral action, additional host-directed mechanisms warrant further investigation.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536108","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":"Photodynamic therapy mediates antitumor effects through multiple non‑apoptotic cell death pathways.","authors":"Kaili Liao, Xiaofei Lin, Hui Liang, Yi Lin, Shuai Liu, Xiwen Yan, Xinrui Liu, Minqi Zhu, Jingyi Gan, Xiya Yan, Zijia Li, Yanxin Luo, Xiaozhong Wang, Jiasheng Xu","doi":"10.1186/s12929-026-01222-5","DOIUrl":"10.1186/s12929-026-01222-5","url":null,"abstract":"<p><p>Photodynamic therapy (PDT) demonstrates remarkable versatility by activating diverse non-apoptotic cell death pathways, effectively circumventing apoptosis resistance and enhancing tumor eradication. Key mechanisms include autophagic cell death, regulated necrosis-driven immune activation, ferroptosis-mediated oxygen replenishment, pyroptosis-induced immunogenic cell death (ICD), and paraptosis. These pathways collectively highlight PDT's capacity to disrupt tumor survival mechanisms and stimulate systemic anti-tumor immunity. However, several challenges remain, including precise spatiotemporal control of ROS, hypoxia mitigation, and selective photosensitizer delivery. Advances in nanotechnology, hypoxia-responsive agents, and combination therapies (e.g., immune checkpoint inhibitors or chemotherapy) hold promise for overcoming these limitations. In this review, we discuss multiple types of non-apoptotic cell death pathways activated by PDT and the underlying mechanisms of each distinct cell death process. We also review the clinical applications and current challenges of leveraging these pathways to enhance tumor treatment in PDT. Future research should prioritize the development of subcellular-targeted photosensitizers, deeper light-penetration technologies, and biomarker-guided personalized regimens for more precise and effective PDT.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456005","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":"Arginase-2 enhances monocyte-endothelial interaction through regulation of integrin and membrane receptor expression: role in atherogenesis.","authors":"Guillaume Ajalbert, Yuejun Yao, Sophie Rohrer, Matteo Caretti, Santhoshkumar Sundaramoorthy, Anastasia Rigkou, Michael Stumpe, Xiu-Fen Ming, Duilio M Potenza, Zhihong Yang","doi":"10.1186/s12929-026-01278-3","DOIUrl":"10.1186/s12929-026-01278-3","url":null,"abstract":"<p><strong>Background: </strong>Circulating monocyte trans-endothelial migration is critical for vascular diseases. The monocyte surface proteins, i.e., integrins and membrane receptors are central in this process. Previous studies demonstrate that ablation of the mitochondrial arginase-2 (ARG2) reduces monocyte/macrophage infiltration in cardiovascular disease. We further investigate whether ARG2 regulates integrin and surface receptor levels in monocytes and facilitates trans-endothelial migration, contributing to atherogenesis.</p><p><strong>Methods: </strong>For this purpose, human THP1 cells deficient in ARG2 gene (THP1^ARG2-/-) were generated by CRISPR-U^™-mediated genome engineering. Atherosclerotic Apoe^-/-Arg2^+/+ mice and Apoe^-/-Arg2^-/- mouse models are used. Proteomic profiling, cellular/molecular biology methods, and confocal microscopy were utilized for gene or protein expression analysis.</p><p><strong>Results: </strong>As compared to the control THP1^WT cells, the THP1^ARG2-/- cells reveal decreased adhesion and trans-endothelial migratory activities towards chemoattractants in a transwell co-culture system, accompanied by lower levels of αL and α4 integrins, CD99 and PECAM1 (CD31) (surface molecules for trans-endothelial activity) and CCR2 (the chemoattractant receptor). The monocyte adhesion to endothelial cells is reduced by blocking LFA-1 (αLβ2) or VLA-4 (α4β1) integrin. Pro-inflammatory polarization of the THP1 cells with LPS does not affect the integrin and surface receptor levels, however, enhances release of several pro-inflammatory cytokines, which is reduced in THP1^ARG2-/- cells due to reduced TLR4-ERK-NF-κB signaling. Conditioned medium from the LPS-primed THP1^WT reveals higher capacity to enhance endothelial VCAM-1 and ICAM-1 levels than the THP1^ARG2-/- cells, that is partly mediated by IL-1β. Moreover, ARG2-dependent TGF-β signaling was found to selectively regulate αL expression in monocytes. Finally, as compared to Apoe^-/-Arg2^+/+ mice, the ApoE^-/-Arg2^-/- mice show significantly decreased macrophage integrin, chemoattractant receptor levels, and atherosclerosis.</p><p><strong>Conclusions: </strong>Our study identifies ARG2 as a key regulator of monocyte-mediated vascular inflammation and atherogenesis by controlling integrin, chemoattractant receptor expression, and pro-inflammatory cytokine release through TLR4-ERK-NFκB signaling, highlighting ARG2 as a potential therapeutic target for vascular and chronic inflammatory diseases.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436779","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}