Journal of Biomedical Science最新文献

{"title":"Phosphatidylinositol transfer protein-1 integrates insulin/IGF-1 and TOR signaling to negatively regulate lifespan and healthspan in Caenorhabditis elegans.","authors":"Yen-Hung Lin, Yun-Hsun Liao, Sin-Bo Liao, Tzu-Yu Lin, Muniesh Muthaiyan Shanmugam, Pei-Jia Hsu, Chang-Shi Chen, Tsiu-Ting Ching, Oliver Ingvar Wagner, Chiou-Hwa Yuh, Horng-Dar Wang","doi":"10.1186/s12929-026-01246-x","DOIUrl":"10.1186/s12929-026-01246-x","url":null,"abstract":"<p><strong>Background: </strong>Phosphatidylinositol transfer protein-1 (pitp-1) is involved in the phosphoinositide (PIP) cycle. The role of pitp-1 in promoting healthy longevity remains unknown. Our previous work showed that the PIP cycle-related genes diacylglycerol lipase-1 (dagl-1) and diacylglycerol kinase-5 (dgk-5) regulate lifespan, as overexpression of dagl-1 or knockdown of dgk-5 prolongs lifespan and enhances oxidative stress resistance through target of rapamycin (TOR) signaling. As pitp-1 is a key component of this pathway, we investigated its role in lifespan regulation and the underlying mechanisms, aiming to clarify whether it represents a critical regulator of healthy longevity and how it coordinates conserved signaling pathways to regulate aging.</p><p><strong>Methods: </strong>Caenorhabditis elegans (C. elegans) mutants, RNAi-mediated knockdown, and transgenic overexpression were applied to assess lifespan, motility, and stress resistance. Temporal and tissue-specific RNAi were applied to identify critical time window and tissue for pitp-1-mediated lifespan regulation. TOR signaling was measured by phosphorylated S6 kinase (p-S6K) and puromycin incorporation, and transcriptomic analysis identified affected pathways.</p><p><strong>Results: </strong>pitp-1 negatively regulated lifespan and healthspan in C. elegans. Genetic deletion or RNAi-mediated knockdown of pitp-1 extended lifespan, attenuated age-related motility decline, and increased oxidative stress resistance. Temporal and spatial analyses revealed that suppression of pitp-1 in neurons during early adulthood was sufficient to promote healthy longevity. Mechanistically, these beneficial effects upon pitp-1 reduction were associated with suppression of TOR signaling. Conversely, pitp-1 overexpression shortened lifespan and impaired healthspan via TOR activation. Moreover, pitp-1 was transcriptionally repressed by DAF-16 downstream of insulin/IGF-1 signaling (IIS), and contributed to IIS-mediated longevity regulation. Furthermore, pitp-1 reduction also improved organismal proteostasis, as evidenced by decreased polyglutamine (polyQ) aggregation and enhanced motility in a neuronal proteotoxicity model.</p><p><strong>Conclusions: </strong>These findings identify pitp-1 as a novel regulator of healthy aging, suggesting a role in coordinating IIS and TOR signaling and providing new insights into conserved mechanisms of longevity regulation.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147772803","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":"Structure, mechanism and clinical relevance of NRG1 fusions in cancer.","authors":"Clarisse Thiollier-Schmitt, Manon Barre, Marie Issenmann, Emeline Cros-Perrial, Michaël Duruisseaux, Lars Petter Jordheim","doi":"10.1186/s12929-026-01242-1","DOIUrl":"10.1186/s12929-026-01242-1","url":null,"abstract":"<p><p>NRG1 gene fusions have been identified in patients with various solid tumors. Such patients have aggressive tumors and respond poorly to currently available treatments. There are many gene partners described for NRG1 fusions, and the structures and roles of the chimeric proteins are not always correctly understood. Here, we gather information on 665 reported patients with a total of 115 different known gene partners, and discuss structural elements supposed to play important roles in the biology of NRG1 fusions in cancer. This gives a better understanding of the biology of NRG1 fusions, and will help in the development of new therapeutic approaches. Our methodology described in this review can also be used for the study of other genes with disease-related fusions.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13085346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699055","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":"Comparison of hybrid-and mono-pathotype Escherichia coli isolates from South Korea based on whole genome analysis and cytotoxicity assay.","authors":"Jong Hyun Shin, Min Seok Kim, Ji Young Choi, Sunju Kim, Kun Taek Park, Mi-Ran Seo, Seung-Hyun Jung, Yeun-Jun Chung, Hyeri Seok, Hae Suk Cheong, Ki-Tae Kwon, Bo Kyeung Jung, Cheol-In Kang, Doo-Ryeon Chung, Dongwoo Shin, Kwan Soo Ko","doi":"10.1186/s12929-026-01243-0","DOIUrl":"10.1186/s12929-026-01243-0","url":null,"abstract":"<p><strong>Background: </strong>Among intestinal pathogenic Escherichia coli, hybrid pathotypes carrying virulence determinants of multiple classical pathotypes have recently been identified.</p><p><strong>Methods: </strong>A total of 292 E. coli isolates were collected from human, livestock, and environmental sources in South Korea, and their whole genome sequences were determined. They were classified into pathotypes based on virulence gene profiles. We constructed a phylogenetic tree based on cgSNPs. Synteny analysis on the LEE pathogenicity island was performed, and enriched accessory gene repertoires in particular hybrid-pathotypes were identified. Bacterial virulence was measured by lactate dehydrogenase (LDH) cytotoxicity assays. Genetic factors associated with increased cytotoxicity in the LDH assay were identified using SPLASH.</p><p><strong>Results: </strong>Among 192 intestinal pathogenic E. coli isolates, 63 hybrid pathotype isolates (38 STEC/EPEC, 23 STEC/ETEC, and 2 STEC/EAEC) were identified. Two main groups of STEC/EPEC hybrid-pathotype isolates and one major STEC/ETEC group were identified. Both groups of STEC/EPEC hybrid isolates were closely associated with EPEC mono-pathotype isolates, and most STEC/ETEC hybrid groups clustered with STEC mono-pathotype isolates. Synteny analysis on the LEE pathogenicity island also showed that some STEC/EPEC hybrids might originate from EPEC genomic backbone. Based on the LDH assay, cytotoxicity was higher in STEC/ETEC, but lower in STEC/EPEC. Five gene modules (adhesion-pili, plasmid conjugation, flagella-motility, iron uptake, and T3SS) were identified to be genetic factors correlated with increased cytotoxicity in STEC/ETEC.</p><p><strong>Conclusion: </strong>High prevalence of hybrid-pathotype E coli isolates was identified. They might emerge repeatedly by independent incorporation of additional virulence factors, and genomic backbones and cytotoxicity differed according to the specific hybrid pathotype.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13072654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147673693","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":"Many but not all pathogen-associated molecular patterns aggravate neurogenic heterotopic ossification after spinal cord injury.","authors":"Selwin G Samuel, Hsu-Wen Tseng, Bastien Rival, Valérie Barbier, Kavita Bisht, Marjorie Salga, Shrutika M Mate, Whitney Fleming, François Genêt, Sébastien Banzet, Jean-Pierre Lévesque, Dorothée Girard, Kylie A Alexander","doi":"10.1186/s12929-026-01237-y","DOIUrl":"10.1186/s12929-026-01237-y","url":null,"abstract":"<p><strong>Background: </strong>Neurogenic heterotopic ossifications (NHOs) are heterotopic bones that develop in periarticular muscles after traumatic brain (TBI) and spinal cord injuries (SCI). The mechanisms leading to NHO are incompletely understood and the only effective treatment to-date remains surgical resection. We previously established that several inflammatory pathways drive NHO pathogenesis in injured muscles in a mouse model of NHO and in humans. We also demonstrated a functional association between gram-negative bacterial infections and NHO development via lipopolysaccharide (LPS), a pathogen associated molecular pattern (PAMP), which exacerbated NHO in a Toll-like receptor-4 (TLR4)-dependent manner in mice.</p><p><strong>Methods: </strong>Using our mouse model of NHO induced by SCI and muscle injury in mice, we tested the effect of a large array of purified PAMPs post-surgery to mimic fungal, viral and bacterial infections and measured NHO bone volumes by micro-computerized tomography (microCT). The effect of PAMPs was also tested in vitro on human muscle progenitors and monocyte/macrophage populations.</p><p><strong>Results: </strong>Muscle progenitors and monocyte/macrophage populations from humans and mice express numerous pattern recognition receptors. In mice, numerous PAMPs produced by bacteria, viruses and fungi exacerbated NHO formation, and the majority of these PAMPs indirectly stimulated fibro-adipogenic progenitor (FAP) calcium mineralization in vitro via macrophages. Likewise, in humans, some PAMPs, particularly those binding to TLR2, directly and indirectly increased the calcium mineralization and osteogenic differentiation of human FAPs isolated from muscles surrounding human NHO. Finally, we established that the indirect stimulation of human FAP mineralization was mediated by inflammatory cytokines IL-1 and oncostatin M secreted by monocytes in response to PAMPs. Overall, our findings suggest that numerous types of infection have the potential to exacerbate NHO development and further highlight the role of oncostatin M and IL-1 signaling pathways in NHO pathophysiology.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13067622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654158","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":"Dual suppression of stemness and redox adaptation in glioblastoma through filaggrin upregulation by an abiraterone-based HDAC inhibitor.","authors":"Hoang Yen Tran, Ram Sharma, Hong-Yi Lin, Tzu-Yi Yeh, Chih-Jie Shen, Tsung-I Hsu, Jing-Ping Liou","doi":"10.1186/s12929-026-01241-2","DOIUrl":"10.1186/s12929-026-01241-2","url":null,"abstract":"<p><strong>Background: </strong>Temozolomide (TMZ) resistance in glioblastoma (GBM) remains a critical barrier to treatment success, driven by O⁶-methylguanine-DNA methyltransferase (MGMT) overexpression, glioma stem cell (GSC) persistence, and redox adaptation.</p><p><strong>Methods: </strong>We developed cp8, a first-in-class abiraterone-based histone deacetylase (HDAC) inhibitor, to simultaneously target these resistance mechanisms. The orthotopic mouse models were used to evaluate the efficacy of cp8 compared to SAHA (vorinostat). The mouse survival period was recorded, and the tumor growth was monitored using the IVIS imaging system.</p><p><strong>Results: </strong>Cp8 demonstrated approximately tenfold greater potency than SAHA, with IC₅₀ values ≤ 3 µM against TMZ-resistant GBM cells (compared with ≥ 30 µM for SAHA). Transcriptomic analysis revealed a unique ability of cp8 to upregulate filaggrin (FLG), a structural protein whose expression correlated with improved patient survival in TCGA and CGGA datasets (p = 0.001). Functional studies showed that FLG knockdown increased GSC-associated markers (Oct4, 2.1-fold; SOX2, 1.8-fold) and enhanced TMZ resistance, whereas cp8 treatment reduced MGMT protein expression by 68% and significantly decreased glioma sphere size by 54% (p < 0.01). In orthotopic models, cp8 extended median survival to 59 days compared with 34 days for controls (p < 0.001) and 49 days for SAHA (p < 0.01), while reducing tumor volume by 72% (p < 0.001) without systemic toxicity. Mechanistically, dual inhibition of HDAC6 and CYP17A1 by cp8 disrupted redox homeostasis and stemness-associated pathways, leading to altered ROS metabolism, reduced MGMT expression, and attenuation of GSC-driven tumor growth while restoring FLG-mediated tumor suppression.</p><p><strong>Conclusion: </strong>This study establishes FLG as a novel therapeutic target in GBM and validates the suppressive efficacy of cp8 on the characteristics of TMZ resistance, highlighting the translational potential as a multitargeted therapy against TMZ-resistant GBM.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13051497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627966","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":"Protein arginine methyltransferases in cancer: mechanisms, functions, and therapeutic opportunities.","authors":"Yoonae Jeong, Yena Cho, Yong Kee Kim","doi":"10.1186/s12929-026-01240-3","DOIUrl":"10.1186/s12929-026-01240-3","url":null,"abstract":"<p><p>Protein arginine methyltransferases (PRMTs) catalyze the methylation of arginine residues on both histone and non-histone substrates, orchestrating cellular processes such as transcriptional regulation, RNA splicing, signal transduction, and DNA damage response. Because dysregulated methylation reprograms epigenetic and post-transcriptional landscapes to promote malignant transformation, aberrant PRMT activity is closely associated with tumorigenesis and cancer progression. Major family members, containing PRMT1, CARM1, PRMT5, and PRMT6, regulate gene expression through site-specific histone methylation, thereby contributing to the transcriptional activation or repression. PRMTs also methylate a wide range of non-histone proteins, including transcription factors, splicing regulators, and signaling intermediates, to coordinate cell cycle progression, DNA repair, and RNA metabolism. Collectively, PRMT-mediated methylation contributes to higher-order cancer phenotypes, including metabolic reprogramming-through modulation of glycolytic flux, lipid biosynthesis, and redox homeostasis-and immune evasion via altered immune signaling and checkpoint pathways within the tumor microenvironment. Recent advances in chemical biology have led to the development of selective PRMT inhibitors, several of which are currently under clinical evaluation. In this review, we provide a comprehensive and integrative overview of PRMT biology, systematically organizing current knowledge from multilayered regulatory mechanisms to downstream oncogenic effects and emerging therapeutic opportunities.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13047808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147609056","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":"IFI35 suppresses the transcription of hepatitis B virus cccDNA minichromosome via promoting HNF4α proteasomal degradation.","authors":"Nayeon Kim, Jae Jin Shin, Jae Won Oh, Juhee Won, Ah Ram Lee, Mehrangiz Dezhbord, Jeongwoo Park, Ki-Young Lee, Dong-Sik Kim, Kwang Pyo Kim, Kyun-Hwan Kim","doi":"10.1186/s12929-026-01239-w","DOIUrl":"10.1186/s12929-026-01239-w","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis B virus (HBV) infection is a major health problem with hundreds of millions of people still chronically infected worldwide. Although it is known that cytokines can inhibit HBV replication in infected hepatocytes, much is still unknown about the underlying mechanisms or mediators.</p><p><strong>Methods: </strong>In this study, we systematically analyzed tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) induced proteins by proteomic analysis and identified interferon-inducible protein 35 (IFI35) as a novel host restriction factor for HBV replication.</p><p><strong>Results: </strong>Overexpression of IFI35 suppressed HBV transcription, while its reduction showed the opposite effect. Mechanistically, IFI35 regulated the stability of hepatocyte nuclear factor 4α (HNF4α), which is essential for cccDNA transcription. IFI35 did not regulate the transcription of HNF4α but rather promoted its degradation. We found that IFI35 recruits tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase, for K48-linked ubiquitination of HNF4α. Results were further validated using patient-derived primary human hepatocytes (PHHs) and mouse model of HBV infection. Our results revealed that cytokines, especially IFN-γ, induced IFI35 in hepatocytes. IFI35 promoted the degradation of HNF4α via the TRIM21-mediated ubiquitination, which, in turn, leads to the suppression of cccDNA transcription and viral replication.</p><p><strong>Conclusions: </strong>Our findings demonstrate that IFI35-TRIM21-HNF4α axis may play a crucial role in TNF-α and IFN-γ induced suppression of HBV. Consequently, these results reveal a novel antiviral action of IFI35 against HBV. These findings may hold value in the development of alternative anti-HBV drugs.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13034610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581133","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":"OPRM1/MRGPRX1 heterodimers drive opioid-induced itch through a peripheral mechanism.","authors":"Babina Sanjel, Diwas Rawal, Myeong Ryeo Kim, Wook-Joo Lee, Kwang Won Jeong, Won-Sik Shim","doi":"10.1186/s12929-026-01238-x","DOIUrl":"10.1186/s12929-026-01238-x","url":null,"abstract":"<p><strong>Background: </strong>Opioid-induced itch is a common and distressing side effect of opioid analgesics, yet its underlying mechanisms remain poorly understood. While central µ-opioid receptor (OPRM1) signaling has been implicated, emerging evidence suggests that peripheral mechanisms also contribute, although their specific roles have not been clearly defined.</p><p><strong>Methods: </strong>We investigated the interaction between OPRM1 and the itch-specific receptor MRGPRX1 in sensory neurons using bimolecular fluorescence complementation (BiFC), calcium and cAMP imaging, siRNA knockdown, and pharmacological inhibition assays. Behavioral assays in mice were conducted to assess scratching responses. We also employed immunohistochemistry, RT-qPCR, and ELISA to evaluate gene and protein expression levels in dorsal root ganglia (DRG) and skin tissues, including a mouse model of atopic dermatitis (AD).</p><p><strong>Results: </strong>OPRM1 formed heterodimers with MRGPRX1 in HEK293T cells and sensory neurons, triggering a signaling switch from Gα_i/o-mediated cAMP inhibition to Gα_q/11-driven calcium mobilization upon activation with DAMGO or endogenous opioids. This heterodimerization elicited robust intracellular calcium responses and scratching behavior in mice, which were attenuated by OPRM1 or MRGPRX1 antagonists. In the AD mouse model, increased OPRM1 expression and β-endorphin levels were observed in DRG neurons, correlating with heightened scratching and calcium responses. In contrast, although the δ-opioid receptor (OPRD1) associated with MRGPRX2, it did not trigger mast cell degranulation, suggesting a limited contribution to peripheral itch signaling.</p><p><strong>Conclusions: </strong>Our findings identify a novel peripheral mechanism of opioid-induced itch mediated by OPRM1/MRGPRX1 heterodimers in sensory neurons. This receptor complex promotes calcium signaling and itch behavior, distinct from central or mast cell-dependent pathways. Targeting this heterodimer may offer new therapeutic strategies to alleviate opioid-induced itch without impairing analgesia.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13032443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574182","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":"Coxsackie B1 virus-like particle that lacks VP4 protein demonstrates improved vaccine scalability, stability and immunogenicity.","authors":"Saana Soppela, Henna-Maarit Kyröläinen, Alesia Levanova, Magloire Pandoua Nekoua, Martín González-Rodríguez, Heini Lehto, Kiran L L Ahmad, Sergey Guryanov, Vesa P Hytönen, Olli H Laitinen, Ilkka S Junttila, Didier Hober, Sarah J Butcher, Minna M Hankaniemi","doi":"10.1186/s12929-026-01229-y","DOIUrl":"10.1186/s12929-026-01229-y","url":null,"abstract":"<p><strong>Background: </strong>Enteroviruses, including coxsackievirus B1 (CVB1), cause severe diseases such as myocarditis and meningitis, but vaccines are lacking for most enteroviruses. Conserved and immunodominant epitopes, such as VP4 region and VP1 N-terminus may limit vaccine efficacy by inducing non-neutralizing antibody responses. Virus-like particles (VLPs) mimic native viruses without genetic material and can be engineered to exclude epitopes. To address these challenges, we developed a CVB1-VLP lacking VP4.</p><p><strong>Methods: </strong>Sequence conservation of CVB VP4 protein and the VP1 N-terminal PALXA region was assessed, and BALB/c mice were sequentially immunized with different formalin inactivated CVB vaccines. VLPΔVP4 was produced using baculovirus-insect cell expression system, was purified, and characterized by SDS-PAGE, transmission electron microscopy, dynamic light scattering, cryogenic electron microscopy, three-dimensional image reconstruction and atomic modelling. VLPΔVP4 stability was monitored over five years at 8 °C. Comprehensive preclinical experiments were conducted in mice with VLPΔVP4, VLPΔpalxa and inactivated CVB1. Vaccine immunogenicity was evaluated by neutralization assay, ELISA, ELISpot, and in vitro infection assays.</p><p><strong>Results: </strong>VP4- and PALXA-regions were conserved among CVB serotypes and sequential mouse vaccinations confirmed the induction of antibodies against these regions, that should be avoided in vaccination. VLPΔVP4 exhibited > 95% purity, expected morphology (~ 30 nm), exceptional stability at 8 °C for five years, and the atomic modelling to 2.7 Å resolution showed that the particles were entirely in expanded form. Excluding VP4 from VLP improved production yield 3.5-fold, enhancing scalability of production. Immunological assays demonstrated that VLPΔVP4 induced slightly Th2-skewed response, but including adjuvant system 04 (AS04) in the vaccine induced balanced humoral and cellular immune response in mice. Sera from all vaccine groups modulated CVB1 infection, but IFN-α induction was lowest in VLP groups, suggesting reduced risk for antibody dependent enhancement of infection. VLPΔVP4 elicited significantly higher IFN-γ responses compared to other vaccines, indicating robust cellular immune response. Antibody responses were comparable across adjuvanted groups, but inclusion of VP4 in the vaccine correlated with weaker systemic T-cell responses.</p><p><strong>Conclusions: </strong>VLPΔVP4 represents a promising next-generation CVB vaccine candidate with broad applicability against enteroviruses. Removal of VP4 may mitigate the risk for non-beneficial immune imprinting while enabling high purity, long-term stability, and improved manufacturing efficiency.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13019872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521215","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":"CEP170 as a novel molecular link between centrosomal function and cerebral cortical development.","authors":"Yu-Ching Liao, Meng-Han Tsai, Nian-Hsin Chao, Yu-Syuan Chang, Tzu-Wei Lin, I-Hsuan Lin, Pei-Shan Hou, Won-Jing Wang, Jin-Wu Tsai","doi":"10.1186/s12929-026-01236-z","DOIUrl":"10.1186/s12929-026-01236-z","url":null,"abstract":"<p><strong>Background: </strong>The centrosome is a critical regulator of cortical development, orchestrating microtubule dynamics, cell cycle progression, and neuronal migration. Disruptions in centrosome-associated proteins have been associated with a range of neurodevelopmental disorders. CEP170, a microtubule-binding protein localized to the subdistal appendages (SDA) of centrioles, has been implicated in centrosome function, yet its role in corticogenesis remains poorly defined.</p><p><strong>Methods: </strong>We analyzed CEP170 expression in mouse cortex using western blotting, qPCR, scRNA-seq, and spatial transcriptomics, and examined its transcript expression in the developing human cortex using scRNA-seq. Loss-of-function phenotypes were assessed via in utero electroporation of Cep170-targeting shRNAs in embryonic mouse cortex. Cell proliferation and microtubule dynamics were analyzed using CRISPR/Cas9-generated CEP170-knockout cells, flow cytometry, microtubule regrowth assays, and immunofluorescence microscopy. Protein interactions were examined via co-immunoprecipitation and subcellular localization studies.</p><p><strong>Results: </strong>We show that CEP170 is expressed in both neural progenitors and postmitotic neurons during cortical development. Cep170 knockdown in embryonic mouse cortex resulted in profound neuronal migration deficits, altered laminar fate, and abnormal dendritic morphology. CEP170 depletion also impaired progenitor cell proliferation both in vitro and in vivo. Mechanistically, C-terminal truncations disrupted CEP170 centrosomal and microtubule localization, mediated via impaired interactions with CCDC120. These truncations impaired microtubule regrowth and organization. Strikingly, partial deletion of CEP170's centrosomal targeting and microtubule-binding domains led to severe migration deficits in the developing cortex.</p><p><strong>Conclusion: </strong>Our findings identify CEP170 as a critical regulator of neural progenitor proliferation, neuronal migration, and cortical architecture via centrosome-microtubule interactions, providing new insights into centrosome-linked neurodevelopmental disorders.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13019896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521162","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}