Journal of Biomedical Science最新文献

{"title":"Tau profiling of brain extracellular vesicles reveals PHF6 peptide as core for pathological tau seeding in Alzheimer's disease.","authors":"Marie Oosterlynck, Laura Fichter, Elodie Leroux, Sabiha Eddarkaoui, Thomas Bouillet, Camille Lefebvre, Marine Nguyen, Claude-Alain Maurage, Bertrand Accart, Elian Dupré, Isabelle Landrieu, Clément Danis, Sylvain Lehmann, Jérôme Vialaret, Luc Buée, Christophe Hirtz, Morvane Colin","doi":"10.1186/s12929-026-01250-1","DOIUrl":"10.1186/s12929-026-01250-1","url":null,"abstract":"<p><strong>Background: </strong>Tauopathies are neurodegenerative diseases all characterized by tau lesions in the brain. Nevertheless, a clinical and pathophysiological heterogeneity is present among them. This includes the dominant tau isoform found within aggregates (3R and/or 4R tau) along with different brain regions being affected. For some tauopathies, especially in Alzheimer's disease, a specific spatio-temporal staging of tau lesions is present. This staging has been the basis for the prion-like propagation hypothesis, which describes a cell-to-cell transfer of pathological tau species resulting in new aggregates formation in recipient neurons. Human extracellular vesicles isolated from the brain-derived fluid (BD-EVs) of Alzheimer's disease patients contain seeds that contribute to this tau pathology spreading. However, the nature of these tau species responsible for this nucleation activity remains unknown. Additionally, heterogeneity in seeding activity of BD-EVs of Alzheimer's disease, progressive supranuclear palsy and Pick's disease patients is known.</p><p><strong>Methods: </strong>Here, EVs were isolated from human frozen tissue (Alzheimer's disease, Progressive Supranuclear Palsy, Pick disease and non-demented controls). We used a tau immunoprecipitation followed by high-resolution mass spectrometry to define their proteomic profile and test their seeding capacity in vitro.</p><p><strong>Results: </strong>We show that the tau profile present within BD-EVs is different among tauopathies. Interestingly, multiple tau peptides located in the microtubule binding region were specifically enriched in Alzheimer's disease extracellular vesicles. Of these, mainly the PHF6 (VQIVYK) containing proteins mediate tau seeding activity.</p><p><strong>Conclusions: </strong>PHF6 is a driver for the higher EVs-mediated tau propagation in AD patients, revealing an interesting therapeutic target to prevent tau pathology spreading.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258233","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":"Selective molecular and network architecture features underlie brain cortical atrophy in dementia with Lewy bodies.","authors":"Aline Delva, Stephen Joza, Christina Tremblay, Andrew Vo, Marie Filiatrault, Madeleine Carrier, John-Paul Taylor, John T O'Brien, Michael Firbank, Alan Thomas, Paul C Donaghy, Richard Camicioli, Howard Chertkow, Alain Dagher, Ronald B Postuma, Shady Rahayel","doi":"10.1186/s12929-026-01267-6","DOIUrl":"10.1186/s12929-026-01267-6","url":null,"abstract":"<p><strong>Background: </strong>Dementia with Lewy bodies shares clinical and pathological features with both Parkinson's disease and Alzheimer's disease, but the local biological factors that render specific cortical regions vulnerable to atrophy remain poorly defined. In particular, it is unclear whether cortical thinning in dementia with Lewy bodies reflects generic neurodegenerative mechanisms, processes shared with Parkinson's disease and Alzheimer's disease, or dementia with Lewy bodies-specific molecular and network susceptibilities.</p><p><strong>Methods: </strong>A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and identified genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process.</p><p><strong>Results: </strong>Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body- and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABA_A, serotoninergic 5-HT_1A, 5-HT_1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity.</p><p><strong>Conclusions: </strong>MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13251274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211446","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":"Exploring CAR cell therapies beyond CAR-T for myeloid malignancies.","authors":"Yan-Ruide Li, Yuning Chen, Lili Yang","doi":"10.1186/s12929-026-01265-8","DOIUrl":"10.1186/s12929-026-01265-8","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cells have demonstrated remarkable efficacy in several hematologic malignancies; however, their application in myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remains limited, with no FDA-approved products to date. This limited progress largely reflects both efficacy challenges and safety concerns. CAR-T cells demonstrate poor trafficking and persistence within the bone marrow, limited activity against leukemia stem cells (LSCs), and reliance on antigens such as CD33 and CD123 that are also expressed on normal hematopoietic stem and progenitor cells, resulting in significant on-target off-tumor toxicity. Given these limitations, attention has increasingly shifted toward alternative CAR-engineered immune cells, including CAR-natural killer (CAR-NK) cells, CAR-invariant natural killer T (CAR-NKT) cells, and CAR-macrophages (CAR-Ms). These platforms offer unique advantages, such as intrinsic antitumor activity, distinct trafficking properties, reduced risk of graft-versus-host disease (GvHD), and potentially safer antigen recognition profiles, that may help overcome barriers faced by CAR-T cells. In this review, we highlight the challenges of applying conventional CAR-T cells to myeloid malignancies, examine emerging alternative CAR-cell platforms, and discuss how their unique biology and engineering strategies may provide safer, more effective, and more accessible therapeutic options for patients with these difficult-to-treat cancers.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13237903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163270","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":"Primary cilia and neural computation.","authors":"Andrew Teoh, Mishra Arinjay, Dwaipayan Giri, Siew Cheng Phua","doi":"10.1186/s12929-026-01264-9","DOIUrl":"10.1186/s12929-026-01264-9","url":null,"abstract":"<p><p>Ciliopathies frequently involve abnormal brain development and affected individuals often present with varying degrees of cognitive impairment and behavioral alterations. In parallel, genetic studies have linked primary cilia to neurodevelopmental disorders such as autism spectrum disorder (ASD). Together, these observations point to a role for primary cilia in cognition, yet their mechanistic contribution to neural function remains unclear. To address this, we define neural computation as the integration of inputs, dynamic thresholding, and routing of outputs, and propose that primary cilia function not as passive sensory antennae, but as dynamic computational microdomains. Within this framework, cilia integrate extrinsic signals and intrinsic cellular states through modular signaling pathways, including GPCR-cAMP-PKA cascades and tightly regulated trafficking mechanisms. These processes are spatially constrained by ciliary gating and transport systems, enabling selective filtering, amplification, and transformation of inputs into context-dependent outputs. During development, these molecular computations scale to shape neural circuit architecture. Ciliary signaling regulates neurogenesis, specifies neuronal identity, and guides neuronal migration and connectivity, thereby embedding computational parameters into the physical structure of the brain. In the mature brain, ciliary GPCRs modulate neuronal and circuit-level dynamics. Receptors such as 5HT6 and SSTR3 influence neuronal excitability and excitation-inhibition balance, while hypothalamic MC4R functions as a rheostat to stabilize state-dependent signaling. In parallel, dynamic trafficking of DRD1 receptors enables flexible regulation of dopaminergic signaling across subcellular compartments. Disruption of ciliary function has been linked to memory impairments, suggesting a role in regulating the stability and competition of memory engrams. These effects may involve multiple plasticity mechanisms, including synaptic tagging and capture, activity-dependent synchronization, and adult neurogenesis. Together, these findings support a unifying view in which primary cilia perform molecular computations that scale across development and adult brain function to influence neural circuits and behavior. Future integration of cilia-targeted molecular tools with systems-level approaches will be essential for disentangling developmental effects from active computational roles in the mature brain.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148149966","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":"Conditional deletion of Cc2d1a increases irritability-like behavior by decreasing oxytocin expression via the prelimbic-hypothalamic pathway.","authors":"Kuan-Hsiang Cheng, Yu-Chieh Hung, Pin Ling, Kuei-Sen Hsu","doi":"10.1186/s12929-026-01263-w","DOIUrl":"10.1186/s12929-026-01263-w","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of the oxytocin (OXT) system is implicated in the pathophysiology of several neuropsychiatric and neurological disorders, particularly autism spectrum disorder (ASD). Our previous study using the Coiled-coil and C2 domain containing 1a (Cc2d1a) conditional knockout (cKO) mouse model of ASD showed that restoring OXT levels effectively ameliorates irritability-like behavior; however, the mechanisms by which loss of Cc2d1a in forebrain excitatory neurons leads to decreased OXT expression in the paraventricular nucleus of the hypothalamus (PVN) remain elusive.</p><p><strong>Methods: </strong>We used the bottle-brush test (BBT) to assess irritability-like behavior in wild-type (WT) and Cc2d1a cKO mice. Retrograde and anterograde trans-synaptic viral tracing were used to map associated neural circuits, and chemogenetic methods were employed to modify neuronal activity. Fiber photometry monitored OXT dynamics in situ, and whole-cell voltage-clamp recordings in ex vivo brain slices assessed synaptic transmission onto PVN OXT neurons.</p><p><strong>Results: </strong>We found that decreased OXT expression in both magnocellular and parvocellular PVN neurons is evident in adult male Cc2d1a cKO mice, without corresponding changes in mRNA levels. Chronic silencing of PVN OXT neurons during adolescence leads to fewer OXT-immunoreactive neurons and heightened irritability-like behavior in adult male WT mice. Using both retrograde and anterograde trans-synaptic viral tracing techniques, we identified that the prelimbic cortex (PrL) indirectly regulates PVN OXT neuronal activity. In male Cc2d1a cKO mice, there was a preferential decrease in excitatory synaptic transmission onto PVN OXT neurons. In vivo real-time measurements of OXT dynamics in the posteroventral medial amygdala revealed reduced OXT release during the BBT in male Cc2d1a cKO mice. Chronic chemogenetic silencing of the PrL-PVN pathway during adolescence reduces irritability-like behavior in adult male Cc2d1a cKO mice.</p><p><strong>Conclusions: </strong>Our study unveils how forebrain Cc2d1a loss reduces OXT expression in the PVN at both molecular and circuit levels, underscoring the critical role of the OXT system as a potential therapeutic target for managing irritability in individuals with ASD.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150016","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":"Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia.","authors":"Erika B Villanueva, Zala Zebec, Marina Cisquella-Serra, Jon Lundstrøm, Jens V Andersen, Filippa L Qvist, Emil W Westi, Andrea Marin, Gisela Jimenez-Duran, Lluís Riera-Ponsati, Emilie Tresse, Oliver Kretz, Desiree Loreth, Tobias Goldmann, Thomas Blank, Marco Prinz, Blanca I Aldana, Matthias Mann, Niels H Skotte, Shohreh Issazadeh-Navikas","doi":"10.1186/s12929-026-01257-8","DOIUrl":"10.1186/s12929-026-01257-8","url":null,"abstract":"<p><strong>Background: </strong>Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson's disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets.</p><p><strong>Methods: </strong>Single nuclei RNA sequencing (snRNA-seq), liquid chromatography tandem mass spectrometry (LC-MS/MS), functional metabolic mapping, flow cytometry, quantitative PCR (qPCR), in situ hybridization, immunofluorescence and immunohistochemistry, Western blotting, and behavior analyses were used to investigate the molecular, cellular, and phenotypic impacts of IFNAR1 loss in vivo.</p><p><strong>Results: </strong>Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls. Neuron- and astrocyte-specific transcriptomic and proteomic alterations in Ifnar1^-/- mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, Ifnar1^-/- mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1.</p><p><strong>Conclusions: </strong>IFNAR1 plays a crucial role in brain and mitochondrial homeostasis, loss of which results in neurodegeneration and neuropathology resembling PDD. Differential neuropathology and behavioral outcomes upon neuronal vs astrocytic IFNAR1 loss emphasizes a need for understanding neurodegenerative pathophysiology in cell-specific contexts. Trial registration Not applicable as the study does not include a clinical trial.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143539","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":"Crystal structure of the CD33/Fab-10C8 complex elucidates the mechanism of antibody antagonism in HBV-induced immunosuppression.","authors":"Yi-Hung Yeh, Min-Guan Lin, Pei-Shan Sung, Shie-Liang Hsieh, Chwan-Deng Hsiao","doi":"10.1186/s12929-026-01248-9","DOIUrl":"10.1186/s12929-026-01248-9","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis B virus (HBV) infection persists through immune evasion strategies, including engagement of the inhibitory receptor CD33 (Siglec-3) by α2,6-linked sialoglycans on HBsAg. This interaction induces ITIM phosphorylation and SHP-1/2 recruitment, dampening myeloid cell activation. The monoclonal antibody 10C8 has been identified as a potent antagonist of CD33, but the structural basis for its inhibitory activity remains unclear.</p><p><strong>Methods: </strong>We determined the 3.2 Å crystal structure of the human CD33 extracellular domain (CD33-ECD) in complex with the Fab fragment of 10C8 (Fab-10C8). The stoichiometry and assembly of the complex in solution were validated by size-exclusion chromatography and analytical ultracentrifugation (AUC). Structural comparisons with apo CD33 were performed to assess potential Fab-induced conformational changes, and buried surface area analyses were conducted to characterize binding interfaces.</p><p><strong>Results: </strong>The structure reveals a 2:2 stoichiometry complex comprising two CD33-ECD molecules and two Fab-10C8 fragments, consistent with the 157 kDa molecular mass determined by AUC. Each Fab engages the V-set domain through extensive complementarity-determining region (CDR) interactions, burying ~612 Å² of surface area, while inter-Fab contacts stabilize a compact dimeric arrangement of CD33-ECD. This geometry differs markedly from the relaxed apo state, showing a ~21° reduction in the dimer angle. The antibody-binding epitope is adjacent to, but not overlapping with, the canonical sialic acid-binding cleft, leading to steric occlusion that prevents HBsAg engagement. Together with a potential Fab-induced ectodomain compaction, this conformation restricts CD33 clustering and likely precludes SHP-1/2 recruitment, providing a mechanistic explanation for the antagonistic activity of 10C8.</p><p><strong>Conclusions: </strong>This study provides the structural insight into antibody-mediated inhibition of CD33. By locking CD33 into a sterically occluded, signaling-refractory conformation, 10C8 effectively reverses HBV-induced immunosuppression, thereby restoring host antiviral activity. These findings establish a structural framework for rational design of Siglec-targeted immunotherapies against chronic viral infections and other immune regulatory disorders.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054730","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":"Targeting a genomic RNA G-quadruplex of dengue virus with small molecules as an alternative to protein-targeted therapeutics.","authors":"Yeong Jun Kim, Moumita Das, JunYoung Song, Shreyasi Das, Han-Jun Kim, Jeong-Ki Kim, Ki-Young Lee, Kyeong Kyu Kim, Hye-Ra Lee","doi":"10.1186/s12929-026-01262-x","DOIUrl":"10.1186/s12929-026-01262-x","url":null,"abstract":"<p><strong>Background: </strong>Given the increasing global incidence of dengue virus (DENV) infections and the lack of approved antiviral therapies, developing a new antiviral strategy against DENV is urgently required. However, despite considerable efforts to develop protein-targeted antivirals, clinical translation has largely failed, highlighting the need for alternative, non-protein targets.</p><p><strong>Methods: </strong>Here, we investigated a novel therapeutic approach that targets RNA G-quadruplexes (G4s), highly conserved secondary structures across viral strains, including all serotypes. Bioinformatic predictions and biophysical analyses identified conserved G4-forming sequences within the DENV genome.</p><p><strong>Results: </strong>Among the tested representative G4-binding ligands, BRACO-19 showed the highest stabilizing effect on G4 structures, particularly at the G4-3 region corresponding to the NS3 gene with high binding affinity. Functionally, BRACO-19 treatment significantly reduced viral translation resulting in strong antiviral effects in a mouse model of DENV infection. Consistently, recombinant DENV carrying a G4-3-disrupting mutation showed enhanced viral gene expression and attenuated sensitivity to BRACO-19. These findings establish DENV RNA G4 as a druggable structural element and position BRACO-19 as a promising lead compound for dengue therapeutics. Furthermore, we also demonstrated that BRACO-19 exhibits broad-spectrum activity against all DENV serotypes. This RNA structure-based approach offers an alternative to protein-targeted therapeutics, helping to mitigate mutational escape and serotype variability in dengue virus.</p><p><strong>Conclusion: </strong>Collectively, our study highlights a novel therapeutic strategy that directly targets conserved RNA secondary structures, paving the way for the development of broad-spectrum antivirals against flaviviruses by targeting a non-canonical nucleic acid structure.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13217665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148042384","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":"Mechanistic insight into complement C3 regulation during chronic HBV infection: effect on viral persistence and host immune response.","authors":"Ayana Baidya, Debangana Dey, Shreya Mallik, Sudeshna Halder, Najma Khatun, Rambha Jha, Sarthak Nandi, Bidhan Chandra Chakraborty, Amrita Dutta, Soma Banerjee, Abhijit Chowdhury, S K Mahiuddin Ahammed, Simanti Datta","doi":"10.1186/s12929-026-01259-6","DOIUrl":"10.1186/s12929-026-01259-6","url":null,"abstract":"<p><strong>Background: </strong>The complement system (CS) is central to antiviral defence, yet many viruses subvert it to escape clearance. Complement-component C3 is the key effector molecule of CS that plays diverse roles in pathogen elimination, inflammation and immune responses, but its regulation during chronic HBV infection (CHI) remains poorly understood. This study examined the mechanisms governing C3 expression in hepatocytes and immune cells during CHI and evaluated the impact of altered C3 levels on viral persistence and host immunity.</p><p><strong>Methods: </strong>C3 expression was evaluated in blood and liver-tissue samples from patients with CHI and healthy controls using ELISA and RT-PCR. HBV-transfected hepatoma cells were used to examine epigenetic regulation of C3, including promoter methylation, histone deacetylation, and transcription factor phosphorylation. Autophagy-related functions of C3 were assessed by immunofluorescence. Flow cytometry was used to determine the intracellular C3 levels in immune cells of HBV-infected patients and the influence of viral and host factors on C3 expression. Additionally, cytokine production by immune cells and the modulating effect of recombinant C3a on these cytokines was studied. The effect of Tenofovir therapy on C3 concentration was also evaluated.</p><p><strong>Results: </strong>C3 level was found to be significantly diminished in sera and liver-tissues of HBV-infected patients and HBV-expressing hepatoma cells relative to controls. HBX suppressed C3 transcription by restricting the availability of the crucial transcription factor, C/EBPβ through its promoter hypermethylation and by enhancing histone deacetylation at C3-promoter including C/EBPβ binding-sites whereas, HBV surface proteins (HBS) further blocked C/EBPβ phosphorylation essential for transcription. Functionally, C3 deficiency disrupted autophagosome-lysosome fusion and prevented autophagic degradation of viral proteins, leading to enhanced HBV release. Reduced intracellular C3 was noted in monocytes and virus-specific T cells of HBV-infected patients that could be attributed to exposure to HBS and cytokines (IL-4/IL-1β). The decline in C3 skewed the immune responses toward an anti-inflammatory phenotype with diminished pro-inflammatory activities, which were reversed by recombinant C3a. One-year of Tenofovir therapy partially restored serum but not immune-cell C3 levels.</p><p><strong>Conclusion: </strong>HBV downregulates C3 through epigenetic and signalling mechanisms, facilitating viral persistence and dampening antiviral immunity. Targeting complement regulation may represent a novel therapeutic strategy in CHI.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13200380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015734","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":"Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation.","authors":"Ji-Soo Lim, Soo-Jin Oh, Ji-Yeun Hur, Subin Oh, Seuk-Min Ryu, Rafael T Han, Hosun Park, Dawn M E Bowdish, Ok Sarah Shin","doi":"10.1186/s12929-026-01256-9","DOIUrl":"10.1186/s12929-026-01256-9","url":null,"abstract":"<p><strong>Background: </strong>Varicella zoster virus (VZV) is a human neurotropic virus that can establish latency in sensory neurons. Microglia play a complex role during neurotropic virus infections; however, their role during VZV infection remains to be determined. In the present study, we explored the role of VZV-induced alterations in the morphodynamics and function of microglia in triggering neuroinflammation.</p><p><strong>Methods: </strong>We prepared cell-free VZV and compared replication efficiencies of wild-type (YC01) and attenuated (MAV/06, MAV) VZV in two transformed human microglial cell lines (HMC3 and HIM) and human embryonic stem cell (ESC)-derived microglia (ESC-MG). Bulk RNA sequencing was used to assess molecular signatures of microglia following VZV infection in ESC-MG, and cytokine profiles were determined to further investigate neuroinflammation. To further examine the impact of VZV-induced microglial inflammation on neuronal responses, we generated ESC-derived sensory neurons (ESC-SN) and evaluated nociceptor expression and calcium flux as a readout for SN activities following microglial secretome treatment.</p><p><strong>Results: </strong>VZV upregulates its gene and protein expression and triggered morphological changes in various microglia cultures. Transcriptomic analysis of YC01-infected ESC-MG revealed a robust induction of genes associated with antiviral innate immunity, alongside a pronounced upregulation of macrophage receptor with collagenous structure (MARCO). Functional studies demonstrated that MARCO facilitates VZV uptake in microglia by binding to the viral glycoprotein E (gE) via its C-terminal scavenger receptor cysteine-rich (SRCR) domain, thereby promoting viral entry and phagocytosis. Moreover, VZV infection elicited neuroinflammation in an ORF62-dependent manner, while MARCO activation triggered toll-like receptor 2 (TLR2)-mediated inflammatory signaling. This cascade further amplified the expression of pain-associated molecular mediators in an ESC-SN model, highlighting a potential mechanistic link between microglial MARCO and VZV-triggered neuropathic processes.</p><p><strong>Conclusion: </strong>Our results show, for the first time, that microglia are susceptible to VZV infection and identify MARCO as an important mediator for regulating TLR2-mediated neuroinflammation and promoting an upregulation of factors associated with neuropathic pain.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13198062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005315","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}