Journal of Biomedical Science最新文献

{"title":"Aptamer-based inhibition of MNK1 reduces pancreatic ductal adenocarcinoma growth by targeting cancer stem cells.","authors":"Alberto Pérez-Ruiz, Laura Ruiz-Cañas, Sandra Batres, Raquel Ferreras-Martín, Celia Pinto-Díez, Balbino Yagüe, Maria Isabel Pérez-Morgado, Silvia Sacristán, Ignacio Ruz-Caracuel, Sonia Camaño Páez, Isabel Sanchez-Perez, Víctor M González, Sonia Alcalá, María Elena Martín, Bruno Sainz","doi":"10.1186/s12929-026-01275-6","DOIUrl":"10.1186/s12929-026-01275-6","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to late diagnosis, early metastasis and resistance to therapy. Cancer stem cells (CSCs) have been implicated in PDAC aggressiveness and treatment failure. MAP kinase-interacting kinase 1 (MNK1) is overexpressed in PDAC and plays a critical role in tumor progression and CSC maintenance. Here, we show the potential of apMNKQ2, a DNA aptamer targeting MNK1, to therapeutically target CSCs and reduce PDAC tumor burden in patient-derived xenografts (PDXs).</p><p><strong>Methods: </strong>PDX cell lines and in vivo mouse models were used to assess the effects of apMNKQ2 on cell viability, apoptosis, cell cycle progression, migration, epithelial-to-mesenchymal transition (EMT) and CSC properties. Functional CSC targeting was validated through clonogenic and self-renewal assays as well as extreme limiting dilution analysis. Systemic administration of free apMNKQ2 was tested for biodistribution, pharmacokinetics, toxicity, and antitumor efficacy at escalating doses.</p><p><strong>Results: </strong>apMNKQ2 downregulated MNK1 and anti-apoptotic proteins (MCL1, XIAP), impaired cell proliferation, induced apoptosis, and disrupted cell cycle progression in PDX PDAC cells. Importantly, apMNKQ2 also inhibited migration, mesenchymal properties and angiogenesis in vitro, and lung colonization in vivo. Notably, apMNKQ2 strongly targeted PDAC CSCs, reducing CD24, CD133, CXCR4 and ALDH expression, clonogenicity and in vivo tumor initiation over 600-fold. Free apMNKQ2 (without transfection agents) entered PDAC cells efficiently, retaining anti-CSC activity. Systemic delivery of free apMNKQ2 accumulated in tumors, was well tolerated up to 400 mg/kg and showed no toxicity. Importantly, 10 mg/kg of apMNKQ2 produced strong antitumor effects in PDX models. Increasing the dose 20-fold enhanced tumor uptake but not efficacy, suggesting a therapeutic plateau at 10 mg/kg.</p><p><strong>Conclusions: </strong>MNK1 plays a central role in PDAC progression and CSC maintenance. apMNKQ2 is a potent anti-MNK1 DNA aptamer with robust preclinical activity, including CSC-targeting and anti-invasive effects. Its low toxicity, systemic bioavailability, and efficacy at low doses support further development as a novel therapeutic strategy for PDAC.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13335277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396726","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":"Antifungal resistance: from classical mechanisms to the expanding role of acetyltransferases.","authors":"Silvia Maria Cordeiro Werneck, Ludmila Gouveia-Eufrasio, Gustavo José Cota de Freitas, Daniel Santana de Carvalho, Isabela da Costa César, Luana Rossato, Rafael Wesley Bastos, Nalu Teixeira Aguiar Peres, Daniel Assis Santos","doi":"10.1186/s12929-026-01273-8","DOIUrl":"10.1186/s12929-026-01273-8","url":null,"abstract":"<p><p>Antifungal resistance represents a growing global health challenge, driven by limited therapeutic options, inadequate use of both clinical and environmental drugs, and the remarkable adaptive capacity of fungal pathogens. While resistance has classically been attributed to genetic alterations affecting drug targets and efflux systems, accumulating evidence indicates that regulatory mechanisms play a critical role in shaping antifungal susceptibility. This review highlights that acetyltransferases constitute important and active components of antifungal resistance, operating through multiple integrated mechanisms. Notably, recent studies have extended this framework by identifying the direct enzymatic inactivation of antifungal agents by acetyltransferases, which emerges as an additional resistance mechanism and establishes a functional parallel with antibiotic acetylation in bacteria. These findings highlight acetyltransferases as clinically relevant drivers of antifungal resistance and suggest that targeting these enzymes may enhance the efficacy of existing antifungal therapies and reduce treatment failure.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375889","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":"Calcium and phosphorylation coordination is a novel mechanism that stabilises protein-complexes during HIV assembly.","authors":"Erwan Brémaud, Biswa Prasanna Mishra, Ablikim Baqi, Veronika Masic, Thibaut Flipo, Arun Everest-Dass, Lauren Hartley-Tassell, Paul R Gorry, Thomas Ve, Belinda L Spillings, Johnson Mak","doi":"10.1186/s12929-026-01274-7","DOIUrl":"10.1186/s12929-026-01274-7","url":null,"abstract":"<p><strong>Background: </strong>Calcium (Ca²⁺) signalling and phosphorylation are independent mechanisms that regulate diverse biological processes. It is, however, not appreciated that a normal function of phospho-mimic amino acids (aspartate/glutamate) is to interact with Ca²⁺ at the atomic level.</p><p><strong>Methods: </strong>In this work, we have utilised a combination of molecular virology, phosphorylation proteomics mass spectrometry, surface plasmon resonance, nuclear magnetic resonance, AlphaFold structural prediction, and electron microscopy imaging to systematically evaluated the biology of calcium - phosphorylation interplay.</p><p><strong>Results: </strong>Here, we leveraged HIV-Ca²⁺ biology to enable polarised targeting in primary cells to describe an unknown layer of regulatory processes via Ca²⁺-phosphate (PO₄^3-) bridge to support protein complex formation. We identified novel HIV phosphorylation sites proximal to Endosomal Sorting Complex Required for Transport (ESCRT) binding motifs and potential Ca²⁺ binding sites through phospho-proteomics. Integrating primary cells, molecular virology, structural biology, biophysical and ultrastructural analyses, we presented multiple examples of coordination between calcium and phosphorylated amino acids to support HIV assembly and function. Our data suggest Ca²⁺-PO₄^3- could form a bridge between intrinsically disordered protein regions of HIV to: (i) stabilise Pr55^Gag-Pr160^GagPol complex for virus function; (ii) mediate p6^Pol dimerization to support virion maturation; and (iii) modulate viral complex formation to package both viral enzymatic- and cellular- proteins.</p><p><strong>Conclusions: </strong>Our work has identified the coordination between calcium and phosphorylated amino acids (presumably via the formation of a salt-bridge) is an unknown layer of regulation that support protein complex formation. In the context of HIV, these Ca²⁺-PO₄^3- cooperation via the intrinsically disordered protein regions regulates the assembly of HIV complex and modulates its interactions with ESCRT cellular proteins. Importantly, the convergent enrichment of calcium-phosphorylation domains across a wide range of viral and cellular intrinsically disordered protein regions implies Ca²⁺-PO₄^3- cooperation to be a general regulatory principle in biology.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13326380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368578","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":"CLEC5A/TLR2 bispecific antibody suppresses dengue virus-induced pro-inflammatory cytokines production from macrophages.","authors":"Sheng-Hsuan Wang, Wei-Tzu Kuo, Dayna Cheng, Pei-Shan Sung, Shin-Ru Shih, Shie-Liang Hsieh, Jen-Ren Wang","doi":"10.1186/s12929-026-01272-9","DOIUrl":"10.1186/s12929-026-01272-9","url":null,"abstract":"<p><strong>Background: </strong>Dengue virus (DENV) infection drives pathological inflammation through coordinated activation of pattern recognition receptors (PRRs) in myeloid cells, yet no approved immunomodulatory therapy exists to interrupt this process. CLEC5A and Toll-like receptor 2 (TLR2) have each been implicated in DENV-induced cytokine production, but whether their co-engagement represents a convergent and therapeutically targetable axis remains unclear.</p><p><strong>Methods: </strong>We define the cytokine landscape of human macrophages infected with all four DENV serotypes and reverse genetics DENV2 (rgDV2) strains carrying NS1 mutations derived from the severe 2015 Taiwan outbreak. We further demonstrate the potential therapeutic effect of bispecific antibodies simultaneously targeting CLEC5A and TLR2-engineered in both IgG1 and IgG4 formats.</p><p><strong>Results: </strong>Human macrophages infected with all four DENV serotypes, as well as reverse genetics DENV2 (rgDV2), exhibit a consistently dominant pro-inflammatory program driven by CLEC5A-TLR2 co-signaling. Treatment with bispecific antibodies, in both IgG1 and IgG4 formats, potently suppress the production of TNF-α, IL-6, IL-8, and MCP-1 production across all viral strains tested. Notably, the IgG4 format preserves robust inhibitory efficacy while minimizing Fc receptor engagement, thereby offering a rational strategy to mitigate the risk of antibody-dependent enhancement (ADE). This dual-targeting approach also remains effective against NS1 mutant strains linked to enhanced virulence and cytokine storm.</p><p><strong>Conclusion: </strong>Together, these findings identify CLEC5A-TLR2 co-signaling as a convergent inflammatory axis in dengue pathogenesis and establish bispecific dual-receptor blockade as a mechanistically grounded, ADE-aware immunomodulatory strategy to mitigate cytokine-driven pathology.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351627","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":"Offense and defense: itaconate mediates bidirectional immune regulation of host-bacteria interaction.","authors":"Zhaoyue Men, Zishen Lin, Zhe Wang, Peng Tan, Shuyang Yu, Xi Ma","doi":"10.1186/s12929-026-01266-7","DOIUrl":"10.1186/s12929-026-01266-7","url":null,"abstract":"<p><p>Itaconate has garnered significant attention in recent years due to its immunomodulatory and antimicrobial functions. During inflammation and pathogenic infections, itaconate is formed through the decarboxylation of cis-aconitate in the mitochondrial tricarboxylic acid cycle and accumulates in large quantities to counteract excessive inflammation and pathogenic infections. However, many pathogenic bacteria have also evolved pathways to directly degrade itaconate or indirectly resist its stimulatory effects. We first review the research history and metabolic pathways of itaconate. Then we focus on exploring its direct mechanism of inhibiting pathogenic bacteria growth and reproduction by post-translational modification of metabolic enzymes such as isocitrate lyase, aldolase, and IMP dehydrogenase. Additionally, we examine its indirect mechanism of coordinating immune cell functions to eliminate pathogenic bacteria. Pathogenic bacteria counteract this by directly degrading itaconate through the IcT-IcH-CcL cascade reaction or by adapting through metabolic reprogramming to enable chronic infection. Subsequently, we discuss the spatiotemporal specificity of itaconate during the early and late stages of pathogenic bacteria infection, highlighting its role in regulating immune defense strategies at different phases. Finally, we discuss the potential and limitations of itaconate-related interventions as adjunctive strategies for bacterial disease control, particularly in the context of drug-resistant infections. This review elucidates the mechanism of itaconate in host-microbial crosstalk from the perspective of bidirectional resistance between host and bacteria, emphasizing its crucial role as a metabolic messenger in mediating co-evolutionary, co-developmental, and co-metabolic interactions between the host and bacteria. Current evidence of itaconate-mediated bidirectional interactions may help guide future mechanistic studies and the development of itaconate-related adjunctive strategies for bacterial disease control. Further in vivo, clinical, and field validation is still required before these findings can be translated into therapeutic or agricultural applications.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13307414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338773","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":"Mechanobiology of the tumor microenvironment: a review of therapeutic interactions and in vitro elasticity measurement techniques.","authors":"Ting-Wei Chen, Shu-Han Yu, Shao-Lun Lu, Chih-Hung Yeh, Pai-Chi Li","doi":"10.1186/s12929-026-01270-x","DOIUrl":"10.1186/s12929-026-01270-x","url":null,"abstract":"<p><p>The stiffness of the extracellular matrix (ECM) regulates cellular behavior, influencing tumor progression and therapeutic resistance. In cancer, aberrant ECM stiffening can reduce immune cell infiltration and treatment efficacy, which can in turn alter the tumor microenvironment. Here, we review the role of ECM stiffness in cancer biology and its relevance to matrix-targeted therapies and biomaterial design. We discuss three-dimensional (3D) in vitro models that mimic native tissues and the bidirectional interactions between ECM mechanics and therapeutic interventions. A comparative analysis of measurement modalities is presented for characterizing complex 3D environments, including shear-wave-based techniques such as optical and ultrasound elastography and non-shear-wave-based approaches such as atomic force microscopy and rheology. Future directions include developing matrix-modulating therapies, integrating elasticity sensors into microfluidic devices for higher throughputs and physiological relevance, and applying machine learning to interpret heterogeneous mechanical properties. Collectively, these engineering and biological advances highlight ECM stiffness as a tractable target and open translational opportunities for predictive modeling, diagnostic platforms, and matrix-directed therapies to improve cancer treatment.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301773","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":"Enhanced expression of ADAMTS1 in ovarian carcinomas: loss of ADAMTS1 expression instigates cellular reprogramming of extracellular matrix ensuing altered plasticity, augmented migration and attenuated adhesion.","authors":"Ruth M Escalona, Dylan King, Noor A Lokman, Martin K Oehler, Carmela Ricciardelli, George Kannourakis, Nuzhat Ahmed","doi":"10.1186/s12929-026-01260-z","DOIUrl":"10.1186/s12929-026-01260-z","url":null,"abstract":"<p><strong>Background: </strong>ADAMTS1, a disintegrin and metalloproteinase with thrombospondin motif 1, plays a role in inflammation, organogenesis, and ovulation. Up or downregulation of ADAMTS1 has been implicated in tissue remodelling leading to cancer. We analysed the expression of ADAMTS1 in different stages/grades of primary and metastatic serous ovarian tumours and ascites-derived tumour cells from patients and assessed the functional role of ADAMTS1 in ovarian cancer (OC) cell lines.</p><p><strong>Methods: </strong>The expression and localisation of ADAMTS1 was assessed by immunohistochemistry (IHC) and Opal Multiplex IHC staining of OC tissues. Functional roles of ADAMTS1 in OC cell lines were assessed by using siRNA-mediated knockdown (KD), MTT assay, cell migration by xCELLigence, cell adhesion, ELISA, qRT-PCR, Western blot, immunofluorescence (IF) and activity of Cdc42 GTPase.</p><p><strong>Results: </strong>The expression of ADAMTS1 was significantly enhanced in higher stages/grades of ovarian tumours compared to benign tumours. In high-grade tumours, ADAMTS1 was localised more in the nucleus of epithelial cells while localisation in stromal cells was mostly in the cytoplasm. Significantly higher mRNA expression of ADAMTS1 was noted in epithelial compared to mesenchymal ascites-derived tumour cells. The expression of ADAMTS1 was significantly higher in metastatic high-grade tumours compared to primary tumours. KD of ADAMTS1 expression by siRNA in OC cell lines had no effect on cell proliferation but resulted in decreased cell adhesion, increased cell migration accompanied by increased expression of markers (CDH1 and EPCAM) associated with epithelial plasticity. Remodelling of ECM accompanied by increased intra- and extracellular production of VCAN and enhanced Cdc42 GTPase activity was also noted in cell lines with ADAMTS1 KD. Cdc42 GTPase specific inhibitor, ML141, reversed ADAMTS1 KD-mediated enhanced migration. On the other hand, VCAN KD inhibited ADAMTS1 KD-mediated migration and reversed the effect on cell adhesion.</p><p><strong>Conclusions: </strong>These results suggest that the expression of ADAMTS1 progressively enriches ovarian tumours and promotes OC progression. Its knock down in in vitro cell culture impacts ECM remodelling through enhanced Cdc42GTPase activity and VCAN production resulting in epithelial cell plasticity, accelerated migration, and reduced cell adhesion.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301760","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":"Lack of cortistatin drives neuroimmune and vascular dysfunction in brain ischemia.","authors":"Julia Castillo-González, Pablo Vargas-Rodríguez, Ignacio Serrano-Martínez, Alejandro Cuenca-Martagón, Irene Forte-Lago, Melanie Price, Lara Buscemi, Lorenz Hirt, José Luis Ruiz, Elena González-Rey","doi":"10.1186/s12929-026-01271-w","DOIUrl":"10.1186/s12929-026-01271-w","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke remains a leading cause of death and disability, with limited therapies addressing its pathophysiology. Neuroinflammation, blood-brain barrier disruption, and immune dysregulation critically contribute to both acute neuronal injury and chronic functional decline. Elucidating the endogenous factors that govern these processes and understanding the intricate interplay among them is essential for developing effective therapeutic strategies. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory actions, but its role in neuroinflammatory diseases remains unclear.</p><p><strong>Methods: </strong>In this study, we combined human and murine transcriptomic analyses with a preclinical stroke model in cortistatin-deficient mice to investigate the endogenous and therapeutic roles of cortistatin during the acute (48 h) and subacute (7 days) phases of ischemic stroke.</p><p><strong>Results: </strong>We demonstrate for the first time that cortistatin deficiency amplified ischemia-induced transcriptional programs, heightening neuroinflammation and glial/neurovascular dysfunction, and worsening neurological outcomes. Interestingly, cortistatin deficiency accelerated aging-associated pathological features, underscoring its essential role in neuroimmune and cerebrovascular homeostasis. Conversely, cortistatin administration improved neuronal survival, mitigated immune dysfunction, and preserved myelin and vascular integrity during both the acute and subacute stages.</p><p><strong>Conclusions: </strong>These findings provide the first evidence identifying cortistatin as an endogenous neuroimmune regulator in ischemic stroke and a promising multimodal therapeutic agent for improving acute and long-term outcomes.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283912","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":"ENT1 inhibitor J4 restores cognitive function and white-matter integrity in a mouse model of tuberous sclerosis complex.","authors":"Christine Chin-Jung Hsieh, Yi-Syue Tsou, Nai-Kuei Huang, Ting-Chieh Chen, Ssu-Ju Li, Ching-Wen Chang, Wei-Xuan Lin, Szu-Yu Tung, Yijuang Chern, You-Yin Chen, Yi-Chao Lee","doi":"10.1186/s12929-026-01269-4","DOIUrl":"10.1186/s12929-026-01269-4","url":null,"abstract":"<p><strong>Background: </strong>Tuberous sclerosis complex (TSC) is a hereditary disease caused by pathogenic mutations in the TSC1 or TSC2 genes, leading to overactivation of mTOR signaling and dysregulation of downstream pathways. The majority of individuals with TSC develop psychiatric and neurodevelopmental comorbidities-including intellectual disability, autism spectrum disorders, anxiety and other behavioral manifestations-collectively termed TSC-associated neuropsychiatric disorders. Over the past decade, increasing evidence from clinical and preclinical studies has highlighted a significant myelination deficit in the brains of TSC patients and animal models. Although mTOR inhibition can alleviate myelination defects and improve cognition in rodent models, clinical studies using the mTOR inhibitor, everolimus, has limited cognitive benefits in TSC individuals. Adenosine signaling has been recognized as a key player in oligodendrocyte maturation and myelin formation and may represent a promising target for therapeutic intervention.</p><p><strong>Methods: </strong>In the present study, we treated Tsc2^+/- mice with J4, an equilibrative nucleoside transporter 1 inhibitor that has been demonstrated to increase adenosine level, and used diffusion MRI and relevant imaging modalities to assess its therapeutical effects on behavioral deficits and white matter defects in Tsc2^+/- mice. We also analyzed the myelin ultrastructural changes using transmission electron microscopy and examined the expression oligodendrocytes- and myelination-associated proteins after the treatment.</p><p><strong>Results: </strong>J4 treatment improved both cognitive deficits and anxiety-like behavior in Tsc2^+/- mice, and ameliorated white matter abnormalities through enhancing myelin sheath integrity. We also demonstrated that J4 mitigates gray matter cytoskeletal disorganization, along with increased expression of key mature oligodendrocyte- and myelin-associated proteins. Furthermore, J4 significantly reduced the aberrant overexpression of pS6 and cFos, both of which are elevated in Tsc2^+/- mice as a result of hyperactivation of mTOR and heightened neuronal activity.</p><p><strong>Conclusion: </strong>Altogether, these findings indicate that J4 modulates oligodendroglial lineage populations, enhances myelination, and improves neural connectivity by regulating neuronal hyperactivity. Our results suggest that J4 is a strong therapeutic candidate for addressing the neuropsychiatric manifestations of TSC.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13274077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271593","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":"Nuclear PD-L1: an emerging oncogenic driver and promising therapeutic target in cancer.","authors":"Citing Guo, Zenan Fan, Cuiyan Guo, Yaning Yang, Helei Hou, Dantong Sun","doi":"10.1186/s12929-026-01268-5","DOIUrl":"10.1186/s12929-026-01268-5","url":null,"abstract":"<p><p>Programmed cell death-ligand 1 (PD-L1) is best known as a membrane immune checkpoint; however, accumulating evidence indicates that PD-L1 can also localize to the nucleus, where it may exert PD-1-independent, cell-intrinsic functions in cancer. Emerging studies associate nuclear PD-L1 (nPD-L1) with aggressive disease, therapeutic resistance, and poor outcomes across multiple malignancies. In this review, we summarize current evidence regarding the regulatory mechanisms that may govern PD-L1 nuclear translocation, including post-translational modifications, stress-responsive signaling, and importin-dependent trafficking. We further discuss how nPD-L1 has been linked to adaptive programs involving DNA damage repair, metabolic rewiring, transcriptional regulation, and tumor microenvironment remodeling in context-dependent models. Clinically, nPD-L1 has potential relevance as a prognostic biomarker and as a candidate indicator of resistance to immunotherapy, radiotherapy, and chemotherapy, although prospective validation remains limited. We also highlight current challenges in detection and quantification, including the need for standardized multiplex imaging and digital pathology approaches. Finally, we discuss emerging therapeutic strategies aimed at disrupting PD-L1 nuclear trafficking or selectively targeting nuclear PD-L1-associated functions. Collectively, these findings support nPD-L1 as an important and potentially actionable dimension of PD-L1 biology that warrants further mechanistic and translational investigation.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271562","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}