Journal of Biomedical Science最新文献

{"title":"Association of antibody and T cell receptor repertoires in Trypanosoma cruzi infected rhesus macaques and host response to infection.","authors":"Rachel M Clear, Weihong Tu, Kelly Goff, Preston A Marx, Claudia Herrera, Eric Dumonteil","doi":"10.1186/s12929-025-01152-8","DOIUrl":"10.1186/s12929-025-01152-8","url":null,"abstract":"<p><strong>Background: </strong>Chagas disease, caused by Trypanosoma cruzi parasites, leads to chronic cardiac disease in 20-40% of infected patients, while the majority remain asymptomatic. The mechanisms and drivers of pathogenesis are still poorly understood, limiting treatment options. We tested for differences in immunoglobulin (Ig) and T cell receptor (TCR) repertoires and their association with T. cruzi parasite diversity (i.e. the cruziome) and host responses in naturally infected rhesus macaques.</p><p><strong>Methods: </strong>Ig and TCR complementarity-determination region (CDR)3 sequences were identified from RNA-sequencing data from peripheric blood mononuclear cells of T. cruzi infected rhesus macaques and analyzed for composition and diversity.</p><p><strong>Results: </strong>T. cruzi chronic infection was associated with a broader Ig clonotype repertoire, while TCR repertoire presented limited clonal expansion. There was a high individual diversity as most of these repertoires were private, although a few public clonotypes were detected. Remarkably, limited differences in Ig and TCR repertoires were found in association with the cruziome of infected macaques, even though parasite diversity seemed to play an important in shaping the immune response.</p><p><strong>Conclusion: </strong>Chronic T. cruzi infection is associated with strong alterations in Ig and TCR repertoires in rhesus macaques, but these repertoires are minimally affected by parasite diversity and host responses to infection. A better understanding of these processes could help develop new immunotherapies against T. cruzi infection.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"58"},"PeriodicalIF":9.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325915","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 neuroinflammation: 3-monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration.","authors":"Shih Chang Hsueh, Pathik Parekh, Buyandelger Batsaikhan, Neil Vargesson, David Tweedie, Weiming Luo, Chirag N Patel, Dong Liu, Ross A McDevitt, Abdul Mannan Baig, Yu Kyung Kim, Sun Kim, Inho Hwang, Juwan Kim, Mee Youn Lee, Anna R Carta, Warren R Selman, Barry J Hoffer, Dong Seok Kim, Nigel H Greig","doi":"10.1186/s12929-025-01150-w","DOIUrl":"10.1186/s12929-025-01150-w","url":null,"abstract":"<p><strong>Background: </strong>Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuroinflammation holds significant therapeutic promise, clinical trials of available anti-inflammatory agents have fallen short. 3-Mono-thiopomalidomide (3-MP), a novel immunomodulatory imide drug (IMiD), was designed to curb inflammation without the adverse effects of traditional IMiDs and was evaluated across models involving neuroinflammation.</p><p><strong>Methods: </strong>3-MP anti-inflammatory activity was evaluated across cellular (RAW 264.7, IMG cells) and mouse studies following lipopolysaccharide (LPS)-challenge (for pro- and anti-inflammatory cytokines/chemokines), and mice subjected to controlled cortical impact (CCI) moderate traumatic brain injury (TBI). 3-MP human cereblon binding, including neosubstrate and molecular modeling evaluation, as well as chicken teratogenicity, ex vivo mouse and human stability studies, and mouse pharmacokinetics were appraised.</p><p><strong>Results: </strong>3-MP binds human cereblon, a key protein in the E3 ubiquitin ligase complex, without triggering downstream cascades leading to thalidomide-like teratogenicity in chicken embryos. 3-MP reduces pro-inflammatory markers in LPS-stimulated mouse macrophage and microglial cell cultures, and lowers pro-inflammatory cytokine/chemokine levels in plasma and brain of mice challenged with systemic LPS without lowering anti-inflammatory IL-10. 3-MP readily enters brain following systemic administration, and achieves a brain/plasma concentration ratio of 0.44-0.47. 3-MP mitigates behavioral impairments and reduces activation of astrocytes and microglia in mice challenged with CCI TBI.</p><p><strong>Conclusion: </strong>3-MP represents a promising new class of thalidomide-like IMiDs with potent anti-inflammatory effects that offers potential for treating TBI and possibly other neurodegenerative diseases possessing a prominent neuroinflammatory component.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"57"},"PeriodicalIF":9.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309989","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":"Involvement of nucleic acid-sensing toll-like receptors in human diseases and their controlling mechanisms.","authors":"You-Sheng Lin, Yung-Chi Chang, Tzu-Yu Pu, Tsung-Hsien Chuang, Li-Chung Hsu","doi":"10.1186/s12929-025-01151-9","DOIUrl":"10.1186/s12929-025-01151-9","url":null,"abstract":"<p><p>The innate immune system is the host's initial response to eliminate pathogens and repair tissue damage. Innate immune cells, such as macrophages and dendritic cells, use pattern recognition receptors (PRRs) to recognize microbial structures and stress-induced molecules released from dead or damaged cells, thereby initiating immune responses. Among PRRs, Toll-like receptors (TLRs) are well-studied and are located either on the cell surface or in endosomal compartments. Most endosomal TLRs specifically recognize nucleic acids and are thus referred to as nucleic acid (NA)-sensing TLRs. Upon activation, these receptors induce the production of inflammatory cytokines and type I interferons and initiate subsequent adaptive immunity. These immune responses work to suppress pathogens and inhibit tumor growth. However, excessive cytokine and interferon production can lead to various inflammatory diseases. This review focuses on mammalian nucleic acid-sensing TLRs, summarizing the molecular regulation of their activations, the impact of their dysregulation on human diseases, and therapeutic strategies that target these TLRs.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"56"},"PeriodicalIF":9.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266278","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":"Probiotics ameliorate H. pylori-associated gastric β-catenin and COX-2 carcinogenesis signaling by regulating miR-185.","authors":"Yao-Jong Yang, Chung-Tai Wu, Hsiu-Chi Cheng, Wei-Ying Chen, Joseph T Tseng, Wei-Lun Chang, Bor-Shyang Sheu","doi":"10.1186/s12929-025-01149-3","DOIUrl":"10.1186/s12929-025-01149-3","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to investigate whether probiotics can ameliorate the H. pylori-induced Wnt/β-catenin-related COX-2 carcinogenesis signaling pathway by regulating the expression of microRNAs (miRNAs).</p><p><strong>Methods: </strong>An H. pylori isolate and GES-1 cells were used to establish a COX-2-associated carcinogenesis axis. Western blot analysis was conducted to investigate Wnt/β-catenin and COX-2 signaling. Next-generation sequencing and DIANA Tools identified significant differences in miRNA expressions. The probiotics Lactobacillus acidophilus and Bifidobacterium lactis were used to study anti-carcinogenesis effects in GES-1 and miRNA-transfected GES-1 cells. The H. pylori-infected patients with intestinal metaplasia (IM) were randomly allocated into probiotic treatment or not after successful eradication, the IM regression was assessed by the 2nd esophagogastroduodenoscopy one year after treatment.</p><p><strong>Results: </strong>Pretreatment with probiotics significantly reduced H. pylori-induced nuclear β-catenin phosphorylation and COX-2 levels in GES-1 cells. Among 9 significantly altered miRNAs, miR-185 was the only miRNA targeting the Wnt/β-catenin signaling pathway. H. pylori increased miR-185 expression and upregulated COX-2 carcinogenesis through the Wnt/β-catenin pathway, but not the JAK2/STAT3 pathway. B. lactis ameliorated H. pylori-induced miR-185 expression and nuclear β-catenin/COX-2 signaling in a dose-dependent manner. In the 6-month probiotic-treated patients had a significantly higher IM regression rate than controls (intention-to-treat: 37.5 vs 11.5%, OR: 4.60, 95% CI: 1.134-18.65, p = 0.025; per-protocol: 46.2 vs 17.6%, OR: 4.00, 95% CI: 0.923-17.33, p = 0.055). Patients without IM regression had significantly higher miR-185 levels in follow-up biopsies (p < 0.01).</p><p><strong>Conclusions: </strong>Pretreatment with B. lactis ameliorated the H. pylori-induced COX-2 carcinogenesis pathway by reducing miR-185 expression, which targets Wnt/β-catenin signaling. (ClinicalTrials.gov, NCT05544396).</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"55"},"PeriodicalIF":9.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215967","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":"USP24 upregulation stabilizes PKA-Cα to promote lipogenesis, inflammation, and fibrosis during MASH progression.","authors":"Beh Ning, Shao-An Wang, Ming-Jer Young, Yung-Ching Chen, Yun Hung, Tran Thu Huong, Wen-Chang Chang, Yi-Ching Wang, Ming-Lung Yu, Kai-Cheng Hsu, Jan-Jong Hung","doi":"10.1186/s12929-025-01148-4","DOIUrl":"10.1186/s12929-025-01148-4","url":null,"abstract":"<p><strong>Background: </strong>Ubiquitin-specific peptidase 24 (USP24), a deubiquitinating enzyme, regulates protein stability by removing ubiquitin. This study investigates the role of UPS24 in lipid metabolism, inflammation, and fibrosis. It also explores the effect of targeting USP24 on metabolic disorders, focusing on high-fat diet (HFD)-induced obesity and liver diseases.</p><p><strong>Methods: </strong>This study utilized CRISPR/Cas9 to create functional knockout mice (USP24^C1695A) and treated HFD-fed mice with USP24 inhibitor (USP24-i-101). The effects of USP24 inhibition or knockout on 3T3-L1 derived adipocytes, primary hepatocytes, hepatic stellate cells, and murine hepatocyte cell line AML12 (alpha mouse liver 12) cells were assessed with RNA-sequencing. Molecular mechanisms and the interaction between USP24 and PKA-Cα were studied with co-immunoprecipitation. Downstream signaling pathways involving CREB, SREBP1, PPARγ, and C/EBPβ, as well as USP24 role in liver inflammation and fibrosis, were studied using western blot and real-time PCR. Clinical and animal tissue samples were examined with immunohistochemistry to identify the correlations between USP24 and metabolic-associated liver diseases.</p><p><strong>Results: </strong>Knockout or inhibition of USP24 reduced body weight, lipid accumulation, inflammation, and fibrosis in HFD-fed mice. The expression of genes related to lipogenesis, inflammation, and fibrosis was downregulated in USP24^C1695A mice and those treated with USP24 inhibitor (USP24-i-101). USP24 inhibition decreased lipid droplet accumulation in adipocytes and hepatocytes, suppressed inflammation in hepatocytes and AML12 cells, and reduced fibrosis in hepatic stellate cells. Mechanistically, USP24 expression was upregulated by PKA activation during adipocyte differentiation, leading to increased PKA-Cα stability and CREB phosphorylation, which promoted lipogenic gene expression. Free fatty acids (FFA) increased USP24 expression, activating NF-κB and TGFβ pathways to induce inflammation (Cox2) and fibrosis (α-SMA). USP24 was highly expressed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and correlated with Cox2 and α-SMA levels.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"54"},"PeriodicalIF":9.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187122","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":"AbOmpA in Acinetobacter baumannii: exploring virulence mechanisms of outer membrane-integrated and outer membrane vesicle-associated AbOmpA and developing anti-infective agents targeting AbOmpA.","authors":"Man Hwan Oh, Md Minarul Islam, Nayeong Kim, Chul Hee Choi, Minsang Shin, Woo Shik Shin, Je Chul Lee","doi":"10.1186/s12929-025-01147-5","DOIUrl":"10.1186/s12929-025-01147-5","url":null,"abstract":"<p><p>Acinetobacter baumannii is notorious for its antimicrobial resistance and its potential to cause epidemics in hospital settings, which pose a global health threat. Although this microorganism is traditionally considered a low-virulence pathogen, extensive research has been conducted on its virulence and pathogenesis in recent years. Advances in understanding the virulence mechanisms of A. baumannii have prompted a shift in the development of anti-infective agents. The outer membrane protein A (AbOmpA) of A. baumannii is a key virulence factor both in vitro and in vivo. AbOmpA exists in three forms: outer membrane-integrated AbOmpA, outer membrane vesicle (OMV)-associated AbOmpA, and free proteins. Given that outer membrane-integrated AbOmpA has been implicated in the virulence and antimicrobial resistance of A. baumannii, many studies have focused on outer membrane-integrated AbOmpA as a therapeutic target for combating drug-resistant A. baumannii, and have led to the discovery of small molecules, polypeptides, and antimicrobial peptides targeting AbOmpA. However, the pathophysiological role of OMV-associated AbOmpA and its impact on AbOmpA-targeting agents remain unclear. This review summarizes the current knowledge of AbOmpA and critically discusses OMV-associated AbOmpA in relation to virulence and its potential impact on AbOmpA-targeted therapies to provide a better understanding of AbOmpA for the development of novel therapeutics against A. baumannii.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"53"},"PeriodicalIF":9.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12108004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159345","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":"Adjunctive beneficial effect of c-di-GMP, a STING agonist, in enhancing protective efficacy of TLR4-adjuvanted tuberculosis subunit vaccine formulations.","authors":"Kee Woong Kwon, Eunsol Choi, Hagyu Kim, Hyeong Woo Kim, Sangwon Choi, Seunghyun Lee, Sang-Jun Ha, Sung Jae Shin","doi":"10.1186/s12929-025-01144-8","DOIUrl":"10.1186/s12929-025-01144-8","url":null,"abstract":"<p><strong>Background: </strong>Effective subunit vaccine development requires selecting appropriate adjuvant formulations to trigger desired adaptive immune responses. This study explores the immunogenicity and tuberculosis (TB) vaccine potential of antigens (Ags) combined with Toll-like receptor 4 (TLR4) adjuvants and a stimulator of interferon genes (STING) agonist.</p><p><strong>Methods: </strong>In this work, we investigated the combination of Ags with TLR4 adjuvants (monophosphoryl lipid A / dimethyldioctadecylammonium bromide; MPL/DDA or glucopyranosyl lipid adjuvant-stable emulsion; GLA-SE) and a STING agonist, c-di-GMP (CDG). Mice were immunized three times by intramuscular injections at 3-week intervals. The effects of integrating Ags in these adjuvant formulations on the immune response were evaluated, focusing on the generation of Th1-biased, polyfunctional Ag-specific CD4⁺ T cells and their localization in the lung and spleen. To assess protection, immunized mice were aerogenically challenged with either conventional or ultra-low doses of Mycobacterium tuberculosis (Mtb) 4 weeks after the last immunization. Subsequently, bacterial load and pulmonary inflammation were assessed.</p><p><strong>Results: </strong>Integrating ESAT6 Ag in TLR4 and CDG adjuvant formulations remarkably boosted Th1-biased, polyfunctional ESAT6-specific CD4⁺ T cells in the lungs and spleen, providing durable protection against Mtb infection. The inclusion of CDG promoted mucosal localization of ESAT6-specific CD4⁺ T cells resembling resident memory phenotypes in the lung parenchyma and increased Ag-specific CD4⁺ T cells in lung vasculature. Immunization with another vaccine Ag candidate, Ag85B, in GLA-SE plus CDG similarly increased Ag85B-specific CD4⁺ T cells in the spleen and both lung compartments. Following ultra-low dose Mtb challenge, ESAT6 or Ag85B/GLA-SE/CDG immunizations significantly reduced bacterial loads compared to non-, Bacillus Calmette-Guérin (BCG)-, and ESAT6 or Ag85B/GLA-SE-immunized groups. Importantly, the inclusion of CDG decreased killer cell lectin-like receptor subfamily G member 1 (KLRG1) expression among Ag-specific CD4⁺ T cells in the lung, correlating with enhanced lung-homing evidenced by expanded lung parenchyma Ag-specific CD4⁺ T cells, including less-differentiated Th1 cells.</p><p><strong>Conclusions: </strong>This study highlights that CDG, when used in combination with TLR4 adjuvants, enhances long-term protective immunity, offering a promising strategy for subunit TB vaccine development.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"52"},"PeriodicalIF":9.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12105139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142590","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":"Meta-epigenetic shifts in T cell aging and aging-related dysfunction.","authors":"Lorène Rousseau, Karina L Hajdu, Ping-Chih Ho","doi":"10.1186/s12929-025-01146-6","DOIUrl":"10.1186/s12929-025-01146-6","url":null,"abstract":"<p><p>Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases. In CD8⁺ T cells, chromatin closure at key regulatory regions suppresses activation and migration, while chromatin opening in pro-inflammatory gene loci amplifies inflammation. These changes drive terminal differentiation, characterized by increased expression of senescence-associated markers, impaired migration and loss of epigenetic plasticity. CD4⁺ T cells experience fewer but critical epigenetic alterations, including disrupted pathways, a skewed Th1/Th2 balance, and reduced Treg functionality. These epigenetic changes, compounded by metabolic dysfunctions, such as mitochondrial deficiency and oxidative stress, impair T-cell adaptability and resilience in the aging organism. Therefore, understanding the interplay between epigenetic and metabolic factors in T cell aging offers promising therapeutic opportunities to mitigate immunosenescence and enhance immune function in aging populations. This review explores the interplay between DNA methylation, histone alterations, and metabolic changes underlying T cell aging.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"51"},"PeriodicalIF":9.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132437","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 the genomic and transcriptomic profiles of glycemic traits and drug repurposing.","authors":"Min-Rou Lin, Cheng-Lin Tsai, Cai-Sian Liao, Chun-Yu Wei, Wan-Hsuan Chou, Tzu-Hung Hsiao, Wei-Chiao Chang","doi":"10.1186/s12929-025-01137-7","DOIUrl":"10.1186/s12929-025-01137-7","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes is an increasingly prevalent metabolic disorder with moderate to high heritability. Glycemic indices are crucial for diagnosing and monitoring the disease. Previous genome-wide association study (GWAS) have identified several risk loci associated with type 2 diabetes, but data from the Taiwanese population remain relatively sparse and primarily focus on type 2 diabetes status rather than glycemic trait levels.</p><p><strong>Methods: </strong>We conducted a comprehensive genome-wide meta-analysis to explore the genetics of glycemic traits. The study incorporated a community-based cohort of 145,468 individuals and a hospital-based cohort of 35,395 individuals. The study integrated genetics, transcriptomics, biological pathway analyses, polygenic risk score calculation, and drug repurposing for type 2 diabetes.</p><p><strong>Results: </strong>This study assessed hemoglobin A1c and fasting glucose levels, validating known loci (FN3K, SPC25, MTNR1B, and FOXA2) and discovering new genes, including MAEA and PRC1. Additionally, we found that diabetes, blood lipids, and liver- and kidney-related traits share genetic foundations with glycemic traits. A higher PRS was associated with an increased risk of type 2 diabetes. Finally, eight repurposed drugs were identified with evidence to regulate blood glucose levels, offering new avenues for the management and treatment of type 2 diabetes.</p><p><strong>Conclusions: </strong>This research illuminates the unique genetic landscape of glucose regulation in Taiwanese Han population, providing valuable insights to guide future treatment strategies for type 2 diabetes.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"50"},"PeriodicalIF":9.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119819","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":"Gemcitabine resistance by CITED4 upregulation via the regulation of BIRC2 expression in pancreatic cancer.","authors":"Eun-Jeong Jeong, Yuna Roh, Eunsun Jung, Jin-Seong Hwang, Taesang Son, Hyun Seung Ban, Tae-Su Han, Young-Kug Choo, Jang-Seong Kim","doi":"10.1186/s12929-025-01140-y","DOIUrl":"10.1186/s12929-025-01140-y","url":null,"abstract":"<p><strong>Background: </strong>Gemcitabine (GEM) is used as a first-line therapy for patients diagnosed with any stage of pancreatic cancer (PC); however, patient survival is poor because of GEM resistance. Thus, new approaches to overcome GEM resistance in PC are urgently needed. Here, we aimed to establish an in vivo drug-resistant PC model and identify genes involved in GEM resistance. We focused on one of these factors, CITED4, and elucidated its mechanisms of action in GEM resistance in PC.</p><p><strong>Methods: </strong>L3.6pl, a GEM-sensitive PC cell line, was orthotopically injected into the pancreas of BALB/c nude mice to establish a GEM-resistant PC animal model. Transcriptomic data from control or GEM-resistant tumor-derived cells were analyzed. GEM resistance was evaluated using cell viability, clonogenicity, and apoptosis assays. An apoptosis array was used to identify genes downstream of CITED4. A CITED4 knockout-mediated GEM sensitivity assay was performed in an orthotopic xenograft mouse model using PANC-1 cells, which are GEM-resistant cells.</p><p><strong>Results: </strong>From the RNA sequencing data of isolated GEM-resistant PC cells and The Cancer Genome Atlas dataset, 15 GEM resistance-related genes were found to be upregulated, including CITED4, the gene encoding a type of CBP/p300-interacting transactivator implicated in several cancers. CITED4 knockdown in drug-resistant cells reduced cell proliferation and migration but increased apoptosis. To identify the molecular mechanism underlying CITED4-mediated induction of GEM resistance, alterations in Baculoviral IAP Repeat Containing 2 (BIRC2) levels were observed using an apoptosis array. BIRC2 expression was downregulated following CITED4 knockdown in GEM-resistant PC cell lines. Furthermore, chromatin immunoprecipitation and promoter assays showed that BIRC2 was directly regulated by CITED4. Consistent with the CITED-knockdown experiments, silencing of BIRC2 increased the sensitivity of L3.6pl-GEM-resistant and PANC-1 cell lines to GEM. Furthermore, CITED4 knockout using the CRISPR-Cas9 system in PANC-1 cells increased the sensitivity to GEM in orthotopic mice. Moreover, elevated CITED4 and BIRC2 expression levels were associated with poorer outcomes in human PC clinical samples.</p><p><strong>Conclusions: </strong>Collectively, these results indicate that CITED4 regulates GEM resistance via inhibition of apoptosis by upregulating BIRC2 expression in PC cells. Therefore, CITED4 may serve as a valuable diagnostic marker and therapeutic target for GEM-resistant PC.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"49"},"PeriodicalIF":9.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101833","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}