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Associated Press
02-04-2025
- Health
- Associated Press
YTHDF1 Identified As a Potential Therapeutic Target for Autoimmune Hepatitis
New Study Underscores The Pivotal Role Of YTHDF1 In Immune-Mediated Hepatitis / -- Autoimmune hepatitis (AIH) is a severe autoimmune disease characterized by immune-mediated hepatocyte destruction, leading to hepatic necroinflammation, cirrhosis, and potential fatality. N6-methyladenosine (m6A), a prevalent post-transcriptional mRNA modification, dynamically regulates various cellular processes. However, the relationship between AIH and m6A and its regulators remains poorly understood. This research, published in the Genes & Diseases journal by a team from Xiamen University, addresses the role of m6A and its regulators in T cell-mediated hepatitis. In this study, the researchers utilized concanavalin A (ConA)-induced mouse liver damage as an experimental model for T cell-mediated hepatitis. Initial investigations revealed that the protein expression of m6A readers, YTHDF1, YTHDF2, and YTHDF3, during the early stage of ConA-induced hepatitis was dramatically decreased in the liver. Notably, YTHDF1-deficient (Ythdf1−/−) mice showed more susceptibility to ConA-induced liver injury, along with an intensified inflammatory storm accompanied by an aggravated hepatic inflammatory response via ERK and nuclear factor-kappa B (NF-κB) pathways. This study not only highlights the crucial role of YTHDF1 in hematopoietic cells in suppressing T cell-mediated liver injury but also suggests an immunomodulatory and anti-inflammatory role for YTHDF1 in T cell-mediated hepatitis. Furthermore, Ythdf1−/− mice exhibited higher serum levels of proinflammatory cytokines upon ConA challenge, indicating that YTHDF1 deficiency sensitizes inflammatory cells to ConA, intensifying cytokine production and exacerbating hepatic inflammation. Interestingly, the activation of the NF-κB pathway and MAPKs signaling after ConA treatment in Ythdf1−/− mice further emphasizes the role of YTHDF1 in suppressing inflammatory responses. Additionally, immunohistochemical staining results revealed significantly higher CD4+ cell numbers in the ConA-treated Ythdf1−/− mice livers than in wild type mice, implying that YTHDF1 deficiency could increase the infiltration and activation of inflammatory cells. Furthermore, this study demonstrates that YTHDF1 deletion in macrophages exacerbates lipopolysaccharide-induced inflammatory responses, emphasizing the necessity of YTHDF1 in immune cells for an effective inflammatory response. In summary, this study uncovered that YTHDF1 deficiency exacerbates the immune response in ConA-induced hepatitis by modulating the expression of inflammatory mediators, highlighting the potential of YTHDF1 as a promising therapeutic target for clinical hepatitis. Reference Title of Original Paper: YTHDF1 shapes immune-mediated hepatitis via regulating inflammatory cell recruitment and response Journal: Genes & Diseases Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch DOI: Funding Information: National Natural Science Foundation of China (No. 81772539, 81972238) Fundamental Research Funds for the Central Universities of China-Xiamen University (No. 20720180048) # # # # # # Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine. # # # # # # CN: 50-1221/R X (formerly Twitter): @GenesNDiseases ( Genes & Diseases Editorial Office Genes & Diseases +86 23 6571 4691 X LinkedIn Instagram YouTube Other Legal Disclaimer:
Associated Press
28-03-2025
- Health
- Associated Press
Sexual Dimorphism in Cystinuria- The Mitochondria Link
Unravelling the role of mitochondrial Slc3a1 in regulating mitochondrial functions and sexual dimorphism in cystinuria CHINA, March 28, 2025 / / -- Cystinuria is the most common inheritable cause of kidney stone disease, characterized by impaired reabsorption of cystine and dibasic amino acids in the renal proximal tubules. It exhibits a sex-dependent response, with males experiencing an earlier onset of stone formation and a high number of large-sized stones; however, the cellular origin and mechanisms underlying this sexual dimorphism remains elusive. Recent studies have shown that mitochondrial dysfunction plays a key role in the pathogenesis of renal diseases. It has also been evidenced that there are significant sex-related differences in mitochondrial morphology, function, and homeostasis, as well as variations in response to acute kidney injury and progression of chronic kidney disease. In a recent study published in the Genes & Diseases journal, researchers from Shanghai Jiao Tong University School of Medicine, East China Normal University, Shanghai University of Traditional Chinese Medicine, Tongji University, and Fudan University unravel the critical role of mitochondrial Slc3a1 in regulating mitochondrial functions and sexual dimorphism in cystinuria. To investigate the mechanisms underlying sexual dimorphism in cystinuria, the authors examined stone formation and kidney injury in Slc3a1 knock-out (KO) mice, Slc3a1, Slc7a13 double KO mice, and orchiectomized Slc3a1 KO mice. The Slc3a1 KO female mice had smaller and less severe bladder stones, concomitant with a lower expression of fibrotic and immune markers than the Slc3a1 KO male mice, showing that cystinuria was more pronounced in males than in females. This severity could not be rescued even upon double KO of Slc3a1 and Slc7a13 or orchidectomy, which establishes that the male susceptibility to cystinuria is dependent on Slc3a1 and independent of Slc7a13. Mitochondrial functions were found to be impaired in the renal tubule cells of Slc3a1 KO male kidneys, resulting in exacerbated damage caused by the accumulating debris and formation of cystine crystal-containing stones; whereas, high SLC3A1 protein levels were associated with enhanced mitochondrial functions in the kidney. By integrating unbiased bulk RNA sequencing, single-cell RNA sequencing, and molecular experiments, the authors showed that i) the differential mitochondrial functions between SLC3A1high male kidneys and SLC3A1low female kidneys primarily arise in the proximal tubule cells; and ii) Slc3a1 enhances mitochondrial functions by increasing mitochondrial NAD+ uptake in the proximal tubules. In conclusion, this study highlights the critical role of mitochondrial functions in regulating sexual dimorphism in cystinuria. It also suggests that restoring mitochondria in renal tubules of male cystinuria patients may improve mitochondrial function, leading to reduced cell death and attenuation of fibro-inflammation in the renal tubules. Reference Title of the original paper - Mitochondrial SLC3A1 regulates sexual dimorphism in cystinuria. Journal - Genes & Diseases Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. DOI - Funding Information: Science and Technology Commission of Shanghai Municipality of China (No. 23Y21900102; 23ZR1467900 to Q.W.) Shanghai Rising-Star Program (No. 22QA1405900) The National Key R&D Program of China (No. 2022YFC2505400, 2022YFC3400203) The National Natural Science Foundation of China (No. 82100773; 82101486, 82371426) The Natural Science Foundation of Chongqing, China (No. CSTB2022NSCQ-MSX1621) The Ningxia Hui Autonomous Region Key Research and Development Project (China) (No. 2022BFH02012) # # # # # # Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine. # # # # # # CN: 50-1221/R Genes & Diseases Editorial Office Genes & Diseases +86 23 6571 4691 X LinkedIn Instagram YouTube Other Legal Disclaimer:
Associated Press
25-03-2025
- Health
- Associated Press
New genetic insights into hypospadias: MAFB and CEBPA's role in urothelial growth
GA, UNITED STATES, March 25, 2025 / / -- A recent study has unveiled the critical roles of two transcription factors, MAFB and CEBPA, in the development of hypospadias, a common congenital malformation affecting male urethral development. The research reveals that MAFB and CCAAT/enhancer-binding protein alpha (CEBPA) regulate urothelial cell growth via the Wnt/β-catenin signaling pathway, offering new insights into the genetic mechanisms underlying this condition. These findings pave the way for innovative therapeutic strategies and a deeper understanding of the genetic and molecular foundations of hypospadias. Hypospadias is characterized by an ectopic urethral opening and abnormal penile curvature, affecting approximately 1 in 200 live male births. While its origins are believed to stem from a combination of genetic and environmental factors, androgen signaling pathways are thought to play a significant role in the condition's development. Despite progress in identifying the genetic components, the precise molecular mechanisms remain poorly understood. Previous studies have suggested that the Wnt/β-catenin signaling pathway is involved in urethral development, but the specific contributions of transcription factors such as MAFB and CCAAT/enhancer-binding protein alpha (CEBPA) have yet to be fully explored. This gap in understanding highlights the need for in-depth research to elucidate the pathways involved in hypospadias. On September 13, 2024, a study (DOI: 10.1016/ published in Genes & Diseases and led by researchers from the Children's Hospital of Chongqing Medical University in China identified MAFB and CEBPA as crucial regulators of urothelial cell growth. By influencing cell proliferation and apoptosis through the Wnt/β-catenin signaling pathway, MAFB and CEBPA play a significant role in the genetic mechanisms of hypospadias. This research lays a strong foundation for future studies aimed at developing targeted therapies for this prevalent congenital condition. The study focused on the roles of MAFB and CEBPA in urothelial cell growth, utilizing human foreskin samples and mouse models. The researchers found that expression levels of MAFB and CEBPA were significantly reduced in the foreskin tissues of hypospadias patients. Using RNA sequencing and Western blot analysis, they discovered that MAFB knockdown led to suppressed CEBPA protein expression, inhibiting the Wnt/β-catenin pathway and causing cell cycle arrest and increased apoptosis in urothelial cells. Furthermore, MAFB overexpression promoted cell proliferation and activated the Wnt/β-catenin pathway, while CEBPA knockdown reversed these effects. These findings highlight the pivotal role of the MAFB-CEBPA axis in regulating urothelial cell growth and suggest that disruptions in this pathway may contribute to hypospadias development. The study also pinpointed potential therapeutic targets for future interventions. Dr. Xing Liu, the corresponding author of the study, commented, 'Our findings provide a deeper understanding of the molecular mechanisms underlying hypospadias. By identifying the roles of MAFB and CEBPA in urothelial growth, we have uncovered potential targets for therapeutic intervention, which could lead to improved outcomes for patients with this condition.' The discovery of the MAFB-CEBPA regulatory pathway holds immense potential for advancing the treatment and prevention of hypospadias. By targeting this pathway, researchers could develop novel therapies to correct or prevent the malformation during early development. Additionally, the study opens exciting new avenues for exploring the genetic and molecular underpinnings of other congenital disorders related to urethral development. Future research may focus on identifying additional genetic factors and environmental influences that interact with the MAFB-CEBPA pathway, further advancing our understanding of hypospadias and related conditions. DOI 10.1016/ Original Source URL Funding information This work was financed by the National Natural Science Foundation of China (No. 81970571), the Natural Science Foundation of Chongqing Municipality, China (No. CSTB2022NSCQ-MSX1001), and the Program for Youth Innovation in Future Medicine, Chongqing Medical University (No. W0109). Lucy Wang Legal Disclaimer:
Associated Press
17-03-2025
- Health
- Associated Press
Transcriptional Landscape of PDAC Shows Distinct Cell Populations
Single-cell RNA sequencing (scRNA-seq) on a PDAC cohort identified distinct cell populations associated with tumor initiation and progression CHINA, March 17, 2025 / / -- Pancreatic cancer is one of the leading causes of cancer-related mortality, with pancreatic ductal adenocarcinoma (PDAC) accounting for 90% of all cases. As most PDAC cases are diagnosed at advanced stages, surgical interventions are ineffective, and consequently, lymph node metastasis manifests in 70% of PDAC patients. Moreover, since the number of genetic mutations giving rise to PDAC are low, there are fewer available targeted therapeutic modalities. Analysis of gene expression at the single-cell level may help understand the tumor dynamics of PDAC. In a recent study published in the Genes & Diseases journal, researchers at Fudan University Shanghai Cancer Center and Shanghai Jiao Tong University School of Medicine performed single-cell RNA sequencing (scRNA-seq) on eight PDAC patients with varying lymph node metastasis (LNM) statuses to understand the transcriptional landscape regulating PDAC development and identify novel therapeutic targets. scRNA-seq of LNM and non-LNM primary PDAC showed a heterogeneous cellular composition and identified four distinct cell populations: the MMP1+ & S100A2+ tumor cells, CCL2+ macrophages, and OMD+ fibroblasts. An integrated analysis comparing PDAC and normal pancreatic epithelial tissues revealed a pancreatic intraepithelial neoplasia (PanIN) subset with increased ONECUT2 (one cut domain family member 2) expression. This subset had a high MMP1 expression and is an intermediary between normal acinar cells and PDAC cells. Further results showed that MMP1 predicts unfavorable prognosis in PDAC patients and plays an important role in sustaining ductal identity in PDAC. The S100A2+subset cells had increased expression of genes associated with tumor progression and poor prognosis. In vitro studies showed that S100A2 enhances the migratory capability of cancer cells while its knockdown led to decreased expression of EMT genes and cell-adhesion mediated drug resistance. Analysis of the immune cell subsets in the PDAC microenvironment showed a higher presence of pro-metastatic sub-populations within the immune cell milieu in PDAC tumors with LNM than in PDAC without LNM. This population was rich in CCL2+ macrophages, which play a role in EMT, immunosuppression, and indirect activation of cytotoxic CD8+ cells and are associated with poor disease-specific survival. Analysis of the stromal compartment revealed a subset of OMD+ fibroblasts that regulate tumorigenesis and metastasis by recruiting CCL2+ macrophages to create a pro-tumor environment. In conclusion, this study identified OMD+ fibroblasts, CCL2+ macrophages, S100A2+, and MMP1+ tumor cells as key cell subsets that collectively contribute to a pro- tumor microenvironment conducive to LNM in PDAC and may serve as potential therapeutic targets. Reference Title of the original paper - The scRNA-sequencing landscape of pancreatic ductal adenocarcinoma revealed distinct cell populations associated with tumor initiation and progression Journal: Genes & Diseases Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. DOI: Funding Information: National Natural Science Foundation of China (No. 82272095, 82072638 and 82002537). Zhangjiang National Innovation Demonstration Zone (Shanghai, China) (No. ZJ2021-ZD-007) The Biobank Program of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China) (No. YBKB202217) # # # # # # Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine. # # # # # # X (formerly Twitter): @GenesNDiseases ( Genes & Diseases Editorial Office Genes & Diseases +86 23 6571 4691 X LinkedIn Instagram YouTube Other Legal Disclaimer:
Associated Press
11-03-2025
- Health
- Associated Press
AI-Driven Advancements in Neuroblastoma Diagnosis and Bone/Bone Marrow Metastasis Prediction
Groundbreaking Study Unveils Key Mechanisms in Neuroblastoma Bone and Bone Marrow Metastasis / -- Neuroblastoma (NB), the most prevalent extracranial solid tumor among children, is characterized by a high rate of metastasis. The pathogenesis of NB with bone or bone marrow metastasis (NB-BBM) and its complex immune microenvironment remain poorly understood, posing challenges for effective risk prediction for BBM and limiting therapeutic strategies. This research, published in the Genes & Diseases journal by a team from The Children's Hospital of Chongqing Medical University, highlights key genomic and single-cell transcriptomic alterations in NB-BBM, underscoring the significance of predictive pathology for NB-BBM and its role in understanding tumor onset, progression, and heterogeneity. The researchers used a Swin-Transformer deep learning model to analyze 142 paraffin-embedded hematoxylin-eosin-stained tumor section images to predict NB-BBM occurrence, achieving a classification accuracy exceeding 85%. In parallel, single-cell transcriptomics identified a tumor cell subpopulation (NB3) and two tumor-associated macrophage (TAM) subpopulations (SPP1+ TAMs and IGHM+ TAMs) closely associated with BBM progression. Interestingly, findings reveal that oxidative phosphorylation (OXPHOS) also plays a crucial role in BBM development. Additionally, this study highlighted transketolase (TKT) as a crucial metabolic molecule linked to BBM. The researchers showed that the TKT gene was strongly associated with the clinical features of NB patients, especially in the BBM group. Functional experiments validated TKT's involvement in malignant behavior, while pathway enrichment analysis showed correlations between high TKT expression and cell cycle activity. Moreover, expression analysis of immune checkpoint genes CD274, LAG3, and TIGIT revealed their significant upregulation in NB-BBM, suggesting potential targets for antibody-based immunotherapies. Furthermore, immunohistochemical validation demonstrated a pronounced expression of PD-L1 in NB-BBM, indicating its potential as a biomarker. Although this research provides a predictive model for NB-BBM risk assessment, it has certain limitations, including the need for multicenter validation of the predictive model and prospective studies to confirm clinical utility. Despite these challenges, this study offers a pathodiagnostic prediction for the risk of NB-BBM, enhances other imaging diagnoses, and elucidates the cellular heterogeneity of initial, progressive, and distant metastatic sites in NB. Reference Title of the original paper - Integrated multi-omics characterization of neuroblastoma with bone or bone marrow metastasis Journal: Genes & Diseases Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. DOI: Funding Information: Key Project of the National Key R&D Plan 'Research on Prevention and Control of Major Chronic Non-Communicable Diseases' (China) Ministry of Science and Technology of the People's Republic of China National Key R&D Program of China (No. 2018YFC1313000, 2018YFC1313004) # # # # # # Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine. # # # # # # CN: 50-1221/R Genes & Diseases +86 23 6571 4691 X LinkedIn Instagram YouTube Other Legal Disclaimer:
