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1.
Hepatology ; 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38385945

RESUMEN

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD. APPROACH AND RESULTS: RNA-Seq profiling (n = 146) and whole-exome sequencing (n = 132) of MASLD liver tissue samples identified 3 transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key feature for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A>T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals through mitochondrial dysfunction-related signaling of the IFI16-PYCARD-CASP1 pathway. CONCLUSIONS: This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.

2.
Biomol Ther (Seoul) ; 32(3): 291-300, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38589290

RESUMEN

Autosomal dominant polycystic kidney disease (ADPKD), a congenital genetic disorder, is a notable contributor to the prevalence of chronic kidney disease worldwide. Despite the absence of a complete cure, ongoing research aims for early diagnosis and treatment. Although agents such as tolvaptan and mTOR inhibitors have been utilized, their effectiveness in managing the disease during its initial phase has certain limitations. This review aimed to explore new targets for the early diagnosis and treatment of ADPKD, considering ongoing developments. We particularly focus on cell polarity, which is a key factor that influences the process and pace of cyst formation. In addition, we aimed to identify agents or treatments that can prevent or impede the progression of renal fibrosis, ultimately slowing its trajectory toward end-stage renal disease. Recent advances in slowing ADPKD progression have been examined, and potential therapeutic approaches targeting multiple pathways have been introduced. This comprehensive review discusses innovative strategies to address the challenges of ADPKD and provides valuable insights into potential avenues for its prevention and treatment.

3.
Sci Rep ; 14(1): 10072, 2024 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-38698208

RESUMEN

Drug repositioning aims to identify new therapeutic indications for approved medications. Recently, the importance of computational drug repositioning has been highlighted because it can reduce the costs, development time, and risks compared to traditional drug discovery. Most approaches in this area use networks for systematic analysis. Inferring drug-disease associations is then defined as a link prediction problem in a heterogeneous network composed of drugs and diseases. In this article, we present a novel method of computational drug repositioning, named drug repositioning with attention walking (DRAW). DRAW proceeds as follows: first, a subgraph enclosing the target link for prediction is extracted. Second, a graph convolutional network captures the structural features of the labeled nodes in the subgraph. Third, the transition probabilities are computed using attention mechanisms and converted into random walk profiles. Finally, a multi-layer perceptron takes random walk profiles and predicts whether a target link exists. As an experiment, we constructed two heterogeneous networks with drug-drug similarities based on chemical structures and anatomical therapeutic chemical classification (ATC) codes. Using 10-fold cross-validation, DRAW achieved an area under the receiver operating characteristic (ROC) curve of 0.903 and outperformed state-of-the-art methods. Moreover, we demonstrated the results of case studies for selected drugs and diseases to further confirm the capability of DRAW to predict drug-disease associations.


Asunto(s)
Reposicionamiento de Medicamentos , Reposicionamiento de Medicamentos/métodos , Humanos , Biología Computacional/métodos , Curva ROC , Redes Neurales de la Computación , Algoritmos , Descubrimiento de Drogas/métodos
4.
Invest Ophthalmol Vis Sci ; 65(3): 30, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38517430

RESUMEN

Purpose: Intraflagellar transport 46 (IFT46) is an integral subunit of the IFT-B complex, playing a key role in the assembly and maintenance of primary cilia responsible for transducing signaling pathways. Despite its predominant expression in the basal body of cilia, the precise role of Ift46 in ocular development remains undetermined. This study aimed to elucidate the impact of neural crest (NC)-specific deletion of Ift46 on ocular development. Methods: NC-specific conditional knockout mice for Ift46 (NC-Ift46F/F) were generated by crossing Ift46F mice with Wnt1-Cre2 mice, enabling the specific deletion of Ift46 in NC-derived cells (NCCs). Sonic Hedgehog (Shh) and Notch signaling activities in NC-Ift46F/F mice were evaluated using Gli1lacZ and CBF:H2B-Venus reporter mice, respectively. Cell fate mapping was conducted using ROSAmTmG reporter mice. Results: The deletion of Ift46 in NCCs resulted in a spectrum of ocular abnormalities, including thickened corneal stroma, hypoplasia of the anterior chamber, irregular iris morphology, and corneal neovascularization. Notably, this deletion led to reduced Shh signal activity in the periocular mesenchyme, sustained expression of key transcription factors Foxc1, Foxc2 and Pitx2, along with persistent cell proliferation. Additionally, it induced increased Notch signaling activity and the development of ectopic neovascularization within the corneal stroma. Conclusions: The absence of primary cilia due to Ift46 deficiency in NCCs is associated with anterior segment dysgenesis (ASD) and corneal neovascularization, suggesting a potential link to Axenfeld-Rieger syndrome, a disorder characterized by ASD. This underscores the pivotal role of primary cilia in ensuring proper anterior segment development and maintaining an avascular cornea.


Asunto(s)
Cilios , Neovascularización de la Córnea , Anomalías del Ojo , Ratones , Animales , Cilios/metabolismo , Cresta Neural/metabolismo , Neovascularización de la Córnea/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Córnea , Ratones Noqueados , Proteínas del Citoesqueleto/metabolismo
5.
Cancers (Basel) ; 16(9)2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38730618

RESUMEN

Dysregulated DNA methylation in cancer is critical in the transcription machinery associated with cancer progression. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, but no treatment targeting TNBC biomarkers has yet been developed. To identify specific DNA methylation patterns in TNBC, methyl-binding domain protein 2 (MBD) sequencing data were compared in TNBC and the three other major breast cancer subtypes. Integrated analysis of DNA methylation and gene expression identified a gene set showing a correlation between DNA methylation and gene expression. ATPase Na+/K+-transporting subunit alpha 1 (ATP1A1) was found to be specifically hypomethylated in the coding sequence (CDS) region and to show increased expression in TNBC. The Cancer Genome Atlas (TCGA) database also showed that hypomethylation and high expression of ATP1A1 were strongly associated with poor survival in patients with TNBC. Furthermore, ATP1A1 knockdown significantly reduced the viability and tumor-sphere formation of TNBC cells. These results suggest that the hypomethylation and overexpression of ATP1A1 could be a prognostic marker in TNBC and that the manipulation of ATP1A1 expression could be a therapeutic target in this disease.

6.
Clin Mol Hepatol ; 30(2): 247-262, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38281815

RESUMEN

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat accumulation in the liver. MASLD encompasses both steatosis and MASH. Since MASH can lead to cirrhosis and liver cancer, steatosis and MASH must be distinguished during patient treatment. Here, we investigate the genomes, epigenomes, and transcriptomes of MASLD patients to identify signature gene set for more accurate tracking of MASLD progression. METHODS: Biopsy-tissue and blood samples from patients with 134 MASLD, comprising 60 steatosis and 74 MASH patients were performed omics analysis. SVM learning algorithm were used to calculate most predictive features. Linear regression was applied to find signature gene set that distinguish the stage of MASLD and to validate their application into independent cohort of MASLD. RESULTS: After performing WGS, WES, WGBS, and total RNA-seq on 134 biopsy samples from confirmed MASLD patients, we provided 1,955 MASLD-associated features, out of 3,176 somatic variant callings, 58 DMRs, and 1,393 DEGs that track MASLD progression. Then, we used a SVM learning algorithm to analyze the data and select the most predictive features. Using linear regression, we identified a signature gene set capable of differentiating the various stages of MASLD and verified it in different independent cohorts of MASLD and a liver cancer cohort. CONCLUSION: We identified a signature gene set (i.e., CAPG, HYAL3, WIPI1, TREM2, SPP1, and RNASE6) with strong potential as a panel of diagnostic genes of MASLD-associated disease.


Asunto(s)
Hígado Graso , Neoplasias Hepáticas , Humanos , Algoritmos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Progresión de la Enfermedad
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