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1.
Adv Healthc Mater ; : e2401994, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39235381

ABSTRACT

Ceria-based nanoparticles are versatile in treating various inflammatory diseases, but their feasibility in clinical translation is undermined by safety concerns and a limited delivery system. Meanwhile, the idiopathic nature of inflammatory bowel disease (IBD) calls for a wider variety of therapeutics via moderation of the intestinal immune system. In this regard, the synthesis and oral formulation of iron-ceria nanoparticles (CF NPs) with enhanced nanozymic activity and lower toxicity risk than conventional ceria-based nanoparticles are reported. CF NPs are clustered in calcium phosphate (CaP) and coated with a pH-responsive polymer to provide the enteric formulation of iron-ceria nanotablets (CFNT). CFNT exhibits a marked alleviative efficacy in the dextran sodium sulfate (DSS)-induced enterocolitis model in vivo by modulating the pro-inflammatory behavior of innate immune cells including macrophages and neutrophils, promoting anti-inflammatory cytokine profiles, and downregulating key transcription factors of inflammatory pathways.

2.
Clin Mol Hepatol ; 30(2): 247-262, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38281815

ABSTRACT

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.


Subject(s)
Fatty Liver , Liver Neoplasms , Humans , Algorithms , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Disease Progression
3.
Mol Cells ; 45(5): 343-352, 2022 May 31.
Article in English | MEDLINE | ID: mdl-35422452

ABSTRACT

The advent of the assay for transposase-accessible chromatin using sequencing (ATAC-seq) has shown great potential as a leading method for analyzing the genome-wide profiling of chromatin accessibility. A comprehensive reference to the ATAC-seq dataset for disease progression is important for understanding the regulatory specificity caused by genetic or epigenetic changes. In this study, we present a genome-wide chromatin accessibility profile of 44 liver samples spanning the full histological spectrum of nonalcoholic fatty liver disease (NAFLD). We analyzed the ATAC-seq signal enrichment, fragment size distribution, and correlation coefficients according to the histological severity of NAFLD (healthy control vs steatosis vs fibrotic nonalcoholic steatohepatitis), demonstrating the high quality of the dataset. Consequently, 112,303 merged regions (genomic regions containing one or multiple overlapping peak regions) were identified. Additionally, we found differentially accessible regions (DARs) and performed transcription factor binding motif enrichment analysis and de novo motif analysis to determine new biomarker candidates. These data revealed the generegulatory interactions and noncoding factors that can affect NAFLD progression. In summary, our study provides a valuable resource for the human epigenome by applying an advanced approach to facilitate diagnosis and treatment by understanding the non-coding genome of NAFLD.


Subject(s)
Chromatin , Non-alcoholic Fatty Liver Disease , Chromatin/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , Non-alcoholic Fatty Liver Disease/genetics , Sequence Analysis, DNA/methods , Transposases/genetics , Transposases/metabolism
4.
Cell Death Differ ; 29(11): 2151-2162, 2022 11.
Article in English | MEDLINE | ID: mdl-35473985

ABSTRACT

Hematopoiesis occurs within a unique bone marrow (BM) microenvironment, which consists of various niche cells, cytokines, growth factors, and extracellular matrix components. These multiple components directly or indirectly regulate the maintenance and differentiation of hematopoietic stem cells (HSCs). Here we report that BAP1 in BM mesenchymal stromal cells (MSCs) is critical for the maintenance of HSCs and B lymphopoiesis. Mice lacking BAP1 in MSCs show aberrant differentiation of hematopoietic stem and progenitor cells, impaired B lymphoid differentiation, and expansion of myeloid lineages. Mechanistically, BAP1 loss in distinct endosteal MSCs, expressing PRX1 but not LEPR, leads to aberrant expression of genes affiliated with BM niche functions. BAP1 deficiency leads to a reduced expression of pro-hematopoietic factors such as Scf caused by increased H2AK119-ub1 and H3K27-me3 levels on the promoter region of these genes. On the other hand, the expression of myelopoiesis stimulating factors including Csf3 was increased by enriched H3K4-me3 and H3K27-ac levels on their promoter, causing myeloid skewing. Notably, loss of BAP1 substantially blocks B lymphopoiesis and skews the differentiation of hematopoietic precursors toward myeloid lineages in vitro, which is reversed by G-CSF neutralization. Thus, our study uncovers a key role for BAP1 expressed in endosteal MSCs in controlling normal hematopoiesis in mice by modulating expression of various niche factors governing lymphopoiesis and myelopoiesis via histone modifications.


Subject(s)
Lymphopoiesis , Mesenchymal Stem Cells , Mice , Animals , Lymphopoiesis/genetics , Bone Marrow/metabolism , Mesenchymal Stem Cells/metabolism , Hematopoietic Stem Cells/metabolism , Hematopoiesis/genetics , Bone Marrow Cells , Cell Differentiation/genetics , Granulocyte Colony-Stimulating Factor , Epigenesis, Genetic , Stem Cell Niche/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism
5.
Cell Death Differ ; 27(11): 3053-3064, 2020 11.
Article in English | MEDLINE | ID: mdl-32424141

ABSTRACT

CD4/CD8 T-cell lineage differentiation is a key process in immune system development; however, a defined regulator(s) that converts the signal from T-cell receptor and co-receptor complexes into lineage differentiation remains unclear. Here, we show that Twist2 is a critical factor in CD4/CD8 thymocyte differentiation. Twist2 expression is differentially regulated by T-cell receptor signaling, leading to differentiation into the CD4 or CD8 lineage. Forced Twist2 expression perturbed CD4+ thymocyte differentiation while enhancing CD8+ thymocyte differentiation. Furthermore, Twist2 expression produced mature CD8+ thymocytes in B2m-/- mice, while its deficiency significantly impaired CD8+ cells in MHC class-II-/- and TCR transgenic mice, favoring CD8 T-cell differentiation. During CD8 lineage differentiation, Twist2 interacted with Runx3 to bind to the silencer region of the ThPOK locus, thereby blocking ThPOK expression. These findings indicate that Twist2 is a part of the transcription factor network controlling CD8 lineage differentiation.


Subject(s)
CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Cell Differentiation/immunology , Gene Expression Regulation/immunology , Repressor Proteins/genetics , Transcription Factors/genetics , Twist-Related Protein 1/genetics , Animals , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation/genetics , Gene Expression Regulation/genetics , HEK293 Cells , HeLa Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, T-Cell/metabolism , Repressor Proteins/metabolism , Signal Transduction/genetics , Signal Transduction/immunology , Thymus Gland/cytology , Thymus Gland/immunology , Transcription Factors/biosynthesis , Twist-Related Protein 1/metabolism
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