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1.
Mol Cell Biochem ; 2023 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-37659973

RESUMO

Intracranial aneurysm (IA), is a localized dilation of the intracranial arteries, the rupture of which is catastrophic. Hypertension is major IA risk factor that mediates endothelial cell damage. Sox17 is highly expressed in intracranial vascular endothelial cells, and GWAS studies indicate that its genetic alteration is one of the major genetic risk factors for IA. Vascular endothelial cell injury plays a vital role in the pathogenesis of IA. The genetic ablation of Sox17 plus hypertension induced by AngII can lead to an increased incidence of intracranial aneurysms had tested in the previous animal experiments. In order to study the underlying molecular mechanisms, we established stable Sox17-overexpressing and knockdown cell lines in human brain microvascular endothelial cells (HBMECs) first. Then flow cytometry, western blotting, and immunofluorescence were employed. We found that the knockdown of Sox17 could worsen the apoptosis and autophagy of HBMECs caused by AngII, while overexpression of Sox17 had the opposite effect. Transmission electron microscopy displayed increased autophagosomes after the knockdown of Sox17 in HBMECs. The RNA-sequencing analysis shown that dysregulation of the Sox17 gene was closely associated with the autophagy-related pathways. Our study suggests that Sox17 could protect HBMECs from AngII-induced injury by regulating autophagy and apoptosis.

2.
Curr Med Sci ; 44(3): 519-528, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38842774

RESUMO

OBJECTIVE: Intestinal fibrosis is a refractory complication of inflammatory bowel disease (IBD). Tumor necrosis factor ligand-related molecule-1A (TL1A) is important for IBD-related intestinal fibrosis in a dextran sodium sulfate (DSS)-induced experimental colitis model. This study aimed to explore the effects of TL1A on human colonic fibroblasts. METHODS: A trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis model of LCK-CD2-TL1A-GFP transgenic (Tg) or wild-type (WT) mice was established to determine the effect and mechanism of TL1A on intestinal fibrosis. The human colonic fibroblast CCD-18Co cell line was treated concurrently with TL1A and human peripheral blood mononuclear cell (PBMC) supernatant. The proliferation and activation of CCD-18Co cells were detected by BrdU assays, flow cytometry, immunocytochemistry and Western blotting. Collagen metabolism was tested by Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The level of collagen metabolism in the TNBS+ethyl alcohol (EtOH)/Tg group was greater than that in the TNBS+EtOH/WT group. Transforming growth factor-ß1 (TGF-ß1) and p-Smad3 in the TNBS+EtOH/Tg group were upregulated as compared with those in the TNBS+EtOH/WT group. The proliferation of CCD-18Co cells was promoted by the addition of human PBMC supernatant supplemented with 20 ng/mL TL1A, and the addition of human PBMC supernatant and TL1A increased CCD-18Co proliferation by 24.4% at 24 h. TL1A promoted cell activation and increased the levels of COL1A2, COL3A1, and TIMP-1 in CCD-18Co cells. Treatment of CCD-18Co cells with TL1A increased the expression of TGF-ß1 and p-Smad3. CONCLUSION: TL1A promotes TGF-ß1-mediated intestinal fibroblast activation, proliferation, and collagen deposition and is likely related to an increase in the TGF-ß1/Smad3 signaling pathway.


Assuntos
Proliferação de Células , Fibroblastos , Fibrose , Transdução de Sinais , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Humanos , Fibroblastos/metabolismo , Fibroblastos/patologia , Animais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Camundongos , Colo/metabolismo , Colo/patologia , Colite/metabolismo , Colite/induzido quimicamente , Colite/patologia , Colite/genética , Linhagem Celular , Camundongos Transgênicos , Ácido Trinitrobenzenossulfônico , Modelos Animais de Doenças , Leucócitos Mononucleares/metabolismo
3.
Nat Commun ; 8: 14828, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28425483

RESUMO

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.


Assuntos
Colangite/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Doenças Autoimunes/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Proteína Ribossômica L3 , Adulto Jovem
4.
Zhonghua Liu Xing Bing Xue Za Zhi ; 30(8): 829-31, 2009 Aug.
Artigo em Zh | MEDLINE | ID: mdl-20193208

RESUMO

OBJECTIVE: By sequenceing the Cj1136, Cj1138 and Cj1139 gene of Campylobacter jejuni (C. jejuni) strains associated with Guillain-Barré Syndrome (GBS), features of Cj1136, Cj1138 and Cj1139 gene were studied. Results were compared with the C. jejuni strain NCTC11168, to find the mutations in sequence of C. jejuni which inducing GBS and their polygenetic relationship was analyzed. METHODS: Three GBS-associated C. jejuni strains were isolated from stools of GBS patients from Hebei province who had been diagnosed as clinical AMAN pattern and electrophysiological tests were performed. After distilling and sequencing Cj1136, Cj1138 and Cj1139 genes, results were spliced and assembled into a complete sequence by the terminals overlapped with each other. Sequences of Cj1136, Cj1138 and Cj1139 genes were compared with NCTC11168, to find the mutations and gene feature. RESULTS: The Cj1136, Cj1138 and Cj1139 gene of the three GBS- associated C. jejuni strains were composed by 1173 base pairs, 1170 base pairs, 912 base pairs respectively. The alignment with the related sequence of NCTC11168 showed that there were two same mutations in the Cj1138 gene of the three C. jejuni stains. Data from phylogenetic analysis demonstrated that the three C. jejuni strains were genetically closed to NCTC11168, with the biggest phylogenetic distance between the three of them as 2.1%. CONCLUSION: When compared with NCTC11168 the Cj1138 gene of the three GBS-associated C. jejuni strains had the same mutations which might be related to the development of GBS. Relation between the variation and GBS-pathogenesis remained to be confirmed. The mutations found in the three C. jejuni strains established the foundation for exploring the biological characteristics of GBS-associated C. jejuni strains and demonstrated that the GBSassociated C. jejuni strains of Hebei province having its regional features.


Assuntos
Campylobacter jejuni/genética , Genes Bacterianos , Síndrome de Guillain-Barré/microbiologia , Sequência de Bases , Infecções por Campylobacter/microbiologia , Campylobacter jejuni/classificação , Campylobacter jejuni/isolamento & purificação , Fezes/microbiologia , Humanos , Mutação , Filogenia
5.
J Biol Chem ; 281(30): 21480-21490, 2006 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-16720581

RESUMO

Ubiquitin-conjugating enzyme Ubc6p is a tail-anchored protein that is localized to the cytoplasmic face of the endoplasmic reticulum (ER) membrane and has been implicated in the degradation of many misfolded membrane proteins in yeast. We have undertaken characterization studies of two human homologs, hsUbc6 and hsUbc6e. Both possess tail-anchored protein motifs, display high conservation in their catalytic domains, and are functional ubiquitin-conjugating enzymes as determined by in vitro thiol-ester assay. Both also display induction by the unfolded protein response, a feature of many ER-associated degradation (ERAD) components. Post-translational modification involving phosphorylation of hsUbc6e was observed to be ER-stress-related and dependent on signaling of the PRK-like ER kinase (PERK). The phosphorylation site was mapped to Ser-184, which resides within the uncharacterized region linking the highly conserved catalytic core and the C-terminal transmembrane domain. Phosphorylation of hsUbc6e also did not alter stability, subcellular localization, or interaction with a partner ubiquitin-protein isopeptide ligase. Assays of hsUbc6e(S184D) and hsUbc6e(S184E), which mimic the phosphorylated state, suggest that phosphorylation may reduce capacity for forming ubiquitin-enzyme thiol-esters. The occurrence of two distinct Ubc6p homologs in vertebrates, including one with phosphorylation modification in response to ER stress, emphasizes diversity in function between these Ub-conjugating enzymes during ERAD processes.


Assuntos
Retículo Endoplasmático/metabolismo , Enzimas de Conjugação de Ubiquitina/química , Enzimas de Conjugação de Ubiquitina/fisiologia , eIF-2 Quinase/fisiologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Desnaturação Proteica , Dobramento de Proteína , Processamento de Proteína Pós-Traducional , Proteínas de Saccharomyces cerevisiae/química , Homologia de Sequência de Aminoácidos , Ubiquitina/química , eIF-2 Quinase/química
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