Protective effect and mechanism of lipid perioxide in TNF-a induced apoptosis of intestinal epithelial cells in IBD.
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ABSTRACT:
PROVIDER: PRJNA1051056 | ENA |
REPOSITORIES: ENA
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Project description:Ulcerative colitis (UC) is an inflammatory disease characterized by an uncontrolled inflammatory response. Previous study showed that the immunological impairment elicted the alteration of inflammatory mediators, and ferroptosis was implicated with the lethal accumulation of reactive oxygen species (ROS).We performed lipidomics sequencing of TNF-a treated cell line mimicking the colitis in vivo.Surprisingly, we found that 4-HDHA,an autoxidation product of docosahexaenoic acid (DHA),had anti-apoptosis effect on colon epithelial cell line.To evaluate the underlying mechanism of the specific lipid perioxidin’s anti-apoptosis effect, we performed the experiment using high-throughput sequencing and get data to explain the reason why 4-HDHA could decrease TNF-induced cell apoptosis.
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Project description:Ulcerative colitis (UC) is an inflammatory disease characterized by an uncontrolled inflammatory response. Previous study showed that the immunological impairment elicted the alteration of inflammatory mediators, and ferroptosis was implicated with the lethal accumulation of reactive oxygen species (ROS).We have already found that lipid ROS level was elevated in both murine DSS colitis model and TNF-a-induced cell apoptosis model in vitro.Then we here use two ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 trying to eliminate lipid ROS in order to relive the symptoms of colitis.But we strikingly notice that liproxstatin-1 could increase TNF-induced cell apoptosis instead of protecting cells from death as we expected before while the other inhibitor ferrostatin-1 could protect cells from death indeed.To evaluate the underlying mechanism, we performed the experiment using high-throughput sequencing and get data to explain the reason why liproxstatin-1 could increase TNF-induced cell apoptosis .
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Project description:Deficiency in the X-linked inhibitor of apoptosis protein (XIAP) is the cause for the X-linked lymphoproliferative syndrome 2 (XLP2). About one third of all patients suffers from severe and therapy refractory inflammatory bowel disease (IBD), but the exact pathogenesis remains undefined. We examined the differences in gene expression of pediatric XLP2 patients with IBD to healthy controls and pediatric IBD patients.
2021-09-20 | GSE183069 | GEO
Project description:Chronic ulcerative colitis (CUC) is characterized by increased intestinal epithelial cell (IEC) apoptosis associated with elevated tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), and p53. We previously showed that p53 is increased in crypt IECs in human colitis and is needed for IEC apoptosis in chronic dextran sulfate sodium-colitis. Herein, we examined the roles of TNF and iNOS in regulating p53-induced IEC apoptosis in CUC. The IEC TUNEL staining, caspases 3, 8, and 9, and p53 protein levels, induced by anti-CD3 monoclonal antibody (mAb) activation of T cells, were markedly reduced in TNF receptor 1 and 2 gene knockout mice. Induction of IEC apoptosis correlated with increased p53, which was attenuated in iNOS(-/-) mice. IEC p53 levels and apoptosis were reduced in IL-10(-/-) colitic mice treated with neutralizing TNF mAb and the iNOS inhibitor, aminoguanidine, further suggesting that TNF and iNOS are upstream of p53 during colitis-induced IEC apoptosis. IEC apoptosis and p53 levels were assessed in control versus untreated or anti-TNF-treated CUC patients with equivalent levels of inflammation. Data indicated that IEC apoptosis and p53 levels were clearly higher in untreated CUC but markedly reduced in patients treated with anti-TNF mAb. Therefore, TNF-induced iNOS activates a p53-dependent pathway of IEC apoptosis in CUC. The inhibition of IEC apoptosis may be an important mechanism for mucosal healing in anti-TNF-treated CUC patients.
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Project description:Disease causal mechanism remains largely unknown for most Alzheimer’s disease (AD) genome-wide association studies (GWAS) risk loci, including the Clusterin (CLU) locus. Here, leveraging our approach to identify functional GWAS risk variants that show allele-specific open chromatin (ASoC), we nominated a putative AD causal SNP rs1532278 (T/C) of CLU that showed strong ASoC specifically in iPSC-derived excitatory neurons (iGlut). We found the AD protective allele T of rs1532278 elevated neuronal CLU and promoted neuron excitability. Transcriptomic analysis of iGlut (T/T vs. C/C) co-cultured with mouse astrocytes surprisingly showed allele T upregulated lipid synthesis and astrocytic lipid metabolism pathways. Further corroborative functional studies mechanistically tied allele T to CLU-facilitated neuron-glia lipid transfer and astrocytic lipid droplet (LD) formation. Interestingly, astrocytes with more LD were found to uptake less glutamate likely due to reactive oxygen species (ROS), which may contribute to CLU-promoted neuron excitability. Our study uncovered a previously unappreciated protective role of neuronal CLU in maintaining proper neuronal excitability through lipid-mediated neuron-glia communication.
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Project description:Effect of 4-HDHA during TNF-induced HT-29 cells apoptosis
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2023-03-19 | GSE227206 | GEO
Project description:Recent evidence suggests that hypoxia caused by acute myocardial infarction (AMI) can induce evident cardiomyocyte apoptosis. Exosomes, as paracrine signaling mediators by delivering cytosolic components (including miRNA, mRNA, protein), play crucial roles in intercellular communication. However, the systemic regulation of exosome-mediated miRNA delivery and subsequent regulation effect underlying AMI are not well-understood to date. Here, using small RNA-seq, we investigated the miRNAome of H9C2 cells and corresponding paracrine exosmes after hypoxia stress, and identified total of 92 and 62 differentially expressed (DE) miRNAs in cells and exosomes from hypoxia vs. normoxia condition. We found that hypoxia strongly induced the expression of hypoxamiRs in H9C2 cells and altered cardiomyocyte-derived exosomal miRNAome. Functional enrichment analysis revealed extensive roles of DE exosomal miRNAs in HIF-1 signaling pathway and cell apoptosis process, such as TNF signaling pathway, MAPK signaling pathway, mTOR signaling pathway. Furthermore, the gain- and loss-of-function analysis demonstrated the anti-apoptotic effects of hypoxia-induced exosomal miRNAs, i.e. miR-21-5p, miR-378-3p, miR-152-3p, let-7i-5p, and then the luciferase reporter assay confirmed that miR-152-3p and let-7i-5p implemented their anti-apoptotic function by directly targeting Atg12 and Faslg, respectively. In short, this study revealed that hypoxia-exosomes derived from cardiomyocyte, loaded abundant cardio-protective miRNAs, mediate crosstalk among cardiomyocytes and prevent cardiomyocytes apoptosis after hypoxia. Methods: we established the anoxia model using H9C2 cells, an immortal cardiac muscle cell line, to imitate hypoxia condition caused by AMI in vitro, and then small RNA-seq were employed to investigate the miRNA transcriptome of H9C2 cells and its exosomes collected from hypoxia and normoxia culture medium. Results: we identified the miRNAome of H9C2 cells and its exosmes under both hypoxia and normoxia, including 331, 338, 144, 74 unique mature miRNAs from hypoxia-cells, normoxia-cells, hypoxia-exosomes, normoxia-exosomes, respectively. Total of 92 and 62 DE miRNAs were identified from cells and exosomes. Among of which, the DE exosomal miRNAs were mainly involved in HIF-1 signaling pathway and cell apoptosis process, such as TNF signaling pathway, MAPK signaling pathway, mTOR signaling pathway. Interestingly, we found that some DE exosomal miRNAs, including miR-21-5p, miR-378-3p, miR-152-3p, let-7i-5p, have an anti-apoptotic and pro-viability effects in H9C2 cells under hypoxic stress. In addition, Atg12 and Faslg to be respective target of miR-152-3p and let-7i-5p were partly elucidated the anti-apoptosis mechanism of hypoxia-exosomes. Conclusions:In brief, this study illustrated a potential mechanism that, under hypoxic stress, hypoxia pre-perceived cardiomyocytes can spontaneously secrete the hypoxamiRs enriched exosomes, loaded a large amount of cardio-protective miRNA, which mediate crosstalk among cardiomyocytes and prevent apoptosis to heighten the hypoxia adaptability of cardiomyocytes. In more detail, we first discovered that miR-152-3p and let-7i-5p, enriched in hypoxia-exosomes derived by cardiomyocytes, played an anti-apoptosis role via mitochondrial pathway(intrinsic pathway) and death receptor pathway (extrinsic pathway), respectively.
2017-06-14 | GSE90123 | GEO