Chronic Colitis Impairs Cardiac Function by Suppressing Brain-Derived Neurotrophic Factor in the Adult Heart
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PROVIDER: PRJNA667265 | ENA |
REPOSITORIES: ENA
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2020-10-05 | GSE158991 | GEO
Project description:Ulcerative colitis and Crohn's disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1β as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1β neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1β→miR-155→BDNF signaling axis.
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Project description:Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding the link between inflammation and cancer. Intestinal stem cells (ISCs) marked by LGR5 expression are of importance in both the inflammatory response to colitis and progression to colitis-associated colon cancer (CACC). Here, we report in human MUC1-transgenic mouse models of CACC that targeting the MUC1-C oncogenic protein, which is upregulated in inflammation, suppresses the (i) Lgr5+ ISC population, (ii) induction of Myc and core pluripotency stem cell factors, and (iii) severity and progression of colitis to dysplasia and cancer. By extension to human colon cancer cells, we demonstrate that MUC1-C drives MYC, forms a complex with MYC on the LGR5 promoter and activates LGR5 expression. We also show in CRC cells that MUC1-C induces the cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2 and NANOG pluripotency factors. Consistent with conferring the CSC state, targeting MUC1-C suppresses the capacity of CRC cells to promote wound healing, invasion, self-renewal and tumorigenicity. In analysis of human tissues, MUC1 expression associates with activation of inflammatory pathways, development of colitis and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a previously unrecognized target that is druggable for treating progression of colitis and CRC.
2020-10-12 | GSE144319 | GEO
Project description:Neurotrophic factors (NTFs) are a relevant group of secreted proteins that modulate growth, differentiation, repair, and survival of neurons; playing a role in the maintenance of the synaptic unions, dendrites and axons; also, being crucial for peripheral nervous system development and regulating plasticity in the adult central nervous system. On the other hand, insulin-like growth factor 1 (IGF-1) has been ascertained multiple beneficial actions in the brain: neuro-development, -protection, -genesis and plasticity. To further investigate the possible mechanisms underlying IGF-1 deficiency in the establishment of neurological disease, microarray and RT-qPCR gene expression analyses coupled with in silico processing were performed in an experimental model of partial IGF-1 deficiency. Results show that the mere IGF-1 deficiency seems to be responsible for an altered expression of genes coding for neurotrophic factors (particularly ciliary neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor), their receptors and signaling pathways (specially RET). The presented findings support that IGF-1 deficiency might be involved in the establishment and progression of neurodegenerative disorders.
2018-12-29 | E-MTAB-7508 | biostudies-arrayexpress
Project description:MUC1-c is a target for suppressing stemness in the progression of colitis and colorectal cancer
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Project description:<p>Zhuyu pill (ZYP) is a traditional Chinese medicine prescription composed of two drugs, <em>Coptis chinensis</em> Franch. and <em>Tetradium ruticarpum</em> (A. Jussieu) T. G. Hartley, and is commonly used in the clinical treatment of diseases of the digestive system. However, the mechanism underlying the effect of ZYP on colitis remains unclear. In this study, a colitis rat model was induced with 2,4,6-trinitro-benzenesulfonic acid (TNBS, 100 mg/kg) and treated with ZYP (low dose: 0.6 g/kg, high dose: 1.2 g/kg). Disease activity index, colonic weight index and weight change ratio were used to evaluate the model and efficacy. LC-MS and 16S rRNA gene sequencing were used to measure differences in fecal metabolism and microorganism population among the control, model, low-dose ZYP and high-dose ZYP groups. To elucidate the mechanism of interventional effect of ZYP, Spearman correlation analysis was used to analyze the correlation between fecal metabolism and fecal microbial number. High-dose and low-dose ZYP both exhibited significant interventional effects on colitis rat models, and high-dose ZYP produced a better interventional effect compared with low-dose ZYP. Based on a metabolomics test of fecal samples, significantly altered metabolites in the model and high-dose ZYP treatment groups were identified. In total, 492 metabolites were differentially expressed. Additionally, sequencing of the 16S rRNA gene in fecal samples revealed that the high-dose ZYP could improve TNBS-induced fecal microbiota dysbiosis. Ultimately, changes in tryptophan metabolism and <em>Firmicutes</em> and <em>Gammaproteobacteria</em> populations were detected after ZYP treatment in both colitis and cholestasis. Therefore, we conclude that tryptophan metabolism and <em>Firmicutes</em> and <em>Gammaproteobacteria</em> populations are the core targets of the anti-inflammatory effect of ZYP. These findings provide a scientific basis for further investigation of the anti-inflammatory mechanism of ZYP in the future.</p>
2022-11-02 | MTBLS4980 | MetaboLights
Project description:Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identified as a regulator of cardiac function in the failing mouse heart, and pharmaceutically inhibition of miR-132 is beneficial for heart failure. In this study, we further investigated the molecular mechanisms of miR-132/212 in modulating cardiomyocyte contractility in the context of the pathological progression of heart failure. We found that upregulated miR-132/212 expressions in all examined hypertrophic heart failure mice models. The overexpression of miR-132/212 prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. In response to chronic pressure-overload, miR-132/212 KO mice exhibited a blunted deterioration of cardiac function. Using a combination of biochemical approaches and in vitro assays, we confirmed that miR-132/212 regulates SERCA2a by targeting the 3'-end untranslated region of SERCA2a. Additionally, we also confirmed PTEN as a direct target of miR-132/212 and potentially participates in the cardiac response to miR132/212. In end-stage heart failure patients, miR-132/212 is upregulated and correlates with reduced SERCA2a expression. The up-regulation of miR-132/212 in heart failure impairs cardiac contractile function by targeting SERCA2a, suggesting that pharmaceutical inhibition of miR-132/212 might be a promising therapeutic approach to promote cardiac function in heart failure patients.
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