Identification of miRNAs that mediate protective function of anti-cancer drugs during white matter ischemic injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171568 | GEO | 2021/04/07
REPOSITORIES: GEO
Similar Datasets
Project description:We have previously shown that two anti-cancer drugs, CX-4945 and MS-275, protect and preserve white matter (WM) architecture and improve functional recovery in a model of WM ischemic injury. While both compounds promote recovery, CX-4945 is a selective Casein kinase 2 (CK2) inhibitor and MS-275 is a selective Class I histone deacetylase (HDAC) inhibitor. Alterations in microRNAs (miRNAs) mediate some of the protective actions of these drugs. In this study, we aimed to (1) identify miRNAs expressed in mouse optic nerves (MONs); (2) determine which miRNAs are regulated by oxygen glucose deprivation (OGD); and (3) determine the effects of CX-4945 and MS-275 treatment on miRNA expression. RNA isolated from MONs from control and OGD-treated animals with and without CX-4945 or MS-275 treatment were quantified using NanoString nCounter® miRNA expression profiling. Comparative analysis of experimental groups revealed that 12 miRNAs were expressed at high levels in MONs. OGD upregulated five miRNAs (miR-1959, miR-501-3p, miR-146b, miR-201, and miR-335-3p) and downregulated two miRNAs (miR-1937a and miR-1937b) compared to controls. OGD with CX-4945 upregulated miR-1937a and miR-1937b, and downregulated miR-501-3p, miR-200a, miR-1959, and miR-654-3p compared to OGD alone. OGD with MS-275 upregulated miR-2134, miR-2141, miR-2133, miR-34b-5p, miR-153, miR-487b, miR-376b, and downregulated miR-717, miR-190, miR-27a, miR-1959, miR-200a, miR-501-3p, and miR-200c compared to OGD alone. Interestingly, miR-501-3p and miR-1959 were the only miRNAs upregulated by OGD, and downregulated by OGD plus CX-4945 and MS-275. Therefore, we suggest that protective functions of CX-4945 or MS-275 against WM injury maybe mediated, in part, through miRNA expression.
| S-EPMC8642107 | biostudies-literature
Project description:Identification of miRNAs that mediate protective function of anti-cancer drugs during white matter ischemic injury
| PRJNA720106 | ENA
Project description:Genome-wide DNA methylation profiling of human B-ALL cell line SEM after 48 h incubation with DMSO (control), CX-4945 (Silmitasertib), Decitabine (DEC) or combined CX-4945 + DEC treatment. The Infinium MethylationEPIC BeadChip was used to obtain DNA methylation profiles across approximately 866,895 CpG islands.
2018-02-12 | GSE110454 | GEO
Project description:We report that CK2 inhibition with CX-4945 broadly suppresses Th17-associated effector and metabolic gene expression. CD4+ T cells were cultured in IL-6, IL-23 and TGFb1 for 72 h, in the absence of presence of 2 mM CX-4945, RNA-seq was performed and gene expression compared between the control and treatment groups.
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Project description:Multicellular Tumor Spheroids (MCTS) were pre-formed for 3 days with 786-O cell line to better mimic the tumor microenviroenment. These spheroids were treated with either vehicle (DMSO), drugs alone (KU-60019 10 μM; CX-4945 5 μM) or in combination (KU + CX) for 48h before RNA extraction.
2021-02-04 | E-MTAB-9977 | biostudies-arrayexpress
Project description:Chronic alcohol consumption can lead to alchohol-related brain damage (ARBD). Despite the well known acute effects of alcohol the mechanism responsible for chronic brain damage is largely unknown. Pathologically the major change is the loss of white matter while neuronal loss is mild and restricted to a few areas such as the prefrontal cortex. In order to improve our understanding of ARBD pathogenesis we used microarrays to explore the white matter transcriptome of alcoholics and controls. Our results suggest that hepatic encephalopathy, along with two confounders, gray matter contamination and low RNA quality, are major drivers of gene expression in ARBD. All three exceeded the effects of alcohol itself. In particular, low quality RNA samples were characterized by an upregulation of protein translation machinery while hepatic encephalopathy was associated with a downregulation of mitochondrial energy metabolism pathways. The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non-HE alcoholics had widespread but only subtle changes in gene expression in their white matter. The initial cohort was compromised of four alcoholics without hepatic encephalopathy (non-HE alcoholics), three alcoholics with HE (HE alcoholics) and three neurologically normal controls. For each indvidual frozen white matter was sampled in the superior frontal gyrus (prefrontal cortex) and the precentral gyrus (motor cortex). These two cortices experience either moderate (prefrontal cortex) or no neuronal loss (motor cortex) with alcohol-related brain damage. Each white matter sample was divided in two before RNA was extracted to give two 'biological' repeats and a total of 40 samples. Subsequently eight duplicates were removed due to their gray matter contamination or low RNA quality to leave a 32-sample cohort (23 alcoholic (including eight with HE ) and nine control samples.
2014-01-04 | E-GEOD-53808 | biostudies-arrayexpress
Project description:Aging results in both grey and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and grey matter separately, we identified white matter associated microglia (WAM), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by the activation of genes implicated in phagocytic activity and lipid metabolism. WAM depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAM form independently of apolipoprotein E (APOE), which is in contrast to mouse models of Alzheimer’s disease, in which microglia with WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAM. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAM may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.
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Project description:Despite the intensive search for an effective drug to treat steroid-producing adrenocortical carcinomas, there are few therapeutic options. We sought whether splicing modifying compounds are effective on this devastating disease. Here, we show that a chemical compound in clinical trial, CX-4945, suppressed the expression of NR5A1 through aberrant multiple exon skipping leading to suppressed steroidogenesis and induced dysfunctional autophagy and progression to ER-stress-related apoptosis. A circular RNA of NR5A1 exons with an IRE1α-cleavage site on the ligated ends (circAd4BP HAC1-type ex1-6 RNA) is expressed in normal adrenal cortex but not in H295R adrenocortical cancer cells, and CX-4945 induced a different circular RNA of NR5A1 exons (circAd4BP ex2-4 RNA). This potential pharmacological control of abnormal steroidogenesis through NR5A1 aberrant splicing and interplay with its circAd4BP makes CX-4945 a strong candidate novel drug for the treatment of adrenocortical carcinomas.
2018-09-25 | GSE120325 | GEO
Project description:Chronic alcohol consumption can lead to alchohol-related brain damage (ARBD). Despite the well known acute effects of alcohol the mechanism responsible for chronic brain damage is largely unknown. Pathologically the major change is the loss of white matter while neuronal loss is mild and restricted to a few areas such as the prefrontal cortex. In order to improve our understanding of ARBD pathogenesis we used microarrays to explore the white matter transcriptome of alcoholics and controls. Our results suggest that hepatic encephalopathy, along with two confounders, gray matter contamination and low RNA quality, are major drivers of gene expression in ARBD. All three exceeded the effects of alcohol itself. In particular, low quality RNA samples were characterized by an upregulation of protein translation machinery while hepatic encephalopathy was associated with a downregulation of mitochondrial energy metabolism pathways. The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non-HE alcoholics had widespread but only subtle changes in gene expression in their white matter.
2014-01-04 | GSE53808 | GEO