Nanostring derived microRNA of rats treated with lithium alone and in combination with amiloride for 6 months
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE178695 | GEO | 2022/08/31
REPOSITORIES: GEO
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Project description:Purpose: The goal of this study is to understand the role of co-administred amiloride. This was derived through RNAseq of kidney cortex and determining differential genes in response to lithium, lithium+amiloride and control at 14 days, 28 days and 6 months. Methods: RNAseq of kidney cortex treated with either lithium alone, lithium+amiloride or control. Deseq2 was performed using contrast argument with Wald test to identify significant differentially expression genes at each time point individually. Result & Conclusion: Co-administration with amiloride at all time points contributed in the reduction of inflammation and fibrosis caused by lithium.
2022-08-31 | GSE178950 | GEO
Project description:The introduction of novel therapeutic agents has considerably improved the median survival of patients with multiple myeloma (MM). However, the natural history of the disease is characterized by continuous relapses over time. As a consequence, the development of new drugs is still required to treat MM recurrence. Here, we report for the first time the potent anti-myeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure. Amilorideinduced apoptosis was observed in a broad panel of MM cell lines and in xenograft mouse models. Moreover, amiloride also had a synergistic effect when combined with dexamethasone and melphalan. RNA-seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. Additionally, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, the manageable toxicity profile of amiloride is well known and we did not find a significant systemic toxicity in mice treated with amiloride. Overall, our results provide a mechanistic rationale for the use of amiloride as an alternative treatment option for relapsed MM patients.
2018-09-10 | GSE95077 | GEO
Project description:Expression profiles of 7-day cultured HSPCs in the presence or absence of valproic acid and/or lithium. Two small molecules, valproic acid (VPA) and lithium (Li), were tested to inhibit differentiation of hematopoietic stem/progenitor (HSPC) cells in culture. HSPCs exposed to VPA and Li during differentiation-inducing culture preserved an immature cell phenotype, provided radioprotection to lethally irradiated recipients and enhanced in vivo repopulating potential. Furthermore, VPA and Li synergistically preserved expression of stem cell-related genes and repressed genes involved in differentiation. Target genes were collectively co-regulated during normal hematopoietic differentiation. Additionally, transcription factor networks were identified as possible primary regulators. Our results demonstrate that the combination of VPA and Li potently prevents differentiation at the biological and the molecular level, and provide evidence to suggest that combinatorial screening of chemical compounds may uncover possible additive/synergistic effects to modulate stem cell fate decisions. These data consist of total mRNA obtained from hematopoietic cells cultured for 7 days in the presence or absence of valproic acid and/or lithium. All samples were analyzed in independent biological triplicates.
2011-12-15 | E-GEOD-34088 | biostudies-arrayexpress
Project description:Screening small molecules and drugs for activity to modulate alternative splicing, we found that amiloride, distinct from four other intracellular pH-affecting analogues, could “normalize” the splicing of BCL-X, HIPK3 and RON/MISTR1 transcripts in human hepatocellular carcinoma Huh-7 cells. To elucidate the underlying mechanisms, our proteomic analyses of amiloride-treated cells detected hypo-phosphorylation of splicing factor SF2/ASF and also decreased levels of SRp20 and two un-identified SR proteins. We further observed decreased phosphorylation of AKT, ERK1/2 and PP1, while increased phosphorylation of p38 and JNK, suggesting that amiloride treatment down-regulated kinases and up-regulated phosphatases in the signal pathways known to affect the splicing factor protein phosphorylation. The amiloride effects of splicing factor protein hypo-phosphorylation and“normalized”oncogenic RNA splicing were both abrogated by pre-treatment with a PP1 inhibitor. We then performed global exon array analysis of Huh-7 cells treated with amiloride for 24 hours. Using gene array chips (Affymetrix GeneChip® Human Exon 1.0 ST Array of >518000 exons of 42974 genes) for exon array analysis (set parameters of correlation coefficient ≥ 0.7, splicing index ≤ -1.585 , and log2 ratio ≤ -1.585), we found that amiloride influenced the splicing patterns of 551 genes involving at least 584 exons, which included 495 known protein-coding genes involving 526 exons, many of which play key roles in functional networks of ion transport, extracellular matrix, cytoskeletons and genome maintenance. Cellular functional analyses revealed subsequent invasion and migration defects, cell cycle disruption, cytokinesis impairment, and lethal DNA degradation in amiloride-treated Huh-7 cells. This study thus provides mechanistic underpinnings for exploiting small molecule modulation of abnormal RNA splicing for cancer therapeutics. Target was prepared from 3 biological replicates of 0.5mM amiloride-treatment for 24hr and 3 control untreatment from Huh7 cell line and hybridized to the Affymetrix Human Exon 1.0 ST Array. The values of the hybridized probesets were normalized and analyzed for gene expression using dChip2010 software.
2011-03-31 | E-GEOD-24581 | biostudies-arrayexpress
Project description:Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies have shown that lithium accumulates in the hippocampus and that chronic use amongst bipolar disorder patients is associated with larger hippocampal volumes. Here, we tested the chronic effects of low (0.75 mM) and high (2.25 mM) doses of lithium on human hippocampal progenitor cells and used immunocytochemistry to investigate the effects of lithium on cell parameters implicated in neurogenesis. Corresponding RNA-sequencing and gene-set enrichment analyses were used to evaluate whether genes affected by lithium in our model overlap with those regulating the volume of specific layers of the dentate gyrus. We observed that high-dose lithium treatment in human hippocampal progenitors increased the generation of neuroblasts (P ≤ 0.01), neurons (P ≤ 0.01), and glia (P ≤ 0.001), alongside the expression of genes which regulate the volume of the molecular layer of the dentate gyrus. This study provides empirical support that adult hippocampal neurogenesis and gliogenesis are mechanisms that could contribute to the effects of lithium on human hippocampal volume.
2021-09-30 | GSE184930 | GEO
Project description:Background: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of amiloride for ameliorating muscle wasting in murine models of cancer cachexia. Methods: CT26 and LLC tumor cells were subcutaneously injected into mice to induce cancer cachexia. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 and LLC models, respectively, were characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results: The CT26 and LLC models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. The CT26 and LLC cachexia mice showed increased particle density of plasma exosomes which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions: Our results demonstrated the efficacy of amiloride in ameliorating cachectic muscle wasting and elucidated the underlying mechanistic rationale for its use as an alternative strategy to improve CAC treatments.
2021-07-14 | GSE173250 | GEO
Project description:We have discovered that amiloride can produce a genome-wide effect on alternative splicing of various RNA transcripts, most importantly including those of the apoptotic factors, in K562 leukemic cells. Target was prepared from 4 biological replicates of 0.5 mM amiloride-treatment for 24hr and 3 control untreatment from K562 cells and hybridized to the Affymetrix Human Exon 1.0 ST Array. The values of the hybridized probesets were normalized and analyzed for gene expression using Partek software.
2012-09-17 | E-GEOD-24976 | biostudies-arrayexpress
Project description:Lithium treatment is commonly used to treat bipolar disorder. However, this treatment disrupts kidney fuctionality. We used microdissected cortical collecting ducts to study proteomics and ultimately discover what changes occur in protein expression after 72-hr lithium treatment.
2019-07-01 | PXD010118 | Pride
Project description:Screening small molecules and drugs for activity to modulate alternative splicing, we found that amiloride, distinct from four other intracellular pH-affecting analogues, could “normalize” the splicing of BCL-X, HIPK3 and RON/MISTR1 transcripts in human hepatocellular carcinoma Huh-7 cells. To elucidate the underlying mechanisms, our proteomic analyses of amiloride-treated cells detected hypo-phosphorylation of splicing factor SF2/ASF and also decreased levels of SRp20 and two un-identified SR proteins. We further observed decreased phosphorylation of AKT, ERK1/2 and PP1, while increased phosphorylation of p38 and JNK, suggesting that amiloride treatment down-regulated kinases and up-regulated phosphatases in the signal pathways known to affect the splicing factor protein phosphorylation. The amiloride effects of splicing factor protein hypo-phosphorylation and“normalized”oncogenic RNA splicing were both abrogated by pre-treatment with a PP1 inhibitor. We then performed global exon array analysis of Huh-7 cells treated with amiloride for 24 hours. Using gene array chips (Affymetrix GeneChip® Human Exon 1.0 ST Array of >518000 exons of 42974 genes) for exon array analysis (set parameters of correlation coefficient ≥ 0.7, splicing index ≤ -1.585 , and log2 ratio ≤ -1.585), we found that amiloride influenced the splicing patterns of 551 genes involving at least 584 exons, which included 495 known protein-coding genes involving 526 exons, many of which play key roles in functional networks of ion transport, extracellular matrix, cytoskeletons and genome maintenance. Cellular functional analyses revealed subsequent invasion and migration defects, cell cycle disruption, cytokinesis impairment, and lethal DNA degradation in amiloride-treated Huh-7 cells. This study thus provides mechanistic underpinnings for exploiting small molecule modulation of abnormal RNA splicing for cancer therapeutics.
2011-03-31 | GSE24581 | GEO
Project description:Lithium has been used for more than 50 years as the primary therapy for bipolar affective disorder (BPD) and is highly effective in its treatment. However, the molecular and cellular mechanisms underlying the lithium’s therapeutic action still remains elusive. The goal of the proposed study is to identify genes involved in the lithium-responsive neurological pathway using the fruit fly as a model organism. Based on the fact that the fundamental molecular and cellular mechanisms are well conserved between the fruit fly and vertebrates, the outcomes of this project are expected to lead to the recognition of uncharacterized players or processes responsible for the lithium action in the vertebrates, which would open up the future possibility to develop novel and improved therapies for BPD. The proposed gene-profiling experiment is designed to identify candidate genes and genetic pathways involved in the lithium-responsive biological process. Specific aims of this project are; 1) identify genes whose expression levels are significantly different between the wild type and Shu, 2) identify genes whose expression levels are enhanced or suppressed after lithium treatment, and 3) identify genes whose expression is differentially regulated in the wild type and Shu after lithium treatment. We expect that the genes identified through the proposed microarray analysis will provide important clues for elucidating the molecular and cellular processes responsible for the lithium action. A Drosophila mutant Shudderer (Shu) exhibits various neurological phenotypes, including hyperactivity, uncoordinated movements, and sporadically occurring jerks. Interestingly, many of these phenotypes are greatly suppressed by lithium with the internal concentrations used for treatment of human BPD patients. In addition, Shu mutant is more resistant to the toxic effects of lithium than the wild type strain. These data have led us to the hypothesis that the biological process responsive to lithium is affected in the Shu mutant. We expect that we will be able to identify genes and genetic pathways involved in the lithium-responsive process by comparing the gene expression profiles between the wild type and the Shu mutant with or without lithium treatment. Newly eclosed Canton-S (wild type) and Shu mutant females will be placed in vials containing fly food with or without 50mM LiCl. They will be cultured at 25oC with 65% humidity for 5 days. Three groups of fifty flies (150 flies in total) will be collected for each experimental condition (i.e., genotype and lithium treatment) and frozen on dry ice. The head will be separated and total RNA will be extracted from each group using the TRIzol Reagent (Life Technologies) followed by an RNeasy (Qiagen) cleanup step and a DNase I digestion step. The RNA will be resuspended in DEPC-treated water and the absorbance will be checked at 260 and 280 nm for determination of sample purity and concentration. The GeneChip Drosophila Genome 2.0 Arrays will be used to quantify the levels of transcripts in each sample. The total number of samples will be 4 (2 genotypes and 2 treatments) X 3 (triplicate) = 12. Keywords: dose response
2007-06-30 | GSE8330 | GEO