Matrine derivative 1b(MASM) offers radioprotection and modulates acute lethal total-body irradiation-induced alterations of gene expression
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE56263 | GEO | 2014/03/28
SECONDARY ACCESSION(S): PRJNA242798
REPOSITORIES: GEO
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Project description:To further investigate the potential molecular basis of the protective effects of MASM on irradiation (6.5Gy) damage, gene expression analysis was conducted on rats liver tissues using microarrays. Pre-treatment with MASM prevented differential expression of 53% (766 genes) of 1445 genes differentially expressed in response to radiation. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 21 pathways, such as metabolic pathways, pathways in cancer, and MAPK signaling pathway. The rats were randomly assigned to one of the three following treatment groups (10-12 animals per group): normal control, radiation and MASM dose (30 mg/kg body weight/day) + radiation. MASM dissolved in double distilled water were administered intragastrically to the male animals for 3 consecutive days before irradiation. Radiation induced gene expression in rat liver was measured at 24 hours after 6.5 Gy exposure.
2014-03-28 | E-GEOD-56263 | biostudies-arrayexpress
Project description:Matrine is an alkaloid extracted from Sophora flavescens Ait and has many biological activities, such as anti-inflammatory, antitumor, anti-fibrosis, and immunosuppressive properties. In our previous studies, the matrine derivative MASM was synthesized and exhibited potent inhibitory activity against liver fibrosis. In this study, we mainly investigated its protection against lethal total-body irradiation (TBI) in rats. Administration of MASM reduced the radiation sickness characteristics and increased the 30-day survival of rats before or after lethal TBI. Ultrastructural observation illustrated that pretreatment of rats with MASM significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed that pretreatment with MASM had a dramatic effect on gene expression changes caused by TBI. Pretreatment with MASM prevented differential expression of 53% (765 genes) of 1445 differentially expressed genes induced by TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 21 pathways, such as metabolic pathways, pathways in cancer, and mitogen-activated protein kinase (MAPK) pathways. Our data indicated that pretreatment of rats with MASM modulated these pathways induced by TBI, suggesting that the pretreatment with MASM might provide the protective effects on lethal TBI mainly or partially through the modulation of these pathways, such as multiple MAPK pathways. Therefore, MASM has the potential to be used as an effective therapeutic or radioprotective agent to minimize irradiation damages and in combination with radiotherapy to improve the efficacy of cancer therapy.
| S-EPMC6273364 | biostudies-literature
Project description:To further investigate the potential molecular basis of the protective effects of HSC on irradiation (6.5Gy) damage, gene expression analysis was conducted on rats liver tissues using microarrays.Pre-treatment with HSC prevented differential expression of 66% (1,398 genes) of 2,126 genes differentially expressed in response to radiation. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as olfactory transduction, uroactive ligand-receptor interaction, pathways in cancer, calcium signaling pathway, vascular smooth muscle contraction, cytokine-cytokine receptor interaction, mitogen-activated protein kinase (MAPK) signaling pathway, peroxisomal proliferator-activated receptor (PPAR）signaling pathway, gonadotropin-releasing hormone (GnRH) signaling pathway, Wnt signaling pathway, janus kinase-signal transducers and activators of transcription (Jak-STAT) signaling pathway, Notch signaling pathway.Our analysis indicated that the pretreatment of rats with HSC attenuated radiation-induced these pathways, such as multiple MAPK pathways, suggesting that the protective effect of HSC acts mainly through the attenuation of these pathways.
2014-05-15 | GSE57692 | GEO
Project description:To further investigate the potential molecular basis of the protective effects of HSC on irradiation (6.5Gy) damage, gene expression analysis was conducted on rats liver tissues using microarrays.Pre-treatment with HSC prevented differential expression of 66% (1,398 genes) of 2,126 genes differentially expressed in response to radiation. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as olfactory transduction, uroactive ligand-receptor interaction, pathways in cancer, calcium signaling pathway, vascular smooth muscle contraction, cytokine-cytokine receptor interaction, mitogen-activated protein kinase (MAPK) signaling pathway, peroxisomal proliferator-activated receptor (PPAR）signaling pathway, gonadotropin-releasing hormone (GnRH) signaling pathway, Wnt signaling pathway, janus kinase-signal transducers and activators of transcription (Jak-STAT) signaling pathway, Notch signaling pathway.Our analysis indicated that the pretreatment of rats with HSC attenuated radiation-induced these pathways, such as multiple MAPK pathways, suggesting that the protective effect of HSC acts mainly through the attenuation of these pathways. The rats were randomly assigned to one of the three following treatment groups (10-12 animals per group): normal control, radiation and HSC dose (10g/kg body weight/day) + radiation. HSC dissolved in double distilled water were administered intragastrically to the male animals for 3 consecutive days before irradiation. Radiation induced gene expression in rat liver was measured at 24 hours after 6.5 Gy exposure.
2014-05-15 | E-GEOD-57692 | biostudies-arrayexpress
Project description:DmPGE2 predominantly interferes with IR-induced p53-downstream apoptotic gene expression at 1 h, and suppresses IR-induced cell cycle gene expression at 24 h.
2020-07-15 | GSE151799 | GEO
Project description:BackgroundIonizing radiation (IR) exposure often occurs for human beings through occupational, medical, environmental, accidental and/or other sources. Thus, the role of radioprotector is essential to overcome the complex series of overlapping responses to radiation induced DNA damage.Methods and resultsTreatment of human glioma U87 cells with DMA (5- {4-methylpiperazin-1-yl}-2-[2'-(3, 4-dimethoxyphenyl)-5'-benzimidazolyl] in the presence or absence of radiation uncovered differential regulation of an array of genes and proteins using microarray and 2D PAGE techniques. Pathway construction followed by relative quantitation of gene expression of the identified proteins and their interacting partners led to the identification of MAP3K14 (NFκB inducing kinase, NIK) as the candidate gene affected in response to DMA. Subsequently, over expression and knock down of NIK suggested that DMA affects NFκB inducing kinase mediated phosphorylation of IKKα and IKKβ both alone and in the presence of ionizing radiation (IR). The TNF-α induced NFκB dependent luciferase reporter assay demonstrated 1.65, 2.26 and 3.62 fold increase in NFκB activation at 10, 25 and 50 µM DMA concentrations respectively, compared to control cells. This activation was further increased by 5.8 fold in drug + radiation (50 µM +8.5 Gy) treated cells in comparison to control. We observed 51% radioprotection in control siRNA transfected cells that attenuated to 15% in siRNA NIK treated U87 cells, irradiated in presence of DMA at 24 h.ConclusionsOur studies show that NIK/IKK mediated NFκB activation is more intensified in cells over expressing NIK and treated with DMA, alone or in combination with ionizing radiation, indicating that DMA promotes NIK mediated NFκB signaling. This subsequently leads to the radioprotective effect exhibited by DMA.
| S-EPMC3382165 | biostudies-literature
Project description:Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.
| S-EPMC6374382 | biostudies-literature
Project description:BACKGROUND: Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC) transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals. METHODS AND FINDINGS: Mouse mesenchymal stromal cells (mMSCs) were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures) and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i) decreased proinflammatory, ECM formation and adhesion properties and (ii) boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals. CONCLUSIONS: Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis thereby serving as fast and effective first-line treatment to combat radiation-induced hematopoietic failure.
| S-EPMC3016319 | biostudies-literature
Project description:To identify genes affected by miR-766-5p overexpression, we transfected with 10nmol of miR-766-5p or miR-negative control (NC) in HCT116-/-, or MIAPaCa2 cells. After 2 days, RNA was extracted, and then expression analysis was performed using agilent microarray.
2021-07-25 | GSE180688 | GEO
