Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: James MacDonald
PROVIDER: E-GEOD-50994 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Knowing the gene expression profiles of drug-metabolizing enzymes and transporters throughout gestation is important for understanding the mechanisms of pregnancy-induced changes in drug pharmacokinetics. In this study, we compared gene expression of drug-metabolizing enzymes and transporters in the maternal liver, kidney, small intestine, and placenta of pregnant mice throughout gestation by microarray analysis. Specifically, we investigated cytochrome P450 (Cyp), UDP-glucuronosyltranserase (Ugt), and sulfotransferase (Sult), as well as ATP-binding cassette (Abc) and solute carrier (Slc) transporters. We found that relatively few Ugt and Sult genes were impacted by pregnancy in maternal tissues and placenta. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 in the liver were down-regulated, with the greatest changes occurring on gestation days (gd) 15 and 19 compared to non-pregnant controls (gd 0). However, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. Cyp expression in mid-gestation placenta (gd 10 and 15) was generally greater than that in term placenta (gd 19). There were also notable changes in Abc and Slc transporters. Abcc3 in the liver was down-regulated by 60%, and Abcb1a, Abcc4, and Slco4c1 in the kidney were down-regulated by 30-60% on gd 15 and 19 versus gd 0. Abcc5 in the placenta was induced 3-fold on gd 10 versus gd 15 and 19, whereas Slc22a3 expression in the placenta on gd 10 was 90% lower than that on gd 15 and 19. Overall, this study demonstrates important gestational age-dependent expression of drug-metabolizing enzymes and transporter genes, which may have mechanistic relevance to human pregnancy. Ninety pregnant mice at gestational days 0, 7.5, 10, 15, and 19 (n = 5-6 per gestational age) were used for the maternal liver, kidney, small intestine and placenta. The placentas were collected on gestational days 10, 15, and 19.
2013-10-08 | E-GEOD-41438 | biostudies-arrayexpress
Project description:Critically ill preterm infants experience multiple stressors while hospitalized. Morphine is commonly prescribed to ameliorate their pain and stress. We hypothesized that neonatal stress will have a dose-dependent effect on hippocampal gene expression, and these effects will be altered by morphine treatment. Male C57BL/6 mice were exposed to 5 treatment conditions between postnatal day 5 and 9: 1) Control, 2) mild stress + saline, 3) mild stress + morphine, 4) severe stress + saline and 5) severe stress + morphine. Hippocampal RNA was extracted and analyzed using Affymetrix Mouse Gene 1.0 ST Arrays. Single gene analysis and gene set analysis were used to compare groups with validation by qPCR. Stress resulted in enrichment of genes sets related to fear response, oxygen carrying capacity and NMDA receptor synthesis. Morphine downregulated gene sets related to immune function. Stress plus morphine resulted in enrichment of mitochondrial electron transport gene sets, and down-regulation of gene sets related to brain development and growth. We conclude that neonatal stress alone influences hippocampal gene expression, morphine alters a subset of stress-related changes in gene expression and influences other gene sets. Stress plus morphine show interaction effects not present with either stimulus alone. These changes may alter neurodevelopment. Male mice were exposed to 5 treatment conditions between postnatal day (P)5 and P9 (n=3/group), with birth recorded as P1. Litters were culled to n=7 maximum per dam. Groups included: 1) Untreated controls (CC), 2) mild stress + saline (MSS), 3) mild stress + morphine (MSM), 4) severe stress + saline (SSS) and 5) severe stress + morphine (SSM).
2013-08-30 | E-GEOD-50382 | biostudies-arrayexpress
Project description:Early events leading to intrauterine infection remain poorly defined, but may hold the key to a therapeutic intervention for preterm delivery. To determine early molecular pathways associated with membrane weakening that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of Group B Streptococcus (GBS) on fetal membranes after a choriodecidual infection. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n=5) or 2) saline (n=5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. Macaca nemestrina chorioamnion samples were obtained at the site of inocculation immediately after cesarean delivery 4 days after GBS inoculation and 7 days after saline inoculation. RNA was extracted and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.
2014-11-18 | E-GEOD-46290 | biostudies-arrayexpress
Project description:Liver cirrhosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet the mechanisms by which cirrhosis predisposes patients to tumorigenesis are not well understood. Transgenic mice expressing platelet-derived growth factor C (Pdgf-c) under the control of the albumin promoter provide a unique animal model that mimics the step-wise disease progression in humans from fibrosis to HCC. The livers of Pdgf-c Tg mice show evidence of liver injury, including inflammation, proliferation, fibrosis and steatosis, and as the mice age, angiogenesis and dysplasia. Eighty-five percent of these mice develop HCC spontaneously, and have reduced survival that is related to their liver pathology. Through measurement of protein, RNA, and histological markers, we provide evidence to support the hypothesis that changes in liver stromal cells play an essential role in tumorigenesis in this model. A paracrine signaling model is proposed where ectopic expression of Pdgf-c in hepatocytes results in activation of hepatic stellate cells, which subsequently activates endothelial and Kupffer cells. Activation of these non-parenchymal cells promotes the release of hepatocyte growth factors that, together with changes in extracellular matrix, lead to the formation of HCC. Pdgf-c Tg mice provide a useful pre-clinical model in which to test novel drugs for chronic liver disease and HCC that focus on blocking the processes that alter the liver's fibrotic microenvironment. Two strains of mice, C57BL/6 and C57/BL6 Pdgf-c transgenic, were analyzed to see if liver stromal cells play an essential role in tumorigenesis.
2014-05-12 | E-GEOD-38199 | biostudies-arrayexpress
Project description:Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children and is characterized by myogenic differentiation arrest. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of HDACs in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. To identify candidate genes that are differentially regulated in histone deacetylase inhibitor-treated embryonal rhabdomyosarcoma, a gene expression profiling study using the Affymetrix Human Gene 2.0 microarray platform and ingenuity pathway analysis of differentially expressed genes were performed on RD and 381T cells treated with trichostatin A or dimethyl sulfoxide (treatment vehicle).
2015-12-21 | E-GEOD-74970 | biostudies-arrayexpress
Project description:Chemical exposures in fish have been linked to loss of olfaction leading to an inability to detect predators and prey and decreased survival. However, the mechanisms underlying olfactory neurotoxicity are not well characterized, especially in environmental exposures which involve chemical mixtures. We used zebrafish to characterize olfactory transcriptional responses by two model olfactory inhibitors, the pesticide chlorpyrifos (CPF) and mixtures of CPF with the neurotoxic metal copper (Cu). 30 one-year-old adult AB strain zebrafish were exposed, in groups of three, to CPF/Cu concentrations of 0/0, 0.1/0, 0.25/0, 0.6/0, 0/0.1, 0/0.25, 0/0.6, 0.1/0.25, 0.25/0.25, 0.6/0.25.
2013-05-21 | E-GEOD-47039 | biostudies-arrayexpress
Project description:Although environmental trace metals, such as copper (Cu), can disrupt normal olfactory function in fish, the underlying molecular mechanisms of metal-induced olfactory injury have not been elucidated. Current research has suggested the involvement of epigenetic modifications. To address this hypothesis, we analyzed microRNA (miRNA) profiles in the olfactory tissues of Cu-exposed zebrafish. Our data revealed 2, 10, and 28 differentially expressed miRNAs in a dose response pattern to three increasing Cu concentrations. Numerous deregulated miRNAs were involved in neurogenesis (let-7, miR-7a, miR-128 and miR-138), indicating a role for Cu-mediated toxicity via interference with olfactory neurogenesis. Putative gene targets of deregulated miRNAs were identified when interrogating our previously published microarray database, including those involved in olfactory cell growth and proliferation, cell death, and cell morphology. Moreover, several miRNAs (miR-203a, miR-199*, miR-16a, miR-16c, and miR-25) were inversely correlated with the depression of key genes within olfactory signal transduction pathways, which likely contributed to the inhibition of olfactory function. Our findings provide novel insight into the epigenetic regulatory mechanisms of metal-induced neurotoxicity of fish olfactory system, and identify novel miRNA biomarkers of metal exposures. 12 one-year-old adult AB strain zebrafish were exposed to Cu concentrations of 0, 6.3, 16 and 40 ppb Cu.
2014-04-30 | E-GEOD-46891 | biostudies-arrayexpress
Project description:Mechanisms underlying in utero fetal lung injury remain poorly defined, and a greater understanding of pathways regulating these processes may lead to novel therapies that prevent lung injury before birth. MicroRNAs (miRNAs) are small non-coding, endogenous RNAs that regulate gene expression and have been implicated in the pathogenesis of lung disease. We sought to determine whether differentially expressed miRNAs in the fetal lung following choriodecidual infection are associated with elevation of amniotic fluid (AF) cytokine levels and acute lung injury in a nonhuman primate model. After inoculating ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) with either Group B Streptococcus (GBS) 1 x 106 colony forming units (n=5) or saline (n=5) in the choriodecidual space, we extracted fetal lung mRNA and miRNA and profiled changes in expression. We identified 9 differentially expressed miRNAs (p<0.05, >1.5 fold change) in the GBS-exposed fetal lungs by microarray, but of these only miR-155-5p was significantly elevated by qRT-PCR (p=0.016). The microarray log2 intensity of miR-155-5p positively correlated with fetal lung injury scores and AF IL-1? and TNF-??levels (R2=0.54, p=0.016). In situ hybridization revealed that miR-155-5p is expressed throughout the fetal lung, which led us to investigate mechanisms that regulate miR-155-5p expression. Significantly elevated miR-155-5p expression was observed when immortalized human fetal airway epithelial (FeAE) cells were exposed to IL-6 and TNF-??. Overexpression of miR-155-5p in FeAE cells increased production of IL-6, CCL5/RANTES and CXCL10/IP-10. Using a luciferase reporter assay, we validated FGF9 as an authentic target of miR-155-5p, which is essential to development of the lung mesenchyme and distal epithelial branching. Collectively, these results suggest that a choriodecidual inflammatory response leads to increased AF cytokine levels, which induce miR-155-5p expression. In turn, miR-155-5p activates and recruits leukocytes (IL-6, CCL5/RANTES) and inhibits fetal lung angiogenesis (CXCL10/IP-10), meschenchymal development and epithelial branching (targets FGF9 mRNA). A therapy to antagonize miR-155-5p may ameliorate perinatal lung injury. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n=5) or 2) saline (n=5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. RNA was extracted from fetal lungs and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.
2015-08-05 | E-GEOD-60628 | biostudies-arrayexpress
Project description:Uterine stretch is thought to induce preterm labor in women with twin and higher order pregnancies, but the pathophysiology remains unclear. We investigated the pathogenesis of stretch-induced preterm birth for the first time in a pregnant nonhuman primate model. Eleven chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received either: 1) inflation of intra-amniotic balloons (N=6) or 2) saline inoculation (N=5). Cesarean section and fetal necropsy was performed due to preterm labor or to collect tissues, except in one case where the animal delivered spontaneously, reducing samples for microarray analysis to ten (five stretch and five control animals). Amniotic fluid and maternal plasma were analyzed for multiple cytokines and prostaglandins using Luminex, enzyme-linked immunosorbent assay and Analysis of Covariance. Ribonucleic acid was extracted from the myometrium in the lower uterus at Cesarean section and analyzed by microarray and quantitative reverse transcriptase polymerase chain reaction.
2015-09-11 | E-GEOD-63274 | biostudies-arrayexpress
Project description:Intrauterine exposure to amniotic fluid (AF) cytokines is thought to predispose to bronchopulmonary dysplasia (BPD). We evaluated the effects of GBS exposure on RNA expression in fetal lung tissue to determine early molecular pathways associated with fetal lung injury that may progress to BPD. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n=5) or 2) saline (n=5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. RNA was extracted from fetal lungs and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.
2013-04-23 | E-GEOD-39029 | biostudies-arrayexpress