Effect of telmisartan on prostate carcinogenesis in TRAP rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
SUBMITTER: Satoru Takahashi
PROVIDER: E-GEOD-29445 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:To identify potential and novel target genes responsive to the anticancer effect in telmisartan-treated gynecological cancer cells, we examined the global changes in gene expression in HHUA endometrial cancer cells after treatment with telmisartan. Gene expression profile in HHUA endometrial cancer cells treated with telmisartan
2012-03-22 | E-GEOD-36654 | biostudies-arrayexpress
Project description:Objective M-bM-^@M-^S Telmisartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, are antihypertensive agents clinically used as monotherapy or in combination. They exert beneficial cardiovascular effects independently of blood pressure lowering and classic mechanisms of action. In this study, we investigate molecular mechanisms responsible for the off-target effects of telmisartan and telmisartan-amlodipine in endothelial cells (EC), using an unbiased approach. Approach and Results M-bM-^@M-^S In human umbilical vein endothelial cells, microarray analysis of gene expression followed by pathway enrichment analysis and qRT-PCR validation revealed that telmisartan modulates the expression of key genes responsible for cell cycle progression and apoptosis. AmlodipineM-bM-^@M-^Ys effect was similar to control. EC exposed to telmisartan, but not amlodipine, losartan or valsartan, exhibited a dose-dependent impairment of cell growth and failed to enter the S-phase of the cell cycle. Similarly, telmisartan inhibited proliferation in COS-7 cells lacking the AT1 receptor. In telmisartan-treated EC, phosphorylation and activation of Akt as well as MDM2 was reduced, leading to accumulation of p53 in the nucleus, where it represses the transcription of cell cycle promoting genes. Phosphorylation of GSK3M-NM-2 was also reduced, resulting in rapid proteolytic turnover of CyclinD1. Telmisartan induced downregulation of proapoptotic genes and protected EC from serum starvation- and 7-ketocholesterol-induced apoptosis. Conclusions M-bM-^@M-^S Telmisartan exerts antiproliferative and antiapoptotic effects in EC. This may account for the improved endothelial dysfunction observed in the clinical setting. HUVEC were treated with 100 M-BM-5mol/L telmisartan or 5 M-BM-5mol/L amlodipine or both in dimethyl sulfoxide (DMSO) or an equivalent volume of DMSO alone, as control, for 24 hours. Microarray analysis was carried out on two biological replicates per group (total of six samples). See PROTOCOL section for experimental details.
2013-05-14 | E-GEOD-42808 | biostudies-arrayexpress
Project description:Diet-induced obesity is reported to induce a phenotypic switch in adipose tissue macrophages from an antiinflammatory M2 state to a proinflammatory M1 state. Telmisartan, an angiotensin II type 1 receptor antagonist and a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, reportedly has beneficial effects on insulin sensitivity. We studied the effects of telmisartan on the adipose tissue macrophage phenotype in high fat-fed mice. Telmisartan was administered for 5 weeks to high fat-fed C57BL/6 mice. Insulin sensitivity, macrophage infiltration, and the gene expressions of M1 and M2 markers in epididymal fat tissues were examined. Insulin- or a glucose-tolerance test showed that telmisartan treatment improved insulin resistance, decreasing the body weight gain, visceral fat weight and adipocyte size without affecting the amount of food intake. Telmisartan treatment reduced the number of CD11c-positive cells and crown-like structures. Telmisartan reduced the mRNA expressions of M1 macrophage markers, such as TNF-alpha and IL-6, and increased the expression of M2 markers, such as IL-10 and Mgl2. The reduction of M1 macrophage markers, as well as the increased gene expression of M2 markers especially IL-10, is a possible mechanism for the improvement of insulin sensitivity by telmisartan. Six-week-old male C57BL/6J mice were purchased from CLEA Japan. The mice were fed a chow that contained 10% of its calories from fat (control) or a high-fat diet (HFD) that contained 30% of its calories from fat for 24 weeks. The high fat-fed mice were randomized to 3 groups. Either telmisartan (~3 mg/kg/day) in drinking water (HFD+Tel), candesartan (~3 mg/kg/day) in drinking water (HFD+Can), or a HFD without any drugs (HFD) was administered for the next 5 weeks. Two mice were treated per group. Epididymal adipose tissues were rapidly removed from each mouse. Gene expression in epididymal fat tissue was analyzed using a GeneChip® system with the Mouse Genome 430 2.0 Array, which was spotted with 45,101 probe sets (Affymetrix, Santa Clara, CA, USA). Sample preparation for the array hybridization was performed according to the manufacturer’s instructions. In short, 5 μg of total RNA was used to synthesize double-stranded cDNA using the GeneChip® Expression 3′-Amplification Reagents One-Cycle cDNA Synthesis Kit (Affymetrix). Biotin-labeled cRNA was then synthesized from the cDNA using GeneChip® Expression 3′-Amplification Reagents for IVT Labeling (Affymetrix). After fragmentation, the biotinylated cRNA was hybridized to arrays at 45 °C for 16 h. The arrays were washed, stained with streptavidin-phycoerythrin, and scanned using a probe array scanner. The scanned chip was analyzed using the GeneChip Analysis Suite software (Affymetrix). Hybridization intensity data were converted into a presence/absence call for each gene, and changes in gene expression between experiments were detected by a comparison analysis. Data was shown as the fold change relative to the expression level of normal chow-fed mice.
2010-01-22 | E-GEOD-19954 | biostudies-arrayexpress
Project description:Objective – Telmisartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, are antihypertensive agents clinically used as monotherapy or in combination. They exert beneficial cardiovascular effects independently of blood pressure lowering and classic mechanisms of action. In this study, we investigate molecular mechanisms responsible for the off-target effects of telmisartan and telmisartan-amlodipine in endothelial cells (EC), using an unbiased approach. Approach and Results – In human umbilical vein endothelial cells, microarray analysis of gene expression followed by pathway enrichment analysis and qRT-PCR validation revealed that telmisartan modulates the expression of key genes responsible for cell cycle progression and apoptosis. Amlodipine’s effect was similar to control. EC exposed to telmisartan, but not amlodipine, losartan or valsartan, exhibited a dose-dependent impairment of cell growth and failed to enter the S-phase of the cell cycle. Similarly, telmisartan inhibited proliferation in COS-7 cells lacking the AT1 receptor. In telmisartan-treated EC, phosphorylation and activation of Akt as well as MDM2 was reduced, leading to accumulation of p53 in the nucleus, where it represses the transcription of cell cycle promoting genes. Phosphorylation of GSK3β was also reduced, resulting in rapid proteolytic turnover of CyclinD1. Telmisartan induced downregulation of proapoptotic genes and protected EC from serum starvation- and 7-ketocholesterol-induced apoptosis. Conclusions – Telmisartan exerts antiproliferative and antiapoptotic effects in EC. This may account for the improved endothelial dysfunction observed in the clinical setting.
2013-05-14 | GSE42808 | GEO
Project description:This study looks at the effect of glycomacropeptide (GMP) treatment on rats with trinitrobenzene sulfuric acid (TNBS) induced colitis.<br><br> Female Wistar rats (175-225 g) were randomly assigned to three different groups. A control group C (n=3) that did not receive the TNBS challenge but 0.25 ml of phosphate buffered saline (PBS) intrarectally, and two groups (group T (n=3) and group GMP (n=5) that received the TNBS challenge as described below. Group GMP received 500 mg kg-1 day-1 of GMP in 1% methylcellulose p.o, starting two days before the TNBS challenge. Treatment was administered to rats for five days after the TNBS challenge using an oesophageal catheter. The T group received the vehicle. Colitis was induced by the method of Morris et al. with minor modifications (13). Briefly, animals were fasted overnight and anaesthetized with halothane. Under these conditions, animals were given 10 mg of TNBS dissolved in 0.25 ml of 50% ethanol (v v-1) by means of a Teflon cannula inserted 8 cm through the anus. Animals were kept in a head-down position for an additional 30 s and returned to their cage. Distal colon samples were obtained. For TNBS treated animals samples were obtained avoiding necrotic tissue.
2009-05-25 | E-MEXP-1631 | biostudies-arrayexpress
Project description:To identify potential and novel target genes responsive to the anticancer effect in telmisartan-treated gynecological cancer cells, we examined the global changes in gene expression in HHUA endometrial cancer cells after treatment with telmisartan.
2012-03-22 | GSE36654 | GEO
Project description:Androgens are required for prostate development, growth and physiology, by activating the androgen receptor (AR) upon activation by testosterone and dihydrotestosterone (DHT), the AR undergoes conformational changes, dimerizes and translocates to the cell nucleus regulation important genes releted to cell survival. Understanding the mechanisms of androgen regulation in the prostate gland is important, because the prostate is affected by several different diseases, in particular prostate cancer (PCa). Several ways exist to treat prostate cancer and promote epithelial cell death. Treatments involving androgen manipulation include surgical castration (bilateral orchiectomy), antiandrogens (usually AR antagonists), or substances that inhibit androgen synthesis (5 alpha-reductase inhibitors, gonadotrophin-releasing hormone blockers). 17 beta-estradiol exerts anti-androgen effects by blocking the hypothalamic production of gonadotropin-releasing hormone and thereby inhibiting the production of testosterone by the testes , but also acts locally via interactions with either of the estrogen receptors found in the gland. It is known that the kinetics of apoptosis are different in the rat ventral prostate (VP) of castrated rats (Cas group) and in rats subjected to 17 beta-estradiol high dose (group E2) or their combination (group Cas+E2), with an evident additive effect in the latter situation (Garcia-Florez et al, 2005). The microarray approach was done to figure out what genes are expressed and how the cells of ventral prostate gland responses when the androgen is not available comparing three diferent androgen deprivation methods (sirurgical castration, high dose of 17-beta estradiol and both treatment combined). Forty-eight 21-day-old male Wistar rats were obtained from the Multidisciplinary Center for Biological Research (CEMIB), University of Campinas. The animals were kept under normal light conditions (12-h light:dark cycle) and received filtered tap water and Purina rodent chow ad libitum. On the 90th day after birth, the rats were divided in four groups (n=3) and assigned to different treatment groups. To cause androgen deprivation, we utilized three different procedures with different effects on epithelial cell apoptosis. Animals in the first group were castrated (Cas) by orchiectomy via scrotal incision under ketamine (150 mg/Kg body weight) and xylazin (10 mg/kg body weight) anesthesia. Animals in the second group received a 25 mg/Kg body weight dose of 17β-estradiol diluted in corn oil (E2 group). The third group received a combination of both treatments (Cas+E2 group) (combined orchiectomy and 17β-estradiol). In the control group (Ct; normal androgen and estrogen), the animals received only the vehicle. Three days after the treatments, the rats were killed by anesthetic overdose, and the ventral prostate was dissected out for the microarray and immunohistochemistry analyses.
2015-03-28 | E-GEOD-56289 | biostudies-arrayexpress
Project description:Nonalcoholic fatty liver disease (NAFLD) is a rapidly increasing global health problem that is associated with metabolic disorders covering a broad spectrum of pathological abnormalities, including simple steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis, and hepatocellular carcinoma (HCC). Telmisartan is a potential treatment for NAFLD due to its ability to improve insulin sensitivity and decrease hepatic fat accumulation via modulation of peroxisome proliferator-activated receptor gamma (PPARγ), and to suppress hepatic fibrosis by blocking angiotensin II receptors. However, the underlying molecular mechanisms of action of telmisartan, and the interaction between the renin-angiotensin system (RAS) and PPAR, have yet to be fully elucidated. Thus, in the present study, NASH-HCC STAM mice received daily administrations of telmisartan for 6 weeks to assess the prevention of fibrosis and lipid accumulation in the liver, and to evaluate improvements in NASH. Hepatic transcriptome analyses revealed that the amelioration of NASH likely occurred through the regulation of inflammatory- and fibrosis-related gene responses. An integrated protein-protein interaction network analysis including transcriptional and non-transcriptional genes regulated by telmisartan showed that the NAFLD pathway is located at the center of the network and has interconnections with the RAS and PPAR signaling pathways. Additionally, the downstream targets of the transcription factors in the network, PPARα, PPARδ, and RELA, significantly overlapped with telmisartan-induced differentially expressed genes (DEGs). This alternative approach to assessing the transcriptome provided the opportunity to understand the fundamental molecular mechanisms underpinning the therapeutic effects of telmisartan, and will contribute to the establishment of a novel pharmacological treatment for NASH patients.
2019-03-19 | GSE120937 | GEO
Project description:Gene-expression profiles of rat liver cirrhosis induced by diethylnitrosamine and the effect of erlotinib on liver fibrogenesis and liver cancer development Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level. Keywords: Cirrhotic liver, Expression array, Illumina, Signatures, Outcome prediction Animals received humane care according to the criteria outlined in the M-bM-^@M-^\Guide for the Care and Use of Laboratory AnimalsM-bM-^@M-^] of the National Academy of Sciences. All animals were maintained in accordance with the institutional guidelines of the Massachusetts General Hospital Subcommittee on Research Animal Care. Male Wistar rats received weekly IP injections of diethylnitrosamine (DEN) at 50 mg/kg, 100mg/kg, or vehicle control (PBS) for 18 weeks. A subset of rats received either daily (5X a week) IP injections of 2 mg/kg erlotinib or vehicle control during weeks 13 - 18. In a separate study, the erlotinib dose was lowered to 0.5 mg/kg. The vehicle groups from the two studies were not significantly different so they were combined together for analysis. Rats were weighed at the end of each week. Animals were sacrificed at 9, 13 and 19 weeks after a one-week washout period to eliminate acute effects of DEN. At the time of sacrifice, the non-tumor liver tissues were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until RNA extraction.
2014-02-28 | E-GEOD-19057 | biostudies-arrayexpress
Project description:Patients with long-duration diabetes develop cardiovascular complications resulting in highly increased mortality and complications which affect the kidneys, eyes and peripheral nerves associated with high morbidity. Among the diabetic complications, damage in the eye, diabetic retinopathy, is the most common microvascular complication of diabetes. Diabetic retinopathy is a leading cause of vision-loss globally. It is characterized by a number of different patho-mechanisms including changes in vascular permeability, capillary degeneration, and finally at a late stage overshooting formation of new blood vessels. This expression analysis focused on the use of different experimental models for Diabetes Mellitus and its complications (for a review see 1: Al-Awar et al: Experimental Diabetes Mellitus in Different Animal Models. J Diabetes Res. 2016; doi: 10.1155/2016/9051426). By that, we wanted to uncover the relative contributions of systemic hyperinsulinaemia and/or hyperglycemia to molecular regulations. The following models have been used: As insulinopenic, hyperglycemic model reflecting Type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p.) were used. Wistar rats without STZ injection served as non-diabetic controls. Male obese ZDF rats (Fa/Fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male lean ZDF rats (Fa/-) served as non-diabetic controls. Male obese ZF rats (Fa/Fa) hyperglycemia were used reflecting euglycemia and severe insulin resistance. Male lean ZF rats (Fa/-) served as controls. ZDF and ZF rats were obtained in two genotypes, obese (genotype fa/fa) and lean littermates (genotype Fa/?). All rats were housed in standard cages under a normal light-dark cycle for 16 weeks. All animals had free access to food and water. ZF and Wistar rats received a standard chow (Ssniff R/M) and ZDF rats received Purina 5008 chow. A group size of n=8 were used for all study groups. Wistar rats were rendered type-1 like hyperglycemic and hypoinsulinemic via a single injection of streptocotocin (STZ, 60mg/kg; i.p.) at 7 weeks of age. Obese ZDF rats (fa/fa) develop spontaneously a type-2 diabetes phenotype with persisting hyperglycemia and transient hyperinsulinemia (hyperglycemic, hypoinsulinemic). Obese ZF rats (fa/fa) develop insulin resistance with permanent hyperinsulinemia without concomitant hyperglycemia and no overt diabetes phenotype. Non STZ treated Wistar rats, lean ZDF littermates (Fa/?), and lean ZF littermates (Fa/?) served as controls. All groups were kept for 12 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays.
2017-03-31 | E-MTAB-5563 | biostudies-arrayexpress