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1.
Cell Physiol Biochem ; 32(4): 838-48, 2013.
Article in English | MEDLINE | ID: mdl-24081014

ABSTRACT

BACKGROUND: The serum and glucocorticoid inducible kinase SGK1, which was originally cloned from mammary tumor cells, is highly expressed in some but not all tumors. SGK1 confers survival to several tumor cells. Along those lines, the number of colonic tumors following chemical carcinogenesis was decreased in SGK1 knockout mice. Recently, a highly selective SGK inhibitor (EMD638683) has been developed. The present study explored whether EMD638683 affects survival of colon carcinoma cells in vitro and impacts on development of colonic tumors in vivo. METHODS: Colon carcinoma (Caco-2) cells were exposed to EMD638683 with or without exposure to radiation (3 Gray) and cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin V binding, mitochondrial potential from JC-9 fluorescence, caspase 3 activity from CaspGlow Fluorescein staining, DNA degradation from propidium iodide staining as well as late apoptosis from annexin-V FITC and propidium iodide double staining. In vivo tumor growth was determined in wild type mice subjected to chemical carcinogenesis (intraperitoneal injection of 20 mg/kg 1,2-dimethylhydrazine followed by three cycles of 30 g/L synthetic dextran sulfate sodium in drinking water for 7 days). RESULTS: EMD638683 treatment significantly augmented the radiation-induced decrease of forward scatter, increase of phosphatidylserine exposure, decrease of mitochondrial potential, increase of caspase 3 activity, increase of DNA fragmentation and increase of late apoptosis. The in vivo development of tumors following chemical carcinogenesis was significantly blunted by treatment with EMD638683. CONCLUSIONS: EMD638683 promotes radiation-induced suicidal death of colon tumor cells in vitro and decreases the number of colonic tumors following chemical carcinogenesis in vivo.


Subject(s)
Benzamides/pharmacology , Benzamides/therapeutic use , Colonic Neoplasms/drug therapy , Hydrazines/pharmacology , Hydrazines/therapeutic use , Immediate-Early Proteins/antagonists & inhibitors , Membrane Potential, Mitochondrial/drug effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Caco-2 Cells , Caspase 3/metabolism , Flow Cytometry , Humans , Mice
2.
Eur J Pharmacol ; 713(1-3): 78-88, 2013 Aug 05.
Article in English | MEDLINE | ID: mdl-23665494

ABSTRACT

Male hypogonadism is frequently accompanied with type 2 diabetes due to testicular dysfunction, but the origin of the pathogenesis is not known. We measured whether pro-inflammatory factors including endoplasmic reticulum (ER) stress chaperones and inhibitory κBß (IκBß) contribute to testis damage in type 2 diabetic rats produced by a high-fat diet (HFD) and low dose streptozotocin (STZ). We determined whether these can be attenuated by the anti-inflammatory activity of argirein a derivative of rhein as compared to valsartan. Reduced testosterone and LH (luteinizing hormone) levels in serum were significant in association with a decrease in the levels of mRNA and steroidogenic acute regulatory protein (StAR), insulin receptor substrate (IRS-1), activated IκBß and ER stress chaperone C/EBP homologous protein (CHOP) in the diabetic testis and sperm count, motility and sexual behaviors were reduced in vivo. Additionally, Leydig cells cultured with high glucose showed upregulated IκBß, ER stress sensor PERK (PKR-like ER kinase) and p-Akt/Akt in vitro. These changes may be due to a component of inflammation linked to activated NADPH oxidase and were significantly alleviated by either argirein or valsartan. In conclusion, diabetic testopathy induced by a HFD and low STZ is characterized by an entity of inflammation and is alleviated by argirein and valsartan through normalizing activated IκBß and ER stress.


Subject(s)
Anthraquinones/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Arginine/therapeutic use , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/complications , Endoplasmic Reticulum Stress/drug effects , Hypogonadism/prevention & control , I-kappa B Proteins/metabolism , Tetrazoles/therapeutic use , Valine/analogs & derivatives , Animals , Anthraquinones/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Arginine/administration & dosage , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Drug Combinations , Hypogonadism/etiology , Hypogonadism/immunology , Hypogonadism/metabolism , Male , Rats , Rats, Sprague-Dawley , Sexual Behavior, Animal/drug effects , Streptozocin/pharmacology , Tetrazoles/administration & dosage , Valine/administration & dosage , Valine/therapeutic use , Valsartan
3.
J Biomed Sci ; 19: 4, 2012 Jan 08.
Article in English | MEDLINE | ID: mdl-22226148

ABSTRACT

BACKGROUND: Hypoxia exposure initiates low serum testosterone levels that could be attributed to downregulated androgen biosynthesizing genes such as StAR (steroidogenic acute regulatory protein) and 3-beta-HSD (3-beta-hydroxysteroid dehydrogenase) in the testis. It was hypothesized that these abnormalities in the testis by hypoxia are associated with oxidative stress and an increase in chaperones of endoplasmic reticulum stress (ER stress) and ER stress could be modulated by a reduction in calcium influx. Therefore, we verify that if an application of CPU86017-RS (simplified as RS, a derivative to berberine) could alleviate the ER stress and depressed gene expressions of StAR and 3-beta-HSD, and low plasma testosterone in hypoxic rats, these were compared with those of nifedipine. METHODS: Adult male Sprague-Dawley rats were randomly divided into control, hypoxia for 28 days, and hypoxia treated (mg/kg, p.o.) during the last 14 days with nifedipine (Nif, 10) and three doses of RS (20, 40, 80), and normal rats treated with RS isomer (80). Serum testosterone (T) and luteinizing hormone (LH) were measured. The testicular expressions of biomarkers including StAR, 3-beta-HSD, immunoglobulin heavy chain binding protein (Bip), double-strand RNA-activated protein kinase-like ER kinase (PERK) and pro-apoptotic transcription factor C/EBP homologous protein (CHOP) were measured. RESULTS: In hypoxic rats, serum testosterone levels decreased and mRNA and protein expressions of the testosterone biosynthesis related genes, StAR and 3-beta-HSD were downregulated. These changes were linked to an increase in oxidants and upregulated ER stress chaperones: Bip, PERK, CHOP and distorted histological structure of the seminiferous tubules in the testis. These abnormalities were attenuated significantly by CPU86017-RS and nifedipine. CONCLUSION: Downregulated StAR and 3-beta-HSD significantly contribute to low testosterone in hypoxic rats and is associated with ER stress which mediates testis damage caused by oxygen deprivation. CPU86017-RS is potential in ameliorating hypoxia-induced testicular injuries, possibly by its calcium antagonist effects on the testis.


Subject(s)
3-Hydroxysteroid Dehydrogenases/metabolism , Berberine/analogs & derivatives , Calcium Channel Blockers/pharmacology , Endoplasmic Reticulum Stress/drug effects , Hypogonadism/drug therapy , Nifedipine/pharmacology , Phosphoproteins/metabolism , Testosterone/biosynthesis , Animals , Berberine/pharmacology , Calcium/metabolism , Down-Regulation , Glutathione Peroxidase/blood , Hypogonadism/metabolism , Hypoxia/metabolism , Hypoxia/veterinary , L-Lactate Dehydrogenase/blood , Luteinizing Hormone/blood , Male , Malondialdehyde/blood , Random Allocation , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Testis/injuries , Testis/metabolism , Testis/pathology , Testosterone/blood , Up-Regulation
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