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1.
J Pharmacol Exp Ther ; 366(2): 390-396, 2018 08.
Article in English | MEDLINE | ID: mdl-29884626

ABSTRACT

Current pharmacotherapies for lower urinary tract symptoms associated with benign prostate hyperplasia (LUTS/BPH) are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid with various biologic functions. However, its exact role in the lower urinary tract and its target receptor subtype have not been fully elucidated. We investigated the role of LPA and the type 1 LPA receptor (LPA1) in urethral/prostatic contractile function and prostate cell proliferation by pharmacologically characterizing ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}-1,3-thiazole-4-carbonyl)-3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide), a novel LPA1 antagonist. ASP6432 exhibited potent and selective antagonistic activity against LPA1 in cells expressing LPA receptor subtypes. In isolated rat tissue strips and anesthetized rats, ASP6432 concentration-/dose-dependently inhibited LPA-induced urethra and prostate contractions. In addition, in anesthetized rats, ASP6432 maximally decreased the urethral perfusion pressure (UPP) in the absence of exogenous LPA stimulation by 43% from baseline, whereas tamsulosin, an α1-adrenoceptor antagonist, reduced UPP by 22%. Further, in human prostate stromal cells, ASP6432 significantly and concentration-dependently suppressed LPA-induced bromodeoxyuridine incorporation. These results demonstrate a pivotal role for LPA and LPA1 in the regulation of urethral tonus and prostate cell proliferation. The potent urethral relaxation and inhibition of prostatic stromal cell growth indicate the potential of ASP6432 as a novel therapeutic agent for LUTS/BPH.


Subject(s)
Prostate/cytology , Prostate/drug effects , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Thiazoles/pharmacology , Urethra/drug effects , Urethra/physiology , Benzamides , Calcium/metabolism , Cell Proliferation/drug effects , Humans , Intracellular Space/drug effects , Intracellular Space/metabolism , Male , Muscle Contraction/drug effects , Prostate/physiology , Stromal Cells/cytology , Stromal Cells/drug effects
2.
Biochem Biophys Res Commun ; 364(1): 33-9, 2007 Dec 07.
Article in English | MEDLINE | ID: mdl-17931601

ABSTRACT

Obesity is associated with infiltration of macrophages into adipose tissue, and macrophages are an important source of nitric oxide (NO). Dysregulated production of fat-derived secretory factor, adipocytokine, leads to obesity-linked metabolic disorders. However, it has not been fully determined whether NO might have direct effects on adipocytokine expressions. Here, we show that NO donor treatment downregulated gene expression and secretion of adiponectin, and upregulated mRNA levels of PAI-1 and IL-6. NO donor reduced promoter activity of adiponectin through PPARgamma responsive element. Moreover, NO donor activated JNK and NF-kappaB pathways, and inhibitors of these pathways rescued NO-mediated upregulation of PAI-1 and IL-6. Analysis of adipose tissue of high-fat-fed obese mice showed upregulation of PAI-1 and IL-6 expression, increased synthesis of NO, and downregulation of adiponectin. Our results suggest that increased NO synthesis might be partly responsible for dysregulation of adipocytokines in adipose tissue.


Subject(s)
Adipokines/biosynthesis , Nitric Oxide/metabolism , 3T3-L1 Cells , Adiponectin/biosynthesis , Animals , Anthracenes/pharmacology , Down-Regulation , Female , Gene Expression Regulation/drug effects , I-kappa B Proteins/metabolism , MAP Kinase Kinase 4/metabolism , Mice , Mice, Inbred C57BL , Nitric Oxide Donors/pharmacology , Nitriles/pharmacology , Obesity/metabolism , PPAR gamma/biosynthesis , Signal Transduction/drug effects , Sulfones/pharmacology
3.
Diabetes ; 56(4): 901-11, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17395738

ABSTRACT

Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.


Subject(s)
Adipose Tissue/physiopathology , Cytokines/genetics , Hypoxia/physiopathology , Obesity/physiopathology , 3T3 Cells , Animal Feed , Animals , DNA Primers , DNA-Binding Proteins/genetics , Dietary Fats , Disease Models, Animal , Endoplasmic Reticulum Chaperone BiP , Gene Expression Regulation , Male , Mice , Mice, Inbred C57BL , Nuclear Proteins/genetics , Obesity/genetics , Polymerase Chain Reaction , Proteins/genetics , RNA Splicing , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Regulatory Factor X Transcription Factors , Transcription Factors
4.
Biochem Biophys Res Commun ; 349(3): 875-82, 2006 Oct 27.
Article in English | MEDLINE | ID: mdl-16970912

ABSTRACT

Obesity is associated with metabolic disorders, such as insulin resistance. Visfatin is an adipose-derived secretory factor to exert insulin-mimetic effects. Plasma visfatin levels and mRNA levels of visfatin in adipose tissues are increased in obesity. However, the mechanism that mediates induction of visfatin mRNA in adipose tissue of obesity remains unknown. Recent studies have reported that fat tissue is hypoxia in obesity. In this study, we investigated the effects of hypoxia on mRNA expression of visfatin in adipocytes. Hypoxia increased visfatin mRNA expression. Desferoxamine and Cobaltous chloride, two hypoxia mimetic compounds, also increased visfatin mRNA levels. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF1alpha), mimicked the hypoxia-mediated upregulation of visfatin, and YC1, an inhibitor of HIF1 cancelled the hypoxia-induced upregulation of visfatin mRNA. We identified two functional hypoxia responsive elements (HRE) in mouse visfatin promoter. Hypoxic treatment and overexpression of HIF1alpha increased the promoter activity, and mutation of the HRE blunted hypoxia-induced activation of visfatin promoter. Our results suggest that visfatin mRNA expression is upregulated in the fat tissue of obesity through the activation of HIF1alpha pathway due to hypoxia.


Subject(s)
Adipocytes/metabolism , Cytokines/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , 3T3-L1 Cells , Animals , Cell Hypoxia , Cytokines/genetics , Gene Expression , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Mice , Mutation/genetics , Nicotinamide Phosphoribosyltransferase , Promoter Regions, Genetic/genetics , Response Elements , Transcriptional Activation/genetics , Up-Regulation
5.
J Pharmacol Sci ; 99(4): 342-52, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16314690

ABSTRACT

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcriptional factor implicated in regulating adipogenesis, glucose homeostasis, and in mediating the action of the insulin sensitizing anti-diabetic thiazolidinedione (TZD) compounds. [3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-H-benzimidazole-5-carboxamide] (FK614) is a structurally novel PPARgamma agonist that demonstrates potent anti-diabetic activity in vivo. Herein, we describe that FK614 is a selective PPARgamma ligand with specific transactivation properties that are dependent upon the context of coactivators. FK614 dissociates the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) from PPARgamma as effectively as rosiglitazone and pioglitazone, but can also differentially induce a ligand specific interaction of PPARgamma with coactivators. The amount of CBP (CREB-binding protein) and SRC-1 (steroid receptor coactivator-1) recruited by FK614 was less than that induced by rosiglitazone and pioglitazone, but FK614 caused similar PGC-1alpha (PPARgamma coactivator-1alpha) recruitment as these compounds. As a consequence of these ligand-specific differences in the strength of ligand-type specific interactions of PPARgamma and coactivators, FK614 functions as a partial or full agonist for transcriptional activation depending upon the amount of specific coactivators in cells following overexpression. In conclusion, FK614 is a novel, non-TZD type, and selective PPARgamma modulator whose pharmacological properties are distinct from rosiglitazone and pioglitazone.


Subject(s)
Benzimidazoles/pharmacology , PPAR gamma/drug effects , Transcriptional Activation/drug effects , CREB-Binding Protein/metabolism , Genes, Reporter/drug effects , Glutathione/metabolism , Histone Acetyltransferases , Humans , Hybrid Cells , Hypoglycemic Agents/pharmacology , Ligands , Nuclear Receptor Coactivator 1 , PPAR gamma/genetics , Pioglitazone , Plasmids/genetics , Rosiglitazone , Thiazolidinediones/pharmacology , Transcription Factors/metabolism
6.
Eur J Pharmacol ; 477(2): 171-8, 2003 Sep 12.
Article in English | MEDLINE | ID: mdl-14519421

ABSTRACT

Our recent study suggests that there is a reciprocal mechanism to maintain cGMP content, via both a decrease in cGMP degradation (decrease in cGMP-phosphodiesterase activity) and an increase in synthesis of cGMP (increase in guanylate cyclase activity) in the kidney of cyclosporin A-treated rats. We undertook this study to clarify the role of cGMP-phosphodiesterase in cyclosporin A nephrotoxicity by evaluating N-(3,4-dimethoxybenzyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitrobenzamide (FR226807), a phosphodiesterase type 5 inhibitor, in an animal model. Male spontaneous hypertensive rats (SHR) were treated with cyclosporin A (50 mg/kg) for 2 weeks or with cyclosporin A and FR226807 (3.2 mg/kg or 10 mg/kg) for 2 weeks. Cyclosporin A-treated rats showed renal dysfunction and histological change compared with vehicle-treated rats. Administration of FR226807 improved the renal dysfunction (increase in serum creatinine and fractional excretion of sodium, and decrease in creatinine clearance) as well as the pathological changes (tubular vacuolization) induced by cyclosporin A in SHR. At the molecular level, administration of FR226807 resulted in a further increase in cGMP content in the kidney, aorta and platelets from cyclosporin A-treated rats. Our present study demonstrates that cGMP-phosphodiesterase plays an important role in the cyclosporin A nephrotoxicity and also suggests that further inhibition of cGMP-phosphodiesterase is a potential pharmacological target for preventing cyclosporin A nephrotoxicity.


Subject(s)
Benzamides/pharmacology , Cyclosporine/antagonists & inhibitors , Immunosuppressive Agents/antagonists & inhibitors , Kidney Diseases/prevention & control , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Aorta/metabolism , Blood Platelets/metabolism , Body Weight/drug effects , Cyclic GMP/blood , Cyclic GMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5 , Cyclosporine/pharmacology , Guanylate Cyclase/metabolism , Immunosuppressive Agents/pharmacology , Kidney/metabolism , Kidney/pathology , Kidney/physiopathology , Kidney Diseases/chemically induced , Kidney Diseases/physiopathology , Male , Nitric Oxide Synthase/metabolism , Potassium/blood , Rats , Rats, Inbred SHR , Sodium/blood
7.
Eur J Pharmacol ; 473(1): 65-70, 2003 Jul 18.
Article in English | MEDLINE | ID: mdl-12877939

ABSTRACT

Cyclic guanosine-3',5'-monophosphate (cGMP)-mediated mechanisms play an important role in vasodilation and blood pressure regulation. We investigated basal activity of the nitric oxide (NO)-cGMP signal transduction pathway in corpus cavernosum from both middle-aged and young rats, and the electrical field stimulation-induced relaxation in the organ was also evaluated. In middle-aged rats, nitric oxide synthase (NOS) and cGMP-phosphodiesterase activities were significantly decreased; however, guanylate cyclase activity was similar. cGMP concentration, a secondary messenger of NO, remained almost the same level as compared with young rats. These results suggest that decrease in cGMP-phosphodiesterase activity is likely to account for the maintenance of cGMP concentration. In isolated corpus cavernosum from middle-aged rats, electrical field stimulation-induced relaxation was partially impaired. These results suggest that downregulation of the NOS and cGMP-phosphodiesterase activities are early events in the pathogenesis of erectile dysfunction.


Subject(s)
Cyclic GMP/metabolism , Nitric Oxide/metabolism , Penis/drug effects , Penis/enzymology , Adrenergic Agents/pharmacology , Age Factors , Animals , Electric Stimulation , Enzyme Inhibitors/pharmacology , Guanylate Cyclase/metabolism , In Vitro Techniques , Isometric Contraction/drug effects , Isometric Contraction/physiology , Male , Muscle, Smooth/drug effects , Muscle, Smooth/enzymology , Nitric Oxide Synthase/metabolism , Phosphoric Diester Hydrolases/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Soluble Guanylyl Cyclase
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