PURPOSE: The medical treatment for benign prostatic hyperplasia (BPH) had recently been directed at preventing the progression of BPH, which reduces the risk of acute urinary retention (AUR) and BPH-related surgery. This study compared the long-term effectiveness of administering alpha- adrenergic blocker (alpha-blocker) and finasteride, a 5-alpha reductase inhibitor (5ARI), for treating BPH to prevent AUR and BPH-related surgery in real-life clinical practice. MATERIALS AND METHODS: This retrospective study enrolled 166 BPH patients who were treated at our hospital with the alpha-blockers doxazosin, terazosin, prazosin and alfuzosin, or tamsulosin and 5ARI as their first BPH treatment between January 1997 and December 1997, and these treatments lasted at least 12 months. Using follow-up data that was obtained at up to 7 years after treatment, we calculated the AUR and BPH-related surgery percentages in the alpha-blocker only group and in the combination group. RESULTS: During the study period, 17 of 110 patients (15.5%) in the alpha- blocker only group and 4 of 56 patients (7.1%) in the combination group experienced AUR. BPH-related surgery was performed on 10 of 110 patients (9.1%) in the alpha-blocker only group and surgery was performed on 1 of 56 patients (1.8%) in the combination group. Among them, 5 patients in the alpha-blocker only group and 1 patient in the combination group received surgery for AUR, and another 5 patients in the alpha-blocker only group showed insufficient therapeutic response. CONCLUSIONS: Real-life clinical practice showed that long-term combination treatment with alpha-blockers and 5ARI reduced the risk of the progression of BPH, such as AUR or BPH-related surgery, as compared with alpha-blocker-only treatment.
Adrenergic alpha-Antagonists ; Adrenergic Antagonists ; Doxazosin ; Finasteride ; Follow-Up Studies ; Humans ; Oxidoreductases* ; Prazosin ; Prostatic Hyperplasia* ; Retrospective Studies ; Urinary Retention*

PURPOSE: The medical treatment for benign prostatic hyperplasia (BPH) had recently been directed at preventing the progression of BPH, which reduces the risk of acute urinary retention (AUR) and BPH-related surgery. This study compared the long-term effectiveness of administering alpha- adrenergic blocker (alpha-blocker) and finasteride, a 5-alpha reductase inhibitor (5ARI), for treating BPH to prevent AUR and BPH-related surgery in real-life clinical practice. MATERIALS AND METHODS: This retrospective study enrolled 166 BPH patients who were treated at our hospital with the alpha-blockers doxazosin, terazosin, prazosin and alfuzosin, or tamsulosin and 5ARI as their first BPH treatment between January 1997 and December 1997, and these treatments lasted at least 12 months. Using follow-up data that was obtained at up to 7 years after treatment, we calculated the AUR and BPH-related surgery percentages in the alpha-blocker only group and in the combination group. RESULTS: During the study period, 17 of 110 patients (15.5%) in the alpha- blocker only group and 4 of 56 patients (7.1%) in the combination group experienced AUR. BPH-related surgery was performed on 10 of 110 patients (9.1%) in the alpha-blocker only group and surgery was performed on 1 of 56 patients (1.8%) in the combination group. Among them, 5 patients in the alpha-blocker only group and 1 patient in the combination group received surgery for AUR, and another 5 patients in the alpha-blocker only group showed insufficient therapeutic response. CONCLUSIONS: Real-life clinical practice showed that long-term combination treatment with alpha-blockers and 5ARI reduced the risk of the progression of BPH, such as AUR or BPH-related surgery, as compared with alpha-blocker-only treatment.
Adrenergic alpha-Antagonists ; Adrenergic Antagonists ; Doxazosin ; Finasteride ; Follow-Up Studies ; Humans ; Oxidoreductases* ; Prazosin ; Prostatic Hyperplasia* ; Retrospective Studies ; Urinary Retention*

Deoxyhypusine synthase catalyzes the first step in the posttranslational synthesis of an unusual amino acid, hypusine, in the eukaryotic translation initiation factor 5A (eIF-5A) precursor protein. We earlier observed that yeast recombinant deoxyhypusine synthase was phosphorylated by protein kinase C (PKC) in vitro (Kang and Chung, 1999) and the phosphorylation rate was synergistically increased to a 3.5-fold following treatment with phosphatidylserine (P.Ser)/diacylglycerol (DAG)/ Ca2+, suggesting a possible involvement of PKC. We have extended study on the phosphorylation of deoxyhypusine synthase in vivo in different cell lines in order to define its role on the regulation of eIF5A in the cell. Deoxyhypusine synthase was found to be phosphorylated by endogenous kinases in CHO, NIH3T3, and chicken embryonic cells. The highest degree of phosphorylation was found in CHO cells. Moreover, phosphorylation of deoxyhypusine synthase in intact CHO cells was revealed and the expression of phosphorylated deoxyhypusine synthase was significantly diminished by diacyl ethylene glycol (DAEG), a PKC inhibitor, and enhanced by phorbol 12-myristate 13-acetate (PMA) or Ca2+/DAG. Endogenous PKC in CHO cell and cell lysate was able to phosphorylate deoxyhypusine synthase and this modification is enhanced by PMA or Ca2+ plus DAG. Close association of PKC with deoxyhypusine synthase in the CHO cells was evident in the immune coprecipitation and was PMA-, and Ca2+/phospholipiddependent. These results suggest that phosphorylation of deoxyhypusine synthase was PKC-dependent cellular event and open a path for possible regulation in the interaction with eIF5A precursor for hypusine synthesis.
Amine Oxidoreductases/*metabolism ; Animals ; Cell Line ; Chick Embryo ; Female ; Hamsters ; Mice ; Phosphorylation ; Protein Binding ; Protein Kinase C/antagonists & inhibitors/*metabolism

To investigate the effect of a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor MK886 on cell cycle of the human acute myeloid leukemia HL-60 cells. HL-60 cells were treated with different concentration of MK886 (10, 25, 50 µmol/L) for 24 h. Flow cytometry, Western blot and ELISA were used to measure cell cycle, cyclin D1, mPGES-1, PGE(2), Akt, P-Akt and C-MYC. The results indicated that after treated with MK886, the percentage of HL-60 cells decreased in G(0)/G(1) phase and increased in S phase, and expressions of mPGES-1, cyclin D1, P-Akt and C-MYC and synthesis of PGE(2) decreased significantly. It is concluded that MK886 can arrest HL-60 cells in G(0)/G(1) phase, the mechanism of which is possibly associated to inhibition of mPGES-1 expression, reduction of PGE(2) synthesis, suppression of Akt phosphorylation and C-MYC expression, down-regulation of cyclin D1 expression.
Cell Cycle ; drug effects ; HL-60 Cells ; Humans ; Indoles ; pharmacology ; Intramolecular Oxidoreductases ; antagonists & inhibitors ; Leukemia ; metabolism ; pathology ; Prostaglandin-E Synthases

Xanthohumol (XH), the principal prenylflavonoid of the hop plant (Humulus lupulus L.), dose-dependently inhibited isobutylmethylxanthine (IBMX)-induced melanogenesis in B16 melanoma cells, with little cytotoxicity at the effective concentrations. Decreased melanin content was accompanied by reduced tyrosinase enzyme activity, protein and mRNA expression. The levels of tyrosinase-related protein 1 and 2 mRNAs were decreased by XH. XH also inhibited alpha-melanocyte stimulating hormone- or forskolin-induced increases in melanogenesis, suggesting an action on the cAMP-dependent melanogenic pathway. XH downregulated the protein and mRNA expression of microphthalmia-associated transcription factor (MITF), a master transcriptional regulator of key melanogenic enzymes. These results suggest that XH might act as a hypo-pigmenting agent through the downregulation of MITF in the cAMP-dependent melanogenic pathway.
1-Methyl-3-isobutylxanthine/pharmacology ; Animals ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Down-Regulation ; Drug Antagonism ; Forskolin/pharmacology ; *Humulus ; Intramolecular Oxidoreductases/antagonists & inhibitors/biosynthesis ; Melanins/antagonists & inhibitors/*biosynthesis ; Melanocytes/*drug effects/*metabolism ; Melanoma, Experimental ; Membrane Glycoproteins/antagonists & inhibitors/biosynthesis ; Mice ; Microphthalmia-Associated Transcription Factor/antagonists & inhibitors ; Monophenol Monooxygenase/antagonists & inhibitors/biosynthesis/genetics ; Oxidoreductases/antagonists & inhibitors/biosynthesis ; Propiophenones/*pharmacology ; Signal Transduction/drug effects ; alpha-MSH/metabolism

PURPOSE: Some recent studies have demonstrated that finasteride, a well- known 5alpha-reductase inhibitor, can decrease prostate specific antigen (PSA) by approximately 50% during the first 1 year of treatment. We investigated how long-term treatment with finasteride and alpha-blockers impacts on the serum PSA level of men whose final diagnosis was benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In a retrospective trial, we evaluated a total of 293 men with lower urinary tract symptoms (LUTS) that were suggestive of BPH. These men were divided into two treatment groups: group A was treated with alpha-blockers and group C was treated with a combination of finasteride and alpha-blocker. Comparisons of the two groups were performed by using independent t-tests. The changes in the PSA concentrations from baseline to the time of the final measurements were determined by repeated measures of ANOVA. RESULTS: There was no significant difference in the baseline PSA between the two groups. A statistically significant reduction in the PSA levels was observed at 2 years in C group (p<0.05), whereas any significant increase were not observed in group A (p>0.05). In group A, the repeatedly measured PSA levels were 2.67, 2.40, 2.41 and 2.42, respectively. In C group, these were 3.22, 2.09, 1.81 and 1.71 respectively. CONCLUSIONS: Our data showed that there was no clinically significant effect of long term treatment with alpha-blocker on the PSA levels. However, finasteride had significant effect on the serum PSA level during first two years of treatment.
Adrenergic Antagonists ; Diagnosis ; Finasteride* ; Follow-Up Studies* ; Humans ; Lower Urinary Tract Symptoms ; Male ; Oxidoreductases ; Prostate* ; Prostate-Specific Antigen* ; Prostatic Hyperplasia* ; Retrospective Studies

Objective To investigate the effect of 15-Deoxy-△(12,14)-prostaglandin J2 (15 d-PGJ2) on the expression of macrophage migration inhibitory factor (MIF) and its underlying mechanism in J774A.1. Methods The murine monocyte/macrophage cell line J774A.1 were divided into six groups:lipopolysaccharide (LPS) group,incubated with 1 μg/ml LPS for 1 h;normal control group,incubated with PBS for 1 h;negative control group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h;15 d-PGJ2 group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h followed by 1 μg/ml LPS for 1 h;GW9662 group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h following GW9662 10 μmol/L for 1 h,and then incubated with 1 μg/ml LPS for 1 h;and Vehicle group,control of GW9662,GW9662 was replaced by its solvent DMSO. The expression of MIF was detected via immunofluorescence and agarose gel electrophoresis. RT-qPCR and Western blotting were used to test whether 15 d-PGJ2 could regulate mRNA and protein expression of MIF in J774A.1 upon LPS challenge. The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist GW9662 on the regulation of MIF by 15 d-PGJ2 was observed. The effects of 15 d-PGJ2 on the nuclear translocation of PPAR-γ upon LPS challenge were detected via high content screening analysis. Results MIF DNA and protein expressions were detected in J774A.1. MIF mRNA expression was up-regulated (1.75±0.09,P=0.037) when challenged with LPS and 15 d-PGJ2 inhibited its upregulation (0.84±0.08,P=0.026) in J774A.1. The protein level was consistent with the mRNA level. PPAR-γ antagonist GW9662 reversed the effect of 15 d-PGJ2 (mRNA,1.48±0.06,P=0.016;protein,1.28). Furthermore,nuclear translocation of PPAR-γ was regulated by 15 d-PGJ2 in J774A.1 upon LPS challenge(1.39±0.02 vs. 1.01±0.03,P=0.003). Conclusion 15 d-PGJ2 may down-regulate the MIF expression in J774A.1 in a PPAR-γ-dependent manner.
Anilides ; pharmacology ; Animals ; Cell Line ; Intramolecular Oxidoreductases ; metabolism ; Lipopolysaccharides ; Macrophage Migration-Inhibitory Factors ; metabolism ; Mice ; Monocytes ; drug effects ; PPAR gamma ; antagonists & inhibitors ; Prostaglandin D2 ; analogs & derivatives ; pharmacology

In vascular smooth muscle cells, reactive oxygen species (ROS) were known to mediate platelet-derived growth factor (PDGF)-induced cell proliferation and NADH/NADPH oxidase is the major source of ROS. NADH/NADPH oxidase is controlled by rac1 in non-phagocytic cells. In this study, we examined whether the inhibition of rac1 by adenoviral-mediated gene transfer of a dominant negative rac1 gene product (Ad.N17rac1) could reduce the proliferation of rat aortic vascular smooth muscle cells (RASMC) stimulated by PDGF via decreasing intracellular ROS. RASMC were stimulated by PDGF (80 ng/mL) with or without N-acetylcysteine 1 mM or infected with 100 mutiplicity of infection of Ad.N17rac1. Intracellular ROS levels were measured at 12 hr using carboxyl-2', 7'-dichlorodi-hydrofluorescein diacetate confocal microscopy. At 72 hr, cellular proliferation was evaluated by cell number counting and XTT assay. Compared with control, ROS levels were increased by 2-folds by PDGF. NAC and Ad.N17rac1 inhibited PDGF-induced increase of ROS by 77% and 65%, respectively. Cell number was increased by PDGF by 1.6-folds compared with control. NAC and Ad.N17rac1 inhibited PDGF-induced cellular growth by 45% and 87%, respectively. XTT assay also showed similar results. We concluded that inhibition of rac1 in RASMCs could reduce intracellular ROS levels and cellular proliferation induced by PDGF.
Adenoviridae/genetics ; Animal ; Aorta, Thoracic/cytology ; Cell Division/drug effects/physiology ; Cells, Cultured ; Gene Expression/physiology ; Gene Transfer Techniques ; Multienzyme Complexes/antagonists & inhibitors ; Muscle, Smooth, Vascular/*cytology/*metabolism ; NADH, NADPH Oxidoreductases/antagonists & inhibitors ; NADPH Oxidase/antagonists & inhibitors ; Platelet-Derived Growth Factor/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; rac1 GTP-Binding Protein/*genetics/metabolism

BACKGROUND AND OBJECTIVES: Elevated endothelin (ET)-1 level is strongly correlated with the pathogenesis of pulmonary arterial hypertension (PAH). Expression level of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4 is increased in the PAH patients. Ambrisentan, a selective endothelin receptor A (ERA) antagonist, is widely used in PAH therapy. The current study was undertaken to evaluate the effects of ambrisentan treatment in the monocrotaline (MCT)-induced PAH rat model. METHODS: Rats were categorized into control group (C), monocrotaline group (M) and ambrisentan group (Am). The M and Am were subcutaneously injected 60 mg/kg MCT at day 0, and in Am, ambrisentan was orally administered the day after MCT injection for 4 weeks. The right ventricle (RV) pressure was measured and pathological changes of the lung tissues were observed by Victoria blue staining. Protein expressions of ET-1, ERA, endothelial nitric oxide synthase (eNOS) and NOX4 were confirmed by western blot analysis. RESULTS: Ambrisentan treatment resulted in a recovery of the body weight and RV/left ventricle+septum at week 4. The RV pressure was lowered at weeks 2 and 4 after ambrisentan administration. Medial wall thickening of pulmonary arterioles and the number of intra-acinar arteries were also attenuated by ambrisentan at week 4. Protein expression levels of ET-1 and eNOS were recovered at weeks 2 and 4, and ERA levels recovered at week 4. CONCLUSIONS: Ambrisentan administration resulted in the recovery of ET-1, ERA and eNOS protein expression levels in the PAH model. However, the expression level of NOX4 remained unaffected after ambrisentan treatment.
Animals ; Arteries ; Arterioles ; Blotting, Western ; Body Weight ; Endothelin Receptor Antagonists ; Endothelins ; Gene Expression ; Heart Ventricles ; Humans ; Hypertension ; Hypertension, Pulmonary ; Lung ; Models, Animal ; Monocrotaline ; NADP ; NADPH Oxidase ; Nitric Oxide Synthase Type III ; Oxidoreductases ; Rats ; Receptors, Endothelin ; Victoria

Animals ; Betacoronavirus ; Coronavirus Infections ; drug therapy ; Drug Discovery ; Drug Evaluation, Preclinical ; Enzyme Inhibitors ; therapeutic use ; Humans ; Mice ; Molecular Structure ; Orthomyxoviridae Infections ; drug therapy ; Oseltamivir ; therapeutic use ; Oxidoreductases ; antagonists & inhibitors ; Pandemics ; Pneumonia, Viral ; drug therapy ; Pyrimidines ; biosynthesis