Paulus S Wang

Publications (106)292.25 Total impact

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  Available from: Wang Kai-Lee

  Article: Inhibitory effects of isoliquiritigenin on the migration and invasion of human breast cancer cells.

  Kai-Lee Wang, Shih-Min Hsia, Chia-Jung Chan, Full-Young Chang, Chih-Yang Huang, Da-Tian Bau, Paulus S Wang
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  ABSTRACT: Introduction: Isoliquiritigenin (ISL) is a natural phenolic compound extracted from licorice. Previous studies have shown that ISL is a potent antioxidant with anti-inflammatory and antitumor activities. The anti-invasive activity of ISL was still unclear. The actual causes of death for most breast cancer patients were due to the tumor metastasis. Attenuating the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) is well known to prevent tumor metastasis. Objectives: The purpose of this study is to investigate the effects of ISL on VEGF and MMP expression in highly metastatic human breast cancer cell line, MDA-MB-231. Results: ISL reduced the secretions and protein levels of VEGF. The VEGF upstream regulatory protein, hypoxia-inducible factor 1-alpha (HIF-1α), was also reduced after ISL treatment. Moreover, ISL inhibited the expression and gelatinolytic activity of MMP-2 and MMP-9 which were confirmed by western blot and gelatin zymography assay. Additionally, the anti-migratory activity of ISL was further confirmed by chamber migration assay and wound migration assay. Upstream signaling pathways, including the expression of phosphatidylinositol-3 kinase (PI3K), the phosphorylation of p38 and Akt kinase and NF-κB DNA binding activity, were suppressed by ISL. Conclusion: These findings suggest that ISL suppresses the migration of MDA-MB-231 cells by inhibiting the upstream signaling pathways.
  Expert opinion on therapeutic targets 01/2013; · 3.72 Impact Factor
• Article: The role of cholecystokinin 1 receptor in prolactin inhibited gastric emptying of male rat.

  Full-Young Chang, Ching-Liang Lu, Tseng-Shing Chen, Paulus S Wang
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  ABSTRACT: Prolactin (PRL) is essential for the lactating mammals, while cholecystokinin (CCK) does inhibit gastric emptying (GE). Present study attempted to determine whether both peptides interacted on the male rat GE, particularly the role of putative CCK1 receptor. Acute hyperprolactinemia of male rats was induced by the intraperitoneal injection of ovine PRL (oPRL) in several divided doses 15 minutes before motility study. Rat chronic hyperprolactinemia was induced by the graft of 2 pituitary glands into the capsule of left kidney, while control rats received cerebral cortex graft only. Motility study was conducted 6 weeks later after graft surgery. Fifteen minutes after the intragastric feeding of radiochromium, rat was sacrificed to measure GE via the distribution of radioactivities within stomach and intestine. Among the CCK1 receptor blocking study using lorglumide, rats were divided to receive the regimens in terms of oPRL-vehicle plus lorglumide-vehicle, oPRL plus lorglumide-vehicle, oPRL-vehicle plus lorglumide and oPRL plus lorglumide. Plasma CCK level was measured using a homemade radioimmunoassay kit. Compared to vehicle treatment, acute hyperprolactinemic rats under highest dose (2.0 mg/kg) of oPRL treatment showed delayed GE (70.6% ± 3.0% vs 42.1% ± 6.6%, P < 0.05). Chronic hyperprolactinemic rats under graft surgery also showed inhibited GE (70.5% ± 1.7% vs 54.5% ± 4.7%, P < 0.05). Both models finally obtained elevated plasma CCK levels (P < 0.05). Lorglumide itself did not influence GE, however, delayed GE under oPRL treatment was restored following the concomitant lorglumide treatment. Our study suggests that PRL may delay male rat GE via a mechanism of endogenous CCK activation involving the peripheral CCK1 receptor.
  Journal of neurogastroenterology and motility 10/2012; 18(4):385-90.
• Article: In utero and neonate exposure to nonylphenol develops hyperadrenalism and metabolic syndrome later in life. I. First generation rats (F(1)).

  Ling-Ling Chang, Wan-Song A Wun, Paulus S Wang
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  ABSTRACT: Nonylphenol (NP) is an endocrine disruptor (ENDR). It is a chemical associated with the production and degradation of nonylphenol ethoxylates (NPE). NPE is widely used as nonionic surfactants. Previously, we observed that NP increased the production of corticosterone and aldosterone from zona fasciculata-reticularis, and zona glomerulosa cells, respectively. By the "fetal origins adult diseases" (Barker hypothesis), we examined the possible impact of NP exposure during developmental (in utero and neonatal) period with focus on disturbed adrenal function and related hyperadrenal syndrome, i.e. Cushings syndrome/metabolic syndrome. In this study, female rats drink NP water during pregnancy and lactation conferred F(1) generation: (1) increase the corticosterone, aldosterone concentration in plasma; (2) increase 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity in liver and adipose tissue; (3) increase aldosterone synthase activity in adrenal for adult offspring. Furthermore, it can increase body weight, adrenocorticotropin (ACTH) concentration in plasma, 11β-HSD1 protein expression in liver, steroidogenic acute regulatory (StAR) protein expression and 11β-hydroxylase activity in adrenal for male adult offspring. In summary, NP exposure during developmental period bestowed F(1) generation with hyperadrenalism and its consequence of metabolic syndrome.
  Toxicology 07/2012; 301(1-3):40-9. · 3.68 Impact Factor
• Article: Antisteroidogenic effects of hydrogen peroxide on rat granulosa cells.

  Po-Ling Yu, Tzu-Miao Lin, Shyi-Wu Wang, Paulus S Wang
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  ABSTRACT: Rat granulosa cells (GCs) were treated with human chorionic gonadotropin (hCG), 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP), forskolin, phorbol 12-myristate 13-acetate (PMA), A23187 or pregnenolone in the absence or presence of hydrogen peroxide (H(2)O(2)). Different doses of trilostane were applied to GCs treated with steroidogenic precursors, that is, 25-hydroxy-cholesterol (25-OH-C) in the absence or presence of H(2)O(2). Results showed that all of the chemicals stimulated the progesterone (PG) release from rat GCs, but the stimulatory effects were inhibited by H(2)O(2) dose-dependently. 25-OH-C stimulated the PG release, which was inhibited by H(2)O(2) in the presence of trilostane. H(2)O(2) attenuated steroidogenic acute regulatory (StAR) protein expression, but did not alter the expression of cytochrome P450 side chain cleavage (P450scc) in Western blotting. This study indicated that H(2)O(2) inhibited PG production by GCs via cAMP pathway, protein kinase C (PKC) and the activities of intracellular calcium, P450scc and StAR protein.
  Free radical research 03/2012; 46(6):718-25. · 2.22 Impact Factor
• Article: Motor performance improved by exercises in cerebral ischemic rats.

  Yea-Ru Yang, Heng-Chih Chang, Paulus S Wang, Ray-Yau Wang
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  ABSTRACT: Physical exercise may induce neuroprotective effects against brain damage after stroke. The authors aimed to investigate the effects of various exercises on motor function, striatal angiogenesis, and infarct volume in cerebral ischemic rats. Adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion and randomly assigned to 1 of the 4 groups: Rota-rod training, lower speed treadmill training, higher speed treadmill training, or no exercise control. Motor function, striatal angiogenesis, and infarct volume were evaluated before or after motor training. After training, motor function and striatal angiogenesis changed significantly in Rota-rod and higher speed treadmill training groups as compared with the control group. Improvement in motor function significantly correlated with striatal angiogenesis after motor training. Infarct volumes were significantly decreased in lower and higher speed treadmill training groups. The results indicated that both motor training procedures can be used as effective training programs in stroke rehabilitation.
  Journal of Motor Behavior 02/2012; 44(2):97-103. · 1.64 Impact Factor
• Article: Effects of nonylphenol on aldosterone release from rat zona glomerulosa cells.

  Ling-Ling Chang, Wan-Song Alfred Wun, Paulus S Wang
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  ABSTRACT: Alkylphenol ethoxylate, which consists of approximately 80% nonylphenol ethoxylate (NPE), is a major nonionic surfactant. Nonylphenol (NP), the primary degradation product of NPE, has been reported to interfere with reproduction in fish, reptiles, and mammals by inducing cell death in the gonads and by affecting other reproductive parameters. However, the effects of NP on rat adrenal zona glomerulosa cells (ZG) and the underlying mechanisms remain unclear. In this study, we explored the effects of NP on aldosterone release. ZG cells were incubated with NP in the presence or absence of the secretagogues angiotensin II (ANG II), potassium, 8-Br-cAMP, 25-OH-cholesterol, corticosterone or cyclopiazonic acid (CPA). After performing radioimmunoassay (RIA) and Western blot analysis, we found that (1) NP stimulated aldosterone release in cells induced by ANG II, KCl, 8-Br-cAMP, 25-OH-cholesterol, corticosterone, and CPA; (2) NP triggered the release of higher amounts of pregnenolone in cells treated with vehicle and 25-OH-cholesterol+trilostane than in cells treated with other compounds; and (3) the stimulatory effect of NP seemed to be mediated through steroidogenic acute regulatory protein (StAR) and aldosterone synthase activity. These observations suggest that the effects of NP are mediated via increased free Ca(2+) in the cytoplasm.
  Chemico-biological interactions 01/2012; 195(1):11-7. · 2.46 Impact Factor
• Article: Effect of interleukin-6 (IL-6) on the vascular smooth muscle contraction in abdominal aorta of rats with streptozotocin-induced diabetes.

  Wen-Bo Tang, Yu-Qin Zhou, Ting Zhao, Jing-Li Shan, Peng Sun, Ting-Ting Yang, Xin-Wen Chang, Sen Li, Paulus S Wang, Dong-Ping Xie
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  ABSTRACT: Patients with type 1 diabetes are at a risk of hypertension. However, the mechanisms behind the findings are not completely known. The aim of the present study was to investigate involvement of interleukin-6 (IL-6) on the contraction of abdominal aorta in rats with type 1 diabetes. IL-6 levels in the plasma of rats with streptozotocin (STZ)-induced diabetes were determined by ELISA. The abdominal aorta was dissected free of fat and connective tissues and then cut into spiral rings. The endothelium-denuded strip was vertically suspended in tissue chambers containing 5 ml Krebs solution at 37 degrees C and bubbled continuously with 95% O2-5% CO2. The effects of phenylephrine (Phe) on the contractile responses of abdominal aorta were recorded. The effects of IL-6 and anti-rat IL-6 antibody on the Phe-induced response were also examined. Plasma levels of IL-6 increased time-dependently in rats with STZ-induced diabetes. Phe caused concentration-dependent contraction in aortic rings. Phe-induced contractions were higher in vascular strips of STZ-induced diabetic rats than that of control rats. Pretreatment of vascular strips with IL-6 for 1 h did not cause contraction but enhanced the contraction in response to Phe. Treatment of the vascular strips with an anti-IL-6 antibody for 1 h decreased the Phe-induced contractions. These results suggest that IL-6 causes vascular smooth muscle contraction in abdominal aorta of rats with type 1 diabetes.
  The Chinese journal of physiology 10/2011; 54(5):318-23. · 0.56 Impact Factor
• Article: A radioimmunoassay for rat ghrelin: evaluation of method and effects of nonylphenol on ghrelin secretion in force-fed young rats.

  Yen-Jui Chang, Wei-Ju Huang, Han-Wei Lin, Ling-Ling Chang, Full-Young Chang, Paulus S Wang
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  ABSTRACT: Antiserum YJC 13-31 against the rat ghrelin conjugated to bovine serum albumin (BSA) was produced in the rabbit and a double antibody radioimmunoassay (RIA) for ghrelin has been developed. Characterization results of this antiserum revealed no cross-reaction with human growth hormone and somatostatin. Weak cross-reactions with insulin (0.1%), rat growth hormone (0.1%) and glucagon (0.3%) were observed, which scarcely interfered the assay system. The sensitivity of this RIA was 5 pg per assay tube. With the rat serum samples, the within-assay precision was 7.1% and the between-assay precision was 12.3%. The RIA was also available to detect the ghrelin in rat tissue extracts with good parallelism to the rat ghrelin standard. In application, the serum ghrelin and corticosterone levels in weaned rats were measured by RIA. Gavage of saline was sufficient to raise serum ghrelin from 2.6 +/- 0.18 to 6.7 +/- 0.7 ng/ml (P < 0.01). Gavage with nonylphenol (NP) suppressed the elevation of serum ghrelin levels in a dose-dependent manner. Besides, gavages of saline elevated the serum levels of corticosterone from 108.8 +/- 13.5 to 188.7 +/- 23.5 ng/ml (P < 0.01) but the elevation effects of corticosterone from gavages were overcome by NP in the low dose of 50 mg/kg. It can be speculated that ingestion of NP is harmful to young animals during growth and environmental adaptation.
  The Chinese journal of physiology 10/2011; 54(5):324-31. · 0.56 Impact Factor
• Article: Inhibitory effect of bufalin and cinobufagin on steroidogenesis via the activation of ERK in human adrenocortical cells.

  Mei-Mei Kau, Jiing-Rong Wang, Shiow-Chwen Tsai, Ching-Han Yu, Paulus S Wang
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  ABSTRACT: Bufalin and cinobufagin exhibit cardiotonic and natriuretic activities. The aim of this study was to evaluate the effects of bufalin and cinobufagin on aldosterone and cortisol secretion and their mechanisms of action in human adrenocortical cells (NCI-H295). H295 cells were incubated with bufalin or cinobufagin in the presence or absence of angiotensin II (Ang II), forskolin, 8-Br-cAMP, corticosterone or deoxycortisol. The role of ERK1/2 was studied by use of the inhibitor of MEK (U0126). The binding of transcription factor steroidogenic factor 1 (SF-1) to steroidogenic acute regulatory (StAR) gene promoter was analysed by EMSA. Bufalin and cinobufagin markedly inhibited basal, Ang II-, forskolin- or 8-Br-cAMP-stimulated aldosterone and cortisol secretion, and the conversions of corticosterone to aldosterone and deoxycortisol to cortisol. Bufalin and cinobufagin also inhibited StAR protein expression and SF-1 binding to StAR gene promoter. They both increased phosphorylation of ERK1/2, and U0126 fully abolished these effects on ERK1/2 in H295 cells. Furthermore, U0126 reversed the inhibitory effects of bufalin and cinobufagin on StAR protein expression and the binding of SF-1 to StAR gene promoter. However, U0126 did not completely reverse their inhibitory effects on aldosterone and cortisol release. The inhibitory effects of bufalin and cinobufagin on steroidogenesis of aldosterone and cortisol were associated with inhibition of aldosterone synthase and 11β-hydroxylase, as well as the suppression of StAR protein expression and SF-1 binding to StAR promoter via the phosphorylation of ERK1/2 in H295 cells.
  British Journal of Pharmacology 09/2011; 165(6):1868-76. · 4.41 Impact Factor
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  Article: Effects of polybrominated diphenyl ethers on steroidogenesis in rat Leydig cells.

  Kai-Lee Wang, Shih-Min Hsia, I-Fang Mao, Mei-Lien Chen, Shyi-Wu Wang, Paulus S Wang
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  ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that have been defined as major environmental pollutants. While previous studies have found that PBDEs may enhance the levels of sex-steroid hormones, their effects on testosterone secretion from rat Leydig cells are unclear. This study investigated the effects and mechanisms of PBDE-710, a mixture of tetra- and penta-PBDEs, on testosterone biosynthesis in rat Leydig cells. Leydig cells from adult male rats were challenged with different concentrations of PBDE-710 (0.5-15 ng/ml) to evaluate the effects on testosterone steroidogenesis. Concentrations of testosterone and of cAMP and pregnenolone in medium were measured by radioimmunoassay (RIA) and by enzyme-linked immunosorbent assay, respectively. Nuclear translocation of protein kinase A α (PKAα) was determined by immunofluorence assay and western blot assay, and the mRNA expression of steroidogenic acute regulatory protein (StAR) was analyzed by quantitative real-time polymerase chain reaction. In this in vitro study, PBDE-710 (5 or 15 ng/ml) increased basal testosterone secretion and cAMP production by 3- and 2-fold, respectively. The stimulatory effect was abolished by adenylyl cyclase inhibitor. Enzyme activity of CYP11A1, as determined by the pregnenolone concentration, was stimulated by PBDE-710 treatment. Furthermore, nuclear translocation of PKAα was increased by 20% and StAR gene expression was elevated by 4-fold after PBDE-710 treatment. These results suggest that low concentrations of PBDE-710 could stimulate testosterone secretion by acting directly on Leydig cells to activate the cAMP pathway and increase expression of StAR.
  Human Reproduction 06/2011; 26(8):2209-17. · 4.47 Impact Factor
• Article: Insulin-like growth factor I signaling for brain recovery and exercise ability in brain ischemic rats.

  Heng-Chih Chang, Yea-Ru Yang, Paulus S Wang, Chia-Hua Kuo, Ray-Yau Wang
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  ABSTRACT: Exercise increases neuron survival and plasticity in the adult brain by enhancing the uptake of insulin-like growth factor I (IGF-I). Exercise also reduces the infarct volume in the ischemic brain and improves motor function after such a brain insult. However, the underlying mechanisms are not fully known. The purpose of this study was to investigate the involvement of IGF-I signaling in neuroprotection after exercise. Rats were assigned to one of four groups: middle cerebral artery occlusion (MCAO) without exercise training (MC), MCAO with exercise training (ME), MCAO with IGF-I receptor inhibitor and without exercise training (MAg), and MCAO with IGF-I receptor inhibitor and exercise training (MEAg). Rats in the ME and MEAg groups underwent treadmill training for 14 d, and rats in the MC and MAg groups served as controls. After the final intervention, rats were sacrificed under anesthesia, and samples were collected from the affected motor cortex, striatum, and plasma. IGF-I and p-Akt levels in the affected motor cortex and the striatum of the ME group were significantly higher than those in the MC group, with significant decreases in infarct volume and improvements in motor function. However, IGF-I receptor inhibitor eliminated these effects and decreased the exercise ability. The brain IGF-I signaling strongly correlated with exercise ability. Exercise-enhanced IGF-I entrance into ischemic brain and IGF-I signaling was related to exercise-mediated neuroprotection. IGF-1 signaling also affected the ability to exercise after brain ischemia.
  Medicine and science in sports and exercise 05/2011; 43(12):2274-80. · 3.71 Impact Factor
• Article: Effects of nonylphenol on the production of progesterone on the rats granulosa cells.

  Po-Ling Yu, Han-Wei Lin, Shyi-Wu Wang, Paulus S Wang
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  ABSTRACT: We investigated the effects of nonylphenol (NP) on release of progesterone (PG) by granulosa cells (GCs) of rats in vitro and in vivo. First, GCs were treated with different doses of NP for 2-24 h alone or with human chorionic gonadotropin (hCG). Maximal PG secretion at 8 h noted, GCs were treated for 2 h with hCG, 8-bromo-adenosine 3':5'-cyclic monophosphate (8-Br-cAMP), forskolin, A23187, nifedipine, and pregnelonone to evaluate the NP effects on PG steroidogenesis. Results indicated that all of chemicals except nifedipine stimulated the PG release compared to vehicle, but the stimulatory effects could not be enhanced by different doses of NP. Second, GCs were isolated to react with hCG, 8-Br-cAMP and PD98059 after the immature female rats gavaged with different doses of NP (ONP) for 7 days. PG released significantly when rats treated with oral NP 100 compared to 0 µg/kg/day. Third, GCs collected from the female offspring of mother rats which gavaged with NP 100 µg/kg/day for 21 days during pregnancy (MONP) reacted with different doses of chemicals. The results showed that PG release in the presence of chemicals was significantly higher in ONP and MONP groups; however, this stimulation was not noted by dose-dependent. The plasma concentration of PG was higher in ONP (100 µg/kg/day) and the offspring of MONP groups. The steroidogenic acute regulatory (StAR) protein expressed higher in all three groups by Western blotting. This study results indicated that low dose of NP stimulated PG release in rat GCs by activation of StAR protein.
  Journal of Cellular Biochemistry 05/2011; 112(9):2627-36. · 2.87 Impact Factor
• Chapter: An Evidence-based Perspective of Bufo Gargarizans (Asiatic Toad) for Cancer Patients

  Paulus S. Wang, Jiun-Yih Yeh, Ching-Han Yu, Shyi-Wu Wang
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  ABSTRACT: Bufalin and cinobufagin are cardiotonic steroids extracted from Chansu, a galenical preparation of the dried white venom of Chinese Bufo gargarizans (Asiatic toad). Chansu is also one of the major components of Kyushin, a traditional Chinese medicine. It has been shown that bufalin and cinobufagin increase vascular resistance, vasoconstriction, and blood pressure via an inhibition of Na+,K+-ATPase. This evidence indicates that bufalin and cinobufagin are endogenous digitalis-like factors. Since bufalin, cinobufagin, and digoxin share the similarity in the chemical structure, it is not surprising that bufalin and cinobufagin have digoxin-like effects. It is well-known that bufalin, cinobufagin, and digoxin as well as ouabain are specific blockers of the sodium pump. The digoxin-like immunoactivity has been observed in Chansu. It has been shown that bufalin and cinobufagin possess antitumor effects on human lung adenocarcinoma cells, leukemia cells, pancreatic cancer cells, gastric cancer cells, prostate cancer cells, endometrial cancer cells, ovarian cancer cells, and hepatocellular carcinoma via induction of growth inhibition, cell cycle arrest and/or apoptosis. Reactive oxygen species-dependent Bax translocation, PI3K/Akt and apoptotic modulators including Bax, cytochrome c, and caspases are involved in bufalin-induced apoptosis or anticancer pathways. In the present chapter, we shall review antitumor effects of bufalin on human cancer cells. Although in most studies, human carcinoma cells or cell lines were employed, we expect that more in vivo studies and clinical trials will be performed in the near future.
  03/2011: pages 389-407;
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  Article: Effects of resveratrol, a grape polyphenol, on uterine contraction and Ca²+ mobilization in rats in vivo and in vitro.

  Shih-Min Hsia, Kai-Lee Wang, Paulus S Wang
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  ABSTRACT: Dysmenorrhea is directly related to elevate prostaglandin F (PGF)(₂α) levels. In Western medicine, this condition is treated using nonsteroidal antiinflammatory drugs. Because nonsteroidal antiinflammatory drugs produce many side effects, Chinese medicinal therapy is considered as a feasible alternative for treating dysmenorrhea. Many special physiological components used in Chinese medicine, such as resveratrol, have been isolated and identified. Resveratrol has many physiological functions, such as antioxidation and anticarcinogenic effects. However, the relationship between uterine smooth muscle contraction and resveratrol remains unknown. Here, we studied the in vitro and in vivo effects of resveratrol on uterine smooth muscle contraction. The uterus was separated from a female Sprague Dawley rat, and uterine smooth muscle contraction activity was measured and recorded. The results demonstrated that 1) resveratrol treatment inhibited PGF(₂α)-, oxytocin-, acetylcholine-, and carbachol-induced uterine contractions in rats; 2) resveratrol inhibited uterine contractions stimulated by the Ca²(+) channel activator (Bay K 8644) and depolarization in response to high K(+) (KCl); 3) resveratrol inhibited PGF(₂α)-induced increases in the [Ca²(+)]i in human uterine smooth muscle cells; 4) resveratrol could mimic Ca²(+) channel blockers to block Ca²(+) influx through voltage-operated Ca²(+) channels in the plasma membrane; and 5) resveratrol inhibited PGF(₂α)-induced uterine contractions in rats in vivo. Resveratrol inhibited uterine contractions induced by PGF(₂α) and high K(+) in a concentration-dependent manner in vitro; furthermore, it inhibited Ca²(+)-dependent uterine contractions. Thus, resveratrol consistently suppressed the increases in intracellular Ca²(+) concentrations ([Ca²(+)]i) induced by PGF(₂α) and high K(+) concentrations. It can be assumed that resveratrol probably inhibited uterine contraction by blocking external Ca²(+) influx, leading to decreased [Ca²(+)]i. Therefore, resveratrol can be considered as a feasible alternative therapeutic agent for dysmenorrhea.
  Endocrinology 03/2011; 152(5):2090-9. · 4.46 Impact Factor
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  Available from: PubMed Central

  Article: Intermittent hypoxia after transient focal ischemia induces hippocampal neurogenesis and c-Fos expression and reverses spatial memory deficits in rats.

  Yi-Wei Tsai, Yea-Ru Yang, Paulus S Wang, Ray-Yau Wang
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  ABSTRACT: Memory impairment is a frequent complication of brain ischemia. Neurogenesis is implicated in learning and memory and is regulated by the transcription factor c-Fos. Preconditioning intermittent hypoxia (IH) attenuates ischemia-related memory impairments, but it is not known whether post-ischemia IH intervention has a similar effect. We investigated the effects of post-ischemia IH on hippocampal neurogenesis and c-Fos expression as well as spatial learning and memory in rats. Focal cerebral ischemia was induced in some rats by middle cerebral artery occlusion (MCAO), while other rats received sham MCAO surgery. Beginning a week later, half of the rats of each group received IH interventions (12% oxygen concentration, 4 hrs/d, for 7 d) and half received sham IH sessions. An additional group of rats received MCAO, IH, and injections of the neurogenesis-impairing agent 3'-AZT. Spatial learning and memory was measured in the Morris water maze, and hippocampal neurogenesis and c-Fos expression were examined. Hypoxia-inducible factor 1α (HIF-1α) and phosphorylated mitogen-activated protein kinase (pMAPK) were considered as possible mediators of IH-induced changes in neurogenesis and c-Fos expression. IH intervention following MCAO resulted in recovered spatial memory, increased hippocampal neurogenesis, and increased expression of c-Fos in newborn hippocampal cells. These effects were blocked by 3'-AZT. IH intervention following MCAO also was associated with increased hippocampal pMAPK and HIF-1α expression. IH intervention following MCAO rescued ischemia-induced spatial learning and memory impairments, likely by inducing hippocampal neurogenesis and c-Fos expression through mediators including pMAPK and HIF-1α.
  PLoS ONE 01/2011; 6(8):e24001. · 4.09 Impact Factor
• Article: Effects and mechanisms of nonylphenol on corticosterone release in rat zona fasciculata-reticularis cells.

  Ling-Ling Chang, Wan-Song Alfred Wun, Paulus S Wang
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  ABSTRACT: Alkylphenol ethoxylate, consisting of ∼80% nonylphenol ethoxylate (NPEO), is a major group of nonionic surfactant. The primary degradation product of NPEO, nonylphenol (NP), interferes with reproduction, induces cell death in gonads, and leads to changes in other reproductive parameters. With such apparent stress, NP is believed to induce stress response mechanism, i.e., adrenal cortical hormone. However, the effects and action mechanisms of NP on rat adrenal zona fasciculata-reticularis (ZFR) cells are still unclear. This study explored the effects of NP on corticosterone release. ZFR cells were incubated with NP in the presence or absence of adrenocorticotropin (ACTH), 8-bromo-cyclic 3',5'-adenosine monophosphate (8-Br-cAMP), forskolin (FSK), 25-hydroxyl cholesterol (25-OH-cholesterol), pregnenolone, progesterone, or deoxycorticosterone at 37°C for 1 h. The concentrations of corticosterone or pregnenolone in the spent media were measured by radioimmunoassay. The expressions of steroidogenic acute regulatory (StAR) protein, cytochrome P450 side-chain cleavage (P450scc) protein, and 11β-hydroxylase in the cells were measured by Western blot. The data demonstrated that (1) NP stimulated corticosterone release induced by ACTH, 8-Br-cAMP, FSK, 25-OH-cholesterol, pregnenolone, progesterone, or deoxycorticosterone; (2) NP significantly increased pregnenolone release in the control, 25-OH-cholesterol, trilostane, and 25-OH-cholesterol + trilostane groups; (3) NP-stimulated corticosterone release was estrogen receptor dependent, but mediated by nitric oxide and p38 mitogen-activated protein kinase pathway independent; and (4) NP did not affect StAR, 11β-hydroxylase, or P450scc protein expression. These results suggest that NP acts directly on rat ZFR cells to stimulate corticosterone release and that the stimulation mechanism of NP mediates through post-cAMP corticosterone manufacture enzymes, i.e., P450scc and 11β-hydroxylase.
  Toxicological Sciences 12/2010; 118(2):411-9. · 4.65 Impact Factor
• Article: Aging effects on exercise-induced alternations in plasma acylated ghrelin and leptin in male rats.

  Ya-Wen Hsu, Yi-Ju Pan, Yu-Min Cho, Tsan-Hon Liou, Pesus Chou, Paulus S Wang
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  ABSTRACT: Ghrelin and exercise have been known to stimulate the release of growth hormone which is related to the glucose metabolism. However, the age effects of exercise on ghrelin in energy consumption remain unclear. Young (3 month old) and middle-aged (12 month old) Sprague-Dawley male rats were overnight fasted, and then randomly partitioned into exercise and control groups. Exercise groups swam for 20 min in 25°C water. Rats immersed in 25°C water for 20 min were used as control animals. All blood samples were collected before and 10, 20, 30, and 60 min after initiation of exercise via the right jugular vein. Our results indicated that the swimming regimen decreased the secretion of acylated ghrelin and insulin, but increased the secretion of leptin, lactate, and glucose. In addition, exercise significantly amplified the inverse correlation between leptin and acylated ghrelin (r < -0.6) in middle-age group. Both the above findings were not emphasized in related articles before. Moreover, the time courses of these changes were slightly different in young and middle-aged rats. In basal metabolic characteristics, body weight and the plasma lactate, glucose, insulin, and leptin are higher in middle-age group than that in young group. In conclusion, compared with young rats, middle-aged rats have higher basal body weight, plasma glucose, insulin, and leptin, but age had no effect on the level of plasma acylated ghrelin. A 20-min exercise regimen decreased acylated ghrelin and increased leptin with inverse correlation between them which was strengthened during exercise, but were not influenced by age.
  Arbeitsphysiologie 11/2010; 111(5):809-17. · 2.15 Impact Factor
• Article: Effects of insulin-like growth factor 1 on muscle atrophy and motor function in rats with brain ischemia.

  Heng-Chih Chang, Yea-Ru Yang, Paulus S Wang, Chia-Hua Kuo, Ray-Yau Wang
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  ABSTRACT: Although insulin-like growth factor 1 (IGF 1) has been used in immobilizated muscles to prevent muscle atrophy, its effects on muscle atrophy after brain ischemia are not known. This study aimed to determine the effects of IGF 1 on preventing muscle atrophy in rats with brain ischemia. Middle cerebral artery occlusion (MCAO) was used to induce the brain ischemia. In the first part of the study, rats were assigned to sham control, ischemic control, and ischemia with different dosages of IGF 1 injection groups to determine the optimal dosage of IGF 1 on preventing muscle atrophy after brain ischemia. In the second part of the study, rats were assigned to sham control, ischemic control, ischemia with IGF 1, or with IGF 1 receptor inhibitor (AG1024) injection groups to determine the specificity of IGF 1 on preventing muscle atrophy after brain ischemia. IGF 1 or AG1024 was injected locally to calf muscles and anterior tibialis (TA) starting from one day after brain ischemia and injections were carried out every other day for 4 times. Muscle weight and myosin heavy chain (MHC) expression in both red (red gastrocnemius and soleus) and white (white gastrocnemius and TA) muscles were significantly decreased after brain ischemia. With at least moderate-dosage (200 ng/100 microl PBS) IGF 1 injection, the muscle weight and MHC protein could be restored in both red and white muscles resulting in better motor performance. However, the high-dose injection of IGF 1 (400 ng/100 microl PBS) did not result in further effects. IGF 1 increased the expression of p-Akt, but such effects were prevented by AG1024 resulting in muscle atrophy and poor motor function. In conclusion, peripheral application of IGF 1 not only prevented muscle atrophy but also enhanced motor function in rats with brain ischemia. The IGF 1-induced PI3K/Akt pathways are important for preventing muscle atrophy induced by brain ischemia.
  The Chinese journal of physiology 10/2010; 53(5):337-48. · 0.56 Impact Factor
• Article: Stimulatory effects of propylthiouracil on pregnenolone production through upregulation of steroidogenic acute regulatory protein expression in rat granulosa cells.

  Mei-Chih Chen, Shyi-Wu Wang, Shu-Fen Kan, Shiow-Chwen Tsai, Yu-Ching Wu, Paulus S Wang
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  ABSTRACT: Propylthiouracil (PTU) is a common and effective clinical medicine for the treatment of hyperthyroidism. Our previous study demonstrated that short-term treatment with PTU inhibits progesterone production in rat granulosa cells. However, our present results indicate that a 16-h treatment with PTU was able to stimulate pregnenolone production in rat granulosa cells, although progesterone production was diminished by PTU through inhibition of 3β-hydroxysteroid dehydrogenase. Notably, we found that PTU treatment enhanced the conversion of cholesterol into pregnenolone, whereas the protein level of the cytochrome P450 side-chain cleavage enzyme (P450scc, which is the enzyme responding to this conversion) was not affected. Interestingly, the levels of steroidogenic acute regulatory protein (StAR) in both total cell lysate and the mitochondrial fraction were significantly increased by PTU treatment. Furthermore, the binding of steroidogenic factor-1 (SF-1) to the StAR promoter region was also enhanced by PTU treatment, which suggests that PTU could upregulate StAR gene expression. In addition to SF-1 regulation, we found that mitogen-activated protein (MAP) kinase kinase activation is an important regulator of PTU-stimulated StAR protein expression, based on the effects of the MEK inhibitor PD98059. In conclusion, these results indicate that PTU plays opposite roles in the production of progesterone and its precursor, pregnenolone. The regulation of negative feedback on speeding the cholesterol transportation and pregnenolone conversion after a 16-h PTU treatment may be the mechanism explaining PTU's inhibition of progesterone production in rat granulosa cells.
  Toxicological Sciences 10/2010; 118(2):667-74. · 4.65 Impact Factor
• Article: The effects of anti-TNF-α antibody on hyperprolactinemia-related suppression of hCG-induced testosterone release in male rats.

  William J S Huang, Ling-Yu Yang, Hsiao-Fung Pu, Yi-Ting Tsai, Paulus S Wang
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  ABSTRACT: Hyperprolactinemia (hyperPRL)-related hypogonadism or suppression of human chorionic gonadotropin (hCG)-induced testosterone (T) release is hypothesized to be mediated by a testicular interstitial macrophage and tumor necrosis factor alpha (TNF-α)-involved blockage. To test if the lower T response after hCG challenge in the hyperPRL rats is reversed by administrating anti-TNF-α antibody (Ab). HyperPRL was induced by allografting two anterior pituitary (AP) glands per rat. Control rats were grafted with similar amount of cerebral cortex. The testicular interstitial cells (TIC) were isolated from the testis 6 weeks after grafting. TIC was treated with anti-TNF-α Ab with or without hCG. The other groups of rats received intra-testicular or intra-muscular anti-TNF-α Ab 7 days before in vitro study. The TIC isolated from each testis was incubated and T release with or without hCG challenge were measured. Prolactin (PRL) and T were measured by radioimmunoassay. TNF-α was measured by enzyme-linked immunosorbent assay (ELISA). When low dose of anti-TNF-α Ab was administered to the TIC incubation, the effects of PRL-related suppression of hCG-stimulated T release were not significant. While a higher dose of anti-TNF-α Ab almost abolished the suppressive effects of PRL to hCG-stimulated T release. Prior intra-testicular or intra-muscular administration of anti-TNF-α Ab reversed the suppressive effects of AP grafting on TIC's T release. This was demonstrated in groups with anti-TNF-α Ab injection both 7 and 1 day prior to TIC incubations. The data support the hypothesis that the suppression of hCG-induced T release associated with hyperPRL is through a TNF-α-mediated mechanism to suppress the Leydig cells. The effect of anti-TNF-α Ab is durable for at least 7 days. Besides intra-testicular injection, there might be other ways available for administrating Ab. Anti-TNF-α Ab has a potential therapeutic application on hyperPRL-induced hypogonadism or suppression of hCG-induced T release.
  Journal of Sexual Medicine 10/2010; 9(4):1005-14. · 3.55 Impact Factor