PubMed Health⌕ Search

Biomedical subjects

P R Wang

Publications and source records attributed to P R Wang.

15 recordsLinked to original sources
PubMed2005

Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats.

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.

Adamantane↗
PubMed2001

Regulation of lipid metabolism and gene expression by fenofibrate in hamsters.

Fenofibrate is a potent hypolipidemic agent that lowers plasma lipid levels and may thus decrease the incidence of atherosclerosis. Here we investigated the molecular mechanism of fenofibrate's hypolipidemic action by characterizing its in vivo effects on the expression of mRNAs and the activities of pivotal enzymes in cholesterol and triglyceride metabolism in the hamster. Treatment of hamsters with fenofibrate led to a dose-dependent reduction in serum cholesterol concentrations. Studies on the incorporation of [(14)C]acetate and [(14)C]mevalonate into cholesterol suggested that this effect occurs primarily through inhibition of cholesterol biosynthesis at steps prior to mevalonate. Fenofibrate decreased levels of hepatic enzyme activities and mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase. A potential mechanism for transcriptional regulation of these enzymes is via SREBP-2 that we found to be suppressed 2-fold by fenofibrate. Fenofibrate also lowered circulatory triglyceride levels. In keeping with the effect, we observed strong suppression of fatty acid synthase, acetyl-CoA carboxylase and apolipoprotein C-III mRNA and stimulation of lipoprotein lipase and acyl-CoA oxidase mRNA in the liver of fenofibrate-treated hamsters. These observations suggest that the effect of fenofibrate on triglyceride metabolism is likely to be a result of both decreased fatty acid synthesis and increased lipoprotein lipase and acyl-CoA oxidase gene expression in the liver. Surprisingly, alterations in lipoprotein lipase, acyl-CoA oxidase, acetyl-CoA carboxylase, and apolipoprotein C-III could not be observed in hamster hepatocytes incubated with fenofibric acid in vitro. These observations raise the possibility that changes in these genes may be secondary to the metabolic alterations occurring in animals but not in cultured cells and thus that the effect of fenofibrate on these genes may be indirect.

Animals↗
PubMed2001

High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists.

Dyslipidemia, a major risk factor for cardiovascular disease, may be directly linked to diabetic hyperglycemia and insulin resistance. An appropriate dyslipidemic animal model that has diabetes would provide an important tool for research on the treatment of diabetic dyslipidemia. Ten days of high fat feeding in golden Syrian hamsters resulted in a significant increase in insulin resistance and baseline serum lipid levels accompanied by a pronounced dyslipidemia. Thirteen days of treatment with fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) selective agonist, produced a dose-dependent decrease in serum lipid levels. The pattern observed was characterized by lowered very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) and raised high-density lipoprotein (HDL) cholesterol in a fashion similar to that seen in man. Diabetic conditions were also significantly improved by fenofibrate with a normalization of impaired glucose tolerance and an improvement of insulin sensitivity during an oral glucose tolerance test. These data suggest that fenofibrate may correct not only the dyslipidemia but also the insulin resistance caused by a high fat diet, and the high fat fed hamster may be a good animal model for research on the treatment of diabetic dyslipidemia with PPARalpha selective agonists.

Animals↗
PubMed2001

Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering.

Inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, such as simvastatin, lower circulating cholesterol levels and prevent myocardial infarction. Several studies have shown an unexpected effect of HMG-CoA reductase inhibitors on inflammation. Here, we confirm that simvastatin is anti-inflammatory by using a classic model of inflammation: carrageenan-induced foot pad edema. Simvastatin administered orally to mice 1 hour before carrageenan injection significantly reduced the extent of edema. Simvastatin was comparable to indomethacin in this model. To determine whether the anti-inflammatory activity of simvastatin might affect atherogenesis, simvastatin was tested in mice deficient in apoE. Mice were dosed daily for 6 weeks with simvastatin (100 mg/kg body wt). Simvastatin did not alter plasma lipids. Atherosclerosis was quantified through the measurement of aortic cholesterol content. Aortas from control mice (n=20) contained 56+/-4 nmol total cholesterol/mg wet wt tissue, 38+/-2 nmol free cholesterol/mg, and 17+/-2 nmol cholesteryl ester/mg. Simvastatin (n=22) significantly (P<0.02) decreased these 3 parameters by 23%, 19%, and 34%, respectively. Histology of the atherosclerotic lesions showed that simvastatin did not dramatically alter lesion morphology. These data support the hypothesis that simvastatin has antiatherosclerotic activity beyond its plasma cholesterol-lowering activity.

Administration, Oral↗
PubMed2001

Tubulointerstitial injury of Thy-1 nephritis in uninephrectomized stroke-prone spontaneously hypertensive rats.

Thy-1 nephritis was induced in stroke-prone spontaneously hypertensive rats (SHR-SP) with unilateral nephrectomy (UNX) and normotensive same genetic strain Wistar-Kyoto (WKY) rats with UNX to evaluate whether the tubulointerstitial injury in Thy-1 nephritis is accelerated by long-term systemic and intraglomerular hypertension. SHR-SP that underwent UNX at twelve weeks of age were randomly assigned to receive monoclonal anti-thy 1.1 antibody (group SP), and normal saline (group SC). Age-matched normotensive WKY rats served as controls and were given the same dose of monoclonal anti-thy 1.1 antibody after UNX (group WK). In all groups, the blood pressure and renal function were assessed, and morphologic changes of tubulointerstitium were examined by using immunohistochemistry and light microscopy twelve weeks after Thy-1 nephritis induction (in groups SP and WK) and UNX alone (in group SC). In all groups, histological findings, the degree of monocyte/macrophage infiltration, interstitial expression of alpha-smooth muscle actin (alpha-SMA), which is a marker for myofibroblasts, and the degree of tubular cell proliferation were examined. In addition, assessments of blood pressure, serum creatinine and BUN levels, and the degree of proteinuria were made. In parallel to glomerular structural damage, interstitial fibrosis with predominant monocyte/macrophage influx, increased interstitial expression of alpha-SMA and tubular cell proliferation were observed in group SP. A significant increase in serum creatinine and proteinuria were also present in this group. In contrast, the changes observed in group SC were not so evident or extensive as in group SP. The level of proteinuria was lower than that in group SP. No evident tubulointerstitial changes were found in group WK. The results showed that tubulointerstitial injury was prominently progressed in the hypertensive model with Thy-1 nephritis. This suggests that sustained systemic and glomerular hypertension is not only ultimately responsible for the progression of immunologically mediated glomerular injury, but is also responsible for subsequent tubulointerstitial changes. Migration and proliferation of myofibroblasts and intense influx of monocytes/macrophages may contribute to the development of tubulointerstitial fibrosis.

Animals↗
PubMed2001

[Contrastive study of two methods("programmed temperature vaporization with back flushing" and "head space") for light hydrocarbon analysis].

Light hydrocarbon analytical method of "PTV with Back Flushing" presented here is characterized as follows: a) with "PTV" inlets temperature programmed; b) with gas line system of "Back Flushing"; c) with direct injection of oil samples. After oil sample injection, "Back Flushing" is on when light hydrocarbon components enter into analytical chromatographic column. At the same time, the temperature of inlet increases. The high temperature and "Back Flushing" blow the heavy components in the oil samples out of the analytical system. Besides, the analytical method of "Head Space" was established. Both "PTV with Back Flushing" and "Head Space" have the advantages of long column life and short analysis time. The resolution for lighter components < C9 meets the criterion of ASTM D5134-98, with the good repeatability. Ten oil samples from 6 oil areas were analysed by using the two methods. The relative deviations between the two analytical results represented by 19 geochemistry parameters were about +/- (1%-25%). The reasons for the deviation are discussed. It is pointed out that in geochemistry study it is not acceptable to combine the data obtained from two analytical methods. The analytical results obtained by injecting crude oil directly into injector are more reliable. The results obtained in "Head Space" analytical method should be calibrated when used in geochemistry study.

English Abstract↗
PubMed2000

PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver.

11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol-cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11betaHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11betaHSD1 expression and activity after chronic treatment of wild-type mice with PPARalpha agonists, while 11betaHSD1 in the livers of PPARalpha knockout mice, or in mice treated for only 7 h with PPARalpha agonists, was unaltered. Our results are the first to show PPARalpha agonists can affect glucocorticoid metabolism in the liver by altering 11betaHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARalpha agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

[Gas chromatographic and gas chromatography-mass spectrometric analyses of aromatic hydrocarbons in oils and rock extracts simultaneously by using bench-top gas chromatograph-mass spectrometer].

This article reports a successful example that an injected sample is simultaneously introduced into two fused silica capillary columns and detected separately by a flame ionization detector (FID) and an HP 5973 mass selective detector (MSD) both installed on an HP 6890 Gas Chromatograph. This GC and GC/MS analyses of aromatic hydrocarbons in oils and rock extracts were carried out by using this method and good results were achieved. This method is of great value in organic geochemistry research because it is efficient and economical.

English Abstract↗
PubMed1998

Visualization of sulfated glycoconjugates in the chicken embryonic heart by whole-mount alcian blue staining.

In the atrioventricular canal (AVC) and outflow tract (OT) of the developing heart, endothelial cells transform specifically to mesenchymal cells. The mesenchymal cells migrate into the underlying acellular matrix termed cardiac jelly and form endocardial cushion tissue. It is believed the that the highly hydrated nature of cardiac jelly is ascribed to sulfated glycoconjugates in the components of jelly matrix. In the present study, we have visualized the distribution and its temporal changes of sulfated glycoconjugates in the embryonic heart from stage 12 to 26 using whole mount alcian blue (AB) histochemistry. Atrial matrix was AB-negative in all the stages examined. Cardiac jelly in the AVC and OT were positive and the staining intensity increased as heart development proceeded, while AB-positive staining in the matrix of the ventricle became negative by stage 19. At stages later than 19, AB-positive matrix was localized in only the AVC and OT where endothelially-derived mesenchymal cells populated.

Alcian Blue↗
PubMed1996

Day-night differences in the kinetics and dynamics of insulin: diabetic versus normal Yucatan minipigs.

Time-dependent variations in the pharmacokinetics and pharmacodynamics of insulin were studied at two times, 10:30 and 20:30 during the same day in normal and streptozotocin (STZ)-induced diabetic minipigs housed in L(06:00):D(18:00) using the intravenous insulin tolerance test. Following intravenous insulin (0.1 IU/kg) administration in normal minipigs, the time for the glucose level to reach nadir (tnadir) was significantly longer in the evening than the morning [(A.M.; 30.4 (+/- 2.4) vs. P.M.: 38.5 (+/- 3.3) min] (p < 0.01), although maximum reduction of glucose level (nadir) in the morning and evening was not significantly different [A.M.: (-70 (+/- 2) vs. P.M.: -65 (+/- 5) %]. The rate of glucose decline (Kin) was significantly decreased in the evening [A.M.: 5.33 (+/- 0.71) vs. P.M.: 4.44 (+/- 0.54) %dBG/min] (p < 0.01), and the integrated glucose-lowering response (ABCB) was significantly higher in the evening than the morning [A.M.: 3.18 (+/- 0.38) vs. P.M.: 4.52 (+/- 0.30) (g/dl)* min] (p < 0.01). The area under the plasma insulin concentration curve was increased significantly in the evening [A.M.: 2.26 (+/- 0.174) vs. P.M.: 2.74 (+/- 0.18) (mU/ml)* min], while the morning plasma insulin half-life did not differ significantly from that in the evening [A.M.: 4.79 (+/- 0.36) vs. P.M.: 5.47 (+/- 0.47) min]. After induction of diabetes by intravenous STZ injections, minipigs became diabetic, baseline blood glucose was observed to increase from the range of 45-55 to 200-250 mg/dl while plasma insulin levels decreased from 7-12 to 3-5 uU/ml. In the STZ-induced diabetic minipigs, a higher dose (0.2 IU/kg) was used in the intravenous insulin tolerance test in an attempt to normalize the high glucose levels. Following intravenous administration of insulin, the evening Kin and ABCB were significantly higher than they were in the morning [Kin = A.M.: 0.99 (+/- 0.25) vs. P.M.: 1.75 (+/- 0.44) %dBG/min (p < 0.01); ABCB = A.M.: 12.63 (+/- 1.91) vs. P.M.: 19.09 (+/- 5.43) (g/dl)* min (p < 0.01)]. However, there was no significant difference between tnadir and nadir values obtained in the morning and evening [tnadir = A.M.: 81.4 (+/- 9.2) vs. P.M.: 92.8 (+/- 13.7) min; nadir = A.M.: 39.6 (+/- 5.2) vs P.M.: 48.0 (+/- 9.0) %]. The pharmacodynamics and pharmacokinetics of IV insulin both were found to be highly dose-dependent (r > 0.90).

Animals↗
PubMed1989

Effect of propranolol on the myocardial contractility of normotensive and spontaneously hypertensive rabbits: relationship of pharmacokinetics and pharmacodynamics.

Myocardial contractility of normotensive and spontaneously hypertensive rabbits was determined following an iv bolus injection of propranolol HCl. Left ventricular pressure and dimension were used to calculate the contractility parameters of (dP/dt)max, maximum fiber shortening velocity (Vcf), and the slope of the end systolic pressure-end systolic volume line (ESP-ESV line). Hypertension was induced by a methoxamine HCl iv infusion which mimicked the cardiac effects seen in essential hypertension. Propranolol caused a significant decrease in all contractility parameters (p less than 0.05) within 15 min after administration, with a peak effect occurring after 30-35 mins. The pharmacokinetics and pharmacodynamics of propranolol were fit using Hill's equation in conjunction with the concentration of drug in the theoretical effect compartment. The normotensive group of rabbits had a calculated EC(50) of 12.7 ng/ml, while the hypertensive group had an EC(50) of 6.9 ng/ml, indicating that the hypertensive rabbits were much more sensitive to the propranolol than the normotensive group. In addition, the normotensive group of rabbits demonstrated a much different pharmacokinetic-pharmacodynamic relationship than that of the hypertensive group, indicating that the hypertensive state of the animal has a significant effect upon the concentration-effect relationship.

Animals↗