Eun Jin Sohn

Effects of Cudrania tricuspidata water extract on blood pressure and renal functions in NO-dependent hypertension.

A pharmacological inhibition of nitric oxide synthase (NOS) in rats for 4-6 weeks produces renal vasoconstriction, renal dysfunction, and severe hypertension. The present study was aimed at investigating whether Cudrania tricuspidata (C. tricuspidata) water extract ameliorates N(G)-Nitro-L-arginine methylester (L-NAME)-induced hypertension. Treatment of L-NAME (60 mg/L drinking water, 4 weeks) causes a sustained increase in systolic blood pressure (SBP). The concentration of plasma NO metabolites and NO/cGMP productions in the vascular tissues of the L-NAME-treated group were significantly reduced as compared with those in the control. C. tricuspidata water extract blocked increase of SBP in the L-NAME-treated group and restored SBP to normal level. Futhermore, C. tricuspidata water extract was able to preserve the vascular NO/cGMP production and plasma NO metabolites concentration. However, there are no changes in the expression of ecNOS and iNOS of thoracic aorta among the rats of control, L-NAME-treated group, and L-NAME and C. tricuspidata water extract co-treated group. The urinary sodium level, urine volume, and creatinine clearance were significantly higher in rats co-treated with C. tricuspidata water extract and L-NAME than in L-NAME-treated group. Taken together, these results suggest that C tricuspidata water extract prevents the increase of SBP in the L-NAME-induced hypertension that may have been caused by enhanced generation of vascular NO/cGMP.

Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels

The present study was designed to examine the relaxant and anticonstrictive effects of berberine in the isolated thoracic aorta in rats. Intravenous injection of berberine lowered the mean arterial pressure (MAP) of anesthesized rats in a dose-dependent manner. The angiotensin-converting enzyme (ACE) activities were inhibited significantly by the addition of berberine in a dose-dependent manner of which the IC50 value of berberine for ACE was 42 micrograms/ml (125 microM). In the endothelium-intact rings, angiotensin I-induced contraction was markedly attenuated by prior exposure of aortic rings to berberine. Treatment of the intact aortic rings with berberine (10 micrograms/ml) increased the NOx and cGMP productions relative to the vehicle-treated group. Berberine induced a dose-dependent relaxation in phenylephrine-precontracted aortic rings, but NG-nitro-L-arginine methyl ester (L-NAME)-pretreated intact aortic rings or functional removal of the endothelium attenuated the berberine-induced relaxation without an effect on maximum response. These results suggest that berberine has a hypotensive effect, at least in part, via the inhibition of ACE and direct release of NO/cGMP in the vascular tissues.

KIOM-79, an Inhibitor of AGEs–Protein Cross-linking, Prevents Progression of Nephropathy in Zucker Diabetic Fatty Rats

Advanced glycation end products (AGEs) have been implicated in the development of diabetic complications, including diabetic nephropathy. KIOM-79, an 80% ethanolic extract obtained from parched Puerariae Radix, gingered Magnolia Cortex, Glycyrrhiza Radix and Euphorbia Radix, was investigated for its effects on the development of renal disease in Zucker diabetic fatty rats, an animal model of type 2 diabetes. In vitro inhibitory effect of KIOM-79 on AGEs cross-linking was examined by enzyme-linked immunosorbent assay (ELISA). KIOM-79 (50 mg/kg/day) was given to Zucker diabetic fatty rats for 13 weeks. Body and kidney weight, blood glucose, glycated hemoglobin, urinary albumin and creatinine excretions were monitored. Kidney histopathology, collagen accumulation, fibrinogen and transforming growth factor-beta 1 (TGF-β1) expression were also examined. KIOM-79 reduced blood glucose, kidney weight, histologic renal damage and albuminuria in Zucker diabetic fatty rats. KIOM-79 prevented glomerulosclerosis, tubular degeneration, collagen deposition and podocyte apoptosis. In the renal cortex, TGF-β1, fibronectin mRNA and protein were significantly reduced by KIOM-79 treatment. KIOM-79 reduces AGEs accumulation in vivo, AGE–protein cross-linking and protein oxidation. KIOM-79 could be beneficial in preventing the progression of diabetic glomerularsclerosis in type 2 diabetic rats by attenuating AGEs deposition in the glomeruli.

KIOM-79 prevents apoptotic cell death and AGEs accumulation in retinas of diabetic db/db mice

AIM OF THE STUDY KIOM-79 retards the development of diabetic nephropathy in animal models of type 1 and type 2 diabetes. In this study, we evaluated whether KIOM-79 could prevent apoptotic cell death and advanced glycation end products (AGEs) accumulation in the retinas of diabetic db/db mice. MATERIAL AND METHODS Mice were treated orally with KIOM-79 (150 mg/kg body weight) once daily for 12 weeks. Levels of retinal ganglion cell death were measured by terminal dUTP nick-end labeling (TUNEL) assay. In the retina, the activity of caspase-3 (a marker of apoptosis) and the formation of AGEs were measured by immunohistochemical staining. RESULTS KIOM-79 reduced the number of TUNEL-immunoreactive retinal cells. KIOM-79 attenuated caspase-3 expression and AGEs accumulation in the retina. CONCLUSIONS These data show that KIOM-79 can prevent apoptosis in neuronal cells, AGEs accumulation in the retina, and retard the development of diabetic retinopathy.

Ethyl Pyruvate Inhibits Retinal Pathogenic Neovascularization by Downregulating HMGB1 Expression

Retinal pathogenic angiogenesis in the eyes is a causative factor in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. This study was designed to examine the pathogenic role of the high-mobility group box-1 (HMGB1) protein and the inhibitory effect of ethyl pyruvate (EP), a well-known antioxidant substance, in retinal pathogenic angiogenesis in mice with oxygen-induced retinopathy (OIR), one of the animal models of proliferative ischemic retinopathy. The OIR mouse model was used for our in vivo studies. The mice were exposed to 75% oxygen from postnatal day 7 (P7) to P11, after which the mice were brought to room air and intraperitoneally injected with EP (50 mg/kg, or 100 mg/kg) for five days. At P17, the mice were perfused with fluorescein isothiocyanate-dextran, and flat-mounted retinas were used to measure nonperfused and neovascular tufts. In OIR mice, an intraperitoneal injection of EP reduced the nonperfused retinal area in the treatment group and significantly reduced the retinal neovascular tufts. In addition, EP inhibited the overexpression of HMGB1 in the retinas of OIR mice. These data suggest that EP could serve as an innovative pharmaceutical agent to prevent retinal neovascularization through inhibiting HMGB1 expression.

Methanol Extract of Sorbus Commixta Cortex Prevents Vascular Inflammation in Rats with a High Fructose-Induced Metabolic Syndrome

Feeding high fructose (Frc) to rats induces a moderate increase in blood pressure, which is associated with insulin resistance. The present study was designed to evaluate the effect of the methanol extract of Sorbus commixta cortex (MSC) on vascular inflammation in a rat model of the metabolic syndrome induced by a high Frc-diet. Male Sprague-Dawley rats were divided into 4 groups and treated for 7 weeks as follows: 1) control, 2) high Frc-diet group, 3) Frc/MSC1 group; high Frc-diet group treated with MSC (100 mg/kg/day), and 4) Frc/MSC2 group; high Frc-diet group treated with MSC (200 mg/kg/day). High Frc-induced decreases of the expression level of aortic endothelial nitric oxide synthase (ecNOS) while the production of cyclic GMP (cGMP) was restored by treatment with MSC. On the contrary, increases of the expression level of endothelin-1 (ET-1) in the aorta, the transcription factor, the cytokine related with vascular inflammation, and the adhesion molecules were suppressed by MSC treatment. Moreover, MSC treatment was shown to lessen the thickening noted in the aortic intima and media of the high Frc-diet group. Our findings suggest that MSC may have an anti-vascular inflammatory effect on rats with a high Frc-induced metabolic syndrome.

Effects of glycyrrhizin on renal functions in association with the regulation of water channels.

It is well-known that the mineralocorticoid action of glycyrrhizin, which is the major component of Glycyrrhiza uralensis, is caused by a defect in the conversion of cortisol to cortisone by the inhibition of 11-beta-hydroxysteroid dehydrogenase enzyme activity. In the present study, we investigated the mechanisms of salt and water retention in the kidney of rats administered excess amounts of glycyrrhizin (200 mg/kg/day, p.o.). Up-regulation of aquaporin (AQP) 2 and 3 water channels was detected in the renal inner and outer medulla by Western blot analysis in rats treated with glycyrrhizin for 0.5, 1 and 2 consecutive weeks. Our results show that urine flow rates and sodium excretion rates in glycyrrhizin-treated rats were decreased significantly, but creatinine clearance (Ccr) was not altered. The decreases of urine volume and urinary sodium excretion in glycyrrhizin-treated rats were reversed by a 2-week injection of spironolactone, which is a well-known mineralocorticoid receptor (MR) blocker. These results suggest that the retention of water and salt in glycyrrhizin-treated rats is, at least in part, accounted for by the increased expression of AQP 2 and 3 in the kidney, which may be causally related to the MR.