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ABSTRACT: Pyruvate is an endogenous antioxidant substance. The aim of this study was to investigate the protective effects of ethyl pyruvate (EP) on retinal vascular injury in diabetic retinopathy. To investigate the protective effect of EP on vascular cell apoptosis and blood-retinal barrier (BRB) breakage, we have used intravitreally methylglyoxal-(MGO-) injected rat eyes. Apoptosis of the retinal vascular cell that was stimulated by the intravitreal injection of MGO was evidently attenuated by the EP treatment. EP exerts inhibitory effect on MGO-induced vascular cell apoptosis by blocking oxidative injury. In addition, EP treatment prevented MGO-induced BRB breakage and the degradation of occludin, an important tight junction protein. These observations suggest that EP acts through an antioxidant mechanism to protect against oxidative stress-induced apoptosis in retinal vessels.
Journal of diabetes research. 01/2013; 2013:460820.
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ABSTRACT: Six new cycloartane-type triterpenes (1-6), 24-methylenecycloartane-3β,6β,7β-triol (1), 24-methylenecycloartane-3β,6β,7β,16β-tetraol (2), 24-methylenecycloartane-3β,6β,16β-triol (3), 24-methylenecycloartane-3β,7β,16β-triol 3-O-β-d-xylopyranoside (4), 24-methylenecycloartane-3β,6β,16β-triol 3-O-β-d-xylopyranoside (5), and 24-methylenecycloartane-3β,6β,7β-triol 3-O-β-d-xylopyranoside (6), were isolated from the leaves of Homonoia riparia, together with one known compound, 24-methylenecycloartane-3β,6β,7β,16β-tetraol 3-O-β-d-xylopyranoside (7). The structures of the new triterpenes were established by spectroscopic studies and from chemical evidence, and the inhibitory effects of compounds 1 and 3-7 on VEGF-induced vascular permeability were examined in vivo in rats using the Miles assay. In addition, the inhibitory effect of 7 on VEGF-induced tube formation by HUVECs in vitro was investigated.
Journal of Natural Products 06/2012; 75(7):1312-8. · 3.13 Impact Factor
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ABSTRACT: Retinal pericyte loss is one of the histopathological hallmarks of early diabetic retinopathy. Puerarin (4'-7-dihydroxy-8-beta-d-glucosylisoflavone), which is an isoflavone-C-glucoside, causes various pharmacological effects that include antihyperglycemic and anti-inflammatory activities. In the present study, we determined the efficacy and possible mechanism of puerarin on the advanced glycation end product (AGE)-modified bovine serum albumin (BSA)-induced apoptosis of cultured bovine retinal pericytes and rat retinal pericytes in intravitreally AGE-modified rat serum albumin (RSA)-injected eyes. Puerarin significantly inhibited pericyte apoptosis, the generation of reactive oxygen species (ROS), and NADPH oxidase activity by inhibiting the phosphorylation of p47phox and Rac1 which were induced by the AGE-BSA treatment. The puerarin treatment markedly suppressed the activation of nuclear factor-kappaB (NF-κB). In addition, the in vivo apoptosis of the retinal pericyte of rats that was stimulated by the intravitreal injection of AGE-RSA was evidently attenuated by the puerarin treatment. These results demonstrate that puerarin may exert inhibitory effects on AGE-induced pericyte apoptosis by interfering with the NADPH oxidase-related ROS pathways and blocking NF-κB activation, thereby ameliorating retinal microvascular dysfunction.
Free radical biology & medicine 05/2012; 53(2):357-65. · 5.42 Impact Factor
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ABSTRACT: One of the early signs of diabetic retinopathy is the alteration of the blood-retinal barrier (BRB), which may involve the breakdown of endothelial cell tight junctions. Methylglyoxal (MGO) is a cytotoxic metabolite that is produced from glycolysis in vivo. Elevated levels of MGO are observed in a number of pathological conditions, including neurodegenerative disorders and diabetic complications. Herein, we hypothesize that increased levels of MGO disrupt the tight junction protein known as occludin protein by matrix metalloproteinases (MMPs), leading to breakage of the BRB.
MGO was intravitreally injected into eyes of rats. BRB leakage, MMPs activity, and occludin were investigated in intravitreally MGO-injected eyes.
When normoglycemic rats were intravitreally injected with 400 μM MGO, there was widespread leakage of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) from the retinal vasculature when compared to control retinas. In addition, MGO-injected retinas demonstrated increases of both activity and expression of MMP-2 and MMP-9, and the degradation of occludin was found in the MGO-injected retinas.
The results suggest that the activation of MMPs by elevated levels of MGO in the retina may facilitate an increase in vascular permeability by a mechanism involving proteolytic degradation of occludin. These findings may have implications for the role of MGO in the pathogenesis of diabetic retinopathy.
Albrecht von Graæes Archiv für Ophthalmologie 01/2012; 250(5):691-7. · 2.17 Impact Factor
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ABSTRACT: KIOM-79 is an herbal mixture of parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix. In the present study, we determined the efficacy and possible mechanism of KIOM-79 on the advanced glycation end product (AGE)-modified bovine serum albumin (BSA)-induced apoptosis of cultured bovine retinal pericytes and rat retinal pericytes in Zucker diabetic fatty (ZDF) rats. Seven-week-old male ZDF rats were treated with KIOM-79 (50 mg/kg body weight) once a day orally for 13 weeks. KIOM-79 significantly inhibited pericyte apoptosis which were induced by the AGE-BSA treatment. The KIOM-79 treatment markedly suppressed the activation of nuclear factor-kappaB (NF-κB) through the inhibition of inhibitory κB kinase complex. In addition, the oral administration of KIOM-79 inhibited the changes in retinal vasculature (vascular hyperpermeability, acellular capillary). KIOM-79 strongly inhibited pericyte apoptosis, NF-κB activation and the expression of pro-apoptotic Bax and tumor necrosis factor-α. Our results suggest that KIOM-79 may exert inhibitory effects on AGE-induced pericyte apoptosis by blocking NF-κB activation, thereby ameliorating retinal microvascular dysfunction.
PLoS ONE 01/2012; 7(8):e43591. · 4.09 Impact Factor
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ABSTRACT: Low-density lipoprotein (LDL) is subjected to glycoxidation in diabetes, and a novel signalling mechanism by which glycoxidised LDL functions in glomerular mesangial cells remains to be ascertained.
We performed gene expression analysis in mouse glomerular mesangial cells treated with LDL modified by glycation and oxidation (GO-LDL, 100 µg/ml) for 48 h by using DNA microarray analysis and quantitative real-time PCR. We examined the GO-LDL-specific changes in gene and protein expression in mesangial cells and glomeruli of type 2 diabetic Zucker diabetic fatty (ZDF) rats.
By microarray profiling, we noted that GO-LDL treatment increased Axl receptor tyrosine kinase (Axl) mRNA expression (∼2.5-fold, p<0.05) compared with normal LDL (N-LDL) treatment in mesangial cells. Treatment with GO-LDL also increased the protein levels of Axl and its ligand Gas6 as measured by Western blotting. These increases were inhibited by neutralising Axl receptor-specific antibody. Silencing Gas6 by siRNA inhibited GO-LDL-induced Axl expression in mesangial cells. Axl and Gas6 protein were also increased in cells cultured in high glucose (30 mM) or methylglyoxal (200 µM). Gas6 treatment increased the expression and secretion of TGF-β1 protein, a key regulator of extracellular matrix expression in the glomeruli of diabetic kidneys. Immunohistochemical analyses of glomeruli from 20-week-old ZDF rats exhibited increased Axl protein expression. Rottlerin, a selective PKC-δ inhibitor, completely blocked Gas6-induced TGF-β1 expression.
These data suggest that LDL modified by glycoxidation may mediate Axl/Gas6 pathway activation, and this mechanism may play a significant role in the pathogenesis of diabetic nephropathy.
PLoS ONE 01/2012; 7(11):e50297. · 4.09 Impact Factor
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Young Sook Kim,
Youngseop Lee, Junghyun Kim,
Eunjin Sohn,
Chan Sik Kim,
Yun Mi Lee,
Kyuhyung Jo,
Sodam Shin,
Yoojin Song,
Joo Hwan Kim,
Jin Sook Kim
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ABSTRACT: To identify effective herb to treat obesity, we screened 115 herbal extracts for inhibition of porcine pancreatic lipase (triacylg-ycerol acylhydrolase, EC 3.1.1.3) activity in vitro. Of the extracts tested, Cudrania tricuspidata leaves exhibited the most pronounced inhibitory effect on lipase activity with an IC(50) value of 9.91 μg/mL. Antilipid absorption effects of C. tricuspidata leaves were examined in rats after oral administration of lipid emulsions containing 50 or 250 mg C. tricuspidata/kg body weight. Plasma triacylglycerol levels 2 h after the oral administration of emulsions containing C. tricuspidata were significantly reduced compared to the untreated group (P < 0.05). These results suggest that C. tricuspidata leaves may be useful for the treatment of obesity.
Evidence-based Complementary and Alternative Medicine 01/2012; 2012:878365. · 4.77 Impact Factor
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ABSTRACT: Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Metformin, an oral hypoglycemic drug, possesses antioxidant effects. The aim of this paper is to investigate the protective effects of metformin on the injury of renal podocytes in spontaneously diabetic Torii (SDT) rats, a new model for nonobese type 2 diabetes. Metformin (350 mg/kg/day) was given to SDT rats for 17 weeks. Blood glucose, glycated haemoglobin (HbA1c), and albuminuria were examined. Kidney histopathology, renal 8-hydroxydeoxyguanosine (8-OHdG) levels and apoptosis were examined. In 43-week-old SDT rats, severe hyperglycemia was developed, and albuminuria was markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, urinary and renal 8-OHdG levels were highly increased, and podocyte loss was shown through application of the TUNEL and synaptopodin staining. However, treatment of SDT rats with metformin restored all these renal changes. Our data suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxidative injury.
Experimental Diabetes Research 01/2012; 2012:210821. · 1.20 Impact Factor
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ABSTRACT: The formation of advanced glycation end products (AGEs) has been considered to be a potential causative factor of injury to lens epithelial cells (LECs). Damage of LECs is believed to contribute to cataract formation. The purpose of this study was to investigate the cytotoxic effect of AGEs on LECs both in vitro and in vivo. We examined the accumulation of argpyrimidine, a methylglyoxal-derived AGE, and the expression of apoptosis-related molecules including nuclear factor- kappaB (NF-κB), Bax, and Bcl-2 in the human LEC line HLE-B3 and in cataractous lenses of Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes. In cataractous lenses from twenty-oneweek- old ZDF rats, LEC apoptosis was markedly increased, and the accumulation of argpyrimidine as well as subsequent activation of NF-κB in LECs were significantly enhanced. The ratio of Bax to Bcl-2 protein levels was also increased. In addition, the accumulation of argpyrimidine triggered apoptosis in methylglyoxal- treated HLE-B3 cells. However, the presence of pyridoxamine (an AGEs inhibitor) and pyrrolidine dithiocarbamate (a NF-κB inhibitor) prevented apoptosis in HLE-B3 cells through the inhibition of argpyrimidine formation and the blockage of NF-κB nuclear translocalization, respectively. These results suggest that the cellular accumulation of argpyrimidine in LECs is NF-κB-dependent and pro-apoptotic.
Experimental and Molecular Medicine 12/2011; 44(2):167-75. · 2.48 Impact Factor
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ABSTRACT: Betulinic acid is a pentacyclic triterpenic acid that exists naturally in many kinds of food and has many biological functions. The present study investigated the antiobesity properties of betulinic acid and possible mechanisms by which betulinic acid functions. To examine the antilipase function of betulinic acid, the ability of betulinic acid to inhibit pancreatic lipase activity in vitro and to prevent the elevation of plasma triacylglycerol levels was tested after oral administration of a lipid emulsion in rats. In addition, the lipolytic effects of betulinic acid were assayed in rat adipose tissues. The activity of cAMP-dependent phosphodiesterase was also measured in vitro. Betulinic acid inhibited pancreatic lipase activity in a dose-dependent manner at concentrations of 1.5-100 µM (IC₅₀ value of 21.10 µM) and prevented the elevation of plasma triacylglycerol levels 2 h after oral administration of the lipid emulsion at a dose of 100 mg/kg. In addition, betulinic acid had a strong lipolytic effect, which was mediated by cAMP-dependent phosphodiesterase inhibition. In conclusion, betulinic acid may exert antiobesity effects by directly inhibiting pancreatic lipase, which would prevent the absorption of lipid from the small intestine. In addition, it was found that betulinic acid may further accelerate fat mobilization by enhancing the levels of lipolysis in adipose tissues.
Phytotherapy Research 11/2011; 26(7):1103-6. · 2.09 Impact Factor
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ABSTRACT: To find new pancreatic lipase (triacylglycerol acylhydrolase, EC 3.1.1.3) inhibitors from natural products, 61 medicinal plants from Korea were screened for their antilipase activity for prevention of obesity. Dried and powdered plants were extracted three times with EtOH and extracts were obtained by removal of the solvent in vacuo. Lipase activity was determined by measuring the hydrolysis of p-nitrophenyl butyrate to p-nitrophenol. Also, the inhibitory effect was measured on phosphodiesterase (PDE), another therapeutic target for obesity. Of the extracts tested, Sorbus commixta (stem, leaf) and Viscum album (whole plant) exhibited antilipase activity (with IC(50) values of 29.6 µg/mL and 33.3 µg/mL, respectively) and only anti-PDE activity (IC(50) values of 20.08 µg/mL and 35.15 µg/mL, respectively).
Phytotherapy Research 11/2011; 26(5):778-82. · 2.09 Impact Factor
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ABSTRACT: KIOM-79, a combination of four plant extracts, has a preventive effect on diabetic nephropathy and retinopathy in diabetic animal models. In this study, we have investigated the inhibitory effects of KIOM-79 on diabetic cataractogenesis.
We evaluated aldose reductase activity during cataractogenesis using Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. ZDF rats were treated orally with KIOM-79 (50 mg/kg body weight) once a day for 13 weeks.
In vehicle-treated ZDF rats, lens opacity was increased, and lens fibre swelling and membrane rupture were observed. In addition, aldose reductase activity and aldose reductase protein expression in diabetic lens were markedly enhanced. However, the administration of KIOM-79 inhibited the development of diabetic cataract through the inhibition of aldose reductase activity and protein expression in diabetic lenses.
These observations suggested that KIOM-79 was useful against the treatment of diabetic cataractogenesis.
The Journal of pharmacy and pharmacology. 10/2011; 63(10):1301-8.
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ABSTRACT: Chlorogenic acid (5-O-caffeoylquinic acid, CA), a phenolic compound found ubiquitously in plants, has antidiabetic effect in diabetic animal models. In this study, we investigated the inhibitory effect of CA on diabetic cataractogenesis. We evaluated the aldose reductase (AR) activity during cataract development in 50% galactose-fed rats, an animal model of sugar cataract. Galactose-fed rats were treated orally with CA (10 and 50 mg/kg body weight) once a day for 2 weeks. In vehicle-treated galactose-fed rats, lens opacity was increased, and lens fiber swelling and membrane rupture were observed. In addition, AR protein was highly expressed in lens epithelial cells and lens cortical fibers of galactose-fed rats. However, CA inhibited the rat AR activity in vitro, and the administration of CA prevented the development of sugar cataract through the inhibition of AR activity. These observations suggest that CA is useful for the treatment of sugar cataract.
Archives of Pharmacal Research 05/2011; 34(5):847-52. · 1.59 Impact Factor
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ABSTRACT: KIOM-79 is a mixture of 80% ethanol extracts of parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix. The preventive effect of KIOM-79 on the development of diabetic keratopathy has been investigated.
Seven-week-old male Zucker diabetic fatty (ZDF) rats were treated with KIOM-79 (50 mg/kg body weight) once a day orally for 13 weeks. The thickness of the cornea was measured and the extent of corneal cell death was detected by a terminal deoxynucleotidyl transferase dUTP nick-end labelling assay. The expression of advanced glycation end products (AGEs), 8-hydroxydeoxyguanosine, nuclear factor-kappaB (NF-κB), Bax and Bcl-2 were evaluated in corneal tissues.
The administration of KIOM-79 prevented corneal oedema and apoptotic cell death of corneal cells. The accumulation of AGE in corneal tissues was reduced in ZDF rats treated with KIOM-79. Moreover, KIOM-79 attenuated oxidative DNA damage, NF-κB activation and Bax overexpression in the cornea.
The results suggested that KIOM-79 exhibited corneal protective properties by not only reducing oxidative stress but inhibiting the AGEs/NF-κB downstream signal pathway during the development of diabetic keratopathy.
The Journal of pharmacy and pharmacology. 04/2011; 63(4):524-30.
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ABSTRACT: Advanced glycation end products (AGEs) play an important role in the development of chronic diabetic complications. Chlorogenic acid (CGA) is a phenolic compound formed by the esterification of caffeic and quinic acids. In this study, we evaluated the inhibitory effects of CGA against the formation of AGEs and AGEs protein cross-linking in vitro. An in vitro assay for glycation of bovine serum albumin by high glucose showed that CGA inhibited AGEs formation with an IC(50) value of 148.32 μM and was found to be more effective than aminoguanidine, a well-known AGEs inhibitor (IC(50); 807.67 μM). In an indirect AGE-ELISA assay, the CGA exhibited more potent inhibitory activity on the cross-linking of AGEs to collagen than aminoguanidine. In addition, the inhibitory effects of CGA on AGEs formation and on its cross-linking with collagen might be caused by its interactions with reactive decarbonyl compounds, such as methylglyoxal. These results suggest that CGA could be beneficial in the prevention of AGEs progression in patients with diabetes because CGA can attenuate AGEs deposition in glucose.
Archives of Pharmacal Research 03/2011; 34(3):495-500. · 1.59 Impact Factor
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2011 International Conference on Parallel Architectures and Compilation Techniques, PACT 2011, Galveston, TX, USA, October 10-14, 2011; 01/2011
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ABSTRACT: The purpose of the experiment reported here was to assess the involvement of high-mobility group box-1 (HMGB1), receptor for advanced glycation end products (RAGE) and nuclear factor (NF)-κB signaling pathway in the development of rat diabetic nephropathy.
Diabetes was induced by intraperitoneal streptozotocin injection in 7-week-old male rats. At 20 weeks of age, renal expression of HMGB1 was detected by immunohistochemistry. The expression of RAGE and NF-κB activity was studied by Western blot and electrophoretic mobility shift assay in renal tissues of normoglycemic and diabetic rats, respectively.
HMGB1 was highly expressed in both the cytoplasmic and nuclear patterns in diabetic renal glomerular cells and tubular epithelial cells, although in normal rats, HMGB1 was expressed only in the cell nuclei. The expression of RAGE, a potential receptor for HMGB1, and NF-κB activity were also greater in diabetic than in normal rats. Moreover, diabetes increased the binding of NF-κB to the RAGE promoter.
These findings suggest that hyperglycemia-induced HMGB1 release may induce the renal injury in diabetic rats, and that the pathogenic role of HMGB1 might be dependent on RAGE and through activation of NF-κB.
American Journal of Nephrology 01/2011; 33(6):524-9. · 2.54 Impact Factor
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ABSTRACT: Advanced glycation end products including Nε-(carboxymethyl)lysine (CML) are believed to contribute to retinal pericyte loss in diabetic retinopathy. Nuclear factor-κB (NF-κB) activation has been considered as a potential cytotoxic modulator of retinal pericytes. Herein, we investigated whether CML accumulation can trigger NF-κB activation and apoptosis of retinal pericytes in streptozotocin (STZ)-induced diabetic rats. Seven-week-old Sprague-Dawley rats were made diabetic (STZ, 60 mg/kg). After 5 months, CML level and NF-κB activation were measured in trypsin-digested retinal vessels. In diabetic rats, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive and caspase 3-positive retinal pericytes were significantly increased. CML and NF-κB activation was also markedly increased in diabetic retinal vessels. Moreover, the immunoreactivity of NF-κB was localized within the region where CML were accumulated. Apoptosis occurred in CML-accumulating retinal pericytes. These results suggest that NF-κB could be activated in CML-accumulating pericytes from diabetic retina. CML accumulation is responsible, at least in part, for the apoptosis of retinal pericytes.
Ophthalmic Research 01/2011; 46(2):92-7. · 1.56 Impact Factor
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ABSTRACT: Previous studies have reported that KIOM-79 shows a strong inhibitory effect on AGE formation and inhibited a proinflammatory state in a murine macrophage cell line. In the present study, we investigated the effect of KIOM-79 on AGE accumulation and vascular inflammation in the aorta of Zucker diabetic fatty (ZDF) rats, a commonly used model of type 2 diabetes. Seven-week-old male ZDF rats were treated with KIOM-79 (50 mg/kg) once a day orally for 13 weeks. We examined the dissected aortas for AGE accumulation, expression of the receptor for AGEs (RAGE), and the expression of proinflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and vascular adhesion molecule-1 (VCAM-1). Nuclear factor-kappaB (NF-κB) and inducible nitric oxide synthase (iNOS) were also measured by Southwestern histochemistry, electrophoretic mobility shift assay (EMSA), and immunohistochemistry, respectively. KIOM-79 markedly reduced the accumulation of AGEs and the expression of RAGE in the aorta. We also found that KIOM-79 attenuated the expression of inflammatory factors including NF-κB, MCP-1, VEGF, VCAM-1, and iNOS in the aortas of ZDF rats. These data suggest that KIOM-79 may prevent or retard the development of inflammation in diabetic vascular disease.
Evidence-based Complementary and Alternative Medicine 01/2011; 2011:784136. · 4.77 Impact Factor
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ABSTRACT: Damage of lens epithelial cells (LECs) has been implicated in cataract formation. The aim of this study was to investigate the protective effect of KIOM-79, a combination of four plant extracts, on LECs. We examined the levels of advanced glycation end products (AGEs), nuclear factor-kappaB (NF-κB) activation and inducible nitric oxide synthase (iNOS) expression in LECs during cataract development using the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. KIOM-79 was orally administered by gavage to ZDF rats once a day for 13 weeks. Apoptosis was detected by TUNEL assay, and NF-κB activation and iNOS expression were studied by southwestern histochemistry and immunohistochemistry, respectively. In diabetic cataractous lenses, TUNEL-positive LECs were markedly increased 20-fold, and AGEs were highly accumulated (2.7-fold) in LECs. In addition, both NF-κB activation, and iNOS expression were significantly enhanced 3- to 5-fold, respectively, compared to levels found in normal ZL rats. However, the administration of KIOM-79 delayed the development of diabetic cataracts and prevented LEC apoptosis (70%) through the inhibition of AGEs, NF-κB-activation and iNOS expression. These observations suggest that KIOM-79 is useful in inhibiting diabetic cataractogenesis and acts through an antiapoptotic mechanism to protect LECs from injury.
Evidence-based Complementary and Alternative Medicine 01/2011; 2011. · 4.77 Impact Factor
