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Satish K Srivastava - One of the best experts on this subject based on the ideXlab platform.
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prevention of posterior capsular opacification through Aldose Reductase inhibition
Investigative Ophthalmology & Visual Science, 2009Co-Authors: Umesh C S Yadav, Satish K Srivastava, Farshid Ighanihosseinabad, Frederik J G M Van Kuijk, Kota V RamanaAbstract:Purpose The purpose of this study was to evaluate the effect of Aldose Reductase (AR) inhibition on Posterior capsular opacification (PCO) using pig eye capsular bag model.
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Aldose Reductase Inhibition Prevents Endotoxin-Induced Uveitis in Rats
Investigative Ophthalmology & Visual Science, 2007Co-Authors: Umesh C S Yadav, Satish K Srivastava, Kavuluri Venkata RamanaAbstract:Purpose The purpose of the present study was to elucidate the role of the polyol pathway enzyme, Aldose Reductase (AR) in the mediation of ocular inflammation in rat model of endotoxin-induced uveitis (EIU).
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endotoxin induced cardiomyopathy and systemic inflammation in mice is prevented by Aldose Reductase inhibition
Circulation, 2006Co-Authors: Kota V Ramana, Aruni Bhatnagar, Monte S Willis, Michael D White, Jureta W Horton, Michael J Dimaio, Deepak Srivastava, Satish K SrivastavaAbstract:Background—Sepsis is a systemic inflammatory response syndrome characterized by excessive production of inflammatory cytokines and cardiovascular collapse. Postreceptor signaling events that lead to stress responses and cytokine production are sensitive to redox changes and products of lipid peroxidation. Methods and Results—We tested the hypothesis that inflammatory signaling and cytokine generation during sepsis depend on the activity of the enzyme Aldose Reductase, which catalyzes the reduction of lipid peroxidation–derived aldehydes and their glutathione conjugates. The results of the present study show that pharmacological inhibition of Aldose Reductase by sorbinil or knockdown of the enzyme by small interfering RNA prevents the activation of nuclear factor-B and the release of tumor necrosis factor- from lipopolysaccharide-stimulated RAW264.7 or H9c2 cells. Increases in serum and cardiac cytokines in response to lipopolysaccharide challenge were suppressed by inhibition of Aldose Reductase. Treatment with sorbinil blunted the activation of protein kinase C, c-Jun NH2-terminal kinase, and p38, as well as phosphorylation of interleukin receptor–associated kinase, IB- ,I B kinase complex-/, and phospholipase-1 and -1. These changes were associated with decreased myocardial nuclear factor-B and activating protein-1 activity, prostaglandin E2 production, induction of cyclooxygenase 2, and inducible nitric oxide synthase. Sorbinil treatment also induced functional recovery in myocardial fractional shortening in vivo and preserved contractile function of isolated perfused hearts. Inhibition of Aldose Reductase increased survival in mice injected with lethal doses of lipopolysaccharide. Conclusions—The present demonstration that Aldose Reductase mediates endotoxin-induced inflammation and cardiomyopathy suggests that inhibition of this enzyme may be useful to attenuate maladaptive host responses and to treat acute cardiovascular dysfunction associated with endotoxic shock. (Circulation. 2006;114:1838-1846.)
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requirement of Aldose Reductase for the hyperglycemic activation of protein kinase c and formation of diacylglycerol in vascular smooth muscle cells
Diabetes, 2005Co-Authors: Kota V Ramana, Brian M. Friedrich, Aruni Bhatnagar, Matthew B West, Ravinder Tammali, Satish K SrivastavaAbstract:Activation of protein kinase C (PKC) has been linked to the development of secondary diabetes complications. However, the underlying molecular mechanisms remain unclear. We examined the contribution of Aldose Reductase, which catalyzes the first, and the rate-limiting, step of the polyol pathway of glucose metabolism, to PKC activation in vascular smooth muscle cells (VSMCs) isolated from rat aorta and exposed to high glucose in culture. Exposure of VSMCs to high glucose (25 mmol/l), but not iso-osmotic mannitol, led to an increase in total membrane-associated PKC activity, which was prevented by the Aldose Reductase inhibitors tolrestat or sorbinil or by the ablation of Aldose Reductase by small interfering RNA (siRNA). The VSMCs were found to express low levels of sorbitol dehydrogenase, and treatment with the sorbitol dehydrogenase inhibitor CP-166572 did not prevent high-glucose-induced PKC activation. Stimulation with high glucose caused membrane translocation of conventional (α, β1, β2, and γ) and novel (δ and e) isoforms of PKC. Inhibition of Aldose Reductase prevented membrane translocation of PKC-β2 and -δ and delayed the activation of PKC-β1 and -e, whereas membrane translocation of PKC-α and -γ was not affected. Treatment with tolrestat prevented phosphorylation of PKC-β2 and -δ. High glucose increased the formation of diacylglycerol (DAG) and enhanced phosphorylation of phospholipase C-γ1 (PLC-γ1). Inhibition of Aldose Reductase prevented high glucose-induced DAG formation and phosphorylation of PLC-γ1 and PLC-β2 and -δ. Inhibition of phospholipid hydrolysis by D609, but not by the synthetic alkyl-1-lysophospholipid 1-O-octadecyl-2-O-methyl- rac -glycerophosphocholine, or edelfosine, prevented DAG formation. Treatment with sorbinil decreased the levels of reactive oxygen species in high-glucose-stimulated VSMCs. Hence, inhibition of Aldose Reductase, independent of sorbitol dehydrogenase, appears to be effective in diminishing oxidative stress and hyperglycemic changes in signaling events upstream to the activation of multiple PKC isoforms and PLC-γ1 and may represent a useful approach for preventing the development of secondary vascular complications of diabetes.
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Activation of Nulcear Factor-κB by Hyperglycemia in Vascular Smooth Muscle Cells Is Regulated by Aldose Reductase
Diabetes, 2004Co-Authors: Kavuluri Venkata Ramana, Brian M. Friedrich, Aruni Bhatnagar, Sanjay Srivastava, Satish K SrivastavaAbstract:Activation of the polyol pathway has been linked to the development of secondary diabetic complications. However, the underlying molecular mechanisms remain unclear. To probe the contribution of this pathway, we examined whether inhibition of Aldose Reductase, which catalyzes the first step of the pathway, affects hyperglycemia-induced activation of the inflammatory transcription factor nuclear factor (NF)-κB. Treatment of vascular smooth muscle cells with the Aldose Reductase inhibitors tolrestat and sorbinil prevented high-glucose–induced protein kinase C (PKC) activation, nuclear translocation of NF-κB, phosphorylation of IKK, and the increase in the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and Aldose Reductase. High-glucose–induced NF-κB activation was also prevented by the PKC inhibitors chelerythrine and calphostin C. Ablation of Aldose Reductase by small interference RNA (siRNA) prevented high-glucose–induced NF-κB and AP-1 activation but did not affect the activity of SP-1 or OCT-1. Stimulation with iso-osmotic mannitol activated NF-κB and increased the expression of Aldose Reductase but not ICAM-1 and VCAM-1. Treatment with Aldose Reductase inhibitors or Aldose Reductase siRNA did not affect mannitol-induced NF-κB or AP-1 activation. Administration of tolrestat (15 mg · kg −1 · day −1 ) decreased the abundance of activated NF-κB in balloon-injured carotid arteries of diabetic rats. Collectively, these results suggest that inhibition of Aldose Reductase, which prevents PKC-dependent nonosmotic NF-κB activation, may be a useful approach for treating vascular inflammation caused by diabetes.
Soon Sung Lim - One of the best experts on this subject based on the ideXlab platform.
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inhibitory effects of colocasia esculenta l schott constituents on Aldose Reductase
Molecules, 2014Co-Authors: Seung Hwan Hwang, Beom Goo Kang, Jae Seung Hong, Soon Sung LimAbstract:The goal of this study was to determine the rat lens Aldose Reductase-inhibitory effects of 95% ethanol extracts from the leaves of C. esculenta and, its organic solvent soluble fractions, including the dichloromethane (CH2Cl2), ethyl acetate (EtOAc), n-butanol (BuOH) and water (H2O) layers, using dl-glyceraldehyde as a substrate. Ten compounds, namely tryptophan (1), orientin (2), isoorientin (3), vitexin (4), isovitexin (5), luteolin-7-O-glucoside (6), luteolin-7-O-rutinoside (7), rosmarinic acid (8), 1-O-feruloyl-d-glucoside (9) and 1-O-caffeoyl-d-glucoside (10) were isolated from the EtOAc and BuOH fractions of C. esculenta. The structures of compounds 1–10 were elucidated by spectroscopic methods and comparison with previous reports. All the isolates were subjected to an in vitro bioassay to evaluate their inhibitory activity against rat lens Aldose Reductase. Among tested compounds, compounds 2 and 3 significantly inhibited rat lens Aldose Reductase, with IC50 values of 1.65 and 1.92 μM, respectively. Notably, the inhibitory activity of orientin was 3.9 times greater than that of the positive control, quercetin (4.12 μM). However, the isolated compounds showed only moderate ABTS+ [2,29-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)] activity. These results suggest that flavonoid derivatives from Colocasia esculenta (L.) Schott represent potential compounds for the prevention and/or treatment of diabetic complications.
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synthesis of flavonoids and their effects on Aldose Reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Soon Sung Lim, Sang Hoon Jung, Kuk Hyun Shin, Sam Rok KeumAbstract:Aldose Reductase, the key enzyme of the polyol pathway, and oxidative stress are known to play important roles in the complications of diabetes. A drug with potent inhibition of Aldose Reductase and oxidative stress, therefore, would be a most promising drug for the prevention of diabetic complications. The purpose of this study was to develop new compounds with these dual-effects through synthesis of chalcone derivatives and by examining the structure-activity relationships on the inhibition of rat lens Aldose Reductase as well as on antioxidant effects. A series of 35 flavonoid derivatives were synthesized by Winget's condensation, oxidation, and reduction of appropriate acetophenones with appropriate benzaldehydes. The inhibitory activity of these derivatives on rat lens Aldose Reductase and their antioxidant effects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro, were evaluated. Their effect on sorbitol accumulation in the red blood cells, lenses and sciatic nerves of streptozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2′,4′-dihydroxyl groups in the A ring such as 2,4,2′,4′-tetrahydroxychalcone (22), 2,2′,4′-trihydroxychalcone (11), 2′,4′-dihydroxy-2,4-dimethylchalcone (21) and 3,4,2′,4′-tetrahydroxychalcone (18) were found to possess the highest rat lens Aldose Reductase inhibitory activity in-vitro, their IC50 values (concentration of inhibitors giving 50% inhibition of enzyme activity) being 1.6 times 10−7, 3.8 times 10−7, 4.0 times 10−7 and 4.6 times 10−7 M, respectively. All of the chalcones tested except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak free radical scavenging activity. In the in-vivo experiments, however, compound 18 with o-dihydroxy moiety in the B ring showed the strongest inhibitory activity in the accumulation of sorbitol in the tissues. It also showed the strongest activity in transition metal chelation and free radical scavenging activity. Of the 35 4,2′-dihydroxyl and 2′,4′-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol and dihydrochalcone, some chalcone derivatives synthesized were found to possess Aldose Reductase inhibition and antioxidant activities in-vitro as well as inhibition in the accumulation of sorbitol in the tissues in-vivo. 3,4,2′,4′-Tetrahydroxychalcone (18, butein) was the most promising compound for the prevention or treatment of diabetic complications.
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rat lens Aldose Reductase inhibitory constituents of nelumbo nucifera stamens
Phytotherapy Research, 2006Co-Authors: Soon Sung Lim, Yu Jung Jung, Sook Kyung Hyun, Yeon Sil Lee, Jae Sue ChoiAbstract:Aldose Reductase, the principal enzyme of the polyol pathway, has been shown to play an important role in the complications associated with diabetes. A methanol extract of the stamens of Nelumbo nucifera Gaertn. was shown to exert an inhibitory effect on rat lens Aldose Reductase (RLAR), and thus was fractionated using several organic solvents, including dichloromethane, ethyl acetate and n-butanol. The ethyl acetate-soluble fraction, which manifested potent RLAR-inhibitory properties, was then purified further via repeated measures of silica gel and Sephadex LH-20 column chromatography. Thirteen flavonoids: kaempferol (1) and seven of its glycosides (2-9), myricetin 3',5'-dimethylether 3-O-beta-d-glucopyranoside (10), quercetin 3-O-beta-d-glucopyranoside (11) and two isorhamnetin glycosides (12, 13) were isolated from N. nucifera, as well as four non-flavonoid compounds: adenine (14), myo-inositol (15), arbutin (16) and beta-sitosterol glucopyranoside (17). These compounds were all assessed with regard to their RLAR-inhibitory properties. Among the isolated flavonoids, those harboring 3-O-alpha-l-rhamnopyranosyl-(1-->6)-beta-d-glucopyranoside groups in their C rings, including kaempferol 3-O-alpha-l-rhamnopyranosyl-(1-->6)-beta-d-glucopyranoside (5) and isorhamnetin 3-O-alpha-l-rhamnopyranosyl-(1-->6)-beta-d-glucopyranoside (13), were determined to exhibit the highest degree of rat lens Aldose Reductase inhibitory activity in vitro, evidencing IC(50) values (concentration required for a 50% inhibition of enzyme activity) of 5.6 and 9.0 microm, respectively.
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isoflavonoids from the rhizomes of belamcanda chinensis and their effects on Aldose Reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues
Archives of Pharmacal Research, 2002Co-Authors: Sang Hoon Jung, Soon Sung Lim, Yeon Sil Lee, Sanghyun Lee, Yeong Shik Kim, Kuk Hyun ShinAbstract:Aldose Reductase, the key enzyme of the polyol pathway, is known to play important roles in the diabetic complication. The inhibitors of Aldose Reductase, therefore, would be potential agents for the prevention of diabetic complications. To evaluate active principles for the inhibition of Aldose Reductase from the rhizomes ofBelamcanda chinensis, twelve phenolic compounds were isolated and tested for their effects on rat lens Aldose Reductase. As a result, isoflavones such as tectorigenin, irigenin and their glucosides were found to show a strong Aldose Reductase inhibition. Tectoridin and tectorigenin, exhibited the highest Aldose Reductase inhibitory potency, their IC50 values, being 1.08x 10-6 M and 1.12 x 10-6 M, respectively, for DL-glyceraldehyde as a substrate. Both compounds, when administered orally at 100 mg/kg for 10 consecutive days to streptozotocin-induced diabetic rats, caused a significant inhibition of sorbitol accumulation in the tissues such as lens, sciatic nerves and red blood cells. Tectorigenin showed a stronger inhibitory activity than tectoridin. From these results, it is suggested that tectorigenin is attributed to be a promising compound for the prevention and/or treatment of diabetic complications.
Aruni Bhatnagar - One of the best experts on this subject based on the ideXlab platform.
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endotoxin induced cardiomyopathy and systemic inflammation in mice is prevented by Aldose Reductase inhibition
Circulation, 2006Co-Authors: Kota V Ramana, Aruni Bhatnagar, Monte S Willis, Michael D White, Jureta W Horton, Michael J Dimaio, Deepak Srivastava, Satish K SrivastavaAbstract:Background—Sepsis is a systemic inflammatory response syndrome characterized by excessive production of inflammatory cytokines and cardiovascular collapse. Postreceptor signaling events that lead to stress responses and cytokine production are sensitive to redox changes and products of lipid peroxidation. Methods and Results—We tested the hypothesis that inflammatory signaling and cytokine generation during sepsis depend on the activity of the enzyme Aldose Reductase, which catalyzes the reduction of lipid peroxidation–derived aldehydes and their glutathione conjugates. The results of the present study show that pharmacological inhibition of Aldose Reductase by sorbinil or knockdown of the enzyme by small interfering RNA prevents the activation of nuclear factor-B and the release of tumor necrosis factor- from lipopolysaccharide-stimulated RAW264.7 or H9c2 cells. Increases in serum and cardiac cytokines in response to lipopolysaccharide challenge were suppressed by inhibition of Aldose Reductase. Treatment with sorbinil blunted the activation of protein kinase C, c-Jun NH2-terminal kinase, and p38, as well as phosphorylation of interleukin receptor–associated kinase, IB- ,I B kinase complex-/, and phospholipase-1 and -1. These changes were associated with decreased myocardial nuclear factor-B and activating protein-1 activity, prostaglandin E2 production, induction of cyclooxygenase 2, and inducible nitric oxide synthase. Sorbinil treatment also induced functional recovery in myocardial fractional shortening in vivo and preserved contractile function of isolated perfused hearts. Inhibition of Aldose Reductase increased survival in mice injected with lethal doses of lipopolysaccharide. Conclusions—The present demonstration that Aldose Reductase mediates endotoxin-induced inflammation and cardiomyopathy suggests that inhibition of this enzyme may be useful to attenuate maladaptive host responses and to treat acute cardiovascular dysfunction associated with endotoxic shock. (Circulation. 2006;114:1838-1846.)
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requirement of Aldose Reductase for the hyperglycemic activation of protein kinase c and formation of diacylglycerol in vascular smooth muscle cells
Diabetes, 2005Co-Authors: Kota V Ramana, Brian M. Friedrich, Aruni Bhatnagar, Matthew B West, Ravinder Tammali, Satish K SrivastavaAbstract:Activation of protein kinase C (PKC) has been linked to the development of secondary diabetes complications. However, the underlying molecular mechanisms remain unclear. We examined the contribution of Aldose Reductase, which catalyzes the first, and the rate-limiting, step of the polyol pathway of glucose metabolism, to PKC activation in vascular smooth muscle cells (VSMCs) isolated from rat aorta and exposed to high glucose in culture. Exposure of VSMCs to high glucose (25 mmol/l), but not iso-osmotic mannitol, led to an increase in total membrane-associated PKC activity, which was prevented by the Aldose Reductase inhibitors tolrestat or sorbinil or by the ablation of Aldose Reductase by small interfering RNA (siRNA). The VSMCs were found to express low levels of sorbitol dehydrogenase, and treatment with the sorbitol dehydrogenase inhibitor CP-166572 did not prevent high-glucose-induced PKC activation. Stimulation with high glucose caused membrane translocation of conventional (α, β1, β2, and γ) and novel (δ and e) isoforms of PKC. Inhibition of Aldose Reductase prevented membrane translocation of PKC-β2 and -δ and delayed the activation of PKC-β1 and -e, whereas membrane translocation of PKC-α and -γ was not affected. Treatment with tolrestat prevented phosphorylation of PKC-β2 and -δ. High glucose increased the formation of diacylglycerol (DAG) and enhanced phosphorylation of phospholipase C-γ1 (PLC-γ1). Inhibition of Aldose Reductase prevented high glucose-induced DAG formation and phosphorylation of PLC-γ1 and PLC-β2 and -δ. Inhibition of phospholipid hydrolysis by D609, but not by the synthetic alkyl-1-lysophospholipid 1-O-octadecyl-2-O-methyl- rac -glycerophosphocholine, or edelfosine, prevented DAG formation. Treatment with sorbinil decreased the levels of reactive oxygen species in high-glucose-stimulated VSMCs. Hence, inhibition of Aldose Reductase, independent of sorbitol dehydrogenase, appears to be effective in diminishing oxidative stress and hyperglycemic changes in signaling events upstream to the activation of multiple PKC isoforms and PLC-γ1 and may represent a useful approach for preventing the development of secondary vascular complications of diabetes.
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Aldose Reductase catalyzed reduction of aldehyde phospholipids
Journal of Biological Chemistry, 2004Co-Authors: Sanjay K Srivastava, Matthew Spite, John O Trent, Matthew B West, Yonis Ahmed, Aruni BhatnagarAbstract:Abstract Oxidation of unsaturated phospholipids results in the generation of aldehyde side chains that remain esterified to the phospholipid backbone. Such “core” aldehydes elicit immune responses and promote inflammation. However, the biochemical mechanisms by which phospholipid aldehydes are metabolized or detoxified are not well understood. In the studies reported here, we examined whether Aldose Reductase (AR), which reduces hydrophobic aldehydes, metabolizes phospholipid aldehydes. Incubation with AR led to the reduction of 5-oxovaleroyl, 7-oxo-5-heptenoyl, 5-hydroxy-6-oxo-caproyl, and 5-hydroxy-8-oxo-6-octenoyl phospholipids generated upon oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). The enzyme also catalyzed the reduction of phospholipid aldehydes generated from the oxidation of 1-alkyl, and 1-alkenyl analogs of PAPC, and 1-palmitoyl-2-arachidonoyl phosphatidic acid or phosphoglycerol. Aldose Reductase catalyzed the reduction of chemically synthesized 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine (POVPC) with a Km of 10 μm. Addition of POVPC to the culture medium led to incorporation and reduction of the aldehyde in COS-7 and THP-1 cells. Reduction of POVPC in these cells was prevented by the AR inhibitors sorbinil and tolrestat and was increased in COS-7 cells overexpressing AR. Together, these observations suggest that AR may be a significant participant in the metabolism of several structurally diverse phospholipid aldehydes. This metabolism may be a critical regulator of the pro-inflammatory and immunogenic effects of oxidized phospholipids.
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Activation of Nulcear Factor-κB by Hyperglycemia in Vascular Smooth Muscle Cells Is Regulated by Aldose Reductase
Diabetes, 2004Co-Authors: Kavuluri Venkata Ramana, Brian M. Friedrich, Aruni Bhatnagar, Sanjay Srivastava, Satish K SrivastavaAbstract:Activation of the polyol pathway has been linked to the development of secondary diabetic complications. However, the underlying molecular mechanisms remain unclear. To probe the contribution of this pathway, we examined whether inhibition of Aldose Reductase, which catalyzes the first step of the pathway, affects hyperglycemia-induced activation of the inflammatory transcription factor nuclear factor (NF)-κB. Treatment of vascular smooth muscle cells with the Aldose Reductase inhibitors tolrestat and sorbinil prevented high-glucose–induced protein kinase C (PKC) activation, nuclear translocation of NF-κB, phosphorylation of IKK, and the increase in the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and Aldose Reductase. High-glucose–induced NF-κB activation was also prevented by the PKC inhibitors chelerythrine and calphostin C. Ablation of Aldose Reductase by small interference RNA (siRNA) prevented high-glucose–induced NF-κB and AP-1 activation but did not affect the activity of SP-1 or OCT-1. Stimulation with iso-osmotic mannitol activated NF-κB and increased the expression of Aldose Reductase but not ICAM-1 and VCAM-1. Treatment with Aldose Reductase inhibitors or Aldose Reductase siRNA did not affect mannitol-induced NF-κB or AP-1 activation. Administration of tolrestat (15 mg · kg −1 · day −1 ) decreased the abundance of activated NF-κB in balloon-injured carotid arteries of diabetic rats. Collectively, these results suggest that inhibition of Aldose Reductase, which prevents PKC-dependent nonosmotic NF-κB activation, may be a useful approach for treating vascular inflammation caused by diabetes.
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structural and kinetic determinants of aldehyde reduction by Aldose Reductase
Biochemistry, 1999Co-Authors: Sanjay K Srivastava, Mark J Petrash, Satish K Srivastava, Stanley J Watowich, Aruni BhatnagarAbstract:Aldose Reductase (AR) is a member of the aldo-keto Reductase superfamily. Due to its ability to catalyze the formation of sorbitol from glucose during hyperglycemic and hypertonic stress, the aldos...
Kuk Hyun Shin - One of the best experts on this subject based on the ideXlab platform.
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synthesis of flavonoids and their effects on Aldose Reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Soon Sung Lim, Sang Hoon Jung, Kuk Hyun Shin, Sam Rok KeumAbstract:Aldose Reductase, the key enzyme of the polyol pathway, and oxidative stress are known to play important roles in the complications of diabetes. A drug with potent inhibition of Aldose Reductase and oxidative stress, therefore, would be a most promising drug for the prevention of diabetic complications. The purpose of this study was to develop new compounds with these dual-effects through synthesis of chalcone derivatives and by examining the structure-activity relationships on the inhibition of rat lens Aldose Reductase as well as on antioxidant effects. A series of 35 flavonoid derivatives were synthesized by Winget's condensation, oxidation, and reduction of appropriate acetophenones with appropriate benzaldehydes. The inhibitory activity of these derivatives on rat lens Aldose Reductase and their antioxidant effects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro, were evaluated. Their effect on sorbitol accumulation in the red blood cells, lenses and sciatic nerves of streptozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2′,4′-dihydroxyl groups in the A ring such as 2,4,2′,4′-tetrahydroxychalcone (22), 2,2′,4′-trihydroxychalcone (11), 2′,4′-dihydroxy-2,4-dimethylchalcone (21) and 3,4,2′,4′-tetrahydroxychalcone (18) were found to possess the highest rat lens Aldose Reductase inhibitory activity in-vitro, their IC50 values (concentration of inhibitors giving 50% inhibition of enzyme activity) being 1.6 times 10−7, 3.8 times 10−7, 4.0 times 10−7 and 4.6 times 10−7 M, respectively. All of the chalcones tested except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak free radical scavenging activity. In the in-vivo experiments, however, compound 18 with o-dihydroxy moiety in the B ring showed the strongest inhibitory activity in the accumulation of sorbitol in the tissues. It also showed the strongest activity in transition metal chelation and free radical scavenging activity. Of the 35 4,2′-dihydroxyl and 2′,4′-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol and dihydrochalcone, some chalcone derivatives synthesized were found to possess Aldose Reductase inhibition and antioxidant activities in-vitro as well as inhibition in the accumulation of sorbitol in the tissues in-vivo. 3,4,2′,4′-Tetrahydroxychalcone (18, butein) was the most promising compound for the prevention or treatment of diabetic complications.
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isoflavonoids from the rhizomes of belamcanda chinensis and their effects on Aldose Reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues
Archives of Pharmacal Research, 2002Co-Authors: Sang Hoon Jung, Soon Sung Lim, Yeon Sil Lee, Sanghyun Lee, Yeong Shik Kim, Kuk Hyun ShinAbstract:Aldose Reductase, the key enzyme of the polyol pathway, is known to play important roles in the diabetic complication. The inhibitors of Aldose Reductase, therefore, would be potential agents for the prevention of diabetic complications. To evaluate active principles for the inhibition of Aldose Reductase from the rhizomes ofBelamcanda chinensis, twelve phenolic compounds were isolated and tested for their effects on rat lens Aldose Reductase. As a result, isoflavones such as tectorigenin, irigenin and their glucosides were found to show a strong Aldose Reductase inhibition. Tectoridin and tectorigenin, exhibited the highest Aldose Reductase inhibitory potency, their IC50 values, being 1.08x 10-6 M and 1.12 x 10-6 M, respectively, for DL-glyceraldehyde as a substrate. Both compounds, when administered orally at 100 mg/kg for 10 consecutive days to streptozotocin-induced diabetic rats, caused a significant inhibition of sorbitol accumulation in the tissues such as lens, sciatic nerves and red blood cells. Tectorigenin showed a stronger inhibitory activity than tectoridin. From these results, it is suggested that tectorigenin is attributed to be a promising compound for the prevention and/or treatment of diabetic complications.
Sang Hoon Jung - One of the best experts on this subject based on the ideXlab platform.
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synthesis of flavonoids and their effects on Aldose Reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Soon Sung Lim, Sang Hoon Jung, Kuk Hyun Shin, Sam Rok KeumAbstract:Aldose Reductase, the key enzyme of the polyol pathway, and oxidative stress are known to play important roles in the complications of diabetes. A drug with potent inhibition of Aldose Reductase and oxidative stress, therefore, would be a most promising drug for the prevention of diabetic complications. The purpose of this study was to develop new compounds with these dual-effects through synthesis of chalcone derivatives and by examining the structure-activity relationships on the inhibition of rat lens Aldose Reductase as well as on antioxidant effects. A series of 35 flavonoid derivatives were synthesized by Winget's condensation, oxidation, and reduction of appropriate acetophenones with appropriate benzaldehydes. The inhibitory activity of these derivatives on rat lens Aldose Reductase and their antioxidant effects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro, were evaluated. Their effect on sorbitol accumulation in the red blood cells, lenses and sciatic nerves of streptozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2′,4′-dihydroxyl groups in the A ring such as 2,4,2′,4′-tetrahydroxychalcone (22), 2,2′,4′-trihydroxychalcone (11), 2′,4′-dihydroxy-2,4-dimethylchalcone (21) and 3,4,2′,4′-tetrahydroxychalcone (18) were found to possess the highest rat lens Aldose Reductase inhibitory activity in-vitro, their IC50 values (concentration of inhibitors giving 50% inhibition of enzyme activity) being 1.6 times 10−7, 3.8 times 10−7, 4.0 times 10−7 and 4.6 times 10−7 M, respectively. All of the chalcones tested except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak free radical scavenging activity. In the in-vivo experiments, however, compound 18 with o-dihydroxy moiety in the B ring showed the strongest inhibitory activity in the accumulation of sorbitol in the tissues. It also showed the strongest activity in transition metal chelation and free radical scavenging activity. Of the 35 4,2′-dihydroxyl and 2′,4′-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol and dihydrochalcone, some chalcone derivatives synthesized were found to possess Aldose Reductase inhibition and antioxidant activities in-vitro as well as inhibition in the accumulation of sorbitol in the tissues in-vivo. 3,4,2′,4′-Tetrahydroxychalcone (18, butein) was the most promising compound for the prevention or treatment of diabetic complications.
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Aldose Reductase inhibitory activity of the compounds from the seed of psoralea corylifolia
Journal of The Korean Society for Applied Biological Chemistry, 2009Co-Authors: Sang Hee Shim, Daegeun Song, Sang Hoon JungAbstract:The purpose of this study was to evaluate the active properties of Psoralea corylifolia seed for the treatment of diabetic complications. 6-Prenylnaringenin (5) and corylin (6) isolated from P. corylifolia could possibly be acting as the active compounds for the inhibition of Aldose Reductase and would be the lead compounds for the Aldose Reductase inhibitors.
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isoflavonoids from the rhizomes of belamcanda chinensis and their effects on Aldose Reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues
Archives of Pharmacal Research, 2002Co-Authors: Sang Hoon Jung, Soon Sung Lim, Yeon Sil Lee, Sanghyun Lee, Yeong Shik Kim, Kuk Hyun ShinAbstract:Aldose Reductase, the key enzyme of the polyol pathway, is known to play important roles in the diabetic complication. The inhibitors of Aldose Reductase, therefore, would be potential agents for the prevention of diabetic complications. To evaluate active principles for the inhibition of Aldose Reductase from the rhizomes ofBelamcanda chinensis, twelve phenolic compounds were isolated and tested for their effects on rat lens Aldose Reductase. As a result, isoflavones such as tectorigenin, irigenin and their glucosides were found to show a strong Aldose Reductase inhibition. Tectoridin and tectorigenin, exhibited the highest Aldose Reductase inhibitory potency, their IC50 values, being 1.08x 10-6 M and 1.12 x 10-6 M, respectively, for DL-glyceraldehyde as a substrate. Both compounds, when administered orally at 100 mg/kg for 10 consecutive days to streptozotocin-induced diabetic rats, caused a significant inhibition of sorbitol accumulation in the tissues such as lens, sciatic nerves and red blood cells. Tectorigenin showed a stronger inhibitory activity than tectoridin. From these results, it is suggested that tectorigenin is attributed to be a promising compound for the prevention and/or treatment of diabetic complications.