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Inhibition of Aldose Reductase Prevents Experimental Allergic Airway Inflammation in Mice  [PDF]
Umesh C. S. Yadav, Kota V. Ramana, Leopoldo Aguilera-Aguirre, Istvan Boldogh, Hamid A. Boulares, Satish K. Srivastava
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006535
Abstract: Background The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR), contributes to the pathogenesis of oxidative stress–induced inflammation by affecting the NF-κB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma. Methods and Findings Primary Human Small Airway Epithelial Cells (SAEC) were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE)-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-κB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS), cycloxygenase (COX)-2, Prostaglandin (PG) E2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results indicate that inhibition of AR prevents airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid and airway hyperresponsiveness in mice. Conclusions These results suggest that airway inflammation due to allergic response to RWE, which subsequently activates oxidative stress-induced expression of inflammatory cytokines via NF-κB-dependent mechanism, could be prevented by AR inhibitors. Therefore, inhibition of AR could have clinical implications, especially for
Aldose Reductase Inhibition Prevents Allergic Airway Remodeling through PI3K/AKT/GSK3β Pathway in Mice  [PDF]
Umesh C. S. Yadav, Amarjit S. Naura, Leopoldo Aguilera-Aguirre, Istvan Boldogh, Hamid A. Boulares, William J. Calhoun, Kota V. Ramana, Satish K. Srivastava
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057442
Abstract: Background Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR), an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA)-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs) and mouse lung fibroblasts (mLFs). Methods Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR) in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT) in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s) of airway remodeling. Results In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3. Conclusion Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.
Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity  [PDF]
Xiaoyong Wei,Dan Chen,Yanchun Yi,Hui Qi,Xinxin Gao,Hua Fang,Qiong Gu,Ling Wang,Lianquan Gu
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/426537
Abstract: Objective. Effects of Syringic acid (SA) extracted from dendrobii on diabetic cataract (DC) pathogenesis were explored. Methods. Both in vitro and in vivo DC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using qRT-PCR. Interaction sites and binding characteristics were determined by molecule-docking techniques and dynamic models. Results. Targeting AR, SA provided protection from D-gal-induced damage by consistently maintaining lens transparency and delaying lens turbidity development. Inhibition of AR gene expression by SA was confirmed by qRT-PCR. IC50 of SA for inhibition of AR activity was 213.17?μg/mL. AR-SA binding sites were Trp111, His110, Tyr48, Trp20, Trp79, Leu300, and Phe122. The main binding modes involved hydrophobic interactions and hydrogen bonding. The stoichiometric ratio of non-covalent bonding between SA and AR was 1.0 to 13.3. Conclusion. SA acts to prevent DC in rat lenses by inhibiting AR activity and gene expression, which has potential to be developed into a novel drug for therapeutic management of DC. 1. Introduction Increasing population senescence due to improved living standards and diet has increased the incidence rate of diabetic cataract, a frequent cause of vision impairment and blindness [1]. A complex pathogenic mechanism underlies diabetic cataract. Though the exact mechanism remains uncertain, a large body of research indicates that aldose reductase (AR) is a key enzyme involved in DC development [2]. In order to reduce diabetic cataract incidence and slow the progression of diabetic cataract in current patients, further understanding of the mechanistic involvement of AR in diabetic cataract development and progression is required. In diabetic patients, AR activation increases polyalcohol metabolism rates. As a result, glucitol accumulation in the eye caused increased osmotic pressure, alterations to cell membrane permeability, edema, and damage to cells of the optical lens. These changes block the passage of nutrients into the lens, further resulting in reduced amino acid levels accompanied by protein denaturation and polymerization. The end result of this process is cataract formation and progression [3]. Previous studies of the experimental aldose reductase inhibitors GP-1447 and KIOM-79 have demonstrated a relationship between AR
Inhibitory action on aldose reductase by soybean flavonoids
Oliveira, Tania Toledo de;Nagem, Tanus Jorge;Miranda, Luiz Carlos Guedes de;Paula, Vanderlúcia Fonseca de;Teixeira, Marco Ant?nio;
Journal of the Brazilian Chemical Society , 1997, DOI: 10.1590/S0103-50531997000300004
Abstract: the flavonoids kaempherol, genistein, naringenin, quercetin, morin, rutin and quercitrin isolated from ufv-5’soybean’s cultivars were tested as inhibitors of aldose reductase. the best results were obtained by using morin and quercitrin.
Binding of Fidarestat Stereoisomers with Aldose Reductase  [PDF]
Dooil Kim,Suk-In Hong,Dae-Sil Lee
International Journal of Molecular Sciences , 2006, DOI: 10.3390/i7110519
Abstract: The stereospecificity in binding to aldose reductase (ALR2) of two fidarestat {6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide} stereoisomers [(2S,4S)and (2R,4S)] has been investigated by means of molecular dynamics simulations using freeenergy integration techniques. The difference in the free energy of binding was found to be2.0 ± 1.7 kJ/mol in favour of the (2S,4S)-form, in agreement with the experimentalinhibition data. The relative mobilities of the fidarestats complexed with ALR2 indicate alarger entropic penalty for hydrophobic binding of (2R,4S)-fidarestat compared to (2S,4S)-fidarestat, partially explaining its lower binding affinity. The two stereoisomers differmainly in the orientation of the carbamoyl moiety with respect to the active site and rotationof the bond joining the carbamoyl substituent to the ring. The detailed structural andenergetic insights obtained from out simulations allow for a better understanding of thefactors determining stereospecific inhibitor-ALR2 binding in the EPF charges model.
INHIBITORY ACTIVITY OF FLAVONOIDS ON THE LENS ALDOSE REDUCTASE OF HEALTHY AND DIABETIC RATS
M. T. Goodarzi,F. Zal,M. Malakooti,M. R. Safari S. Sadeghian
Acta Medica Iranica , 2006,
Abstract: Aldose reductase is a critical enzyme in the polyol pathway that plays an important role in diabetes mellitus. Inhibition of the activity of this enzyme can prevent cataract in diabetic patients’lenses. In this study the inhibitory effect of two flavonoids, quercetin and naringin, in the activity of aldose reductase in streptozotocin-induced diabetic and healthy rats were investigated. Thirty male rats were divided in six groups. The first, second and third group were healthy rats that received water,quercetin and naringin, respectively. The fourth, fifth and sixth groups were streptozocin-induced diabetic rats that received water, quercetin and naringin, respectively. These rats were fed orally in a definite dose from each substance for 12 days. After this period rats were scarified and their lenses were separated and homogenized. The activity of aldose reductase was measured in each homogenized sample separately. The effect of feeding of these substances in blood sugar was also determined. Aldose reductase activity was reduced 73 and 69 percent in diabetic rats fed by quercetin and naringin, respectively, and the difference compared to control group was significant. In healthy rats this reduction was 63 and 59 percent, respectively, and the difference was significant compared to those who did not receive flavonoids. It was concluded that these substances were effective in reduction of aldose reductase activity in vivo and consequently could delay the progress of cataract.
Inhibition of Aldose Reductase by Gentiana lutea Extracts  [PDF]
Chandrasekhar Akileshwari,Puppala Muthenna,Branislav Nastasijevi ,Gordana Joksi ,J. Mark Petrash,Geereddy Bhanuprakash Reddy
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/147965
Abstract: Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. Thus, ALR2 inhibition could be an effective strategy in the prevention or delay of certain diabetic complications. Gentiana lutea grows naturally in the central and southern areas of Europe. Its roots are commonly consumed as a beverage in some European countries and are also known to have medicinal properties. The water, ethanol, methanol, and ether extracts of the roots of G. lutea were subjected to in vitro bioassay to evaluate their inhibitory activity on the ALR2. While the ether and methanol extracts showed greater inhibitory activities against both rat lens and human ALR2, the water and ethanol extracts showed moderate inhibitory activities. Moreover, the ether and methanol extracts of G. lutea roots significantly and dose-dependently inhibited sorbitol accumulation in human erythrocytes under high glucose conditions. Molecular docking studies with the constituents commonly present in the roots of G. lutea indicate that a secoiridoid glycoside, amarogentin, may be a potential inhibitor of ALR2. This is the first paper that shows G. lutea extracts exhibit inhibitory activity towards ALR2 and these results suggest that Gentiana or its constituents might be useful to prevent or treat diabetic complications.
Inhibition of Aldose Reductase by Gentiana lutea Extracts  [PDF]
Chandrasekhar Akileshwari,Puppala Muthenna,Branislav Nastasijevi?,Gordana Joksi?,J. Mark Petrash,Geereddy Bhanuprakash Reddy
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/147965
Abstract: Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. Thus, ALR2 inhibition could be an effective strategy in the prevention or delay of certain diabetic complications. Gentiana lutea grows naturally in the central and southern areas of Europe. Its roots are commonly consumed as a beverage in some European countries and are also known to have medicinal properties. The water, ethanol, methanol, and ether extracts of the roots of G. lutea were subjected to in vitro bioassay to evaluate their inhibitory activity on the ALR2. While the ether and methanol extracts showed greater inhibitory activities against both rat lens and human ALR2, the water and ethanol extracts showed moderate inhibitory activities. Moreover, the ether and methanol extracts of G. lutea roots significantly and dose-dependently inhibited sorbitol accumulation in human erythrocytes under high glucose conditions. Molecular docking studies with the constituents commonly present in the roots of G. lutea indicate that a secoiridoid glycoside, amarogentin, may be a potential inhibitor of ALR2. This is the first paper that shows G. lutea extracts exhibit inhibitory activity towards ALR2 and these results suggest that Gentiana or its constituents might be useful to prevent or treat diabetic complications. 1. Introduction According to the latest WHO estimates, currently approximately 200 million people all over the world are suffering from diabetes. This may increase to at least 350 million by the year 2025, which could have a severe impact on human health [1]. Prolonged exposure to chronic hyperglycemia in diabetes can lead to various complications affecting the cardiovascular, renal, neurological, and visual systems [2]. Although mechanisms leading to diabetic complications are not completely understood, many biochemical pathways associated with hyperglycemia have been implicated [2]. Among these, the polyol pathway has been extensively studied [3]. Aldose reductase (ALR2; EC: 1.1.1.21) belongs to aldo-keto reductases (AKR) super family. It is the first and rate-limiting enzyme in the polyol pathway where it reduces glucose to sorbitol utilizing NADPH as a cofactor. Subsequently, sorbitol dehydrogenase catalyzes the conversion of sorbitol to fructose, thus constituting the polyol pathway [3]. Accumulation of sorbitol leads to osmotic swelling, changes in membrane permeability, and also oxidative stress culminating in tissue injury [4]. Experimental animal models suggest
Inhibition of aldose reductase by herbs extracts and natural substances and their role in prevention of cataracts
Guzmán,ángel; Guerrero,Ricardo O;
Revista Cubana de Plantas Medicinales , 2005,
Abstract: cataractogenesis is a common complication that occurs in diabetes mellitus. aldose reductase is a lens enzyme probably involved in the development of this eye problem. the purpose of this investigation was to screen plant extracts for aldose reductase inhibitors (ari) and to investigate their possible influence in diabetic cataractogenesis prevention. 13 plants and 3 natural products were randomly selected for our experiment. the 19 extracts originated from plant material which was extracted with ethanol, water and dcm, and assessed for inhibitors of aldose reductase. this enzyme was isolated from bovine lenses homogenates. the enzyme was incubated in a reaction mixture containing 50 mm na-phosphate buffer (ph 6.2), nadph, 400 mm liso4 and dl-glyceraldehyde. a spectrophotometrical assay was performed in which nadp is produced and its absorption read at 340 nm. eugenia borinquensis, mangifera indica, eucalyptus deglupta, and syzygium malaccense were among the best inhibitors. normal and diabetic sprague dawley rats were used to evaluate the in vivo effect of e. deglupta, m. indica, and e. borinquensis in cataractogenesis prevention. all of these extracts had preventive effects on the formation of cataracts. it is concluded that further investigation to explain the above findings is necessary. perhaps the next step will include an activity monitored isolation of the effective principles. future investigation will ince the isolation of the active principles in these extracts.
Aldose reductase inhibitory activity and antioxidant capacity of pomegranate extracts
imen Karasu, Ahmet Cumao lu, Ali Rifat Gúrpinar, Murat Kartal, Lucia Kovacikova, Ivana Milackova, Milan Stefek
Interdisciplinary Toxicology , 2012, DOI: 10.2478/v10102-012-0003-8
Abstract: The pomegranate, Punica granatum L., has been the subject of current interest as a medicinal agent with wide-ranging therapeutic indications. In the present study, pomegranate ethanolic seed and hull extracts were tested, in comparison with a commercial sample, for the inhibition of aldose reductase, an enzyme involved in the etiology of diabetic complications. In vitro inhibition of rat lens aldose reductase was determined by a conventional method. Pomegranate ethanolic hull extract and commercial pomegranate hull extract exhibited similar aldose reductase inhibitory activity characterized by IC50 values ranging from 3 to 33.3 μg/ml. They were more effective than pomegranate ethanolic seed extract with IC50 ranging from 33.3 to 333 μg/ml. Antioxidant action of the novel compounds was documented in a DPPH test and in a liposomal membrane model, oxidatively stressed by peroxyl radicals. All the plant extracts showed considerable antioxidant potential in the DPPH assay. Pomegranate ethanolic hull extract and commercial pomegranate hull extract executed similar protective effects on peroxidatively damaged liposomal membranes characterized by 10 < IC50 < 100 μg/ml. Pomegranate ethanolic seed extract showed significantly lower antioxidant activity compared to both hull extracts studied. Pomegranate extracts are thus presented as bifunctional agents combining aldose reductase inhibitory action with antioxidant activity and with potential therapeutic use in prevention of diabetic complications.
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