Aldose Reductase Activity Research Articles

Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.

Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.

Retracted: Two Cu(II)‐based coordination polymers: Treatment activity on diabetic nephropathy via reducing aldose reductase activity and blood glucose concentration

AbstractRetraction: [Li‐Hua Zhou, Ya‐Lian Huang, Shu‐Chang Lai, Zong‐Cun Chen, Xian‐Ying Chen, Feng Ju, Mao‐Xiong Fu, Two Cu(II)‐based coordination polymers: Treatment activity on diabetic nephropathy via reducing aldose reductase activity and blood glucose concentration, J. Chin. Chem. Soc. (https://doi.org/10.1002/jccs.202000344)].The above article, published online on 22 January 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor‐in‐Chief, Jye‐Shane Yang, and Wiley‐VCH GmbH, Weinheim. The retraction has been agreed due to major overlap between this article and the following article published in Polyhedron, "Three Co(II) coordination polymers constructed from 2,5‐di(4‐pyridyl)thiazolo[5,4‐d]thiazole and V‐shaped dicarboxylic acids: Syntheses, characterizations, structural diversity and optical properties" by Mürsel Arıcıa, Okan Zafer Yeşilela, Necmi Degeb, Volume 163 (2019); 77‐83: doi.org/10.1016/j.poly.2019.02.021. Furthermore, investigation of the thermogravimetric and elemental analysis of the materials presented in the article revealed inconsistencies that render the conclusions unreliable.

Identification and characterization of in vitro and in vivo fidarestat metabolites: Toxicity and efficacy evaluation of metabolites.

The progression of diabetic complications can be prevented by inhibition of aldose reductase and fidarestat considered to be highly potent. To date, metabolites of the fidarestat, toxicity, and efficacy are unknown. Therefore, the present study on characterization of hitherto unknown in vitro and in vivo metabolites of fidarestat using liquid chromatography-electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) is undertaken. In vitro and in vivo metabolites of fidarestat have been identified and characterized by using LC/ESI/MS/MS and accurate mass measurements. To identify in vivo metabolites, plasma, urine, and feces samples were collected after oral administration of fidarestat to Sprague-Dawley rats, whereas for in vitro metabolites, fidarestat was incubated in human S9 fraction, human liver microsomes, and rat liver microsomes. Furthermore, in silico toxicity and efficacy of the identified metabolites were evaluated. Eighteen metabolites have been identified. The main in vitro phase I metabolites of fidarestat are oxidative deamination, oxidative deamination and hydroxylation, reductive defluroniation, and trihydroxylation. Phase II metabolites are methylation, acetylation, glycosylation, cysteamination, and glucuronidation. Docking studies suggest that oxidative deaminated metabolite has better docking energy and conformation that keeps consensus with fidarestat whereas the rest of the metabolites do not give satisfactory results. Aldose reductase activity has been determined for oxidative deaminated metabolite (F-1), and it shows an IC50 value of 0.44 μM. The major metabolite, oxidative deaminated, did not show any cytotoxicity in H9C2, HEK, HEPG2, and Panc1 cell lines. However, in silico toxicity, the predication result showed toxicity in skin irritation and ocular irritancy SEV/MOD versus MLD/NON (v5.1) model for fidarestat and its all metabolites. In drug discovery and development research, it is distinctly the case that the potential for pharmacologically active metabolites must be considered. Thus, the active metabolites of fidarestat may have an advantage as drug candidates as many drugs were initially observed as metabolites.

Contribution of polyol pathway, p16, and tristetraprolin to chemically induced liver injury

Background Hepatocellular carcinoma (HCC) is the most common cause of mortality and morbidity related to cancer in Egypt. Garlic with its organosulfur content has the ability to lower the risk of certain cancers. Aims The aim was to see the importance of polyol pathway, redox status, p16, and RNA-binding protein tristetraprolin (TTP) in chemically induced liver injury and subsequent cancer in addition to the role played by garlic extract in chemoprevention. Materials and methods In total, 50 male rats were allocated in four groups at random. Group II received garlic extract (0.4 g/100 g body weight) by oral gavage, HCC was induced chemically in groups III and IV by single intraperitoneal dose of diethylnitrosamine (200 mg/kg body weight) and maintained on a weekly subcutaneous injection of carbon tetrachloride (3 ml/kg body weight) for 10 weeks. Group IV received garlic extract in parallel with the induction. Hepatic p16 and TTP levels were immunoassayed. Moreover, hepatic function tests, aldose reductase activity, and redox status (malondialdehyde and catalase) were evaluated, in addition to the histological evaluation. Results Aspartate aminotransferase, alanine aminotransferase, hepatic malondialdehyde level, and aldose reductase activity were increased in the HCC group upon induction. Meanwhile, serum albumin, hepatic p16 and TTP level, and catalase activity were decreased. Garlic administration in parallel with the induction reverses the obtained biochemical changes and protected against chemical induction of HCC. Histological findings confirmed the laboratory results. Conclusion Garlic could protect against diethylnitrosamine/carbon tetrachloride −induced HCC and so it may be effective in protecting the liver against chemically induced hepatocyte damage and cancer.

Oridonin Attenuates the Effects of Chronic Alcohol Consumption Inducing Oxidative, Glycative and Inflammatory Injury in the Mouse Liver.

Oridonin (Ori) is a diterpenoid naturally present in medicinal plants with a potential as an antioxidant agent. This study aimed to evaluate the hepatic anti-oxidative, anti-glycative and anti-inflammatory properties of Ori at 0.125 and 0.25% against chronic ethanol intake in mice. Mice were divided into five groups: i) normal diet group, ii) Ori group, iii) ethanol diet (Lieber-DeCarli liquid diet with ethanol) group, iv) ethanol diet plus 0.125% Ori and v) ethanol diet plus 0.25% Ori. After 8 weeks of Ori supplementation, blood and liver tissue were used for analyses. Ethanol increased the production of reactive oxygen species and nitric oxide, decreased glutathione content, and lowered the activity of glutathione peroxide, glutathione reductase and catalase. Ethanol suppressed the hepatic mRNA expression of nuclear factor E2-related factor 2. Ori supplements reversed these changes. Ethanol increased hepatic Ne-(carboxyethymethyl)-lysine (CML) and pentosidine levels, and enhanced aldose reductase (AR) activity and mRNA expression. Ori supplements at only 0.25% decreased CML and pentosidine levels, and lowered the AR activity as well as its mRNA expression. Ethanol increased the hepatic release of tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin (IL)-1beta and IL-6. Histological data showed that ethanol induced necrosis and inflammatory cell infiltration, while Ori supplements alleviated these inflammatory responses. Ethanol up-regulated the hepatic mRNA expression of nuclear factor kappa B, myeloperoxidase and p38. Ori supplements reversed these changes. These novel findings suggest that Ori could be used as a potent agent against alcohol-induced hepatotoxicity.

Современные концепции и перспективы воздействия на катарактогенез

This paper highlights current pharmacotherapeutic modalities for various metabolic disorders which result in cataract. This therapy is preferable for the prevention and treatment of lens opacities due to less financial costs and ease of use. A novel strategy of the medical treatment for cataract was developed. Several compounds prevent the generation of lens protein aggregates and to contribute to their degradation. Oxidative stress, excessive quinoid substances, and activation of aldose reductase promote cataract progression. Quinoid theory suggests that quinones, which are produced because of impaired metabolism of aromatic amino acids (tryptophan, tyrosine etc.) are important for cataractogenesis. Lens opacity occurs when its water-soluble proteins denature and transform into dense compounds under the influence of quinones. Many studies clearly demonstrate that Catalin (pirenoxine) eye drops provide anti-cataract effect on all layers of the lens, in particular, cortex and posterior capsule. High therapeutic efficacy and long-term safety allow for recommending Catalin to slow the progression of cataract, in particular, early cataracts in patients under 59 years of age. Further studies are needed to assess the effects of pirenoxine in various cataracts and risk of cataracts. Cited published data best illustrate the crux of this issue. Keywords: lens, cataract, antioxidants, quinoid compounds, cataractogenesis, medical treatment, pirenoxine, oxidative stress. For citation: Kovalevskaya M.A., Vladimirova Yu.V., Filina L.A., Kokorev V.L. Current conceptions and promising tools to prevent cataractogenesis. Russian Journal of Clinical Ophthalmology. 2021;21(1):24–28. DOI: 10.32364/2311-7729-2021-21-1-24-28.

QM/MM analysis, synthesis and biological evaluation of epalrestat based mutual-prodrugs for diabetic neuropathy and nephropathy

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T1/2) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy.

Repression of Polyol Pathway Activity by Hemidesmus indicus var. pubescens R.Br. Linn Root Extract, an Aldose Reductase Inhibitor: An In Silico and Ex Vivo Study

Development of diabetic cataract is mainly associated with the accumulation of sorbitol via the polyol pathway through the action of Aldose reductase (AR). Hence, AR inhibitors are considered as potential agents in the management of diabetic cataract. This study explored the AR inhibition potential of Hemidesmus indicus var. pubescens root extract by in silico and ex vivo methods. Molecular docking studies (Auto Dock tool) between β-sitosterol, hemidesminine, hemidesmin-1, hemidesmin-2, and AR showed that β-sitosterol (− 10.2 kcal/mol) and hemidesmin-2 (− 8.07 kcal/mol) had the strongest affinity to AR enzyme. Ex vivo studies were performed by incubating isolated goat lenses in artificial aqueous humor using galactose (55 mM) as cataract inducing agent at room temperature (pH 7.8) for 72 h. After treatment with Vitamin E acetate − 100 µg/mL (standard) and test extract (500 and 1000 µg/mL) separately, the estimation of biochemical markers showed inhibition of lens AR activity and decreased sorbitol levels. Additionally, extract also normalized the levels of antioxidant markers like SOD, CAT, GSH. Our results showed evidence that H. indicus var. pubescens root was able to prevent cataract by prevention of opacification and formation of polyols that underlines its potential as a possible therapeutic agent against diabetic complications.Graphic

Carica papaya Linn. fruit extract inhibited the activities of aldose reductase and sorbitol dehydrogenase: possible mechanism for amelioration of diabetic complications

BackgroundDiabetes mellitus is a metabolic disorder which is associated with debilitating complications including eye disease, kidney disorder, and diabetic foot disease. One of the mechanisms implicated in the pathogenesis of diabetic complications is the polyol pathway. This study evaluated the inhibitory effect of aqueous extract of four tropical fruits, namely apple (Malus domestica Borkh.), banana (Musa paradisiaca Linn.), pawpaw (Carica papaya Linn.), and watermelon (Citrullus lanatus (Thunb.) Matsum & Nakai), on the activities of polyol pathway enzymes (aldose reductase and sorbitol dehydrogenase).ResultsAll the fruits, with the exception of banana, displayed stronger inhibition of sorbitol dehydrogenase than aldose reductase which culminated in low IC50 for the inhibition of sorbitol dehydrogenase. Of the fruit extracts tested, pawpaw inhibited both aldose reductase and sorbitol dehydrogenase most effectively with IC50 of 150.78 μg/mL and 46.30 μg/mL, respectively. Lineweaver-Burk plot also revealed that the pawpaw extract inhibited aldose reductase competitively while sorbitol dehydrogenase was inhibited in a mixed non-competitive manner.ConclusionAqueous extract of pawpaw fruit effectively inhibited polyol pathway enzymes, and this may be attributed to rich nutritional and phytochemical composition of the fruit. Consequently, the consumption of pawpaw fruit may contribute to the amelioration of diabetic complications.

Advances in pharmacotherapy of cataracts

Cataracts, the leading cause of vision impairment worldwide, arise from abnormal aggregation of lens proteins. According to the World Health Organization, cataracts cause more than 40% of blindness cases. As the population ages, the prevalence of cataracts will increase rapidly. Although cataract surgery is regarded as effective, it still suffers from complications and high cost, and could not meet the increasingly surgery demand. Therefore, pharmacological treatment for cataracts is a cheaper and more readily available option for patients, which is also a hot topic for years. Anti-cataract drug screening was previously mainly based on the specific pathogenic factors: oxidative stress, excess of quinoid substances, and aldose reductase (AR) activation. And several anti-cataract drugs have been applied in the clinic, while the effect is still unsatisfied. Makley and Zhao recently identified two kinds of novel pharmacological substances (25-hydroxycholesterol, lanosterol) that can reverse lens opacity by dissolving the aggregation of crystallin proteins, indicating that protein aggregation is not an endpoint and could be reversed with specific small-molecule drugs, significantly boosting the development of the cataract pharmacopeia and being regarded as a new dawn for cataract treatment. Our team built a novel optimized platform and had screened several potential therapeutic agents from a collection of lanosterol derivatives. In this review, we would mainly focus on the advancement of cataract pharmacotherapy based on the targets for anti-cataract drugs.

Aldosereductase: structure, mechanism of action, biological role and functioning according to normo and hyperglycemia

The review summarizes the literature on the structure, biological role and mechanism of action of aldose reductase at different blood glucose levels. Aldosereductase is the first enzyme of the sorbitol (polyol) pathway to glucose metabolism. In mammals, it is a monomeric protein with a molecular weight of 32–56 kDa, has 347–370 amino acid remainders. Its secondary structure consists of α-helices and β-bends, which alternate in 8 units. The active site of the enzyme is located at the C-terminus of the β-bend and contains a glutathione-binding domain. The active site of aldose reductase consists of two sites: substrate-binding and catalytic. The first is formed mainly by the residues of hydrophilic amino acids, and the second, by hydrophobic ones. The interaction of the enzyme with a coenzyme causes conformational changes in aldose reductase. It is believed that the enzyme functions according to the principle of an ordered “bi-bi” mechanism, that is, the coenzyme binds first, and the oxidized product is released last. The reduction of aldehydes of aldose reductase includes several stages: the interaction of the enzyme with NADPH and the formation of a binary complex, the acceptance of the substrate and the formation of a ternary complex (enzyme-coenzyme-substrate) and the separation of the alcohol-reaction product and the oxidized coenzyme. According to normoglycemia in mammalian cells via the sorbitol pathway, up to 1–3 % of intracellular glucose is restored. Under these conditions, it reduces the content of toxic and reactive aldehydes such as: 4-hydroxy-trans-2-nonenal, malondialdehyde, glyoxal, acrolein and their conjugates with reduced glutathione and carnosine, which are also toxic. Before being excreted from the body, they are reduced by aldose reductase to non-toxic compounds. Thus, the enzyme is one of the components of the body's antioxidant system. Hyperglycemia, which is most pronounced in diabetes, significantly increases the flow of glucose through the sorbitol pathway. The activation of aldosereductase and sorbitol dehydrogenase causes the use of a significant amount of NADPH, which leads to a decrease in antioxidant protection, and the excessive formation of NADH leads to a violation of the ratio of reduced and oxidized forms, known as “pseudohypoxia”. Metabolites of the sorbitol pathway, which are formed in excessive amounts, get toxic effects on metabolism and cellular structures, in particular: sorbitol, as an osmotically active component, causes lens edema, leads to the formation of cataracts, and fructose, fructose-phosphate and 3-deoxyglucasone underlie the pathogenesis of secondary diabetic complications.

Natural Compounds as Source of Aldose Reductase (AR) Inhibitors for the Treatment of Diabetic Complications: A Mini Review.

Aldol reductase (AR) is the polyol pathway's main enzyme that portrays a crucial part in developing 'complications of diabetes' involving cataract, retinopathy, nephropathy, and neuropathy. These diabetic abnormalities are triggered tremendously via aggregation of sorbitol formation (catalyzed by AR) in the polyol pathway. Consequently, it represents an admirable therapeutic target and vast research was done for the discovery of novel molecules as potential AR inhibitors for diabetic complications. This review article has been planned to discuss an outline of diabetic complications, AR and its role in diabetic complications, natural compounds reported as AR inhibitors, and benefits of natural/plant derived AR inhibitors for the management of diabetic abnormalities. The goal of AR inhibition remedy is to stabilize the increased flux of blood glucose and sorbitol via the 'polyol pathway' in the affected tissues. A variety of synthetic inhibitors of AR have been established such as tolrestat and sorbinil, but both of these face limitations including low permeability and health problems. Pharmaceutical industries and other scientists were also undertaking work to develop newer, active, and 'safe' AR inhibitors from natural sources. Therefore, several naturally found molecules were documented to possess a potent inhibitory action on AR activity. Natural inhibitors of AR appeared as harmless pharmacological agents for controlling diabetic complications. The detailed literature throughout this article shows the significance of herbal extracts and phytochemicals as prospective useful AR inhibitors in treating diabetic complications.

Promising Anti-stroke Signature of Voglibose: Investigation through In- Silico Molecular Docking and Virtual Screening in In-Vivo Animal Studies.

Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications. The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes. In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity. In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate. In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.

Status of oxidative stress markers, advanced glycation index, and polyol pathway in age-related cataract subjects with and without diabetes

One of the major public health issues is the rising prevalence of cataracts, a primary reason for preventable blindness. The causes for the development of age-related cataracts and accelerated cataractogenesis in diabetes are multifactorial. Hence, this study was designed to examine the status and relationship between the three majorly associated molecular events, namely, oxidative stress, non-enzymatic glycation, and polyol pathway in age-related cataracts with and without diabetes. A total of 472 subjects were distributed into four groups: non-diabetic subjects with clear lens (135), diabetic subjects with clear lens (40), non-diabetic subjects with cataract (174), and diabetic subjects with cataract (123). Cataracts were graded by slit-lamp examination according to the Lens Opacities Classification System III. Age at onset of cataract, type of opacity, anthropometric measurements, and sociodemographic characteristics were recorded, and clinical profile was examined. Plasma oxidative stress markers were assessed by estimating the lipid peroxidation end product malondialdehyde, protein oxidation products protein carbonyls, and DNA oxidative damage marker 8-hydroxy-2-deoxyguanosine. Plasma advanced glycation end products index, erythrocyte aldose reductase activity, and sorbitol levels were evaluated. After adjusting for age, plasma malondialdehyde levels were significantly higher in diabetic cataracts (P < 0.001) and non-diabetic cataract subjects (P < 0.05), compared to non-diabetic subjects with clear lens. Plasma advanced glycation end products index was significantly higher (P < 0.05) only in diabetic cataracts, but not in non-diabetic subjects with cataracts. Aldose reductase activity and sorbitol levels were significantly higher (P < 0.001) in both diabetic and non-diabetic subjects with cataract compared to non-diabetic subjects with clear lens. The data indicated that plasma lipid peroxidation in age-related cataracts was independent of diabetes. An association of pronounced glycation was observed only in diabetic cataracts but not in non-diabetic cataracts and polyol flux between diabetic cataracts and non-diabetic cataracts was comparable.

Prevention of Diabetic Complications by Walnut Leaf Extract via Changing Aldose Reductase Activity: An Experiment in Diabetic Rat Tissue.

Background Increased activity of aldose reductase (AR) is one of the mechanisms involved in the development of diabetic complications. Inhibiting AR can be a target to prevent diabetes complications. This study is aimed at evaluating the effect of cyclohexane (CH) and ethanol extracts (ET) of walnut leaves on AR activity in the lens and testis of diabetic rats. Methods Fifty-six male rats classified into seven groups as control and treatment groups and treated for 30 days. The treatment groups were treated with different concentrations of ET and CH. The diabetic control (DC) group was exposed to streptozotocin. AR activity was measured in the lens and testis. The expression of AR in the testis was evaluated by the immunohistochemistry method. Results Both extracts significantly reduced the AR activity (ng/mg of tissue protein) in the testis (0.034 ± 0.004, 0.038 ± 0.010, and 0.040 ± 0.007 in the treatment groups vs. 0.075 ± 0.007 in the DC group) and lens (1.66 ± 0.09, 2.70 ± 0.47, and 1.77 ± 0.20 in the treatment groups vs. 6.29 ± 0.48 in the DC group) of the treatment group compared to those of the DC group (P < 0.05). AR expression in the testes of the treatment groups was decreased compared with that of the DC group (P < 0.0001). Conclusion Walnut leaf extracts can reduce the activity and localization of AR in the testes and its activity in the lens of diabetic rats.

Citrus aurantifolia (Christm.) Swingle (lime) Fruit Extract Inhibits the Activities of Polyol Pathway Enzymes

Diabetes mellitus is associated with several complications, which may result from one or more factors including increased flux of polyol pathway. This study evaluated the inhibitory potential of four citrus fruits namely Citrus paradisi Macfad. (grape), Citrus limon (L.) Osbeck (lemon), Citrus aurantifolia (Christm.) Swingle (lime) and Citrus sinensis (L.) Osbeck (orange), on the activities of aldose reductase and sorbitol dehydrogenase – the two enzymes that mediate the polyol pathway. This is determined by incubating citrus extracts with appropriate enzymes and substrates. Fruit extract with the lowest half maximal inhibitory concentration (IC50) was used to assess the mode of inhibition of the enzymes by preparing Lineweaver–Burk plot. Citrus fruits tested inhibited sorbitol dehydrogenase more than aldose reductase, which resulted in lowered IC50 values. Of all the citrus fruits tested, lime fruit extract displayed potent inhibition of aldose reductase (IC50: 138.66 μg/mL) and sorbitol dehydrogenase (IC50: 47.21 μg/mL). Kinetic studies also revealed that lime fruit extract inhibited the activities of both enzymes in a competitive manner. In conclusion, the inhibition of the polyol pathway enzymes by the lime fruit extract may be attributed to the presence of phytochemicals such as flavonoids and limonoids.

Inhibitory effects of curcumin on aldose reductase and cyclooxygenase-2 enzymes

Diabetes is very much known as a wide-spread disorder all around the world with serious complications for the diabetic patient. In order to reduce these complications, inhibition the activity of aldose reductase (AR) and cyclooxygenase-2 (COX-2) enzymes is a proposed pathway. Within this work potency of curcumin (CUR) for the proposed enzymatic inhibition has been performed by the in silico methodologies. The main purposes of this work; evaluating first, the effect of original CUR on each of AR and COX-2 enzymes; second, the best CUR derivative for the individual action; third, the best CUR derivative with common effect on both enzymes, the results have been analyzed. The results based on the scoring factors of 66 derivatives indicated that C60 could be seen specific for AR and C62 could be seen specific for COX-2 enzyme. Further analysis indicated that C19 could be considered as a ligand with common Rank for interactions with both enzymes. The quantitative EB results indicated that the strength of interacting ligand…target complexes of C19, C60 and C62 are stronger than original inhibitors of AR and COX-2 whereas this trend has not been seen for the complexes of original CUR. The qualitative representations of interacting counterparts revealed that he proposed ligands could interact with those important parts of enzymes, especially NADPH of AR besides proper amino acids of active site for both of AR and COX-2 enzymes. The in silico methodologies have been performed based on Density Functional Theory calculations and Molecular Docking simulations. Communicated by Ramaswamy H. Sarma

Reverse Docking, Molecular Docking, Absorption, Distribution, and Toxicity Prediction of Artemisinin as an Anti-diabetic Candidate

Aldose reductase is an enzyme that catalyzes one of the steps in the sorbitol (polyol) pathway that is responsible for fructose formation from glucose. In diabetes, aldose reductase activity increases as the glucose concentration increases. The purpose of this research was to identify and develop the use of artemisinin as an anti-diabetic candidate through in silico studies, including reverse docking, receptor analysis, molecular docking, drug scan, absorption, and distributions and toxicity prediction of artemisinin. Based on the results, we conclude that artemisinin can be used as an anti-diabetic candidate through inhibition of aldose reductase

Biochemical Evidence Indicates the Preventive Effect of Resveratrol and Nicotinamide in the Treatment of STZ-induced Diabetic Cataract

ABSTRACT Purpose High glucose level is a strong initiator of both oxidative stress and DNA damage to various cellular proteins. This activates the poly ADP-ribose polymerase (PARP) enzyme, which is responsible for disturbing physiological energy metabolic homeostasis. The present study aimed to elucidate the association between stress and the PARP pathway by using resveratrol (RSV) and nicotinamide (NAM, PARP inhibitor) to treat diabetic cataract. Method Albino rats were used for the experimental study. A single streptozotocin administration (55 mg/kg, i.p.) prompted diabetes in the animals. The experimental groups were the normal group (non-diabetic) and the diabetic groups: the diabetic control animals (group D), the diabetic animals treated with RSV at 40 mg/kg/day, i.p. (D+ RSV group), NAM at 100 and 300 mg/kg/day, i.p. (D+ NAM100, D+ NAM300 groups, respectively), and a combination of RSV and NAM i.p. (D+ RSV+NAM100 = Combi 1 group, D+ RSV+NAM300 = Combi 2 group). Glucose levels and the eyes were examined biweekly; various cataractogenic parameters in the lenses were examined after completion of the eight-week experimental protocol. Results Compared to diabetic control, RSV monotherapy significantly decreased hyperglycemia and other lenticular alterations. NAM at the high dose only showed beneficial effects without altering the blood glucose level, lenticular aldose reductase (AR) activity, and sorbitol content, primarily restored the lenticular NAD level and decreased oxidative stress in diabetic rats. These findings regarding NAM treatment indicate that a pathway other than the antioxidant defense system and the polyol pathway, which might be due to PARP inhibition, is involved in diabetic cataracts. Moreover, compared to RSV monotherapy, combination treatments were effective. Conclusion These results indicate that hyperglycemia and oxidative-osmotic-nitrosative stress play central roles in the pathophysiology of diabetic cataracts. Moreover, our study also revealed that concurrent treatment with the RSV and NAM may prove useful in the pharmacotherapy of diabetes and its secondary complications such as cataract.

Effect of Berberine on Glycation, Aldose Reductase Activity, and Oxidative Stress in the Lenses of Streptozotocin-Induced Diabetic Rats In Vivo-A Preliminary Study.

Diabetes mellitus affects the eye lens, leading to cataract formation by glycation, osmotic stress, and oxidative stress. Berberine, an isoquinoline alkaloid, is a natural compound that has been reported to counteract all these pathological processes in various tissues and organs. The goal of this study was to evaluate whether berberine administered at a dose of 50 mg/kg by oral gavage for 28 days to rats with streptozotocin-induced diabetes reveals such effects on the biochemical parameters in the lenses. For this purpose, the following lenticular parameters were studied: concentrations of soluble protein, non-protein sulfhydryl groups (NPSH), advanced oxidation protein products (AOPP), advanced glycation end-products (AGEs), thiobarbituric acid reactive substances (TBARS), and activities of aldose reductase (AR), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Diabetes induced unfavorable changes in the majority of the examined parameters. The administration of berberine resulted in an increased soluble protein level, decreased activity of AR, and lowered AOPP and AGEs levels. The results suggest that berberine administered orally positively affects the lenses of diabetic rats, and should be further examined with regard to its anticataract potential.