Laurus nobilis Linn. Inhibits Polyol Pathway Enzymes: Strategy for Managing Diabetic Complications

2021 ◽  
Vol 17 ◽  
Author(s):  
Habeeb Adebodun Bankole ◽  
Azeez Ayomide Fatai ◽  
Sulihat Motunrayo Aleshe ◽  
Mutiu Idowu Kazeem ◽  
Abidemi Paul Kappo
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Curcuma Longa ◽  
Polyol Pathway ◽  
Sorbitol Dehydrogenase ◽  
Thymus Vulgaris ◽  
Laurus Nobilis ◽  
Pharmacological Agents ◽  
Rising Incidence ◽  
Inhibitory Potential

Background: The rising incidence of diabetic complications necessitate the continuous search for safer, cheaper and effective pharmacological agents. Polyol pathway is an underlying process implicated in the pathogenesis of diabetic complications. Inhibition of enzymes in the polyol pathway is a veritable means of ameliorating diabetic complications. Objective: This study evaluated the inhibitory potential of some spicy plants on the activities of polyol pathway enzymes (aldose reductase and sorbitol dehydrogenase). Method: Aqueous extracts of Laurus nobilis (bay), Cinnamomum zeylanicum (cinnamon), Murraya koenigii (curry), Thymus vulgaris (thyme) and Curcuma longa (turmeric) were incubated with appropriate enzymes and substrates, and percentages inhibition determined. Results: Results showed that bay extract had effective IC50 for inhibition of both aldose reductase (174.87 µg/mL) and sorbitol dehydrogenase (37.08 µg/mL). It also revealed that bay extract inhibited aldose reductase and sorbitol dehydrogenase in a non-competitive and competitive manner respectively. Conclusion: It is therefore concluded that bay extract effectively inhibited activities of polyol pathway enzymes, and may contribute to the amelioration of diabetic complications.

scholarly journals Curcumin Analogues with Aldose Reductase Inhibitory Activity: Synthesis, Biological Evaluation, and Molecular Docking

Processes ◽  
2019 ◽  
Vol 7 (7) ◽  
pp. 417 ◽  
Author(s):  
Dasharath Kondhare ◽  
Sushma Deshmukh ◽  
Harshad Lade
Keyword(s):  
Molecular Docking ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Curcuma Longa ◽  
Polyol Pathway ◽  
Biological Evaluation ◽  
Curcumin Analogues ◽  
Ic50 Values ◽  
Rate Limiting

Curcumin, a constituent of Curcuma longa, has shown numerous biological and pharmacological activities, including antidiabetic effects. Here, a novel series of curcumin analogues were synthesized and evaluated for in vitro inhibition of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which plays a key role in the onset and progression of diabetic complications. Biological activity studies showed that all the curcuminoids exhibited moderate to good AR inhibitory (ARI) activities compared with that of the quercetin standard. Importantly, compounds 8d, 8h, 9c, 9e, and 10g demonstrated promising ARI activities, with the 50% inhibitory concentration (IC50) values of 5.73, 5.95, 5.11, 5.78, and 5.10 µM, respectively. Four other compounds exhibited IC50 values in the range of 6.04–6.18 µM. Methyl and methoxy derivatives showed a remarkable ARI potential compared with that of other substitutions on the aromatic ring. Molecular docking experiments demonstrated that the most active curcuminoid (10g) was able to favorably bind in the active site of the AR enzyme. The potent ARI activities exhibited by the curcuminoids were attributed to their substitution patterns on the aromatic moiety, which may provide novel leads in the development of therapeutics for the treatment of diabetic complications.

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

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Mutiu Idowu Kazeem ◽  
Ayotomiwa Adeyinka Adeyemi ◽  
Abiola Fatimah Adenowo ◽  
Mushafau Adewale Akinsanya
Keyword(s):  
Aldose Reductase ◽  
Aqueous Extract ◽  
Diabetic Complications ◽  
Carica Papaya ◽  
Citrullus Lanatus ◽  
Polyol Pathway ◽  
Inhibitory Effect ◽  
Sorbitol Dehydrogenase ◽  
Diabetic Foot Disease ◽  
Foot Disease

Abstract Background Diabetes 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). Results All 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. Conclusion Aqueous 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.

scholarly journals Glycation and inactivation of sorbitol dehydrogenase in normal and diabetic rats

1996 ◽  
Vol 318 (1) ◽  
pp. 119-123 ◽  
Author(s):  
Ayumu HOSHI ◽  
Motoko TAKAHASHI ◽  
Junichi FUJII ◽  
Theingi MYINT ◽  
Hideaki KANETO ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Diabetic Complications ◽  
Polyol Pathway ◽  
Diabetic Rats ◽  
Sorbitol Dehydrogenase ◽  
Enzyme Content ◽  
Glycated Protein ◽  
Liver And Kidney

Sorbitol dehydrogenase (SDH) is involved in the polyol pathway, which plays an important role in the pathogenesis of diabetic complications. We have measured the tissue distributions of SDH mRNA, both the immunoreactive enzyme levels and the enzyme activity. SDH mRNA was especially abundant in liver, kidney and testis. Both the activity and enzyme content are high in liver and kidney but not in testis. The discrepancy between mRNA and immunoreactive enzyme levels and the activity of SDH observed in testis was also seen in livers of streptozotocin-induced diabetic rats. SDH was found to exist in both glycated and non-glycated forms, with larger amounts of the glycated protein in the diabetic liver. Moreover, after incubation of purified enzyme with glucose or fructose, its activity was markedly decreased. These results indicate that glycation causes a decrease in SDH activity in liver under diabetic conditions. The same post-transcriptional event might occur to decrease the activity of SDH in testis in normal animals.

scholarly journals Molecular Docking Evaluation of Some Natural Phenolic Compounds as Aldose Reductase Inhibitors for Diabetic Complications

2017 ◽  
Vol 5 (2) ◽  
pp. 135-148 ◽  
Author(s):  
Ajmer Singh Grewal ◽  
Neelam Sharma ◽  
Sukhbir Singh ◽  
Sandeep Arora
Keyword(s):  
Molecular Docking ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Binding Free Energy ◽  
Docking Study ◽  
Polyol Pathway ◽  
Binding Modes ◽  
Active Site Residues ◽  
Molecular Docking Study ◽  
Natural Phenols

The enzyme aldose reductase (AR) is a member of aldoketoreductase super-family which catalyzes the formation of sorbitol from glucose through polyol pathway of glucose catabolism. Reduced sorbitol production via polyol pathway due to AR inhibition is a target of choice for controlling major complications of diabetes. Epalrestat is the only commercially available inhibitor of AR till date,thus, there is a great need to search for more economical, nontoxic and safer inhibitors of AR enzyme. Flavonoids,the polyphenol compounds in plants have been reported for inhibitory effects against AR. The objective of this study is to explore the binding modes of naturalphenolic compounds with AR to design safer natural drugs as alternatives to synthetic drugs. We conducted a molecular docking study on some naturalphenolic compounds with AR enzyme in complex with the synthetic inhibitor. The overlay of the docked pose of the selected natural phenols with the ARreference inhibitor complex showed that the selected natural compounds have the similar binding pattern with the active site residues of the enzyme as that of co-crystallized inhibitor. The results of docking study showed the best binding affinity of AR with that of 2-(4-hydroxy-3-methoxyphenyl) ethanoic acid and butein, having the lowest binding free energy of –9.8 kcal/mol and–9.7 kcal/mol, respectively. This information can be utilized to design potent, economical and non-toxic natural AR inhibitors from natural phenols for the therapeutics of diabetic complications.

Sorbinil, an Aldose Reductase Inhibitor, in Fighting Against Diabetic Complications

2019 ◽  
Vol 15 (1) ◽  
pp. 3-7 ◽  
Author(s):  
Qi Huang ◽  
Qiong Liu ◽  
Dongsheng Ouyang
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Polyol Pathway ◽  
Review Article ◽  
Global Public Health ◽  
Model Studies ◽  
Human Use ◽  
Pathway Inhibition

Background: Aldose reductase (AR) is involved in the pathogenesis of diabetes, which is one of the major threats to global public health. Objective: In this review article, we have discussed the role of sorbinil, an AR inhibitor (ARI), in preventing diabetic complications. Results: AR contributes in diabetes by generating excess intracellular superoxide and other mediators of oxidative stress through polyol pathway. Inhibition of AR activity thus might be a potential approach for the management of diabetic complications. Experimental evidences indicated that sorbinil can decrease AR activity and inhibit polyol pathway. Both in vitro and animal model studies reported the efficacy of sorbinil in controlling the progression of diabetes. Moreover, Sorbinil has been found to be comparatively safer than other ARIs for human use. But, it is still in earlyphase testing for the treatment of diabetic complications clinically. Conclusion: Sorbinil is an effective ARI, which could play therapeutic role in treating diabetes and diabetic complications. However, advanced clinical trials are required for sorbinil so that it could be applied with the lowest efficacious dose in humans.

scholarly journals Rhodanine-3-acetamide derivatives as aldose and aldehyde reductase inhibitors to treat diabetic complications: synthesis, biological evaluation, molecular docking and simulation studies

BMC Chemistry ◽  
2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Mohsinul Mulk Bacha ◽  
Humaira Nadeem ◽  
Sumera Zaib ◽  
Sadia Sarwar ◽  
Aqeel Imran ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Molecular Docking ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Active Sites ◽  
Polyol Pathway ◽  
Biological Evaluation ◽  
Aldehyde Reductase ◽  
Standard Drug

AbstractIn diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a–g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a–g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall, the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2. The binding site analysis of potent compounds revealed similar interactions as were found by cognate ligands within the active sites of enzymes.

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

2020 ◽  
Vol 21 (14) ◽  
pp. 1091-1116
Author(s):  
Ajmer Singh Grewal ◽  
Komal Thapa ◽  
Neha Kanojia ◽  
Neelam Sharma ◽  
Sukhbir Singh
Keyword(s):  
Diabetic Complications ◽  
Polyol Pathway ◽  
Natural Compounds ◽  
Review Article ◽  
Low Permeability ◽  
Herbal Extracts ◽  
Pharmacological Agents ◽  
Pharmaceutical Industries ◽  
Crucial Part ◽  
Natural Inhibitors

Background: 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. Objective: 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. Results: 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. Conclusion: 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.

scholarly journals The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient

2007 ◽  
Vol 2007 ◽  
pp. 1-10 ◽  
Author(s):  
Mara Lorenzi
Keyword(s):  
Diabetic Retinopathy ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Polyol Pathway ◽  
New Drugs ◽  
Reductase Gene ◽  
Attractive Candidate ◽  
Rate Limiting ◽  
Intracellular Glucose

The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of polyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered.

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