Aldose Reductase Research Articles

Effect of Various Solvents Extraction on the Antioxidant and Aldose Reductase Inhibition Activities of the Tamarind Leaves (Tamarindus indica L.)

Diabetes and its complications are major causes of illness and death all over the world. Present study aimed to evaluate the effect of varying polarity solvents on the extraction of tamarind leaves antioxidant polyphenols and in vitro aldose reductase inhibition. In all the extracts, total phenol, total flavonoids, antioxidant activities, and in vitro aldose reductase inhibition activity were measured. Distilled water extract had the highest phenolic content, flavonoid content, DPPH-RSA, ABTS-RSA, and aldose reductase inhibition among all the extracts while the aqueous methanol extract showed the highest FRAP value among all the extracts. A positive Pearson’s correlation existed between total polyphenol content and antioxidant activities. Significant Pearson’s correlation was found between aldose reductase and polyphenol compounds. Overall, distilled water was the most effective solvent for polyphenol extraction and had the highest aldose reductase inhibition of all the tamarind leaves solvents. Thus, tamarind leaves can be used as nutraceuticals to show beneficial effects to minimize diabetic secondary complications.

Pharmacophore derived 3D-QSAR, molecular docking, and simulation studies of quinoxaline derivatives as ALR2 inhibitors

Aldose Reductase 2 (ALR2), a key enzyme of the polyol pathway, plays a crucial role in the pathogenesis of diabetic complications. Quinoxaline scaffold-based compounds have been identified as potential ALR2 inhibitors for the management of diabetic complications. In the present work, molecular dynamic simulation studies in conjugation with pharmacophore mapping and atom-based 3D-QSAR were performed on a dataset of 99 molecules in comparison with Epalrestat (reference) to mark the desirable structural features of quinoxaline analogs to generate a probable template for designing novel and effective ALR2 inhibitors. The most potent compound 81 was subjected to MD simulation studies and found to be stable, with better interactions with the binding pocket as compared to Epalrestat. The MM-GBSA and MM-PBSA calculations showed that compound 81 possessed binding free energies of −35.96 and −4.92 kcal/mol, respectively. Atom-based 3D-QSAR yielded various pharmacophoric features with excellent statistical measures, such as correlation coefficient (R 2 value), F-value (Fischer ratio), Q 2 value (cross-validated correlation coefficient), and Pearson’s R-value for training and test sets. Furthermore, the pharmacophore mapping provided a five-point hypothesis (AADRR) and docking analysis revealed the active ligand-binding orientations on the active site’s amino acid residues TYR 48, HIE 110, TRP 111, and TRP 219. The results of this study will help in designing potent inhibitors of ALR2 for the management of diabetic complications. Communicated by Ramaswamy H. Sarma

APPA Increases Lifespan and Stress Resistance via Lipid Metabolism and Insulin/IGF-1 Signal Pathway in Caenorhabditis elegans.

Animal studies have proven that 1-acetyl-5-phenyl-1H-pyrrol-3-yl acetate (APPA) is a powerful antioxidant as a novel aldose reductase inhibitor independently synthesized by our laboratory; however, there is no current information on APPA's anti-aging mechanism. Therefore, this study examined the impact and mechanism of APPA's anti-aging and anti-oxidation capacity using the Caenorhabditis elegans model. The results demonstrated that APPA increases C. elegans' longevity without affecting the typical metabolism of Escherichia coli OP50 (OP50). APPA also had a non-toxic effect on C. elegans, increased locomotor ability, decreased the levels of reactive oxygen species, lipofuscin, and fat, and increased anti-stress capacity. QRT-PCR analysis further revealed that APPA upregulated the expression of antioxidant genes, including sod-3, gst-4, and hsp-16.2, and the critical downstream transcription factors, daf-16, skn-1, and hsf-1 of the insulin/insulin-like growth factor (IGF) receptor, daf-2. In addition, fat-6 and nhr-80 were upregulated. However, the APPA's life-prolonging effects were absent on the daf-2, daf-16, skn-1, and hsf-1 mutants implying that the APPA's life-prolonging mechanism depends on the insulin/IGF-1 signaling system. The transcriptome sequencing also revealed that the mitochondrial route was also strongly associated with the APPA life extension, consistent with mev-1 and isp-1 mutant life assays. These findings aid in the investigation of APPA's longevity extension mechanism.

Intriguing Thiazolidinediones as PPAR γ Agonists: A Review

Diabetes mellitus is a chronic metabolic disorder marked by persistently elevated blood sugar levels. left untreatedover a long duration can cause multiple body disorders and may cause a person's early death. Though a traditional disorder, typeII diabetes prevalence is increasing daily, especially in the adolescent population worldwide. Peroxisome proliferator-activatedreceptor (PPAR) is a group of receptors consisting of three isoforms (PPAR α, PPAR β/δ, and PPAR γ. PPAR γ is involved inglucose metabolism by facilitating insulin's actions. Thiazolidinedione is a heterocyclic moiety standing pre-eminent in treatingdiabetes mellitus as a PPAR Gamma activator. Thiazolidinedione is a five-membered heterocyclic organic compound, athiazolidine derivative consisting of two carbonyl groups at positions 2 and 4 of the thiazolidine ring. Thiazolidinediones possessan idiosyncratic scaffold featuring a hydrogen bond acceptor region and hydrogen bond donating region at the third and fifthpositions. Thiazolidinedione is an indispensable pharmacophore with many pharmacological activities like antiproliferative,antiviral, antibacterial, tyrosine kinase inhibitory, aldose reductase inhibitory, alpha-glucosidase inhibitory, anti-inflammatory,antioxidant, antitubercular, antihyperlipidemic, etc. Many drugs have been introduced but later have been reticent because ofserious side effects like liver toxicity, CVS toxicity, etc. Pioglitazone and Rosiglitazone have been marketed medications fortreating type II diabetes. This review article deliberates all the cardinal points of thiazolidinediones as PPAR agonists in treatingdiabetes mellitus, which were precluded in some articles. We aim to have an all-embracing review of thiazolidinediones as PPARgamma agonists. The review's objective is to inspire researchers to develop a more superior, secure, and efficient anti-diabeticmedication by thoroughly understanding the molecular mechanisms of thiazolidinediones at the PPAR gamma receptors, theirrisks, and the effect of the various substitutions on the thiazolidinedione.

The role of aldose reductase in polyol pathway: An emerging pharmacological target in diabetic complications and associated morbidities.

The expression of aldose reductase leads to a variety of biological and pathological effects. It is a multifunctional enzyme which has a tendency to reduce aldehydes to the corresponding sugar alcohol. In diabetic conditions, the aldose reductase enzyme converts glucose into sorbitol using nicotinamide adenine dinucleotide phosphate as a cofactor. It is a key enzyme in polyol pathway which is a surrogate course of glucose metabolism. The polyol pathway has a significant impact on the aetiology of complications in individuals with end-stage diabetes. The exorbitant level of sorbitol leads to the accumulation of intracellular reactive oxygen species in diabetic heart, neurons, kidneys, eyes and other vasculatures, leading to many complications and pathogenesis. Recently, the pathophysiological role of aldose reductase has been explored with multifarious perspectives. Research on aldose reductase suggest that besides implying in diabetic complications, the enzyme also turns down the lipid-derived aldehydes as well as their glutathione conjugates. Although aldose reductase has certain lucrative role in detoxification of toxic lipid aldehydes, its overexpression leads to intracellular accumulation of sorbitol which is involved in secondary diabetic complications, such as neuropathy, cataractogenesis, nephropathy, retinopathy and cardiovascular pathogenesis. Osmotic upset and oxidative stress are produced by aldose reductase via the polyol pathway. The inhibition of aldose reductase alters the activation of transcription factors like NF-ƙB. Moreover, in many preclinical studies, aldose reductase inhibitors have been observed to reduce inflammation-related impediments, such as asthma, sepsis and colon cancer, in diabetic subjects. Targeting aldose reductase can bestow a novel cognizance for this primordial enzyme as an ingenious strategy to prevent diabetic complications and associated morbidities. In this review article, the significance of aldose reductase is briefly discussed along with their prospective applications in other afflictions.

Computational Analysis of ZINC Analogues for Antidiabetic Phytochemical with Inhibitory Activity against Aldose Reductase Enzyme

The pathognomonic role of sorbitol pathway in the development of microvascular complications cannot go underappreciated; while it may not be a sole independent initiator, it remains a key contributor to the initiation and progression of diabetic microangiopathies, particularly retinopathy, neuropathy, and nephropathy. The sorbitol pathway is a two-step reaction process initiated by the rate-limiting enzyme aldose reductase. This study aimed to screen ZINC databases for chemical compounds similar to Ellagic acid, Kaempferol, and Mangiferin and analyze their pharmacokinetic, toxicological and docking profile using computational methods. These phytochemicals were chosen based on literature review of ethnobotanical studies and validated via SwissTargetPrediction. An in-silico study design was employed using computational algorithms. Molecular structures of analogues were obtained from ZINC database and prepared using Avogadro software. Docking analysis was carried out using AutoDock Vina embedded in Chimera. Visualization of ligand-enzyme interactions was done using Discovery studio. SWISSADME and Protox-II were used to profile pharmacokinetic and toxicity of the analogs. A total of 44 analogs were analyzed. Sulindac and parent phytochemicals were used as comparators. Kaempferol had strongest binding affinity (-8.7) followed by Ellagic acid and Mangiferin tying at -8.4. Kaempferol analogs had highest binding affinity compared to analogues of Ellagic acid and Mangiferin. In terms of Pharmacokinetic profile, analogues of Ellagic acid demonstrated a favorable profile with no Lipinski rule violations, high GI absorption, and inhibition limited to CYP1A2, which plays a minor role in drug metabolism compared to other enzymes. Toxicology predictions indicated that Kaempferol exhibited a higher safety profile compared to Ellagic acid and Mangiferin, with LD50 values of 3919 mg/kg, 2991 mg/kg, and 2 mg/kg, respectively. Ellagic acid analogues demonstrated chemical safety, absence of mutagenicity, hepatotoxicity, cytotoxicity, and activation of various pathways. Among the Kaempferol analogues, a subset was potentially carcinogenic and mutagenic, while all exhibited potential pathway activation. Mangiferin analogues, except for a few compounds, did not activate specific pathways, nor did they demonstrate hepatotoxicity or cytotoxicity. However, some analogues exhibited potential immunogenicity and mutagenicity. Kaempferol and some of its ZINC analogues had strongest binding affinity compared to Ellagic acid, Mangiferin and their analogues. This can be attributed to the simpler structure of Kaempferol, allowing it to fit snugly into the hydrophobic pocket of aldose reductase. Ellagic acid, with its planar and rigid structure, interacted primarily with the outer surface of the hydrophobic pocket. Similarly, due to its complex and large structure, Mangiferin demonstrated a relatively lower affinity. Analogues ZINC000005004393, ZINC000003872446, and ZINC000031156069 for Kaempferol, Ellagic acid, and Mangiferin respectively depicted the best optimal characteristics required for further development. We recommend an in vitro study be conducted to assess and validate the claims arrived at in this study

Biological Potential of Kakkalide in medicine for the Treatment of Human disorders: An Overview of Pharmacological aspects.

Pueraria lobata is an important herbal medicine of Fabaceae family that has been clinically used in Traditional Chinese Medicine to counteract human disorders and associated secondary complications. Kakkalide also called irisolidone 7-xylosylglucoside is an isoflavonoid of Puerariae flos, Pueraria lobata and Flos Puerariae. Moreover, Kakkalide has a wide range of bioactivities in medicine. Biological potential of kakkalide was investigated in the present work through scientific data analysis of different scientific research work on kakkalide in order to know its therapeutic potential in medicine. Scientific data on Pueraria lobata were collected and analyzed in the present work. All the scientific data were collected from Google, Google Scholar, Scopus, and Science Direct in the present work. Scientific data analysis of kakkalide revealed its biological importance and therapeutic potential in medicine. The present investigation signified kakkalide's effectiveness in inflammatory diseases, prostaglandin E2 production, liver complication, gastric injury, alcoholism, insulin-resistant endothelial dysfunction, aldose reductase enzyme, hyperlipidemia, estrogenic activity, and stroke. In addition, the bioavailability of kakkalide was also discussed in the present paper. Present work also revealed the significance of analytical techniques for the separation, isolation and identification of kakkalide in different biological and non-biological samples. Present paper signified the health-beneficial aspects of kakkalide in medicine.

Astragalin attenuates diabetic cataracts via inhibiting aldose reductase activity in rats.

To investigate the aldose reductase (AR) inhibition capacity of astragalin (AST) against streptozoticin-induced diabetic cataracts (DCs) in rats. Ex vivo investigations were conducted by treating the lens of a goat placed for 72h in artificial aqueous humor (AAH) of pH 7.8 at room temperature with cataract-causing substance (55 mmol/L of galactose) and in vivo studies were performed on rats via induction with streptozotocin. AST was administered at different dose levels and scrutinize for DC activity. In diabetic rats, AST improved the body weight, blood insulin, and glucose as well as the levels of galactitol in a dose-dependent way, other biochemical parameters i.e. inflammatory mediators and cytokines, and also suppress AR activity. The level of the antioxidant parameters such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activity were also altered on a diabetic lens after the administration of the AST. AST protects against lens opacification to avoid cataracts and polyols formation, indicating that it could be used as a potential therapeutic agent for diabetes.

Network pharmacology based anti-diabetic attributes of bioactive compounds from Ocimum gratissimum L. through computational approach

The present research was framed to determine the key compounds present in the plant Ocimum gratissimum L. targeting protein molecules of Diabetes Mellitus (DM) by employing In-silico approaches. Phytochemicals previously reported to be present in this herb were collated through literature survey and public phytochemical databases, and their probable targets were anticipated using BindingDB (p ≥ 0.7). STRING and KEGG pathway databases were employed for pathway enrichment analysis. Homology modelling was executed to elucidate the structures of therapeutic targets. Further, Phytocompounds from O. gratissimum were subjected for docking with four therapeutic targets of DM by using AutoDock vina through POAP pipeline implementation. 30 compounds were predicted to target 136 protein molecules including aldose reductase, DPP4, alpha-amylase, and alpha-glucosidase. Neuroactive ligand-receptor interaction, MAPK, PI3K-Akt, starch and insulin resistance were predicted to have potentially modulation by phytocompounds. Based on the phytocompound’s binding score with the four targets of DM, Rutin scored the lowest binding energy (-11 kcal/mol) with Aldose reductase by forming 17 intermolecular interactions. In conclusion, based on the network and binding score, phytocompounds from O. gratissimum have a synergistic and considerable effect in the management of DM via multi-compound, multi-target, and multi-pathway mechanisms.

Abstract P3086: Aldose Reductase Deletion Protects Ischemic Murine Hearts By Modulating Immune Cell Dynamics

Cardiac injury remains a major cause of death worldwide. Previous studies have demonstrated that chronic unchecked inflammation, during post ischemic reperfusion, adversely affects adaptive repair and augments tissue damage. Nature of the infiltrating immune cells determines the extent of repair vs exacerbation of tissue damage during post myocardial ischemia. Understanding mechanisms by which ischemia-mediated inflammatory responses exacerbate tissue damage and mitigate repair pathways are vital to discover therapeutics for myocardial infarction. Our earlier studies demonstrated that aldose reductase (AR) is a key mediator of myocardial ischemia-reperfusion (I/R) injury. Specifically, it established that cardio myocyte AR drives metabolic and signalling mechanisms leads to injury and impaired function in hearts. In this study we investigated the role of AR in influencing time dependent changes in recruitment of immune cells, during in vivo myocardial I/R injury. AR knockout (ARKO) and littermate controls (WT) mice were subjected to LAD sugery followed by reperfusion ( In vivo I/R) and the temporal changes in recruitment of immune cells were determined at earlier (day 3) and later (day 7) time points. We found ablation of AR leads to significant (p<0.0001) cardiac protection during post I/R in mice. Cardiac function measurements revealed greater recovery of ejection fraction and fractional shortening after I/R in ARKO vs WT hearts (p<0.05). Deletion of AR leads to a significant (p =0.0053) reduction in T cells infiltration post I/R in the heart. We observed 2-fold reduction in CD8+ cells, and 2-fold increase in CD4+ cells in ARKO vs WT mice hearts post I/R injury. Specifically, 2-fold reduction in pro-inflammatory Th1, Th2 and Th17 cells and 3-fold increases in anti-inflammatory Treg cells (p = 0.0091) were observed in ARKO vs WT hearts at post I/R injury. In addition, we observed reduction in infiltration of pro-inflammatory macrophages, dendritic cells, and B cells in ARKO vs WT hearts post I/R. Taken together, our data suggests that deletion of AR protects I/R hearts by promoting increases in anti-inflammatory immune cells and paves the way for addressing immune cell-cardiomyocyte crosstalk mechanisms by which AR deletion protects from I/R injury.

Novel thiazolidinedione (TZD) scaffolds as aldose reductase inhibitors, synthesis and molecular docking studies

A series of Thiazolidinedione (TZD) scaffold libraries 6(a-o) and 7(a-o) were synthesized and confirmed their structures by interpretation of FTIR, 1H NMR, 13C NMR and Mass spectroscopic investigations. They were screened for the inhibitory activity against aldose reductase enzyme. The intermediates 6(a-o) with ester moiety series showed potent antidiabetic activity. Further, conversion of ester 6(a-o) into acids 7(a-o) showed additional increase in the antidiabetic activity ranging from 0.24 ± 0.34 to 2.38 ± 0.76 µM with respect to the standard drug Sorbinil 2.01 ± 0.25 µM. The molecular docking studies performed against the crystal structure of aldose reductase (PDB ID: 1PWM) well defined the binding interactions compounds with notable docking scores, in which compounds 6g, 6h and 7h showed good hydrogen bonding interactions and 7h showed highest docking score.

The Aqueous Stem Bark Extract of Alstonia boonei Exhibits Anticataract Activity in Sprague Dawley Rat.

In Africa, Alstonia boonei is used folklorically for the management of the multitude of conditions including cataract, which accounts for 50% of cases of blindness in the region. The current study set out to probe the traditional use of the aqueous extract of Alstonia boonei stem bark (ABE) as an anticataract remedy using Sprague Dawley rat models. We investigated the probable phytochemical constituents in the extract, in vitro antioxidant potential, and its in vitro aldose reductase inhibition. For the anticataract investigations, diabetic cataract was induced using galactose in 3-week-old Sprague Dawley rats, and age-related cataract was induced by the administration of sodium selenite to 10-day-old rat pups. Cataract scores in both models were determined after treatment with 30, 100, and 300 mgkg-1 doses of ABE and 10 mlkg-1 of distilled water. Lens glutathione, total lens protein, soluble lens proteins (alpha-A) crystallin, and aquaporin 0 levels in the enucleated lens homogenates were determined. Changes in lens to body weight were also determined with histopathological analysis done on the lenses in the selenite-induced cataract model. The presence of alkaloids, tannins, flavonoids, glycosides, and triterpenoids was identified in the extract. The extract inhibited aldose reductase activity with IC50 of 92.30 μgml-1. The 30, 100, and 300 mgkg-1ABE-treated rats recorded significantly (p < 0.05) reduced cataract scores indicating a delay in cataractogenesis in galactose-induced cataract and in selenite-induced cataractogenesis as well. Markers of lens transparency such as AQP0, alpha-A crystallin, and total lens proteins and lens glutathione levels were significantly (p < 0.05) preserved. In conclusion, this study establishes the anticataract potential of the aqueous stem bark extract of Alstonia boonei in Sprague Dawley rat models.

Molecular Docking and Pharmacokinetic Prediction of Potential Compounds from Luffa acutangula as Antidiabetic Candidates

Luffa acutangula is commonly used, but its considerable potential as an alternative treatment for diabetics with a molecular target action is not yet known. Preliminary study of bioinformatics to decipher the compounds of L. acutangulaable to interact with the protein targets of antidiabetic therapy. This study aims to identify the potential compounds of L. acutangula that are thought to interact with the insulin receptor, aldose reductase, and PTP-1B, as well as provide predictions of pharmacokinetics and toxicity. Molecular docking was conducted in AutoDock 4.2.6 with the stages initiated by the preparation of macromolecules (PDB ID: 1IR3; 2PEV; 4Y14) and ligands, molecular docking, and visualization. The pharmacokinetic profiles are predictable by using the Swiss ADME and toxicity estimates by Toxtree. The results showed that cucurbitacin B, cucurbitacin E, oleanolic acid, catechin, ferulic acid and apigenin are the most potential compounds to interact with the macromolecular with a binding energy response similar to the native ligand. Pharmacokinetic predictions show that cucurbitacin B and cucurbitacin E deviate from one Lipinski rule (BM&gt; 500), do not diffuse into the blood brain barrier, are not CYP450 inhibitors, as well as classified as Pgp substrates. The prediction of toxicity indicates that all potential compounds are classified as high toxicity compounds with a risk of narcosis, except oleanolic acid and ferulic acid. These compounds are not genotoxic or non-genotoxic carcinogens.

Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.

Araucaria heterophylla oleogum resin essential oil is a novel aldose reductase and butyryl choline esterase enzymes inhibitor: in vitro and in silico evidence

The essential oil isolated by hydrodistillation of the oleogum resin of Araucaria heterophylla has been analyzed by GC–MS. Twenty-four components accounting to 99.89% of the total detected constituents of this essential oil were identified. The major ones were: caryophyllene oxide (14.8%), ( +)-sabinene (12.07%), D-limonene (11.22%), caryophyllene (10.36%), α-copaene (8.00%), β-pinene (6.44%), trans-verbenol (5.88%) and α-pinene oxide (5.18%). The in vitro inhibitory activities of this oil against aldose reductase, BuCHE, COX-2 and SARS-CoV-2 Mpro enzymes were evaluated. This revealed promising inhibitory activity of the essential oil against both aldose reductase and BuCHE enzymes. The molecular docking study of the major components of the Araucaria heterophylla essential oil was carried out to correlate their binding modes and affinities for aldose reductase and BuCHE enzymes with the in vitro results. In conclusion, the in vitro inhibitory activity of the essential oil attributed to the synergistic effect between its components and the in silico study suggested that compounds containing epoxide and hydroxyl groups may be responsible for this activity. This study is preliminary screening for the oil to be used as antidiabetic cataract and Alzheimer’s disease therapeutics and further investigations may be required.

Biochemical Analysis and Human Aldose Reductase Inhibition Activity of Selected Medicinal Plants of Nepal

Aldose reductase has received extensive research as a key enzyme in the development of long-term problems linked to diabetes mellitus. Overexpression of this enzyme or with exceeded glucose concentration in the blood increases sorbitol on the retina leading to retinopathy, which is the adverse effect of type II diabetes. Approximately 100 million people are suffering from diabetic retinopathy globally. This research is focused on studying the total phenolic content (TPC), total flavonoid content (TFC), antioxidant potential, and aldose reductase inhibiting properties of selected medicinal plants such as Anacyclus pyrethrum, Bergenia ciliata, Rhododendron arboreum, and Swertia chirayita. In addition, ADMET analysis and molecular docking of seven previously identified compounds from the chosen medicinal plants were carried out against human aldose reductase (PDB ID: 4JIR). The ethanol extract of S. chirayita exhibited the highest TPC (4.63 ± 0.16 mg GAE/g) and TFC (0.90 ± 0.06 mg QE/g). Analysis of 2,2-diphenyl-1-picrylhydrazyl (DPPH)-based antioxidant assay showed that IC50 of the ethanolic extract of B. cilata and R. arboreum showed a significant antioxidant activity with IC50 value of 0.05 mg/mL. The percentage inhibition of AR by extract of B. ciliata (94.74 ± 0.01%) was higher than other plant extracts. A molecular docking study showed that morin isolated from B. ciliata showed a good binding interaction with AR. This study showed that the extracts of A. pyrethrum, B. ciliata, and R. arboreum could be potential sources of inhibitors against AR to treat retinopathy.

Mutational Studies of Aldose Reductase to Trace a Transient Pocket Opening and to Explain Ligand Affinity Cliffs.

Human aldose reductase, a target for the development of inhibitors for preventing diabetic complications, displays a transient specificity pocket which opens upon binding with specific, potent inhibitors. We investigated the opening mechanism of this pocket by mutating leucine residues involved in the gate keeping mechanism to alanine. Two isostructural inhibitors distinguished only by a single nitro to carboxy group replacement, have a 1000-fold difference in their binding affinity to the wild type. This difference is reduced to 10-fold in the mutated variants as the nitro derivative loses in affinity but conserves binding to the open transient pocket. The affinity of the carboxylate analog is minimally altered but the analog binding preference changes from the closed to open state of the transient pocket. Differences in the solvation properties of ligands and the transient pocket as well as changes from induced fit to conformational selections provide an explanation for the altered behavior of the ligands with respect to their binding to the different variants.

Aldose reductase and glutathione in senile cataract nucleus of diabetics and non-diabetics

PurposeThe aim is to evaluate the aldose reductase (AR) and glutathione (GSH) activity in the nucleus of senile cataract in type 2 diabetes and non-diabetic group of patients.MethodsA total of 62 patients including 31 diabetics and 31 non- diabetics who were undergoing cataract surgery were included. Nucleus extracted was sent for analysis of AR and GSH activity while blood sample was taken for glycated haemoglobin (HbA1c) levels.Statistical analysisData were analysed using IBM SPSS 25. Comparison was carried out by unpaired T-test and correlations were established by Pearson’s correlation. The p value less than 0.05 was considered significant for all analyses.Study designThis is a prospective cross-sectional comparative study.ResultsIn this study, diabetic group patients showed earlier progression of cataract as compared to the non-diabetic group (p-value 0.0310). Mean HbA1c in the diabetic group was 7.34% compared to the non-diabetic group of 5.7% (p value < 0.001). AR in the diabetic patients was 2.07 mU/mg while the non-diabetic group was 0.22 mU/mg (p-value < 0.001). GSH in the diabetic group was 3.38 μMol/g and the non-diabetic group was 7.47 μMol/g (p value < 0.001). HbA1c showed positive correlation with AR among the diabetic group (p-value 0.028).ConclusionElevated oxidative stress can be strongly attributed to high AR and low GSH activity among the diabetic group as compared to the non-diabetic group and can lead to early cataract formation.

Inhibitory effect of Nifedipine on aldose reductase delays cataract progression.

Aldose reductase (ALR2) is a rate-limiting component of the polyol pathway, which is essential for the NADPH-mediated conversion from glucose to sorbitol. ALR2 dysregulation has been linked to α-crystallin aggregation, increased oxidative stress, and calcium inflow, all of which contribute to a diabetic cataract. Given its crucial role in occular pathologies, ALR2 has emerged as a promising target to treat oxidative stress and hyperglycaemic condition which form the underlying cause of diabetic cataracts. However, several of them had issues with sensitivity and specificity to ALR2, despite being screened as effective ALR2 inhibitors from a wide range of structurally varied molecules. The current study investigates the inhibitory potential of Nifedipine, an analog of the dihydro nicotinamide class of compounds against ALR2 activity. The enzyme inhibition studies were supported by in vitro biomolecular interactions, molecular modeling approaches, and in vivo validation in diabetic rat models. Nifedipine demonstrated appreciable inhibitory potential with the purified recombinant hAR (human aldose reductase; with an IC50 value of 2.5µM), which was further supported by Nifedipine-hAR binding affinity (Kd = 2.91 ± 1.87 × 10-4M) by ITC and fluorescence quenching assays. In the in vivo models of STZ-induced diabetic rats, Nifedipine delayed the onset progression of cataracts by preserving the antioxidant enzyme activity (SOD, CAT, and GPX GSH, TBARS, and protein carbonyls) and was shown to retain the α-crystallin chaperone activity by reducing the calcium levels in the diabetic rat lens. In conclusion, our results demonstrate effective inhibition of ALR2 by Nifedipine, resulting in amelioration of diabetic cataract conditions by lowering oxidative and osmotic stress while retaining the chaperone activity of α-crystallins. The present study could be envisaged to improve the eye condition in older adults upon Nifedipine treatment.

Cheminformatics identification of modulators of key carbohydrate-metabolizing enzymes from C. cujete for type-2 diabetes mellitus intervention

PurposeThe therapeutic use of oral hypoglycaemic agents in the management of type-2 diabetes mellitus (T2DM) is without adverse effects; thus, calls for alternative and novel candidates from natural products in medicinal plants.MethodThe study explored molecular docking and molecular dynamics (MD) simulation approaches to identify key antidiabetic metabolites from Crescentia cujete.ResultsMolecular docking results identified four and/or five best compounds against each target enzyme (alpha-glucosidase, dipeptidyl peptidase-IV, aldose reductase, and protein tyrosine phosphatase-1B (PTP-1B)) implicated in diabetes. The resulting complexes (except against PTP-1B) had higher docking scores above respective standards (acarbose, Diprotin A, ranirestat). The MD simulation results revealed compounds such as benzoic acid (-48.414 kcal/mol) and phytol (-45.112 kcal/mol) as well as chlorogenic acid (-42.978 kcal/mol) and naringenin (-31.292 kcal/mol) had higher binding affinities than the standards [acarbose (-28.248 kcal/mol), ranirestat (-21.042 kcal/mol)] against alpha-glucosidase and aldose reductase, respectively while Diprotin A (-45.112 kcal/mol) and ursolic acid (-18.740 kcal/mol) presented superior binding affinities than the compounds [luteolin (-41.957 kcal/mol and naringenin (-16.518 kcal/mol)] against DPP-IV and PTP-1B respectively.ConclusionWhile isoflavone (alpha-glucosidase), xylocaine (DPP-IV), luteolin (aldose reductase,) and chlorogenic acid (PTP-1B) were affirmed as the best inhibitors of respective enzyme targets, luteolin, and chlorogenic acid may be suggested and proposed as probable candidates against T2DM and related retinopathy complication based on their structural stability, compactness and affinity for three (DPP-IV, aldose reductase, and PTP-1B) of the four targets investigated. Further studies are warranted in vitro and in vivo on the antihyperglycaemic effects of these drug candidates.