Aldose Reductase Inhibitory Activity Research Articles

Antidiabetic and aldose reductase inhibitory activity and LC-MS/MS compositional polyphenol determination of aqueous extract of Ammodaucus leucotrichus fruits

This study's objective was to examine the antidiabetic effect of the aqueous extract of Ammodaucus leucotrichus Coss. (AEAL) in diabetic rats, its aldose reductase inhibitory activity, as well as identify its major phytochemical components using LC-MS. Rats were divided into five groups: normal and diabetic control groups, three diabetic groups received 150 and 300 mg/kg of AEAL and metformin (150 mg/kg) per day for 4 weeks. Blood glucose, body weight, urinary volume, daily food consumption, water intake, hepatic glycogen, catalase, malondialdehyde. After the experimental period, the rats were sacrificed to collect blood for biochemical analysis (level of creatinine, uric acid, alanine aminotransferase, aspartate aminotransferase, triglycerides, and cholesterol). Moreover, AEAL was tested against aldose reductase, in vitro. Phytochemical analysis of the AEAL revealed a rich composition and especially high amounts of phenolic acid. The administration of the AEAL significantly reduced glycemia, triglycerides, alanine aminotransferase, aspartate aminotransferase, creatinine, uric acid, and increased the amount of hepatic glycogen. In addition, AEAL decreased urinary volume per day, induced body weight gain in diabetic rats, and inhibited aldose reductase activity.

Aldose Reductase and Protein Glycation Inhibitory Activity of Dark Chocolate-Assisted Zinc Oxide Nanoparticles.

Introduction One of the most common health issues that the global population is dealing with is the associated complications of diabetes, which encompasses cataracts, peripheral neuropathy, vascular damage, impaired wound healing, retinal issues, and arterial wall stiffening. The present study is aimed to evaluate the effect of dark chocolate and its assisted zinc oxide nanoparticles against diabetes-associated complications. Materials and methods Zinc oxide nanoparticles were synthesized using commercially dark chocolate (DC-ZnO NP). The synthesized DC-ZnO NPs were evaluated against recombinant aldose reductase (AR) activity and the formation of advanced glycation end products (AGEs). Aminoguanidine and gallic acid were used as reference standards for AGE assay and sorbitol accumulation inhibition, respectively. Results The results of the present study showed that green synthesized DC-ZnO NP had a significant dose-dependent inhibitory activity on both AR and AGEs. The inhibitory activity was compared to that of quercetin and aminoguanidine, respectively. Conclusion Targeting the endogenous antioxidant systems like AGEs and AR enzymes seems to provide a promising therapeutic approach, thus concluding that ZnO-NP could be a promising agent for treating diabetes-related complications such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy that provide grounds for further clinical investigations and trials.

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.

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.

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.

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.

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.

Anticataract Effect of the Aqueous Extract of the Flowers of Aspilia africana in Murine Model of Diabetic and Age-Related Cataracts.

The use of Aspilia africana in traditional medicine for the management of ocular diseases has been reported in India and some indigenous communities of Africa. The aim of this study was to investigate the aqueous extract of the flowers of A. africana (AAE) as an anticataract remedy using murine models of diabetic and senile cataracts. Preliminary phytochemical screening of the extract, in vitro antioxidant assays, and in vitro aldose reductase inhibitory activity were performed. For anticataract investigations of the extracts, diabetic cataract was induced by galactose administration in 3-week-old Sprague Dawley rats. The evaluation of experimentally induced age-related cataract was performed by administering sodium selenite to 10-day-old rat pups. The phytochemical analysis revealed the presence of alkaloids, tannins, flavonoids, glycosides, and saponins. In vitro aldose reductase inhibitory property of the extract on rat lenses revealed that the AAE inhibited the enzyme activity with IC50 of 12.12 µg/ml. For the anticataract investigations, 30, 100, and 300 mg·kg-1AAE-treated rats recorded significantly low (p ≤ 0.0001) cataract scores compared to the negative control rats, indicating a delay in cataractogenesis from the second week of treatment in the galactose-induced cataractogenesis. Similarly, the treatment with AAE caused a significant reduction (p ≤ 0.0001) in cataract scores compared to the negative control rats in the selenite-induced cataractogenesis. Markers of lens transparency, such as aquaporin 0, alpha-A crystallin, and total lens proteins and lens glutathione levels, were significantly preserved (p ≤ 0.05-0.0001) in each cataract model after AAE treatment. The study established the anticataract potential of the aqueous extract of flowers of A. africana in murine models, hence giving scientific credence to its folkloric use in the management of cataract.

Protective Effect of Rutaecarpine in Streptozotocin-Induced Diabetes Cataracts Through the Inhibition of Aldose Reductase Activity in Male Albino Rats

Protective Effect of Rutaecarpine in Streptozotocin-Induced Diabetes Cataracts Through the Inhibition of Aldose Reductase Activity in Male Albino Rats

Two New Phenolic Compounds with Aldose Reductase Inhibitory Activities from Polygonatum cyrtonema Leaves

Two New Phenolic Compounds with Aldose Reductase Inhibitory Activities from Polygonatum cyrtonema Leaves

Design and synthesis of novel quinazolin-4(1H)-one derivatives as potent and selective inhibitors targeting AKR1B1.

Inhibition of aldose reductase (AKR1B1) is a promising option for the treatment of diabetic complications. However, most of the developed small molecule inhibitors lack selectivity or suffer from low bioactivity. To address this limitation, a novel series of quinazolin-4(1H)-one derivatives as potent and selective inhibitors of AKR1B1 were designed and synthesized. Aldose reductase inhibitory activities of the novel compounds were characterized by IC50 values ranging from 0.015 to 31.497 μM. Markedly enhanced selectivity of these derivatives was also recorded, which was further supported by docking studies. Of these inhibitors, compound 5g exhibited the highest inhibition activity with selectivity indices reaching 1190.8. The structure-activity relationship highlighted the importance of N1-acetic acid and N3-benzyl groups with electron-withdrawing substituents on the quinazolin-4(1H)-one scaffold for the construction of efficient and selective AKR1B1 inhibitors.

Two New Phenolic Compounds from Polygonatum cyrtonema Flowers and Their Aldose Reductase Inhibitory Activities

Two New Phenolic Compounds from Polygonatum cyrtonema Flowers and Their Aldose Reductase Inhibitory Activities

Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer.

Synthetic trans-(±)-kusunokinin ((±)KU), a potential anticancer substance, was revealed to have an inhibitory effect on breast cancer. According to the computational modeling prediction, AKR1B1, an oxidative stress and cancer migration protein, could be a target protein of trans-(-)-kusunokinin. In this study, we determined the binding of (±)KU and AKR1B1 on triple-negative breast and non-serous ovarian cancers. We found that (±)KU exhibited a cytotoxic effect that was significantly stronger than zopolrestat (ZP) and epalrestat (EP) (known AKR1B1 inhibitors) on breast and ovarian cancer cells. (±)KU inhibited aldose reductase activity that was stronger than trans-(-)-arctiin ((-)AR) but weaker than ZP and EP. Interestingly, (±)KU stabilized AKR1B1 on SKOV3 and Hs578T cells after being heated at 60 and 75 °C, respectively. (±)KU decreased malondialdehyde (MDA), an oxidative stress marker, on Hs578T cells in a dose-dependent manner and the suppression was stronger than EP. Furthermore, (±)KU downregulated AKR1B1 and its downstream proteins, including PKC-δ, NF-κB, AKT, Nrf2, COX2, Twist2 and N-cadherin and up-regulated E-cadherin. (±)KU showed an inhibitory effect on AKR1B1 and its downstream proteins, similar to siRNA-AKR1B1. Interestingly, the combination of siRNA-AKR1B1 with EP or (±)KU showed a greater effect on the suppression of AKR1B1, N-cadherin, E-cadherin and NF-κB than single treatments. Taken together, we concluded that (±)KU-bound AKR1B1 leads to the attenuation of cellular oxidative stress, as well as the aggressiveness of breast cancer cell migration.

Novel rhodanine based inhibitors of aldose reductase of non-acidic nature with p-hydroxybenzylidene functional group

Aldose reductase, the first enzyme of the polyol pathway represents a key drug target in therapy of diabetic complications. In this study a series of six novel rhodanine based inhibitors of aldose reductase was designed, synthesized, and tested for their ability to inhibit aldose reductase and for selectivity relative to structurally related aldehyde reductase. Aldose reductase inhibitory activities of the compounds were characterized by the IC50 values ranging from 2000 nM to 20 nM. The values of selectivity factors relative to aldehyde reductase were decreasing in the same array from 24 to 5. In silico docking into the inhibitor binding site of aldose reductase revealed a specific binding pattern of the compounds comprising interaction of the deprotonated 4-hydroxybenzylidene group with the anion-binding sub-pocket of aldose reductase, creating a strong H-bond and charge interactions. Predicted pH-distribution profiles of the novel compounds into octanol, supported by experimentally determined distribution ratios, favour drug uptake at the physiological pH, as a result of the presence of the low-acidic phenolic group, instead of the more acidic carboxymethyl functional group.

Structural properties and hypoglycaemic activity of polysaccharides extracted from the fruits of Lycium barbarum L. using various extraction media

The physical and chemical changes that occur during the preparation of polysaccharides are accompanied by changes in structure and biological activity. Different extraction media can affect the bioactivity of polysaccharides by altering their structural properties, including 1D composition, 2D conformation, and 3D morphology. In this study, polysaccharides from the fruits of Lycium barbarum L. were comparatively extracted using water (LBPs-W), 0.1 M HCl (LBPs-Ac), 0.1 M NaOH (LBPs-Al), 0.1% enzyme (LBPs-E), and 6% ionic liquid (LBPs-ILs) aqueous solution, respectively. The physicochemical properties and structures of the five LBPs were compared, and significant differences existed in their chemical components, monosaccharide composition, molecular weight distribution, glycosidic bond ratio, molecular conformation, and morphology. Of note, LBPs-ILs had the highest α-glucosidase, α-amylase, and aldose reductase (AR) inhibitory activities, which may be related to the different monosaccharide compositions, high branching degrees, rich porous structure, and triple helix structure. These results indicated that different media induce differences in structure and function in the process of polysaccharide extraction and dissolution. In addition, ILs are a promising and practical medium to extract hypoglycaemic LBPs from the fruits of Lycium barbarum L. and may be used to extract polysaccharides from other plant resources. ● LBPs extracted from different extraction media showed different structural properties and physiological activity. ● LBPs-ILs had highest α-glucosidase, α-amylase and aldose reductase inhibitory activity. ● ILs was a most suitable media for the extraction of hypoglycemic LBPs from Lycium barbarum L.

Two new phenolic allopyranosides and their analogues from the stems of Viburnum luzonicum Rolfe guided by LC-MS

Two new phenolic allopyranosides, named viburluzosides A and B (1, 2), together with eight known phenolic glycosides (3 − 10) were discovered from the stems of Viburnum luzonicum Rolfe under the guidance of LC-MS analyses coupled with bioactivity evaluation. They were purified through various chromatography methods and identified by extensive spectroscopic analyses (1H and 13C NMR, HSQC, HMBC, and HRESIMS) and chemical methods. The in vitro evaluation on α-glucosidase and aldose reductase (AR) inhibitory activities of isolated compounds were conducted. Compounds 1 − 4 and 6 − 9 exhibited α-glucosidase inhibitory activities with IC50 values of 5.35 − 21.34 μM and AR inhibitory activities with IC50 values of 6.21 − 40.06 μM. Moreover, the inhibitory kinetics analyses of compounds 1 and 2 were also performed.

A molecular hybridization approach for the design of selective aldose reductase (ALR2) inhibitors and exploration of their activities against protein tyrosine phosphatase 1B (PTP1B)

Type II diabetes mellitus is a metabolic disease associated with insulin resistance and high blood glucose levels. Under hyperglycemic conditions the polyol pathway is significantly activated resulting in a series of stress conditions and, finally, in cellular damage. Aldose reductase is the first enzyme of the polyol pathway which is implicated in the onset of long-term diabetic complications. Although many efforts have been focused on developing clinical aldose reductase inhibitors in previous years, they were fruitless due to the poor selectivity profile over the detoxifying aldehyde reductase enzyme. A series of novel benzothiazole-based 4-oxothiazolidin-2-yl-imino acetic acid derivatives has been designed based on our experience from previously reported (Z)-2-(benzo[d]thiazol-2-ylimino)thiazolidin-4-one derivatives. In addition, we followed a molecular hybridization of two well-known aldose reductase inhibitors (zopolrestat and epalrestat) by replacing toxicophore moieties and combining crucial fragments for aldose reductase inhibitory activity as well as selectivity. The most promising compounds in this series (5b and 5d) exhibited potent aldose reductase inhibitory activity with IC50 values of 46 and 67 nM, respectively, and optimal selectivity towards aldehyde reductase. Moreover, inspired by the idea that certain pharmacophoric features of aldose reductase inhibitors overlap with that of protein tyrosine phosphatase 1B inhibitors, we investigated the inhibitory activity of synthesized compounds towards this enzyme. Finally, an extensive docking simulation study was carried out in order to explore the binding modes of examined compounds in the active sites of these enzymes and to interpret the influence of fluorinated moieties in compounds 5b and 5d on their selectivity profiles.

Lanceolanone A, a new biflavanone, and a chalcone glucoside from the flower heads of Coreopsis lanceolata and their aldose reductase inhibitory activity and AMPK activation.

The MeOH extract of the flower heads of Coreopsis lanceolata L. (Asteraceae) exhibited aldose reductase (AR) inhibitory activity (IC50 8.36µg/mL). Bioassay-guided fractionation of the extract resulted in the isolation of a new biflavanone-named Lanceolanone A (1) and a chalcone glucoside (6), along with 12 known compounds (2-5 and 7-14), of which 4, 7, 9, 10, and 12 were isolated from C. lanceolata for the first time. The structures of the new compounds (1 and 6) were determined by extensive spectroscopic analysis, including two-dimensional (2D) NMR, and ECD calculation method. Compounds 2, 4, 11, 13, and 14 exhibited AR inhibitory activities with IC50 values between 2.40 and 9.99µM. Furthermore, 8-13 at 1.0mM activated AMPK expression in HepG2 human hepatoma cells compared to the control.

Lignans with α-glucosidase, protein tyrosine phosphatase 1B, and aldose reductase inhibitory activities from the fruits of Viburnum cylindricum

Viburnum cylindricum Buch.-Ham. ex D. Don is widely cultivated in China due to its considerable economic value. In this study, the EtOAc fraction (VCFE) of V. cylindricum fruits (VCF) was first reported to obviously reduce postprandial blood glucose levels in normal and diabetic ICR mice at 100 mg/kg, and significantly inhibit α-glucosidase, PTP1B, and AR activities in vitro. In order to clarify its antidiabetic components, nine undescribed lignans, including seven 9,9′-epoxylignans, viburindrins A−G (1−7), one rare variable 9,9′-epoxylignan, viburindrin H (8), and one furofuran lignan, viburindrin I (9), were isolated from VCFE by bioassay-guided fractionation, and their structures including absolute configurations were identified by comprehensive spectroscopic analyses and the comparison of the experimental and calculated ECD spectra. Compounds 1−8 exhibited significant inhibitory activities against these enzymes. Among them, compounds 1, 4, and 8 possessed the most potent inhibitory effects on α-glucosidase, PTP1B, and AR with the IC50 values of 14.21, 6.14, and 1.08 μM, respectively. In addition, their inhibitory kinetics and molecular modeling analyses were also investigated. These results uncovered that VCF with the active lignans could be the potential resource for the improvement and treatment of diabetes and related complications.

Screening for Aldose Reductase Inhibitory Activity of 92 Crude Drugs, and Isolation and Identification of Active Ingredients from Clove

Screening for Aldose Reductase Inhibitory Activity of 92 Crude Drugs, and Isolation and Identification of Active Ingredients from Clove