Aldose Reductase Inhibitory Activity Research Articles

Determination of flavonoids in Acer okamotoanum and their aldose reductase inhibitory activities

Plants in the genus Acer include medicinal plants and deciduous tree species in which several bioactive compounds have been isolated. In this study, flavonoids were isolated from the aerial parts of Acer okamotoanum by open column chromatography and identified by spectroscopic analysis as afzelin, quercitrin, and isoquercitrin. Among these flavonoids, quercitrin and isoquercitrin exhibited potent aldose reductase inhibitory activity (IC50 value of 0.40 and 0.63 μM, respectively). Almost all studied tissues of Acer spp. contained high amounts of quercitrin. The leaf of A. mono had the highest amount of quercitrin (61.90 μg g−1). Our results demonstrated that Acer species contain high concentrations of flavonoids with promising aldose reductase inhibitory activity that could be utilized to develop novel therapeutics for diabetic disorders.

Ex vivo and in silico Molecular Docking Studies of Aldose Reductase Inhibitory Activity of Apigenin from Morus indica L.

Objective: An investigation on Aldose Reductase Enzyme (ALR) inhibitory activity of apigenin (API) isolated from Morus indica L. was evaluated by ex vivo and molecular docking studies. Materials and Methods: The inhibitory efficacy of API from M. indica was evaluated against ALR in lens tissue of mice by ex vivo and their binding mechanism through molecular docking was carried out by AutoDock. Results: The API (10-50 µg mL-1) concentration exhibited significant inhibition (p ≤ 0.05) of ALR enzyme in a dose dependent manner with IC50 value of 39.23 µg mL-1. The positive control aminoguanidine (AG) at 10 mM inhibited 42.96% of ALR. The molecular docking studies revealed that API showed better binding energy (-9.15 kJ mol-1) when compared to AG (-3.78 kJ mol1 ). Molecular interaction analysis showed that API interrupts the proton donation mechanism which is necessary for the catalytic activity of ALR by forming H-bond with Trp20 (proton donor). Conclusion: The ALR inhibition potential offered by API was further confirmed through molecular docking studies. The present findings support the pharmacological application of API for the treatment of diabetes cataract. Key words: Mulberry, Antiglycation, Retinopathy, Eye lens.

Synthesis and biological evaluation of stilbene derivatives coupled to NO donors as potential antidiabetic agents

The work is focused on the design of drugs that prevent and treat diabetes and its complications. A novel class of stilbene derivatives were prepared by coupling NO donors of alkyl nitrate and were fully characterised by NMR and other techniques. These compounds were tested in vitro activity, including α-glucosidase inhibitory activity, aldose reductase (AR) inhibitory activity and advanced glycation end products (AGEs) formation inhibitory activity. A class of modified compounds could play a significant effect for treatment of diabetic complications. Target compounds 3e and 7c offered a potential drug design concept for the development of therapeutic or preventive agents for diabetes and its complications.

Evaluation of Aldose Reductase, Protein Glycation, and Antioxidant Inhibitory Activities of Bioactive Flavonoids in Matricaria recutita L. and Their Structure-Activity Relationship.

The inhibitory activities of Matricaria recutita L. 70% methanol extract were evaluated by isolating and testing 10 of its compounds on rat lens aldose reductase (RLAR), advanced glycation end products (AGEs), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging. Among these compounds, apigenin-7-O-β-D-glucoside, luteolin-7-O-β-D-glucoside, apigenin-7-O-β-D-glucuronide, luteolin-7-O-β-D-glucuronide, 3,5-O-di-caffeoylquinic acid, apigenin, and luteolin showed potent inhibition, and their IC50 values in RLAR were 4.25, 1.12, 1.16, 0.85, 0.72, 1.72, and 1.42 μM, respectively. Furthermore, these compounds suppressed sorbitol accumulation in rat lens under high-glucose conditions, demonstrating their potential to prevent sorbitol accumulation ex vivo. Notably, luteolin-7-O-β-D-glucuronide and luteolin showed antioxidative as well as AGE-inhibitory activities (IC50 values of these compounds in AGEs were 3.39 and 6.01 μM). These results suggest that the M. recutita extract and its constituents may be promising agents for use in the prevention or treatment of diabetic complications.

Dihydroxanthyletin-type coumarins from Angelica decursiva that inhibits the formation of advanced glycation end products and human recombinant aldose reductase.

The formation of advanced glycation end-products (AGE) and aldose reductase activity have been implicated in the development of diabetic complications. The present study was aimed to evaluate human recombinant aldose reductase (HRAR) and AGE inhibitory activity of seven natural dihydroxanthyletin-type coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), Pd-C-I (3), Pd-C-II (4), Pd-C-III (5), decursidin (6), and (+)-trans-decursidinol (7) from Angelica decursiva. Coumarins 1-7 showed potent HRAR and AGE inhibitory activities with ranges of IC50 values of 1.03-21.31 and 0.41-5.56µM, respectively. In the kinetic study for HRAR enzyme inhibition, coumarins 1, 3, 4, and 7 were competitive-type inhibitors, 6 was a mixed-type inhibitor, whereas 2 and 5 were noncompetitive-type inhibitors. Furthermore, we also predicted the docking interactions of HRAR with coumarins 1-7 using AutoDock Vina, and as a result, the simulated enzyme-inhibitor complexes exhibited negative binding energies (Autodock Vina=-9.6 to -8.1kcal/mol for HRAR), indicating a high affinity and tight binding capacity for the HRAR active site. Our results clearly indicate the potential HRAR and AGE formation inhibitory activities of dihydroxanthyletin-type coumarins, which could be further explored to develop therapeutic modalities for the treatment of diabetes and related complications.

Novel quinazolinone-based 2,4-thiazolidinedione-3-acetic acid derivatives as potent aldose reductase inhibitors.

Targeting aldose reductase enzyme with 2,4-thiazolidinedione-3-acetic acid derivatives having a bulky hydrophobic 3-arylquinazolinone residue. All the target compounds were structurally characterized by different spectroscopic methods and microanalysis, their aldose reductase inhibitory activities were evaluated, and binding modes were studied by molecular modeling. All the synthesized compounds proved to inhibit the target enzyme potently, exhibiting IC50 values in the nanomolar/low nanomolar range. Compound 5i (IC50=2.56nM), the most active of the whole series, turned out to be almost 70-fold more active than the only marketed aldose reductase inhibitor epalrestat. This work represents a promising matrix for developing new potential therapeutic candidates for prevention of diabetic complications through targeting aldose reductase enzyme. [Formula: see text].

Phytochemical profile, aldose reductase inhibitory, and antioxidant activities of Indian traditional medicinal Coccinia grandis (L.) fruit extract.

Coccinia grandis (L.) fruits (CGFs) are commonly used for culinary purposes and has several therapeutic applications in the Southeast Asia. The aim of this work was to evaluate phytochemical profile, aldose reductase inhibitory (ARI), and antioxidant activities of CGF extract. The CGFs were extracted with different solvents including petroleum ether, dichloromethane, acetone, methanol, and water. The highest yield of total extractable compounds (34.82%) and phenolic content (11.7±0.43mg of GAE/g dried extract) was found in methanol extract, whereas water extract showed the maximum content of total flavonoids (82.8±7.8mg QE/g dried extract). Gas chromatography-mass spectroscopy (GC-MS) analysis of methanol and water extract revealed the presence of flavonoids, phenolic compounds, alkaloids, and glycosides in the CGFs. Results of the in vitro ARI activity against partially purified bovine lens aldose reductase showed that methanol extract of CGFs exhibited 96.6% ARI activity at IC50 value 6.12µg/mL followed by water extract 89.1% with the IC50 value 6.50µg/mL. In addition, methanol and water extracts of CGF showed strong antioxidant activities including ABTS*+ scavenging, DPPH* scavenging, and hydroxyl radical scavenging. Our results suggest that high percentage of both flavonoids and phenolic contents in the CGFs are correlated with the ARI and antioxidant activities. The fruits of C. grandis are thus potential bifunctional agents with ARI and antioxidant activities that can be used for the prevention and management of DM and associated diseases.

Aldose reductase inhibitory activity studies of THERACURMIN

THERACURMIN a commercially available nano-dispersion of curcumin used to treat after effects of alcohol has been evaluated for in vitro ARI activity on Aldose reductase isolated from the bovine lens. As envisaged, the product displays better ARI activity with IC50 value of 3 μM. The observed ARI activity of THERACURMIN is of therapeutic significance as the limited bioavailability of curcumin limits its clinical use.

Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.

Characterization of DHDP, a novel aldose reductase inhibitor isolated from Lysimachia christinae

The aldose reductase (AR) inhibitory effect of Lysimachia christinae was investigated as a functional food ingredient and a new AR inhibitor, DHDP, was isolated from L. christinae, guided by an affinity-based ultrafiltration-HPLC assay. The chemical structure of DHDP was determined to be 1,5-di-hydroxy-1,5-di-[(E)-3-(4-hydroxyphenyl)-2-propenoic]-3-pentanonyl ester by one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR), fast atom bombardment ionization mass spectrometry (FAB-MS), and ultraviolet (UV) and (IR) infrared spectroscopy. In addition, the AR inhibitory activity and mechanism of DHDP were characterized. In vitro and in silico results demonstrated that DHDP binds to the AR active site rapidly, blocking it and competitively preventing substrate access and product formation (IC50, 194.67μM; Ki, 29.68μM). Ex vivo experiments indicated that DHDP can penetrate the eye lens and successfully inhibit AR under hyperglycemic conditions, thus preventing the accumulation of sorbitol and subsequent osmotic stress.

Aldose reductase inhibitory potential and anti-cataract activity of Punica granatum Linn. leaves against glucose-induced cataractogenesis in goat eye lens

Cataract is one of the primitive secondary complications of diabetes mellitus and contributes to 50% blindness worldwide. Aldose reductase (AR) is the first and rate limiting enzyme in the intracellular polyol pathway responsible for the development of cataract. Thus, there is an imperative need for modest, non-surgical way in order to treat cataract. In Ayurveda, Punica granatum (Pomegranate) is considered as “a pharmacy unto itself”. Pomegranate leaves are traditionally used for their anti-diabetic activity. In this study, we investigated AR inhibitory activity and anti-cataract potential of Pomegranate leaves in glucose - induced cataract in goat lens. AR inhibitory activity was evaluated in vitro in goat lenses. In glucose induced cataract model, goat lenses were incubated in artificial aqueous humor containing 55 mM glucose along with methanolic extract of Punica granatum leaves (MPGL) or quercetin for 72 h. After 72 h, photographic evaluation of the lens was carried out and the lens antioxidant parameters were determined. Different concentrations of MPGL were found to inhibit lens AR activity with an IC50 value of 83.55 ± 3.92 μg/ml. Quercetin was taken as positive control which exhibited 56.461% AR inhibition at a concentration of 500 μg/ml. Cataractous lenses exhibited marked opacity and decrease in the levels of reduced glutathione and superoxide dismutase. Treatment with MPGL and quercetin prevented the opacity and restored back the antioxidant activity. Together, Punica granatum leaves ameliorated glucose-induced cataractogenesis via AR inhibition, reduction in oxidative stress and improvement in antioxidant defense system.

A novel polycyclic meroterpenoid with aldose reductase inhibitory activity from medicinal mushroom Ganoderma leucocontextum.

A novel polycyclic meroterpenoid with aldose reductase inhibitory activity from medicinal mushroom Ganoderma leucocontextum

Quercetin inhibited epithelial mesenchymal transition in diabetic rats, high-glucose-cultured lens, and SRA01/04 cells through transforming growth factor-β2/phosphoinositide 3-kinase/Akt pathway

Diabetic cataract (DC), an identified life-threatening secondary complication of diabetes mellitus, has proven to be a dilemma because of its multifactorial caused and progression. An increasing number of studies have shown that in addition to the maillard reaction, enhanced polyol pathway, and oxidative insults, epithelial mesenchymal transition (EMT) is related to the prevalence of DC. Quercetin, a classic flavonoid with multiple pharmacological effects has been reported to possess therapeutic efficacy in the management and treatment of this disease. However, the mechanism underlying its therapeutic efficacy in EMT of lens epithelial cells (SRA01/04) and contribution to resolving DC remains a mystery. Therefore, in this study, we investigated the effects of quercetin on EMT of SRA01/04 and high-glucose (HG)-induced lens opacity accompanied by lens fibrosis induced by type-1 diabetes. Furthermore, we sought to clarify the specific mechanisms underlying these effects. At week 14 after streptozotocin (STZ) intraperitoneal administration, diabetic rats showed lens opacity accompanied with diminished antioxidant function, enhanced polyol pathway activity, and non-enzymatic glycation. Western blotting confirmed EMT in rat SRA01/04 cells with significantly increased α-smooth muscle actin (α-SMA) and decreased E-cadherin expressions. Treatment of the lens with quercetin ameliorated the oxidative stress, inhibited aldose reductase (AR) activation, reduced advanced glycation end product (AGE) production, and finally suppressed EMT in the early stages. Our in vitro results showed that high-glucose activated the transforming growth factor-β2/phosphoinositide 3-kinase/protein kinase B (TGF-β2/PI3K/Akt) signalling and EMT in SRA01/04 cells. Further, induced oxidative stress, activation of aldose reductase, and accumulation of advanced glycation end products were also involved in this process. Quercetin was potent enough to effectively ameliorate the high glucose (HG)-induced EMT of SRA01/04 cells by inhibiting the activation of TGF-β2/PI3K/Akt, enhancing the antioxidant capacity, inhibiting AR activity, and reducing AGE production. From the whole animal to tissues, and finally the cellular level, our results provide considerable evidence of the therapeutic potential of quercetin for DC. This might be due to its inhibition of EMT mediated through inhibition of the TGF-β/PI3K/Akt pathway.

Enzymatic Synthesis of a Novel Kaempferol-3-O-β-d-glucopyranosyl-(1→4)-O-α-d-glucopyranoside Using Cyclodextrin Glucanotransferase and Its Inhibitory Effects on Aldose Reductase, Inflammation, and Oxidative Stress.

Kaempferol-3-O-β-d-glucopyranoside (astragalin, AS), a major flavonoid that exists in various plants, exerts antioxidant, antitumor, anti-human immunodeficiency virus (HIV), and anti-inflammatory effects. However, the low water solubility of AS limits its use. In this study, we used cyclodextrin glucanotransferase (CGTase) with maltose (G2) as a donor molecule to enzymatically modify AS to improve its water solubility and physiochemical properties. We isolated the glycosylated astragalin (G1-AS) and identified the structure of G1-AS as kaempferol-3-O-β-d-glucopyranosyl-(1→4)-O-α-d-glucopyranoside, where one glucose residue was transferred to AS. G1-AS retained the antioxidative activity of the original AS compound; however, the solubility of G1-AS was 65-fold higher than that of AS. In addition, G1-AS showed enhanced anti-inflammatory effects and aldose reductase inhibitory activity compared to AS when applied to rat lenses.

Investigation of the antioxidant and aldose reductase inhibitory activities of extracts from Peruvian tea plant infusions

In the present study, the antioxidant and aldose reductase inhibitory activities of 24 Peruvian infusion tea plants were investigated by 2,2′-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and aldose reductase assays. Phoradendron sp. showed the highest inhibition of aldose reductase (IC50, 1.09±0.06μg/mL) and considerable antioxidant (IC50 of DPPH, 58.36±1.65μg/mL; IC50 of ABTS, 9.91±0.43μg/mL) effects. In order to identify the antioxidants and aldose reductase inhibitors of Phoradendron sp., DPPH-high performance liquid chromatography (HPLC) and ultrafiltration-HPLC assays were performed. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid, and 1,3,5-tri-O-caffeoylquinic acid were identified as the antioxidants and aldose reductase inhibitors; apigenin was identified as the antioxidant. Finally, Phoradendron sp. and its aldose reductase inhibitors also showed a dose-dependent anti-inflammatory effect without cellular toxicity. These results suggested that Phoradendron sp. can be a potent functional food ingredient as an antioxidant, aldose reductase inhibitor and anti-inflammatory agent.

Chemical Constituents of Smilax china L. Stems and Their Inhibitory Activities against Glycation, Aldose Reductase, α-Glucosidase, and Lipase.

The search for natural inhibitors with anti-diabetes properties has gained increasing attention. Among four selected Smilacaceae family plants, Smilax china L. stems (SCS) showed significant in vitro anti-glycation and rat lens aldose reductase inhibitory activities. Bioactivity-guided isolation was performed with SCS and four solvent fractions were obtained, which in turn yielded 10 compounds, including one phenolic acid, three chlorogenic acids, four flavonoids, one stilbene, and one phenylpropanoid glycoside; their structures were elucidated using nuclear magnetic resonance and mass spectrometry. All solvent fractions, isolated compounds, and stem extracts from plants sourced from six different provinces of South Korea were next tested for their inhibitory effects against advanced glycation end products, as well as aldose reductase. α-Glucosidase, and lipase assays were also performed on the fractions and compounds. Since compounds 3, 4, 6, and 8 appeared to be the superior inhibitors among the tested compounds, a comparative study was performed via high-performance liquid chromatography with photodiode array detection using a self-developed analysis method to confirm the relationship between the quantity and bioactivity of the compounds in each extract. The findings of this study demonstrate the potent therapeutic efficacy of SCS and its potential use as a cost-effective natural alternative medicine against type 2 diabetes and its complications.

Determination of flavonoids from Perilla frutescens var. japonica seeds and their inhibitory effect on aldose reductase

Perilla frutescens var. japonica (PF) is an annual aromatic herb has been consumed as a food ingredient and medicinal crop in Asian countries. To evaluate the therapeutic efficacy of aldose reductase (AR) inhibition, we tested the PF seeds. The stepwise polarities of PF were tested for AR inhibition, and we determined the CH2Cl2 and EtOAc fractions to be good inhibitors (5.81 and 3.99 μg/mL, respectively). Compounds 1–3 were isolated from the CH2Cl2 and EtOAc fractions and identified as luteolin (1), apigenin (2), and diosmetin (3) by physicochemical and spectroscopic data. Among them, luteolin (1) and apigenin (2) had high AR inhibitory activity (1.89 and 4.18 μM). Deulsaem, a variety of PF, was determined to have the highest flavonoid content among ten PF seeds tested (2.10 mg/g). This study suggests that PF could be utilized as a natural source to treat diabetic complications.

An efficient synthesis of flavanones and their docking studies with aldose reductase

A series of flavanone derivatives have been synthesized from 2-hydroxy acetophenone and benzaldehyde using fused calcium chloride in good to moderate yields, and their in vitro aldose reductase inhibitory activity has been tested on aldose reductase purified enzyme from Bovine lens. Most of the synthesized compounds exhibited potent aldose reductase inhibitory activity, and the obtained results are supported by the docking studies. Among the tested derivatives, 2, 3, 4-methoxy derivative 19 (IC50 5.88 ± 0.03 µM) exhibited the highest inhibitory activity whereas 2-methoxy derivative 12 showed the lowest, and the remaining compounds exhibited moderate activity with IC50 in the range of 6.09–7.89 µM. The spatial configuration of the most active derivative 19 was compared with pharmacophore requirements of the aldose reductase inhibitor site using a molecular modeling system.

Inhibition of aldose reductase ameliorates alcoholic liver disease by activating AMPK and modulating oxidative stress and inflammatory cytokines.

Aldose reductase (AR) expression is elevated in the livers of patients with alcoholic liver diseases. However, the role of AR in the development of alcoholic liver diseases remains unclear. The aim of the present study was to determine the effect of AR inhibition on ethanol‑induced hepatosteatosis invivo and invitro, and to identify possible underlying molecular mechanisms. Alcoholic fatty livers were induced in C57BL/6 mice by feeding the mice with Lieber‑DeCarli liquid diets. The expression of AR protein was elevated in the liver tissue of C57BL/6 mice fed with an ethanol diet and in mouse AML12 liver cells exposed to ethanol. In addition to the elevation in AR, hepatic steatosis was observed in ethanol diet‑fed mice, and this ethanol‑induced steatosis was significantly attenuated by inhibiting AR activity with a specific inhibitor, zopolrestat. The suppressive effect of AR inhibition was associated with decreased levels of hepatic lipoperoxides, decreased protein expression of hepatic cytochrome P450 2E1 (CYP2E1), increased phosphorylation of 5'‑AMP‑activated protein kinase (AMPK) and decreased mRNA expression of tumor necrosis factor‑α (TNF‑α). Treatment with the AR inhibitor attenuated the level of lipid accumulation and oxidative stress, activated AMPK, and suppressed the mRNA expression of TNF‑α, interleukin‑6 and transforming growth factor‑β1 in ethanol‑treated AML12 cells. The results of the present study demonstrated that inhibition of AR ameliorated alcoholic liver disease invivo and invitro, in part by activating AMPK, decreasing CYP2E1‑mediated oxidative stress and ameliorating the expression of pro‑inflammatory cytokines.

Mechanism of capsaicin inhibition of aldose reductase activity.

Aldose reductase (AR) inhibitors play a vital importance as a potential therapeutic and preventive medicine when it comes to hyperglycemia associated diabetic complications. Additionally, capsaicin is used as a food additive and a drug in a number of diverse clinical trials. The aim of this study is to determine the in vitro inhibition behavior of capsaicin on AR enzyme activity, which was obtained from different rat tissues (heart, kidney, liver, and brain). We showed that AR was inhibited by capsaicin in the micromolar range and noncompetitive manner in all of the tissues. Ki values of capsaicin were found to be 8.87, 264, 535, and 597, respectively, in heart AR, kidney AR, liver AR, and brain AR. In conclusion, capsaicin may be an effective molecule when used in low concentrations to prevent diabetic complications associated with the polyol pathway.