Potent Aldose Reductase Research Articles

Novel insights into the mechanisms whereby isoflavones protect against fatty liver disease.

Fatty liver disease (FLD) is a growing public health problem worldwide. There is an urgent requirement for alternative and natural medicine to treat this disease. As phytochemicals, isoflavones have attracted considerable attention for the prevention of FLD. Numerous studies have revealed that isoflavones protect against FLD through various pathways which modulate fatty acid β-oxidation, lipid synthesis, and oxidative stress. Recently, the aldose reductase (AR)/polyol pathway has been reported to be involved in the development of FLD by modulating hepatic fructose production, peroxisome proliferator-activated receptor (PPAR)α activity, cytochrome P450 (CYP)2E1 expression, and gut bacterial endotoxin-induced cytokine release. It has been reported that some isoflavones are potent AR inhibitors. Here, we review the anti-FLD actions of isoflavones and the proposed mechanism whereby isoflavones protect against FLD, with regard to the AR/polyol pathway. We propose that isoflavones block the AR/polyol pathway and in turn reduce fructose production and subsequent fat accumulation in the liver in diabetic or high-glucose-diet mice. In addition, in rodents with alcoholic liver disease or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, inhibition of AR by isoflavones may improve PPARα-mediated fatty acid oxidation, reduce hepatic steatosis, and attenuate CYP2E1-mediated oxidative stress or AR/gut bacterial endotoxin-mediated cytokine overproduction, to alleviate progression of FLD.

Studies on α-glucosidase, aldose reductase and glycation inhibitory properties of sesquiterpenes and flavonoids of Zingiber zerumbet Smith

Eight known phytochemicals, four sesquiterpenes and four flavonoids of Zingiber zerumbet were screened against α-glucosidase enzyme, aldose reductase enzyme and antiglycation property under in vitro conditions. The results established kaempferol-3-O-methylether as a potent inhibitor of α-glucosidase enzyme with an IC50 value of 7.88 μM. In aldose reductase enzyme inhibition assay, all the compounds except zerumbone epoxide showed good to excellent inhibition properties. Among these, the flavonoid compounds were found to be potent aldose reductase inhibitors compared with the four sesquiterpenes. In addition, compounds such as α-humulene, kaempferol, kaempferol-3-O-methylether and 3″,4″-O-diacetylafzelin displayed potent antiglycation properties. From overall results, we found that kaempferol and kaempferol-3-O-methylether are potent inhibitors of α-glucosidase enzyme, aldose reductase enzyme and glycation reaction, the three main targets of drugs for the treatment of diabetes and its complications.

Fungal metabolite nigerloxin ameliorates diabetic nephropathy and gentamicin-induced renal oxidative stress in experimental rats.

Elevated polyol pathway enzyme activities and oxidative stress play an important role in the development and progression of diabetic nephropathy. Here, we investigated the beneficial influence of nigerloxin, a fungal metabolite and a potent aldose reductase inhibitor and free radical scavenger in the kidney of streptozotocin-induced diabetic rats. A group of diabetic rats was orally administered with nigerloxin for 30days (100mg/kg). Diabetic rats showed increased lipid peroxides, advanced glycation end products (AGEs), elevated activities of polyol pathway enzymes, and lowered antioxidant defense system in kidney. Administration of nigerloxin decreased kidney lipid peroxides and AGEs. Activities of polyol pathway enzymes were reduced while activities of all antioxidant enzymes, glutathione, and ascorbic acid were elevated in the kidney of nigerloxin-treated diabetic rats. We also investigated antioxidant potential of nigerloxin in gentamicin-induced nephrotoxicity in Wistar rats. Groups of rats were orally administered with nigerloxin for 8days (25mg or 100mgkg(-1) body weight day(-1)) along with gentamicin (80mg/kg, i.p., for 8days). Gentamicin induced increase in lipid peroxides, decrease in glutathione and activities of antioxidant enzymes in the kidney, and increase in blood creatinine, and urea concentrations were significantly countered by nigerloxin treatment. Thus, the results indicated the beneficial influence of nigerloxin on polyol pathway and oxidative stress associated with diabetes, which are implicated in ameliorating the development of diabetic nephropathy. Nigerloxin also ameliorated oxidative stress induced by gentamicin in the renal tissue.

Therapeutic potential of resveratrol in diabetic complications: In vitro and in vivo studies

BackgroundVarious mechanisms with a complex integrating paradigm have been implicated in diabetic complications. The present study was aimed to evaluate the aldose reductase (AR) and advanced glycation end products (AGEs) inhibitory activity of resveratrol (RSV) and its potential in the treatment of diabetic complications such as cataract and nephropathy. MethodsRSV was studied for its inhibitory activity against rat lens AR (RLAR) and rat kidney AR (RKAR) in vitro along with its ability to inhibit formation of AGEs. Anticataract activity of RSV was demonstrated using sugar induced lens opacity model in isolated cattle lens. Furthermore the involvement of RSV in streptozotocin-induced diabetic nephropathy was investigated by assessing the key markers of kidney function along with the formation of AGEs. The potent AR inhibitor, fidarestat was as a standard. ResultsRSV exhibited inhibitory activity against RLAR and RKAR with IC50 values of 4.99μg/ml (21.9μM) and 5.49μg/ml (24.5μM), respectively. It also showed a significant inhibition of AGEs formation in vitro. In sugar-induced lens opacity model, RSV displayed a significant protective effect preventing opacification and formation of polyols in cattle lens. RSV significantly improved glycaemic status and renal function in diabetic rats with a significant decrease in the formation of AGEs in the kidneys. ConclusionsThe results obtained in this study underline the potential of RSV as a possible therapeutic agent against long-term diabetic complications.

Alkaloids as Aldose Reductase Inhibitors, with Special Reference to Berberine

Aldose reductase is the rate-limiting enzyme of the polyol pathway that leads to conversion of glucose to sorbitol. Its increased activity, which results in abnormal activation of the polyol pathway, is implicated in the development of long-term complications of diabetes mellitus. Different plant species and their active components have shown potent in vitro and in vivo aldose reductase inhibitory activity. Among different phyto-constituents, alkaloids that contain isoquinoline/bis(isoquinoline)and related ring structures (such as berberine, palmatine, coptisine, and jateorrhizine) have shown very potent aldose reductase inhibitory activity. The structural activity relationship has revealed the importance of hydrophobic and hydrophilic groups of isoquinoline/bis(isoquinoline)for binding to an enzyme. The dioxymethylene group in the D ring (hydrophobic group) of these alkaloids binds tightly to the site adjacent to the anionic binding site (active site), while the methoxyl groups (polar) bind to the site adjacent to the nicotinamide ring of the coenzyme. On the basis of these findings, it may be proposed that the presence of isoquinoline/bis(isoquinoline)ring structures is the most important requirement for alkaloids to behave as potent aldose reductase inhibitors. Thus, other plants may also be screened for the same activity. The present review discusses these isoquinoline/bis(isoquinoline)-based alkaloids as aldose reductase inhibitors that may be used to manage diabetic complications and may substitute for the chemically synthesized aldose reductase inhibitors.

Evaluation of in vitro aldose reductase inhibitory potential of alkaloidal fractions of Piper nigrum, Murraya koenigii, Argemone mexicana, and Nelumbo nucifera

Aldose reductase is primarily involved in development of long-term diabetic complications due to increased polyol pathway activity. The synthetic aldose reductase inhibitors are not very successful clinically. Therefore, the natural sources may be exploited for safer and effective aldose reductase inhibitors. In the present study, the aldose reductase inhibitory potential of hydroalcoholic and alkaloidal extracts of Piper nigrum, Murraya koenigii, Argemone mexicana, and Nelumbo nucifera was evaluated. The hydroalcoholic and alkaloidal extracts of the selected plants were prepared. The different concentrations of hydroalcoholic and alkaloidal extracts of these plants were evaluated for their goat lens aldose reductase inhibitory activity using dl-glyceraldehyde as substrate. The aldose reductase inhibitory potential of extracts was assessed in terms of their IC50 value. Amongst the hydroalcoholic extracts, the highest aldose reductase inhibitory activity was shown by P. nigrum (IC50 value 35.64±2.7 μg/mL) followed by M. koenigii (IC50 value 45.67±2.57 μg/mL), A. mexicana (IC50 value 56.66±1.30 μg/mL), and N. nucifera (IC50 value 59.78±1.32 μg/mL). Among the alkaloidal extracts, highest inhibitory activity was shown by A. mexicana (IC50 value 25.67±1.25 μg/mL), followed by N. nucifera (IC50 value 28.82±1.85 μg/mL), P. nigrum (IC50 value 30.21±1.63 μg/mL), and M. koenigii (IC50 value 35.66±1.64 μg/mL). It may be concluded that the alkaloidal extracts of these plants possess potent aldose reductase inhibitory activity and may be therapeutically exploited in diabetes-related complications associated with increased activity of aldose reductase.

Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors

Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O7-Nitrooxyethyl-O3′,O4′-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure–activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications.

X-ray structure of the V301L aldo–keto reductase 1B10 complexed with NADP+ and the potent aldose reductase inhibitor fidarestat: Implications for inhibitor binding and selectivity

Only one crystal structure is currently available for tumor marker AKR1B10, complexed with NADP+ and tolrestat, which is an aldose reductase inhibitor (ARI) of the carboxylic acid type. Here, the X-ray structure of the complex of the V301L substituted AKR1B10 holoenzyme with fidarestat, an ARI of the cyclic imide type, was obtained at 1.60Å resolution by replacement soaking of crystals containing tolrestat. Previously, fidarestat was found to be safe in phase III trials for diabetic neuropathy and, consistent with its low in vivo side effects, was highly selective for aldose reductase (AR or AKR1B1) versus aldehyde reductase (AKR1A1). Now, inhibition studies showed that fidarestat was indeed 1300-fold more selective for AR as compared to AKR1B10, while the change of Val to Leu (found in AR) caused a 20-fold decrease in the IC50 value with fidarestat. Structural analysis of the V301L AKR1B10-fidarestat complex displayed enzyme-inhibitor interactions similar to those of the AR-fidarestat complex. However, a close inspection of both the new crystal structure and a computer model of the wild-type AKR1B10 complex with fidarestat revealed subtle changes that could affect fidarestat binding. In the crystal structure, a significant motion of loop A was observed between AR and V301L AKR1B10, linked to a Phe-122/Phe-123 side chain displacement. This was due to the presence of the more voluminous Gln-303 side chain (Ser-302 in AR) and of a water molecule buried in a subpocket located at the base of flexible loop A. In the wild-type AKR1B10 model, a short contact was predicted between the Val-301 side chain and fidarestat, but would not be present in AR or in V301L AKR1B10. Overall, these changes could contribute to the difference in inhibitory potency of fidarestat between AR and AKR1B10.

Effects of Long-Term Treatment with Ranirestat, a Potent Aldose Reductase Inhibitor, on Diabetic Cataract and Neuropathy in Spontaneously Diabetic Torii Rats

We evaluated ranirestat, an aldose reductase inhibitor, in diabetic cataract and neuropathy (DN) in spontaneously diabetic Torii (SDT) rats compared with epalrestat, the positive control. Animals were divided into groups and treated once daily with oral ranirestat (0.1, 1.0, 10 mg/kg) or epalrestat (100 mg/kg) for 40 weeks, normal Sprague-Dawley rats, and untreated SDT rats. Lens opacification was scored from 0 (normal) to 3 (mature cataract). The combined scores (0–6) from both lenses represented the total for each animal. DN was assessed by measuring the motor nerve conduction velocity (MNCV) in the sciatic nerve. Sorbitol and fructose levels were measured in the lens and sciatic nerve 40 weeks after diabetes onset. Cataracts developed more in untreated rats than normal rats (P < 0.01). Ranirestat significantly (P < 0.01) inhibited rapid cataract development; epalrestat did not. Ranirestat significantly reversed the MNCV decrease (40.7 ± 0.6 m/s) in SDT rats dose-dependently (P < 0.01). Epalrestat also reversed the prevented MNCV decrease (P < 0.05). Sorbitol levels in the sciatic nerve increased significantly in SDT rats (2.05 ± 0.10 nmol/g), which ranirestat significantly suppressed dose-dependently, (P < 0.05, <0.01, and <0.01); epalrestat did not. Ranirestat prevents DN and cataract; epalrestat prevents DN only.

&lt;i&gt;In silico&lt;/i&gt; docking studies of aldose reductase inhibitory activity of commercially available flavonoids

The primary objective of this study was to investigate the aldose reductase inhibitory activity of flavonoids using in silico docking studies. In this perspective, flavonoids like biochanin, butein, esculatin, fisetin and herbacetin were selected. Epalrestat, a known aldose reductase inhibitor was used as the standard. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. The results showed that all the selected flavonoids showed binding energy ranging between -9.33 kcal/mol to -7.23 kcal/mol when compared with that of the standard (-8.73 kcal/mol). Inhibition constant (144.13 µM to 4.98 µM) and intermolecular energy (-11.42 kcal/mol to -7.83 kcal/mol) of the flavonoids also coincide with the binding energy. All the selected flavonoids contributed aldose reductase inhibitory activity because of its structural properties. These molecular docking analyses could lead to the further development of potent aldose reductase inhibitors for the treatment of diabetes.

Synthesis and biological evaluation of new piplartine analogues as potent aldose reductase inhibitors (ARIs)

As a continuation of our efforts directed towards the development of anti-diabetic agents from natural sources, piplartine was isolated from Piper chaba, and was found to inhibit recombinant human ALR2 with an IC50 of 160 μM. To improve the efficacy, a series of analogues have been synthesized by modification of the styryl/aromatic and heterocyclic ring functionalities of this natural product lead. All the derivatives were tested for their ALR2 inhibitory activity, and results indicated that adducts 3c, 3e and 2j prepared by the Michael addition of piplartine with indole derivatives displayed potent ARI activity, while the other compounds displayed varying degrees of inhibition. The active compounds were also capable of preventing sorbitol accumulation in human red blood cells.

Pharmacologically tested aldose reductase inhibitors isolated from plant sources — A concise report

Aldose reductase (AR), a cytosolic, monomeric oxidoreductase, is a key enzyme in the polyol pathway which controls the conversion of glucose to sorbitol. The accumulation of sorbitol by the activation of AR enzymes in lens, retina, and sciatic nerves leads to the cause of diabetic defects resulting in various secondary complications, viz. retinopathy, neuropathy, nephropathy and Alzheimer's disease. Thus, reduction of the polyol pathway flux by AR inhibitors could be a potential therapeutic opening in the treatment and prevention of diabetic complications. At present, the AR inhibitors belong to two different chemical classes. One is the hydantoin derivatives, such as Sorbinil, Dilantin, and Minalrestat, and the other is the carboxylic acid derivatives, such as Epalrestat, Alrestatin, and Tolrestat. However, it is known that most of these synthethic compounds have unacceptable side-effects. Well known medicinal plants like Chrysanthemum indicum, Chrysanthemum morifolium, Prunus mume, Myrcia multiflora, Centella asiatica, and Salacia reticulata, Salacia oblonga, and Salacia chinensis exhibited potent AR inhibitory activity. The present review summarizes the list of plant material, and their isolated phytoconstituents which have been tested for their AR inhibitory activity. This litreature review covers the period to 2011, and a total of 72 plants are listed.

Discovery of potential aldose reductase inhibitors using in silico docking studies

The primary objective of this study was to investigate the aldose reductase inhibitory activity of flavonoids using in silico docking studies. In this perspective, flavonoids like Apigenin, Baicalin, Daidzein, Epigallocatechin, Galangin, Genistein, Hesperitin, Naringenin, and Scopoletin were selected. Epalrestat, a known aldose reductase inhibitor was used as the standard. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. In the docking studies, three important parameters like binding energy, inhibition constant and intermolecular energy were determined. The results showed that all the selected flavonoids showed binding energy ranging between −9.91 kcal/mol to −7.52 kcal/mol when compared with that of the standard (−8.73 kcal/mol). Intermolecular energy (−11.40 kcal/mol to −8.71 kcal/mol) and inhibition constant (54.78 nM to 3.10 μM) of the flavonoids also coincide with the binding energy. All the selected flavonoids contributed aldose reductase inhibitory activity because of its functional groups. These molecular docking analyses could lead to the further development of potent aldose reductase inhibitors for the treatment of diabetes.

Inhibition of aldose reductase and anti-cataract action of trans-anethole isolated from Foeniculum vulgare Mill. fruits

Foeniculum vulgare fruits are routinely consumed for their carminative and mouth freshening effect. The plant was evaluated for aldose reductase inhibition and anti-diabetic action. Bioguided fractionation using silica gel column chromatography, HPLC, and GC–MS analysis revealed trans-anethole as the bioactive constituent possessing potent aldose reductase inhibitory action, with an IC50 value of 3.8μg/ml. Prolonged treatment with the pet ether fraction of the F. vulgare distillate demonstrated improvement in blood glucose, lipid profile, glycated haemoglobin and other parameters in streptozotocin-induced diabetic rats. Trans-anethole could effectively show anti-cataract activity through the increase in soluble lens protein, reduced glutathione, catalase and SOD activity on in vitro incubation of the eye lens with 55mM glucose. Trans-anethole demonstrated noncompetitive to mixed type of inhibition of lens aldose reductase using Lineweaver Burk plot.

Structure–activity relationships of ganoderma acids from Ganoderma lucidum as aldose reductase inhibitors

A series of lanostane-type triterpenoids, known as ganoderma acids were isolated from the fruiting body of Ganoderma lucidum. Some of these compounds were identified as active inhibitors of the in vitro human recombinant aldose reductase. To clarify the structural requirement for inhibition, some structure-activity relationships were determined. Our structure-activity studies of ganoderma acids revealed that the OH substituent at C-11 is an important feature and the carboxylic group in the side chain is essential for the recognition of aldose reductase inhibitory activity. Moreover, double bond moiety at C-20 and C-22 in the side chain contributes to improving aldose reductase inhibitory activity. In the case of ganoderic acid C2, all of OH substituent at C-3, C-7 and C-15 is important for potent aldose reductase inhibition. These results provide an approach to understanding the structural requirements of ganoderma acids from G. lucidum for aldose reductase inhibitor. This understanding is necessary to design a new-type of aldose reductase inhibitor.

Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages

The bacterial endotoxin lipopolysaccharide (LPS) is known to induce release of arachidonic acid (AA) and its metabolic products, which play important roles in the inflammatory process. We have shown earlier that LPS-induced signals in macrophages are mediated by aldose reductase (AR). Here we have investigated the role of AR in LPS-induced release of AA metabolites and their modulation using a potent pharmacological inhibitor, fidarestat, and AR siRNA ablation in RAW264.7 macrophages and AR-knockout mouse peritoneal macrophages and heart tissue. Inhibition or genetic ablation of AR prevented the LPS-induced synthesis and release of AA metabolites such as PGE2, TXB, PGI2, and LTBs in macrophages. LPS-induced activation of cPLA2 was also prevented by AR inhibition. Similarly, AR inhibition also prevented the calcium ionophore A23187-induced cPLA2 and LTB4 in macrophages. Further, AR inhibition by fidarestat prevented the expression of AA-metabolizing enzymes such as COX-2 and LOX-5 in RAW264.7 cells and AR-knockout mouse-derived peritoneal macrophages. LPS-induced expression of AA-metabolizing enzymes and their catalyzed metabolic products was significantly lower in peritoneal macrophages and heart tissue from AR-knockout mice. LPS-induced activation of redox-sensitive signaling intermediates such as MAPKs, transcription factor NF-κB, and EGR-1, a transcriptional regulator of mPGES-1, which in collaboration with COX-2 leads to the production of PGE2, was also significantly prevented by AR inhibition. Taken together, our results indicate that AR mediates LPS-induced inflammation by regulating the AA-metabolic pathway and thus provide a novel role for AR inhibition in preventing inflammatory complications such as sepsis.

ChemInform Abstract: Design and Synthesis of Potent and Selective Aldose Reductase Inhibitors Based on Pyridylthiadiazine Scaffold.

AbstractSeveral newly synthesized pyrido[2,3‐e]‐[1,2,4]thiadiazine 1,1‐dioxide derivatives (VII) are found to be potent aldose reductase inhibitors with compound (VIId) exhibiting the highest activity.

Curcumin analogues as possible anti-proliferative & anti-inflammatory agents

A series of novel curcumin analogues has been designed, synthesized and tested in vitro/ in vivo as potential multi-target agents. Their anti-proliferative and anti-inflammatory activities were studied. Compounds 1b and 2b were stronger inhibitors of soybean lipoxygenase (LOX) than curcumin. Analogue 1b was also the most potent aldose reductase (ALR2) inhibitor. Two compounds, ( 1a and 1f) exhibited in vivo anti-inflammatory activity comparable to that of indomethacin, whereas derivative 1i exhibited even higher activity. The derivatives were also tested for their anti-proliferative activity using three different human cancer cell lines. Compounds 1a, 1b, 1d and 2b exhibited significant growth inhibitory activity as compared to curcumin, against all three cancer cell lines. Lipophilicity was determined as R M values using RPTLC and theoretically. The results are discussed in terms of the structural characteristics of the compounds. Docking simulations were performed on LOX and ALR2 inhibitor 1b and curcumin. Compound 1b is well fitted in the active site of ALR2, binding to the ALR2 enzyme in a similar way to curcumin. Allosteric interactions may govern the LOX-inhibitor binding.

Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold

A series of pyrido[2,3- e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC 50 values ranging from 0.038 μM to 11.29 μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure–activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.

Acetic Acid Derivatives of 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide as a Novel Class of Potent Aldose Reductase Inhibitors

A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective aldose reductase inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 μM. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure-activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a remarkably strong effect on ALR2 inhibition potency.