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Aldose reductase inhibitor

Jan Moritz Seliger, Livia Misuri, Edmund Maser, Jan Hintzpeter
Xanthohumol (XN), a prenylated chalcone unique to hops (Humulus lupulus) and two derived prenylflavanones, isoxanthohumol (IX) and 8-prenylnaringenin (8-PN) gained increasing attention as potential anti-diabetic and cancer preventive compounds. Two enzymes of the aldo-keto reductase (AKR) superfamily are notable pharmacological targets in cancer therapy (AKR1B10) and in the treatment of diabetic complications (AKR1B1). Our results show that XN, IX and 8-PN are potent uncompetitive, tight-binding inhibitors of human aldose reductase AKR1B1 (Ki  = 15...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Seung Hwan Hwang, Zhiqiang Wang, Hong-Won Suh, Soon Sung Lim
This study aimed to better understand the functional properties of ribose and 20 amino acid Maillard reaction products (MRPs). The ABTS+ radical scavenging ability of the ribose-20 amino acid MRPs was evaluated. Among the MRPs, ribose-histidine MRPs (RH-MRPs) showed the highest inhibitory activities on the ABTS+ radical scavenging ability, aldose reductase (AR), and tyrosinase compared to other MRPs. Functional compounds with antioxidant and AR inhibitory activities have been recognized as an important strategy in the prevention and treatment of diabetic complications, and the search for tyrosinase inhibitors is important for the treatment of hyperpigmentation, development of skin-whitening agents, and use as preservatives in the food industry...
March 7, 2018: Food & Function
Tsuyoshi Tanimoto
 Aldose reductase (AR) is involved in the pathogenesis of complications in diabetes. In this study, the enzymatic properties of AR isolated from various sources and a recombinant human AR (rh-AR) were analyzed in detail. The sensitivity of different forms of AR to several AR inhibitors (ARIs) was compared. Our findings enabled us to propose that human AR should be used as the target enzyme in the development of ARIs. An enzyme-linked immunosorbent assay (ELISA) for human AR which employed monoclonal antibodies against rh-AR was created, and this method was used to demonstrate the distribution of AR in human tissues...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Himangshu Sonowal, Pabitra Pal, Kirtikar Shukla, Ashish Saxena, Satish K Srivastava, Kota V Ramana
Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy...
February 16, 2018: Biochemical Pharmacology
Antonella Smeriglio, Salvatore V Giofrè, Enza M Galati, Maria T Monforte, Nicola Cicero, Valeria D'Angelo, Gianpaolo Grassi, Clara Circosta
Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes...
February 7, 2018: Fitoterapia
Blanca Colín-Lozano, Samuel Estrada-Soto, Fabiola Chávez-Silva, Abraham Gutiérrez-Hernández, Litzia Cerón-Romero, Abraham Giacoman-Martínez, Julio Cesar Almanza-Pérez, Emanuel Hernández-Núñez, Zhilong Wang, Xin Xie, Mario Cappiello, Francesco Balestri, Umberto Mura, Gabriel Navarrete-Vazquez
We have synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40), aldose reductase (AKR1B1), peroxisome proliferator-activated receptor gama (PPARγ) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound 1 displayed an EC50 value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7...
February 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Shalini Jamwal, Saurabh Sharma
AIM: Vascular endothelium plays a role in capillary transport of nutrients and drugs and regulates angiogenesis, homeostasis, as well as vascular tone and permeability as a major regulator of local vascular homeostasis. The present study has been designed to investigate the role of endothelium in metabolic disorders. METHODS: The endothelium maintains the balance between vasodilatation and vasoconstriction, procoagulant and anticoagulant, prothrombotic and antithrombotic mechanisms...
January 25, 2018: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Zhihua Wang, Sheng Yuan, Yanbing Li, Zhe Zhang, Wei Xiao, Dan Tang, Kaihe Ye, Zhijun Liu, Congcong Wang, Yixiong Zheng, Hong Nie, Heru Chen
(R,E)-N-(3-(2-acetamido-3-(benzyloxy) propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide (hr5F) was design-synthesized based on bioactivity focus strategy as a potential agent to treat diabetic complicates. With in vitro enzyme assay, it is confirmed that hr5F is an effective ALR2 inhibitor with IC50 value of 2.60±0.15 nM, and selectivity index of 86.0 over ALR1, which is a little bit better than the reference Epalrestat (Epa). hr5F inhibits the increase of ALR2 enzyme activity and expression in human lens epithelial cells (HLECs) induced by high glucose...
January 22, 2018: Biochemical Pharmacology
Diganta Kalita, David G Holm, Daniel V LaBarbera, J Mark Petrash, Sastry S Jayanty
Diabetes mellitus is a chronic disease that is becoming a serious global health problem. Diabetes has been considered to be one of the major risks of cataract and retinopathy. Synthetic and natural product inhibitors of carbohydrate degrading enzymes are able to reduce type 2 diabetes and its complications. For a long time, potatoes have been portrayed as unhealthy for diabetic patients by some nutritionist due to their high starch content. However, purple and red potato cultivars have received considerable attention from consumers because they have high levels of polyphenolic compounds that have potent antioxidant activities...
2018: PloS One
Victoria A Serhiyenko, Alexandr A Serhiyenko
Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of "silent" myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications...
January 15, 2018: World Journal of Diabetes
Md Yousof Ali, Hyun Ah Jung, Susoma Jannat, Jae Sue Choi
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...
February 2018: Archives of Pharmacal Research
Devi Thiagarajan, Karen O' Shea, Gopalkrishna Sreejit, Radha Ananthakrishnan, Nosirudeen Quadri, Qing Li, Ann Marie Schmidt, Kenneth Gabbay, Ravichandran Ramasamy
Aldose reductase (AR: human, AKR1B1; mouse, AKR1B3), the first enzyme in the polyol pathway, plays a key role in mediating myocardial ischemia/reperfusion (I/R) injury. In earlier studies, using transgenic mice broadly expressing human AKR1B1 to human-relevant levels, mice devoid of Akr1b3, and pharmacological inhibitors of AR, we demonstrated that AR is an important component of myocardial I/R injury and that inhibition of this enzyme protects the heart from I/R injury. In this study, our objective was to investigate if AR modulates the β-catenin pathway and consequent activation of mesenchymal markers during I/R in the heart...
2017: PloS One
Tuzz-Ying Song, Nae-Cherng Yang, Chien-Lin Chen, Thuy Lan Vo Thi
Diabetic encephalopathy (DE) is often a complication in patients with Alzheimer's disease due to high blood sugar induced by diabetic mellitus. Ergothioneine (EGT) and hispidin (HIP) are antioxidants present in Phellinus linteus. Methylglyoxal (MGO), a toxic precursor of advanced glycated end products (AGEs), is responsible for protein glycation. We investigated whether a combination EGT and HIP (EGT + HIP) protects against MGO-induced neuronal cell damage. Rat pheochromocytoma (PC12) cells were preincubated with EGT (2  μ M), HIP (2  μ M), or EGT + HIP, then challenged with MGO under high-glucose condition (30  μ M MGO + 30 mM glucose; GLU + MGO) for 24-96 h...
2017: Oxidative Medicine and Cellular Longevity
Radhakrishnan Narayanaswamy, Lam Kok Wai, Norhaizan Mohd Esa
Background: The phytoconstituents phytic acid and 4-hydroxyisoleucine have been reported to posses various biological properties. Objective: This prompted us to carry out the docking study on these two ligands (phytic acid & 4-hydroxyisoleucine) against eleven targeted enzymes. Materials and Methods: Phytic acid & 4-hydroxyisoleucine were evaluated on the docking behaviour of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), tyrosinase, human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), xanthine oxidase (XO), squalene synthase (SQS), nitric oxide synthase (NOS), human aldose reductase (HAR) and lipoxygenase (LOX) using Discovery Studio Version 3...
October 2017: Pharmacognosy Magazine
Kamel Metwally, Harris Pratsinis, Dimitris Kletsas, Luca Quattrini, Vito Coviello, Concettina La Motta, Ahmed A El-Rashedy, Mahmoud Es Soliman
AIM: Targeting aldose reductase enzyme with 2,4-thiazolidinedione-3-acetic acid derivatives having a bulky hydrophobic 3-arylquinazolinone residue. MATERIALS & METHODS: 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. RESULTS: All the synthesized compounds proved to inhibit the target enzyme potently, exhibiting IC50 values in the nanomolar/low nanomolar range...
December 2017: Future Medicinal Chemistry
Fernando Alvarez-Rivera, Angel Concheiro, Carmen Alvarez-Lorenzo
Most treatments for diabetic eye conditions rely on systemic (oral) or intravitreal administration, and there is still a demand of efficient and comfortable ocular dosage forms. Our purpose was to design contact lenses (CLs) suitable for local prophylaxis/treatment of diabetes-related ocular pathologies, by means of the incorporation of bioinspired functional groups that can reversibly interact with epalrestat, an aldose reductase inhibitor. Several sets of silicone hydrogels were synthesized varying the contents in 2-hydroxyethyl methacrylate (HEMA), monomethacryloxypropyl-sym-polydimethylsiloxane hydroxypropyl terminated (MCS-MC12), and aminopropyl methacrylamide (APMA)...
October 24, 2017: European Journal of Pharmaceutics and Biopharmaceutics
Magdalena Majekova, Jana Ballekova, Marta Prnova, Milan Stefek
In our previous study, tetrahydropyridoindoles carboxymethylated in position 8 were identified as aldose reductase (ALR2) inhibitors with mild efficacy and selectivity yet with significant antioxidant activity. In the present study we proceeded with optimization of the tetrahydropyridoindole scaffold by shifting the carboxymethyl pharmacophore from position 8 to position 5, with the aim to improve the biological activity. Commercial databases were screened for the presence of tetrahydropyridoindoles carboxymethylated in position 5 and an experimental set of eight compounds was created...
December 15, 2017: Bioorganic & Medicinal Chemistry
David L Williams
Blinding cataract is a significant effect of canine diabetes with 75% of animals affected two years after diagnosis. Lens opacification occurs primarily through the generation of sorbitol, a sugar alcohol, through the action of aldose reductase (AR). The osmotic effect of sorbitol draws water into the lens, causing opacification. Inhibition of AR should thus prevent the generation of cataracts. A topical AR inhibitor has been shown to have this effect, as has the commercially available neutraceutical OcuGLO, containing the AR inhibitor alpha lipoic acid (ALA) together with other plant-based antioxidants...
March 16, 2017: Veterinary Sciences
Lixia Ji, Lixia Cheng, Zhihong Yang
OBJECTIVE: To seek efficient aldose reductase inhibitors (ARIs) with excellent in vitro and in vivo biological activities against rat galactosemic cataract. METHODS: The method was firstly optimized to screen strong ARIs from nonoriented synthetic compounds and natural extracts. Then, diosgenin was assessed on osmotic expansion of primarily cultured lens epithelial cells (LECs) induced by galactose (50 mM). Diosgenin was administered to galactosemic rats by oral (100 and 200 mg/kg) or direct drinking (0...
2017: Journal of Diabetes Research
Kirtikar Shukla, Himangshu Sonowal, Ashish Saxena, Kota V Ramana, Satish K Srivastava
Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, fidarestat augmented the EGF-induced expression of Nrf2 in CRC cells...
December 28, 2017: Cancer Letters
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