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Jared Tur, Sachin L Badole, Feng Cheng, Aparoop Das, Rakesh C Kukreja, Srinivas M Tipparaju
We previously demonstrated the role of Kvβ1.1 subunit of voltage-activated potassium channel in heart for its sensory roles in detecting changes in NADH/NAD and modulation of ion channel. However, the pharmacological role for the association of Kvβ1 via its binding to ligands such as cortisone and its analogs remains unknown. Therefore, we investigated the significance of Kvβ1.1 binding to cortisone analogs and AR inhibitor epalrestat. In addition, the aldose reductase (AR) inhibitor epalrestat was identified as a pharmacological target and modulator of cardiac activity via binding to the Kvβ1 subunit...
June 5, 2017: Molecular and Cellular Biochemistry
Takayuki Furuishi, Shoma Takahashi, Noriko Ogawa, Mihoko Gunji, Hiromasa Nagase, Toyofumi Suzuki, Tomohiro Endo, Haruhisa Ueda, Etsuo Yonemochi, Kazuo Tomono
Epalrestat (EPL) is a water-insoluble drug (14μM) that inhibits aldose reductase. This study investigated the interactions between β-cyclodextrin (CD) derivatives and EPL to determine the solubilizing effect on EPL from phase solubility diagrams. We improved the solubility of EPL in water by adding β-CD derivatives. Moreover, the solubility of EPL mixed with β-CD derivatives by cogrinding in a ball mill method was about 2-3 times higher than those of EPL with the same CD concentration (5mM) calculated from phase solubility diagrams...
August 30, 2017: European Journal of Pharmaceutical Sciences
Jingqiu Huang, Runbin Sun, Siqi Feng, Jun He, Fei Fei, Haoxue Gao, Yuqing Zhao, Yue Zhang, Huilin Gu, Jiye Aa, Guangji Wang
Epalrestat is clinically applied for the management of diabetic peripheral neuropathy, yet its pharmacokinetic properties are not well understood. In this study, a rapid and sensitive LC-MS/MS method was established for assaying epalrestat in bio-samples of mice. The method was validated and it showed a good linearity over the range of 2-5000ng/mL, a precision of less than 12.3%, and recovery and matrix effects of 112.5-123.6% and 87.9-89.5%, respectively. After administration of a single dose of epalrestat administered, the exposure level of AUC0-∞ was positively dose-dependent and the mean Cmax, AUC0-12h, T1/2, and MRT were 36...
June 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Heba El Gamal, Ali Hussein Eid, Shankar Munusamy
Diabetic nephropathy (DN) is the leading cause of end stage renal disease worldwide. Increased glucose flux into the aldose reductase (AR) pathway during diabetes was reported to exert deleterious effects on the kidney. The objective of this study was to investigate the renoprotective effects of AR inhibition in high glucose milieu in vitro. Rat renal tubular (NRK-52E) cells were exposed to high glucose (30 mM) or normal glucose (5 mM) media for 24 to 48 hours with or without the AR inhibitor epalrestat (1 μM) and assessed for changes in Akt and ERK1/2 signaling, AR expression (using western blotting), and alterations in mitochondrial membrane potential (using JC-1 staining), cell viability (using MTT assay), and cell cycle...
2017: BioMed Research International
Xuebiao Wu, Xiaoli Li, Qiang Fu, Qianhua Cao, Xingyu Chen, Mengjie Wang, Jie Yu, Jingpei Long, Jun Yao, Huixin Liu, Danping Wang, Ruocen Liao, Chenfang Dong
Basal-like breast cancer (BLBC) is associated with high-grade, distant metastasis and poor prognosis. Elucidating the determinants of aggressiveness in BLBC may facilitate the development of novel interventions for this challenging disease. In this study, we show that aldo-keto reductase 1 member B1 (AKR1B1) overexpression highly correlates with BLBC and predicts poor prognosis in breast cancer patients. Mechanistically, Twist2 transcriptionally induces AKR1B1 expression, leading to nuclear factor κB (NF-κB) activation...
April 3, 2017: Journal of Experimental Medicine
Yuan Le, Liming Chen, Yue Zhang, Pengli Bu, Guoli Dai, Xingguo Cheng
No abstract text is available yet for this article.
February 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Zhiyong Huang, Quan Hong, Xueguang Zhang, Wenzhen Xiao, Liyuan Wang, Shaoyuan Cui, Zhe Feng, Yang Lv, Guangyan Cai, Xiangmei Chen, Di Wu
BACKGROUND: Uric acid (UA) is an antioxidant found in human serum. However, high UA levels may also have pro-oxidant functions. According to previous research, aldose reductase (AR) plays a vital role in the oxidative stress-related complications of diabetes. We sought to determine the mechanism by which UA becomes deleterious at high concentrations as well as the effect of AR in this process. METHOD: Endothelial cells were divided into three groups cultured without UA or with 300 μM or 600 μM UA...
January 5, 2017: Cell Communication and Signaling: CCS
Patrick K K Yeung, Angela K W Lai, Hyo Jin Son, Xu Zhang, Onyou Hwang, Stephen S M Chung, Sookja K Chung
Fungicide exposure causes degeneration of dopaminergic neurons and contributes to Parkinson's disease (PD). Benomyl inhibits enzymes responsible for detoxifying the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde. Aldose reductase (AR) is known as tetrahydrobiopterin (BH4) reductase that generates BH4, a cofactor for tyrosine hydroxylase (TH) involved in dopamine synthesis. AR also acts as an aldehyde reductase involved in detoxifying 3,4-dihydroxyphenylacetaldehyde. In PD patients, the level of AR is significantly lower in the cerebellum...
February 2017: Neurobiology of Aging
Jayshree Shriram Dawane, Vijaya Anil Pandit, Madhura Shirish Kumar Bhosale, Pallawi Shashank Khatavkar
INTRODUCTION: Diabetic neuropathy is one of the most common complications affecting 50% of diabetic patients. Neuropathic pain is the most difficult types of pain to treat. There is no specific treatment for neuropathy. Nishamalaki (NA), combination of Curcuma longa and Emblica officinalis used to treat Diabetes Mellitus (DM). So, efforts were made to test whether NA is useful in prevention of diabetic neuropathy. AIM: To evaluate the effect of NA on diabetic neuropathy in type 2 diabetic wistar rats...
October 2016: Journal of Clinical and Diagnostic Research: JCDR
Srinivasan Senthilkumari, Rajendran Sharmila, Gowripriya Chidambaranathan, Ayyasamy Vanniarajan
PURPOSE: Aldose reductase (ALR), the first and rate-limiting enzyme involved in polyol pathway plays a central role in diabetes and its related complications, including diabetic retinopathy (DR). Inhibition of ALR may also be an ideal target for reducing the deleterious effects of DR. Therefore, the purpose of the present study was to investigate the protective effect of epalrestat (EPL), ALR inhibitor on glucose-induced toxicity in ARPE-19 cells. METHODS: ARPE-19 cells were challenged with normal glucose (NG, 5 mM) and high glucose (HG1, 25 mM and HG2, 50 mM) in the presence or absence of EPL...
January 2017: Journal of Ocular Pharmacology and Therapeutics
Ryota Saito, Saori Suzuki, Kaname Sasaki
Aldose reductase is related to the onset and progression of diabetic complications, such as neuropathy, retinopathy, angiopathy, and so on: therefore molecules that are capable of inhibiting the enzyme are potential drugs for treatment of diabetic complications. Epalrestat is the sole aldose reductase inhibitor that is clinically used, but still has some drawbacks. Thus, the development of new aldose reductase inhibitors is still desired. We have synthesized a series of new pterin-7-carboxamides, and evaluated their in vitro inhibitory activities against human aldose reductase...
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
Hong Sun, Yunhai Bo, Mingjie Zhang, Xiao Wu, Mingyang Zhou, Longshan Zhao, Zhili Xiong
In the present study, a simple, rapid and reliable ultrahigh-performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method was developed and validated to determine simultaneously epalrestat (EPA) and puerarin (PUE) in rat plasma for evaluation of the pharmacokinetic interaction of these two drugs. Both the analytes and glipizide (internal standard, IS) were extracted using a protein precipitation method. The separation was performed on a C18 reversed phase column using acetonitrile and 5 mmol/L ammonium acetate in water as the mobile phase with a gradient elution program...
April 2017: Biomedical Chromatography: BMC
Kaori Yama, Keisuke Sato, Yu Murao, Ryosuke Tatsunami, Yoshiko Tampo
Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells...
September 1, 2016: Biological & Pharmaceutical Bulletin
Yuji Ishibashi, Takanori Matsui, Takafumi Matsumoto, Hiroshi Kato, Sho-Ichi Yamagishi
OBJECTIVE: Under diabetic conditions, glucose is converted to sorbitol via aldose reductase, whose process could contribute to diabetic vascular complications. However, effects of aldose reductase inhibitors are modest in diabetic patients. This may be attributed to weak inhibitory activity of aldose reductase inhibitors. We compared effects of ranirestat on endothelial cell damage with those of epalrestat. MATERIALS AND METHODS: Intracellular formations of sorbitol and superoxide were measured by liquid chromatography-mass spectrometry-mass spectrometry and dihydroethidium staining, respectively...
July 2016: Diabetes & Vascular Disease Research
Qing-Rong Li, Zhuo Wang, Wei Zhou, Shou-Rui Fan, Run Ma, Li Xue, Lu Yang, Ya-Shan Li, Hong-Li Tan, Qing-Hua Shao, Hong-Ying Yang
Epalrestat is a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy. This study assumed that epalrestat had a protective effect on diabetic peripheral nerve injury by suppressing the expression of aldose reductase in peripheral nerves of diabetes mellitus rats. The high-fat and high-carbohydrate model rats were established by intraperitoneal injection of streptozotocin. Peripheral neuropathy occurred in these rats after sustaining high blood glucose for 8 weeks...
February 2016: Neural Regeneration Research
Xuyu Zu, Ruilan Yan, Jishen Pan, Linlin Zhong, Yu Cao, Jun Ma, Chuan Cai, Dan Huang, Jianghua Liu, Fung-Lung Chung, Duan-Fang Liao, Deliang Cao
Electrophilic carbonyl compounds are highly cytotoxic and genotoxic. Aldo-keto reductase 1B10 (AKR1B10) is an enzyme catalyzing reduction of carbonyl compounds to less toxic alcoholic forms. This study presents novel evidence that AKR1B10 protects colon cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 is specifically expressed in epithelial cells of the human colon, but this study found that AKR1B10 expression was lost or markedly diminished in colorectal cancer, precancerous tissues, and a notable portion of normal adjacent tissues (NAT)...
January 2017: Molecular Carcinogenesis
Battini Swapna, Kuthuru Suresh, Ashwini Nangia
We report five crystalline polymorphs and an amorphous phase of epalrestat together with configurational isomerism and color behavior: form I (deep red), form II (deep orange), form III (bright yellow), form IV (yellow), and form V (orange) are in the E,Z configuration of the drug, and a Z,Z isomer (bright yellow). Two pathways are identified for polymorph conversion: direct transformation of the E,Z isomer and another pathway via the Z,Z isomer to the E,Z polymorphs. From a pharmaceutical perspective, the stability of polymorphs was established under grinding, solvent slurry and thermal conditions: form I (thermodynamic) > form II > form V > form III > form IV (least stable)...
March 14, 2016: Chemical Communications: Chem Comm
Beatriz Díez-Dacal, Francisco J Sánchez-Gómez, Pedro A Sánchez-Murcia, Ivana Milackova, Tahl Zimmerman, Jana Ballekova, Elena García-Martín, José A G Agúndez, Severine Gharbi, Federico Gago, Milan Stefek, Dolores Pérez-Sala
Aldose reductase (AKR1B1) is a critical drug target because of its involvement in diabetic complications, inflammation, and tumorigenesis. However, to date, development of clinically useful inhibitors has been largely unsuccessful. Cyclopentenone prostaglandins (cyPGs) are reactive lipid mediators that bind covalently to proteins and exert anti-inflammatory and antiproliferative effects in numerous settings. By pursuing targets for modification by cyPGs we have found that the cyPG PGA1 binds to and inactivates AKR1B1...
January 2016: Molecular Pharmacology
Priya Antony, Ranjit Vijayan
Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek)...
2015: PloS One
Ajmer Singh Grewal, Shashikant Bhardwaj, Deepti Pandita, Viney Lather, Bhupinder Singh Sekhon
Diabetes mellitus occurrence has been associated to the modification of the physiological levels of glucose and is often accompanied by several long-term complications, namely neuropathy, nephropathy, retinopathy, cataract, and cardiovascular. Aldose reductase (AR) is an enzyme of aldoketo reductase super-family that catalyzes the conversion of glucose to sorbitol in the polyol pathway of glucose metabolism. In this context, aldose reductase inhibitors (ARIs) have received much attention worldwide. Decreased sorbitol flux through polyol pathway by ARIs could be an emerging target for the management of major complications of diabetes...
2016: Mini Reviews in Medicinal Chemistry
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