Kinedak (epalrestat) / Ono Pharma - LARVOL DELTA

Targeting AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma. (PubMed, Signal Transduct Target Ther) - "In terms of overcoming resistance, the AKR1B1 inhibitor epalrestat significantly mitigated drug resistance when it was used in combination with standard therapies. These findings underscore the importance of metabolic reprogramming in the development of HCC resistance. AKR1B1, a key enzyme that regulates metabolic reprogramming, has been identified as a potential biomarker and therapeutic target, providing new insights into overcoming resistance in HCC treatment."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • AKR1B1

N-substituted phthalimide-carboxylic acid hybrids as dual-targeted aldose reductase inhibitors: Synthesis, mechanistic insights, and cancer-relevant profiling. (PubMed, Bioorg Chem) - "Among the series, compound 5f demonstrated the highest inhibitory potency (KI = 7.34 nM), outperforming epalrestat (KI = 232.1 nM)...Transcriptomic data from CCLE and DepMap confirmed AKR1B1 overexpression in these cancer models. Network analysis linked ALR2 to redox imbalance and inflammation, suggesting its broader role in tumorigenesis."

Journal • Diabetes • Inflammatory Arthritis • Lung Cancer • Oncology • Solid Tumor • AKR1B1

Effects of High Glucose on Simulated Ischemia/Reperfusion Injury in Isolated Cardiomyocytes. (PubMed, Int J Mol Sci) - "These findings suggest that high glucose exacerbates IR injury in cardiomyocytes, with the polyol pathway playing a critical role. Targeting this pathway with AR inhibitors like Epalrestat may offer a protective strategy against diabetic heart complications."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • Reperfusion Injury • Type 2 Diabetes Mellitus • AKR1B1

Targeted Inhibition of Aldose Reductase by Isoliquiritigenin Suppresses Fatty Acid Synthesis to Inhibit Macrophage M2 Polarization and Alleviate Pulmonary Fibrosis. (PubMed, J Agric Food Chem) - "This study demonstrates that ISL mitigates bleomycin-induced pulmonary fibrosis and macrophage M2 polarization...AR knockdown and AR inhibitor epalrestat suppressed the ERK-MYC signaling pathway, FAS, and macrophage M2 polarization...Collectively, these findings suggest that ISL inhibits FAS, thereby suppressing macrophage M2 polarization and improving pulmonary fibrosis through modulation of the ERK signaling pathway by targeting AR. ISL may be a potentially effective medicine and food additive for the treatment of pulmonary fibrosis."

Journal • Immunology • Pulmonary Disease • Respiratory Diseases • AKR1B1

Molecular docking analysis of aldose reductase with herbal compounds from selected siddha medicine for anti-cataract treatment. (PubMed, Bioinformation) - "Analysis shows that berberine, piperine, sesamin and carinol have optimal binding interactions with aldose reductase, performing similar to the standard drug epalrestat having estimated free energy values of -10.37 kcal/mol and -10.13 kcal/mol, respectively for further consideration. Thus, the traditional use of these herbs in Siddha medicine as a potential, affordable and non-surgical cataract-preventative agent is shown."

Journal • Cataract • Ophthalmology • AKR1B1

Antidiabetic Properties of Dihydrooxazole Derivatives: In Vitro and In Silico Evaluation as Potential Aldose Reductase and α-Glucosidase Inhibitors. (PubMed, Arch Biochem Biophys) - "The experimental inhibitory effect towards aldose reductase (ALR2) and α-glucosidase (α-Glu) was followed, with some of the compounds showing higher activity than standard compounds, epalrestat, and acarbose. The interactions at the molecular level were investigated by molecular docking simulation, and the specific binding explained the relative reactivity order. The toxicity of compounds was assessed through ecotoxicology examination."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

Epalrestat, an aldose reductase inhibitor, mitigates doxorubicin-induced cardiotoxicity by inhibiting glycometabolism. (PubMed, Int Immunopharmacol) - "EPS is a promising pharmacological agent for protection against DOX-induced cardiotoxicity due to its antioxidative and antiapoptotic effects and its ability to inhibit AGE/RAGE/NF-κB signaling."

IO biomarker • Journal • Cardiovascular • Metabolic Disorders • AKR1B1 • BAX • BCL2 • CASP3 • NPPB

Cellular senescence and its association with aldose reductase promote cyst growth in autosomal dominant polycystic kidney disease. (PubMed, Kidney Int) - "Our study supports the idea that senescence-targeting interventions including senolytics, removal of p16 positive senescent cells, and inhibition of AKR1B1 are promising therapeutic strategies to delay cyst growth in ADPKD."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • AKR1B1 • CDKN2A • PKD1 • PRKD1

Quinazolin-4(3H)-One-Based New Glitazones as Dual Inhibitors of α-Glucosidase and Aldose Reductase: Comprehensive Approaches for Managing Diabetes Mellitus and Its Complications. (PubMed, Arch Pharm (Weinheim)) - "In vitro assays revealed that compounds 8 (cyclohexyl substituted), 9 (phenethyl substituted), and 11 (phenyl substituted) exhibited potent inhibitory effects on both enzymes, with 11 being the most active, showing an ALR2 inhibition (Ki = 0.106 µM) approximately nine times more effective than the standard epalrestat (EPR) (Ki = 0.967 µM) and α-Glu inhibition (Ki = 0.648 µM) about six times stronger than acarbose (ACR) (Ki = 0.3.775 µM). Cytotoxicity assays performed on healthy cell lines (HUVEC and BEAS-B2) revealed that the tested compounds were nontoxic at inhibitory concentrations. These findings highlight the potential of compound 11 as a promising dual inhibitor for managing diabetes and its complications, providing a foundation for further optimization and therapeutic exploration."

Journal • Diabetes • Metabolic Disorders • AKR1B1

Fluorenyl-phthalimide hybrids as potent aldose reductase inhibitors with selective anticancer activity: Rational design, synthesis, and molecular insights. (PubMed, Bioorg Chem) - "Among them, compound 5a exhibited the strongest ALR2 inhibition with a KI of 8.71 ± 0.81 nM, far surpassing the clinical comparator epalrestat (KI = 232.10 ± 14.42 nM)...In silico ADME/Tox profiling supported the drug-like nature of compound 5a, with no major CYP or hERG liabilities predicted. Collectively, these findings position 5a as a first-in-class ALR2-targeted anticancer lead, introducing a chemically novel and mechanistically validated chemotype for further development within the framework of metabolically targeted precision therapies."

Journal • Oncology • AKR1B1

NARI-29: A Novel Epalrestat Derivative Attenuates Pulmonary Fibrosis by Modulating the TGF-β/Smad Signaling. (PubMed, ACS Pharmacol Transl Sci) - "Though pirfenidone and nintedanib are approved drugs, their efficacy is suboptimal...The TGF-β-induced differentiation model utilized LL29/DHLF cells, while the bleomycin (BLCN)-induced pulmonary fibrosis (intratracheal route) model in rats was employed to evaluate the antifibrotic effects of NARI-29 using various molecular biology, histopathology, and lung function techniques...The mechanistic evaluation revealed that NARI-29 alleviated fibrosis by modulating TGF-β/Smad signaling in lung tissues, as corroborated by molecular docking studies. Overall, the results of the current study demonstrated that treatment with NARI-29 significantly improved pulmonary fibrosis and lung function, highlighting its potential as a therapeutic candidate for IPF."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • AKR1B1 • TGFB1

Corrigendum: Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway. (PubMed, Neural Regen Res) - No abstract available

Journal • Diabetic Neuropathy • Pain

An in silico Approach for Identification of Novel Natural Selective ALR2 Inhibitors from Cynomorium songaricum for Treating Diabetic Complications. (PubMed, Curr Pharm Des) - "These promising in silico findings suggest that CID: 8468 and CID: 135 merit further evaluation through in vitro, in vivo, and clinical studies as potential selective inhibitors for the treatment of diabetic complications."

Journal • Atherosclerosis • Diabetes • Metabolic Disorders • Pain • Renal Disease • Retinal Disorders • AKR1B1

The Relationship Between Aldose Reductase and Isoxazole Derivatives: An In Vitro and In Silico Approach to Its Correlation With Diabetic Conditions. (PubMed, Biotechnol Appl Biochem) - "In comparison to the reference pharmaceutical epalrestat (EPR, KI 232.70 ± 15.51 nM), our results demonstrate that these isoxazoles efficiently inhibit ALR2 at nanomolar doses, with inhibition constants (KI) ranging from 12.13 ± 1.24 nM to 89.51 ± 4.68 nM. Important interactions between these isoxazoles and ALR2 are highlighted by the combined in vitro and in silico studies, indicating their potential as therapeutic agents against a range of pathological diseases. Furthermore, these substances that have ALR2 inhibitory properties could be useful as stand-in treatments or preventative measures for diabetes problems."

Journal • Preclinical • Cardiovascular • Cataract • Diabetes • Metabolic Disorders • Ophthalmology • Pain • Renal Disease • Retinal Disorders • AKR1B1

A new naphthalene-based fluorogenic substrate for cytochrome P450 4A11. (PubMed, Biochem J) - "The studies with Fluvoxamine and Epalrestat, specific inhibitors of CYP1A2 and CYP4A11, respectively, showed that despite the activity of recombinant CYP1A2 with MONACRA, it does not take part in its metabolism in HLM. We developed a robust and sensitive automated fluorimetric assay of MONACRA demethylation and used it to compare the substrate saturation profiles (SSP) in seven pooled HLM preparations with the known composition of the P450 pool. These studies demonstrated a close correlation between the of the main kinetic phase of MONACRA metabolism and the fractional content of CYP4A11 in the P450 pool."

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Development and Certification of a Reference Material for Aflatoxins and Zearalenone in Corn/Peanut Blended Vegetable Oil. (PubMed, Foods) - "A certified reference material (CRM) for aflatoxins (AFTB1, AFTB2, AFTG1, AFTG2) and zearalenone (ZEN) in corn/peanut blended vegetable oil (GBW(E)100863) was developed to address the critical need for matrix-specific reference materials in mycotoxin analysis...The CRM provided a robust metrological tool for mycotoxin analysis in complex oil matrices. This study not only enriches the national reference materials library but also supports food safety initiatives by facilitating accurate and reliable mycotoxin detection in vegetable oils, thereby enhancing regulatory compliance and public health protection."

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A rapid and sensitive UHPLC-MS/MS method for epalrestat detection in micro-volumes of human plasma for the first time. (PubMed, Bioanalysis) - "No significant matrix effects were observed and the recovery rate was high. The method was fully validated, including reinjection reproducibility in human plasma, and was successfully applied in a pharmacokinetic study, in which 100% incurred sample reanalysis met the criteria."

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Benchmarking Differential Abundance Tests for 16S microbiome sequencing data using simulated data based on experimental templates. (PubMed, PLoS One) - "2021;17(9):e1008913...Our prior study, where we used simulated data without incorporating a known truth, demonstrated the feasibility of using synthetic data to validate experimental findings. This current study aims to enhance our understanding by systematically evaluating the impact of known truth incorporation on DA test performance, thereby providing further information for the selection and application of DA methods in microbiome research."

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Design, synthesis, and aldose reductase inhibition assessment of novel Quinazolin-4(3H)-one derivatives with 4-Bromo-2-Fluorobenzene functionality. (PubMed, Bioorg Chem) - "Among the synthesized compounds, the cyclohexyl-substituted derivative (compound 9) exhibited the highest potency as a competitive ALR2 inhibitor, with a Ki of 0.064 μM-15 times more effective than the standard inhibitor epalrestat (EPR) (Ki = 0.967 μM)...Overall, compound 9 emerges as a potent and selective ALR2 inhibitor with significant potential for further optimization. Future studies will focus on enhancing its solubility and refining its pharmacokinetic and pharmacodynamic profiles to support its development as a therapeutic candidate for diabetes-associated complications."

Journal • Diabetes • Metabolic Disorders • Pain • Renal Disease • Retinal Disorders • AKR1B1

Therapeutic effects of mecobalamin combined with epalrestat on diabetic peripheral neuropathy: reduction of inflammatory factors and improvement in electromyogram indices. (PubMed, Am J Transl Res) - "Mecobalamin combined with epalrestat substantially alleviates DPN, improves electromyogram indices, and reduces inflammatory factors and oxidative stress response, without increasing adverse reactions."

Journal • Diabetic Neuropathy • Pain • CRP • IL6 • MMP9

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 1,3,4-Thiadiazole Derivatives Targeting Both Aldose Reductase and α-Glucosidase for Diabetes Mellitus. (PubMed, ACS Omega) - "All of the members of the series showed a higher potential of aldose reductase inhibition (K I: 15.39 ± 1.61-176.50 ± 10.69 nM and IC50: 20.16 ± 1.07-175.40 ± 6.97 nM) compared to the reference inhibitor epalrestat (K I: 837.70 ± 53.87 nM, IC50: 265.00 ± 2.26 nM). Furthermore, compounds 6a, 6g, 6h, 6j, 6o, 6p, and 6q showed significantly higher inhibitory activity (K I: 4.48 ± 0.25 μM-15.86 ± 0.92 μM and IC50: 4.68 ± 0.23 μM-34.65 ± 1.78 μM) toward α-glucosidase compared to the reference acarbose (K I: 21.52 ± 2.72 μM, IC50: 132.51 ± 9.86 μM)...A cytotoxicity study was carried out with the L929 fibroblast cell line in vitro, revealing that all of the synthesized compounds were noncytotoxic. Furthermore, AMES test has been added to show the low mutagenic potential of the compounds 6h and 6o."

Journal • Diabetes • Metabolic Disorders • AKR1B1

Tandem reaction-powered near-infrared fluorescent molecular reporter for real-time imaging of lung diseases. (PubMed, Chem Sci) - "Streptozotocin (STZ)-induced diabetic mice and metformin (MET)/epalrestat (EPS)-repaired model studies demonstrated that NBON allowed the sensitive imaging of NADH for lung disease diagnosis and therapeutic monitoring. Furthermore, NBON was successfully applied in the detection of NADH in tumors and lung metastases. Overall, this work provides a general platform for a NIR NADH probe design, and advances the development of NADH probes for mechanistic studies in lung diseases."

Journal • Diabetes • Metabolic Disorders • Oncology • Pulmonary Disease • Respiratory Diseases

Repurposing of epalrestat for neuroprotection in parkinson's disease via activation of the KEAP1/Nrf2 pathway. (PubMed, J Neuroinflammation) - "Collectively, EPS attenuates oxidative stress and mitochondrial dysfunction by directly binding KEAP1 to activate the KEAP1/Nrf2 signaling pathway, further reducing DAergic neurons damage. These findings suggest that EPS has great potential to become a therapeutic for PD as a clinically effective and safe medicine."

Journal • CNS Disorders • Diabetes • Metabolic Disorders • Movement Disorders • Parkinson's Disease • AKR1B1

Retraction notice to "Toxicological profile, phytochemical analysis and anti-inflammatory properties of leaves of Vitex doniana Sweet. (Verbenaceae)" [Heliyon 8 (2022) e10080]. (PubMed, Heliyon) - "[This retracts the article DOI: 10.1016/j.heliyon.2022.e10080.]."

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Isoindole-1,3-Dione Sulfonamides as Potent Inhibitors of Glucosidase, Aldose Reductase, and Tyrosinase: A Molecular Docking and Enzyme Inhibition Study. (PubMed, Biotechnol Appl Biochem) - "Conventional inhibitors have drawbacks such as gastrointestinal side effects and regional availability, examples being acarbose and epalrestat. Structure-activity relationships reflected that compounds with strong hydrogen bonding and hydrophobic interactions led to higher potency. These findings highlight the importance of isoindole-1,3-dione-based sulfonamides as therapeutic agents and will provide valuable leads for developing multifunctional enzyme inhibitors for such diabetic complications and hyperpigmentation."

Journal • Diabetes • Gastrointestinal Disorder • Metabolic Disorders • AKR1B1 • Tyrosinase