Aldose Reductase Inhibitor Research Articles

Recent advances in the treatment and delivery system of diabetic retinopathy.

Diabetic retinopathy (DR) is a highly tissue-specific neurovascular complication of type 1 and type 2 diabetes mellitus and is among the leading causes of blindness worldwide. Pathophysiological changes in DR encompass neurodegeneration, inflammation, and oxidative stress. Current treatments for DR, including anti-vascular endothelial growth factor, steroids, laser photocoagulation, and vitrectomy have limitations and adverse reactions, necessitating the exploration of novel treatment strategies. This review aims to summarize the current pathophysiology, therapeutic approaches, and available drug-delivery methods for treating DR, and discuss their respective development potentials. Recent research indicates the efficacy of novel receptor inhibitors and agonists, such as aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, peroxisome proliferator-activated receptor alpha agonists, and novel drugs in delaying DR. Furthermore, with continuous advancements in nanotechnology, a new form of drug delivery has been developed that can address certain limitations of clinical drug therapy, such as low solubility and poor penetration. This review serves as a theoretical foundation for future research on DR treatment. While highlighting promising therapeutic targets, it underscores the need for continuous exploration to enhance our understanding of DR pathogenesis. The limitations of current treatments and the potential for future advancements emphasize the importance of ongoing research in this field.

Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase

Novel oxotriazinoindoles (OTIs) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novel N(2)-substituted oxotriazinoindoles was developed with the aim to investigate molecular interactions within the aldose reductase (ALR2) inhibitor binding site. About twice increased inhibition efficacy of the most efficient derivative 14 (N(2)-CH2CH2COOH) compared to the unsubstituted lead OTI was obtained, yet at the expense of selectivity relative to anti-target aldehyde reductase (ALR1). To explain the major drop in selectivity, observed also in other N(2)-substituted derivatives, in silico molecular modeling approach revealed the role of extra interactions with the residues of Arg309, Arg312 and Met302 located in the additional C-terminal loop of ALR1 missing in ALR2, which can prevent or enhance binding in ALR1. These key findings will be used for development of the next generation of selective OTI inhibitors.

An aldose reductase inhibitor, WJ-39, ameliorates renal tubular injury in diabetic nephropathy by activating PINK1/Parkin signaling

Renal tubular injury is a critical factor during the early stages of diabetic nephropathy (DN). Proximal tubular epithelial cells, which contain abundant mitochondria essential for intracellular homeostasis, are susceptible to disruptions in the intracellular environment, making them especially vulnerable to diabetic state disorders, which may be attributed to their elevated energy requirements and reliance on aerobic metabolism. It is widely thought that overactivation of the polyol pathway is implicated in DN pathogenesis, and inhibition of aldose reductase (AR), the rate-limiting enzyme in this pathway, represents a promising therapeutic avenue. WJ-39, a novel aldose reductase inhibitor, was investigated in this study for its protective effects on renal tubules in DN and the underlying mechanisms. Our findings revealed that WJ-39 significantly ameliorated the renal tubular morphology in high-fat diet (HFD)/streptozotocin (STZ)-induced DN rats, concurrently inhibiting fibrosis. Notably, WJ-39 safeguarded the structure and function of renal tubular mitochondria by enhancing mitochondrial dynamics. This involved the regulation of mitochondrial fission and fusion proteins and the promotion of PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. Furthermore, WJ-39 demonstrated the inhibition of endogenous apoptosis by mitigating the production of mitochondrial reactive oxygen species (ROS). The protective effects of WJ-39 on mitochondria and apoptosis were countered in high glucose-treated HK-2 cells upon transfection with PINK1 siRNA. Overall, our findings suggest that WJ-39 protects the structural and functional integrity of renal tubules in DN, which may be attributed to its capacity to inhibit aldose reductase activity, activate the PINK1/Parkin signaling pathway, promote mitophagy, and alleviate apoptosis.

Onion (Allium cepa L.) Skin Waste Valorization: Unveiling the Phenolic Profile and Biological Potential for the Creation of Bioactive Agents through Subcritical Water Extraction.

Onion skin waste (OSW), the primary non-edible byproduct from onion processing, offers a renewable source of bioactive compounds. This study aims to valorize OSW through subcritical water extraction (SWE), aligning with a circular economy and biorefinery principles. SWE was carried out at 145 °C and 50 bar for 50 min in a discontinuous reactor, producing a phenolic-rich extract (32.3 ± 2.6 mg/g) dominated by protocatechuic acid (20.3 ± 2.5 mg/g), quercetin-4'-O-glucoside (7.5 ± 0.2 mg/g), and quercetin (3.2 ± 0.6 mg/g). Additionally, the extract contains sugars (207.1 ± 20.3 mg sucrose-Eq/g), proteins (22.8 ± 1.6 mg BSA-Eq/g), and free amino acids (20.4 ± 1.2 mg arginine-Eq/g). Its phenolic richness determines its scavenging activity against ●NO and O2●- radicals and its α-glucosidase and aldose-reductase inhibition without affecting α-amylase. Notably, the extract demonstrates significant α-glucosidase inhibition (IC50 = 75.6 ± 43.5 µg/mL), surpassing acarbose (IC50 = 129.5 ± 1.0 µg/mL) in both pure enzyme and cell culture tests without showing cytotoxicity to AGS, HepG2, and Caco-2 human cell lines. The extract's bioactivity and nutritional content make it suitable for developing antioxidant and antidiabetic nutraceutical/food components, highlighting SWE's potential for OSW valorization without using organic solvents.

The potency of lempuyang wangi (Zingiber zerumbet) as aldose reductase inhibitor: an alternative of anti-diabetes drugs

Aldose reductase is an enzyme that plays a role in glucose metabolism. An increase in aldose reductase will trigger an increase in blood sugar concentration by converting glucose to sorbitol. Increased sorbitol conditions will result in diabetes complications such as diabetic cataracts. So we need an inhibitor that can inhibit the working system of the aldose reductase enzyme. One of the medicinal plants that has anti-diabetic properties is lempuyang wangi. Lempuyang wangi has a secondary metabolite compound which has the potential as an antidiabetic. The purpose of this study was to examine the anti-diabetic properties of lempuyang wangi using the in silico method. In this research, docking was carried out with Pymol and Pyrx software, and visualization using Biovia Discovery Studio to see the interaction between zerumbone compounds and aldose reductase and compared with zopolrestat compounds. The docking result of zopolrestat as a comparison compound is -9 kcal/mol, while xanthorrhizol has a binding affinity value of -8,7 kcal/mol and has the same amino acid bonds with zopolrestat, making it a potential candidate as an antidiabetic herbal drug in inhibiting the working system of the aldose reductase enzyme

An Overview on Naturally Occurring Phytoconstituent: Lithospermic Acid

Abstract: Lithospermic acid is a phenylpropanoid oligomer isolated from an aqueous extract of dried roots of various Lamiaceae and Boraginaceae plants and used as a folk medicine to treat cardiovascular disease and to improve body functions. The manuscript has been written to provide valuable insights into naturally occurring phytocomponent, Lithospermic acid, and even explore its therapeutic potential. The data have been gathered from books and web sources, including Science Direct, Publons, Web of Science, and Scopus of the latest year. Lithospermic acid is a conjugate of rosmarinic and caffeic acid with a dihydro benzofuran nucleus and possesses a high antioxidant potential and prevents the production of superoxide radicals and lipid peroxidation and protects the tissue from deleterious effects of reactive oxygen species. In addition, it also possesses a wide range of pharmacological activities, including reducing atherosclerosis, anti-inflammatory, hepatoprotective, anti-viral, HIV-1 integrase, and hyaluronidase inhibition, aldose reductase inhibition and improvement in uremic symptoms guanidino succinic acid level. Due to its anti-HIV activity, LA has gained much attention among the scientific community. Moreover, it is widely distributed to all the peripheral tissue in rats, and its metabolites undergo enterohepatic circulation and are excreted through biliary excretion. In this review, we concluded LA with its phytochemistry, pharmacokinetics, and pharmacological activities.

Characterizing diabetic cardiomyopathy: baseline results from the ARISE-HF trial

BackgroundDiabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM.MethodsAmong study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified.ResultsAmong 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy.ConclusionsBaseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM.Trial RegistrationARISE-HF, NCT04083339.

Mitigation of lens opacification by a functional food in a diabetic rodent model

The current study was designed to test a functional food (FF) mixture containing aldose reductase inhibitors and antiglycation bioactive compounds for suppressing the onset and progression of cataracts in a diabetic rat model. Two-month-old Sprague Dawley rats were grouped as control (C), diabetes untreated (D), and diabetic rats treated with FF at two doses (FF1 = 1.35 g and FF2 = 6.25 g/100g of diet). Diabetes was induced by a single injection of streptozotocin. The FF is a mixture of amla, turmeric, black pepper, cinnamon, ginger, and fenugreek added to the rodent diet. The status of cataracts was monitored weekly by a slit lamp examination for 20 weeks, after which animals were sacrificed to collect eye lenses. Feeding FF1 and FF2 to diabetic rats yielded a significant anti-hyperglycaemic effect and marginally prevented body weight loss. FF delayed cataract progression, and FF2 showed better efficacy than FF1. FF prevented the loss of lens crystallins and their insolubilization in diabetic rats. The antioxidant potential of FF was evident with the lowered protein carbonyls, lipid peroxidation, and prevention of altered antioxidant enzyme activities induced by diabetes. These studies demonstrate the efficacy of plant-derived dietary supplements against the onset and progression of cataracts in a well-established rat model of diabetic eye disease.

DEMETHOXYLATED CURCUMINOIDS AS ANTIDIABETIC COMPLICATION DRUG LEADS – IN SILICO STUDIES

Curcuma longa is used traditionally in the treatment of diabetes and diabetic complications. Aldose Reductase (ALR2) inhibition is a plausible therapeutic strategy against diabetic complications. This work was aimed at evaluating Curcuma longa phytochemicals, in silico, for their ALR2 inhibitory potentials. Thirty-nine (39) phytoconstituents of Curcuma longa were subjected to a succession of in silico screenings comprising molecular docking, drug-likeness and safety profiling to identify ALR2 inhibitor leads, validating their binding interactions with molecular dynamics simulations at 50 ns simulation time. The in silico evaluations afforded two demethoxylated curcuminoids, bisdemethoxycurcumin and demethoxycurcumin, as potential ALR2 inhibitor leads forming stable ALR2 complexes, their relative potencies correlating to their degrees of demethoxylation. The two curcuminoids are herein recommended as leads for the discovery of ALR2 inhibitory antidiabetic complication drug leads.

Aldose reductase is a potential therapeutic target for neurodegeneration

Neurodegeneration is a complex process involving various inflammatory mediators and cellular responses. Aldose reductase (AR) is a key enzyme in the polyol pathway, which converts glucose to sorbitol. Beyond its metabolic role, AR has also been found to play a significant role in modulating neuroinflammation. This review aims to provide an overview of the current knowledge regarding the involvement of AR inhibition in attenuating neuroinflammation and complications from diabetic neuropathies. Here, we review the literature regarding AR and neuropathy/neurodegeneration. We discuss the mechanisms underlying the influence of AR inhibitors on ocular inflammation, beta-amyloid-induced neurodegeneration, and optic nerve degeneration. Furthermore, potential therapeutic strategies targeting AR in neurodegeneration are explored. The understanding of AR's role in neurodegeneration may lead to the development of novel therapeutic interventions for other neuroinflammatory disorders.

Proteomics-based screening of AKR1B1 as a therapeutic target and validation study for sepsis-associated acute kidney injury.

Sepsis and sepsis-associated acute kidney injury (SA-AKI) pose significant global health challenges, necessitating the development of innovative therapeutic strategies. Dysregulated protein expression has been implicated in the initiation and progression of sepsis and SA-AKI. Identifying potential protein targets and modulating their expression is crucial for exploring alternative therapies. We established an SA-AKI rat model using cecum ligation perforation (CLP) and employed differential proteomic techniques to identify protein expression variations in kidney tissues. Aldose reductase (AKR1B1) emerged as a promising target. The SA-AKI rat model received treatment with the aldose reductase inhibitor (ARI), epalrestat. Blood urea nitrogen (BUN) and creatinine (CRE) levels, as well as IL-1β, IL-6 and TNF-α levels in the serum and kidney tissues, were monitored. Hematoxylin-eosin (H-E) staining and a pathological damage scoring scale assessed renal tissue damage, while protein blotting determined PKC (protein kinase C)/NF-κB pathway protein expression. Differential proteomics revealed significant downregulation of seven proteins and upregulation of 17 proteins in the SA-AKI rat model renal tissues. AKR1B1 protein expression was notably elevated, confirmed by Western blot. ARI prophylactic administration and ARI treatment groups exhibited reduced renal injury, low BUN and CRE levels and decreased IL-1β, IL-6 and TNF-α levels compared to the CLP group. These changes were statistically significant (P<0.05). AKR1B1, PKC-α, and NF-κB protein expression levels were also lowered in the ARI prophylactic administration and ARI treatment groups compared to the CLP group (P<0.05). Epalrestat appeared to inhibit the PKC/NF-κB inflammatory pathway by inhibiting AKR1B1, resulting in reduced inflammatory cytokine levels in renal tissues and blood. This mitigated renal tissue injuries and improved the systemic inflammatory response in the severe sepsis rat model. Consequently, AKR1B1 holds promise as a target for treating sepsis-associated acute kidney injuries.

Hyperglycemia exacerbates cerebral ischemia/reperfusion injury by up-regulating autophagy through p53-Sesn2-AMPK pathway

Hyperglycemia exacerbates ischemic brain injury by up-regulating autophagy. However, the underlying mechanisms are unknown. This study aims to determine whether hyperglycemia activates autophagy through the p53-Sesn2-AMPK signaling pathway. Rats were subjected to 30-min middle cerebral artery occlusion (MCAO) with reperfusion for 1- and 3-day under normo- and hyperglycemic conditions; and HT22 cells were exposed to oxygen deprivation (OG) or oxygen–glucose deprivation and re-oxygenation (OGD/R) with high glucose. Autophagy inhibitors, 3-MA and ARI, were used both in vivo and in vitro. The results showed that, compared with the normoglycemia group (NG), hyperglycemia (HG) increased infarct volume and apoptosis in penumbra area, worsened neurological deficit, and augmented autophagy. after MCAO followed by 1-day reperfusion. Further, HG promoted the conversion of LC-3I to LC-3II, decreased p62, increased protein levels of aldose reductase, p53, P-p53ser15, Sesn2, AMPK and numbers of autophagosomes and autolysosomes, detected by transmission electron microscopy and mRFP-GFP-LC3 molecular probe, in the cerebral cortex after ischemia and reperfusion injury in animals or in cultured HT22 cells exposed to hypoxia with high glucose content. Finally, experiments with autophagy inhibitors 3-MA and aldose reductase inhibitor (ARI) revealed that while both inhibitors reduced the number of TUNEL positive neurons and reversed the effects of hyperglycemic ischemia on LC3 and p62, only ARI decreased the levels of p53, P-p53ser15. These results suggested that hyperglycemia might induce excessive autophagy to aggravate the brain injury resulted from I/R and that hyperglycemia might activate the p53-Sesn2-AMPK signaling pathway, in addition to the classical PI3K/AKT/mTOR autophagy pathway.

Aldo-keto reductases: Role in cancer development and theranostics.

Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized.

Harnessing the therapeutic potential of Coccinia grandis phytochemicals in diabetes: A computational, DFT calculation and MMGBSA perspective on aldose reductase inhibition

The role of aldose reductase (ALR), the key enzyme of the polyol pathway, has been firmly established in hyperglycemia-induced diabetic complications. Therefore, the present study focused on the screening of phytochemicals reported in Coccinia grandis against ALR using in-silico methodologies encompassing molecular docking, pharmacokinetics, molecular dynamic simulation, free energy calculation (MMGBSA), and quantum mechanics. A comprehensive array of 101 compounds from C. grandis documented in IMPPAT database and different literatures have been selected in this study. These compounds were meticulously docked with the ALR (PDB ID: 1EL3), yielding docking scores spanning a range of −5.8 to −11.0 kcal/mol compared to the positive control epalrestat with a score of −7.9kcal/mol. Among them, four compounds have been emerged as the most promising ALR inhibitors: tiliroside, lukianol B, formononetin, and trachelogenin, with docking scores of −11.0, −10.7, −10.4, and −10.2, respectively. Importantly, these compounds exhibited notable stability throughout 100 ns dynamic simulations compared to the control drug, aligning with Lipinski's rule of 5, standard ADME properties, and evincing an absence of anomalous toxic effects. Therefore, these compounds hold great promise as leads to the development of potent ALR inhibitors; however, further studies are needed to warrant their uses in ameliorating diabetic complications.

Carbene and photocatalyst-catalyzed 3-acylation of indoles for facile access to indole-3-yl aryl ketones.

3-Acyl indoles play important roles in both organic synthesis and diverse types of functional molecules. Herein, a facile nitrogen heterocyclic carbene (NHC) and photocatalyst cooperatively-catalyzed 3-acylation of indoles was disclosed. The reaction proceeded via radical cross-coupling of indole-based aryl radical cations with NHC-bound ketyl radical species, which are less explored in radical NHC catalysis. The reaction exhibits mild reaction conditions, broad substrate scope, and good functional group tolerance. Mechanistic studies support our proposed reaction pathway. The synthesis of structurally diverse analogs of an aldose reductase inhibitor and antibacterial activity investigation further demonstrated the utility of the current acylation reaction.

Docking Techniques for Unravelling the Molecular Mechanisms of Specioside of Kigelia africana Fruits

In this study, the inhibitors of α-amylase and aldose reductase, the key of proteins in diabetes mellitus, were isolated as compound speciosides from the Kigelia africana fruit Benth. Speciosides were selected as ligands for the receptors of α-amylase and aldose reductase in the molecular docking studies used by PyRx (0.8) for the inhibition of α-amylase and aldose reductase. The results showed that the α-amylase binding energy was 8.1 kcal/mol and aldose reductase was -9 kcal/mol. The ADME process showed that it was easily absorbed orally and distributed through the CNS, metabolized by CYP2D6, and excreted through renal Toxicity studies of speciosides showed no hepatotoxicity or skin sensitization. The in-silico studies of specioside compounds led to the development of potent α-amylase and aldose reductase inhibitors used to treat diabetic mellitus.

Discovery of a Novel Benzothiadiazine-Based Selective Aldose Reductase Inhibitor as Potential Therapy for Diabetic Peripheral Neuropathy.

Aldose reductase2 (ALR2), an activated enzyme in polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for diabetic complications especially in diabetic peripheral neuropathy (DPN). However, lots of ALR2 inhibitors showed serious sideeffects due to poor selectivity over aldehyde reductase (ALR1). Herein, we described the discovery of a series of benzothiadiazine acetic acid derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities in vivo. Compound 15c carrying carbonyl group at the 3-position of thiadiazine ring showed high potent inhibition against ALR2 (IC50 = 33.19 nM) and about 16109-fold selectivity for ALR2 over ALR1. Cytotoxicity assays ensured the primary biosafety of 15c. Further pharmacokinetic assay in rats indicated 15c had a good pharmacokinetic feature (T1/2 = 5.60 h, AUC(0-t) = 598.57±216.5 μg/mL*h), which was superior to Epalrestat (T1/2 = 2.23 h, AUC(0-t) = 20.43±3.7 μg/mL*h). Finally, in streptozotocin (STZ)-induced diabetic rat model, 15c significantly increased the nerve conduction velocities (NCVs) of impaired sensory and motor nerve, achieved potent inhibition of D-sorbitol production in the sciatic nerves, and significantly increased the paw withdrawal mechanical threshold (PWMT). Combined the above investigations, we proposed that 15c might represent a promising lead compound for discovery of anti-diabetic peripheral neuropathy drug.

Key Therapeutic Targets to Treat Hyperglycemia-Induced Atherosclerosis Analyzed Using a Petri Net-Based Model.

Chronic superphysiological glucose concentration is a hallmark of diabetes mellitus (DM) and a cause of damage to many types of cells. Atherosclerosis coexists with glucose metabolism disturbances, constituting a significant problem and exacerbating its complications. Atherosclerosis in DM is accelerated, so it is vital to slow its progression. However, from the complex network of interdependencies, molecules, and processes involved, choosing which ones should be inhibited without blocking the pathways crucial for the organism's functioning is challenging. To conduct this type of analysis, in silicotesting comes in handy. In our study, to identify sites in the network that need to be blocked to have an inhibitory effect on atherosclerosis in hyperglycemia, which is toxic for the human organism, we created a model using Petri net theory and performed analyses. We have found that blocking isoforms of protein kinase C (PKC)-PKCβ and PKCγ-in diabetic patients can contribute to the inhibition of atherosclerosis progression. In addition, we have discovered that aldose reductase inhibition can slow down atherosclerosis progression, and this has been shown to reduce PKC (β and γ) expression in DM. It has also been observed that diminishing oxidative stress through the inhibitory effect on the AGE-RAGE axis may be a promising therapeutic approach in treating hyperglycemia-induced atherosclerosis. Moreover, the blockade of NADPH oxidase, the key enzyme responsible for the formation of reactive oxygen species (ROS) in blood vessels, only moderately slowed down atherosclerosis development. However, unlike aldose reductase blockade, or direct PKC (β and γ), the increased production of mitochondrial ROS associated with mitochondrial dysfunction effectively stopped after NADPH oxidase blockade. The results obtained may constitute the basis for further in-depth research.

Tetrazoles and Related Heterocycles as Promising Synthetic Antidiabetic Agents.

Tetrazole heterocycle is a promising scaffold in drug design, and it is incorporated into active pharmaceutical ingredients of medications of various actions: hypotensives, diuretics, antihistamines, antibiotics, analgesics, and others. This heterocyclic system is metabolically stable and easily participates in various intermolecular interactions with different biological targets through hydrogen bonding, conjugation, or van der Waals forces. In the present review, a systematic analysis of the activity of tetrazole derivatives against type 2 diabetes mellitus (T2DM) has been performed. As it was shown, the tetrazolyl moiety is a key fragment of many antidiabetic agents with different activities, including the following: peroxisome proliferator-activated receptors (PPARs) agonists, protein tyrosine phosphatase 1B (PTP1B) inhibitors, aldose reductase (AR) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, G protein-coupled receptor (GPCRs) agonists, glycogen phosphorylases (GP) Inhibitors, α-glycosidase (AG) Inhibitors, sodium glucose co-transporter (SGLT) inhibitors, fructose-1,6-bisphosphatase (FBPase) inhibitors, IkB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) inhibitors, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In many cases, the tetrazole-containing leader compounds markedly exceed the activity of medications already known and used in T2DM therapy, and some of them are undergoing clinical trials. In addition, tetrazole derivatives are very often used to act on diabetes-related targets or to treat post-diabetic disorders.

Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss

Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.