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The escalating global prevalence of diabetes mellitus (DM) over the past two decades has led to a persistent high incidence of diabetic retinopathy (DR), necessitating screening for early symptoms and proper treatment. Effective management of DR aims to decrease vision impairment by controlling modifiable risk factors including hypertension, obesity, and dyslipidemia. Moreover, systemic medications and plant-based therapy show promise in advancing DR treatment. One of the key mechanisms related to DR pathogenesis is the polyol pathway, through which aldose reductase (AR) catalyzes the conversion of glucose to sorbitol within various tissues, including the retina, lens, ciliary body and iris. Elevated glucose levels activate AR, leading to osmotic stress, advanced glycation end-product formation, and oxidative damage. This further implies chronic inflammation, vascular permeability, and angiogenesis. Our comprehensive narrative review describes the therapeutic potential of aldose reductase inhibitors in treating DR, where both synthetic and natural inhibitors have been studied in recent decades. Our synthesis aims to guide future research and clinical interventions in DR management.

BACKGROUND: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity.
OBJECTIVE: This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo2).
METHODS: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables.
RESULTS: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10).
CONCLUSIONS: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

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.

Aldose reductase (AR) is an important enzyme involved in the reduction of various aldehyde and carbonyl compounds, including the highly reactive and toxic 4-hydroxynonenal (4-HNE), which has been linked to the progression of various pathologies such as atherosclerosis, hyperglycemia, inflammation, and tumors. AR inhibitors have potential therapeutic benefits for these diseases by reducing lipid peroxidation and mitigating the harmful effects of reactive aldehydes. In this study, we found that torachrysone-8-O-β-d-glucoside (TG), a natural product isolated from Polygonum multiflorum Thunb., functions as an effective inhibitor of AR, exhibiting potent effects in clearing reactive aldehydes and reducing inflammation. TG up-regulated the mRNA levels of several antioxidant factors downstream of NRF2, especially glutathione S-transferase (GST), which is significantly increased, thus detoxifying 4-HNE by facilitating the conjugation of 4-HNE to glutathione, forming glutathione-4-hydroxynonenal (GS-HNE). By employing a combination of molecular docking, cellular thermal shift assay, and enzyme activity experiments, we demonstrated that TG exhibited strong binding affinity with AR and inhibited its activity and blocked the conversion of GS-HNE to glutathionyl-1,4-dihydroxynonene (GS-DHN), thereby preventing the formation of protein adducts and inducing severe cellular damage. This study provides novel insights into the anti-inflammatory mechanisms of AR inhibitors and offers potential avenues for developing therapeutic strategies for AR-related pathologies. Our findings suggest that TG, as an AR inhibitor, may hold promise as a therapeutic agent for treating conditions characterized by excessive lipid peroxidation and inflammation. Further investigations are needed to fully explore the clinical potential of TG and evaluate its efficacy in the treatment and management of these complex diseases.

UNASSIGNED: Patients with diabetes mellitus have an elevated chance of developing cataracts, a degenerative vision-impairing condition often needing surgery. The process of the reduction of glucose to sorbitol in the lens of the human eye that causes cataracts is managed by the Aldose Reductase Enzyme (AR), and it is been found that AR inhibitors may mitigate the onset of diabetic cataracts. There exists a large pool of natural and synthetic AR inhibitors that can prevent diabetic complications, and the development of a machine-learning (ML) prediction model may bring new AR inhibitors with better characteristics into clinical use.
UNASSIGNED: Using known AR inhibitors and their chemical-physical descriptors we created the ML model for prediction of new AR inhibitors. The predicted inhibitors were tested by computational docking to the binding site of AR.
UNASSIGNED: Using cross-validation in order to find the most accurate ML model, we ended with final cross-validation accuracy of 90%. Computational docking testing of the predicted inhibitors gave a high level of correlation between the ML prediction score and binding free energy.
UNASSIGNED: Currently known AR inhibitors are not used yet for patients for several reasons. We think that new predicted AR inhibitors have the potential to possess more favorable characteristics to be successfully implemented after clinical testing. Exploring new inhibitors can improve patient well-being and lower surgical complications all while decreasing long-term medical expenses.

Cemtirestat, a bifunctional drug acting as an aldose reductase inhibitor with antioxidant ability, is considered a promising candidate for the treatment of diabetic neuropathy. Our study firstly examined the effects of prolonged cemtirestat treatment on bone parameters reflecting bone quality in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Experimental animals were assigned to four groups: non-diabetic rats, non-diabetic rats treated with cemtirestat, diabetic rats, and diabetic rats treated with cemtirestat. Higher levels of plasma glucose, triglycerides, cholesterol, glycated hemoglobin, magnesium, reduced femoral weight and length, bone mineral density and content, parameters characterizing trabecular bone mass and microarchitecture, cortical microarchitecture and geometry, and bone mechanical properties were determined in STZ-induced diabetic versus non-diabetic rats. Treatment with cemtirestat did not affect all aforementioned parameters in non-diabetic animals, suggesting that this drug is safe. In diabetic rats, cemtirestat supplementation reduced plasma triglyceride levels, increased the Haversian canal area and slightly, but insignificantly, improved bone mineral content. Nevertheless, the insufficient effect of cemtirestat treatment on diabetic bone disease does not support its use in the therapy of this complication of type 1 diabetes mellitus.

BACKGROUND: To assess the safety, tolerability and pharmacokinetics of a single dose of SYHA1402 in healthy Chinese subjects.
METHODS: This was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy subjects. Subjects received a single dose of SYHA1402 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg, or matching placebo. Safety and tolerability were assessed throughout the study. The pharmacokinetic (PK) parameters of SYHA1402 were estimated using non-compartmental analysis.
RESULTS: In all, 54 subjects were enrolled and completed the study. Specifically, there were no deaths, serious adverse events or withdrawals from study due to adverse events. All treatment-emergent adverse events were mild. The most common drug-related adverse event was sinus bradycardia. The time to maximum concentration ranged from 1.13 to 2.25 h, and the terminal elimination half-life range was 1.51-4.70 h. SYHA1402 exhibited nonlinear PK parameters with less than dose-proportional increases in exposure after single oral doses of 25 to 800 mg.
CONCLUSIONS: SYHA1402 administered as a single dose was well tolerated and safe over the dose range of 25-800 mg. More than 50% of the unchanged SYHA1402 was excreted in urine within the dose range of 25-100 mg.
BACKGROUND: NCT03988413 ( https://www.
RESULTS: gov/ ; registration date: 17 June 2019).

Lukianol A (1a) and its six derivatives 1b-1g, in which each hydroxyl groups of 1a was individually modified, were synthesized via the common intermediate 7a, which was obtained by condensation of the styryl carbazate 10 with p-hydroxyphenylpyruvic acid and subsequent [3,3]-sigmatropic rearrangement. The synthesized lukianol derivatives were evaluated for their ability to inhibit human aldose reductase. 4\'-O-methyl (1b) and 4\'-dehydroxy (1g) derivatives showed the same level of inhibitory activity as 1a (IC50 2.2 µm), indicating that the 4\'-OH is irrelevant for the activity. In contrast, methylation of the hydroxyl group at the 4″\'-position (1d) resulted in the loss of activity at a concentration of 10 µm, and masking the hydroxyl group at the 4″-position (1e) caused a 9-fold decrease in activity compared with that of 1b, suggesting that the 4″-OH is an essential group, and the 4″\'-OH is required for higher activity.

Sorbitol is known as a biomarker for the evaluation of the progress of diabetic complications. We have developed a sorbitol biosensor using an optical fiber for rapid diagnosis and pathological evaluation of diabetic complications. In this paper, we measured blood sorbitol in diabetic rats using an improved biosensor, and discussed the effectiveness of the developed biosensor and the significance of sorbitol measurement. In order to investigate the effectiveness of the developed biosensor, the blood sorbitol level of type II diabetic rats prepared by streptozotocin administration was measured with the developed sensor. The values of sorbitol were highly correlated with the values measured by the F-kit of food analysis and that we confirmed the sorbitol concentration could be quantified using the developed biosensor. Furthermore, the aldose reductase inhibitor \"eparlrestat\", which is a therapeutic drug that suppresses the accumulation of sorbitol, was administered to diabetic rats, and the blood sorbitol level was measured with the developed biosensor. As a result, the blood glucose level was high in both the treated group and the non-treated group, but the blood sorbitol level in the treated group decreased. The results suggest that the measurement of the sorbitol level with the developed biosensor in addition to the blood glucose level enables evaluation of complications like diabetic neuropathy. In the future, we expected that the developed sorbitol biosensor will be miniaturized, the pretreatment method for blood samples will be simplified, and it will be applied to the development of therapeutic agents for diabetic complications and personalized medicine.