Investigation of antidiabetic properties of shikonin by targeting aldose reductase enzyme: In silico and in vitro studies

Tasleem, Munazzah; Shoaib, Ambreen; Alabdallah, Nadiyah M.; Alam, Md. Jahoor; Asmar, Zeina El; Jamal, Qazi Mohammad Sajid; Bardakçı, Fevzi; Ansari, Irfan Ahmad; Ansari, Mohammad Javed; Wang, Feng; Badraoui, Riadh; Yadav, Dharmendra Kumar

doi:10.1016/j.biopha.2022.112985

Cited by 10 publications

(10 citation statements)

References 32 publications

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“…These drugs can also avoid the metabolic and biochemical alterations linked to the pathogenesis of diabetes complications. [56,57] AR inhibitors have been developed for diabetic complications in good numbers, but none have proven particularly effective due to low potency or unfavorable side effects. It has therefore attracted much attention to preventing polyol buildup by inhibiting AR to prevent retinopathy and other diabetes-related ocular disease.…”

Section: Resultsmentioning

confidence: 99%

“…Recent data suggests that the polyol pathway is involved in its etiology, and treatment with AR inhibitors can significantly improve symptoms. These drugs can also avoid the metabolic and biochemical alterations linked to the pathogenesis of diabetes complications [56,57] . AR inhibitors have been developed for diabetic complications in good numbers, but none have proven particularly effective due to low potency or unfavorable side effects.…”

Section: Resultsmentioning

confidence: 99%

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Investigation of The Effect of Acylthiourea Derivatives on Diabetes‐Associated Enzymes

et al. 2022

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One of the most prevalent chronic metabolic disorders, diabetes mellitus, is defined by chronic hyperglycemia and the emergence of microvascular and macrovascular pathology unique to diabetes. Several diabetes problems are primarily caused by persistent hyperglycemia. In this study, aldose reductase (AR) and sorbitol dehydrogenase (SDH) enzymes were purified using chromatographic techniques from sheep kidneys and α-glycosidase purchased commercially. The inhibitory effect of seven acylthiourea compounds on the activity of these enzymes associated with diabetes was investigated. As a result of the studies, the acyl thioureas showed an inhibition effect at the micromolar level on the activity of studied enzymes. The most active compound dimethyl 1-((4-methoxybenzoyl)carbamothioyl)-5,5-diphenylpyrrolidine-2,4-dicarboxylate (2 c) had an excellent selectivity on AR with K i : 0.200 � 0.024 μM and dimethyl 1-((2,4-dichlorobenzoyl)carbamothioyl)-5,5-diphenylpyrrolidine-2,4-dicarboxylate (2 g) on SDH and αglycosidase with K i : 0.114 � 0.01 μM and K i : 055 � 0.01 μM, respectively. The findings suggest that our study will contribute to the development of innovative and/or alternative treatment strategies in the treatment of diabetes in the future since acylthiourea compounds have an effective inhibition capacity on critical enzymes associated with diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Investigation of The Effect of Acylthiourea Derivatives on Diabetes‐Associated Enzymes

et al. 2022

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“…A key enzyme for the polyol pathway, [57] which is an alternative pathway for the metabolism of a small quantity of nonphosphorylated glucose, [58] ALR2 is an NADPH‐dependent oxidoreductase [59] that catalyzes the conversion of glucose to sorbitol in a hyperglycemic condition [60] . Sorbitol dehydrogenase enzyme reduces sorbitol to fructose.…”

Section: Resultsmentioning

confidence: 99%

“…Schematic of the role of aldose reductase (ALR2) in diabetic complications. [49] ChemistrySelect phosphorylated glucose, [58] ALR2 is an NADPH-dependent oxidoreductase [59] that catalyzes the conversion of glucose to sorbitol in a hyperglycemic condition. [60] Sorbitol dehydrogenase enzyme reduces sorbitol to fructose.…”

Section: Biological Evaluation and Structure-activity Relationshipmentioning

confidence: 99%

Exploration of Some Bis‐Sulfide and Bis‐Sulfone Derivatives as Non‐Classical Aldose Reductase İnhibitors

et al. 2023

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Aldose reductase (AR, ALR2; EC 1.1.1.21), an enzyme that converts glucose to fructose on the polyol pathway, is an important member of the Aldo-keto reductase superfamily. ALR2 is part of the rate-limiting step, which is associated with diabetic complications in this process, and plays a role in regulating reactive oxygen species induced by growth factors and cytokines. Despite the fact that sulfides and sulfones have been discovered to have a variety of other biological functions, in the current study, we assessed the ALR2 inhibitory potential of the derivatives of bis-sulfide (5 a-i) and bis-sulfone (6 a-i) in order to further our interest in designing and discovering powerful ALR2 inhibitors. The results of the biological investigations showed that all of the derivatives exhibit activity against ALR2, with K I values ranging from 0.53 � 0.03 to 4.20 � 0.06 μM.Among these agents, 2,6-bis((4-chlorophenyl)(phenylthio)methyl)cyclohexan-1-one (5 h), 2,6bis((3-nitrophenyl)(phenylthio)methyl)cyclohexan-1-one (5 c), and 2,6-bis((3-chlorophenyl)(phenylthio)methyl)cyclohexan-1one (5 g) exhibited prominent inhibitory activity with K I constants of 0.53 � 0.03 μM, 0.65 � 0.04 μM, and 0.71 � 0.05 μM, respectively, against ALR2 and were found to be more potent than epalrestat (K I = 0.79 � 0.01 μM) is currently, the only ALR2 inhibitor (ALR2I) utilized in treatment. Additionally, in silico molecular docking experiments were carried out to explain how these bis-sulfides (5 a-i) and bis-sulfones (6 a-i) interacted with the target enzyme ALR2's binding site. According to the ADME-Tox study, these compounds are predicted to be ALR2Is with appropriate drug-like characteristics. The study's findings on sulfides and sulfones could be exploited to create innovative therapeutics that prevent diabetes complications.

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“…It has a significant hypoglycemic effect and is not affected by the hypofunction of pancreatic β cells and the degree of IR. Diabetes mellitus is a heterogeneous clinical entity, characterized by high blood glucose levels or hyperglycaemia, accompanied by “polydipsia”, “polyphagia” and “emaciation” symptoms [ 30 , 31 ]. Low glucose tolerance is a necessary stage in the development of diabetes and is also regarded as the gold standard for the diagnosis of diabetes [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Anemoside B4 Exerts Hypoglycemic Effect by Regulating the Expression of GLUT4 in HFD/STZ Rats

Gong

Yin²,

Wang³

et al. 2023

Molecules

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Anemoside B4 (B4) is a saponin that is extracted from Pulsatilla chinensis (Bge.), and Regel exhibited anti-inflammatory, antioxidant, antiviral, and immunomodulatory activities. However, its hypoglycemic activity in diabetes mellitus has not been evaluated. Here, we explored the effect of B4 on hyperglycemia and studied its underlying mechanism of lowering blood glucose based on hyperglycemic rats in vivo and L6 skeletal muscle cells (L6) in vitro. The rats were fed a high-fat diet (HFD) for one month, combined with an intraperitoneal injection of 60 mg/kg streptozotocin (STZ) to construct the animal model, and the drug was administrated for two weeks. Blood glucose was detected and the proteins and mRNA were expressed. Our study showed that B4 significantly diminished fasting blood glucose (FBG) and improved glucose metabolism. In addition, B4 facilitated glucose utilization in L6 cells. B4 could enhance the expression of glucose transporter 4 (GLUT4) in rat skeletal muscle and L6 cells. Mechanistically, B4 elevated the inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Furthermore, we confirmed the effect of B4 on glucose uptake involved in the enhancement of GLUT4 expression in part due to PI3K/AKT signaling by using a small molecule inhibitor assay and constructing a GLUT4 promoter plasmid. Taken together, our study found that B4 ameliorates hyperglycemia through the PI3K/AKT pathway and promotes GLUT4 initiation, showing a new perspective of B4 as a potential agent against diabetes.

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Investigation of antidiabetic properties of shikonin by targeting aldose reductase enzyme: In silico and in vitro studies

Cited by 10 publications

References 32 publications

Investigation of The Effect of Acylthiourea Derivatives on Diabetes‐Associated Enzymes

Investigation of The Effect of Acylthiourea Derivatives on Diabetes‐Associated Enzymes

Exploration of Some Bis‐Sulfide and Bis‐Sulfone Derivatives as Non‐Classical Aldose Reductase İnhibitors

Anemoside B4 Exerts Hypoglycemic Effect by Regulating the Expression of GLUT4 in HFD/STZ Rats

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