Plasma Insulin/Erythrocytic Aldose Reductase Ratio as a Predictor for Hepatocellular Carcinoma Among Type II Diabetics and Hepatitis C Virus-Infected Patients

Purpose Hepatocellular carcinoma (HCC) is a possible oncogenic progression during persistent hepatitis C-infection +/- type II diabetes mellitus (DM). To investigate the plasma insulin, erythrocytic aldose reductase (AR) and sorbitol dehydrogenase (SDH) as possible predictive tools for HCC in hepatitis C-infected patients (HCV) +/- DM. Erythrocytes (RBCs) were adopted as a possible vehicle for pre-malignant variations being of short life span. Methods The study included 20 healthy control and 100 patients of 48–64 years old, divided into 5 equal groups as; type II DM, HCC, HCC with DM, DM- HCV infected and non-DM HCV infected. Plasma levels of AFP and insulin were measured. Results It showed an elevated AR, significant reduction of SDH in RBCs and plasma of DM patients. These values were greatly elevated among HCV, HCC, diabetic HCV, and diabetic HCC patients. All DM patients showed elevated insulin levels than normoglycemic controls. Conclusion The study substantiated the use of RBCs as a vehicle for early diagnostic markers better than plasma. We recommend the use of insulin/ erythrocytic AR ratio as a new laboratory marker for predicting HCC among type II diabetics or non-treated HCV-infected patients with control insulin/ erythrocytic AR ratio by each laboratory.

Separation and Identification of Antioxidants and Aldose Reductase Inhibitors in Lepechinia meyenii (Walp.) Epling

We previously reported that Lepechinia meyenii (Walp.) Epling has antioxidant and aldose reductase (AR) inhibitory activities. In this study, L. meyenii was extracted in a 50% MeOH and CH2Cl2/MeOH system. The active extracts of MeOH and 50% MeOH were subjected to fractionation, followed by separation using high-speed counter-current chromatography (HSCCC) and preparative HPLC. Separation and identification revealed the presence of caffeic acid, hesperidin, rosmarinic acid, diosmin, methyl rosmarinate, diosmetin, and butyl rosmarinate. Of these, rosmarinic acid, methyl rosmarinate, and butyl rosmarinate possessed remarkable antioxidant and AR inhibitory activities. The other compounds were less active. In particular, rosmarinic acid is the key contributor to the antioxidant and AR inhibitory activities of L. meyenii; it is rich in the MeOH extract (333.84 mg/g) and 50% MeOH extract (135.41 mg/g) of L. meyenii and is especially abundant in the EtOAc and n-BuOH fractions (373.71–804.07 mg/g) of the MeOH and 50% MeOH extracts. The results clarified the basis of antioxidant and AR inhibitory activity of L. meyenii, adding scientific evidence supporting its traditional use as an anti-diabetic herbal medicine. The HSCCC separation method established in this study can be used for the preparative separation of rosmarinic acid from natural products.

Screening of potential antidiabetic phytochemicals from Gongronema latifolium leaf against therapeutic targets of type 2 diabetes mellitus: multi-targets drug design

Diabetes mellitus (DM) is the most predominant group of metabolic disorders wreaking havoc on the wellbeing of man, with type 2 diabetes mellitus (type 2 DM) accounting for most DM related cases. This study, hence, investigated the antidiabetic potential of Gongronema latifolium leaf fractionated compounds against proteins implicated in different molecular pathways related to the onset and progression of type 2 DM. A total of fifteen proteins that can act as type 2 DM therapeutic targets were identified from the literature and downloaded/modelled using respective repositories. After docking the compounds with the fifteen proteins, glycogen synthase kinase 3 beta (GSK 3β), glucagon-like peptide-1 receptor (GLP-1R) and human aldose reductase were chosen as the ideal targets due to their high binding affinities with the compounds. Subsequent in silico analysis like binding free energy, ADMET predictions using different servers, and machine-learning predictive models (QSAR) using kernel partial least square regression were employed to identify promising compounds against the three targets. The eleven identified compounds (Luteonin, Kampferol, Robinetin, Gallocatechin, Baicalin, Apigenin, Genistein, Rosmaric acid, Chicoric acid and Naringenin) formed stable complexes with the proteins, showed moderation for toxicity, drugability, GI absorptions and drug-drug interactions, though structure modifications may be needed for lead optimization. The predictive QSAR models with reliable correlation coefficient (R2) showed the potency of the compounds to act as inhibitors (pIC50) of aldose reductase and GSK 3β, and act as agonists (pEC50) of GLP-1R. Thus, this study experimental framework can be used to design compounds that can modulate proteins related to type 2 DM without inducing off-target effects.

Describing a novel chemotherapeutic drug formulated by Diosmin for the treatment of acute lymphoblastic leukemia and diabetes mellitus

IntroductionDiosmin is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features. Acute leukemia is a common type of cancer that is caused in the blood.Material and methodsAlpha amylase activity was determined by a method adapted from the work of Taha et al.ResultsIn this study, we examined its effect on some important enzymes, the IC50 values were 196.07 for Aldose reductase, and 76.40 for alpha amylase. The molecular docking study was performed to assess the binding affinity and biological activities of diosmin in the presence of alpha amylase and aldose reductase. The results of the docking study indicated that diosmin has a remarkable binding affinity to these enzymes with a docking score of -9.768 and -140469 for alpha-amylase and aldose reductase, respectively. Therefore, this compound could be used as a potential inhibitor for these enzymes. In the cellular and molecular part of the recent study, the treated cells with Diosmin were assessed by MTT assay for 48h about the cytotoxicity and anti-human acute lymphoblastic leukemia properties on HL-60, Clone 15 HL-60, HL-60/MX1, and HL-60/MX2 cell lines. The IC50 of Diosmin were 466, 323, 502, and 537 µg/mL against HL-60, Clone 15 HL-60, HL-60/MX1, and HL-60/MX2 cell lines, respectively.ConclusionsThe viability of acute lymphoblastic leukemia cell lines reduced dose-dependently in the presence of Diosmin. It appears that the anti-human acute lymphoblastic leukemia effect of Diosmin is due to their antioxidant effects.

Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase?

The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties allow an inhibitor to bind in the specificity pocket. A series of inhibitors that share the same parent scaffold but differ in their attached aromatic substituents were screened using ITC and X-ray crystallography for their ability to occupy the pocket. Additionally, we investigated the electrostatic potentials and charge distribution across the attached terminal aromatic groups with respect to their potential to bind to the transient pocket of the enzyme using ESP calculations. These methods allowed us to confirm the previously established hypothesis that an electron-deficient aromatic group is an important prerequisite for opening and occupying the specificity pocket. We also demonstrated from our crystal structures that a pH shift between 5 and 8 does not affect the binding position of the ligand in the specificity pocket. This allows for a comparison between thermodynamic and crystallographic data collected at different pH values.