The synergistic effect of fenretinide and metformin to achieve a decrease in insulin resistance and inflammatory mediators: an <i>in vivo</i> study

Hussein, Mohamed M. A.; El-Belbasi, Hussein I.; Morsy, Mohamed A.; Saadeldin, Islam M.; Alshammari, Ghedeir M.

doi:10.1080/26895293.2020.1732483

Cited by 3 publications

(2 citation statements)

References 41 publications

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“…The serum levels of glucose, total protein, albumin, alkaline phosphatase (ALP), total cholesterol, and triglycerides were measured following previously described protocols (Hussein et al 2020). The serum levels of HDL-C, LDL-C, and very low-density lipoprotein-cholesterol (VLDL-C) were determined following previously described protocols (Burstein et al 1970;Wieland and Siedel 1983;and Wilson et al 1985, respectively).…”

Section: Biochemical Analysismentioning

confidence: 99%

Anti-obesity effects of individual or combination treatment with Spirulina platensis and green coffee bean aqueous extracts in high-fat diet-induced obese rats

et al. 2020

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Section: Biochemical Analysismentioning

confidence: 99%

Anti-obesity effects of individual or combination treatment with Spirulina platensis and green coffee bean aqueous extracts in high-fat diet-induced obese rats

et al. 2020

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“…A study conducted on type 2 diabetes patients also demonstrated that serum RBP4 levels were associated with insulin resistance and severity of coronary artery disease [55]. Metformin intervention in an in vivo study demonstrated a decrease in RBP4, thereby improving the insulin sensitivity [56].…”

Section: Retinol Metabolismmentioning

confidence: 96%

Pharmacokinetic–Pharmacometabolomic Approach in Early-Phase Clinical Trials: A Way Forward for Targeted Therapy in Type 2 Diabetes

et al. 2022

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Pharmacometabolomics in early phase clinical trials demonstrate the metabolic profiles of a subject responding to a drug treatment in a controlled environment, whereas pharmacokinetics measure the drug plasma concentration in human circulation. Application of the personalized peak plasma concentration from pharmacokinetics in pharmacometabolomic studies provides insights into drugs’ pharmacological effects through dysregulation of metabolic pathways or pharmacodynamic biomarkers. This proof-of-concept study integrates personalized pharmacokinetic and pharmacometabolomic approaches to determine the predictive pharmacodynamic response of human metabolic pathways for type 2 diabetes. In this study, we use metformin as a model drug. Metformin is a first-line glucose-lowering agent; however, the variation of metabolites that potentially affect the efficacy and safety profile remains inconclusive. Seventeen healthy subjects were given a single dose of 1000 mg of metformin under fasting conditions. Fifteen sampling time-points were collected and analyzed using the validated bioanalytical LCMS method for metformin quantification in plasma. The individualized peak-concentration plasma samples determined from the pharmacokinetic parameters calculated using Matlab Simbiology were further analyzed with pre-dose plasma samples using an untargeted metabolomic approach. Pharmacometabolomic data processing and statistical analysis were performed using MetaboAnalyst with a functional meta-analysis peaks-to-pathway approach to identify dysregulated human metabolic pathways. The validated metformin calibration ranged from 80.4 to 2010 ng/mL for accuracy, precision, stability and others. The median and IQR for Cmax was 1248 (849–1391) ng/mL; AUC0-infinity was 9510 (7314–10,411) ng·h/mL, and Tmax was 2.5 (2.5–3.0) h. The individualized Cmax pharmacokinetics guided the untargeted pharmacometabolomics of metformin, suggesting a series of provisional predictive human metabolic pathways, which include arginine and proline metabolism, branched-chain amino acid (BCAA) metabolism, glutathione metabolism and others that are associated with metformin’s pharmacological effects of increasing insulin sensitivity and lipid metabolism. Integration of pharmacokinetic and pharmacometabolomic approaches in early-phase clinical trials may pave a pathway for developing targeted therapy. This could further reduce variability in a controlled trial environment and aid in identifying surrogates for drug response pathways, increasing the prediction of responders for dose selection in phase II clinical trials.

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Cold Physical Plasma-Mediated Fenretinide Prodrug Activation Confers Additive Cytotoxicity in Epithelial Cells

et al. 2023

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Cold physical plasma is a partially ionized gas operated at body temperature and utilized for heat-sensitive technical and medical purposes. Physical plasma is a multi-component system consisting of, e.g., reactive species, ions and electrons, electric fields, and UV light. Therefore, cold plasma technology is an interesting tool for introducing biomolecule oxidative modifications. This concept can be extended to anticancer drugs, including prodrugs, which could be activated in situ to enhance local anticancer effects. To this end, we performed a proof-of-concept study on the oxidative prodrug activation of a tailor-made boronic pinacol ester fenretinide treated with the atmospheric pressure argon plasma jet kINPen operated with either argon, argon–hydrogen, or argon–oxygen feed gas. Fenretinide release from the prodrug was triggered via Baeyer–Villiger-type oxidation of the boron–carbon bond based on hydrogen peroxide and peroxynitrite, which were generated by plasma processes and chemical addition using mass spectrometry. Fenretinide activation led to additive cytotoxic effects in three epithelial cell lines in vitro compared to the effects of cold plasma treatment alone regarding metabolic activity reduction and an increase in terminal cell death, suggesting that cold physical plasma-mediated prodrug activation is a new direction for combination cancer treatment studies.

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The synergistic effect of fenretinide and metformin to achieve a decrease in insulin resistance and inflammatory mediators: an in vivo study

Cited by 3 publications

References 41 publications

Anti-obesity effects of individual or combination treatment with Spirulina platensis and green coffee bean aqueous extracts in high-fat diet-induced obese rats

Anti-obesity effects of individual or combination treatment with Spirulina platensis and green coffee bean aqueous extracts in high-fat diet-induced obese rats

Pharmacokinetic–Pharmacometabolomic Approach in Early-Phase Clinical Trials: A Way Forward for Targeted Therapy in Type 2 Diabetes

Cold Physical Plasma-Mediated Fenretinide Prodrug Activation Confers Additive Cytotoxicity in Epithelial Cells

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