Browsing by Author "Ramashia, Rudzani"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Evaluating the effect of synthetic curcumin derivatives on skeletal muscle metabolism
    (Stellenbosch : Stellenbosch University, 2024-02) Ramashia, Rudzani; Jack, Babalwa; Pheiffer, Carmen; Titinchi, Salam; Windvogel, Shantal; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology.
    ENGLISH ABSTRACT: Background: Curcumin, a polyphenolic compound derived from the rhizomes of turmeric (Curcuma longa L.), exhibits an extensive range of beneficial health effects, including the modulation of skeletal muscle disorders. Despite its promising therapeutic potential, the poor bioavailability of curcumin has prompted the development of synthetic derivatives to enhance its efficacy. The aim of this study was to evaluate the effects of curcumin and three synthetic curcumin derivatives on skeletal muscle metabolism using in silico and in vitro approaches. Methods: Two chloro-curcumin derivatives (1A6 and 1A8) and an asymmetric curcumin derivative (1B8) were synthesized through a chemical reaction of 3-chloroacetylacetone (1A6 and 1A8) or acetylacetone (1B8) with boric oxide. High resolution - mass spectrometry - electrospray ionization (HR-MS-ESI), fourier transform - infrared (FT-IR) spectroscopy, and proton nuclear magnetic resonance (1H-NMR) spectroscopy were used to characterize the curcumin derivatives. In silico computational tools, Protox II, SwissADME, and SwissTargetPrediction predicted the toxicity profile, absorption, distribution, metabolism, and excretion (ADME) properties, and the biological targets of curcumin, 1A6, 1A8, and 1B8. Molecular docking was conducted to predict the molecular interactions and binding affinities of curcumin, 1A6, 1A8, and 1B8 with the predicted biological targets. The bioactivity of curcumin, 1A6, 1A8, and 1B8 was assessed in vitro in differentiating C2C12 myoblasts and in tumor necrosis factor alpha (TNFα)-treated C2C12 myotubes. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and the adenosine triphosphate (ATP) assays. Oxidative stress was assessed by quantifying total antioxidant capacity (TAC) and lipid peroxidation. The expression of genes involved in insulin signaling, oxidative stress, inflammation, myogenesis and muscle atrophy was measured using quantitative real-time polymerase chain reaction. Results: Curcumin derivatives were synthesized with high purity and the chemical structures were elucidated by HR-MS-ESI, FTIR, and 1H-NMR spectroscopy. In silico prediction showed that curcumin and the curcumin derivatives exhibited favourable pharmacokinetic profiles, low toxicity, and improved drug-likeness. 1A8 had the highest binding affinity and 1A6 had the lowest binding affinity for the majority of predicted biological targets when compared to curcumin. In differentiating C2C12 myoblasts, curcumin, 1A6, 1A8, and 1B8 reduced cell viability at higher doses (10 and 20 µM), while treatment had no effect on TNFα-induced C2C12 myotubes. In TNFα-treated myotubes, 1A6 at 5 µM increased TAC. The expression of phosphoinositide-3-kinase regulatory subunit 1 (Pi3kr1) was upregulated in C2C12 myoblasts treated with curcumin, 1A6, 1A8, and 1B8 at 5 µM. In contrast, myogenic factor 6 (Myf6) expression was downregulated by curcumin, 1A6, 1A8, and 1B8 (5 µM) in https://scholar.sun.ac.za ii differentiating C2C12 myoblasts, while curcumin and 1A8 also decreased the expression of myogenic differentiation 1 (Myod1) at 5 µM. Conclusion: This study showed that curcumin and the three curcumin derivatives had favourable pharmacokinetic profiles and improved molecular interactions with their biological targets. Lower doses did not affect cell viability, while 5 µM increased TAC and Pi3kr1 expression, and reduced Myf6 and Myod1 expression, demonstrating their potential effects to modulate skeletal muscle metabolism, particularly targeting myogenesis. Further exploration of the therapeutic potential of synthetic curcumin derivatives on pathological conditions associated with muscle dysfunction is warranted.