Evaluating the effect of synthetic curcumin derivatives on skeletal muscle metabolism

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dc.contributor.advisorJack, Babalwaen_ZA
dc.contributor.advisorPheiffer, Carmenen_ZA
dc.contributor.advisorTitinchi, Salamen_ZA
dc.contributor.advisorWindvogel, Shantalen_ZA
dc.contributor.authorRamashia, Rudzanien_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology.en_ZA
dc.date.accessioned2024-02-26T12:27:18Zen_ZA
dc.date.accessioned2024-04-26T13:34:28Zen_ZA
dc.date.available2024-02-26T12:27:18Zen_ZA
dc.date.available2024-04-26T13:34:28Zen_ZA
dc.date.issued2024-02en_ZA
dc.descriptionThesis (MSc)--Stellenbosch University, 2024.en_ZA
dc.description.abstractENGLISH 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.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Agtergrond: Kurkumien, 'n polifenoliese verbinding afkomstig van die risome van borrie (Curcuma longa L.), vertoon 'n uitgebreide reeks voordelige gesondheidseffekte, insluitend die modulasie van skeletspier verwante. Ten spyte van sy belowende terapeutiese potensiaal, het die swak biobeskikbaarheid van kurkumien die ontwikkeling van sintetiese afgeleides aangespoor om die doeltreffendheid daarvan te verbeter. Die doel van hierdie studie was om die effekte van kurkumien en drie sintetiese kurkumien-derivate op skeletspiermetabolisme te evalueer deur gebruik te maak van in silico en in vitro benaderings. Metodes: Twee chloor-kurkumien-derivate (1A6 en 1A8) en 'n asimmetriese kurkumien-derivaat (1B8) is gesintetiseer deur 'n chemiese reaksie van 3-chloorasetielasetoon (1A6 en 1A8) of asetielasetoon (1B8) met booroksied. Hoë resolusie - massaspektrometrie - elektrosproei ionisasie (HR-MS-ESI), fourier transform - infrarooi (FTIR) spektroskopie, en proton kern magnetiese resonansie (1H-KMR) spektroskopie is gebruik om die kurkumien afgeleides te karakteriseer. In silico-berekeningsinstrumente het Protox II, SwissADME en SwissTargetPrediction die toksisiteitsprofiel, absorpsie, verspreiding, metabolisme en uitskeiding (ADME) eienskappe voorspel, en die biologiese teikens van kurkumien, 1A6, 1A8 en 1B8. Molekulêre koppeling is uitgevoer om die molekulêre interaksies en bindingsaffiniteite van kurkumien, 1A6, 1A8 en 1B8 met die voorspelde biologiese teikens te voorspel. Die bioaktiwiteit van kurkumien, 1A6, 1A8 en 1B8 is in vitro geassesseer in differensierende C2C12 mioblaste en in tumor nekrose faktor alfa (TNFα)-behandelde C2C12 miobuise. Sellewensvatbaarheid is beoordeel deur gebruik te maak van die 3-(4,5-dimetieltiasool-2-yl)-2,5-difeniel-2Htetrazoliumbromied (MTT) en die adenosientrifosfaat (ATP) toetse. Oksidatiewe stres is geassesseer deur die totale antioksidantkapasiteit (TAC) en lipiedperoksidasie te kwantifiseer. Die uitdrukking van gene betrokke by insuliensein, oksidatiewe stres, inflammasie, miogenese en spieratrofie is gemeet met behulp van kwantitatiewe intydse polimerase kettingreaksie. Resultate: Kurkumien-derivate is met hoë suiwerheid gesintetiseer en die chemiese strukture is toegelig deur HR-MS-ESI, FTIR en 1H-KMR spektroskopie. In silico-voorspelling het getoon dat kurkumien en die kurkumien-derivate gunstige farmakokinetiese profiele, lae toksisiteit en verbeterde geneesmiddelgelykheid vertoon. 1A8 het die hoogste bindingsaffiniteit gehad en 1A6 het die laagste bindingsaffiniteit gehad vir die meerderheid voorspelde biologiese teikens in vergelyking met kurkumien. In die differensiasie van C2C12 mioblaste, het kurkumien, 1A6, 1A8 en 1B8 sellewensvatbaarheid by hoër dosisse (10 en 20 µM) verminder, terwyl behandeling geen effek op TNFα-geïnduseerde C2C12 miobuise gehad het nie. In TNFα-behandelde miobuise het 1A6 by 5 µM TAC verhoog. Die uitdrukking van fosfoinositied-3-kinase regulatoriese subeenheid 1 (Pi3kr1) is opgereguleer in C2C12 mioblaste wat behandel is met kurkumien, 1A6, 1A8 en 1B8 teen 5 µM. In https://scholar.sun.ac.za iv teenstelling hiermee is miogene faktor 6 (Myf6) uitdrukking afgereguleer deur kurkumien, 1A6, 1A8 en 1B8 (5 µM) in die differensiasie van C2C12 mioblaste, terwyl kurkumien en 1A8 ook die uitdrukking van miogene differensiasie 1 (Myod1) by 5 µM verminder het. Gevolgtrekking: Hierdie studie het getoon dat kurkumien en die drie kurkumien-derivate gunstige farmakokinetiese profiele en verbeterde molekulêre interaksies met hul biologiese teikens gehad het. Laer dosisse het nie selflewensvatbaarheid beïnvloed nie, terwyl 5 µM TAC en Pi3kr1 uitdrukking verhoog het, en Myf6 en Myod1 uitdrukking verminder het, wat hul potensiële effekte demonstreer om skeletspiermetabolisme te moduleer, veral gerig op miogenese. Verdere verkenning van die terapeutiese potensiaal van sintetiese kurkumien-derivate op patologiese toestande wat verband hou met spierdisfunksie is geregverdig.af_ZA
dc.description.versionMastersen_ZA
dc.format.extentxix, 122 pagesen_ZA
dc.identifier.urihttps://scholar.sun.ac.za/handle/10019.1/130327
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshCurcumin -- Pharmacokineticsen_ZA
dc.subject.lcshDerivatives (Chemicals)en_ZA
dc.subject.lcshCurcumin -- Molecular aspectsen_ZA
dc.subject.lcshMyoblastsen_ZA
dc.titleEvaluating the effect of synthetic curcumin derivatives on skeletal muscle metabolismen_ZA
dc.typeThesisen_ZA
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