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Doctoral Degrees ( Medical Science)

Permanent URI for this collectionhttps://hdl.handle.net/10413/14011

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Browsing Doctoral Degrees ( Medical Science) by Date Accessioned

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    Strategic application of in silico drug discovery approaches to discover novel TB drugs.
    (2023) Kisten, Kimona.; Mhlongo, Ndumiso Nhlakanipho.; Kumalo, Hezekiel Mathambo.
    Abstract available in a PDF.
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    Drug transporter expression and genetic polymorphisms in HIV endemic settings.
    (2023) Zondo, Nomusa Margaret.; Archary, Derseree.; Sobia, Parveen.
    Abstract available in a PDF.
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    Strategic application of in silico drug discovery approaches to discover novel TB drugs.
    (2023) Kisten, Kimona.; Kumalo, Hezekiel Mathambo.; Mhlongo, Ndumiso Nhlakanipho .
    Abstract available in a PDF.
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    An investigation into kojic acid-associated mitochondrial toxicity and inflammation in melanoma cells (SK-MEL-1).
    (2023) Suritham, Tamzin Kimera.; Chuturgoon, Anil Amichund.; Ghazi, Terisha.
    ojic acid (KA), 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one, is used in agriculture, food, and cosmetics. KA is known to have antimicrobial, antifungal, antioxidant, and anti-inflammatory properties. The cosmetic industry's increasing interest in KA is due to its ability to inhibit tyrosinase activity resulting in skin lightening. The mitochondria play a key role in maintaining homeostasis and ensuring efficient melanin production. Therefore, mitochondrial dysfunction has severe effects on the skin. This study investigates mitochondrial stress, antioxidant responses, protein kinase signalling and inflammation in human melanoma (SK-MEL-1) cells. The mitochondria are important in processing metabolites and supplying the cell with energy in the form of ATP. KA interacts with key mitochondrial homeostasis proteins. Our results found an increase in macromolecule damage specifically lipid peroxidation and protein oxidation. Due to oxidative conditions, increased Nrf2 expression was observed. LON protease is ATP-dependent and regulated by Sirtuin 3 expression. Mitochondrial function was affected illustrated by decreased ATP production leading to decreased LON protease and Sirtuin 3 protein expression. Following increased oxidative stress, KA suppressed the expression of protein kinases but increased inflammatory mediators. There was decreased expression of phospho-Akt, Akt, phospho-GSK3β, p38 and ERK1/2. The mediation of the NLRP3 inflammasome involves priming and activation. At concentrations with high proliferation, NFκB gene and protein expression was activated. The protein kinase signalling pathways are known as mediators of inflammation; however, protein and gene expression of inflammatory mediators was increased following KA treatment. The inflammasome was subsequently activated as shown by an increase in intracellular caspase 1 levels as well as NLRP3, ILβ and IL-6 expression. KA induced mitochondrial stress and suppressed mitochondrial homeostasis proteins. The increased Nrf2 expression could have further downregulated LON protease expression and increased macromolecule damage. Oxidative conditions could have activated the inflammasome pathway independent of protein kinase signalling. In conclusion, KA displayed mitochondrial toxicity following acute exposure by suppressing mitochondrial homeostasis, protein kinase pathways and initiating inflammation. 1