Examining the effects of small molecule tyrosine kinase inhibitors on glucose metabolism in skeletal muscle and liver cell lines in vitro
- Authors: Mugiya, Takudzwa Cleophas
- Date: 2025-04-02
- Subjects: Diabetes , Blood glucose , Cancer , Insulin , Protein kinase B , Glucose transporters
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/478829 , vital:78227
- Description: Diabetes mellitus is rising due to aging, sedentary lifestyles, obesity, and unhealthy diets, posing a global health threat. Due to increase in prevalence together with shortfalls associated with current treatment options, there is still a necessity for a continuous search of new pharmacotherapies. Small molecule tyrosine kinase inhibitors are drugs, used in cancer chemotherapy and have been shown to affect glycaemic control and metabolism variably. Studies have shown that tyrosine kinase inhibitors can alter glycaemic control and glucose metabolism, with some demonstrating hypoglycaemic activities whilst others showing hyperglycaemic properties. The mechanism by which tyrosine kinase inhibitors cause glycaemic dysregulation is not well understood, therefore, the clinical significance of these chemotherapeutic agents on glucose handling is also poorly documented. Aims and objectives: This study aims to elucidate how small molecule tyrosine kinase inhibitors affect glucose metabolism in C2C12 and HepG2 cells in vitro, including their impact on glucose uptake, AKT, GLUT-4, and IL-6 expression, GLUT-4 translocation, and alpha-amylase and alpha-glucosidase activity. Methods: In this study, C2C12 and HepG2 cells were seeded in well plates and the initial media glucose concentration was recorded. Cells were then treated with small molecule tyrosine kinase inhibitors; imatinib, dasatinib, axitinib, and erlotinib for 24 hours. Thereafter, the effect of the test drugs was assessed on cell viability, glucose uptake, expression of AKT GLUT-4 and IL-6, and translocation of GLUT-4. Furthermore, effects of the drugs were assessed on the activities of alpha amylase and glucosidase using calometric assays. Results and Discussion: Cells treated with small molecule tyrosine kinase inhibitors were viable after 24 hours. A concentration-dependent increase in glucose uptake in C2C12 cells treated with imatinib was observed as the concentration of imatinib increased. Axitinib, dasatinib, and erlotinib demonstrated glucose uptake levels comparable to the control across all concentrations. Small molecule tyrosine kinase inhibitors demonstrated an increase in GLUT4 translocation in the absence of insulin. GLUT4 expression was comparable in cells treated with small molecule tyrosine kinase inhibitors and the control. Small molecule tyrosine kinase inhibitors showed an increase in AKT expression. C2C12 cells treated with small molecule tyrosine kinase inhibitors were observed to have elevated IL-6 expression compared to the control. The HepG2 cells treated with erlotinib and imatinib demonstrated elevated glucose uptake while cells treated with axitinib and dasatinib were observed to have a lower glucose uptake. Treatment with dasatinib led to a decrease in Akt expression as concentration increased. Small molecule tyrosine kinase inhibitors demonstrated inhibition of alpha-amylase, while only dasatinib and axitinib showed inhibition of alpha-glucosidase. Conclusion: The results show that small molecule tyrosine kinase inhibitors impact glucose metabolism in C2C12 and HepG2 cells via their effect on GLUT-4 translocation and expression and AKT expression. Dasatinib showed promising potential with regard to antidiabetic capabilities. Further research is needed to better understand these mechanisms' effects on metabolic homeostasis and inform future therapeutic strategies. , Thesis (MSc (Pharm)) -- Faculty of Pharmacy, Pharmacy, 2025
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An investigation into the impact of geographical location on the phytochemical composition, pharmacological and toxicological activities of Tulbaghia violacea collected from the Eastern Cape and Gauteng Province
- Authors: Kader, Tasmeera
- Date: 2024-10-11
- Subjects: Tulbaghia violacea , Phytochemicals , Alliaceae Geographical distribution , Diabetes , Alzheimer's disease
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/461819 , vital:76242
- Description: Introduction: The number of communicable and non-communicable diseases continues to rise and has become more prevalent. While drugs exist to manage and/ or treat majority of the communicable and non-communicable diseases, the rise in disease prevalence puts pressure on researchers to find new drug molecules to treat and manage these ailments. Traditional medicine refers to the knowledge, skills and practices which are based on the beliefs and experiences indigenous to cultures and is used to maintain health. Most of the research into traditional medicine focuses on the medicinal plants used. Medicinal plants are any plants in which one or more of its organs contain substances which are used for therapeutic purposes or for the synthesis of drugs. Tulbaghia violacea is a monocotyledonous genus of herbaceous perennial bulbs which is native to Africa and can be readily found throughout South Africa. It is popular for its antimicrobial, antifungal, anticoagulant, antioxidant and anticancer properties. It has been that ecological factors influence the composition and quantity of phytochemicals present in a plant. Aim of the study: The aim of the study was to investigate the impact of geographical location on the phytochemical composition, pharmacological and toxicological activities of T. violacea collected from the Eastern Cape and Gauteng Province. Methods: The leaves of T. violacea were collected from the Eastern Cape and Gauteng Province. The leaves were dried and extracted using serial maceration with solvents hexane, acetone and methanol. The resulting extracts were subjected to qualitative preliminary phytochemical analysis and a quantitative total phenol content test was carried out using gallic acid as the standard. Thin layer chromatography (TLC) was performed to identify classes of compounds present in T. violacea. xix Antioxidant activity of T. violacea was determined qualitatively using a dot-plot and quantitatively using a DPPH radical scavenging activity assay. Ascorbic acid was used as the standard. Anti-diabetic properties of T. violacea were assessed using an α- amylase inhibition assay and an α- glucosidase inhibition assay. Acarbose was used as the standard for these assays. The anti-Alzheimer properties of T. violacea leaf extracts was determined using and acetylcholinesterase (AChE) inhibition assay. Donepezil was used as the standard for this assay. The DPPH radical scavenging activity, the α- amylase inhibition assay, the α- glucosidase inhibition assay and the AChE inhibition assay was combined with linear regression to determine the IC50 values of the T. violacea extracts and the standards. Statistical analysis was conducted to determine any differences between the plant samples and the standards as well as any differences between the EC and GP sample. Results: The results of the qualitative phytochemical analysis revealed the presence of saponins, flavonoids, tannins, alkaloids, steroids, cardiac glycosides and phenolic compounds present in T. violacea collected from EC and GP. However, their presence in the samples were different based on where the plant was cultivated. The results of the total phenolic content test, revealed that the hexane, acetone and methanol extracts of T. violacea contained phenolic compounds with the highest quantity of phenolic compounds being present in the methanol extracts. Significant statistical difference in total phenolic content between the EC and GP samples were seen for the hexane and methanol extracts. The results of the TLC revealed the presence of multiple bands which confirmed the presence of multiple phytochemicals in T. violacea. All of the extracts of T. violacea from EC and GP, showed antioxidant activity using both the dot-plot and the DPPH radical scavenging activity assay. The highest DPPH radical scavenging activity was seen by the hexane extract of the EC sample of T. violacea. The results showed significant statistical difference between the DPPH radical scavenging activity of the EC and GP samples. , Thesis (Msc (Pharmacy)) -- Faculty of Pharmacy, Pharmacy, 2024
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An in vitro investigation of novel quinolone derivatives on selected pharmacological targets for diabetes mellitus and associated complications
- Authors: Ayodele, Omobolanle Opeyemi
- Date: 2023-03-29
- Subjects: Diabetes , Hyperglycemia , Quinolone antibacterial agents , Cardiovascular system Diseases , Diabetes Alternative treatment , In vitro experiment
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/409813 , vital:70632
- Description: Diabetes mellitus (DM) is a group of endocrine and metabolic disorders characterised and identified by the presence of hyperglycaemia over a long period and, to an extent, accompanied by hyperlipidaemia. CVD has been reported to be the leading cause of mortality in patients with DM. Several antidiabetic agents are available for managing DM, but these agents are not for curative therapy and present with undesirable side effects. In addition, these agents become less effective as the patient's condition progresses to complete beta-cell failure. Therefore, developing newer antidiabetic agents with minimal undesirable side effects, prolonged efficacy and protection against the development of DM complications are necessary. This study was conducted to identify potential novel antidiabetic agents with cardiovascular-protective activity. The compounds of interest for the study were quinolone derivatives since quinolones have been reported to have an antihyperglycaemic effect. , Thesis (MSc) -- Faculty of Pharmacy, 2023
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