In silico AND BIOCHEMICAL STUDIES ON THE MODULATORY EFFECTS OF CALCIFEROL ON PROSTATE AND LIVER CANCER

Cancer is a large group of diseases characterised by the rapid proliferation of abnormal cells. This disease group contributes to global mortality, with prostate cancer (CaP) and hepatocellular carcinoma (HCC) at the forefront. The liver is one of the sites of synchronous distant metastases where metastatic prostate cancer spreads to. Incidentally, the increased prevalence of vitamin D (VD) deficiency is also a global public health challenge. VD is a lipid-soluble vitamin known for primary roles in skeletal mineralisation. However, it is crucial to understand VD’s role in carcinogenesis. This study examined VD metabolism in prostate cancer (CaP) and hepatocellular carcinoma (HCC). Bioinformatics techniques were used to evaluate dysregulated genomic networks in CaP and HCC. The expression of prostate cancer-related transcriptional factors was analysed with immunohistochemistry techniques. Also, in silico antioxidant and anti-inflammatory potentials of VD were evaluated using molecular docking. In the HCC in vivo study, rats were divided into four experimental groups. Groups one and two were administered 30 mg/kg diethylnitrosamine (DEN) for eleven weeks, with groups three and four receiving normal saline. Before DEN administration, endogenous VD was depleted. Additionally, groups one and three received VD-deficient diet, while groups two and four took VD diet. Using enzyme-linked immunosorbent assay (ELISA), various inflammatory cytokines and cancer biomarkers were evaluated, while quantification of antioxidant parameters and lipids were carried out using spectrophotometric methods. Findings from this study showed synergistic network of events between circadian rhythm (CR), inflammation, oxidative stress, and VD metabolism. In CaP and HCC, VD metabolic gene disruption resulted in significant (p < 0.05) alteration of CR genes. Also, significant (p < 0.05) correlations between the disrupted VD metabolic genes and CR genes, inflammatory, and oxidative stress genes were observed. Meanwhile, racial differences in the expression and correlations of CR gene networks were observed in CaP. Results from CaP studies showed significant (p < 0.05) differential expression of VD and CR genes in African Americans (AA) in comparison to European Americans (EA), which could account for more aggressive subtypes in AA. In silico studies showed varying types of VD are strong antioxidant and anti-inflammatory agents via respective binding to KEAP1, Interleukin 1 (IL-1β), and Tumour necrosis factor (TNF-α). Following the in silico analysis, in vivo rat experimental results also showed ameliorative effects of VD in oxidative stress and inflammation. In the rats, dietary VD significantly (p < 0.05) reduce oxidative stress through increased antioxidant enzyme activities, including glutathione S-transferase and nitric oxide. Furthermore, inflammatory effects were reduced with the inclusion of the VD diet. Increased IL-1β and TNF-α production observed in VD deficient group was systematically reduced (p < 0.05) with dietary VD. In line with other results from this study, histopathological examinations indicate dietary VD could prevent cancer progression at the inflammation stage. Therefore, VD deficiency as a part activates and triggers cancer deterioration through alteration of non-classical pathways. In conclusion, increased vitamin D uptake in deficient cases could play integral roles in mitigating cancer progression hence a possible cancer preventive regime

Stevioside modulates oxidative damage in the liver and kidney of high fat/low streptozocin diabetic rats

This study investigated the potential of stevioside to prevent oxidative DNA damage in the liver and kidney of type 2 diabetes mellitus (T2DM) using high fat-low streptozocin rat model. Rats were treated daily with 12.5, 25 and 50 mg/kg stevioside orally for 21 days. Levels of biomarkers of T2DM, lipid profile and oxidative stress were assayed spectrophotometrically. The DNA ladder assay method was used to assess DNA fragmentation in the liver and kidney while computational analysis was used to predict the mechanisms of antidiabetic properties of stevioside. Stevioside significantly (p < 0.05) decreased the levels of plasma glucose, insulin, dipeptidyl peptidase IV and activities of kidney angiotensin converting enzyme. Stevioside significantly reduced oxidative stress by decreasing the levels of lipid peroxidation and nitric oxide in the liver and kidney; thereby, reducing the extent of DNA fragmentation in the liver and kidney of the diabetic rats. The in silico analysis showed that the ability of stevioside to exert these effects is linked to its inhibition of beta-adrenergic receptor kinase and G-protein-coupled receptor kinase. The results of this study suggest that the prevention of DNA fragmentation may be an additional benefit of the use of stevioside in the management of T2DM