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

Adelani, Isaacson Bababode (2021) In silico AND BIOCHEMICAL STUDIES ON THE MODULATORY EFFECTS OF CALCIFEROL ON PROSTATE AND LIVER CANCER. ["eprint_fieldopt_thesis_type_phd" not defined] thesis, Covenant University Ota..

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Abstract

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.

Item Type:	Thesis (["eprint_fieldopt_thesis_type_phd" not defined])
Uncontrolled Keywords:	Vitamin D, hepatocellular carcinoma, circadian rhythm, inflammation, oxidative stress
Subjects:	Q Science > Q Science (General)
Divisions:	Faculty of Medicine, Health and Life Sciences > School of Biological Sciences
Depositing User:	Mrs Patricia Nwokealisi
Date Deposited:	14 Mar 2022 12:08
Last Modified:	14 Mar 2022 12:08
URI:	http://eprints.covenantuniversity.edu.ng/id/eprint/15718

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