ABSTRACT
BACKGROUND: Cholera, an acute enteric infection, is a serious health challenge in both the underdeveloped and the developing world. It is caused by Vibrio cholerae after ingestion of fecal contaminated food or water. Cholera outbreaks have recently been observed in regions facing natural calamities (i.e., earthquake in Haiti 2010) or war (i.e., ongoing civil war in Yemen 2016) where healthcare and sanitary setups have been disrupted as a consequence. Whole-cell oral cholera vaccines (OCVs) have been in market but their regimen efficacy has been questioned. A reverse vaccinology (RV) approach has been applied as a successful anti-microbial measure for many infectious diseases. METHODOLOGY: With the aim of finding new protective antigens for vaccine development, the V. cholerae O1 (biovar eltr str. N16961) proteome was computationally screened in a sequential prioritization approach that focused on determining the antigenicity of potential vaccine candidates. Essential, accessible, virulent and immunogenic proteins were selected as potential candidates. The predicted epitopes were filtered for effective binding with MHC alleles and epitopes binding with greater MHC alleles were selected. RESULTS: In this study, we report lipoprotein NlpD, outer membrane protein OmpU, accessory colonization factor AcfA, Porin, putative and outer membrane protein OmpW as potential candidates qualifying all the set criteria. These predicted epitopes can offer a potential for development of a reliable peptide or subunit vaccine for V. cholerae.
ABSTRACT
BACKGROUND: A positive association between diabetes and breast cancer has been identified by various epidemiological and clinical studies. However, the possible molecular interactions between the two heterogeneous diseases have not been fully determined yet. There are several underlying mechanisms which may increase the risk of breast cancer in diabetic patients. INTRODUCTION: In this study, we focused on the role of O-GlcNAc transferase (OGT) enzyme in the regulation of phosphatidylinositol-3 kinase (PI3K) pathway through activation/deactivation of Akt protein. The efficiency of insulin signaling in adipocytes is reduced as a result of OGT overexpression which further attenuates Akt signaling; as a result, the efficiency of insulin signaling is reduced by downregulation of insulin-responsive genes. On the other hand, increased expression of OGT results in Akt activation in breast cancer cells, leading to enhanced cell proliferation and inhibition of the apoptosis. However, the interplay amongst these signaling pathways is still under investigation. METHODS: In this study, we used Petri nets (PNs) to model and investigate the role of PI3K and OGT pathways, acting as key players in crosstalk between diabetes and breast cancer, resulting in progression of these chronic diseases. Moreover, in silico perturbation experiments were applied on the model to analyze the effects of anti-cancer agents (shRNA and BZX) and anti-diabetic drug (Metformin) on the system. RESULTS: Our PN model reflects the alterations in protein expression and behavior and the correlation between breast cancer and diabetes. The analysis proposed two combination therapies to combat breast cancer progression in diabetic patients including combination of OGTmRNA silencing and OGT inhibitor (BZX) as first combination and BZX and Metformin as the second. CONCLUSION: The PN model verified that alterations in O-GlcNAc signaling affect both insulin resistance and breast cancer. Moreover, the combination therapy for breast cancer patients consisting of anti-diabetic drugs such as Metformin along with OGT inhibitors, for example BZX, can produce better treatment regimens.
