Modulation of Wnt signaling pathway by hepatitis B virus.

Hepatitis B virus (HBV) has a global distribution and is one of the leading causes of hepatocellular carcinoma. The precise mechanism of pathogenicity of HBV-associated hepatocellular carcinoma (HCC) is not yet fully understood. Viral-related proteins are known to take control of several cellular pathways like Wnt/ß-catenin, TGF-ß, Raf/MAPK and ROS for the virus's own replication. This affects cellular persistence, multiplication, migration, alteration and genomic instability. The Wnt/FZD/ß-catenin signaling pathway plays a significant role in the pathology and physiology of the liver and has been identified as a main factor in HCC development. The role of ß-catenin is linked mainly to the canonical pathway of the signaling system. Progression of liver diseases is known to be accompanied by disturbances in ß-catenin expression (mainly overexpression), with its cytoplasmic or nuclear translocation. In recent years, studies have documented that the HBV X protein and hepatitis B surface antigen (HBsAg) can act as pathogenic factors that are involved in the modulation and induction of canonical Wnt signaling pathway. In the present review we explore the interaction of HBV genome products with components of the Wnt/ß-catenin signaling pathway that results in the enhancement of the pathway and leads to hepatocarcinogenesis.

Interplay of Wnt ß-catenin pathway and miRNAs in HBV pathogenesis leading to HCC.

The prevalence of Hepatocellular carcinoma (HCC) has been identified world-wide. Plethora of factors including chronic infection of HBV/HCV has been characterized for the development of HCC. Although the onset and progression of HCC has been linked with awry of various signaling pathways but precise mechanism, still lies under the multitude layers of curiosity. HBV is spreading with insane speed throughout the world and has been found a main culprit in HCC development after regulating the several cellular pathways including Wnt/ß-catenin, Raf/MAPK, Akt and affecting cell multiplication to genomic instability. The role of Wnt/FZD/ß-catenin signaling pathway is centralized in liver functions and its anomalous activation leads to HCC development. ß-catenin mainly plays a pivotal role in canonical pathway of the system. Altered mainly overexpression of ß-catenin along its nuclear localization tunes the aberrations in liver functions and set disease progression. In the development of HCC, modulation of Wnt/FZD/ß-catenin signaling pathway by HBV has been established. As HBV infects the cell it affects the miRNAs, the master regulators of cell. Previous studies showed the connection between HBV and cellular miRNAs. In the present review, we unveiled how HBV is deciphering the cellular miRNAs like miR-26a, miR-15a, miR-16-1, miR-148a, miR-132, miR-122, miR-34a, miR-21, miR-29a, miR-222 and miR-199a/b-3p to modulate the Wnt/FZD/ß-catenin signaling pathway and develop HCC. These HBV mediated miRNAs may prove future therapeutic options to treat HBV-Wnt/FZD/ß-catenin associated HCC.

Antigenic Peptide Prediction From E6 and E7 Oncoproteins of HPV Types 16 and 18 for Therapeutic Vaccine Design Using Immunoinformatics and MD Simulation Analysis.

Human papillomavirus (HPV) induced cervical cancer is the second most common cause of death, after breast cancer, in females. Three prophylactic vaccines by Merck Sharp & Dohme (MSD) and GlaxoSmithKline (GSK) have been confirmed to prevent high-risk HPV strains but these vaccines have been shown to be effective only in girls who have not been exposed to HPV previously. The constitutively expressed HPV oncoproteins E6 and E7 are usually used as target antigens for HPV therapeutic vaccines. These early (E) proteins are involved, for example, in maintaining the malignant phenotype of the cells. In this study, we predicted antigenic peptides of HPV types 16 and 18, encoded by E6 and E7 genes, using an immunoinformatics approach. To further evaluate the immunogenic potential of the predicted peptides, we studied their ability to bind to class I major histocompatibility complex (MHC-I) molecules in a computational docking study that was supported by molecular dynamics (MD) simulations and estimation of the free energies of binding of the peptides at the MHC-I binding cleft. Some of the predicted peptides exhibited comparable binding free energies and/or pattern of binding to experimentally verified MHC-I-binding epitopes that we used as references in MD simulations. Such peptides with good predicted affinity may serve as candidate epitopes for the development of therapeutic HPV peptide vaccines.

Glycosylation of Recombinant Anticancer Therapeutics in Different Expression Systems with Emerging Technologies.

Glycosylation, a posttranslational modification, has a major role in recombinant anticancer therapeutic proteins, as most of the approved recombinant therapeutics are glycoproteins. The constant amino acid sequence of therapeutics determines the enzymatic activity, while the presence of glycans influences their pharmacokinetics, solubility, distribution, serum half-life, effector function, and binding to receptors. Glycoproteins expressed in different expression systems acquire their own oligosaccharides, which increases the protein diversity. The heterogeneity of glycans creates hurdles in downstream processing, ultimately leading to variable anticancer therapeutic efficacy. Therefore, glycoproteins require an appropriate expression system to obtain structurally and functionally identical glycans, as in humans. In many expression systems, the N-glycosylation pathway remains conserved in the endoplasmic reticulum, but divergence is observed when the protein enters the Golgi complex. Hence, in recent decades, numerous approaches have been adopted to engineer the Golgi's N-glycosylation pathway to attain human-like glycans. Several researchers have tried to engineer the N-glycosylation pathway of expression systems. In this review, we examine the glycosylation pattern in various expression systems, along with emerging technologies for glycosylation engineering of anticancer therapeutic drugs. Cancer Res; 78(11); 2787-98. ©2018 AACR.

HIV Diagnosis and Treatment through Advanced Technologies.

Human immunodeficiency virus (HIV) is the chief contributor to global burden of disease. In 2010, HIV was the fifth leading cause of disability-adjusted life years in people of all ages and leading cause for people aged 30-44 years. It is classified as a member of the family Retroviridae and genus Lentivirus based on the biological, morphological, and genetic properties. It infects different cells of the immune system, such as CD4+ T cells (T-helper cells), dendritic cells, and macrophages. HIV has two subtypes: HIV-1 and HIV-2. Among these strains, HIV-1 is the most virulent and pathogenic. Advanced diagnostic methods are exploring new ways of treatment and contributing in the reduction of HIV cases. The diagnostic techniques like PCR, rapid test, EIA, p24 antigen, and western blot have markedly upgraded the diagnosis of HIV. Antiretroviral therapy and vaccines are promising candidates in providing therapeutic and preventive regimes, respectively. Invention of CRISPR/Cas9 is a breakthrough in the field of HIV disease management.