ABSTRACT
Gap junctional intercellular communication (GJIC) involving astrocytes is important for proper CNS homeostasis. As determined in our previous studies, trafficking of the predominant astrocyte GJ protein, Connexin43 (Cx43), is disrupted in response to infection with a neurotropic murine ß-coronavirus (MHV-A59). However, how host factors are involved in Cx43 trafficking and the infection response is not clear. Here, we show that Cx43 retention due to MHV-A59 infection was associated with increased ER stress and reduced expression of chaperone protein ERp29. Treatment of MHV-A59-infected astrocytes with the chemical chaperone 4-sodium phenylbutyrate increased ERp29 expression, rescued Cx43 transport to the cell surface, increased GJIC, and reduced ER stress. We obtained similar results using an astrocytoma cell line (delayed brain tumor) upon MHV-A59 infection. Critically, delayed brain tumor cells transfected to express exogenous ERp29 were less susceptible to MHV-A59 infection and showed increased Cx43-mediated GJIC. Treatment with Cx43 mimetic peptides inhibited GJIC and increased viral susceptibility, demonstrating a role for intercellular communication in reducing MHV-A59 infectivity. Taken together, these results support a therapeutically targetable ERp29-dependent mechanism where ß-coronavirus infectivity is modulated by reducing ER stress and rescuing Cx43 trafficking and function.
Subject(s)
Disease Susceptibility , Endoplasmic Reticulum , Host Microbial Interactions , Molecular Chaperones , Murine hepatitis virus , Animals , Mice , Astrocytoma/pathology , Astrocytoma/virology , Brain Neoplasms/pathology , Brain Neoplasms/virology , Cell Communication , Cell Line, Tumor , Connexin 43/metabolism , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress , Gap Junctions/metabolism , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Murine hepatitis virus/metabolism , Protein Transport , TransfectionABSTRACT
BACKGROUND: Ovarian cancer is usually detected at an advanced stage with frequent recurrence. The recurrence-free survival and overall survival is influenced by the age at diagnosis, tumor stage and histological subtype. Nonetheless, quantifiable prognostic biomarkers are needed for early identification of the high-risk patients and for personalized medicine. Several studies link tumor-specific dysregulated expression of certain proteins with ovarian cancer prognosis. However, careful investigation of presence of these prognostically relevant proteins in ovarian cancer secretome is lacking. OBJECTIVE: To critically analyze the recent published data on prognostically relevant proteins for ovarian cancer and to carefully search how many of them are reported in the published ovarian cancer secretome datasets. DESIGN: A search for relevant studies in the past 2 years was conducted in PubMed and a comprehensive list of proteins associated with the ovarian cancer prognosis was prepared. These were cross-referred to the published ovarian cancer secretome profiles. The proteins identified in the secretome were further shortlisted based on a scoring strategy employing stringent criteria. RESULTS: A panel of seven promising secretory biomarkers associated with ovarian cancer prognosis is proposed. CONCLUSION: Scanning the ovarian cancer secretome datasets provides the opportunity to identify if tumor-specific biomarkers could be tested as secretory biomarkers. Detecting their levels in the body fluid would be more advantageous than evaluating the expression in the tissue, since it could be monitored multiple times over the course of the disease to have a better judgment of the prognosis and response to therapy.
Subject(s)
Ovarian Neoplasms , Secretome , Biomarkers, Tumor/metabolism , Carcinoma, Ovarian Epithelial , Female , Humans , Ovarian Neoplasms/pathology , Prognosis , Proteins/metabolismABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced COVID-19 has emerged as a defining global health crisis in current times. Data from the World Health Organization shows demographic variations in COVID-19 severity and lethality. Diet may play a significant role in providing beneficial host cell factors contributing to immunity against deadly SARS-CoV-2 pathogenesis. Spices are essential components of the diet that possess anti-inflammatory, antioxidant, and antiviral properties. Hyperinflammation, an aberrant systemic inflammation associated with pneumonia, acute respiratory failure, and multiorgan dysfunction, is a major clinical outcome in COVID-19. Knowing the beneficial properties of spices, we hypothesize that spice-derived bioactive components can modulate host immune responses to provide protective immunity in COVID-19. This study emphasizes that biologically active components of spices might alleviate the sustained pro-inflammatory condition by inhibiting the activity of tumor necrosis factor-alpha (TNF-α), interleukins (IL6, IL8), and chemokine (CCL2) known to be elevated in COVID-19. Spices may potentially prevent the tissue damage induced by oxidative stress and pro-inflammatory mediators during SARS-CoV-2 infection. The current study also highlights the effects of spices on the antioxidant pathways mediated by Nrf2 (nuclear factor erythroid 2-related factor 2) and Hmox1 (heme oxygenase 1) to restore oxidative homeostasis and protect from aberrant tissue damage. Taken together, the anti-inflammatory and antioxidant activities of bioactive components of spices may hold a promise to target the cellular pathways for developing antivirals against SARS-CoV-2 and pan ß-coronaviruses.