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Objective: We evaluated the 6-month postpartum risk of metabolic syndrome (MetS), a marker of future cardiovascular disease (CVD) risk, comparing women whose most recent pregnancies were complicated with gestational hypertension (GH) or preeclampsia (PE) versus those who had normotensive pregnancies., Study Design: This was a prospective cohort study in which women with GH or PE and normotensive women were actively enrolled during the first 12 weeks after delivery in Nairobi, Kenya. Participants were interviewed, blood pressures and anthropometric measurements including waist circumference obtained at enrollment and 6 months postpartum. Fasting lipid profile and plasma glucose were measured at 6 months postpartum. A generalized linear regression model with Poisson distribution was used to estimate crude relative risk (RR) of 6-month postpartum MetS and adjusted RR (ARR) after adjusting for apriori potential confounders., Results: Among 194 postpartum women, 63 (32%) had experienced GH or PE. Prevalence of MetS at 6 months postpartum was higher among women whose pregnancies were complicated with GH or PE (34.9%) compared to those who were normotensive (11.5%). GH and PE were associated with a 3-fold or greater risk of MetS (ARR) 3.01; 95% Confidence interval [CI] 1.58, 5.71; p < 0.001) overall and three of the five components, namely hypertension (ARR 3.35 [2.04, 5.51], p < 0.001), hypertriglyceridemia (ARR 3.25 [1.16-9.10], p = 0.01), and fasting hyperglycemia (ARR 6.20 [1.07-35.76], p = 0.03), compared to having normal blood pressures during pregnancy., Conclusion: At 6  months postpartum, GH and PE were associated with three-fold or higher risk of MetS and especially hypertension, fasting hypertriglyceridemia, and fasting hyperglycemia., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. All rights reserved.)

Arbidol (ARB) is a Russian-made small indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It also demonstrates inhibitory activity against other viruses, enveloped or not, responsible for emerging or globally prevalent infectious diseases such as hepatitis B and C, gastroenteritis, hemorrhagic fevers or encephalitis. In this review, we will explore the possibility and pertinence of ARB as a broad-spectrum antiviral, after a careful examination of its physico-chemical properties, pharmacokinetics, toxicity, and molecular mechanisms of action. Recent studies suggest that ARB's dual interactions with membranes and aromatic amino acids in proteins may be central to its broad-spectrum antiviral activity. This could impact on the virus itself, and/or on cellular functions or critical steps in virus-cell interactions, thereby positioning ARB as both a direct-acting antiviral (DAA) and a host-targeting agent (HTA). In the context of recent studies in animals and humans, we will discuss the prospective clinical use of ARB in various viral infections., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background & Aims: The pro-inflammatory chemokine CXCL10 is induced by HCV infection in vitro and in vivo, and is associated with outcome of IFN (interferon)-based therapy. We studied how hepatocyte sensing of early HCV infection via TLR3 (Toll-like receptor 3) and RIG-I (retinoic acid inducible gene I) led to expression of CXCL10., Methods: CXCL10, type I IFN, and type III IFN mRNAs and proteins were measured in PHH (primary human hepatocytes) and hepatocyte lines harboring functional or non-functional TLR3 and RIG-I pathways following HCV infection or exposure to receptor-specific stimuli., Results: HuH7 human hepatoma cells expressing both TLR3 and RIG-I produced maximal CXCL10 during early HCV infection. Neutralization of type I and type III IFNs had no impact on virus-induced CXCL10 expression in TLR3+/RIG-I+ HuH7 cells, but reduced CXCL10 expression in PHH. PHH cultures were positive for monocyte, macrophage, and dendritic cell mRNAs. Immunodepletion of non-parenchymal cells (NPCs) eliminated marker expression in PHH cultures, which then showed no IFN requirement for CXCL10 induction during HCV infection. Immunofluorescence studies also revealed a positive correlation between intracellular HCV Core and CXCL10 protein expression (r(2) = 0.88, p ≤ 0.001)., Conclusions: While CXCL10 induction in hepatocytes during the initial phase of HCV infection is independent of hepatocyte-derived type I and type III IFNs, NPC-derived IFNs contribute to CXCL10 induction during HCV infection in PHH cultures., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Arbidol (ARB) is a broad-spectrum antiviral displaying activity against a number of enveloped and non-enveloped viruses. It was described as a viral entry inhibitor and shown to interact at the molecular level with lipid membranes and viral fusion glycoproteins to impede viral entry and fusion. However its mechanism of action at the cellular level remains unknown. Here, by using live-cell confocal imaging and the hepatitis C virus as a model virus, we show that ARB affects clathrin-mediated endocytosis by impeding dynamin-2-induced membrane scission. Moreover it induces the intracellular accumulation of clathrin-coated structures where viral particles are trapped. Collectively, our results shed light on the mechanistic aspects of ARB antiviral activity and suggest that ARB could prevent cell infection by viruses that enter through clathrin-mediated endocytosis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background & Aims: Hepatitis C virus (HCV) infection affects 3% of the world population and is the leading cause of chronic liver disease worldwide. Current standard of care is effective in only 50% of the patients, poorly tolerated, and associated with significant side effects and viral resistance. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism and that its production is metabolically modulated., Methods: The JFH1/Huh7.5.1 full lifecycle model of HCV was used to study the antiviral effects of naringenin on viral replication, assembly, and production. Activation of PPARα was elucidated using GAL4-PPARα fusion reporters, PPRE reporters, qRT-PCR, and metabolic studies. Metabolic results were confirmed in primary human hepatocytes., Results: We demonstrate that the grapefruit flavonoid naringenin dose-dependently inhibits HCV production without affecting intracellular levels of the viral RNA or protein. We show that naringenin blocks the assembly of intracellular infectious viral particles, upstream of viral egress. This antiviral effect is mediated in part by the activation of PPARα, leading to a decrease in VLDL production without causing hepatic lipid accumulation in Huh7.5.1 cells and primary human hepatocytes. Long-term treatment with naringenin leads to a rapid 1.4 log reduction in HCV, similar to 1000U of interferon. During the washout period, HCV levels returned to normal, consistent with our proposed mechanism of action., Conclusions: The data demonstrates that naringenin is a non-toxic assembly inhibitor of HCV and that other PPARα agonists play a similar role in blocking viral production. The combination of naringenin with STAT-C agents could potentially bring a rapid reduction in HCV levels during the early treatment phase, an outcome associated with sustained virological response., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Interferons (IFN) are multi-functional proteins that induce a large number of genes which mediate many biological processes including host defense, cell growth control, signaling, and metabolism. Bioinformatics analysis of the 3'-untranslated regions of IFN-stimulated genes (ISGs) showed that the AU-rich elements (ARE) exist in approximately 10% of the mRNA induced by IFN. The human epithelial cell lines, WISH and 293, and the human B cell lines, Daudi and RPMI 1788, were assessed for their response to type-I IFN. Due to their differential response to the anti-viral and anti-proliferative action of IFN-alpha, they were used as cellular models for genome wide ARE-gene expression. The anti-viral and anti-proliferative actions of IFN-alpha were substantially more potent against WISH and Daudi cells than 293 and RPMI 1788 cells, respectively. These results correlated with the Stat1-driven gene expression as assessed by monitoring the expression of Stat1-mediated IFN-inducible 6-16 mRNA. Interferons were able to induce a significant proportion of common and distinct ARE-genes, but the patterns of expression were different and dependent on the type of the cell, type of IFN, and status of the cellular sensitivity to IFN. Clustering algorithms generated two informative expressed gene clusters that were selectively associated with cellular sensitivity and resistance to the anti-viral and anti-proliferative action of IFN. Use of rationally designed microarray experiments in IFN biology yielded informative clusters that may provide candidate genes for diagnostic or for evaluation of therapeutic possibilities.