Structure-activity relationship study of itraconazole, a broad-range inhibitor of picornavirus replication that targets oxysterol-binding protein (OSBP)

Itraconazole (ITZ) is a well-known, FDA-approved antifungal drug that is also in clinical trials for its anticancer activity. ITZ exerts its anticancer activity through several disparate targets and pathways. ITZ inhibits angiogenesis by hampering the functioning of the vascular endothelial growth receptor 2 (VEGFR2) and by indirectly inhibiting mTOR signaling. Furthermore, ITZ directly inhibits the growth of several types of tumor cells by antagonizing Hedgehog signaling. Recently, we reported that ITZ also has broad-spectrum antiviral activity against enteroviruses, cardioviruses and hepatitis C virus, independent of established ITZ-activities but instead via a novel target, oxysterol-binding protein (OSBP), a cellular lipid shuttling protein. In this study, we analyzed which structural features of ITZ are important for the OSBP-mediated antiviral activity. The backbone structure, consisting of five rings, and the sec-butyl chain are important for antiviral activity, whereas the triazole moiety, which is critical for antifungal activity, is not. The features required for OSBP-mediated antiviral activity of ITZ overlap mostly with published features required for inhibition of VEGFR2 trafficking, but not Hh signaling. Furthermore, we use in silico studies to explore how ITZ could bind to OSBP. Our data show that several pharmacological activities of ITZ can be uncoupled, which is a critical step in the development of ITZ-based antiviral compounds with greater specificity and reduced off-target effects

Determinants Of Foreign Direct Investment In Ceecs: The Role Of Financial Stability

The globalization process has an important impact on the foreign direct investment flows. The FDI are increasingly important to developing countries, such as the Central and Eastern European countries. The EU accession has stimulated the investors’ confidence, and it has contributed to their economic development. According to the economic theory, the factors influencing the FDI are numerous and related to the country, sector and company’s characteristics. One classification groups these factors in three broad categories: economic policy of host country, economic performance and attractiveness of na-tional economy. In this paper, we point out a new FDI determinant: financial stability. The financial system stability represents an attractive factor for the foreign investors and can be considered as a FDI determinant, alongside the categories mentioned above. Using a large sample of Central and Eastern European countries and panel data techniques, we investigate the impact of the financial stability on the FDI flows. The financial stability’s measure is based on a financial stability aggregate index and we use as control variables the number of inhabi-tants, the trade openness, the labor productivity, and the landing rate. The results show that the stability of the financial systems played a significant role in attracting FDI inflows in Central and Eastern Europe during the 1998-2008 period.foreign direct investment, financial stability, Central and Eastern European countries

Caveolin-1-Knockout Mouse as a Model of Inflammatory Diseases

Caveolin-1 (CAV1) is the scaffold protein of caveolae, which are minute invaginations of the cell membrane that are involved in endocytosis, cell signaling, and endothelial-mediated inflammation. CAV1 has also been reported to have a dual role as either a tumor suppressor or tumor promoter, depending on the type of cancer. Inflammation is an important player in tumor progression, but the role of caveolin-1 in generating an inflammatory milieu remains poorly characterized. We used a caveolin-1-knockout (CAV1−/−) mouse model to assess the inflammatory status via the quantification of the pro- and anti-inflammatory cytokine levels, as well as the ability of circulating lymphocytes to respond to nonspecific stimuli by producing cytokines. Here, we report that the CAV1−/− mice were characterized by a low-grade systemic proinflammatory status, with a moderate increase in the IL-6, TNF-α, and IL-12p70 levels. CAV1−/− circulating lymphocytes were more prone to cytokine production upon nonspecific stimulation than the wild-type lymphocytes. These results show that CAV1 involvement in cell homeostasis is more complex than previously revealed, as it plays a role in the inflammatory process. These findings indicate that the CAV1−/− mouse model could prove to be a useful tool for inflammation-related studies

Investigation of UV Dye-Sensitized Solar Cells Based on Water Electrolyte: A New Insight for Wavelength-Selective Greenhouse

The optimization of the photoactive electrode based on TiO2 with a complex architecture for UV dyes along with water-based electrolyte has successfully allowed us (i) to obtain a photovoltaic efficiency of the dye-sensitized solar cell with 1.45 times higher than the best efficiency reported for synthetic dye and 3 times for curcumin dye so far; (ii) transparency on the entire Photosynthetic Active Radiation domain; (iii) preserving high efficiency for lighting 1 sun (summer) and shading, especially for 60 mW/cm2, which represents the maximum illumination in the rest of the seasons. Our water-based dye-sensitized solar cells loaded with synthetic and natural UV dyes have revealed that the implementation of a dye-sensitized solar cell in autonomous greenhouses is a viable and inexpensive concept

Cholesterol shuttling is important for RNA replication of coxsackievirus B3 and encephalomyocarditis virus

Picornaviruses are a family of positive-strand RNA viruses that represent important human and animal pathogens. Upon infection, picornaviruses induce an extensive remodeling of host cell membranes into replication organelles, which is critical for replication. Membrane lipids and lipid remodeling processes are at the base of RO formation, yet their involvement remains largely obscure. Recently, phosphatidylinositol-4-phosphate (PI4P) was the first lipid discovered to be important for the replication of a number of picornaviruses. Here, we investigate the role of the lipid cholesterol in picornavirus replication. We show that two picornaviruses from distinct genera that rely on different host factors for replication, namely the enterovirus coxsackievirus B3 (CVB3) and the cardiovirus encephalomyocarditis virus (EMCV), both recruited cholesterol to their ROs. Although CVB3 and EMCV both required cholesterol for efficient genome replication, the viruses appeared to rely on different cellular cholesterol pools. Treatments that altered the distribution of endosomal cholesterol inhibited replication of both CVB3 and EMCV, showing the importance of endosomal cholesterol shuttling for the replication of these viruses. Summarizing, we here demonstrate the importance of cholesterol homeostasis for efficient replication of CVB3 and EMCV

Comprehensive In Vitro Testing of Calcium Phosphate-Based Bioceramics with Orthopedic and Dentistry Applications

Recently, a large spectrum of biomaterials emerged, with emphasis on various pure, blended, or doped calcium phosphates (CaPs). Although basic cytocompatibility testing protocols are referred by International Organization for Standardization (ISO) 10993 (parts 1–22), rigorous in vitro testing using cutting-edge technologies should be carried out in order to fully understand the behavior of various biomaterials (whether in bulk or low-dimensional object form) and to better gauge their outcome when implanted. In this review, current molecular techniques are assessed for the in-depth characterization of angiogenic potential, osteogenic capability, and the modulation of oxidative stress and inflammation properties of CaPs and their cation- and/or anion-substituted derivatives. Using such techniques, mechanisms of action of these compounds can be deciphered, highlighting the signaling pathway activation, cross-talk, and modulation by microRNA expression, which in turn can safely pave the road toward a better filtering of the truly functional, application-ready innovative therapeutic bioceramic-based solutions

Fat(al) attraction : Picornaviruses Usurp Lipid Transfer at Membrane Contact Sites to Create Replication Organelles

All viruses that carry a positive-sense RNA genome (+RNA), such as picornaviruses, hepatitis C virus, dengue virus, and SARS- and MERS-coronavirus, confiscate intracellular membranes of the host cell to generate new compartments (i.e., replication organelles) for amplification of their genome. Replication organelles (ROs) are membranous structures that not only harbor viral proteins but also contain a specific array of hijacked host factors that create a unique lipid microenvironment optimal for genome replication. While some lipids may be locally synthesized de novo, other lipids are shuttled towards ROs. In picornavirus-infected cells, lipids are exchanged at membrane contact sites between ROs and other organelles. In this paper, we review recent advances in our understanding of how picornaviruses exploit host membrane contact site machinery to generate ROs, a mechanism that is used by some other +RNA viruses as well

Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP

Enteroviruses, e.g., polio-, coxsackie- and rhinoviruses, constitute a large genus within the Picornaviridae family of positive-strand RNA viruses and include many important pathogens linked to a variety of acute and chronic diseases. Despite their huge medical and economic impact, no approved antiviral therapy is yet available. Recently, the oxysterol-binding protein (OSBP) was implicated as a host factor for enterovirus replication. Here, we investigated the antiviral activity of the natural compound OSW-1, a ligand of OSBP that is under investigation as an anti-cancer drug. OSW-1 potently inhibited the replication of all enteroviruses tested, with IC50 values in the low nanomolar range, acted at the genome replication stage and was effective in all tested cell types of three different species. Importantly, OSBP overexpression rescued viral replication, demonstrating that the antiviral effect of OSW-1 is due to targeting OSBP. Together, we here report the anti-enterovirus activity of the natural anti-cancer compound OSW-1.publisher: Elsevier articletitle: Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP journaltitle: Antiviral Research articlelink: http://dx.doi.org/10.1016/j.antiviral.2015.02.013 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe

Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome

Persistent, low-grade inflammation is now considered a hallmark feature of chronic kidney disease (CKD), being involved in the development of all-cause mortality of these patients. Although substantial improvements have been made in clinical care, CKD remains a major public health burden, affecting 10–15% of the population, and its prevalence is constantly growing. Due to its insidious nature, CKD is rarely diagnosed in early stages, and once developed, its progression is unfortunately irreversible. There are many factors that contribute to the setting of the inflammatory status in CKD, including increased production of proinflammatory cytokines, oxidative stress and acidosis, chronic and recurrent infections, altered metabolism of adipose tissue, and last but not least, gut microbiota dysbiosis, an underestimated source of microinflammation. In this scenario, a huge step forward was made by the increasing progression of omics approaches, specially designed for identification of biomarkers useful for early diagnostic and follow-up. Recent omics advances could provide novel insights in deciphering the disease pathophysiology; thus, identification of circulating biomarker panels using state-of-the-art proteomic technologies could improve CKD early diagnosis, monitoring, and prognostics. This review aims to summarize the recent knowledge regarding the relationship between inflammation and CKD, highlighting the current proteomic approaches, as well as the inflammasomes and gut microbiota dysbiosis involvement in the setting of CKD, culminating with the troubling bidirectional connection between CKD and renal malignancy, raised on the background of an inflammatory condition

Low-Concentrations of Fatty Acids Induce an Early Increase in IL-8 Levels in Normal Human Astrocytes

Fatty acids (FAs) have been shown to exhibit a pro-inflammatory response in various cell types, but astrocytes have been mostly overlooked. FAs, both saturated and unsaturated, have previously been shown to induce pro-inflammatory responses in astrocytes at high concentrations of hundreds of µg/mL. SSO (Sulfo-N-succinimidyl Oleate sodium), an inhibitor of FA translocase CD36, has been shown to prevent inflammation in the mouse brain by acting on local microglia and infiltrating monocytes. Our hypothesis was that SSO treatment would also impact astrocyte pro-inflammatory response to FA. In order to verify our assumption, we evaluated the expression of pro- and anti-inflammatory cytokines in normal human astrocyte cell culture pre-treated (or not) with SSO, and then exposed to low concentrations of both saturated (palmitic acid) and unsaturated (oleic acid) FAs. As a positive control for astrocyte inflammation, we used fibrillary amyloid. Neither Aβ 1–42 nor FAs induced CD36 protein expression in human astrocytes in cell culture At low concentrations, both types of FAs induced IL-8 protein secretion, and this effect was specifically inhibited by SSO pre-treatment. In conclusion, low concentrations of oleic acid are able to induce an early increase in IL-8 expression in normal human astrocytes, which is specifically downregulated by SSO