Cysteine Redox Potential Determines Pro-Inflammatory IL-1β Levels

Cysteine (Cys) and its disulfide, cystine (CySS) represent the major extracellular thiol/disulfide redox control system. The redox potential (E(h)) of Cys/CySS is centered at approximately -80 mV in the plasma of healthy adults, and oxidation of E(h) Cys/CySS is implicated in inflammation associated with various diseases.The purpose of the present study was to determine whether oxidized E(h) Cys/CySS is a determinant of interleukin (IL)-1beta levels. Results showed a 1.7-fold increase in secreted pro-IL-1beta levels in U937 monocytes exposed to oxidized E(h) Cys/CySS (-46 mV), compared to controls exposed to a physiological E(h) of -80 mV (P<0.01). In LPS-challenged mice, preservation of plasma E(h) Cys/CySS from oxidation by dietary sulfur amino acid (SAA) supplementation, was associated with a 1.6-fold decrease in plasma IL-1beta compared to control mice fed an isonitrogenous SAA-adequate diet (P<0.01). Analysis of E(h) Cys/CySS and IL-1beta in human plasma revealed a significant positive association between oxidized E(h) Cys/CySS and IL-1beta after controlling for age, gender, and BMI (P<0.001).These data show that oxidized extracellular E(h) Cys/CySS is a determinant of IL-1beta levels, and suggest that strategies to preserve E(h) Cys/CySS may represent a means to control IL-1beta in inflammatory disease states

Impact of Macrophage Inflammatory Protein-1α Deficiency on Atherosclerotic Lesion Formation, Hepatic Steatosis, and Adipose Tissue Expansion

Macrophage inflammatory protein-1α (CCL3) plays a well-known role in infectious and viral diseases; however, its contribution to atherosclerotic lesion formation and lipid metabolism has not been determined. Low density lipoprotein receptor deficient (LDLR−/−) mice were transplanted with bone marrow from CCL3−/− or C57BL/6 wild type donors. After 6 and 12 weeks on western diet (WD), recipients of CCL3−/− marrow demonstrated lower plasma cholesterol and triglyceride concentrations compared to recipients of C57BL/6 marrow. Atherosclerotic lesion area was significantly lower in female CCL3−/− recipients after 6 weeks and in male CCL3−/− recipients after 12 weeks of WD feeding (P<0.05). Surprisingly, male CCL3−/− recipients had a 50% decrease in adipose tissue mass after WD-feeding, and plasma insulin, and leptin levels were also significantly lower. These results were specific to CCL3, as LDLR−/− recipients of monocyte chemoattractant protein−/− (CCL2) marrow were not protected from the metabolic consequences of high fat feeding. Despite these improvements in LDLR−/− recipients of CCL3−/− marrow in the bone marrow transplantation (BMT) model, double knockout mice, globally deficient in both proteins, did not have decreased body weight, plasma lipids, or atherosclerosis compared with LDLR−/− controls. Finally, there were no differences in myeloid progenitors or leukocyte populations, indicating that changes in body weight and plasma lipids in CCL3−/− recipients was not due to differences in hematopoiesis. Taken together, these data implicate a role for CCL3 in lipid metabolism in hyperlipidemic mice following hematopoietic reconstitution

HMG CoA reductase inhibitors (statins) to treat Epstein–Barr virus-driven lymphoma

While statins have been highly effective for lowering serum cholesterol and reducing the incidence of coronary events, they have multiple other effects. Certain statins block the interaction of adhesion molecules that are important for cell–cell interactions including those between EBV-transformed B cells. These same statins inhibit NF-κB activation in the cells and induce apoptosis of transformed B cells. Studies in severe combined immunodeficiency mice show that simvastatin delays the development of EBV-lymphomas in these animals. These statins might be considered for the treatment of EBV-lymphomas in selected patients

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly

Zika beyond the Americas: Travelers as sentinels of Zika virus transmission. A GeoSentinel analysis, 2012 to 2016.

Background: Zika virus (ZIKV) was first isolated in Africa; decades later, caused large outbreaks in the Pacific, and is considered endemic in Asia. We aim to describe ZIKV disease epidemiology outside the Americas, the importance of travelers as sentinels of disease transmission, and discrepancies in travel advisories from major international health organizations. Methods and findings This descriptive analysis using GeoSentinel Surveillance Network records involves sixty-four travel and tropical medicine clinics in 29 countries. Ill returned travelers with a confirmed or probable diagnosis of ZIKV disease acquired in Africa, Asia and the Pacific seen between 1 January 2012 and 31 December 2016 are included, and the frequencies of demographic, trip, and diagnostic characteristics described. ZIKV was acquired in Asia (18), the Pacific (10) and Africa (1). For five countries (Indonesia, Philippines, Thailand, Vietnam, Cameroon), GeoSentinel patients were sentinel markers of recent Zika activity. Additionally, the first confirmed ZIKV infection acquired in Kiribati was reported to GeoSentinel (2015), and a probable case was reported from Timor Leste (April 2016), representing the only case known to date. Review of Zika situation updates from major international health authorities for country risk classifications shows heterogeneity in ZIKV country travel advisories. Conclusions: Travelers are integral to the global spread of ZIKV, serving as sentinel markers of disease activity. Although GeoSentinel data are collected by specialized clinics and do not capture all imported cases, we show that surveillance of imported infections by returned travelers augments local surveillance system data regarding ZIKV epidemiology and can assist with risk categorization by international authorities. However, travel advisories are variable due to risk uncertainties

The impact of statin treatment on presentation mode and early outcomes in acute coronary syndromes

Objectives: The role of statin use in the treatment of acute coronary syndromes (ACS) is not clear. The aim of our study was to evaluate the role of statins in ACS. Methods: Using data from the Acute Myocardial Infarction in Switzerland (AMIS Plus) Project, we compared the effects of chronic statin use, statin therapy after admission and no statin therapy on presentation mode and outcomes in ACS. Results: Available data from the period 2001-2006 including 11,603 patients were analyzed. Major cardiac event rates and in-hospital mortality were more common in statin-naive patients compared to patients who received statins. Conclusions: Our results support the importance of statin treatment in ACS. Chronic statin therapy seems to alter the initial presentation of ACS but it is questionable whether it provides an additional effect on early outcomes compared to the establishment of statin therapy after admission in statin-naive patients