Accumulation of β-Amyloid (βA) is a key pathogenetic factor in Alzheimer's disease; however, the normal function of βA is unknown. Recent studies have shown that βA can inhibit growth of bacteria and fungi. In this paper we show that βA also inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro. The 42 amino acid fragment of βA (βA42) had greater activity than the 40 amino acid fragment. Direct incubation of the virus with βA42 was needed to achieve optimal inhibition. Using quantitative PCR assays βA42 was shown to reduce viral uptake by epithelial cells after 45 minutes and to reduce supernatant virus at 24 hours post infection. βA42 caused aggregation of IAV particles as detected by light transmission assays and electron and confocal microscopy. βA42 did not stimulate neutrophil H2O2 production or extracellular trap formation on its own, but it increased both responses stimulated by IAV. In addition, βA42 increased uptake of IAV by neutrophils. βA42 reduced viral protein synthesis in monocytes and reduced IAV-induced interleukin-6 production by these cells. Hence, we demonstrate for the first time that βA has antiviral activity and modulates viral interactions with phagocytes.
Objectives Determine the pathological importance of oxidative stress-induced injurious processes in chagasic heart dysfunction. Background Trypanosoma cruzi-induced inflammatory pathology and a feedback cycle of mitochondrial dysfunction and oxidative stress may contribute to Chagas disease. Methods Sprague Dawley rats were infected with T. cruzi, and treated with phenyl-α-tert-butylnitrone (PBN/antioxidant) and/or benzonidazole (BZ/anti-parasite). We monitored myocardial parasite burden, oxidative adducts, mitochondrial complex activities, respiration and ATP synthesis rates, and inflammatory and cardiac remodeling responses during disease development. Cardiac hemodynamics was determined for all rats. Results BZ (not PBN) decreased the parasite persistence and immune adverse events (proinflammatory cytokine expression, NADPH (β-Nicotinamide Adenine Dinucleotide Phosphate, reduced) oxidase and myeloperoxidase activities, and inflammatory infiltrate) in chronic hearts. PBN±BZ (not BZ alone) decreased the mtROS level, oxidative adducts (malonyldialdehyde, 4-hydroxynonenal, carbonyls), hypertrophic gene expression (ANP, BNP, αsk-Actin), and collagen deposition, and preserved the respiratory chain efficiency and energy status in chronic hearts. Subsequently, left ventricular dysfunction was prevented in PBN±BZ-treated chagasic rats. Conclusions BZ treatment after acute stage decreased the parasite persistence and inflammatory pathology. Yet, oxidative adducts, mitochondrial dysfunction and remodeling responses persisted and contributed to declining cardiac function in chagasic rats. Combinatorial treatment (PBN+BZ) was beneficial in arresting the T. cruzi-induced inflammatory and oxidative pathology and chronic heart failure in chagasic rats.
In February 2018, the 6th World Symposium on Pulmonary Hypertension (WSPH) brought together experts from various disciplines to review the most relevant clinical and scientific advances in the field of PH over the last 5 years. Based on careful review and discussions by members of the different task forces, major revisions were made on the hemodynamic definition for various forms of PH and new genes were added to the list of genetic markers associated with pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease. In addition, the use of risk stratification tools was encouraged as a strategy to reduce one-year mortality risk in PAH patients through early implementation of PAH therapies. While members of the medical community are still debating some of the proposed changes, the new WSPH guidelines advocate early diagnosis and initiation of combination therapy to reduce mortality and improve quality of life in patients with PH.
Leishmania major infected human dendritic cells (DCs) exhibit a marked induction of IL-12, ultimately promoting a robust Th1-mediated response associated with parasite killing and protective immunity. The host cell transcription machinery associated with the specific IL-12 induction observed during L. major infection remains to be thoroughly elucidated. In this study, we utilized Affymetrix Genechips to globally assess the host cell genes and pathways associated with early L. major infection in human myeloid-derived DCs. Our data revealed 728 genes were significantly differentially expressed and molecular signaling pathway revealed that the type I IFN pathway was significantly enriched. Addition of a neutralizing type I IFN decoy receptor blocked the expression of IRF7 and IL-12p40 during DC infection, indicating the L. major induced expression of IL-12p40 is dependent upon the type I IFN signaling pathway. In stark contrast, IL-12p40 expression is not elicited by Leishmania donovani, the etiological agent of deadly visceral leishmaniasis. Therefore, we examined the gene expression profile for several IFN response genes in L. major versus L. donovani DC infections. Our data revealed that L. major, but not L. donovani, induces expression of IRF2, IRF7, and IFIT5, implicating the regulation of type I IFN associated signaling pathways as mediating factors toward the production of IL-12.
The past 20 years have seen major advances in the diagnosis and management of pulmonary hypertension, a disease associated with significant morbidity and mortality. The 6th World Symposium in Pulmonary Hypertension (WSPH) took place in February 2018 and attempted to consolidate the current knowledge in the field into practical recommendations to help prioritize an action plan to improve patient outcomes and identify future research directions. In this review, we will summarize the highlights of the 6th WSPH proceedings, including revisions to the hemodynamic definitions and classification of the various types of pulmonary hypertension, genetic advances, approaches to risk stratification, and updated treatment algorithms.
SUMMARY Leishmania major is an etiological agent of cutaneous leishmaniasis. The parasite primarily infects immune sentinel cells, specifically macrophages and dendritic cells, in the mammalian host. Infection is receptor mediated and is known to involve parasite binding to cell surface protein complement receptor 3 (CR3, Mac-1, CD11b/CD18). Engagement of CR3 by various ligands inhibits production of interleukin-12 (IL-12), the cytokine that drives anti-leishmanial T helper 1-type immune responses. Likewise, L. major infection inhibits IL-12 production and activation of host macrophages. Our data indicate that in the absence of CR3, L. major-infected bone marrow-derived macrophages produce more IL-12 and nitric oxide compared to WT cells upon LPS stimulation. We therefore investigated multiple signaling pathways by which L. major may inhibit IL-12 transcription through CR3 ligation. We demonstrate that L. major infection does not elicit significant NFκB p65, MAPK, IRF-1, or IRF-8 activation in WT or CD11b deficient macrophages. Furthermore, infection neither inhibits LPS-induced MAPK or NFκB activation, nor blocks IFN-γ-activated IRF-1 and IRF-8. ETS-mediated transcription, however, is inhibited by L. major infection independently of CR3. Our data indicate that L. major mediated inhibition of IL-12 occurs through CR3 engagement, however the mechanism of inhibition is independent of NFκB, MAPK, IRF, and ETS.
Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries resulting in right heart failure and death. The majority of research has focused on endothelial dysfunction in the pulmonary circulation without much attention to whether similar pathology may be found in the rest of the circulatory system. However, there is growing evidence that PAH patients also exhibit systemic endothelial dysfunction as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow and intrinsic kidney disease. Besides abnormalities in vascular function and metabolic processes, patients with systemic sclerosis and PAH have been reported to exhibit distinctive morphological changes in kidney, skin, nailfold capillaries and sublingual vessels. 1 The eye is a highly vascularized organ that is sensitive to systemic changes in oxygen and blood flow. Interestingly, abnormally dilated episcleral vessels were found not only in PAH patients but also in unaffected carriers before the development of the disease. A more recent study by Chyou and colleagues using the Multi-Ethnic Study of Atherosclerosis database demonstrated that a higher right ventricular mass and volume by MRI correlated with a wider diameter in retinal vessels in women compared to men independent of body size, diabetes mellitus, cholesterol, age and alcohol use. 2 While this study did not involve PAH * Both authors contributed equally.
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