Mitochondrial Oxidative Stress Mediates Macrophage Pro-inflammatory Metabolic Switch in Atherosclerotic Vascular Disease in Aging

Aging elevates cardiovascular disease risk, including atherosclerosis. Macrophages play crucial role in vascular aging by promoting inflammation and atherosclerosis progression. Age-related increase in NOX4 NADPH oxidase expression correlates with mitochondrial dysfunction, inflammation, and atherosclerosis severity. We hypothesized that NOX4-dependent mitochondrial oxidative stress induces macrophage metabolic dysfunction and an inflammatory phenotype in aging-associated atherosclerotic disease. Aortic and brachiocephalic artery lesion areas were comparable in 5-month-old (young) Nox4-/-/Apoe-/- and Apoe-/- mice, increased significantly in 16-month-old (aged) mice, but were significantly lower in Nox4-/-/Apoe-/- versus Apoe-/- mice. In aged Nox4-/-/Apoe-/- mice, atherosclerotic lesions had reduced CD11b+ area, lower expression of CCL2, IL1β, and IL6, and fewer classically activated pro-inflammatory macrophages (CD38+CD80+). Notably, there was also an increased proportion of alternatively activated pro-resolving macrophages (CD163+CD206+). Spectral flow cytometry and t-SNE analysis revealed a significantly lower proportion of activated inflammatory macrophages and macrophage-like cells in atherosclerotic lesions of aged Nox4-/-/Apoe-/- compared to Apoe-/- mice. Macrophages from aged Apoe-/- mice had altered metabolic function. In contrast, macrophages from Nox4-/-/Apoe-/- mice were less glycolytic, more aerobic, and had preserved basal and maximal respiration and mitochondrial ATP production. Nox4-/-/Apoe-/- macrophages had lower mitochondrial ROS and reduced IL1β secretion, compared with Apoe-/- mice. In aged Apoe-/- mice, inhibition of NOX4 using GKT137831 significantly reduced macrophage ROS and improved mitochondrial function. This resulted in a decreased CD68+CD80+ and increased CD163+CD206+ lesion macrophages and attenuated atherosclerosis. Our results imply that NOX4-dependent mitochondrial oxidative stress in aging contributes to macrophage mitochondrial dysfunction, glycolytic metabolic switch, and pro-inflammatory phenotype, advancing atherosclerosis. Inhibition of NOX4 could alleviate vascular inflammation and atherosclerosis by improving mitochondrial function in macrophages.http://deepblue.lib.umich.edu/bitstream/2027.42/191311/2/AVendrov poster 2023 R.pd

Removal of N-Terminal Peptide Impacts Structural Aspects of an IgE-Reactive Recombinant Der p 5

(1) Background: Modification of the structural elements of allergens is widely used in the field of allergies. The goal of the present research was to express, purify, and characterize the shortened recombinant group 5 allergen of Dermatophagoides pteronyssinus (rDer p 5). (2) Methods: rDer p 5 storage stability and aggregation capacity were explored through in silico analysis, dynamic light scattering (DLS), and SDS-PAGE. Serum IgE reactivity and cytokine amount were investigated in sera or cell culture supernatants through ELISA, MULTIPLEX®, and Western blot analysis using sera from sensitized humans from Brazil, Colombia, and Ecuador. (3) Results: Dimeric rDer p 5 was detected through native PAGE, and this result was confirmed by data from DLS. The protein was thermically stable, as it did not degrade at 4 °C for 21 days. The shortened rDer p 5 was classified as a major IgE allergen in Brazil and Colombia, but minor in Ecuador. IL-13, IL-10, IL-1β, and IL-6 were significantly elevated in the sera of rDer p 5-reactive patients. The same cytokines plus IL-5 were more secreted by human cells upon rDer p 5 stimulation. (4) Conclusions: N-terminal peptide deletion led to a higher rDer p 5 folding stability, which, even though dimeric, was an IgE-reactive protein. Therefore, rDer p 5 could be used for molecular diagnostic applications or as backbone for hypoallergen design

Canine visceral leishmaniasis biomarkers and their employment in vaccines.

The natural history of canine visceral leishmaniasis (CVL) has been well described, particularly with respect to the parasite load in different tissues and immunopathological changes according to the progression of clinical forms. The biomarkers evaluated in these studies provide support for the improvement of the tools used in developing vaccines against CVL. Thus, we describe the major studies using the dog model that supplies the rationale for including different biomarkers (tissue parasitism, histopathology, hematological changes, leucocytes immunophenotyping, cytokines patterns, and in vitro co-culture systems using purified T-cells subsets and macrophages infected with L. infantum) for immunogenicity and protection evaluations in phases I and II applied to pre-clinical and clinical vaccine trials against CVL. The search for biomarkers related to resistance or susceptibility has revealed a mixed cytokine profile with a prominent proinflammatory immune response as relevant for Leishmania replication at low levels as observed in asymptomatic dogs (highlighted by high levels of IFN-? and TNF-? and decreased levels in IL-4, TGF-? and IL-10). Furthermore, increased levels in CD4+ and CD8+ T-cell subsets, presenting intracytoplasmic proinflammatory cytokine balance, have been associated with a resistance profile against CVL. In contrast, a polyclonal B-cell expansion towards plasma cell differentiation contributes to high antibody production, which is the hallmark of symptomatic dogs associated with high susceptibility in CVL. Finally, the different studies used to analyze biomarkers have been incorporated into vaccine immunogenicity and protection evaluations. Those biomarkers identified as resistance or susceptibility markers in CVL have been used to evaluate the vaccine performance against L. infantum in a kennel trial conducted before the field trial in an area known to be endemic for visceral leishmaniasis. This rationale has been a guiding force in the testing and selection of the best vaccine candidates against CVL and provides a way for the veterinary industry to register commercial immunobiological products

The New Coronavirus (SARS-CoV-2): A Comprehensive Review on Immunity and the Application of Bioinformatics and Molecular Modeling to the Discovery of Potential Anti-SARS-CoV-2 Agents

On March 11, 2020, the World Health Organization (WHO) officially declared the outbreak caused by the new coronavirus (SARS-CoV-2) a pandemic. The rapid spread of the disease surprised the scientific and medical community. Based on the latest reports, news, and scientific articles published, there is no doubt that the coronavirus has overloaded health systems globally. Practical actions against the recent emergence and rapid expansion of the SARS-CoV-2 require the development and use of tools for discovering new molecular anti-SARS-CoV-2 targets. Thus, this review presents bioinformatics and molecular modeling strategies that aim to assist in the discovery of potential anti-SARS-CoV-2 agents. Besides, we reviewed the relationship between SARS-CoV-2 and innate immunity, since understanding the structures involved in this infection can contribute to the development of new therapeutic targets. Bioinformatics is a technology that assists researchers in coping with diseases by investigating genetic sequencing and seeking structural models of potential molecular targets present in SARS-CoV2. The details provided in this review provide future points of consideration in the field of virology and medical sciences that will contribute to clarifying potential therapeutic targets for anti-SARS-CoV-2 and for understanding the molecular mechanisms responsible for the pathogenesis and virulence of SARS-CoV-2

Neotropical freshwater fisheries : A dataset of occurrence and abundance of freshwater fishes in the Neotropics

The Neotropical region hosts 4225 freshwater fish species, ranking first among the world's most diverse regions for freshwater fishes. Our NEOTROPICAL FRESHWATER FISHES data set is the first to produce a large-scale Neotropical freshwater fish inventory, covering the entire Neotropical region from Mexico and the Caribbean in the north to the southern limits in Argentina, Paraguay, Chile, and Uruguay. We compiled 185,787 distribution records, with unique georeferenced coordinates, for the 4225 species, represented by occurrence and abundance data. The number of species for the most numerous orders are as follows: Characiformes (1289), Siluriformes (1384), Cichliformes (354), Cyprinodontiformes (245), and Gymnotiformes (135). The most recorded species was the characid Astyanax fasciatus (4696 records). We registered 116,802 distribution records for native species, compared to 1802 distribution records for nonnative species. The main aim of the NEOTROPICAL FRESHWATER FISHES data set was to make these occurrence and abundance data accessible for international researchers to develop ecological and macroecological studies, from local to regional scales, with focal fish species, families, or orders. We anticipate that the NEOTROPICAL FRESHWATER FISHES data set will be valuable for studies on a wide range of ecological processes, such as trophic cascades, fishery pressure, the effects of habitat loss and fragmentation, and the impacts of species invasion and climate change. There are no copyright restrictions on the data, and please cite this data paper when using the data in publications