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      Novel Ocellatin Peptides Mitigate LPS-induced ROS Formation and NF-kB Activation in Microglia and Hippocampal Neurons

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          Abstract

          Cutaneous secretions of amphibians have bioactive compounds, such as peptides, with potential for biotechnological applications. Therefore, this study aimed to determine the primary structure and investigate peptides obtained from the cutaneous secretions of the amphibian, Leptodactylus vastus, as a source of bioactive molecules. The peptides obtained possessed the amino acid sequences, GVVDILKGAAKDLAGH and GVVDILKGAAKDLAGHLASKV, with monoisotopic masses of [M + H] ± = 1563.8 Da and [M + H] ± = 2062.4 Da, respectively. The molecules were characterized as peptides of the class of ocellatins and were named as Ocellatin-K1(1–16) and Ocellatin-K1(1–21). Functional analysis revealed that Ocellatin-K1(1–16) and Ocellatin-K1(1–21) showed weak antibacterial activity. However, treatment of mice with these ocellatins reduced the nitrite and malondialdehyde content. Moreover, superoxide dismutase enzymatic activity and glutathione concentration were increased in the hippocampus of mice. In addition, Ocellatin-K1(1–16) and Ocellatin-K1(1–21) were effective in impairing lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) formation and NF-kB activation in living microglia. We incubated hippocampal neurons with microglial conditioned media treated with LPS and LPS in the presence of Ocellatin-K1(1–16) and Ocellatin-K1(1–21) and observed that both peptides reduced the oxidative stress in hippocampal neurons. Furthermore, these ocellatins demonstrated low cytotoxicity towards erythrocytes. These functional properties suggest possible to neuromodulatory therapeutic applications.

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          Most cited references 47

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          Amphibian fungal panzootic causes catastrophic and ongoing loss of biodiversity

          Anthropogenic trade and development have broken down dispersal barriers, facilitating the spread of diseases that threaten Earth’s biodiversity. We present a global, quantitative assessment of the amphibian chytridiomycosis panzootic, one of the most impactful examples of disease spread, and demonstrate its role in the decline of at least 501 amphibian species over the past half-century, including 90 presumed extinctions. The effects of chytridiomycosis have been greatest in large-bodied, range-restricted anurans in wet climates in the Americas and Australia. Declines peaked in the 1980s, and only 12% of declined species show signs of recovery, whereas 39% are experiencing ongoing decline. There is risk of further chytridiomycosis outbreaks in new areas. The chytridiomycosis panzootic represents the greatest recorded loss of biodiversity attributable to a disease.
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            Redox control of microglial function: molecular mechanisms and functional significance.

            Neurodegenerative diseases are characterized by chronic microglial over-activation and oxidative stress. It is now beginning to be recognized that reactive oxygen species (ROS) produced by either microglia or the surrounding environment not only impact neurons but also modulate microglial activity. In this review, we first analyze the hallmarks of pro-inflammatory and anti-inflammatory phenotypes of microglia and their regulation by ROS. Then, we consider the production of reactive oxygen and nitrogen species by NADPH oxidases and nitric oxide synthases and the new findings that also indicate an essential role of glutathione (γ-glutamyl-l-cysteinylglycine) in redox homeostasis of microglia. The effect of oxidant modification of macromolecules on signaling is analyzed at the level of oxidized lipid by-products and sulfhydryl modification of microglial proteins. Redox signaling has a profound impact on two transcription factors that modulate microglial fate, nuclear factor kappa-light-chain-enhancer of activated B cells, and nuclear factor (erythroid-derived 2)-like 2, master regulators of the pro-inflammatory and antioxidant responses of microglia, respectively. The relevance of these proteins in the modulation of microglial activity and the interplay between them will be evaluated. Finally, the relevance of ROS in altering blood brain barrier permeability is discussed. Recent examples of the importance of these findings in the onset or progression of neurodegenerative diseases are also discussed. This review should provide a profound insight into the role of redox homeostasis in microglial activity and help in the identification of new promising targets to control neuroinflammation through redox control of the brain.
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              Chronic microglial activation and progressive dopaminergic neurotoxicity.

              PD (Parkinson's disease) is characterized by the selective and progressive loss of DA neurons (dopaminergic neurons) in the substantia nigra. Inflammation and activation of microglia, the resident innate immune cell in the brain, have been strongly linked to neurodegenerative diseases, such as PD. Microglia can respond to immunological stimuli and neuronal death to produce a host of toxic factors, including cytokines and ROS (reactive oxygen species). Microglia can also become persistently activated after a single stimulus and maintain the elevated production of both cytokines and ROS, long after the instigating stimulus is gone. Current reports suggest that this chronic microglial activation may be fuelled by either dying/damaged neurons or autocrine and paracrine signals from local glial cells, such as cytokines. Here, we review proposed mechanisms responsible for chronic neuroinflammation and explain the interconnected relationship between deleterious microglial activation, DA neuron damage and neurodegenerative disease.
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                Author and article information

                Contributors
                jandvenes@ufpi.edu.br
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                14 February 2020
                14 February 2020
                2020
                : 10
                Affiliations
                [1 ]Laboratório de Farmacologia da Inflamação e Doenças Gastrintestinais, Universidade Federal do Delta do Parnaíba, UFDPar, Piauí, Brazil
                [2 ]ISNI 0000 0001 2176 3398, GRID grid.412380.c, Núcleo de Pesquisa em Biodiversidade e Biotecnologia, , Universidade Federal do Piauí, UFPI, ; Piauí, Brazil
                [3 ]Instituto de Educação Superior do Vale do Parnaíba, FAHESP/IESVAP/NRE, Parnaíba, Brazil
                [4 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, LAQV/REQUIMTE, Departamento de Química e Bioquímica, , Faculdade de Ciencias da Universidade do Porto, ; Porto, Portugal
                [5 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), , Universidade do Porto, ; Porto, Portugal
                [6 ]ISNI 0000 0001 2181 4263, GRID grid.9983.b, Instituto de Medicina Molecular, IMM, Universidade de Lisboa, ; Lisboa, Portugal
                [7 ]ISNI 0000 0001 2238 5157, GRID grid.7632.0, Laboratório de Síntese e Análise de Biomoléculas, LSAB, Instituto de Química, UnB, ; Brasília, Brazil
                [8 ]ISNI 0000 0004 0541 873X, GRID grid.460200.0, Embrapa Recursos Genéticos e Biotecnologia, ; Brasília, Brazil
                [9 ]ISNI 0000 0001 2238 5157, GRID grid.7632.0, Núcleo de Pesquisa em Morfologia e Imunonologia Aplicada, NuPMIA, Área Morfologia, Faculdade de Medicina, UnB, ; Brasília, Brazil
                Article
                59665
                10.1038/s41598-020-59665-1
                7021831
                32060388
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                peptides, natural product synthesis, pharmacodynamics

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