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      Sequencing Analysis and Identification of the Primary Peptide Component of the Dialyzable Leukocyte Extract “Transferon Oral”: The Starting Point to Understand Its Mechanism of Action

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          Abstract

          “Transferon Oral” is a peptide-derived product with immunomodulatory properties obtained from the lysis and dialysis of human buffy coat. Its active pharmaceutical ingredient, generically known as Dialyzable Leucocyte Extract, is a mixture of peptide populations with reproducible proportions among batches. “Transferon Oral” modulates IFN-γ, TNF-α, and IL-6 and increases the survival rate in a herpes infection murine model when oropharyngeally (ORO) administered, which correlate with clinical observations where “Transferon Oral” is used as a therapeutic auxiliary in inflammatory diseases. Notwithstanding, how a peptide-derived product elicits systemic modulation of cytokines when ORO administered remains unclear. To shed light on the pharmacology of “Transferon Oral” its peptide components must be known. Ten “Transferon Oral” batches were sequenced by mass spectrometry and the intact peptides were identified. The most abundant peptides were the monomeric human Ubiquitin (Ub), a globular low-molecular mass protein, and an Ub variant which lacks the two-terminal Gly (Ub-GG). Recombinant Ub prevented murine death when ORO administered in a herpes infection murine model. Besides, the percentage of survival increased in groups treated with Transferon Oral+Ub and decreased in groups treated with Ub-depleted “Transferon Oral” respect to the group treated with “Transferon Oral” only. Our findings indicate that the biological properties of “Transferon Oral” are partially associated to the Ub content. They suggest that Ub may activate its extracellular receptor (CXCR-4) in the stomach eliciting systemic immunomodulatory effects via vagus nerve. This is the first report that identifies an active component of “Transferon Oral” with the potential for the development of oral peptide immunomodulators.

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          Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective.

          SWISS-MODEL pioneered the field of automated modeling as the first protein modeling service on the Internet. In combination with the visualization tool Swiss-PdbViewer, the Internet-based Workspace and the SWISS-MODEL Repository, it provides a fully integrated sequence to structure analysis and modeling platform. This computational environment is made freely available to the scientific community with the aim to hide the computational complexity of structural bioinformatics and encourage bench scientists to make use of the ever-increasing structural information available. Indeed, over the last decade, the availability of structural information has significantly increased for many organisms as a direct consequence of the complementary nature of comparative protein modeling and experimental structure determination. This has a very positive and enabling impact on many different applications in biomedical research as described in this paper.
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            The vagus nerve and the inflammatory reflex--linking immunity and metabolism.

            The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.
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              Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders

              The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/995228
                URI : https://loop.frontiersin.org/people/1078468
                URI : https://loop.frontiersin.org/people/1076407
                URI : https://loop.frontiersin.org/people/1007964
                URI : https://loop.frontiersin.org/people/1077256
                URI : https://loop.frontiersin.org/people/1077254
                URI : https://loop.frontiersin.org/people/1077268
                URI : https://loop.frontiersin.org/people/574869
                URI : https://loop.frontiersin.org/people/419068
                URI : https://loop.frontiersin.org/people/626277
                URI : https://loop.frontiersin.org/people/1056765
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                07 October 2020
                2020
                : 11
                : 569039
                Affiliations
                [1] 1Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional , Mexico City, Mexico
                [2] 2Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN , Ciudad de México, Mexico
                [3] 3Laboratorio Nacional para Servicios Especializados de Investigación, Desarrollo e Innovación (I + D + i) para Farmoquímicos y Biotecnológicos (LANSEIDI-FarBiotec-CONACyT), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional , Mexico City, Mexico
                [4] 4Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional , Mexico City, Mexico
                [5] 5Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente. , Mexico City, Mexico
                Author notes

                Edited by: Mariusz Skwarczynski, The University of Queensland, Australia

                Reviewed by: Valentin A. Pavlov, Northwell Health, United States; Daniel Carvalho Pimenta, Butantan Institute, Brazil

                *Correspondence: Lenin Pavón, lkuriaki@ 123456imp.edu.mx ; Sonia Mayra Pérez-Tapia, mayra.perez@ 123456udibi.com.mx

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                †ORCID: Luis Vallejo-Castillo, orcid.org/0000-0002-9532-3472; Liliana Favari, orcid.org/0000-0003-4414-966X; Said Vázquez-Leyva, orcid.org/0000-0003-2625-1230; Gabriela Mellado-Sánchez, orcid.org/0000-0002-8299-5958; Zaira Macías-Palacios, orcid.org/0000-0002-9040-7378; Leonardo López-Juárez, orcid.org/0000-0002-5483-8197; Luis Valencia-Flores, orcid.org/0000-0002-4235-5024; Emilio Medina-Rivero, orcid.org/0000-0001-8862-1378; Rommel Chacón-Salinas, orcid.org/0000-0002-4500-0253; Lenin Pavón, orcid.org/0000-0002-6067-6868; Sonia Mayra Pérez-Tapia, orcid.org/0000-0002-2818-8522

                Article
                10.3389/fphar.2020.569039
                7577238
                33117165
                8869db63-7f27-4072-aaa6-75ba7a60eedf
                Copyright © 2020 Vallejo-Castillo, Favari, Vázquez-Leyva, Mellado-Sánchez, Macías-Palacios, López-Juárez, Valencia-Flores, Medina-Rivero, Chacón-Salinas, Pavón and Pérez-Tapia

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 July 2020
                : 16 September 2020
                Page count
                Figures: 10, Tables: 1, Equations: 0, References: 48, Pages: 12, Words: 8317
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                transferon,human dialyzable leukocyte extracts,ms sequencing,immunomodulatory drugs,oral peptides,monomeric ubiquitin

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