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

Vallejo-Castillo, Luis; Favari, Liliana; Vázquez-Leyva, Said; Mellado-Sánchez, Gabriela; Macías-Palacios, Zaira; López-Juárez, Leonardo E; Valencia-Flores, Luis; Medina‐Rivero, Emilio; Chacón‐Salinas, Rommel; Pavón, Lenin; Pérez‐Tapia, Sonia Mayra

doi:10.3389/fphar.2020.569039

Cited by 11 publications

(18 citation statements)

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“…Highly conserved among mammals 16 , the extracellular mUb has a low molecular weight and controls inflammation in sepsis through activation of CXCR4 17 . The anti-inflammatory effect of ubiquitin may be due to direct action with the CXCR4 receptor expressed in macrophages and neutrophils and the vagus nerve 15,38 ; this interaction was indirectly explored in our work. The literature suggests that a systemic effect modulated by the vagal anti-inflammatory arc should generate a decrease in soluble and cellular inflammatory parameters (lymphocyte and neutrophil counts), a reduction of plasmatic levels of epinephrine and cortisol 37 .…”

Section: Discussionmentioning

confidence: 92%

“…The main components of the immunomodulator used in this work have recently been published: mUb and Ub∆GG 15 . Highly conserved among mammals 16 , the extracellular mUb has a low molecular weight and controls inflammation in sepsis through activation of CXCR4 17 .…”

Section: Discussionmentioning

confidence: 99%

“…As previously described, the first one involves the interaction with CXCR4 receptors in macrophages and neutrophils, inducing a decrease of proinflammatory cytokine release, the respiratory burst, and the migratory capacity of these cells 17,38 . On the other hand, mUb and Ub∆GG may interact with CXCR4 receptors expressed on the vagal endings at the site of immunomodulator administration 15 . In vitro studies have demonstrated that β2-adrenergic receptors negatively modulate the neutrophil oxidative burst, chemotaxis, the formation of neutrophil extracellular traps, and the expression of adhesion molecules leukotriene B4, chemokines, and cytokines 39,40 .…”

Section: Discussionmentioning

confidence: 99%

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Increased survival in puppies affected by Canine Parvovirus type II using an immunomodulator as a therapeutic aid

Muñoz

Vallejo-Castillo

Fragozo

et al. 2021

Sci Rep

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Canine parvovirus type II (CPV-2) infection induces canine parvoviral enteritis (CPE), which in turn promotes sepsis and systemic inflammatory response syndrome (SIRS). Mortality in this disease is usually registered within 48–72 h post-hospitalization, the critical period of the illness. It has been recently described that the use of an immunomodulator, whose major component is monomeric ubiquitin (mUb) without the last two glycine residues (Ub∆GG), in pediatric human patients with sepsis augments survival. It is known that CXCR4 is the cell receptor of extracellular ubiquitin in humans. This work aimed to explore the effect of one immunomodulator (human Dialyzable Leukocyte Extract-hDLE) as a therapeutic auxiliary in puppies with sepsis and SIRS induced by CPE. We studied two groups of puppies with CPV-2 infection confirmed by polymerase chain reaction. The first group received conventional treatment (CT) and vehicle (V), while the second group received CT plus the immunomodulator (I). We assessed both groups' survival, clinical condition, number of erythrocytes, neutrophils, and lymphocytes during the hospitalization period. In addition, hematocrit, hemoglobin, plasma proteins and cortisol values, as well as norepinephrine/epinephrine and serotonin concentration were determined. Puppies treated with CT + I showed 81% survival, mild clinical signs, and a significant decrease in circulating neutrophils and lymphocytes in the critical period of the treatment. In contrast, the CT + V group presented a survival of 42%, severe clinical status, and no improvement of the parameters evaluated in the critical period of the disease. We determined in silico that human Ub∆GG can bind to dog CXCR4. In conclusion, the administration of a human immunomodulator (0.5 mg/day × 5 days) to puppies with CPE under six months of age reduces the severity of clinical signs, increases survival, and modulates inflammatory cell parameters. Further studies are necessary to take full advantage of these clinical findings, which might be mediated by the human Ub∆GG to canine CXCR4 interaction.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Increased survival in puppies affected by Canine Parvovirus type II using an immunomodulator as a therapeutic aid

Muñoz

Vallejo-Castillo

Fragozo

et al. 2021

Sci Rep

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“…The treatment was linked to reduced serum concentration of C-reactive protein (CRP) and circulating neutrophils 72 h post-admission as well as increased lymphocyte count [14]. The active ingredient in the immunomodulator is a mixture of low molecular weight peptides (< 10 kDa), the major being monomeric human ubiquitin (mUb) and a variant with the last two glycine residues deleted (Ub∆GG) [15]. Highly conserved among mammals [16], Ub has a low molecular weight and controls in ammation in sepsis when it is extracellular [17], likely through the activation of CXCR4 specially those associated with the vagal afferences [15,18].…”

Section: Introductionmentioning

confidence: 99%

“…The active ingredient in the immunomodulator is a mixture of low molecular weight peptides (< 10 kDa), the major being monomeric human ubiquitin (mUb) and a variant with the last two glycine residues deleted (Ub∆GG) [15]. Highly conserved among mammals [16], Ub has a low molecular weight and controls in ammation in sepsis when it is extracellular [17], likely through the activation of CXCR4 specially those associated with the vagal afferences [15,18]. It is possibility induces the activation of the vagal anti-in ammatory arch by modulating the peripheral in ammatory response and blood cortisol levels [19,20].…”

Section: Introductionmentioning

confidence: 99%

Increased Survival In Puppies Affected By Canine Parvovirus Type II Using An Immunomodulator As A Therapeutic Aid

Muñoz

Vallejo-Castillo

Fragozo

et al. 2021

Preprint

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Background: The canine parvoviral enteritis (CPE) promotes sepsis and systemic inflammatory response syndrome (SIRS). Mortality in this disease is usually registered within 48–72 h post-hospitalization, the critical period of the disease. It has been recently described that the use of an immunomodulator whose major component is monomeric ubiquitin (mUb) without the last two glycine residues (Ub∆GG) in pediatric patients with sepsis improves survival. It is known that CXCR4 is the cell receptor of extracellular ubiquitin in humans. The aim of this work was to explore the effect of one immunomodulator (hDLE) as a therapeutic auxiliary in CPE puppies with sepsis and SIRS.Results: We studied two groups of puppies with CPE confirmed by polymerase chain reaction. The first group received conventional treatment (CT) and vehicle (V), while the second group received CT plus an immunomodulator (I). In both groups, we assessed the survival, clinical condition, number of erythrocytes, neutrophils, and lymphocytes, and values of hematocrit, hemoglobin, plasma proteins, cortisol, and norepinephrine epinephrine, and serotonin, during hospitalization.Puppies treated with CT+I showed 81% survival and milder clinical signs and a significant decrease in circulating neutrophils and lymphocytes in the critical period of the treatment. In contrast, the CT+V group presented a survival of 42%, severe clinical status, and no improvement of the parameters evaluated in the critical period of the disease. We determined in silico that human Ub∆GG can stimulate dog CXCR4.Conclusions: The administration of an immunomodulator (5 mg/day x 5 days) to puppies with CPE under 6 months of age reduces the severity of clinical signs, increases survival, and modulates inflammatory cell parameters. Further studies are necessary to take full advantage of these clinical findings which might be mediated by the human Ub∆GG to canine CXCR4 interaction.

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Immunomodulatory Supplements

Islas-Weinstein

Maldonado-García

2022

Encyclopedia of Infection and Immunity

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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

Abstract: 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.

Cited by 11 publications

References 45 publications

Increased survival in puppies affected by Canine Parvovirus type II using an immunomodulator as a therapeutic aid

Increased survival in puppies affected by Canine Parvovirus type II using an immunomodulator as a therapeutic aid

Increased Survival In Puppies Affected By Canine Parvovirus Type II Using An Immunomodulator As A Therapeutic Aid

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