Peptide VSAK maintains tissue glucose uptake and attenuates pro-inflammatory responses caused by LPS in an experimental model of the systemic inflammatory response syndrome: a PET study

Luna-Reyes, Ismael; Pérez-Hernández, Eréndira G.; Delgado–Coello, Blanca; Ávila‐Rodríguez, Miguel A.; Mas‐Oliva, Jaime

doi:10.1038/s41598-021-94224-2

Cited by 7 publications

(7 citation statements)

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“…During the present investigation, based on the high levels of CETPI found in patients with Gram-negative bacteraemia, we explored its relationship the cytokine plasma levels, and found negative correlations between CETPI with IL-1β, IL-8, and IL-10. These results are consistent with the LPS-binding role of CETPI, showing an interesting correlation with the release of IL-8 by the gut (García-González, et al 2015;Luna-Reyes et al 2021;Liu et al 2006;Angrisano et al 2010).…”

Section: Discussionsupporting

confidence: 88%

“…Experiments from our group where LPS-treated rabbits were administered with a peptide derived from the carboxy-end segment of CETPI, showed attenuated circulating levels of pro-inflammatory molecules (Luna-Reyes et al 2021 ). During the present investigation, based on the high levels of CETPI found in patients with Gram-negative bacteraemia, we explored its relationship with the cytokine plasma levels, and found negative correlations between CETPI with IL-1β, IL-8, and IL-10.…”

Section: Discussionmentioning

confidence: 99%

“…The only structural difference between CETP and CETPI resides in their C-terminal domain, where human CETPI presents a 41 C-terminal segment containing prolines, and a disordered conformation, instead of the normal 24 residues present as an α-helix in CETP (Alonso et al 2003 ). Peptides derived from the C-terminal domain of CETPI bind LPS through electrostatic interactions, and the intravenous administration of one of these peptides, called VSAK, attenuates the harmful effects produced by LPS in a model of the systemic inflammatory response syndrome (Luna-Reyes et al 2021 ). In addition, considering that the expression of CETPI in intestinal cells is upregulated in the presence of LPS (García-González et al 2015 ), we aimed to evaluate the relation of the CETPI plasma levels with disease severity in Gram-negative sepsis.…”

Section: Introductionmentioning

confidence: 99%

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The cholesteryl-ester transfer protein isoform (CETPI) and derived peptides: new targets in the study of Gram-negative sepsis

Pérez-Hernández

León

Luna-Reyes

et al. 2022

Mol Med

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Background Sepsis is a syndrome where the dysregulated host response to infection threatens the life of the patient. The isoform of the cholesteryl-ester transfer protein (CETPI) is synthesized in the small intestine, and it is present in human plasma. CETPI and peptides derived from its C-terminal sequence present the ability to bind and deactivate bacterial lipopolysaccharides (LPS). The present study establishes the relationship between the plasma levels of CETPI and disease severity of sepsis due to Gram-negative bacteria. Methods Plasma samples from healthy subjects and patients with positive blood culture for Gram-negative bacteria were collected at the Intensive Care Unit (ICU) of INCMNSZ (Mexico City). 47 healthy subjects, 50 patients with infection, and 55 patients with sepsis and septic shock, were enrolled in this study. CETPI plasma levels were measured by an enzyme-linked immunosorbent assay and its expression confirmed by Western Blot analysis. Plasma cytokines (IL-1β, TNFα, IL-6, IL-8, IL-12p70, IFNγ, and IL-10) were measured in both, healthy subjects, and patients, and directly correlated with their CETPI plasma levels and severity of clinical parameters. Sequential Organ Failure Assessment (SOFA) scores were evaluated at ICU admission and within 24 h of admission. Plasma LPS and CETPI levels were also measured and studied in patients with liver dysfunction. Results The level of CETPI in plasma was found to be higher in patients with positive blood culture for Gram-negative bacteria that in control subjects, showing a direct correlation with their SOFA values. Accordingly, septic shock patients showing a high CETPI plasma concentration, presented a negative correlation with cytokines IL-8, IL-1β, and IL-10. Also, in patients with liver dysfunction, since higher CETPI levels correlated with a high plasma LPS concentration, LPS neutralization carried out by CETPI might be considered a physiological response that will have to be studied in detail. Conclusions Elevated levels of plasma CETPI were associated with disease severity and organ failure in patients with Gram-negative bacteraemia, defining CETPI as a protein implicated in the systemic response to LPS.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The cholesteryl-ester transfer protein isoform (CETPI) and derived peptides: new targets in the study of Gram-negative sepsis

Pérez-Hernández

León

Luna-Reyes

et al. 2022

Mol Med

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“…In addition, specific tissue activity was measured using 1gm of tissue samples from each animal. Additionally, the level of several pro-inflammatory cytokines was analyzed in the plasma obtained from all experimental animals [5].…”

Section: Methodsmentioning

confidence: 99%

Peptide VSAK Derived from the C-Terminal Region of CETPI Blocks LPS in an Animal Model of SIRS. Evidence Using PET-Imaging

Luna-Reyes¹,

Pérez-Hernández²,

Delgado–Coello³

et al. 2022

Proceedings of the 36th European and the 12th International Peptide Symposium

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“…This was associated with initial hyperglycaemia because of the reduced ability of glucose to enter cells. The animals also became hypothermic also because of the decrease in availability of glucose for most cells and thereby fuel for mitochondria [11].…”

Section: The Hyper Inflammatory Phase Of Sepsismentioning

confidence: 99%

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

Bradley¹

2023

Preprint

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Sepsis is a major health problem and accounts for 20 per cent of deaths worldwide. It is the most expensive condition treated in United States hospitals at $27 billion per year or about $20,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only marginal impact. Mortality is about 27 per cent for hospitalized patients and about 42 per cent for patients in intensive care.There are two phases of sepsis – a hyper inflammatory phase and a subsequent hypo inflammatory phase.During the hyper inflammatory phase the metabolic rate increases associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and migration of those leucocytes to infected and damaged tissues and an increased supply and consumption of glucose to fuel this immune system.During the subsequent hypo inflammatory phase the metabolic rate declines and this is associated with a decrease in body temperature and a generalized decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life threatening circumstances. Thus adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened then mitochondrial production of ATP is partially or substantially suppressed in favor of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischemic, or damaged tissues.However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery.It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients leading to a substantial ATP deficit. This is the fundamental issue of sepsis.This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyper glycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypo metabolic (hypo inflammatory) phase of sepsis should significantly improve survival.

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Peptide VSAK maintains tissue glucose uptake and attenuates pro-inflammatory responses caused by LPS in an experimental model of the systemic inflammatory response syndrome: a PET study

Cited by 7 publications

References 58 publications

The cholesteryl-ester transfer protein isoform (CETPI) and derived peptides: new targets in the study of Gram-negative sepsis

The cholesteryl-ester transfer protein isoform (CETPI) and derived peptides: new targets in the study of Gram-negative sepsis

Peptide VSAK Derived from the C-Terminal Region of CETPI Blocks LPS in an Animal Model of SIRS. Evidence Using PET-Imaging

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

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