Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma

Abstract

Introduction: Nephrilin peptide is a designed inhibitor of Rictor complex (also known as mTORC2), an evolutionarily conserved assembly believed to modulate responses to cellular stress. We previously demonstrated the ability of nephrilin peptide to suppress neuroinflammation, loss of body mass, glycaemic control and kidney function in a rat scald model, as well as sepsis mortality in a mouse model. The present study explores the effect of nephrilin plus iron formulations on clinically relevant outcomes in the rat scald model. Methods: Animals were treated with nephrilin by subcutaneous bolus injection on post-burn days 1–7. Equimolar ferric iron in the formulation improved the positive systemic effects of nephrilin on kidney function, glycaemic control, oxidative stress, early hyperinflammation, late inflammasome activation, hyperangiogenesis and body mass, all variables previously shown to bear upon clinically relevant burn injury outcomes. The sparing effects of nephrilin-iron were demonstrated in both sexes. Discussion: Surprisingly, optimum daily treatment doses were in the range of 2–4 mg/kg, while 8 mg/kg was less effective, suggesting the possibility of marginal pro-oxidant effects from the ‘free’ iron fraction. Thus, although ferric iron in the nephrilin formulation is clearly helpful, care must be exercised to select an optimum treatment dose. Conclusion: Iron increases the efficacy of nephrilin peptide in burns.

Lobe-specific modulation of B16MET melanoma lung metastases by nephrilin peptide

“…Nephrilin's efficacy in reversing the systemic effects of sepsis and burn trauma [9][10][11] appears to involve pro-homeostatic modulation of the underlying immune dysfunction. In this study, we measured the distribution of nephrilin peptide across lung tissues after administration via subcutaneous bolus injection.…”

“…Severe burn trauma is associated with secondary systemic effects including hyper inflammation, hypercatabolism, sepsis, organ failure, loss of glycemic control, delayed wound healing, and cognitive deficits [3][4][5][6][7][8] . We have demonstrated the efficacy of nephrilin peptide in combating many of these pleiotropic effects in burn trauma as well as in several rodent models of metabolic and xenobiotic stress [9][10][11][12][13][14] . When nephrilin peptide is injected subcutaneously into rodents, its Protor sequence is believed to reduce oxidative stress in target tissues by modulation of Rac1 phosphorylation and, more speculatively, its IGFBP3 sequence may mediate homeostatic immunomodulatory functions in addition to its described transporter functions [12] .…”

“…When nephrilin peptide is injected subcutaneously into rodents, its Protor sequence is believed to reduce oxidative stress in target tissues by modulation of Rac1 phosphorylation and, more speculatively, its IGFBP3 sequence may mediate homeostatic immunomodulatory functions in addition to its described transporter functions [12] . Nephrilin treatment following burn injury reverses epigenetic and signaling changes in kidney tissue that lead to the activation of Rac1, and lowers elevations in markers of systemic oxidative stress such as urinary 8-isoprostane and plasma OHDG [10][11][12] . Besides, an analysis of gene expression in the CNS after burn injury showed that nephrilin beneficially modulated the expression of genes associated with astrocytosis, oxidative stress, and immunosuppression [13] .…”

Covalent modification of nephrilin peptide with valproic acid increases its efficacy as a therapeutic in burn trauma

“…These serious and enduring complications can lead to substantial morbidity and mortality [ 4 - 9 ]. We previously demonstrated the efficacy of nephrilin peptide in combating many of the pleotropic effects of burns [ 10 - 12 ]. Nephrilin treatment following burn injury reverses epigenetic and signaling changes in kidney tissue that lead to the activation of Rac1, and lowers elevations in markers of systemic oxidative stress such as urinary 8-isoprostane and plasma OHDG.…”

“…Nephrilin treatment following burn injury reverses epigenetic and signaling changes in kidney tissue that lead to the activation of Rac1, and lowers elevations in markers of systemic oxidative stress such as urinary 8-isoprostane and plasma OHDG. In a recent publication we describe the variables most reliably modulated by nephrilin in the rat scald model, these variables falling into in seven distinct efficacy categories [ 12 , 13 ]. In addition, an analysis of gene expression in the central nervous system after burn injury showed that nephrilin beneficially modulated the expression of genes associated with astrocytosis, oxidative stress and immunosuppression [ 14 ].…”