Exercise benefits the cardiac, autonomic and inflammatory responses to organophosphate toxicity.

The organophosphate, diisopropyl fluorophosphate (DFP), may impair cardiovascular, autonomic and immune function while exercise training is thougt to be restorative. Experiments determined effects of wheel exercise in C57B1 male mice, testing cardiovascular and autonomic function and characterization of the immunological profile. Sedentary (S) and exercise (ET) groups were treated with corticosterone (CORT) followed by injection of DFP. This model was associated with systolic and diastolic dysfunction in the S group, measured using echocardiography (ECHO). Chronic exercise ameliorated the cardiac deficit. Autonomic balance, accessed by heart rate variability (HRV), showed increased sympathetic and decreased parasympathetic modulation in S group. Autonomic balance in ET mice was not affected by DFP. Our DFP model resulted in mild neuroinflammation seen by increased IL5, IL12 and MIP2 in brain and plasma IL6 and IL1a. DFP had a negative impact on cardiac/autonomic function and inflammatory markers, effects reduced by exercise. Data suggest a beneficial effect of exercise training on the cardiovascular and autonomic responses to DFP/CORT.

Structural Motif Descriptors as a Way To Elucidate the Agonistic or Antagonistic Activity of Growth Hormone-Releasing Hormone Peptide Analogues.

The synthesis of analogues of hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) is an efficient strategy for designing new therapeutic agents. Several promising synthetic agonist and antagonist analogues of GHRH have been developed based on amino acid mutations of the GHRH (1-29) sequence. Because structural information on the activity of the GHRH agonists or antagonists is limited, there is a need for more effective analytical workflows capable of correlating the peptide sequence with biological activity. In the present work, three GHRH agonists-MR-356, MR-406, and MR-409-and three GHRH antagonists-MIA-602, MIA-606, and MIA-690-were investigated to assess the role of substitutions in the amino acid sequence on structural motifs and receptor binding affinities. The use of high resolution trapped ion mobility spectrometry coupled to mass spectrometry allowed the observation of a large number of peptide-specific mobility bands (or structural motif descriptors) as a function of the amino acid sequence and the starting solution environment. A direct correlation was observed between the amino acid substitutions (i.e., basic residues and d/l-amino acids), the structural motif descriptors, and the biological function (i.e., receptor binding affinities of the GHRH agonists and antagonists). The simplicity, ease, and high throughput of the proposed workflow based on the structural motif descriptors can significantly reduce the cost and time during screening of new synthetic peptide analogues.