Peptides
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Sepsis is a serious complication for patients with obstructive jaundice. Although administration of adrenomedullin (AM) in combination with its binding protein (AMBP-1) is protective after injury, it remains unknown whether AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in the setting of biliary obstruction. The aim of this study is, therefore, to test the efficacy of human AM/AMBP-1 in a rat model of obstructive jaundice and polymicrobial sepsis. ⋯ Moreover, human AM/AMBP-1 significantly increased the survival rate from 21% (n=14) to 53% (n=15). Thus, human AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in jaundiced rats. Human AM/AMBP-1 can be further developed as a novel treatment for sepsis in jaundiced patients.
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The ventrolateral periaqueductal gray (vlPAG) is a major site of opioid analgesic action and a key locus for the development of morphine tolerance. Previous experimental evidence supports the hypothesis that the brain synthesizes and secretes neuropeptides, which act as a part of the homeostatic system to attenuate the effects of morphine and endogenous opioid peptides. Among the known antiopioid peptides, nociceptin/orphanin FQ (N/OFQ) has been shown to inhibit various opioid effects, especially analgesia. ⋯ Intra vlPAG (i.vlPAG) administration of the NOP receptor antagonist (+/-)-J 113397 restored the opioid's analgesic effect. When (+/-)-J 113397 was administered beginning the first day preceding each morphine administration, tolerance did not develop, but it appeared if the NOP antagonist had been suspended. These data suggest that the N/OFQ in the vlPAG may play a key role in opioid-induced antinociceptive tolerance.
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In vitro and in vivo studies demonstrated that nociceptin/orphanin FQ inhibits norepinephrine release, while the effects of norepinephrine on nociceptin/orphanin FQ release remain unknown. Previous studies in healthy and hypertensive subjects showed that prolonged and forced hyperventilation induces different blood pressure (BP) responses depending on changes in plasma catecholamine levels. We investigated whether the effects of hyperventilation on the sympatho-adrenergic system involve nociceptin/orphanin FQ release. ⋯ A hierarchical cluster analysis based on BP response to hyperventilation identified three groups of subjects: group 1 (n=20) with a decrease in BP, norepinephrine (1311.1+/-45.5 fmol/ml versus 900.0+/-55.3 fmol/ml, P<0.01) and nociceptin/orphanin FQ (13.0+/-0.7 pg/ml versus 7.9+/-0.8 pg/ml, P<0.01), group 2 (n=18) without any change in BP and norepinephrine (1133.0+/-31.5 fmol/ml versus 1176.0+/-44.6 fmol/ml), with a decrease in nociceptin/orphanin FQ (12.5+/-3.2 pg/ml versus 7.4+/-0.6 pg/ml, P<0.01) and group 3 (n=18) with an increase in BP, norepinephrine (1216.7+/-50.9 fmol/ml versus 1666.7+/-44.9 fmol/ml, P<0.01) and nociceptin/orphanin FQ values (11.5+/-1.6 pg/ml versus 19.9+/-1.5 pg/ml, P<0.01). Norepinephrine changes in response to hyperventilation in groups 1 and 3 were directly (P<0.01) correlated with those of nociceptin/orphanin FQ. Our results showed that vigorous and prolonged hyperventilation changes plasma nociceptin/orphanin FQ levels due to the direct effects of hypocapnic alkalosis or to different sympatho-adrenergic system responses.
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The T cell activation Ag CD26/dipeptidylpeptidase IV (DPP IV) combines co-stimulatory and enzymatic properties. Catalytically, it functions as an exopeptidase, modulating biological activity of key chemokines and peptides. Here we investigated the effect of organ-specific inhibition of DPP IV catalytic activity on ischemia/reperfusion injury after extended ischemia in the mouse model of orthotopic single lung transplantation. ⋯ Treatment with the DPP IV inhibitor AB192 resulted in significant improvement of gas exchange, less lipid oxidation, preservation of parenchymal ultrastructure, reduced neutrophil infiltration, reduced myeloperoxidase expression, increased hemoxygenase 1 expression, pronounced expression of VIP in alveolar macrophages and increased mRNA expression of VIP. Inhibition of intragraft DPP IV catalytic activity with AB192 strikingly ameliorates ischemia/reperfusion injury after extended ischemia. Furthermore, preservation of endogenous intragraft VIP levels correlate with maintaining lung function and structural integrity.
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In our previous paper we reported synthesis and biological activity of two cyclic analogs of endomorphin-2 (EM-2): Tyr-c(Lys-Phe-Phe-Asp)-NH(2) and Tyr-c(Asp-Phe-Phe-Lys)-NH(2), achieved by making an amid bond between Lys and Asp side-chains. The first analog did not bind to the mu-opioid receptor, the affinity of the second one was very low. In the present study, we describe the synthesis of four novel cyclic analogs of similar structure, but with d-amino acids in position 2 (D-Lys or D-Asp). ⋯ This analog elicited analgesia also after peripheral administration and this effect was reversed by concomitant i.c.v. injection of the mu-opioid antagonist, beta-funaltrexamine, which indicated that antinociception was mediated by the mu-opioid receptor in the brain. Central action of the cyclic analog gives evidence that it was able to cross the blood-brain barrier, most likely due to the increased lipophilicity. Our results demonstrate that cyclization might be a promising strategy to enhance bioavailability of peptides and may serve a role in the development of novel endomorphin analogs with increased therapeutic potential.