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  • Pituitary adenylate cyclase activating polypeptide

    2024-04-02

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the secretin/growth hormone-releasing hormone (GHRH)/vasoactive intestinal peptide (VIP) family, with potent anti-inflammatory and potent cytoprotective properties [[6], [7], [8], [9], [10], [11], [12], [13]]. PACAP exists as two C-terminally amidated peptides with 38 or 27 amino acids, differing in the C-terminus. PACAP27 is homologous to VIP and secretin. PACAP is most abundant in the brain, but there are significant levels in other organs, including the thymus, spleen, lymph nodes, and duodenal mucosa [10]. The usefulness of PACAP as a drug, however, is limited by its very short Ramiprilat in the circulation following systemic administration due, in part, to rapid proteolysis, especially rapid exopeptidase activity at the amino terminus by the enzyme dipeptidyl peptidase IV (DPP IV) [14]. There is a need for analogs of PACAP38 with increased circulation half-life Ramiprilat and altered receptor activity/selectivity, goals that we have approached with rational design of PACAP analogs [15]. PACAP38 has physicochemical properties that are similar to many natural and synthetic antimicrobial peptides (AMP). For example, PACAP38 carries a highly basic charge of +10 at neutral pH. It has a significant compliment of hydrophobic residues with a structurally amphipathic arrangement, both hallmarks of canonical AMP [16]. Furthermore, there is evidence that other peptide hormones also have antibacterial activity [17,18]. Thus, here we examined the antimicrobial activity of PACAP and some analogs. PACAP38 and many analogs have potent antimicrobial activity against a panel of Gram-positive and Gram-negative pathogens. Activity was comparable to that of known synthetic and natural AMPs. These observations, combined with the potent physiological effects of PACAP, make it an intriguing candidate for development into a treatment for antibiotic resistant infections.
    Materials and methods
    Results
    Discussion
    Authorship contributions
    Funding support This work was supported in part by grants from the National Institutes of Health (Grants AI 119104 and GM 111824 to W.C.W.); and the Akira Arimura Foundation (to J.L.M.).
    Disclosures
    Introduction Docosahexaenoic acid (DHA) is a major constituent of neural membrane, and plays a critical role in nervous system functions such as cortical maturation, synaptogenesis, and myelination [1], [2]. A number of reports have demonstrated that the nutritional deficit of ω-3 polyunsaturated fatty acid (PUFA) was linked to psychiatric disease, particularly to depression [3], [4], [5]. A meta-analytical study showed that there were lower levels of ω-3 PUFA in the peripheral blood tissues in depressed patients [6]. Additionally, several clinical trials showed that supplementation with ω-3 PUFA effectively alleviated depressive symptoms of patients [7], [8]. Given that traditional antidepressants only remit about 30% patients [9], [10], and always produce various side effects, DHA supplementation has become an interest in the treatment of depression [11]. Nevertheless, the cellular and molecular mechanisms underlying the antidepressant effect of DHA are largely undefined. Lipid rafts are specialized membrane microdomains that are characterized by enrichment in cholesterol, sphingomyelin, and glycosylphosphatidylinositol-anchored proteins. Lipid rafts play important roles in compartmentalizing signaling events [12], [13]. Gsα has been shown to be enriched in lipid raft fractions from the cerebral cortex tissue of depressed individuals who committed suicide [14]. Previous studies have suggested that lipid raft regulated G protein-coupled receptor (GPCR) signaling transduction by influencing trafficking of signaling proteins [15], [16]. Using both pharmacologic and genetic manipulations, two studies determined that signaling pathway through Gsα was attenuated in lipid raft [17], [18], whereas Gsα activated adenylate cyclase more efficiently in non-lipid raft [18]. The neurogenesis induced by the up-regulation of the Gsα–adenylate cyclase–cAMP signaling pathway has been implicated in the mechanism of antidepressants [19]. The dysfunctional cAMP signaling also was found in the brain of suicide victims postmortem [20], [21]. It also has been determined that chronic antidepressant treatments could translocate Gsα from lipid raft to non-lipid raft, resulting in increased activity of adenylate cyclase [22], [23], [24].