The corticotropin releasing factor system in cancer: expression and pathophysiological implications

Malignant tumors express multiple factors that have some role in the regulating networks supporting their ectopic growth. Recently, increased interest has been developing in the expression and biological role of the neuropeptides and receptors of the corticotropin releasing factor (CRF) system, the principal neuroendocrine mediator of the stress response, especially in the light of several R&D programs for small molecule antagonists that could present some anticancer therapeutic benefit. In the present article, we review the literature suggesting that the CRF system could be involved in the regulation of human cancer development. Potential implication in growth, metastasis, angiogenesis, or immune parameters via activation of locally expressed receptors could be clinically exploited by presenting targets of new therapeutic approaches.     

The insect gut: A new source of ecdysiotropic peptides

Summary Proctodaea of European corn borer (Ostrinia nubilalis) and gypsy moth (Lymantria dispar) last instars (larvae) contain prothoracicotropic factors that stimulate the prothoracic glands (PGs) of the gypsy moth to produce both ecdysone and 3-dehydroecdysone (precursors to the insect molting hormone) in a dose-dependent manner. In a separate in vivo assay, injections of proctodaeal extracts into gypsy moth larvae that were head-ligated before the release of the molt-stimulating brain hormone, PTTH, resulted in a pupal molt.     

Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches

Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens.     

The insecticidal potential of venom peptides

Pest insect species are a burden to humans as they destroy crops and serve as vectors for a wide range of diseases including malaria and dengue. Chemical insecticides are currently the dominant approach for combating these pests. However, the de-registration of key classes of chemical insecticides due to their perceived ecological and human health risks in combination with the development of insecticide resistance in many pest insect populations has created an urgent need for improved methods of insect pest control. The venoms of arthropod predators such as spiders and scorpions are a promising source of novel insecticidal peptides that often have different modes of action to extant chemical insecticides. These peptides have been optimized via a prey–predator arms race spanning hundreds of millions of years to target specific types of insect ion channels and receptors. Here we review the current literature on insecticidal venom peptides, with a particular focus on their structural and pharmacological diversity, and discuss their potential for deployment as insecticides.     

The Sushi peptides: structural characterization and mode of action against Gram-negative bacteria

The compositional difference in microbial and human cell membranes allows antimicrobial peptides to preferentially bind microbes. Peptides which specifically target lipopolysaccharide (LPS) and palmitoyl-oleoyl-phosphatidylglycerol (POPG) are efficient antibiotics. From the core LPS-binding region of Factor C, two 34-mer Sushi peptides, S1 and S3, were derived. S1 functions as a monomer, while S3 is active as a dimer. Both S1 and S3 display detergent-like properties in disrupting LPS aggregates, with specificity for POPG resulting from electrostatic and hydrophobic forces between the peptides and the bacterial lipids. During interaction with POPG, the S1 transitioned from a random coil to an α-helix, while S3 resumed a mixture of α-helix and β-sheet structures. The unsaturated nature of POPG confers fluidity and enhances insertion of the peptides into the lipid bilayer, causing maximal disruption of the bacterial membrane. These parameters should be considered in designing and developing new generations of peptide antibiotics with LPS-neutralizing capability. Received 2 October 2007; received after revision 2 November 2007; accepted 4 December 2007 J. L. Ding, B. Ho: Co-senior authors.     

Mass spectrometric determination of the amino acid sequence in peptides: Desulfurization of sulfur-containing peptides

, N- 20 - .     

The influence of somatostatin on drug-induced prolactin release in the monkey

Summary The infusion of linear somatostatin did not block prolactin release induced by either perphenazine, TRH or serotonin. Somatostatin infusion, however, potentiated prolactin release induced by perphenazine and TRH but not that induced by serotonin.Supported in part by NIH General Research Support Grant No. RR5384 to Wayne State University School of Medicine and by NIH Research Grant No. HDO7722.The authors wish to express their appreciation to Mrs.Cynthia Van De Walle for her outstanding technical assistance in the performance of the prolactin RIA and the statistical analyses. We also appreciate receiving linear somatostatin from Dr.R. Makineni, Bachem Inc., Marina Del Ray, California, USA and from Dr.N. H. Grant, Wyeth Laboratories, Philadelphia, Pa. USA. We would like to thank Abbott Laboratories, North Chicago, Ill. USA for the gift of TRH and the Schering Corp., Bloomfield, N.J. USA for the gift of perphenazine.     

The endocrine role for chromogranin A: A prohormone for peptides with regulatory properties

Chromogranin A (CgA) belongs to the granin family of uniquely acidic secretory proteins co-stored and co-secreted with other hormones and peptides in elements of the diffuse neuroendocrine system. The granins arise from different genes and are characterized by numerous sites for post-translational cleavage into shorter peptides with postulated regulatory properties. This review is directed towards endocrine aspects of CgA and its biologically active peptides. There is ample evidence from in vitro studies of distinct effects and targets for three CgA-derived peptides, vasostatin-I, pancreastatin and catestatin. Endocrine regulations are indicated from in vivo studies, consistent with the postulated prohormone function of CgA for peptides with regulatory properties. Most of the effects fit into patterns of direct or indirect, inhibitory modulations of major functions, implicating CgA peptides in regulation of calcium and glucose metabolism, cardiovascular functions, gastrointestinal motility and nociception, tissue repair, inflammatory responses and as host defense peptides in the first phase of microbial invasions. Received 1 June 2007; received after revision 11 July 2007; accepted 12 July 2007     

Cationic host defence peptides: Innate immune regulatory peptides as a novel approach for treating infections

An increase in antibiotic resistance and the emergence of new pathogens has led to an urgent need for alternative approaches to infection management. Immunomodulatory molecules that do not target the pathogen directly, but rather selectively enhance and/or alter host defence mechanisms, are attractive candidates for therapeutic development. Natural cationic host defence peptides represent lead molecules that boost innate immune responses and selectively modulate pathogen-induced inflammatory responses. This review discusses recent evidence exploring the mechanisms of cationic host defence peptides as innate immune regulators, their role in the interface of innate and adaptive immunity, and their potential application as beneficial therapeutics in overcoming infectious diseases. Received 3 November 2006; received after revision 14 December 2006; accepted 22 January 2007     

Synthetic peptides related to eledoisin. Physalaemin-like peptides

Riassunto Vengono riportate le proprietà di una serie di peptidi sintetici affini per struttura alla fisalemina.     

Carbon monoxide releasing molecules: New insights for anticoagulation strategy in sepsis

Sepsis is a common and serious medical condition caused by hemorrhage, trauma, or abdominal surgery. Despite new understanding and much progress in therapies that specifically interfere with an interesting target, sepsis remains the leading causes of death in critically ill patients. Various therapies have been studied, but the majority of these treatments fail in clinical trials. It is clear that all septic patients exhibit coagulation abnormalities. These abnormalities range from subtle to marked activation of coagulation system, and finally to fulminant DIC. Studies confirmed that carbon monoxide has important cytoprotective function and anti-inflammatory properties. Until now, the question of whether CO plays a critical role in improving the coagulation system and then decreasing mortality during sepsis has not yet been definitely answered. Attempts to confirm this strategy may lead to new directions in the study of treatment of sepsis and the development of a novel agent for this disorder. Received 13 August 2008; received after revision 29 October 2008; accepted 17 November 2008