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Publication date: May 2014 Source:Peptides, Volume 55

Author(s): William F. Porto , Diego O. Nolasco , Octavio L. Franco

Glycine-rich proteins (GRPs) derived from plants compose a family of proteins and peptides that share a glycine repeat domain and they can perform diverse functions. Two structural conformations have been proposed for GRPs: glycine loops arranged as a Velcro and an anti-parallel β-sheet with several β-strands. The antimicrobial peptide Pg-AMP1 is the only plant GRP with antibacterial activity reported so far and its structure remains unclear. Recently, its recombinant expression was reported, where the recombinant peptide had an additional methionine residue at the N-terminal and a histidine tag at the C-terminal (His6-tag). These changes seem to change the peptide's activity, generating a broader spectrum of antibacterial activity. In this report, through ab initio molecular modelling and molecular dynamics, it was observed that both native and recombinant peptide structures were composed of an N-terminal α-helix and a dynamic loop that represents two-thirds of the protein. In contrast to previous reports, it was observed that there is a tendency to adopt a globular fold instead of an extended one, which could be in both, glycine loops or anti-parallel β-sheet conformation. The recombinant peptide showed a slightly higher solvated potential energy compared to the native form, which could be related to the His6-tag exposition. In fact, the His6-tag could be mainly responsible for the broader spectrum of activity, but it does not seem to cause great structural changes. However, novel studies are needed for a better characterization of its pharmacological properties so that in the future novel drugs may be produced based on this peptide.

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Publication date: Available online 30 April 2014 Source:Peptides

Author(s): Samad Mussa Farkhani , Alireza Valizadeh , Hadi Karami , Samane Mohammadi , Nasrin Sohrabi , Fariba Badrzadeh

Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficult challenge. The cellular membrane is very effective in its role as a selectively permeable barrier. While it is essential for cell survival and function, also presents a major barrier for intracellular delivery of cargo such as therapeutic and diagnostic agents. In recent years, cell-penetrating peptides (CPPs), that are relatively short cationic and/or amphipathic peptides, received great attention as efficient cellular delivery vectors due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargo such as plasmid DNA (pDNA), small interfering RNA (siRNAs), drugs, and nanoparticulate pharmaceutical carriers. This review discusses the various uptake mechanisms of these peptides. Furthermore, we discuss recent advances in the use of CPP for the efficient delivery of nanoparticles, nanocarriers, DNA, siRNA, and anticancer drugs to the cells. In addition, we have been highlighting new results for improving endosomal escape of CPP-cargo molecules. Finally, pH-responsive and activable CPPs for tumor-targeting therapy have been described.

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Publication date: Available online 24 April 2014 Source:Peptides

Author(s): Yi-Ting Tsai , Chung-Yi Lee , Chih-Chin Hsu , Chung-Yi Chang , Ming-Kai Hsueh , Eagle Yi-Kung Huang , Chien-Sung Tsai , Shih-Hurng Loh

The Na⁺-H⁺ exchanger (NHE) and the Na⁺-HCO3 ⁻ co-transporter (NBC) have been confirmed as two major active acid extruders in many mammalian cells. Whether the NHE and NBC functional co-exist in human internal mammary artery smooth muscle cells (HIMASMCs) remains unclear. The aims of the present study were to investigate the acid-extruding mechanisms and to explore the effects of urotensin-II (U-II), a powerful vasoconstrictor, on pHi regulators in HIMASMCs. We investigated the changes of pHi by BCECF-fluorescence in HIMASMCs. We found that (a) two Na⁺-dependent acid extruders, i.e. NHE and NBC, functionally co-exist; (b) U-II (3 ∼ 100nM) induced a concentration-dependent intracellular acidosis; and (c) U-II (3 ∼ 100nM) caused a concentration-dependent increase on NHE activity, while decrease on NBC activity. In summary, we demonstrate for the first time that two acid-extruders, NHE and NBC, functionally co-exist in HIMASMCs. Moreover, U-II induces a concentration-dependent intracellular acidosis through the balanced effect of its effect on increasing NHE activity and decreasing NBC activity

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Publication date: Available online 18 April 2014 Source:Peptides

Author(s): Yuanjie Mao , Takeshi Tokudome , Ichiro Kishimoto , Kentaro Otani , Mikiya Miyazato , Kenji Kangawa

Both hexarelin and its natural analog ghrelin exert comparable cardioprotective activities. A single dose of ghrelin administered at the very acute phase after experimental myocardial infarction positively affects cardiac function in chronic heart failure. Therefore, this study aimed to determine whether a single dose of oral hexarelin has the same effect in the chronic disease phase. Myocardial infarction or sham operation was generated by left coronary artery ligation in male C57BL/6J mice, which subsequently received one dose of hexarelin or vehicle treatment by oral gavage 30min after operation. Although the mortality within 14 days after myocardial infarction did not differ between the groups, hexarelin treatment protected cardiac function in the chronic phase as evidenced by higher ejection fraction and fractional shortening, as well as lower lung weight/body weight and lung weight/tibial length ratios, compared with vehicle treatment. Hexarelin treatment concurrently lowered plasma epinephrine and dopamine levels, and shifted the balance of autonomic nervous activity toward parasympathetic nervous activity as evidenced by a smaller low/high-frequency power ratio and larger normalized high-frequency power on heart rate variability analysis. The results first demonstrate that one dose of oral hexarelin treatment potentially protects chronic cardiac function after acute myocardial infarction, and implicate that activating growth hormone secretagogue receptor 1a might be beneficial for cardioprotection, although other mechanism may also be involved.

Publication date: Available online 18 April 2014 Source:Peptides

Author(s): Abdurrahman Tufan , Rıdvan Mercan , Ozge Tugce Pasaoglu , Hatice Pasaoglu , Mehmet Akif Ozturk , Berna Goker , Seminur Haznedaroglu

Familial Mediterranean fever (FMF) is characterized by recurrent inflammation of serosal and synovial membranes. Despite the fact that it is a genetic disease, environmental factors, including infections, are shown to be triggering factors associated with the precipitation of attacks in FMF. Antimicrobial peptides (AMPs) are components of innate immunity which exert antimicrobial activity against many microorganisms. Human AMPs; cathelicidin (LL37) and defensins have immunomodulatory properties and are involved in the pathogenesis of many inflammatory disorders. Hence, we investigated serum AMPs in 23 newly diagnosed FMF patients. Blood samples were obtained at baseline, 6 months after initiation of colchicine and during an attack. Twenty-four healthy individuals constituted the control group. The concentrations of LL37, alpha-1, beta-1 and beta-2 defensins were determined by ELISA. Serum AMPs did not change during attacks and did not correlate with acute phase reactants. However, serum LL37 and defensins were found to be remarkably higher in FMF patients compared to healthy individuals both at baseline and 6 months after initiation of colchicine therapy which suggest that AMPs might have a role in the pathogenesis of FMF.