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Ctr1 regulates copper uptake and its intracellular distribution. The first 14 amino acid sequence of the Ctr1 ectodomain Ctr1(1-14) encompasses the characteristic Amino Terminal Cu2+ and Ni2+ binding motif (ATCUN) as well as the bis-His binding motif (His5 and His6). We report a combined thermodynamic and spectroscopic (UV-vis, CD, EPR) study dealing with the formation of Cu2+ homobinuclear complexes with Ctr1(1-14), the percentage of which is not negligible even in the presence of a small Cu2+ excess and clearly prevails at a M/L ratio of 1.9. Ascorbate fails to reduce Cu2+ when bound to the ATCUN motif, while it reduces Cu2+ when bound to the His5-His6 motif involved in the formation of binuclear species. The histidine diade characterizes the second binding site and is thought to be responsible for ascorbate oxidation. Binding constants and speciation of Ag+ complexes with Ctr1(1-14), which are assumed to mimic Cu+ interaction with N-terminus of Ctr1(1-14), were also determined. A preliminary immunoblot assay evidences that the anti-Ctr1 extracellular antibody recognizes Ctr1(1-14) in a different way from the longer Ctr1(1-25) that encompasses a second His and Met rich domain. [ABSTRACT FROM AUTHOR]

Carnosine is an endogenously synthesized dipeptide composed of [beta]-alanine and L-histidine. It acts as a free radical scavenger and possesses antioxidant properties. Carnosine reduces proinflammatory and profibrotic cytokines such as transforming growth factor-[beta] (TGF-[beta]), IL-l, and TNF-[alpha] in different experimental settings. In the present study, we investigated the efficacy of carnosine on the animal model of bleomycin-induced lung injury. Mice were subjected to intratracheal administration of bleomycin and were assigned to receive carnosine daily by an oral bolus of 150 mg/kg. One week after fibrosis induction, bronchoalveolar lavage (BAL) cell counts and TGF-[beta] levels, lung histology, and immunohistochemical analyses for myeloperoxidase, TGF-[beta], inducible nitric oxide synthase, nitrotyrosine, and poly(ADP-ribose) polymerase were performed. Finally, apoptosis was quantified by terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay. After bleomycin administration, carnosine-treated mice exhibited a reduced degree of lung damage and inflammation compared with wild-type mice, as shown by the reduction of 1) body weight, 2) mortality rate, 3) lung infiltration by neutrophils (myeloperoxidase activity and BAL total and differential cell counts), 4) lung edema, 5) histological evidence of lung injury and collagen deposition, 6) lung myeloperoxidase, TGF-[beta], inducible nitric oxide synthase, nitrotyrosine, and poly(ADP-ribose) polymerase immunostaining, 7) BAL TGF-[beta] levels, and 8) apoptosis. Our results indicate that orally administered carnosine is able to prevent bleomycin-induced lung injury likely through its direct antioxidant properties. Carnosine is already available for human use. It might prove useful as an add-on therapy for the treatment of fibrotic disorders of the lung where oxidative stress plays a role, such as for idiopathic pulmonary fibrosis, a disease that still represents a major challenge to medical treatment. lung fibrosis; oxidative stress; chelating agent doi:10.1152/ajplung.00283.2006

The characterization of the copper(II) complex species formed with the PrP106-126 peptide bearing both C- and N-termini protected by acetylation and amidation, respectively (HuPrPAc106-126NH2) is reported. The results concerning the copper(II) complexes with Hu-PrPAc106-126NH2 and the related fragments allow a reliable comparison between the metal ions affinities of the two binding sites located within the disordered region, showing the coordination features of the main species formed in the physiological pH range.

The synthesis and spectroscopic characterization of a new cyclodextrin derivative, the platinum complex of 6A,6B-diamino-6A,6B-dideoxycyclomaltoheptaose, are discussed. The complex, which exhibits a square-planar coordination featuring two chlorine atoms and two amino atoms in a cis configuration, crystallizes in the orthorhombic space group P2(sub 1)2(sub 1). In addition, it has a distorted cavity due to the effect of platinum(II) complexation on the protons of the two substituted glucopyranosinic rings.

The chiral recognition properties of copper(II) complexes of 6A,6X-diamino-6A,6X-dideoxy-beta-cyclodextrin (X = A, B, C) were analyzed by electronic spectroscopy. The ligands of the copper(II) complexes did not exhibit enantioselective interactions. Furthermore, chiral recognition acitivity of the complex on amino acids involves monofunctionalized cyclodextrins. The role of the cyclodextrin cavity in chiral recognition is also exhibited by the spectra of the ternary complexes of AB isomers.

The enantioselective binding of tryptophan with copper(II) complex yields a ternary complex of 6-deoxy-6-((2-(4-imidazolyl)ethyl)amino)cyclomaltoheptaose, (Cu(CDhm)(L-TrpO))+. The aromatic side chain of TrpO- is outside the cavity and two nitrogen atoms are cis to each other. The donor atoms form the base of a square pyramid with copper(II) ion at the center and water molecule at the apical position. The weak interactions between the indole ring and CD cavity facilitates the formation of ternary complex having D-TrpO- rather than the pi-pi and d-pi interactions in case of the L-TrpO- isomer.

High performance liquid chromatographic experiments reveal the efficient chiral recognition and separation ability of the Copper(II) complex of 6-deoxy-6-N-histamine-beta-cyclodextrin toward unmodified aromatic amino acids (Phe, Trp and Tyr). Thermodynamic and spectroscopic studies help demonstrate the enantioselectivity and mechanism of chiral recognition by the Cu(II) complex. Calorimetric studies reveal the contribution of enthalpy to enantioselectivity for complexes containing aromatic amino acids and that the enthalpy contribution is more for D-enantiomers. Fluorescence studies demonstrate the participation of the cyclodextrin cavity in the recognition process.

beta-Cyclodextrin (beta-CD) is a cyclic oligosaccharide with a truncated cone-shaped structure containing a cavity with primary hydroxyl groups. Its structure makes it a potentially useful delivery system for dipeptides with hormonal or neurotropic activities. The three-dimensional x-ray structure of one such monosubstituted conjugate, 6-deoxy-6-cyclo(L-histidyl-L-leucyl) -beta-CD was determined. The structure of the dimer assumed a 'sleeping swan'-like shape with the hydrophobic leucine side chain inserted inside the cavity of the cyclodextrin.