Heme oxygenase-1 is required for angiogenic function of bone marrow-derived progenitor cells : role in therapeutic revascularization

Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that can be down-regulated in diabetes. Its importance for mature endothelium has been described, but its role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on the angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin−CD45−cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1−/− BMDCs revealed the attenuated up-regulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/− diabetic mice subjected to hind limb ischemia exhibited reduced local expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), VEGFR-1, VEGFR-2, and CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by an injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. A low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, which can be rescued by a local injection of conditioned media from cultured BMDCs

Delayed fibril formation of amylin(20-29) by incorporation of alkene dipeptidosulfonamide isosteres obtained by solid phase olefin cross metathesis

The synthesis of a new peptidomimetic structure, the alkene dipeptidosulfonamide isostere, is described. The synthesis is based on a cross metathesis reaction between two allylic building blocks, both in solution and on the solid phase. This method was also applicable to the solid phase synthesis of alkene dipeptide isosteres. Derivatives of amylin(20-29) containing the alkene dipeptidosulfonamide isostere as well as the alkene dipeptide isostere were successfully synthesized using the solid phase cross metathesis method. Investigation of relations between structure and fibril formation of these amylin(20-29) derivatives showed retardation of fibril formation and altered secondary structures, compared to native amylin(20-29). © 2007 Elsevier Ltd. All rights reserved

Advances in gene therapy for Wolfram syndrome

The Wolfram Syndrome (WS) is an early onset genetic disease (1/200 000) featuring diabetes mellitus and progressive optic neuropathy ensuing mutations in the WFS1 gene. To date, there is no treatment to stop the progression of the disease. We have characterized the visual impairment of 2 mutants animal models for WFS1 (Wfs1exon8‐/‐ and Wfs1E864K) and shown that these 2 models developed an optic atrophy. We started for 1 year intravitreous micro injections of therapeutic vector AAV2‐CMV‐WFS1 on 1 month‐old Wfs1exon8‐/‐. Our results showed that mice injected exhibited a stabilization of their visual acuity at 3 and 6 months post‐injection, and a decrease of optic disc pallor and optic nerve damage. These promising results demonstrate the validity of the pre‐clinical approach to treat Wolfram Syndrome by gene therapy and encourage further studies under a treatment for the Wolfram Syndrome patients

Intrahepatic cholestasis of pregnancy, worsening after dexamethasone

We present a case of intrahepatic cholestasis of pregnancy (ICP) treated with dexamethasone. Rapid elevation in transaminases was observed, beyond levels usually reported in this condition. The world literature is reviewed, with particular reference to a recently suggested treatment protocol using dexamethasone

Spectroscopic and magnetic properties of two di-copper(II) complexes with macrocyclic Schiff bases

Two binuclear copper(II) complexes with macrocyclic Schiff bases Cu2LI(CH3COO)2·5H2O (complex I) and Cu2LII(CH3COO)2·2H2O (complex II) were synthesized and then characterized by IR, UV, and thermogravimetric analysis (TGA) measurements. TGA was used to investigate the desolvation of lattice water molecules. IR spectra demonstrated the formation of the cyclic compound and together with chemical elemental analysis were used to propose the structure of the complexes. The UV spectra of both complexes are typical for binuclear copper(II) complexes with Robson-type ligands. Variable-temperature magnetic susceptibility measurements corroborated by EPR and low-temperature isothermal magnetization data confirmed the formation of copper dimers with antiferromagnetic exchange coupling constants of -400 and -1250 cm-1 for complexes I and II, respectively, residing outside the usual range for the phenoxide bridged Cu(II) complexes. This implies the possibility that additional superexchange paths through the macrocyclic ligand may affect the intradimer exchange interaction as well as the phenoxide oxygen bridges