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Insulin-like growth factor-1 (IGF-1) is responsible for many systemic growth hormone (GH) functions although it has an extensive number of inherent activities (anabolic, cytoprotective, and anti-inflammatory). The potential options for IGF-1 therapy arise as a promising strategy in a wide list of human diseases. However, deeper studies are needed from a suitable animal model. All human conditions of IGF-1 deficiency consist in partially decreased IGF-1 levels since total absence of this hormone is hardly compatible with life. The aim of this work was to confirm that heterozygous Igf-1 (+/-) mice (Hz) may be considered as an appropriate animal model to study conditions of IGF-1 deficiency, focusing on early ages. Heterozygous Igf-1 (+/-) mice were compared to homozygous Igf-1 (+/+) by assessing gene expression by quantitative PCR, serum circulating levels by ELISA, and tissue staining. Compared to controls, Hz mice (25 days old) showed a partial but significant reduction of IGF-1 circulating levels, correlating with a reduced body weight and diminished serum IGFBP-3 levels. Hz mice presented a significant decrease of IGF-1 gene expression in related organs (liver, bone, testicles, and brain) while IGF-1 receptor showed a normal expression. However, gene expression of growth hormone receptor (GHR) was increased in the liver but reduced in the bone, testicles, and brain. In addition, a significant reduction of cortical bone thickness and histopathological alterations in the testicles were found in Hz mice when compared to controls. Finally, the lifelong evolution of IGF-1 serum levels showed significant differences throughout life until aging in mice. Results in this paper provide evidence for considering heterozygous mice as a suitable experimental model, from early stages, to get more insight into the mechanisms of the beneficial actions induced by IGF-1 replacement therapy.

Hybrid abinitio calculations (GIAO/B3LYP/6-31G*) together with new DNMR experiments (1H and 13C) have been used to clarify the problem of the conformation of 5,6,11,12-tetrahydrodibenzo[a,e]cyclooctene. The carbon-13 chemical shifts have been assigned unambiguously to the chair C and twist-boat TB conformations. Lineshape analysis of the 1H NMR spectra has been carried out at several temperatures using an estimated set of Karplus-type vicinal coupling constants.

A reduction of the tetracyclic skeleton of sordarins and sordaricins to a cyclopentane ring bearing the pharmacophore functional groups led to new derivatives retaining part of their in vitro and whole-cell activity.

BackgroundBone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone.MethodsSeveral proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice,Igf+/+, n = 10), heterozygousIgf+/-group with partial IGF-I deficiency (Hz, n = 10), and heterozygousIgf+/-mice treated with IGF-I for 10 days (Hz + IGF-I, n = 10).ResultsData in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity.ConclusionsLow doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor.

A series of eighteen substituted pyrazoles, bis- and tris-azolyl-methanes or ethanes was investigated for their interaction with the zinc enzyme carbonic anhydrase (CA). Several types of activities were detected, generally as CA activators, but CA inhibitory properties were also discovered for the very sterically-demanding derivatives of these series. Kinetic determinations by a stopped-flow technique for carbon dioxide hydration reaction allowed the determination of Michaelis-Menten constants, which are identical in the absence or in the presence of these modulators, proving a noncompetitive mechanism of activation-inhibition. MNDO calculations were used with moderate success to explain the biological results.

A correlation was found between the carbonic anhydrase II activating power and the pKa values for a series of azoles, bisazolylmethanes and bisazolylethanes. Strong activations were found for compounds with pKa's in the interval 6.5-8.0. The mechanism of action for such activators is discussed.