The 52 amino acid peptide hormone adrenomedullin (ADM) plays a major role in the development and regulation of the cardiovascular and lymphatic system and has therefore gained significant interest for clinical applications. Because adrenomedullin exhibits low metabolic stability, enhancement of the plasma half-life is essential for peptide-based drug design. Fluorescently labeled ADM analogues synthesized by Fmoc/t-Bu solid phase peptide synthesis were used to analyze their enzymatic degradation and specific fragmentation pattern in human blood plasma. The determination of important cleavage sites allowed the development of selectively modified peptides in a rational approach. By combination of palmitoylation, lactam-bridging, and Nα-methylation, ADM analogues protected from enzymatic cleavage in human blood were developed and revealed an explicitly elongated half-life of 5 days in comparison to the wild-type in vitro. This triple-modification did not alter the selectivity of the analogues at the AM1 receptor, highlighting their potential for therapeutic applications.
A. ROMPgel-Supported Horner−Emmons ReagentsThe first supported reagents to be published 67 were the phosphite ROMPgels 32 (R ) CO 2 Et, CN), which Scheme 2. Hydrogenation of the Polymer Backbone a a Reagents and conditions: (a) H2, Rh(PPh3)3Cl, PhH, 200 psi.
The human adrenomedullin (ADM) is a 52 amino acid peptide hormone belonging to the calcitonin family of peptides, which plays a major role in the development and regulation of cardiovascular and lymphatic systems. For potential use in clinical applications, we aimed to investigate the fate of the peptide ligand after binding and activation of the adrenomedullin receptor (AM1), a heterodimer consisting of the calcitonin receptor-like receptor (CLR), a G protein-coupled receptor, associated with the receptor activity-modifying protein 2 (RAMP2). Full length and N-terminally shortened ADM peptides were synthesized using Fmoc/tBu solid phase peptide synthesis and site-specifically labeled with the fluorophore carboxytetramethylrhodamine (Tam) either by amide bond formation or copper(I)-catalyzed azide alkyne cycloaddition. For the first time, Tam-labeled ligands allowed the observation of co-internalization of the whole ligand-receptor complex in living cells co-transfected with fluorescent fusion proteins of CLR and RAMP2. Application of a fluorescent probe to track lysosomal compartments revealed that ADM together with the CLR/RAMP2-complex is routed to the degradative pathway. Moreover, we found that the N-terminus of ADM is not a crucial component of the peptide sequence in terms of AM1 internalization behavior.
The families of 554 type I (insulin-dependent) diabetics were genetically analyzed according to probands' sex and age at onset applying a modification of Strömgren's method of age correction. Lifetime recurrence risk of type I diabetes (risk up to age 80 yr) for first-degree relatives in three consecutive generations was calculated. The overall risk (+/- 1 SE) for siblings was 6.6 +/- 1.1% and for children was 4.9 +/- 1.7%. The similar risks among siblings and children argue against a simple autosomal recessive trait. The results do not permit a conclusion about a distinct mode of inheritance. Regardless of age at onset, offspring of male probands always had a higher risk than offspring of female probands. Among all probands, fathers were significantly more often affected with type I diabetes (about twice) than mothers (4.1 +/- 0.9 vs. 1.7 +/- 0.6%, respectively). The risk for further siblings of the proband was significantly increased in the presence of a type I diabetic parent (25.2 +/- 10.3 vs. 5.8 +/- 1.0% for remaining probands), indicating a nonrandom clustering type I diabetes in families. Younger age at onset (less than 25 yr) was not associated with an increased risk to siblings. Type II diabetes was not more frequent among parents and siblings of type I diabetics than in the general population. The calculated risk estimates are of practical value in genetic counseling and are important for genetic models concerning type I diabetes.
The nature of the disorder in patients with familial lipodystrophy usually escapes recognition for many years and the syndrome is almost certainly much commoner than the few families described to date suggest.Before the description of the syndrome which forms the subject of the present communication, three clinical syndromes were recognised which share as their common distinguishing feature the partial or total absence of subcutaneous fat (lipoatrophy or lipodystrophy). In progressive ,partial lipodystrophy (Barraquer-Simon syndrome' ) fat is lost from the face and, in most cases, from the trunk with normal or excessive fat deposition on the pelvic girdle and lower limbs. Most affected subjects are female and show no other abnormality; a minority develop glomerulonephritis, diabetes, or hyperlipidaemia. The condition is usually sporadic. Seip3 and Berardinelli4 described congenital lipodystrophy in which total loss of subcutaneous fat was noted
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