Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

Treatment of horizontal root‐fractured maxillary incisors – a case report

Abstract – Traumatic dental injuries often occur to the teeth and their supporting tissues and they are the main reasons for emergency visit to a dental clinic. Management of a fracture depends on its position and the extent of root involvement. Horizontal root fractures are not seen frequently and the treatment consists of reduction and long‐term rigid fixation of the coronal segment. The present case demonstrates the successful management of two horizontally fractured maxillary central incisors with a follow‐up period of 9 months.     

Foot Polydactyly and Polysyndactyly: Genetic Implications in Two Families

The purpose of this study was to determine the genetic characteristics of foot polydactyly and identify its inheritance pattern by analyzing familial pedigree. Five cases from 2 Korean families were studied: 1 is a family whose members have been affected for 4 generations and the other for 2 generations. Using peripheral blood samples, we performed chromosomal analysis using the banding technique with Giemsa stain and karyotyping. We investigated the shape and structure of 46 chromosomes, looking for translation, deletion, inversion, ring chromosome, and isochromosome abnormalities. All peripheral blood samples demonstrated no chromosomal abnormalities, though the genetic nature of foot polydactyly and a new genetic locus was identified recently by other studies. Familial pedigree analysis suggested that polydactyly was inherited as an autosomal dominant trait in the first family. The mode of inheritance for the second family could not be determined due to an insufficient number of family members. The result of this study brought us to the conclusion that, while genetic factors play a major role in polydactyly, other factors may contribute to its occurrence.     

Low HDL‐cholesterol is common in European Type 2 diabetic patients receiving treatment for dyslipidaemia: data from a pan‐European survey

Aims To measure the prevalence of low high‐density lipoprotein (HDL)‐cholesterol (men < 1.03 mmol/l; women < 1.29 mmol/l) in European Type 2 diabetic patients receiving treatment for dyslipidaemia. Methods The pan‐European Survey of HDL‐cholesterol measured lipids and other cardiovascular risk factors in 3866 patients with Type 2 diabetes and 4436 non‐diabetic patients undergoing treatment for dyslipidaemia in 11 European countries. Results Diabetic patients were more likely to be obese or hypertensive than non‐diabetic patients. Most patients received lifestyle interventions (87%) and/or a statin (89%); treatment patterns were similar between groups. Diabetic patients had [means (SD)] lower HDL‐cholesterol [1.22 (0.37) vs. 1.35 mmol/l (0.44) vs. non‐diabetic patients, P < 0.001] and higher triglycerides [2.32 (2.10) vs. 1.85 mmol/l (1.60), P < 0.001]. More diabetic vs. non‐diabetic patients had low HDL‐cholesterol (45% vs. 30%), high triglycerides (≥ 1.7 mmol/l; 57% vs. 42%) or both (32% vs. 19%). HDL‐cholesterol < 0.9 mmol/l was observed in 18% of diabetic and 12% of non‐diabetic subjects. Differences between diabetic and non‐diabetic groups were slightly greater for women. LDL‐ and total cholesterol were lower in the diabetic group [3.02 (1.05) vs. 3.30 mmol/l (1.14) and 5.12 (1.32) vs. 5.38 mmol/l (1.34), respectively, P < 0.001 for each]. Conclusions Low HDL‐cholesterol is common in diabetes: one in two diabetic women has low HDL‐cholesterol and one diabetic man in four has very low HDL‐cholesterol. Management strategies should include correction of low HDL‐cholesterol to optimize cardiovascular risk in diabetes.     

MOLECULAR GENETICS OF THE SA GENE

1. We have recently identified a candidate gene for rat genetic hypertension, termed S_a, by identifying an mRN A species that shows markedly higher expression in the kidneys of spontaneously hypertensive rats (SHR) than in those of Wistar-Kyoto rats (WKY). 2. Subsequent genetic co-segregation analyses by ourselves and others indicated that the S_a gene locus did indeed influence blood pressure. Moreover, in a preliminary association study, we found an association of a polymorphism of the human S_a gene with essential hypertension. 3. Further studies to identify functions of the Sa gene products are required before reaching a definite conclusion.