Discovery of novel non-peptide CCR1 receptor antagonists

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.     

Iodine deficiency disorders in Bangladesh

An extensive iodine deficiency disorders survery was conducted in Bangladesh in 1993 to assess the latest iodine nutriture status of the country. The clinical variables of the survey were goitre and cretinism, and the biochemical variable was urinary iodine. The “EPI-30 cluster” sampling methodology was followed for selecting the survey sites. In each survey site, the study population consisted of boys and girls, aged 5–11 years, and men and women, aged 15–44 years, in about equal populations. the total number of survey sites was 78 and the total number of respondents was 30 072. The total number of urine samples was 4512 (15% sub-sample). The current total goitre rate (grade 1+grade 2) in Bangladesh is 47.1% (hilly, 44.4%; flood-prone, 50.7%; and plains, 45.6%). The prevalence of cretinism in the country is 0.5% (hilly, 0.8%; flood-prone, 0.5%; and plains, 0.3%). Nearly 69% of Bangladeshi population have biochemical iodine deficiency (urinary iodine excretion [UIE]<10 mg/dl) (hilly, 84.4; flood-prone, 67.1%; and plains 60.4%). Women and children are more affected than men, in terms of both goitre prevalence and UIE. The widespread severe iodine deficiency in all ecological zones indicates that the country as a whole is an iodine-deficient region. Important recommendations of global interest are made from the experience of the survey. An erratum to this article is available at .     

Reduction of atherosclerosis in cholesterol-fed rabbits and decrease of expressions of intracellular adhesion molecule-1 and vascular endothelial growth factor in foam cells by a water-soluble fraction of Polygonum multiflorum

Polygonum multiflorum stilbeneglycoside （PMS） is a water-soluble fraction of Polygonum multiflorum Thunb. , one of the most famous tonic traditional Chinese medicines, that has protective effects on the cardiovascular system. The purpose of the present study is to elucidate the effects of PMS on macrophage-derived foam cell functions and the reduction of severity of atherosclerosis in hypercholesterolemic New Zealand White （NZW） rabbits. NZW rabbits were fed for 12 weeks with a normal diet, a high cholesterol diet, or a high cholesterol diet associated with irrigation with different doses of PMS （25, 50, or 100 mg/kg）. Treatment of NZW rabbits fed with high cholesterol diet with 100 mg/kg PMS attenuated the increase in plasma cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and plasma triglyceride. Treatment with 50 and 100 mg/kg PMS caused 43% and 60% decrease in atherosclerotic lesioned area ratio to total surface area, respectively. In U937 foam cells, PMS could decrease the high expression of intercellular adhesion molecule （ICAM）-1 protein and the vascular endothelial growth factor （VEGF） protein levels in the medium induced by oxidized lipoprotein when analyzed by flow cytometry. The results proved that PMS is a powerful agent against atherosclerosis and that PMS action could possibly be through the inhibition of the expression of ICAM-1 and VEGF in foam cells.     

Heme oxygenase1 (HSP-32) is induced in myelin-phagocytosing Schwann cells of injured sciatic nerves in the rat

Schwann cells participate in myelin phagocytosis in the early stage of Wallerian degeneration, prior to the recruitment of macrophages. This is the first report that Schwann cells induce heme oxygenase-1 (HO-1), a 32-kDa heat shock protein, only when they have transformed into myelin-phagocytosing cells from myelinating cells (days 2-3) immediately after crush injury of rat sciatic nerves. Double immunofluorescent labelling for HO-1 and transferrin receptors revealed that HO-1-immunoreactive Schwann cells also expressed transferrin receptors suggesting activation of iron metabolism. The transient induction of HO-1 in Schwann cells may contribute to the adaptive function in an altered environment when the cells have lost contact with axons, and may play a crucial role in the ensuing regeneration.     

STRUCTURAL CHARACTERISATION OF AN IMMUNOMODULATING POLYSACCHARIDE ISOLATED FROM AQUEOUS EXTRACT OF PLEUROTUS FLORIDA FRUIT-BODIES

The water-soluble glucan was obtained from Pleurotus florida fruit bodies by hot water extraction, ethanol precipitation, DEAE cellulose dialysis and Sephadex G-75 gel filtration. The structural information of the glucan was achieved by chemical (hydrolysis, methylation, periodate oxidation) and spectroscopic (¹H and ¹³C) analyses, indicated a repeating unit built up of (1→6)-linked D-glucose. The following structure has been determined for the repeating unit: →6)-α-D-Glcp-(1→ This fraction exhibited significant macrophage activity through the release of nitric oxide