Hideho Tanaka

Molecular cloning of a new class of cartilage-specific matrix, chondromodulin-I, which stimulates growth of cultured chondrocytes

Here we report the structure and bioactivity of 25 kDa glycoprotein (chondromodulin-I) as a tissue-specific functional matrix component identified and cloned for the first time. Chondromodulin-I purified from fetal bovine cartilage markedly stimulated DNA synthesis of cultured growth-plate chondrocytes in the presence of basic fibroblast growth factor (FGF). Bovine chondromodulin-I cDNA revealed that the mature protein consists of 121 amino acids with three possible glycosylation sites and is coded as the C-terminal part of a larger precursor. On northern blot analysis, expression of chondromodulin-I mRNA was observed only in cartilage.

Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC-555

We examined the effect of chronic (21 days) oral treatment with the thiazolidinedione, MCC‐555 ((±)‐5‐[{6‐(2‐fluorbenzyl)‐oxy‐2‐naphy}methyl]‐2,4‐thiazolidinedione) on metabolic status and insulin sensitivity in obese (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats which display an impaired glucose tolerance (IGT) or overt diabetic symptoms, respectively. MCC‐555 treatment to obese Zucker rats (10 and 30 mg kg−1) and diabetic ZDF rats (10 mg kg−1) reduced non‐esterified fatty acid concentrations in both rat strains and reduced plasma glucose and triglyceride concentrations in the obese Zucker rats. Liver glycogen concentrations were significantly increased by chronic MCC‐555 treatment in both obese Zucker rats (30 mg kg−1 day−1) and diabetic ZDF rats (10 mg kg−1 day−1), as compared with vehicle‐treated lean and obese rats and there was a significant increase in hepatic glycogen synthase activity in MCC‐555‐treated diabetic ZDF rats as compared to vehicle‐treated controls. During a euglycaemic hyperinsulinaemic clamp, MCC‐555‐treated obese Zucker rats and diabetic ZDF rats required significantly higher glucose infusion rates to maintain stable glucose concentrations (2.01 ± 0.19 mg min−1 and 6.42 ± 1.03 mg min−1, respectively) than vehicle‐treated obese controls (0.71 ± 0.17 mg min−1 and 2.09 ± 0.71 mg min−1; P<0.05), demonstrating improved insulin sensitivity in both Zucker and ZDF rats. MCC‐555 treatment also enhanced insulin‐induced suppression of hepatic glucose production in ZDF rats as measured using infusions of [6‐3H]‐glucose under clamp conditions. In conclusion, we have demonstrated that MCC‐555 improves metabolic status and insulin sensitivity in obese Zucker and diabetic ZDF rats. MCC‐555 may prove a useful compound for alleviating the metabolic disturbances and IGT associated with insulin resistance in man.

The development of overt diabetes in young Zucker Diabetic Fatty(ZDF) rats and the effects of chronic MCC-555 treatment

1 Young (6‐week‐old) pre‐diabetic Zucker Diabetic Fatty (ZDF) rats displaying impaired glucose tolerance (IGT), moderate hyperglycaemia and hyperinsulinaemia were treated with the novel thiazolidinedione, MCC‐555, for 28 days, during which time β‐cell failure and progression to overt diabetes occurs. 2 Treated ZDF rats exhibited consistently lower blood glucose levels than vehicle‐treated diabetic controls, with a delayed rise and lower plateau levels. MCC‐555 maintained plasma insulin levels throughout the treatment period, whereas these fell by 40% in untreated ZDF rats. 3 The rise in body weight was maintained in MCC‐555‐treated rats, whereas vehicle‐treated rats exhibited blunted body weight gain after 8 weeks of age. Daily food intake was higher in diabetic, as compared to non‐diabetic rats, but treatment did not modify food intake in diabetic rats. Water intake was lower in treated ZDF rats, concomitant with lowering of blood glucose. 4 The hyperinsulinaemic‐euglycaemic clamp technique was applied to all rats after treatment to examine the effects of MCC‐555 on insulin sensitivity. The glucose infusion rate to maintain normoglycaemia was lower in diabetic than in non‐diabetic rats, demonstrating reduced glucose entry into insulin‐sensitive tissues in diabetic rats. Increased glucose infusion rates were required to maintain euglycaemia in treated diabetic rats, demonstrating increased insulin sensitivity in these animals. 5 In conclusion, chronic MCC‐555 treatment of young ZDF rats displaying IGT attenuates the development of overt diabetes through improved insulin sensitivity and maintenance of β‐cell function. MCC‐555 may thus be beneficial in humans with IGT, to prevent or delay the progression of diabetes.

A defective non-LTR retrotransposon is dispersed throughout the genome of the silkworm, Bombyx mori

The presence of long repetitive sequences is demonstrated in the genome of the silkworm, Bombyx mori. Members of this BMC1 family reveal several features typical of the L1 (long interspersed sequence one) family of mammals, except for species specific elements. The number of BMC1 elements is estimated to be approximately 3500 per haploid genome. Elements containing the full length unit of 5.1 kb are dispersed throughout the genome and their restriction sites are conserved, although most members are preferentially truncated to varying extents at their 5′ ends. DNA sequencing indicates that this element contains six tandem repeats of 15 bp CpG-rich sequence in the 5′ proximal region. It terminates with a 3′ oligo(A) stretch, and is flanked at both ends by a 7–10 bp target sequence duplication. In addition, there is significant evidence for amino acid sequence homology with reverse transcriptase domains of other L1 families, especially F, Doc and lockey of Drosophila melanogaster. No large open reading frame is present. The BMC1 element is suggested to be dispersed in the genome by a transposition mechanism involving RNA intermediates.