Serum concentrations of BNP and ANP in patients with thyrotoxicosis.

Serum BNP (brain naturiuretic peptide) and ANP (atrial natriuretic peptide) levels are reportedly elevated in patients with thyrotoxicosis. The increases may not be due to thyrotoxicosis itself but to secondary cardiovascular changes such as chronic heart failure (HF) or atrial fibrillation (AF) which frequently accompany thyrotoxicosis. We measured serum ANP and BNP levels in 130 patients with thyrotoxicosis and correlated them with HF severity and thyroid function. Thirty-seven normal subjects served as controls. Serum BNP levels in thyrotoxic patients were significantly higher than those in control subjects and significantly correlated with serum free T4, free T3 and ANP levels. In untreated Graves' disease serum BNP level was significantly elevated in patients with HF or AF. Multiple regression analysis revealed that HF, free T4, female gender and AF are independent contributing factors to the elevated BNP level, and that these four factors contributed about 40%. On the other hand, HF and AF were contributing variables for ANP level but the overall contribution of these factors was only 10%. After normalization of thyroid function, serum BNP levels were normalized in 70.5% of Graves' patients. BNP level in euthyroid state was dependent on the presence of HF and the BNP value before therapy, but not on thyroid hormone levels or AF. These data suggest that the cardiovascular condition is the major factor responsible for the elevated serum BNP and ANP levels in thyrotoxic patients, while thyrotoxicosis itself is an independent but minor contributing factor. Thus, the determination of serum BNP levels in thyrotoxic patients is useful for monitoring cardiovascular conditions of HF.

A naphthoquinone derivative, shikonin, has insulin-like actions by inhibiting both phosphatase and tensin homolog deleted on chromosome 10 and tyrosine phosphatases.

The 1,4-naphthoquinone derivative, shikonin, has been shown to increase glucose uptake by adipocytes and myocytes with minor effects on protein tyrosine phosphorylation in the cells (Biochem Biophys Res Commun 292:642-651, 2002). The present study was performed to examine the mechanism of this action of shikonin. Shikonin inhibited the phosphatidylinositol 3,4,5-triphosphate (PtdIns-3,4,5-P3) phosphatase activity of recombinant phosphatase and tensin homolog deleted on chromosome 10 (PTEN) with an IC50 value of 2.7 microM. Shikonin induced marked accumulation of PtdIns-3,4,5-P3 and activation of protein kinase B (PKB) in Chinese hamster ovary cells expressing insulin receptors. In addition to its effect on PTEN, shikonin was found to inhibit several protein phosphatases in cell-free systems. Its effect on tyrosine phosphorylation in intact cells was far weaker than that of pervanadate, a widely used tyrosine phosphatase inhibitor, despite the observation that the effect of shikonin on PKB was more potent than that of pervanadate. These results suggested that the inhibition of PTEN provides a clue to its potent insulin-like actions. We also found that naphthoquinones, including 1,2-naphthoquinone, inhibit PTEN in the cell-free system, which suggested that the effect on PTEN (and thus the effect on phosphatidylinositol 3-kinase signaling) should be taken into account when examining the pharmacological actions of naphthoquinone derivatives.

Increased expression of phosphorylated p70S6 kinase and Akt in papillary thyroid cancer tissues.

Although a number of abnormalities in oncogenes have been reported in thyroid neoplasms, little information is available on the signal transduction pathway involved in neoplastic thyroid cell growth. Both p70S6 kinase (p70S6K) and Akt are kinases downstream of phosphatidylinositol 3 kinase (PI3K). These kinases are phosphorylated and activated by growth factors including IGF-1, EGF/TGF-alpha, and HGF in thyroid cells. Since the receptors for these growth factors are reportedly overexpressed in human thyroid cancer, we hypothesized that the PI3K-mediated signalings are overactivated in thyroid cancers. Tumorous and adjacent normal tissues of 20 patients with papillary thyroid cancer were obtained at surgery, and expression of p70S6K and Akt were measured by Western blot. Expression of the protein levels of p70S6K was increased in tumor tissues (T) compared to normal thyroid tissues (N), and expression of phosphorylated p70S6K was also significantly increased in tumor than in surrounding normal tissues. Overexpression of p70S6K in tumor tissues was further confirmed by immunohistochemistry. Strong immunoreactivity in the cytoplasm of thyroid cancer cells was seen in the majority of cases, whereas little immunoreactivity was found in the surrounding normal portion. Expression of phosphorylated Akt (pAkt) was also significantly higher in tumor tissues. Phosphorylation of Bad (pBad), a substrate of Akt, was also increased in the tumor tissues in association with activation of Akt, and the T/N ratio for pAkt positively correlated to the T/N ratio for pBad. The data presented here demonstrate that both p70S6K and Akt are activated in the majority of human papillary cancer cells. Activation of these signalings may be involved in the progression of papillary carcinoma by stimulating cell proliferation and/or preventing apoptosis.

Potentiation of mitogenic activity of platelet-derived growth factor by physiological concentrations of insulin via the MAP kinase cascade in rat A10 vascular smooth muscle cells.

Hyperinsulinemia has been shown to be associated with diabetic angiopathy. Migration and proliferation of vascular smooth muscle cells (VSMC) are the processes required for the development of atherosclerosis. In this study, we attempted to determine whether insulin affects mitogenic signaling induced by platelet-derived growth factor (PDGF) in a rat VSMC cell line (A10 cells). PDGF stimulated DNA synthesis which was totally dependent on Ras, because transfection of dominant negative Ras resulted in complete loss of PDGF-stimulated DNA synthesis. Initiation of DNA synthesis was preceded by activation of Raf-1, MEK and MAP kinases (Erk 1 and Erk2). Treatment of the cells with PD98059, an inhibitor of MAPK kinase (MEK) attenuated but did not abolish PDGF-stimulated DNA synthesis, suggesting that MAPK is required but not essential for DNA synthesis. PDGF also stimulated phosphorylation of protein kinase B (Akt/PKB) and p70 S6Kinase (p70S6K) in a wortmannin-sensitive manner. Rapamycin, an inhibitor of p70S6K, markedly suppressed DNA synthesis. Low concentrations of insulin (1-10 nmol/l) alone showed little mitogenic activity and no significant effect on MAPK activity. However, the presence of insulin enhanced both DNA synthesis and MAPK activation by PDGF. The enhancing effect of insulin was not seen in cells treated with PD98059. Insulin was without effect on PDGF-stimulated activations of protein kinase B (Akt/PKB) and p70S6K. We conclude that insulin, at pathophysiologically relevant concentrations, potentiates the PDGF-stimulated DNA synthesis, at least in part, by potentiating activation of the MAPK cascade. These results are consistent with the notion that hyperinsulinemia is a risk factor for the development of atherosclerosis.

Lessons learned from reconstruction following a disaster : enhancement of regional seismic safety attained after the 1976 Tangshan, China earthquake

Comparing an estimated death toll in the reconstructed environment of Tangshan in 1991 with the actual deaths in the 1976 earthquake, we evaluated the enhancements in seismic safety attained during the recontruction. It was found that while the most severely affected area was remarkably improved, the less severely affected ara was not rebuilt to the standards of the most severely affected area. The increased safety of the most severely affected area can be attributed to the reinforced concrete elements of the buildings. The hazardous situation in the less severely affected area is due the collapsible nature of the unreinforced masonry construction (AU)