Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1.

Insulin resistance is often associated with atherosclerotic diseases in subjects with obesity and impaired glucose tolerance. This study examined the effects of insulin resistance on coronary risk factors in IRS-1 deficient mice, a nonobese animal model of insulin resistance. Blood pressure and plasma triglyceride levels were significantly higher in IRS-1 deficient mice than in normal mice. Impaired endothelium-dependent vascular relaxation was also observed in IRS-1 deficient mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, suggesting impaired lipolysis to be involved in the increase in plasma triglyceride levels under insulin-resistant conditions. Thus, insulin resistance plays an important role in the clustering of coronary risk factors which may accelerate the progression of atherosclerosis in subjects with insulin resistance

Dietary Restriction: Standing Up For Sirtuins

We believe that L. Fontana, L. Partridge, and V. D. Longo should have included a discussion of sirtuins in their Review “Extending healthy life span—From yeast to humans” (16 April, p. 321). We also believe that some of the references used are misleading. The authors state that the purpose of their Review is to “consider the role of nutrient-sensing signaling pathways in mediating the beneficial effects of dietary restriction.” Yet there was no mention of the sirtuins, a family of critically important nutrient-sensing proteins that promote health span from yeast to mammals, as shown by more than 1000 peer-reviewed publications from labs around the world. The authors state that “[i]t is unlikely that a single, linear pathway mediates the effects of dietary restriction in any organism,” and we agree. Indeed, the aging field now recognizes that healthy life span is under the influence of several nutrient-sensing pathways, and there is at least as much evidence for the involvement of sirtuins in the dietary restriction response as for any of the pathways discussed in the Review

The Palmar a-b Ridge Count and Sex Chromosomes

The a-b ridge counts on the palms of 480 normal Japanese (351 males and 129 females), plus samples of 25 Japanese with Klinefelter’s syndrome and 5 with Turner’s syndrome were studied. Increased numbers of sex chromosomes were associated with the reduced mean sum of the a-b ridge count

Association of cathepsin E with tumor growth arrest through angiogenesis inhibition and enhanced immune responses

Cathepsin E (CE) is an intracellular aspartic proteinase implicated in various physiological and pathological processes, yet its actual roles in vivo remain elusive. To assess the physiological significance of CE expression in tumor cells, human CE was stably expressed in human prostate carcinoma ALVA101 cells expressing very little CE activity. Tumor growth in nude mice with xenografted ALVA101/hCE cells was slower than with control ALVA101/mock cells. Angiogenesis antibody array and ELISA assay showed that this was partly due to the increased expression of some antiangiogenic molecules including interleukin 12 and endostatin in tumors induced by CE expression. In vitro studies also demonstrated that, among the cathepsins tested, CE most efficiently generated endostatin from the non-collagenous fragment of human collagen XVIII at mild acidic pH. Histological examination revealed that tumors formed by ALVA101/ hCE cells were partitioned by well-developed membranous structures and covered with thickened, wellstratified hypodermal tissues. In addition, both the number and extent of activation of tumor-infiltrating macrophages were more profound in ALVA101/hCE compared to ALVA101/mock tumors. The chemotactic response of macrophages to ALVA101/hCE cells was also higher than that to ALVA/mock cells. These results thus indicate that CE expression in tumor cells induces tumor growth arrest via inhibition of angiogenesis and enhanced immune responses