To propose candidates for the prevention or treatment of osteoporosis, we have screened compounds naturally in food for their ability to regulate the differentiation and function of osteoclasts. One ...of the major green tea flavonoids, (−)-epigallocatechin-3-gallate (EGCG), was found to induce apoptotic cell death of osteoclast-like multinucleated cells after 24 h treatment in a dose-dependent manner (25–100 μM), whereas osteoblasts were not affected. In the present study, we report for the first time a novel cell-death-inducing mechanism triggered by EGCG. The induction of apoptosis by EGCG was suppressed by pretreatment of catalase or calcitonin. It was also suppressed by Fe(III) and Fe(II) chelators. Furthermore, EGCG promoted the reduction of Fe(III) into Fe(II), and the combination of EGCG/Fe(III)/H2O2 induced single-strand DNA breakage in a cell free system. These results indicate that the Fenton reaction is primarily involved in EGCG-induced osteoclastic cell death.
Repeated GPS surveys in the Mariana Islands show that the Mariana block is moving apart from the Philippine Sea plate. The velocities of the islands relative to the Philippine Sea plate range from ...about 15 mm/yr in the northern islands to about 45 mm/yr near Guam. The data also suggest convergence rates for the Mariana forearc with respect to the Pacific plate of 35–45 mm/yr at 19°N increasing to 55–70 mm/yr at 13.5°N. In addition, the velocity vectors show a slight north‐south expansion of the arc. The estimated location of the Euler pole of the Mariana forearc with respect to the Philippine Sea plate is well south of the geographical point where the back‐arc basin narrows to zero width.
Mature bone-resorbing osteoclasts (OCs) mediate excessive bone loss seen in several bone disorders, including osteoporosis. Here, we showed that reveromycin A (RM-A), a small natural product with ...three carboxylic groups in its structure, induced apoptosis specifically in OCs, but not in OC progenitors, nonfunctional osteoclasts, or osteoblasts. RM-A inhibited protein synthesis in OCs by selectively blocking enzymatic activity of isoleucyl-tRNA synthetase. The proapoptotic effect of RM-A was inhibited by neutralization or disruption of the acidic microenvironment, a prominent characteristic of OCs. RM-A was incorporated in OCs but not in nonfunctional osteoclasts and OC progenitors in neutral culture medium. Effects of RM-A on OC apoptosis increased under acidic culture conditions. RM-A not only was incorporated, but also induced apoptosis in OC progenitors in acidic culture medium. RM-A inhibited osteoclastic pit formation, decreased prelabeled$^{45}Ca$release in organ cultures, and antagonized increased bone resorption in ovariectomized mice. These results suggested that preventive effects of RM-A on bone resorption in vitro and in vivo were caused by apoptosis through inhibition of isoleucyl-tRNA synthetase in OCs and that specific sensitivity of OCs to RM-A was due to the acidic microenvironment, which increased cell permeability of RM-A by suppressing dissociation of protons from carboxylic acid moieties, making them less polar. This unique mechanism suggested that RM-A might represent a type of therapeutic agent for treating bone disorders associated with increased bone loss.
Nerve growth factor and other neurotrophins signal to neurons through the Trk family of receptor tyrosine kinases. TrkB is relatively promiscuous in vitro, acting as a receptor for brain-derived ...neurotrophic factor (BDNF), neurotrophin-4 (NT4) and, to a lesser extent, NT3 (refs 3-5). Mice lacking TrkB show a more severe phenotype than mice lacking BDNF, suggesting that TrkB may act as a receptor for additional ligands in vivo. To explore this possibility, we generated mice lacking NT4 or BDNF as well as mice lacking both neurotrophins. Unlike mice lacking other Trks or neurotrophins, NT4-deficient mice are long-lived and show no obvious neurological defects. Analysis of mutant phenotypes revealed distinct neuronal populations with different neurotrophin requirements. Thus vestibular and trigeminal sensory neurons require BDNF but not NT4, whereas nodose-petrosal sensory neurons require both BDNF and NT4. Motor neurons, whose numbers are drastically reduced in mice lacking TrkB, are not affected even in mice lacking both BDNF and NT4. These results suggest that another ligand, perhaps NT3, does indeed act on TrkB in vivo.
Intrahepatic cholestasis of pregnancy has been related to a high frequency of abnormal intrapartum fetal heart rate, amniotic fluid meconium, prematurity, and perinatal mortality. To determine ...whether these adverse perinatal outcomes could be improved with active intervention, we evaluated our results.
We report a retrospective case-control study of 320 consecutive patients with intrahepatic cholestasis of pregnancy management with antepartum testing and active intervention over a 2-year period.
Our results indicate a higher incidence of meconium staining in amniotic fluid at delivery (25% vs 16%, p < 0.05) and spontaneous preterm delivery (12.1% vs 3.9%, p < 0.05), without an increase in the frequency of abnormal intrapartum fetal heart rate (12% vs 11%, not significant), 5-minute Apgar score < 7 (2.0% vs 1.0%, not significant), or perinatal mortality (18/1000 vs 13/1000, not significant).
Antenatal testing and timed intervention of patients with intrahepatic cholestasis of pregnancy is associated with a reduction of the previously reported adverse perinatal outcomes.
Heparan sulfate (HS) can bind a large variety of biological effectors, including extracellular matrix components, growth factors, chemokines, degradative enzymes, and protease inhibitors. Where ...studied, HS is known to be structurally heterogeneous and to vary in sulfation pattern between cells and tissues. Because heparan sulfate can represent several distinct proteoglycans, we asked whether the structural variation in the heparan sulfate chains of a single species of cell surface proteoglycan is a reproducible, differentiated characteristic and whether the variation can result in distinct biological functions. We studied the molecular structure and binding affinity for type I collagen and fibroblast growth factor-2 of syndecan-1 purified from the surfaces of NMuMG normal murine mammary gland epithelia, NIH/3T3 fibroblasts, and BALB/3T3 endothelioid cells. Syndecan-1 from these cell types varied in molecular mass largely due to variation in the length of the HS chains. Although the highly sulfated and N-acetylated domains in these HS chains were organized similarly, the number of highly sulfated domains differed. The disaccharide compositions were also similar except for reproducible and consistent differences in the amount of hexuronic acid-N-sulfated-6-O-sulfated glucosamine and 2-O-sulfated hexuronic acid-N-sulfated glucosamine. These differences were confirmed by oligosaccharide mapping, which showed cell type-specific variations in the composition of the highly sulfated domains. These structural variations correlated with cell type-specific differences in the affinity of syndecan-1 and its isolated HS chains for type I collagen. However, no differences in affinity for fibroblast growth factor-2 were detected. The results indicate that the size, fine structure, and ligand affinity of the HS chains on a single proteoglycan species differ in a consistent and reproducible manner between cell types. Thus, the variation in structure and binding ability of HS on syndecan-1 is a differentiated characteristic of the cell type that can enable cells to respond distinctly to the HS-binding effectors in the cellular microenvironment.
Anatahan Volcano, Northern Mariana Islands, began erupting in May–June 2003. A series of subplinian explosive eruptions of andesite magma began at the Eastern Crater in the eastern part of the summit ...caldera on the evening of 10 May. Brown tephra was sent mainly westward by strong winds. Small-scale pyroclastic surges were discharged eastward outside the caldera in late May. An andesite lava dome that had once filled the inner crater was fragmented by phreatomagmatic explosions in the middle of June. The phreatomagmatic explosions probably occurred due to interaction of the magma head with groundwater around the crater, and abundant very fine ash (“gray tephra”) was discharged within the caldera and over most of the island. The volume of eruption products of the May–June eruption was estimated to be 1.4
×
10
7 m
3 dense-rock-equivalent. Erupted pumices and lava are aphyric andesite and are variously colored depending on their vesicularity. The SiO
2 contents of erupted materials decreased slightly with time. The fine gray ash is depleted in alkalies, probably due to leaching by acid hydrothermal fluids during explosions. Seismic activity resumed in late March 2004, and small strombolian-like explosions were repeated in May and June 2004. About half of the inner crater was filled with new scoria and lava.
Anatahan Island is located at the southern end of the Mariana volcanic chain. On May 10, 2003, the eastern crater of the island erupted for the first time in recorded history. The Plinian eruption ...column reached an altitude as high as 13 km on May 11, and a thick layer of ash covered the island. The eruptive activity continued to June 2003, but most of the erupted material was expelled during the first week. The volcanic activity declined in the second half of 2003, but resumed in April 2004. In order to determine crustal deformation associated with the eruption, we conducted GPS measurements in July 2003 at a benchmark (ANAT) located approximately 7 km west–northwest of the active crater, where GPS campaign measurements had been repeated four times since 1992. In the period from January to July 2003 during the eruption, significant subsidence – as much as 21 cm – was detected, but horizontal movement was negligible. We began taking continuous GPS measurements at the same site in July 2003 to monitor the transient deformation that was probably associated with magma migration. To assess the spatial extent of the deformation more accurately, we established another permanent GPS site (ANA2) at a site approximately 3 km from the active crater in the northeastern part of the island in January 2004. The coordinates of this time series at ANAT probably show a change in trends at the beginning of 2004. Another subsidence of 2.8 cm and a westward motion of 2.1 cm were estimated to have occurred in the period from July to December 2003. This was followed by an uplift of 5.2 cm and movement in an eastward direction of 1.0 cm in the period from January to June 2004. We developed three preliminarily models of inflation/deflation sources for three different time periods. During the period from January to July 2003, a deformation source was located beneath the ANAT site and acted as a deflation source. Considering the gap in the GPS time series and errors in data (especially after July 2003), we expected that the deformation sources were located beneath the western part of Anatahan Island and not below the active crater.
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