PubMed Health⌕ Search

Biomedical subjects

Hiromichi Nakamuta

Publications and source records attributed to Hiromichi Nakamuta.

7 recordsLinked to original sources
PubMed2006

A novel oxazine ring closure reaction affording (Z)-((E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)acetaldehydes and their anti-osteoclastic bone resorption activity.

A novel oxazine ring formation method was established using the reaction of 2-acetyl-(E)-3-styrylcarbonylaminobenzo[b]furans (4) with Vilsmeier-Haack-Arnold reagent to afford (E and Z)-((E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)acetaldehydes (5). (Z)-4-(8-Bromo-(E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)but-(E)-2-enoic acid ethyl ester (6b), derived from (Z)-5a, showed significantly potent anti-osteoclastic bone resorption activity comparable to 17beta-estradiol (E2).

Benzofurans↗
PubMed2006

Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic alpha-helix.

Salmon calcitonin (sCT) forms an amphipathic helix in the region 9-19, with the C-terminal decapeptide interacting with the helix (Amodeo, P., Motta, A., Strazzullo, G., Castiglione Morelli, M. A. (1999) J. Biomol. NMR 13, 161-174). To uncover the structural requirements for the hormone bioactivity, we investigated several sCT analogs. They were designed so as to alter the length of the central helix by removal and/or replacement of flanking residues and by selectively mutating or deleting residues inside the helix. The helix content was assessed by circular dichroism and NMR spectroscopies; the receptor binding affinity in human breast cancer cell line T 47D and the in vivo hypocalcemic activity were also evaluated. In particular, by NMR spectroscopy and molecular dynamics calculations we studied Leu(23),Ala(24)-sCT in which Pro(23) and Arg(24) were replaced by helix inducing residues. Compared with sCT, it assumes a longer amphipathic alpha-helix, with decreased binding affinity and one-fifth of the hypocalcemic activity, therefore supporting the idea of a relationship between a definite helix length and bioactivity. From the analysis of other sCT mutants, we inferred that the correct helix length is located in the 9-19 region and requires long range interactions and the presence of specific regions of residues within the sequence for high binding affinity and hypocalcemic activity. Taken together, the structural and biological data identify well defined structural parameters of the helix for sCT bioactivity.

Amino Acid Sequence↗
PubMed2004

Statins inhibit osteoblast migration by inhibiting Rac-Akt signaling.

Cell migration is a key event in repair and remodeling of skeletal tissues, but the mechanism of osteoblast migration has not been resolved. Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, increase bone. However, the effect of statins on osteoblast migration remains to be clarified. We investigated the effect of fluvastatin and mevastatin on platelet-derived growth factor (PDGF)-induced migration of osteoblastic MC3T3-E1 cells. PDGF promoted osteoblast migration, while the statins inhibited PDGF-induced migration, and mevalonate and geranylgeranylpyrophosphate but not farnesylpyrophosphate abolished the effect of statins. Dominant-negative Rac severely inhibited PDGF-induced osteoblast migration and reduced Akt phosphorylation. Further, fluvastatin reduced Akt phosphorylation and dominant-negative Akt inhibited PDGF-induced osteoblast migration. These results demonstrate that statins inhibit PDGF-induced osteoblast migration and Rac-Akt signaling plays an important role in the osteoblast migration, and suggest that statins restrain Rac function by inhibiting geranylgeranylation of Rac, which leads to the reduction in Akt activation and osteoblast migration.

Animals↗
PubMed2004

Osteoporosis requires bone-specific statins.

Remedies for primary osteoporosis are increasing in brands but not always with concomitant improvements in efficacy and safety. Clinical studies suggest that nitrogen-containing bisphosphonates alone display sufficient practical effectiveness to survive as effective therapy. However, their less effectiveness in highly osteopenic patients due to their lack of genuine bone anabolic effect waits improvements. Pinpointing statins as the inducer of BMP-2 provoked a rush of clinical and laboratory studies to identify bone anabolic properties. Clinical studies, even if only through observational, suggest that under conventional dosing conditions for hyperlipemia, the liver-targeted statins now in use display insufficient bone anabolic effect, although laboratory studies seem to be clarifying the mechanisms underlying intrinsic bone anabolic properties. While incomplete, these studies indicate the possibility that, if bioavailability to bone could be improved by simply changing dosing methods and/or deliberate derivatization, the genuine anabolic properties of statins on bone could be extracted and put into therapeutic use.

Animals↗
PubMed2002

New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells. Checkpoint of modulation by cyclic AMP.

cAMP signaling, activated by extracellular stimuli such as parathyroid hormone, has cell type-specific effects important for cellular proliferation and differentiation in bone cells. Recent evidence of a second enzyme target for cAMP suggests divergent effects on extracellular-regulated kinase (ERK) activity depending on Epac/Rap1/B-Raf signaling. We investigated the molecular mechanism of the dual functionality of cAMP on cell proliferation in clonal bone cell types. MC3T3-E1 and ATDC5, but not MG63, express a 95-kDa isoform of B-Raf. cAMP stimulated Ras-independent and Rap1-dependent ERK phosphorylation and cell proliferation in B-Raf-expressing cells, but inhibited growth in B-Raf-lacking cells. The mitogenic action of cAMP was blocked by the ERK pathway inhibitor PD98059. In B-Raf-transduced MG63 cells, cAMP stimulated ERK activation and cell proliferation. Thus, B-Raf is the dominant molecular switch that permits differential cAMP-dependent regulation of ERK with important implications for cell proliferation in bone cells. These findings might explain the dual functionality of parathyroid hormone on osteoblastic cell proliferation.

3T3 Cells↗
PubMed2002

[Anti-osteopenic effect of taurine: possible involvement of activated MEK-ERK-Cbfa1 signaling].

Previously we first noted that taurine (TR) has anti-osteopenic effect on low Ca diet-induced osteopenia in rats (1). Employing osteoblastic MC3T3-E1 cells, the mechanism of the anti-osteopenic effect was explored in vitro. TR (1 mM) was found to promote mineralization of extracellular matrices, without affecting alkaline phosphataase activity. Gel shift assay using 32P-labeled OSE2 (osteoblast-specific cis-element 2: the consensus sequence for Cbfa1, refer to 2) indicated that TR (1 mM) increased the nuclear localization of Cbfa1, just as TPH (1-34) (3,4) and bisphosphonates did (5). In addition, TR was found to stimulate ERK phosphorylation. PD98059, a MEK inhibitor, suppressed effects of TR on both Cbfa1 transactivation and ERK activation. The results strongly suggest that TR first activates intracellular MEK-ERK-Cbfa1 signaling system thereby promoting mineralization and finally leading to its bone anabolic action.

Animals↗