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Biomedical subjects

K Shin-ya

Publications and source records attributed to K Shin-ya.

At least 19 recordsLinked to original sources
PubMed2006

Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia.

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. Recently, we have demonstrated that treatment with a G-quadruplex-interactive agent, telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines. In the present study, we investigated the mechanisms of apoptosis induced by telomerase inhibition in acute leukemia. We have found the activation of caspase-3 and poly-(ADP-ribose) polymerase in telomestatin-treated U937 cells (PD20) and dominant-negative DN-hTERT-expressing U937 cells (PD25). Activation of p38 mitogen-activated protein (MAP) kinase and MKK3/6 was also found in telomestatin-treated U937 cells (PD20) and dominant-negative DN-hTERT-expressing U937 cells (PD25); however, activation of JNK and ASK1 was not detected in these cells. To examine the effect of p38 MAP kinase inhibition on growth properties and apoptosis in telomerase-inhibited cells, we cultured DN-hTERT-expressing U937 cells with or without SB203580. Dominant-negative-hTERT-expressing U937 cells stopped proliferation on PD25; however, a significant increase in growth rate was observed in the presence of SB203580. Treatment of SB203580 also reduced the induction of apoptosis in DN-hTERT-expressing U937 cells (PD25). These results suggest that p38 MAP kinase has a critical role for the induction of apoptosis in telomerase-inhibited leukemia cells. Further, we evaluated the effect of telomestatin on the growth of U937 cells in xenograft mouse model. Systemic intraperitoneal administration of telomestatin in U937 xenografts decreased tumor telomerase levels and reduced tumor volumes. Tumor tissue from telomestatin-treated animals exhibited marked apoptosis. None of the mice treated with telomestatin displayed any signs of toxicity. Taken together, these results lay the foundations for a program of drug development to achieve the dual aims of efficacy and selectivity in vivo.

Acute Disease↗
PubMed2005

Telomerase inhibition, telomere shortening, cell growth suppression and induction of apoptosis by telomestatin in childhood neuroblastoma cells.

Neuroblastoma is a tumour derived from primitive cells of the sympathetic nervous system and is the most common extracranial solid tumour in childhood. Unfavourable tumours are characterised not only by structural changes, including 1p deletion and amplification of the MYCN proto-oncogene, but also by high telomerase activity. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. In this study, we examined telomestatin, a G-quadruplex interactive agent, for its ability to inhibit telomere maintenance of neuroblastoma cells. Telomere length was determined by the terminal restriction fragment method, telomerase activity was measured by a quantitative telomeric repeat amplification protocol, and the expression of human telomerase by quantitative real-time polymerase chain reaction (RT-PCR). Short-term treatment with telomestatin resulted in dose-dependent cytotoxicity and induction of apoptosis. Long-term treatment with telomestatin at non-cytotoxic, but still telomerase activity-inhibiting, concentrations resulted in telomere shortening, growth arrest and induction of apoptosis. These results suggest that the effect of telomestatin is dose-dependent and at least 2-fold. Prolonged low-dose treatment with telomestatin limits the cellular lifespan of NB cells through disruption of telomere maintenance.

Apoptosis↗
PubMed2001

Time courses of increased expression of signaling transduction molecules induced by basic fibroblast growth factor in PC12 cells.

We previously demonstrated that basic fibroblast growth factor (bFGF) protected neuronal injury in in vivo experimental cerebral ischemia. The precise molecular mechanisms of the neuroprotective effect of bFGF, however, remains unsolved. We investigated time courses of up-regulated molecules involved in intracellular signaling transduction pathways induced by bFGF in PC12 cells to explore the possible neuroprotective mechanism of bFGF action. In Western blot analysis, bFGF increased expression of Ras mainly in the early stage up to 24h, returning to the baseline level at 48 h. Expression of phosphatidylinositol 3-kinase (PI 3-kinase) was enhanced throughout the early and later stages, and was more up-regulated at 48 h compared to 24 h. The present findings suggest that bFGF might promote cell survival or proliferation mainly via Ras, and PI 3-kinase might be involved in cell survival and differentiation in PC12 cells.

Animals↗
PubMed2001

Ammocidin, a new apoptosis inducer in Ras-dependent cells from Saccharothrix sp. I. Production, isolation and biological activity.

A new apoptosis inducer, ammocidin, was isolated from the culture broth of Saccharothrix sp. AJ9571. Ammocidin induced apoptotic cell death in Ras-dependent Ba/F3-V12 cells with an IC50 of 66 ng/ml. No cell death was observed in IL-3-dependent Ba/F3-V12 cells at less than 100 microg/ml of ammocidin. Ammocidin significantly reduced the phosphorylation level of MAPK and S6K that mediate the anti-apoptotic function of Ras.

Actinomycetales↗
PubMed2000

Reconstruction of orbicularis oris and levator labii superioris muscles in secondary repair of unilateral cleft lip.

We devised a new method to repair the depression of the nasal floor and inferolateral displacement of the alar base and to reconstruct the philtrum in the secondary repair of unilateral cleft lip. Depression of the nasal floor and inferolateral displacement of the alar base were corrected by advancing a lump of the levator labii superioris, the levator labii superioris alaeque nasi, and the upper part of the superficial orbicularis oris muscles to the anterior nasal spine. When the depression of the nasal floor was too severe to repair using these muscles only, a cranially-based de-epithelialised flap of the scar region on the upper lip was inserted under the nasal floor. The lower, greater part of the superficial orbicularis oris muscle was dissected to the nasolabial fold, brought towards the midline, and laid on the surface of the same muscle on the medial side to be sutured. When the depression of the nasal floor was not severe, the lower, greater part of the superficial orbicularis oris muscle was passed through a tunnel pierced beneath the de-epithelialised scar tissue and sutured to the corresponding components on the medial side to reinforce the philtral ridge. In both cases, if the deep orbicularis oris muscle in the vermilion had been interrupted, it was reconstructed by end-to-end anastomosis. Operative results were evaluated in 76 patients using photographs taken preoperatively and postoperatively. Elevation of the nasal floor and correction of the alar base were achieved in most patients, while reconstruction of the philtrum was achieved in cases in which the skin tension at the suture line was weak.

Adolescent↗
PubMed1999

Application of artificial dermis prior to full-thickness skin grafting for resurfacing the nose.

Two patients with nasal skin defects resulting from excision of rhinophyma and multiple angiofibromas were treated with artificial dermis followed by full-thickness skin grafts taken from the postauricular region. The secondary skin grafts took completely in both patients, and the postoperative results were excellent. Although a two-stage operation is required, application of artificial dermis prior to full-thickness skin grafting is a reliable method for resurfacing the nose.

Adult↗
PubMed1998

Versatility of modified planimetric Z-plasties in the treatment of scar with contracture.

The planimetric Z-plasty proposed by Roggendorf provides elongation by excision of a pair of triangular pieces of tissue. The application of planimetric Z-plasties has been modified by making the vertical angle flexible, and making them continuous in the same or in opposite directions. Continuous planimetric Z-plasties in the same direction elongate an oblique contracture in the longitudinal direction. Continuous planimetric Z-plasties in an alternative direction elongate a disproportioned scar contracture in the longitudinal direction. Both techniques partially reduce unsightly scarring. Furthermore, they can be used in combination with V-Y-plasties. These modifications permit rational planing of the treatment of complicated scars with contracture.

Adult↗
PubMed1997

Carquinostatin B, a new neuronal cell-protecting substance produced by Streptomyces exfoliatus.

Brain ischemia injury is elicited by the excitotoxicity of L-glutamate. Carquinostatin B was isolated from Streptomyces exfoliatus 2419-SVT2 as a potent neuroprotective substance which protests neuronal hybridoma N18-RE-105 cells from L-glutamate toxicity. The structure of carquinostatin B was established principally by NMR studies to be a carbazole derivative with an ortho quinone function.

Animals↗