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Articles by M Takahashi
Total Records ( 8 ) for M Takahashi
  J Suzuki , M Ueno , M Uno , Y Hirose , Y Zenimaru , S Takahashi , J. i Osuga , S Ishibashi , M Takahashi , M Hirose , M Yamada , F. B Kraemer and I. Miyamori
 

Increased fatty acid (FA) flux and intracellular lipid accumulation (steatosis) give rise to cardiac lipotoxicity in both pathological and physiological conditions. Since hormone-sensitive lipase (HSL) contributes to intracellular lipolysis in adipose tissue and heart, we investigated the impact of HSL disruption on cardiac energy metabolism in response to fasting and refeeding. HSL-knockout (KO) mice and wild-type (WT) littermates were fasted for 24 h, followed by ~6 h of refeeding. Plasma FA concentration in WT mice was elevated twofold with fasting, whereas KO mice lacked this elevation, resulting in twofold lower cardiac FA uptake compared with WT mice. Echocardiography showed that fractional shortening was 15% decreased during fasting in WT mice and was associated with steatosis, whereas both of these changes were absent in KO mice. Compared with Langendorff-perfused hearts isolated from fasted WT mice, the isolated KO hearts also displayed higher contractile function and a blunted response to FA. Although cardiac glucose uptake in KO mice was comparable with WT mice under all conditions tested, cardiac VLDL uptake and lipoprotein lipase (LPL) activity were twofold higher in KO mice during fasting. The KO hearts showed undetectable activity of neutral cholesteryl esterase and 40% lower non-LPL triglyceride lipase activity compared with WT hearts in refed conditions accompanied by overt steatosis, normal cardiac function, and increased mRNA expression of adipose differentiation-related protein. Thus, the dissociation between cardiac steatosis and functional sequelae observed in HSL-KO mice suggests that excess FA influx, rather than steatosis per se, appears to play an important role in the pathogenesis of cardiac lipotoxicity.

  C. M Contreras , E. A Akbay , T. D Gallardo , J. M Haynie , S Sharma , O Tagao , N Bardeesy , M Takahashi , J Settleman , K. K Wong and D. H. Castrillon
  Cristina M. Contreras, Esra A. Akbay, Teresa D. Gallardo, J. Marshall Haynie, Sreenath Sharma, Osamu Tagao, Nabeel Bardeesy, Masaya Takahashi, Jeff Settleman, Kwok-Kin Wong, and Diego H. Castrillon

Endometrial cancer – the most common malignancy of the female reproductive tract – arises from the specialized epithelial cells that line the inner surface of the uterus. Although significant advances have been made in our understanding of this disease in recent years, one significant limitation has been the lack of a diverse genetic toolkit for the generation of mouse models. We identified a novel endometrial-specific gene, Sprr2f, and developed a Sprr2f-Cre transgene for conditional gene targeting within endometrial epithelium. We then used this tool to generate a completely penetrant Lkb1 (also known as Stk11)-based mouse model of invasive endometrial cancer. Strikingly, female mice with homozygous endometrial Lkb1 inactivation did not harbor discrete endometrial neoplasms, but instead underwent diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, suggesting that Lkb1 inactivation was sufficient to promote the development of invasive endometrial cancer. Mice with heterozygous endometrial Lkb1 inactivation only rarely developed tumors, which were focal and arose with much longer latency, arguing against the idea – suggested by some prior studies – that Lkb1 is a haploinsufficient tumor suppressor. Lastly, the finding that endometrial cancer cell lines were especially sensitive to the mTOR (mammalian target of rapamycin) inhibitor rapamycin prompted us to test its efficacy against Lkb1-driven endometrial cancers. Rapamycin monotherapy not only greatly slowed disease progression, but also led to striking regression of pre-existing tumors. These studies demonstrate that Lkb1 is a uniquely potent endometrial tumor suppressor, but also suggest that the clinical responses of some types of invasive cancers to mTOR inhibitors may be linked to Lkb1 status.

  T Takeuchi , K Nishiyama , K. i Sugiura , M Takahashi , A Yamada , S Kobayashi , H Takahashi , H Natsugari and K. i. Kasai
 

Galβ1-4GlcNAc is thought to be a common disaccharide unit preferentially recognized by vertebrate galectins. Eight-amino-acid residues conserved in proteins belonging to the galectin family have been suggested to be responsible for recognition. Meanwhile, we isolated and analyzed endogenous N-glycans of Caenorhabditis elegans that were captured by a C. elegans galectin LEC-6 and demonstrated that the unit of recognition for LEC-6 is a Gal-Fuc disaccharide, though the linkage between these residues was not confirmed. In the present study, we chemically synthesized Galβ1-4Fuc and Galβ1-3Fuc labeled with 2-aminopyridine (PA) and demonstrated that LEC-6 interacts with PA-Galβ1-4Fuc more strongly than PA-Galβ1-3Fuc by frontal affinity chromatography (FAC). Galβ1-4Fuc also inhibited hemagglutination caused by LEC-6 more strongly than Galβ1-3Fuc. FAC analysis using LEC-6 point mutants revealed that some of the conserved amino acid residues which have proven to be important for the recognition of Galβ1-4GlcNAc are not necessary for the binding to Galβ1-4Fuc. Another major C. elegans galectin, LEC-1, also showed preferential binding to Galβ1-4Fuc. These results suggest that Galβ1-4Fuc is the endogenous unit structure recognized by C. elegans galectins, which implies that C. elegans glycans and galectins may have co-evolved through an alteration in the structures of C. elegans glycans and a subsequent conversion in the sugar-binding mechanism of galectins. Furthermore, since glycans containing the Galβ1-4Fuc disaccharide unit have been found in organisms belonging to Protostomia, this unit might be a common glyco-epitope recognized by galectins in these organisms.

  C Nishitani , M Takahashi , H Mitsuzawa , T Shimizu , S Ariki , N Matsushima and Y. Kuroki
 

The role of MD-2 in cell surface expression of Toll-like receptor (TLR) 4 has been controversial. The purposes of this study were to characterize the N-glycan of TLR4 and to investigate the roles of MD-2 in N-linked glycosylation and cell surface expression of TLR4. Lectin blot and cell surface biotinylation revealed that TLR4 exhibited the 110 kDa protein with high mannose type N-glycans and the 130 kDa protein with complex type N-glycans and that only the 130 kDa TLR4 with complex type N-glycans was expressed on the cell surface. The cells transfected with a mutant TLR4C88A alone expressed only the 110 kDa TLR4 with a high mannose type N-glycan, which did not appear on the cell surface. However, TLR4C88A acquired complex type N-glycans and was expressed on the cell surface when MD-2 was co-transfected. The amount of the 130 kDa TLR4C88A with complex type N-glycans expressed on the cell surface depended on that of MD-2 transfected. -Mannosidase II inhibitor blocked the processing N-glycans to complex type, but TLR4 with high mannose type appeared on the cell surface, suggesting that TLR4 is destined to locate on the cell surface before processing N-glycans from a high mannose type to a complex type. From these results, we conclude that MD-2 is critical for cell surface expression of TLR4C88A. This study provides evidence that MD-2 possesses potential ability to play an essential role in cell surface expression of TLR4.

  H Uemura , N Shinohara , T Yuasa , Y Tomita , H Fujimoto , M Niwakawa , S Mugiya , T Miki , N Nonomura , M Takahashi , Y Hasegawa , N Agata , B Houk , S Naito and H. Akaza
  Objective

This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC).

Methods

Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECIST-defined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan–Meier method.

Results

In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%).

Conclusions

In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.

  Y Tomita , N Shinohara , T Yuasa , H Fujimoto , M Niwakawa , S Mugiya , T Miki , H Uemura , N Nonomura , M Takahashi , Y Hasegawa , N Agata , B Houk , S Naito and H. Akaza
  Background

In a phase II, open-label, multicentre Japanese study, sunitinib demonstrated antitumour activity and acceptable tolerability in metastatic renal cell carcinoma patients. Final survival analyses and updated results are reported.

Methods

Fifty-one Japanese patients with a clear-cell component of metastatic renal cell carcinoma (25 treatment-naïve; 26 cytokine-refractory) received sunitinib 50 mg orally, once daily (Schedule 4/2). Overall and progression-free survivals were estimated by the Kaplan–Meier method. Objective response rate (per Response Evaluation Criteria in Solid Tumours) and safety were assessed with an updated follow-up.

Results

First-line and pretreated patients received a median 6.0 and 9.5 treatment cycles, respectively. Investigator-assessed, end-of-study objective response rate was 52.0, 53.8 and 52.9% in first-line, pretreated and overall intent-to-treat populations, respectively. The median progression-free survival was 12.2 and 10.6 months in first-line and pretreated patients, respectively. Fourteen patients per group died (56 and 54%), and the median overall survival was 33.1 and 32.5 months, respectively. The most common treatment-related Grade 3 or 4 adverse events and laboratory abnormalities were fatigue (24%), hand-foot syndrome (18%), decreased platelet count (55%), decreased neutrophil count (53%) and increased lipase (49%). No Grade 5 treatment-related adverse events occurred. Forty patients (78%) required dose reduction, and 13 (25%) discontinued, due to treatment-related adverse events.

Conclusions

With the median overall survival benefit exceeding 2.5 years, and acceptable tolerability, in first-line and pretreated Japanese metastatic renal cell carcinoma patients with Eastern Cooperative Oncology Group performance status 0/1, sunitinib showed a favourable risk/benefit profile, similar to Western studies. However, there was a trend towards greater efficacy and more haematological adverse events in Japanese patients.

  M. G Iwaizumi , M Takahashi , A Watanabe and M. Ubukata
 

When considering the genetic implications of immigrant gene flow, it is important to evaluate both the proportions of immigrant gametes and their genetic composition. We simultaneously investigated paternal and maternal gene flow in dispersed seeds in a natural population of Pinus densiflora located along a ridge. The paternity and maternity of a total of 454 dispersed seeds (in 2004 and 2005) were accurately and separately assigned to 454 candidate adult trees, by analyzing the nuclear DNA of both diploid biparentally derived embryos and haploid maternally derived megagametophytes of the seeds. The relative genetic diversities and differences between within-population and immigrant groups of both paternally and maternally derived gametes (4 groups) that formed the genotypes of the seeds were evaluated. Using 8 microsatellite markers, we found that 64.0–72.6% of paternally derived gametes, and 17.8–20.2% of maternally derived gametes, were from other populations. Principal coordinate analysis showed that the 4 gamete groups tended to be plotted at different locations on the scattergram, indicating that they each have different genetic compositions. Substantial paternal and maternal immigrant gene flow occurred in this population, and therefore, the overall genetic variation of dispersed seeds is enhanced by both paternally and maternally derived immigrant gametes.

  G Muteliefu , A Enomoto , P Jiang , M Takahashi and T. Niwa
 

Background. Previously, we demonstrated that indoxyl sulphate (IS), a uraemic toxin, induced aortic calcification in hypertensive rats. This study aimed to determine if IS induces the production of reactive oxygen species (ROS) and the expression of osteoblast-specific proteins in human aortic smooth muscle cells (HASMCs).

Methods. In order to achieve these goals, HASMCs were incubated with IS. ROS were detected using probes with a fluorescence detector. The expression of alkaline phosphatase (ALP), osteopontin and organic anion transporters (OAT1, OAT3) was studied by western blotting. The expression of core binding factor 1 (Cbfa1), ALP, osteopontin and NADPH oxidases (Nox1, Nox2 and Nox4) was analysed by reverse transcription-polymerase chain reaction (RT-PCR). Knockdown of Nox4 was performed by RNA interference (RNAi).

Results. IS induced ROS generation and the expression of Nox4, Cbfa1, ALP and osteopontin in HASMCs. A NADPH oxidase inhibitor and antioxidants inhibited IS-induced ROS production and mRNA expression of Cbfa1 and ALP. Knockdown of Nox4 using small interfering RNA (siRNA) inhibited IS-induced ROS production and mRNA expression of Cbfa1, ALP and osteopontin. OAT3 was expressed in HASMCs.

Conclusions. IS induces ROS generation by upregulating Nox4, and the expression of osteoblast-specific proteins such as Cbfa1, ALP and osteopontin in HASMCs.

 
 
 
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