Fuji Gotemba Research Laboratories

Gotemba, Japan

Fuji Gotemba Research Laboratories

Gotemba, Japan
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Ohtaki H.,Showa University | Ohara K.,Showa University | Song D.,Showa University | Miyamoto K.,Showa University | And 9 more authors.
Journal of Neuroscience Research | Year: 2012

Autofluorescent storage material (ASM) is an aging pigment that accumulates during the normal course of senescence. Although the role of ASM has yet to be fully elucidated, ASM has been implicated in age-related neurodegeneration. In this study, we determined the level of ASM in chloride channel 3 (ClC-3) gene-deficient (KO) mice both in response to aging and following mild global ischemia. To understand the mechanism of action of the ASM, mice subjected to ischemia were treated with the cyclooxygenase (COX) inhibitor indomethacin or with the noncompetitive glutamate receptor antagonist MK-801. ClC-3 KO mice displayed age-related neurodegeneration of the neocortex as well as the hippocampus. The cortical layers in particular granular layers became thinner with aging. ASM accumulated in the brains of ClC-3 KO mice was increased seven- to 50-fold over that observed in the corresponding regions of their wild-type littermates. Young wild-type mice survived longer than age-matched ClC-3 KO mice after permanent global ischemia. However, in the case of older animals, the survival curves were similar. The ASM also increased four- to fivefold 10 days after mild global ischemia, an effect that was suppressed by treatment with indomethacin and MK-801. These results suggest that temporary ischemia might trigger a process similar to aging in the brain, mimicking the effect of age-related neurodegenerative diseases. © 2012 Wiley Periodicals, Inc.


Hashizume M.,Fuji Gotemba Research Laboratories | Mihara M.,Fuji Gotemba Research Laboratories
European Journal of Pharmacology | Year: 2012

In chronic inflammatory diseases, cardiovascular disease risk is increased and is the main cause of increased mortality. Oxidized LDL (oxLDL) and scavenger receptors participate in atherogenesis. Using human arterial endothelial cells (HAECs), we evaluated the effect of IL-6 and TNF-α on the expression of scavenger receptors. IL-6 induced expression of SR-A mRNA and TNF-α induced both SR-A and LOX-1 mRNA. Both did induce either CD36 or CD68. To assess the function of scavenger receptors, MCP-1 production by oxLDL from cytokine-pretreated HAEC was examined. In accordance with scavenger receptor expression, oxLDL-induced MCP-1 production was increased in IL-6- or TNF-α-pretreatment. Serum from rheumatoid arthritis patients but not from healthy subjects increased mRNA expressions of SR-A, LOX-1 and CD36 in HAEC. SR-A expression was inhibited by both anti-IL-6 receptor antibody (α-IL-6R Ab) and TNF-α receptor (p75)-Fc (TNFR-Fc) and LOX-1 expression was inhibited by TNFR-Fc. CD36 expression was affected by neither. Serum from rheumatoid arthritis patients augmented oxLDL-induced MCP-1 production. Both α-IL-6R Ab and TNFR-Fc partially inhibited this MCP-1 production. In conclusion, our results strongly support that blocking therapy of IL-6 and TNF-α might be beneficial to reduce atherosclerosis risk in chronic inflammatory diseases. © 2012 Elsevier B.V. All rights reserved.


Yoneya T.,Kamakura Research Laboratories | Taniguchi K.,Kamakura Research Laboratories | Nakamura R.,Kamakura Research Laboratories | Tsunenari T.,Kamakura Research Laboratories | And 5 more authors.
Anticancer Research | Year: 2010

Background: Tamoxifen, a selective estrogen receptor modulator, and fulvestrant, a selective estrogen receptor down-regulator (SERD), are now available for estrogen receptor-positive breast cancer patients. However, these patients acquire drug-resistance during the treatments. We identified a new orally active nonsteroidal SERD, CH4986399, which is structurally unrelated to fulvestrant and tamoxifen. Materials and Methods: We examined the oral antitumor activity and down-regulation of ER by CH4986399 in human breast cancer Br-10 and ZR-75-1 xenografts. Results: In the Br-10 xenografts, CH4986399 (100 mg/kg p.o.) as well as fulvestrant (3 mg/body s.c.) strongly reduced tumor weight. In the ZR-75-1 xenografts, CH4986399 (100 mg/kg p.o.) strongly reduced tumor weight and ER content without agonistic activity. In contrast, tamoxifen (100 mg/kg p.o.) showed only moderate antitumor activity and no ER down-regulation. Conclusion: With a chemical structure different from both fulvestrant and tamoxifen, CH4986399, may help overcome drug resistance from the endocrine treatment sequence for breast cancer patients.


Kitazawa T.,Fuji Gotemba Research Laboratories | Igawa T.,Fuji Gotemba Research Laboratories | Sampei Z.,Fuji Gotemba Research Laboratories | Muto A.,Fuji Gotemba Research Laboratories | And 30 more authors.
Nature Medicine | Year: 2012

Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients1-3. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections3-5. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A. © 2012 Nature America, Inc. All rights reserved.


Hashizume M.,Fuji Gotemba Research Laboratories | Mihara M.,Fuji Gotemba Research Laboratories
Biochemical and Biophysical Research Communications | Year: 2010

To investigate the mechanism of the inhibitory action of high molecular weight hyaluronic acid (HA) on production of matrix metalloproteinases (MMPs) induced by IL-6 in human chondrocyte. Human chondrocyte were stimulated by interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) with or without HA for 24. h and the productions of MMP-1, MMP-3 and MMP-13 were measured. Phosphorylations of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase kinase (MEK) in IL-6. +. sIL-6R-treated chondrocytes were detected by western blotting. IL-6. +. sIL-6R induced MMP-1, MMP-3 and MMP-13 productions from human chondrocyte. Inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway resulted in marked decreases of MMP-1, MMP-3 and MMP-13 induction by IL-6. In contrast, STAT inhibition only slightly attenuated the production of MMPs. HA inhibited MMP-1, MMP-3 and MMP-13 induction by IL-6, which was reversed by the addition of anti-CD44 antibody but not anti-ICAM-1 antibody. Pre-treatment of cells with HA reduced the phosphorylation of ERK, but not MEK. Expression levels of mitogen-activated protein kinase phosphatase-1 (MKP-1) in HA-treated chondrocytes were assessed by western blotting. HA induced the expression of MKP-1, a negative regulator of ERK1/2 in IL-6. +. sIL-6R-treated or untreated chondrocytes, and the MKP-1 inhibitor and MKP-1 siRNA reversed the HA-induced suppression of MMP induction by IL-6. Our study is the first to demonstrate that HA suppressed MMPs induction by IL-6 in human chondrocyte via MKP-1 induction through CD44 signaling. © 2010 Elsevier Inc.


PubMed | Fuji Gotemba Research Laboratories
Type: Journal Article | Journal: Nature medicine | Year: 2012

Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the foreignness of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A.

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