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Featured researches published by Takeshi Nikawa.


FEBS Letters | 1991

Novel epoxysuccinyl peptides Selective inhibitors of cathepsin B, in vitro

Mitsuo Murata; Satsuki Miyashita; Chihiro Yokoo; Musaharu Tamai; Kazunori Hanada; Katsuo Hatayama; Takae Towatari; Takeshi Nikawa; Nobuhiko Katunuma

A series of new epoxysuccinyl peptides were designed and synthesized to develop a specific inhibitor of cathepsin B. Of these compounds, N‐(L‐3‐trans‐ethoxycarbonyloxirane‐2‐carbonyl)‐L‐isoleucyl‐L‐proline (compound CA‐030) and N‐(L‐3‐trans‐propylcarbamoyloxirane‐2‐carbonyl)‐L‐isoleucyl‐L‐proline (compound CA‐074) were the most potent and specific inhibitors of cathepsin B in vitro. The carboxyl group of proline and the ethyl ester group or n‐propylamide group in the oxirane ring were necessary, the ethyl ester group or the n‐propylamide group being particularly effective for distinguishing cathepsin B from other cysteine proteinases such as cathepsins L and H, and calpains.


FEBS Letters | 1991

Novel epoxysuccinyl peptides A selective inhibitor of cathepsin B, in vivo

Takae Towatari; Takeshi Nikawa; Mitsuo Murata; Chihiro Yokoo; Masaharu Tamai; Kazunori Hanada; Nobuhiko Katunuma

New derivatives of E‐64 (compound CA‐030 and CA‐074) were tested in vitro and in vivo for selective inhibition of cathepsin B. They exhibited 10000–30000 times greater inhibitory effects on purified rat cathepsin B than on cathepsin H and L; their initial K 1 values for cathepsin B were about 2–5 nM, like that of E‐64‐c, whereas their initial K 1 values for cathepsins H and L were about 40–200 μM. In in vivo conditions, such us intraperitoneal injection of compound CA‐030 or CA‐074 into rats, compound CA‐074 is an especially potent selective inhibitor of cathepsin B, whereas compound CA‐030 does not show selectivity for cathepsin B, although both compounds CA‐030 and CA‐074 show complete selectivity for cathepsin B in vitro.


The FASEB Journal | 2004

Skeletal muscle gene expression in space-flown rats

Takeshi Nikawa; Kazumi Ishidoh; Katsuya Hirasaka; Ibuki Ishihara; Madoka Ikemoto; Mihoko Kano; Eiki Kominami; Ikuya Nonaka; Takayuki Ogawa; Gregory R. Adams; Kenneth M. Baldwin; Natsuo Yasui; Kyoichi Kishi; Shin'ichi Takeda

Skeletal muscles are vulnerable to marked atrophy under microgravity. This phenomenon is due to the transcriptional alteration of skeletal muscle cells to weightlessness. To further investigate this issue at a subcellular level, we examined the expression of ~26,000 gastrocnemius muscle genes in space‐flown rats by DNA microarray analysis. Comparison of the changes in gene expression among spaceflight, tail‐suspended, and denervated rats revealed that such changes were unique after spaceflight and not just an extension of simulated weightlessness. The microarray data showed two spaceflight‐specific gene expression patterns: 1) imbalanced expression of mitochondrial genes with disturbed expression of cytoskeletal molecules, including putative mitochondria‐anchoring proteins, A‐kinase anchoring protein, and cytoplasmic dynein, and 2) up‐regulated expression of ubiquitin ligase genes, MuRF‐1, Cbl‐b, and Siah‐1A, which are rate‐limiting enzymes of muscle protein degradation. Distorted expression of cytoskeletal genes during spaceflight resulted in dislocation of the mitochondria in the cell. Several oxidative stress‐inducible genes were highly expressed in the muscle of spaceflight rats. We postulate that mitochondrial dislocation during spaceflight has deleterious effects on muscle fibers, leading to atrophy in the form of insufficient energy provision for construction and leakage of reactive oxygen species from the mitochondria.


The FASEB Journal | 2001

Space shuttle flight (STS-90) enhances degradation of rat myosin heavy chain in association with activation of ubiquitin–proteasome pathway

Madoka Ikemoto; Takeshi Nikawa; Shin'ichi Takeda; Chiho Watanabe; Takako Kitano; Kenneth M. Baldwin; Ryutaro Izumi; Ikuya Nonaka; Takae Towatari; Shigetada Teshima; Kazuhito Rokutan; Kyoichi Kishi

To elucidate the mechanisms of microgravity‐induced muscle atrophy, we focused on fast‐type myosin heavy chain (MHC) degradation and expression of proteases in atrophied gastrocnemius muscles of neonatal rats exposed to 16‐d spaceflight (STS‐90). The spaceflight stimulated ubiquitination of proteins, including a MHC molecule, and accumulation of MHC degradation fragments in the muscles. Semiquantitative reverse transcriptase‐polymerase chain reaction revealed that the spaceflight significantly increased mRNA levels of cathepsin L, proteasome components (RC2 and RC9), polyubiquitin, and ubiquitin‐conjugating enzyme in the muscles, compared with those of ground control rats. The levels of μ‐calpain, m‐calpain, cathepsin B, and cathepsin H mRNAs were not changed by the spaceflight. We also found that tail‐suspension of rats for 10 d or longer caused the ubiquitination and degradation of MHC in gastrocnemius muscle, as was observed in the spaceflight rats. In the muscle of suspended rats, these changes were closely associated with activation of proteasome and up‐regulation of expression of mRNA for the proteasome components and polyubiquitin. Administration of a cysteine protease inhibitor, E‐64, to the suspended rats did not prevent the MHC degradation. Our results suggest that spaceflight induces the degradation of muscle contractile proteins, including MHC, possibly through a ubiquitin‐dependent proteolytic pathway.


FEBS Letters | 1993

Participation of cathepsin L on bone resorption

Hisao Kakegawa; Takeshi Nikawa; Kahori Tagami; Hiroshi Kamioka; Koji Sumitani; Terushige Kawata; Drobnic-Kosorok M; Brigita Lenarčič; Vito Turk; Nobuhiko Katunuma

The proteinase responsible for bone collagen degradation in osteo‐resorption was examined. The bone pit formation induced by parathyroid hormone (PTH) was markedly suppressed by leupeptin, E‐64 and cystatin A, while no inhibition was observed by CA‐074, a specific inhibitor of cathepsin B. Pig leucocyte cysteine proteinase inhibitor (PLCPI), a specific inhibitor of cathepsin L, and chymostatin, a selective inhibitor of cathepsin L, completely inhibited the pit formation. Cathepsin L activity in osteoclasts was much higher than the other cathepsin activities. Serum calcium in rats placed on a low calcium diet was decreased by treatment of E‐64 or cystatin A, but not by CA‐074. These findings suggest that cathepsin L is the main proteinase responsible for bone collagen degradation.


Molecular and Cellular Biology | 2009

Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading.

Reiko Nakao; Katsuya Hirasaka; Jumpei Goto; Kazumi Ishidoh; Chiharu Yamada; Ayako Ohno; Yuushi Okumura; Ikuya Nonaka; Koji Yasutomo; Kenneth M. Baldwin; Eiki Kominami; Akira Higashibata; Keisuke Nagano; Keiji Tanaka; Natsuo Yasui; Edward M. Mills; Shin'ichi Takeda; Takeshi Nikawa

ABSTRACT Skeletal muscle atrophy caused by unloading is characterized by both decreased responsiveness to myogenic growth factors (e.g., insulin-like growth factor 1 [IGF-1] and insulin) and increased proteolysis. Here, we show that unloading stress resulted in skeletal muscle atrophy through the induction and activation of the ubiquitin ligase Cbl-b. Upon induction, Cbl-b interacted with and degraded the IGF-1 signaling intermediate IRS-1. In turn, the loss of IRS-1 activated the FOXO3-dependent induction of atrogin-1/MAFbx, a dominant mediator of proteolysis in atrophic muscle. Cbl-b-deficient mice were resistant to unloading-induced atrophy and the loss of muscle function. Furthermore, a pentapeptide mimetic of tyrosine608-phosphorylated IRS-1 inhibited Cbl-b-mediated IRS-1 ubiquitination and strongly decreased the Cbl-b-mediated induction of atrogin-1/MAFbx. Our results indicate that the Cbl-b-dependent destruction of IRS-1 is a critical dual mediator of both increased protein degradation and reduced protein synthesis observed in unloading-induced muscle atrophy. The inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy.


Muscle & Nerve | 2006

Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest.

Takayuki Ogawa; Harumi Furochi; Mai Mameoka; Katsuya Hirasaka; Yuko Onishi; Naoto Suzue; Motoko Oarada; Motoki Akamatsu; Hiroshi Akima; Tetsuo Fukunaga; Kyoichi Kishi; Natsuo Yasui; Kazumi Ishidoh; Hideoki Fukuoka; Takeshi Nikawa

In animal models, several ubiquitin ligases play an important role in skeletal muscle atrophy caused by unloading. In this study we examined protein ubiquitination and ubiquitin ligase gene expression in quadriceps femoris muscle from healthy volunteers after 20‐day bedrest to clarify ubiquitin‐dependent proteolysis in human muscles after unloading. During bedrest, thickness and cross‐sectional area of the quadriceps femoris muscle decreased significantly by 4.6% and 3.7%, respectively. Ubiquitinated proteins accumulated in these atrophied human muscles. A real‐time reverse transcription–polymerase chain reaction system showed that bedrest significantly upregulated expression of two ubiquitin ligase genes, Cbl‐b and atrogin‐1. We also performed DNA microarray analysis to examine comprehensive gene expression in the atrophied muscle. Bedrest mainly suppressed the expression of muscle genes associated with control of gene expression in skeletal muscle. Our results suggest that, in humans, Cbl‐b– or atrogin‐1–mediated ubiquitination plays an important role in unloading‐induced muscle atrophy, and that unloading stress may preferentially inhibit transcriptional responses in skeletal muscle. Muscle Nerve, 2006


Diabetes | 2007

Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice.

Katsuya Hirasaka; Shohei Kohno; Jumpei Goto; Harumi Furochi; Kazuaki Mawatari; Nagakatsu Harada; Toshio Hosaka; Yutaka Nakaya; Kazumi Ishidoh; Toshiyuki Obata; Yousuke Ebina; Hua Gu; Shin'ichi Takeda; Kyoichi Kishi; Takeshi Nikawa

OBJECTIVE—c-Cbl plays an important role in whole-body fuel homeostasis by regulating insulin action. In the present study, we examined the role of Cbl-b, another member of the Cbl family, in insulin action. RESEARCH DESIGN AND METHODS—C57BL/6 (Cbl-b+/+) or Cbl-b-deficient (Cbl-b−/−) mice were subjected to insulin and glucose tolerance tests and a hyperinsulinemic-euglycemic clamp test. Infiltration of macrophages into white adipose tissue (WAT) was assessed by immunohistochemistry and flow cytometry. We examined macrophage activation using co-cultures of 3T3-L1 adipocytes and peritoneal macrophages. RESULTS—Elderly Cbl-b−/− mice developed glucose intolerance and peripheral insulin resistance; serum insulin concentrations after a glucose challenge were always higher in elderly Cbl-b−/− mice than age-matched Cbl-b+/+ mice. Deficiency of the Cbl-b gene significantly decreased the uptake of 2-deoxyglucose into WAT and glucose infusion rate, whereas fatty liver was apparent in elderly Cbl-b−/− mice. Cbl-b deficiency was associated with infiltration of macrophages into the WAT and expression of cytokines, such as tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein (MCP)-1. Co-culture of Cbl-b−/− macrophages with 3T3-L1 adipocytes induced leptin expression and dephosphorylation of insulin receptor substrate 1, leading to impaired glucose uptake in adipocytes. Furthermore, Vav1, a key factor in macrophage activation, was highly phosphorylated in peritoneal Cbl-b−/− macrophages compared with Cbl-b+/+ macrophages. Treatment with a neutralizing anti–MCP-1 antibody improved peripheral insulin resistance and macrophage infiltration into WAT in elderly Cbl-b−/− mice. CONCLUSIONS—Cbl-b is a negative regulator of macrophage infiltration and activation, and macrophage activation by Cbl-b deficiency contributes to the peripheral insulin resistance and glucose intolerance via cytokines secreted from macrophages.


Scientific Reports | 2012

The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis

Hirotaka Tanaka; Masamitsu Shimazawa; Masataka Kimura; Masafumi Takata; Kazuhiro Tsuruma; Mitsunori Yamada; Hitoshi Takahashi; Isao Hozumi; Jun-ichi Niwa; Yohei Iguchi; Takeshi Nikawa; Gen Sobue; Takashi Inuzuka; Hideaki Hara

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by the loss of motor neurons. Despite substantial research, the causes of ALS remain unclear. Glycoprotein nonmetastatic melanoma protein B (GPNMB) was identified as an ALS-related factor using DNA microarray analysis with mutant superoxide dismutase (SOD1G93A) mice. GPNMB was greatly induced in the spinal cords of ALS patients and a mouse model as the disease progressed. It was especially expressed in motor neurons and astrocytes. In an NSC34 cell line, glycosylation of GPNMB was inhibited by interaction with SOD1G93A, increasing motor neuron vulnerability, whereas extracellular fragments of GPNMB secreted from activated astrocytes attenuated the neurotoxicity of SOD1G93A in neural cells. Furthermore, GPNMB expression was substantial in the sera of sporadic ALS patients than that of other diseased patients. This study suggests that GPNMB can be a target for therapeutic intervention for suppressing motor neuron degeneration in ALS.


Biological Chemistry | 2002

Cysteine supplementation prevents unweighting-induced ubiquitination in association with redox regulation in rat skeletal muscle

Madoka Ikemoto; Takeshi Nikawa; Mihoko Kano; Katsuya Hirasaka; Takako Kitano; Chiho Watanabe; Reiko Tanaka; Taeko Yamamoto; Mariko Kamada; Kyoichi Kishi

Abstract We have previously reported that spaceflight and tail suspension enhanced degradation of rat myosin heavy chain (MHC) in association with activation of a ubiquitindependent proteolytic pathway [Ikemoto et al., FASEB J. 15 (2001), 1279 1281]. To elucidate whether the ubiquitination is accompanied by oxidative stress, we measured markers for oxidative stress, such as thiobarbituric acidreactive substance (TBARS) and glutathione disulfide (GSSG), in gastrocnemius muscle of tailsuspended rats. Glutathione (GSH) concentration in the muscle significantly decreased from day 5 and reached a minimum value on day 10. Tail suspension reciprocally increased concentrations of TBARS and GSSG in parallel with enhancement of protein ubiquitination, suggesting that oxidative stress may play an important role in protein ubiquitination caused by tail suspension. To prevent ubiquitination associated with oxidative stress, we also administered an antioxidative nutrient, cysteine, to tailsuspended rats. Intragastric supplementation of 140 mg/rat of cysteine for 2 weeks or longer normalized the ratio of GSH to GSSG in the muscle and suppressed protein ubiquitination and MHC fragmentation, compared with supplementation of the equimolar amount of alanine. The cysteine supplementation significantly suppressed the loss of hindlimb muscle mass. Our results suggest that supplementation of antioxidative nutrients, such as cysteine, may be beneficial for preventing ubiquitination of muscle proteins caused by unweighting.

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Tomoki Abe

University of Tokushima

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Shohei Kohno

University of Tokushima

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Ayako Ohno

University of Tokushima

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