59 results on '"Mutsuyoshi Matsushita"'
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2. The Orally Administered Selective TRPV1 Antagonist, JTS-653, Attenuates Chronic Pain Refractory to Non-steroidal Anti-inflammatory Drugs in Rats and Mice Including Post-herpetic Pain
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Yoshihiro Kitagawa, Isao Tamai, Yuji Hamada, Kenji Usui, Masashi Wada, Masahiro Sakata, and Mutsuyoshi Matsushita
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Chronic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) is a major problem and drugs for such pain are needed. Many studies suggest that transient receptor potential vanilloid type 1 (TRPV1) is associated with NSAID-refractory chronic pain. Therefore, we investigated the involvement of TRPV1 in NSAID-refractory chronic pain using experimental models for NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. The selective TRPV1 antagonist JTS-653 {(3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide} reversed mechanical hyperalgesia on day 7 after injection of complete-Freund-adjuvant into the hindpaw in rats at 0.3 mg/kg, whereas indomethacin showed no effect. JTS-653 reduced chronic pain at 0.3 mg/kg in herpes simplex virus-1–inoculated mice that has been reported as NSAID-refractory pain. JTS-653 partially attenuated mechanical hyperalgesia in the L5 spinal nerve ligation model in rats at 0.3 mg/kg, whereas indomethacin showed no effect. Both JTS-653 and indomethacin reduced formalin-induced pain in the second phase, whereas they showed no effect in the first phase. JTS-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. These findings demonstrate the TRPV1 involvement in NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. TRPV1 antagonists would be useful for the treatment of NSAID-refractory chronic pain. Keywords:: transient receptor potential vanilloid type 1 (TRPV1), non-steroidal anti-inflammatory drug (NSAID), chronic pain, post-herpetic pain, herpes simplex virus-1 (HSV-1)
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- 2013
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3. JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor
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Naofumi Uesato, Takahiro Hata, Takayuki Yamaguchi, Yushi Matsuo, Kazutaka Ikegashira, Koji Inagaki, Naoki Miyagawa, Mutsuyoshi Matsushita, Yoshihiro Kitagawa, and Reina Kakefuda
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Male ,Macrophage colony-stimulating factor ,Osteoclasts ,Pharmaceutical Science ,Arthritis ,Inflammation ,Colony stimulating factor 1 receptor ,Mice ,Bone Density ,Osteoclast ,medicine ,Animals ,Humans ,Pharmacology ,Dose-Response Relationship, Drug ,Chemistry ,Synovial Membrane ,General Medicine ,medicine.disease ,Arthritis, Experimental ,medicine.anatomical_structure ,Synovial Cell ,Mice, Inbred DBA ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,Rheumatoid arthritis ,Cancer research ,Azetidines ,medicine.symptom ,Tyrosine kinase - Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.
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- 2020
4. Janus kinase inhibitor delgocitinib suppresses pruritus and nerve elongation in an atopic dermatitis murine model
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Kenji Usui, Tetsuya Honda, Mikio Hayashi, Yuji Hamada, Yasuo Yamamoto, Atsushi Otsuka, Noriko Konishi, Kenji Kabashima, Atsuo Tanimoto, Chisa Nakashima, Wataru Amano, Gyohei Egawa, Mutsuyoshi Matsushita, Yoshihiro Ishida, and Masashi Wada
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Male ,business.industry ,Pruritus ,Antipruritics ,Dermatology ,Atopic dermatitis ,Pharmacology ,Administration, Cutaneous ,medicine.disease ,Biochemistry ,Dermatitis, Atopic ,Disease Models, Animal ,Mice ,Murine model ,Animals ,Humans ,Janus Kinase Inhibitors ,Medicine ,Female ,Pyrroles ,business ,Skin pathology ,Molecular Biology ,Skin ,Janus kinase inhibitor - Published
- 2020
5. Conventional and novel impacts of ferric citrate on iron deficiency anemia and phosphorus metabolism in rats
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Akio Iida, Mutsuyoshi Matsushita, Takeshi Ohta, and Takahisa Yamada
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Male ,medicine.medical_specialty ,040301 veterinary sciences ,Anemia ,medicine.drug_class ,chemistry.chemical_element ,Administration, Oral ,Urine ,Ferric Compounds ,Phosphorus metabolism ,0403 veterinary science ,Rats, Sprague-Dawley ,03 medical and health sciences ,Oral administration ,Laboratory Animal Science ,Internal medicine ,medicine ,Animals ,030304 developmental biology ,0303 health sciences ,iron deficiency anemia ,General Veterinary ,Full Paper ,Anemia, Iron-Deficiency ,Transferrin saturation ,Phosphorus ,phosphorus metabolism ,04 agricultural and veterinary sciences ,Iron Deficiencies ,medicine.disease ,ferric citrate ,Phosphate binder ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,Endocrinology ,chemistry ,Iron-deficiency anemia - Abstract
Ferric citrate is an oral iron-based phosphate binder, being known to affect iron status and improve iron deficiency anemia (IDA) in chronic kidney disease (CKD) patients. We examined whether oral administration of ferric citrate could change iron status and improve anemia without affecting phosphorus metabolism in iron deficiency anemia rats. In Normal rat study, normal rats were fed a diet containing 0.3 or 3% ferric citrate for 11 days for setting the dose and administration period of ferric citrate. The effects of ferric citrate on iron status- and phosphorus metabolism-related parameters were evaluated using blood and urine samples. Next, an iron deficiency anemia was induced by feeding iron-depleted diet in rats. After 7 days of starting the iron-depleted diet, 0.3% ferric citrate was administered for 7 days by dietary admixture. Iron status- and phosphorus metabolism-related parameters were evaluated with blood and urine samples. In Normal rat study, 3% ferric citrate treatment increased serum iron level and transferrin saturation (TSAT), and decreased serum phosphorus level, intact fibroblast growth factor 23 (iFGF23) level, and urinary phosphorus excretion, but 0.3% ferric citrate treatment showed no effects. On the other hand, in Iron deficiency anemia rat study, 0.3% ferric citrate treatment increased iron status-related parameters and improved anemia, but did not show any apparent changes in phosphorus metabolism-related parameters. In conclusion, ferric citrate could have hematopoietic effects without affecting phosphorus metabolism, and could be a potential option for the treatment of IDA in patients without CKD.
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- 2020
6. JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effects while maintaining bone mineral density in mice
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Mutsuyoshi Matsushita, Takahisa Yamada, Yoshinori Kosugi, Takeshi Ohta, Takashi Nakagawa, Takahiro Hata, Takafumi Kurimoto, Katsuya Deai, Atsuko Miyai, Yasuo Yamamoto, and Isao Tamai
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0301 basic medicine ,Male ,Side effect ,Lipopolysaccharide ,Prednisolone ,Anti-Inflammatory Agents ,Arthritis ,Aminopyridines ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Glucocorticoid receptor ,Receptors, Glucocorticoid ,Bone Density ,medicine ,Fosdagrocorat ,Animals ,Humans ,Glucocorticoids ,JTP-117968 ,Transrepression ,Mice, Inbred BALB C ,Osteoblasts ,Glucocorticoid-induced osteoporosis ,business.industry ,Tumor Necrosis Factor-alpha ,PF-802 ,medicine.disease ,Arthritis, Experimental ,030104 developmental biology ,chemistry ,Collagen-induced arthritis model ,Mice, Inbred DBA ,Rheumatoid arthritis ,Intercellular Signaling Peptides and Proteins ,Selective glucocorticoid receptor modulator ,Female ,Joints ,Inflammation Mediators ,business ,030217 neurology & neurosurgery ,medicine.drug ,Phenanthrolines - Abstract
Classic glucocorticoids have been prescribed for various inflammatory diseases, such as rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However, glucocorticoids cause numerous unwanted side effects, including osteoporosis and diabetes. Hence, selective glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of glucocorticoids are largely due to TR, while the side effects associated with glucocorticoids are mostly mediated through TA. We previously reported that JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model and collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation, JTP-117968 reduced the plasma levels of tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by JTP-117968 comparably with prednisolone and PF-802, an active form of fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of JTP-117968 on mouse femoral BMD was much lower than those of PF-802 and prednisolone. Therefore, JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic glucocorticoids.
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- 2021
7. JTZ-951 (enarodustat), a hypoxia-inducible factor prolyl hydroxylase inhibitor, improves iron utilization and anemia of inflammation: Comparative study against recombinant erythropoietin in rat
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Hatsue Kobayashi, Akira Matsuo, Hiromi Yoshiuchi, Mutsuyoshi Matsushita, Yuichi Shinozaki, and Kenji Fukui
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0301 basic medicine ,medicine.medical_specialty ,Erythrocytes ,Anemia ,Pyridines ,Iron ,Inflammation ,Hypoxia-Inducible Factor-Proline Dioxygenases ,03 medical and health sciences ,0302 clinical medicine ,Hepcidins ,Hepcidin ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Animals ,Erythropoiesis ,Enzyme Inhibitors ,Erythropoietin ,Pharmacology ,biology ,Anemia, Iron-Deficiency ,business.industry ,Triazoles ,medicine.disease ,Arthritis, Experimental ,Recombinant Proteins ,030104 developmental biology ,Endocrinology ,Hypoxia-inducible factors ,N-substituted Glycines ,Rats, Inbred Lew ,biology.protein ,Hematinics ,Female ,Hemoglobin ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Biomarkers ,Kidney disease ,medicine.drug - Abstract
Anemia with inflammation-induced defective iron utilization is a pathological condition observed in patients suffering from chronic kidney disease (CKD) or chronic inflammatory disease. There is no reasonable treatment for these conditions, because the effects of erythropoiesis stimulating agents (ESAs) or iron supplementation in the treatment of anemia are insufficient. JTZ-951 (enarodustat) has been characterized as a novel, orally bioavailable inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), and has been developed as a novel therapeutic agent for anemia with CKD. In this study, the effects of JTZ-951 on iron utilization during erythropoiesis and on anemia of inflammation were compared with those of recombinant human erythropoietin (rHuEPO) using normal rat and rat model of anemia of inflammation. In normal rats, under conditions in which JTZ-951 and rHuEPO showed similar erythropoietic effect, repeated doses of JTZ-951 induced erythropoiesis while retaining the hemoglobin content in red blood cells, while administration of rHuEPO resulted in decrease in some erythrocyte-related parameters. As for iron-related parameters during erythropoiesis, JTZ-951 exhibited more efficient iron utilization compared to rHuEPO. A single dose of JTZ-951 resulted in decrease in hepcidin expression observed within 24 h after administration, but a single dose of rHuEPO did not. In a rat model of anemia of inflammation (also known as a model with functional iron-deficiency), JTZ-951 showed erythropoietic effect, in contrast with rHuEPO. These results suggest that, unlike rHuEPO, JTZ-951 stimulates erythropoiesis by increasing iron utilization, and improves anemia of inflammation.
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- 2020
8. Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity
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Yoshihiro Ishida, Judith A. Seidel, Akihiko Kitoh, Mikio Hayashi, Takashi Nomura, Kenji Kabashima, Mutsuyoshi Matsushita, Lai San Wong, Chisa Nakashima, Yasuo Yamamoto, Tetsuya Honda, Saeko Nakajima, Atsushi Otsuka, Noriko Konishi, Wataru Amano, Yumi Nonomura, and Teruki Dainichi
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0301 basic medicine ,Receptors, CCR7 ,Receptors, CXCR4 ,Immunology ,Neurotoxins ,TRPV Cation Channels ,C-C chemokine receptor type 7 ,Inflammation ,Mice, Transgenic ,Dermatitis, Contact ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,Dorsal root ganglion ,Ganglia, Spinal ,medicine ,Immunology and Allergy ,Animals ,Dendritic cell migration ,Denervation ,Mice, Inbred BALB C ,integumentary system ,Chemistry ,Dendritic cell ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Langerhans Cells ,Pituitary Adenylate Cyclase-Activating Polypeptide ,Female ,Lymph Nodes ,medicine.symptom ,Diterpenes ,Haptens ,030217 neurology & neurosurgery ,Sensory nerve - Abstract
Background Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. Objective This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. Methods We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. Results CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. Conclusion These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.
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- 2020
9. Pharmacological Properties of JTE-952, an Orally Available and Selective Colony Stimulating Factor 1 Receptor Kinase Inhibitor
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Mutsuyoshi Matsushita, Kazutaka Ikegashira, Reina Kakefuda, Yushi Matsuo, Naofumi Uesato, Koji Inagaki, Takayuki Yamaguchi, Takahiro Hata, Naoki Miyagawa, and Yoshihiro Kitagawa
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0301 basic medicine ,Macrophage colony-stimulating factor ,Male ,medicine.drug_class ,Pharmaceutical Science ,Pharmacology ,Tyrosine-kinase inhibitor ,Proinflammatory cytokine ,Colony stimulating factor 1 receptor ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Kinase activity ,Receptor, trkA ,Receptor ,Protein Kinase Inhibitors ,Cells, Cultured ,Kinase ,Chemistry ,General Medicine ,Arthritis, Experimental ,030104 developmental biology ,Mice, Inbred DBA ,Rats, Inbred Lew ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,030220 oncology & carcinogenesis ,Azetidines ,Cytokines ,Tumor necrosis factor alpha - Abstract
Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.
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- 2020
10. JTE-852, a novel spleen tyrosine kinase inhibitor, blocks antigen-induced allergic reactions in rats
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Mutsuyoshi Matsushita, Hatsue Kobayashi, Toshinobu Kato, Hidenori Iwasaki, Takahiro Hata, Takeshi Ohta, and Akira Matsuo
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Ketotifen ,Male ,Allergy ,Aminopyridines ,Spleen ,Inflammation ,030204 cardiovascular system & hematology ,Pharmacology ,JTE-852 ,Sneezing ,Pranlukast ,03 medical and health sciences ,spleen tyrosine kinase ,0302 clinical medicine ,Antigen ,Laboratory Animal Science ,Rats, Inbred BN ,medicine ,Hypersensitivity ,Respiratory Hypersensitivity ,Animals ,rat ,Mast Cells ,Antigens ,General Veterinary ,biology ,Full Paper ,business.industry ,disease model ,Protein-Tyrosine Kinases ,medicine.disease ,allergy ,Rats ,Airway Obstruction ,Disease Models, Animal ,Nasal Mucosa ,Thiazoles ,medicine.anatomical_structure ,030228 respiratory system ,biology.protein ,Prednisolone ,Cytokines ,Antibody ,medicine.symptom ,business ,medicine.drug - Abstract
Conventional clinical treatments for allergy management remain suboptimal; new, orally available medications that improve a wide range of allergic signs have been desired. We previously demonstrated that JTE-852, a novel spleen tyrosine kinase inhibitor, potently and simultaneously suppresses secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by immunoglobulin E-crosslinking. In the present study, we investigated the effects of JTE-852 in four rat models (sneezing, rhinorrhea, airway constriction, and airway inflammation) as representatives of allergy models. Rats were sensitized and challenged with antigen. Allergic reactions developed after challenge were detected. JTE-852 and current anti-allergic drugs (ketotifen, pranlukast, and prednisolone) were administered orally before challenge. JTE-852 showed significant blocking effects on antigen-induced allergic reactions in all models, indicating that JTE-852 in oral dosage form would improve a wide range of allergic signs. The current anti-allergic drugs, on the other hand, failed to display significant suppression in several models. Because JTE-852 suppresses the secretion of all three groups of allergic mediators from mast cells, it would be capable of targeting signs that current drugs cannot sufficiently relieve. We anticipate JTE-852 to be a promising new anti-allergic drug that is potentially more effective than conventional drugs.
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- 2018
11. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo
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Keisuke Nozawa, Chika Oki, Akira Matsuo, Satoru Noji, Makoto Shiozaki, Yukari Kimoto, Yoshihiro Ogawa, Mutsuyoshi Matsushita, Yuichi Shinozaki, Atsuo Tanimoto, and Wataru Amano
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genetic structures ,JTE-052 ,T-Lymphocytes ,Immunology ,Pharmacology toxicology ,Anti-Inflammatory Agents ,In Vitro Techniques ,Pharmacology ,Interferon-gamma ,Mice ,Cytokines metabolism ,In vivo ,Animals ,Humans ,Medicine ,Mast Cells ,Protein Kinase Inhibitors ,Cells, Cultured ,Cytokine signaling ,Janus Kinases ,Inflammation ,B-Lymphocytes ,business.industry ,Arthritis, Experimental ,In vitro ,Rats ,Original Research Paper ,Disease Models, Animal ,Methotrexate ,Mice, Inbred DBA ,Rats, Inbred Lew ,Antirheumatic Agents ,Collagen-induced arthritis ,Cytokines ,Interleukin-2 ,Collagen ,biological phenomena, cell phenomena, and immunity ,Janus kinase ,business ,Signal Transduction - Abstract
Objective To evaluate the pharmacological properties of JTE-052, a novel Janus kinase (JAK) inhibitor. Methods The JAK inhibitory activity of JTE-052 was evaluated using recombinant human enzymes. The inhibitory effects on cytokine signaling pathways were evaluated using primary human inflammatory cells. The in vivo efficacy and potency of JTE-052 were examined in a mouse interleukin (IL)-2-induced interferon (IFN)-γ production model and a rat collagen-induced arthritis model. Results JTE-052 inhibited the JAK1, JAK2, JAK3, and tyrosine kinase (Tyk)2 enzymes in an adenosine triphosphate (ATP)-competitive manner and inhibited cytokine signaling evoked by IL-2, IL-6, IL-23, granulocyte/macrophage colony-stimulating factor, and IFN-α. JTE-052 inhibited the activation of inflammatory cells, such as T cells, B cells, monocytes, and mast cells, in vitro. Oral dosing of JTE-052 resulted in potent suppression of the IL-2-induced IFN-γ production in mice with an ED50 value of 0.24 mg/kg, which was more potent than that of tofacitinib (ED50 = 1.1 mg/kg). In the collagen-induced arthritis model, JTE-052 ameliorated articular inflammation and joint destruction even in therapeutic treatments where methotrexate was ineffective. Conclusions The present results indicate that JTE-052 is a highly potent JAK inhibitor, and represents a candidate anti-inflammatory agent for suppressing various types of inflammation. Electronic supplementary material The online version of this article (doi:10.1007/s00011-014-0782-9) contains supplementary material, which is available to authorized users.
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- 2014
12. JTE-852, a novel spleen tyrosine kinase inhibitor, blocks immunoglobulin G-mediated cellular responses and autoimmune reactions in vivo
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Takahiro Hata, Akira Matsuo, Hatsue Kobayashi, Mutsuyoshi Matsushita, Hidenori Iwasaki, Toshinobu Kato, and Takeshi Ohta
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0301 basic medicine ,Male ,Syk ,Arthritis ,Aminopyridines ,Autoimmunity ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Immunoglobulin G ,Monocytes ,Autoimmune Diseases ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,In vivo ,medicine ,Animals ,Humans ,Syk Kinase ,Mast Cells ,General Pharmacology, Toxicology and Pharmaceutics ,Rats, Wistar ,Protein Kinase Inhibitors ,Cells, Cultured ,Autoimmune disease ,Passive Cutaneous Anaphylaxis ,General Medicine ,medicine.disease ,Arthritis, Experimental ,Rats ,Disease Models, Animal ,Thiazoles ,030104 developmental biology ,Rats, Inbred Lew ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Methotrexate ,Tumor necrosis factor alpha ,Female ,medicine.drug - Abstract
Aims Immune and inflammatory responses mediated by immunoglobulin (Ig) G are largely responsible for the pathogenesis of autoimmune diseases. Spleen tyrosine kinase (Syk) plays a pivotal role in the IgG-mediated responses; therefore, Syk has emerged as a new therapeutic target for the treatment of autoimmune diseases. In this study, we investigated the inhibitory actions of JTE-852, a novel Syk inhibitor, on IgG-mediated cellular responses and autoimmune reactions in vivo. Main methods We examined mediator secretion from human monocytes. We also conducted rat models of reversed cutaneous anaphylaxis (RCA) and reversed passive Arthus (RPA), which are classified as type II and type III hypersensitivities, respectively. In a rat collagen-induced arthritis (CIA) model, JTE-852 or methotrexate was administered preventively (before the onset of arthritis) or therapeutically (after the onset of arthritis). Key findings JTE-852 blocked secretion of reactive oxygen species and tumor necrosis factor-α from monocytes stimulated by IgG crosslinking. In the RCA and RPA models, JTE-852 also suppressed edema and dye leakage, respectively. In the CIA model, JTE-852 showed both preventive and therapeutic effects against joint swelling and bone erosion; on the other hand, methotrexate did not show the therapeutic effect. Significance JTE-852 attenuates IgG-mediated responses and signs in animal model of autoimmune diseases. JTE-852 is thus a promising candidate for a novel, orally available drug for the treatment of autoimmune diseases.
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- 2017
13. JTE-852, a novel spleen tyrosine kinase inhibitor, blocks mediator secretion from mast cells with immunoglobulin E crosslinking
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Akira Matsuo, Takahiro Hata, Naoki Miyagawa, Hidenori Iwasaki, Mutsuyoshi Matsushita, Toshinobu Kato, and Hatsue Kobayashi
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0301 basic medicine ,Intracellular Space ,Syk ,Aminopyridines ,Biology ,Pharmacology ,Immunoglobulin E ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Syk Kinase ,Secretion ,Mast Cells ,Kinase activity ,Protein Kinase Inhibitors ,Passive Cutaneous Anaphylaxis ,Mast cell ,Adenosine ,Rats ,Thiazoles ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Tyrosine kinase ,Histamine ,medicine.drug - Abstract
Mast cells stimulated by immunoglobulin E (IgE)-crosslinking secrete mediators, which are mainly categorized into three groups: granule contents, arachidonate metabolites, and cytokines. These mediators play important roles in pathogenesis of allergic diseases; indeed, some conventional drugs which target the mediators are used in clinical practices. However, these drugs are not yet sufficient enough in their efficacy. That is because most of them are blockers of single mediators and are unable to prevent simultaneously various reactions caused by the three group mediators. Spleen tyrosine kinase (Syk) is a non-receptor protein tyrosine kinase. In mast cells, Syk locates at almost top of the signal cascades induced by IgE-crosslinking and plays pivotal roles in secretion of the three groups of mediators. Therefore, inhibition of Syk would suppress the secretion of all the mediators from mast cells and be a promising-treatment strategy for allergic diseases. In the present study, we characterized pharmacological profiles of JTE-852, which was identified as a novel Syk inhibitor. JTE-852 inhibited kinase activity of Syk in an adenosine 5'-triphosphate (ATP)-competitive fashion. JTE-852 also blocked the secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by IgE-crosslinking, with similar potencies. The results suggest that JTE-852 is supposed to prevent various allergic reactions caused by the three group mediators in vivo. In fact, oral gavage of JTE-852 attenuated an allergic reaction mediated by histamine, which is a representative of the three groups of mediators. JTE-852 is expected to be a novel, highly-efficacious, and orally available anti-allergic drug.
- Published
- 2017
14. Discovery of 6-Phenylpyrimido[4,5-b][1,4]oxazines as Potent and Selective Acyl CoA:Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors with in Vivo Efficacy in Rodents
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Masahiro Suzuki, Akio Kobayashi, Mitsuru Takahashi, Steven M. Rubenstein, Takuya Matsui, Bei Shan, Kazuyuki Sugimoto, Marie-Louise Smith, Xiaolin Hao, Kexue Li, Yukihito Ishii, Masahiro Tanaka, Jian Ken Zhang, Frank Kayser, Mutsuyoshi Matsushita, Takashi Inaba, Rebekah Choi, Shoichi Sagawa, Nobuya Ogawa, Daisuke Tomimoto, Hidekazu Ozeki, Marc Labelle, Guosen Ye, Atsuhito Yoshida, Chihiro Okuma, Kiyosei Iio, Simon Jackson, Shichang Miao, Brian M. Fox, Noboru Furakawa, Dustin McMinn, and Ji Ma
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Metabolite ,Oxazines ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Acyl-CoA ,chemistry.chemical_compound ,Dogs ,In vivo ,Drug Discovery ,Animals ,Structure–activity relationship ,Aspartate Aminotransferases ,Diacylglycerol O-Acyltransferase ,Enzyme Inhibitors ,Triglycerides ,chemistry.chemical_classification ,Triglyceride ,Drug discovery ,Alanine Transaminase ,Macaca mulatta ,High-Throughput Screening Assays ,Rats ,Mice, Inbred C57BL ,chemistry ,Biochemistry ,Molecular Medicine ,Diacylglycerol Acyltransferase - Abstract
The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.
- Published
- 2014
15. JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits improved transrepression/transactivation dissociation
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Takashi Nakagawa, Atsuko Miyai, Takayuki Yamaguchi, Yuki Bessho, Katsuya Deai, Takahiro Hata, Yoshinori Kosugi, Mutsuyoshi Matsushita, Takafumi Kurimoto, Isao Tamai, Shohei Misaki, Yasuo Yamamoto, and Tamotsu Negoro
- Subjects
0301 basic medicine ,Transcriptional Activation ,medicine.medical_specialty ,Aminopyridines ,Pharmacology ,Non steroidal ,03 medical and health sciences ,chemistry.chemical_compound ,Transactivation ,Mice ,Glucocorticoid receptor ,Receptors, Glucocorticoid ,In vivo ,Internal medicine ,medicine ,Fosdagrocorat ,Animals ,RNA, Messenger ,Transrepression ,Tyrosine Transaminase ,Mice, Inbred BALB C ,Trifluoromethyl ,In vitro toxicology ,Phenanthrenes ,030104 developmental biology ,Endocrinology ,chemistry ,Hepatocytes ,Female ,Phenanthrolines - Abstract
Classic glucocorticoids that have outstanding anti-inflammatory effects are still widely prescribed for the treatment of various inflammatory and autoimmune diseases. Conversely, glucocorticoids cause numerous unwanted side effects, particularly systemically dosed glucocorticoids. Therefore, selective glucocorticoid receptor modulator (SGRM), which maintains beneficial anti-inflammatory effects while reducing the occurrence of side effects, is one of the most anticipated drugs. However, there have been no SGRMs marketed to date. The assumption is that there are two major mechanisms of action of glucocorticoids via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, the anti-inflammatory effects of glucocorticoids are mostly mediated through TR, while the side effects associated with glucocorticoids are largely caused by TA. We started to evaluate novel orally available SGRMs that maintain anti-inflammatory effects while minimizing adverse effects by favoring TR over TA. Based on this evaluation, we discovered JTP-117968, (4b'S,7'R,8a'S)-4b'-benzyl-7'-hydroxy-N-(2-methylpyridin-3-yl)-7'-(trifluoromethyl)-4b',6',7',8',8a',10'-hexahydro-5'H-spiro[cyclopropane-1,9'-phenanthrene]-2'-carboxamide, a non-steroidal SGRM. JTP-117968 has partial TR activity, but exhibits extremely low TA activity. The maximum TR efficacy of JTP-117968 was comparable to its structural analogue, PF-802, (4bS,7R,8aR)-4b-Benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide, which is the active form of Fosdagrocorat that has been developed clinically as a first-in-class orally available SGRM. Remarkably, the TA activity of JTP-117968 was much weaker than PF-802 not only in in vitro assays, but also in in vivo mice experiments. These findings indicate that JTP-117968 exhibits improved TR/TA dissociation because the compound has significantly lower TA activity compared with an already reported SGRM. Therefore, JTP-117968 is expected to be a useful compound for evaluating ideal SGRMs in the future.
- Published
- 2016
16. JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor
- Author
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Kenji Fukui, Hiromi Yoshiuchi, Hatsue Kobayashi, Mutsuyoshi Matsushita, Masaomi Nangaku, Takuya Matsui, Tetsuhiro Tanaka, Yuichi Shinozaki, Akira Matsuo, and Katsuya Deai
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,medicine.medical_specialty ,Pyridines ,Vascular permeability ,Cell Line ,Hypoxia-Inducible Factor-Proline Dioxygenases ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Humans ,Erythropoiesis ,RNA, Messenger ,Receptor ,Erythropoietin ,Pharmacology ,Dose-Response Relationship, Drug ,Protein Stability ,Prolyl-Hydroxylase Inhibitors ,Retinal ,Triazoles ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,Rats ,Vascular endothelial growth factor ,030104 developmental biology ,Endocrinology ,chemistry ,N-substituted Glycines ,Hemoglobin ,medicine.symptom ,030217 neurology & neurosurgery ,medicine.drug - Abstract
JTZ-951 (enarodustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. JTZ-951 has inhibitory activities on human HIF-prolyl hydroxylase 1-3, but not on various receptors or enzymes. In Hep3B cells, JTZ-951 increased HIF-1α and HIF-2α protein levels, erythropoietin (EPO) mRNA levels, and EPO production. In normal rats, after a single oral dose of JTZ-951, the hepatic and renal EPO mRNA levels and plasma EPO concentrations were also increased. In 5/6-nephrectomized rats, repeated oral doses of JTZ-951 once daily or intermittent dosing showed the erythropoiesis stimulating effect. The administration of JTZ-951 at a high dose increased plasma vascular endothelial growth factor (VEGF) levels; however, retinal VEGF mRNA levels and the retinal vascular permeability were not changed. Finally, we evaluated the effect of JTZ-951 in a colorectal cancer cell-inoculated mouse model. Although JTZ-951 at a high dose increased the plasma VEGF, it had no effect on tumor growth. In summary, JTZ-951 induces erythropoiesis without affecting VEGF function. Therefore, it is expected that JTZ-951 will be a new oral candidate that increases and maintains hemoglobin concentrations in renal anemia patients.
- Published
- 2019
17. Pharmacological Characterization of (3S)-3-(Hydroxymethyl)-4-(5-Methylpyridin-2-yl)-N-[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-3,4-Dihydro-2H-Benzo[b][1,4]Oxazine-8-Carboxamide (JTS-653), a Novel Transient Receptor Potential Vanilloid 1 Antagonist
- Author
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Masashi Wada, Katsuya Deai, Mikio Hayashi, Masahiro Sakata, Atsuko Miyai, Kenji Usui, Yuji Hamada, Makoto Tominaga, Yoshihisa Koga, Yoshihiro Kitagawa, and Mutsuyoshi Matsushita
- Subjects
Pharmacology ,Stereochemistry ,Antagonist ,Resiniferatoxin ,TRPV1 ,chemistry.chemical_compound ,Transient receptor potential channel ,chemistry ,In vivo ,Hyperalgesia ,medicine ,Molecular Medicine ,Hydroxymethyl ,medicine.symptom ,Receptor - Abstract
Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3 S )-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)- N -[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2 H -benzo[ b ][1,4]oxazine-8-carboxamide (JTS-653), a novel TRPV1 antagonist. JTS-653 displaced [ 3 H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with p A 2 values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC 50 values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC 50 values of 1.4 nM. JTS-653 showed weak or no inhibitory effects on other TRP channels, receptors, and enzymes. JTS-653 significantly prevented capsaicin-induced mechanical hyperalgesia at 1 mg/kg p.o. and attenuated carrageenan-induced mechanical hyperalgesia at 0.3 mg/kg p.o. JTS-653 significantly attenuated carrageenan-induced thermal hyperalgesia at 0.1 mg/kg p.o. and fully reversed at 0.3 mg/kg p.o. without affecting the volume of the carrageenan-treated paw. JTS-653 showed a transient increase of body temperature at 0.3 mg/kg p.o. These results indicated that JTS-653 is a highly potent and selective TRPV1 antagonist in vitro and in vivo and suggested that JTS-653 is one of the most potent TRPV1 antagonists. The profiles of JTS-653, high potency in vivo and transient hyperthermia, seem to be associated with polymodal inhibition of TRPV1 activation.
- Published
- 2012
18. Diabetic Peripheral Neuropathy in Spontaneously Diabetic Torii-Leprfa (SDT Fatty) Rats
- Author
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Eimei Sato, Tomohiko Sasase, Mutsuyoshi Matsushita, Daisuke Tomimoto, Yusuke Kemmochi, Takayuki Yamaguchi, Yasuko Mera, Hironobu Tadaki, and Takeshi Ohta
- Subjects
medicine.medical_specialty ,General Veterinary ,business.industry ,Motor nerve conduction velocity ,Sural nerve ,Type 2 diabetes ,medicine.disease ,Nerve conduction velocity ,Animal model ,Peripheral neuropathy ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,business ,Pioglitazone ,medicine.drug - Abstract
Spontaneously Diabetic Torii (SDT) rat is a hereditary model of diabetes. Although the SDT rat shows severe diabetic complications, the onset of hyperglycemia is late. SDT fatty rat, established by introducing the fa allele of the Zucker fatty rat to SDT rat, develops diabetes much faster than SDT rat. In the present study, diabetic peripheral neuropathy (DPN) was evaluated to show the further usefulness of this animal model. Motor nerve conduction velocity (MNCV) was delayed, and the number of sural nerve fibers was decreased in SDT fatty rat. Treatment of pioglitazone lowered blood glucose level and prevented delay of MNCV in SDT fatty rats. SDT fatty rat is a useful animal model for studies of DPN in type 2 diabetes.
- Published
- 2012
19. Changes in protein tyrosine phosphatase activity in Spontaneously Diabetic Torii (SDT) rats
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Eimei Sato, Mutsuyoshi Matsushita, Hisayo Morinaga, akeshi Ohta, Takayuki Yamaguchi, and Takahiro Hata
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Diabetes mellitus ,Protein tyrosine phosphatase activity ,Medicine ,PTPase activity ,Protein tyrosine phosphatase ,Tyrosine ,business ,medicine.disease - Abstract
The Spontaneously Diabetic Torii (SDT) rat is a nonobese type 2 diabetic model, showing the overt hyperglycemia after about 16 weeks of age. In this study, we investigated the protein tyrosine phosphatase (PTPase) activities in insulin-sensitive tissues in SDT rats. PTPase activities in the liver, muscle, and fat were examined at 8 weeks (pre-diabetes), 16 weeks (onset-diabetes), and 24 weeks (diabetes). SDT rats showed glucose intolerance at 8 weeks and hyperglycemia after 16 weeks. The PTPase activities in fat increased at 8 weeks and the increase was sustained to 24 weeks. In the liver, PTPase activities increased only at 24 weeks. On the other hand, the PTPase activities in muscle did not change. The increase of PTPase activity in fat might be related to progression of glucose intolerance and diabetes in SDT rats.
- Published
- 2012
20. Elevated glucagon-like peptide-1 on a high-fat diet feeding prevents the incidence of diabetes mellitus in Spontaneously Diabetic Torii Leprfa rats
- Author
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Takahiro Hata, Mutsuyoshi Matsushita, Gimpei Tanoue, Katsuhiro Miyajima, Takayuki Yamaguchi, Takeshi Ohta, Eimei Sato, Yasuko Mera, Tomohiko Sasase, and Yukihito Ishii
- Subjects
medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Fatty liver ,Adipose tissue ,Type 2 diabetes ,medicine.disease ,Glucagon-like peptide-1 ,Endocrinology ,Fat diet ,Incretin Hormone ,Diabetes mellitus ,Internal medicine ,medicine ,business - Abstract
Nutritional regulation plays a critical role to reduce the incidence or progression of diabetes mellitus. In this study, we investigated the effects of a high-fat diet on Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a novel model for obese type 2 diabetes. The SDT fatty rats were divided into two dietary groups, which were fed a high-fat diet or a standard diet for 18 weeks, from 6 to 24 weeks of age. The calorie intake in the high-fat diet (HF) group was reduced after 10 weeks of age and the group inhibited an incidence of diabetes. Interestingly, the HF induced an increase of serum glucagon-like peptide-1 (GLP-1) levels in SDT fatty rats with refeeding. Fat tissue weights in the HF group increased, but the visceral fat/subcutaneous fat (V/S) ratio decreased. Moreover, histopathological observations revealed an improvement of the pancreatic abnormalities and fatty liver in the HF group. In conclusion, a preventive effect on diabetes in rats fed a high-fat diet has a relation with an increase in incretin hormone, and it might be advantageous for prevention of incidence or progression of diabetes to develop functional foods inducing an increase in incretin hormone.
- Published
- 2012
21. The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR–IL-1R by controlling degradation of regnase-1
- Author
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Daron M. Standley, Hidenori Iwasaki, Takuya Uehata, Tatsuya Saitoh, Takashi Satoh, Kanako Kuniyoshi, Shunsuke Teraguchi, Kazufumi Matsushita, Shizuo Akira, Osamu Takeuchi, and Mutsuyoshi Matsushita
- Subjects
Untranslated region ,RNA Stability ,Amino Acid Motifs ,Immunology ,IκB kinase ,Biology ,Models, Biological ,Mice ,Ribonucleases ,Transcription (biology) ,Cell Line, Tumor ,Animals ,Humans ,Immunology and Allergy ,RNA, Messenger ,Transcription factor ,Mice, Knockout ,Regulation of gene expression ,Messenger RNA ,Interleukin-6 ,Kinase ,Toll-Like Receptors ,Receptors, Interleukin-1 ,Molecular biology ,I-kappa B Kinase ,IκBα ,HEK293 Cells ,Interleukin-1 Receptor-Associated Kinases ,Gene Expression Regulation ,Cytokines ,HeLa Cells ,Protein Binding - Abstract
Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.
- Published
- 2011
22. Pharmacological profiles of a novel protein tyrosine phosphatase 1B inhibitor, JTT-551
- Author
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Nakagawa Yuichi, Takeshi Ohta, Makoto Ito, Mutsuyoshi Matsushita, Hisayo Morinaga, Sumiaki Fukuda, Shohei Sakata, and Michiru Tanaka
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,Glycine ,Mice, Obese ,Protein tyrosine phosphatase ,Carbohydrate metabolism ,Cell Line ,Mice ,Endocrinology ,In vivo ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Hypoglycemic Agents ,Enzyme Inhibitors ,Phosphorylation ,Receptor ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,biology ,business.industry ,Receptor, Insulin ,Rats ,Thiazoles ,Insulin receptor ,Diabetes Mellitus, Type 2 ,Liver ,biology.protein ,Signal transduction ,business ,Signal Transduction - Abstract
Aim: Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signalling, is a novel therapeutic target for type 2 diabetes mellitus. We evaluated in vitro and in vivo the pharmacological profiles of a new PTP1B inhibitor, JTT-551: monosodium ({[5-(1,1-dimethylethyl)thiazol-2-yl]methyl} {[(4-{4-[4-(1-propylbutyl)phenoxy]methyl}phenyl)thiazol-2-yl]methyl}amino)acetate. Methods: PTP1B inhibitory activity and the inhibition mode were assayed with p-nitrophenyl phosphate as a substrate, and the selectivity of JTT-551 against other PTPs, including T-cell protein tyrosine phosphatase (TCPTP), CD45 protein tyrosine phosphatase (CD45) and leucocyte common antigen-related protein tyrosine phosphatase (LAR), was evaluated. Glucose uptake with JTT-551 treatment was evaluated in L6 rat skeletal myoblasts (L6 cells). In the in vivo study, we investigated the effects on insulin receptor (IR) phosphorylation and blood chemical parameters with JTT-551 administration in ob/ob mice and db/db mice. Results: JTT-551 showed an inhibitory effect on PTP1B with a Ki value of 0.22 µM, and a mixed-type inhibition mode. Ki values of TCPTP, CD45 and LAR were 9.3, 30 or higher and 30 or higher µM, respectively, and JTT-551 exhibited clear selectivity against the other PTPs. Moreover, JTT-551 increased the insulin-stimulated glucose uptake in L6 cells. A single administration of JTT-551 in ob/ob mice enhanced the IR phosphorylation of liver and reduced the glucose level. In db/db mice, chronic administration showed a hypoglycaemic effect without an acceleration of body weight gain. Conclusions: JTT-551, a newly developed PTP1B inhibitor, improves glucose metabolism by enhancement of insulin signalling and could be useful in the treatment of type 2 diabetes mellitus.
- Published
- 2010
23. Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage
- Author
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Emiko Nishizawa, Kenichi Matsui, Tomohiko Sasase, Takeshi Ohta, Mutsuyoshi Matsushita, Tomohiro Oda, Ryuhei Sano, Nobuhisa Ueda, Katsuhiro Miyajima, Hiromi Yamamoto, Yukihito Ishii, and Sumiaki Fukuda
- Subjects
Male ,medicine.medical_specialty ,Tolbutamide ,medicine.medical_treatment ,Type 2 diabetes ,Arginine ,Benzoates ,Glucagon ,General Biochemistry, Genetics and Molecular Biology ,Rats, Sprague-Dawley ,Islets of Langerhans ,Organ Culture Techniques ,Glucagon-Like Peptide 1 ,Internal medicine ,Diabetes mellitus ,Insulin Secretion ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Obesity ,Enzyme Inhibitors ,Pancreas ,Dipeptidyl-Peptidase IV Inhibitors ,Glucose tolerance test ,General Veterinary ,medicine.diagnostic_test ,business.industry ,Body Weight ,General Medicine ,Glucose Tolerance Test ,medicine.disease ,Glucagon-like peptide-1 ,Peptide Fragments ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Diabetes Mellitus, Type 2 ,Animal Science and Zoology ,business ,medicine.drug - Abstract
The Spontaneously Diabetic Torii (SDT) rat is a new model for non-obese type 2 diabetes. In the present study, we investigated changes in insulin secretion from the pancreas of male SDT rats aged 8, 16, and 24 weeks in order to analyze pancreatic function. An analysis of glucose-stimulated insulin secretion (GSIS) in isolated islets showed a marked reduction in insulin secretion in pre-diabetic 16-week-old SDT rats. When the islets were treated with tolbutamide or glucagon-like peptide-1 (7-36) amide (tGLP-1) in the presence of 11.2 mM glucose, however, insulin levels were restored to levels of normal rats. In vivo study, SDT rats exhibited a marked reduction in GSIS from 16 weeks of age. However, tolbutamide or JTP-76209, which is a novel dipeptidyl peptidase IV (DPP IV) inhibitor, increased insulin release after glucose loading and improved glucose tolerance. A marked reduction in GSIS was observed in pre-diabetic SDT rats and the reduction was improved by tolbutamide, tGLP-1, and the DPP IV inhibitor. Therefore, we concluded that the SDT rat is useful, as a model of non-obese insulin secretory disorder, for the analysis of the onset of type 2 diabetes and the development of antidiabetic agents.
- Published
- 2009
24. Characterization of Hepatic Glucose Metabolism Disorder with the Progress of Diabetes in Male Spontaneously Diabetic Torii Rats
- Author
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Hisayo Morinaga, Kaoru Sakata, Tomohiko Sasase, Sumiaki Fukuda, Katsuhiro Miyajima, Hiromi Yamamoto, Makoto Ito, Mutsuyoshi Matsushita, Nobuhisa Ueda, and Takeshi Ohta
- Subjects
Male ,Aging ,medicine.medical_specialty ,Type 2 diabetes ,Prediabetic State ,Glycogen phosphorylase ,chemistry.chemical_compound ,Internal medicine ,Diabetes mellitus ,Glucokinase ,Glucose Intolerance ,Animals ,Hypoglycemic Agents ,Insulin ,Medicine ,RNA, Messenger ,Triglycerides ,DNA Primers ,chemistry.chemical_classification ,General Veterinary ,Glycogen ,business.industry ,Gluconeogenesis ,Rats, Inbred Strains ,Metabolism ,medicine.disease ,Rats ,Metabolism disorder ,Cholesterol ,Diabetes Mellitus, Type 1 ,Enzyme ,Endocrinology ,Liver ,chemistry ,Disease Progression ,business - Abstract
The Spontaneously Diabetic Torii (SDT) rat has recently been established as a new model of non-obese type 2 diabetes. In this study, we examined changes in hepatic glucose metabolism in prediabetic and diabetic SDT rats compared with age-matched control rats. The prediabetic state was confirmed at 16 weeks of age, and the diabetic state was confirmed at 24 and 32 weeks of age. Decreases in glucokinase mRNA levels and activity were observed in the prediabetic state. In this state, glycogen synthase activity and glycogen content were also decreased in the SDT rat. In addition to the above changes, glycogen phosphorylase mRNA and activity were decreased and gluconeogenetic enzyme mRNA levels were significantly increased in the diabetic state. These results indicate there is a great potential that abnormalities in hepatic glucose metabolism play a role in the progression to onset of diabetes. We suggest that the SDT rat is a valuable diabetic model for investigations into mechanisms or causes of progression to diabetes.
- Published
- 2008
25. Diabetes-Associated Complications in Spontaneously Diabetic Torii Fatty Rats
- Author
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Tomohiro Oda, Masami Shinohara, Mutsuyoshi Matsushita, Taku Masuyama, Kenichi Matsui, Nobuhisa Ueda, Tomohiko Sasase, Takeshi Ohta, and Katsuhiro Miyajima
- Subjects
Male ,medicine.medical_specialty ,Renal function ,Type 2 diabetes ,Cataract ,Rats, Mutant Strains ,General Biochemistry, Genetics and Molecular Biology ,Diabetes Complications ,Diabetic nephropathy ,Diabetes mellitus ,Internal medicine ,Hyperlipidemia ,Electroretinography ,medicine ,Animals ,Diabetic Nephropathies ,Obesity ,Pathological ,Blood urea nitrogen ,Diabetic Retinopathy ,General Veterinary ,business.industry ,Age Factors ,General Medicine ,medicine.disease ,Rats ,Disease Models, Animal ,Endocrinology ,Diabetes Mellitus, Type 2 ,Animal Science and Zoology ,business ,Erg - Abstract
The Spontaneously Diabetic Torii (SDT) fatty rat, established by introducing the fa allele of the Zucker fatty rat into the SDT rat genome, is a new model of obese type 2 diabetes. The SDT-fa/fa (SDT fatty) rat shows overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with the SDT-+/+ (SDT normal) rat. However, the features of the diabetic complications in the SDT fatty rat have not been reported. In the present study, the incidence and the progression of diabetic complications in the SDT fatty rat were examined, and compared with those of the SDT normal rat. Renal function parameters, such as blood urea nitrogen, urine volume and urinary protein, increased from 4 weeks of age in the SDT fatty rat, and pathological findings in the renal tubule were observed from 8 weeks. Furthermore, cataract was observed in the SDT fatty rat from 8 weeks of age, and prolongation of peak latencies on electroretinograms was observed at 16 and 24 weeks of age. On the other hand, in the SDT normal rat, renal or ocular changes were observed from 24 weeks of age. With early incidence of diabetes mellitus, diabetes-associated complications in the SDT fatty rat were seen at younger ages than those in the SDT normal rat. In conclusion, the SDT fatty rat is expected to be a useful model for the analysis of diabetic complications and the evaluation of drugs related to metabolic diseases.
- Published
- 2008
26. Increased fat absorption and impaired fat clearance cause postprandial hypertriglyceridemia in Spontaneously Diabetic Torii rat
- Author
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Katsuhiro Miyajima, Hiromi Yamamoto, Masami Shinohara, Hisayo Morinaga, Mutsuyoshi Matsushita, Tomohiko Sasase, Takeshi Ohta, Taku Masuyama, Kenichi Matsui, Takashi Kawai, Naoto Ogawa, and Yasuko Mera
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Rats, Mutant Strains ,Hypoinsulinemia ,Diabetes mellitus genetics ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Chylomicrons ,Hyperlipidemia ,Diabetes Mellitus ,Internal Medicine ,medicine ,Animals ,Plant Oils ,RNA, Messenger ,Olive Oil ,Triglycerides ,Triglyceride ,business.industry ,Body Weight ,Hypertriglyceridemia ,Lipid metabolism ,General Medicine ,medicine.disease ,Dietary Fats ,Lipids ,Rats ,Postprandial ,Intestinal Absorption ,chemistry ,Hyperglycemia ,Energy Intake ,business ,Chylomicron - Abstract
In diabetes, postprandial hyperlipidemia is recognized as a risk factor for premature atherosclerosis and following cardiovascular disease. In the present study, features of fat absorption and clearance were examined to clarify the lipid metabolism of Spontaneously Diabetic Torii (SDT) rats. Olive oil was orally administered to evaluate increase of blood triglyceride (TG) level. Mesenteric lymph chylomicron TG was also measured. mRNAs of enzymes and transfer protein related to TG metabolism and histopathological changes were evaluated. In an oil loading test, elevation of TG in plasma and lymph chylomicron was increased in SDT rats. Interestingly, SDT rats showed elevation of plasma TG after oil loading and relatively low epididymal fat lipoprotein lipase (LPL) mRNA expression even at the pre-diabetic state without increase of TG absorption from intestine. In the diabetic state, intestines of SDT rats were hypertrophic and expressed mRNAs of enzymes and transfer protein related to TG absorption highly. From these results, it seems that intestinal abnormalities related to hypoinsulinemia/hyperglycemia cause postprandial hypertriglyceridemia in SDT rats. In addition, our findings suggest that SDT rats have impaired lipid catabolism antecedent to hypoinsulinemia/hyperglycemia. These characteristics of SDT rats can be useful in studies of diabetic hypertriglyceridemia and TG metabolism.
- Published
- 2007
27. Effect of Insulin Therapy on Renal Changes in Spontaneously Diabetic Torii Rats
- Author
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Mutsuyoshi Matsushita, Kenichi Matsui, Toshiyuki Shoda, Tomohiko Sasase, Haruko Koizumi, Katsuhiro Miyajima, Takeshi Ohta, Taku Masuyama, and Masami Shinohara
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Type 2 diabetes ,Kidney ,urologic and male genital diseases ,General Biochemistry, Genetics and Molecular Biology ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,Diabetic nephropathy ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Insulin ,Diabetic Nephropathies ,General Veterinary ,business.industry ,Glomerular basement membrane ,Rats, Inbred Strains ,General Medicine ,medicine.disease ,Rats ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Mesangial proliferative glomerulonephritis ,Animal Science and Zoology ,Histopathology ,business - Abstract
The spontaneously diabetic Torii (SDT) rat has recently been established as an animal model of non-obese type 2 diabetes, in which ocular complications severe occur. However, the function and morphological features of the diabetic renal lesions in SDT rats have not been reported in detail. Therefore, we evaluated changes over time in renal lesions in SDT rats. In addition, SDT rats were treated with insulin to observe whether these renal complications are caused by hyperglycemia. Renal functional parameters and renal lesions were monitored in SDT rats from 8 to 68 weeks of age. Sprague-Dawley (SD) rats of similar age were used as control animals. In the insulin-treated group of SDT rats, insulin pellets were implanted at 24 weeks of age to compare the development of renal lesions. The SDT rats began to develop hyperglycemia at 20 weeks of age. In the histopathological examination of the kidney, glycogen deposition of the renal tubular epithelium and renal tubular dilation were observed from 24 weeks of age in the untreated SDT rats, and the changes in the renal tubules markedly progressed with aging. Moreover, thickening of the glomerular basement membrane was observed from 32 weeks of age. At 50 weeks of age, the glomeruli showed increase of mesangial matrix, with predominantly diffuse lesions showing by 68 weeks of age. The mesangial proliferation gradually progressed. In the SD rats, no renal lesions were present at 50 and 68 weeks of age. SDT rats with insulin treatment remained normoglycemic throughout observation and their renal functional parameters were normal. Glycemic control in SDT rats prevented the development of renal lesions. The features of SDT rats indicate their usefulness as an animal model for investigating diabetic nephropathy.
- Published
- 2007
28. Preventive effects of glycaemic control on ocular complications of Spontaneously Diabetic Torii rat
- Author
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Hisayo Morinaga, Takeshi Ohta, Makoto Ito, Nobuya Ogawa, Katsuhiro Miyajima, Hiromi Yamamoto, Mutsuyoshi Matsushita, and Tomohiko Sasase
- Subjects
Blood Glucose ,Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,genetic structures ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Diabetes Mellitus, Experimental ,Aqueous Humor ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Electroretinography ,Internal Medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Medicine ,Diabetic Retinopathy ,medicine.diagnostic_test ,business.industry ,Aqueous humour ,Retinal Vessels ,Rats, Inbred Strains ,Retinal ,Diabetic retinopathy ,medicine.disease ,eye diseases ,Rats ,Vascular endothelial growth factor ,Disease Models, Animal ,Diabetes Mellitus, Type 2 ,chemistry ,sense organs ,business ,Retinopathy - Abstract
Aim: Spontaneously Diabetic Torii (SDT) rat is a new model of non-obese type 2 diabetes. SDT rats show severe ocular complications such as cataracts, tractional retinal detachment with fibrous proliferation and massive haemorrhaging in the anterior chamber. In the present study, blood glucose levels of SDT rats were controlled in order to examine whether these ocular complications are caused by hyperglycaemia. Methods: SDT rats were treated with an insulin implant to control blood glucose. To evaluate retinal function, we used electroretinograms (ERG) and measured vascular endothelial growth factor (VEGF) concentrations within the aqueous humour. Finally, we studied retinal flat-mounts and trypsin digestion to evaluate vascular abnormalities in SDT rats. Results: Forty-four-week-old SDT rats displayed an increase in VEGF concentrations within the aqueous humour and significant prolongation of the peak latencies in ERG (Σ(OP1–OP4); Sprague–Dawley (SD): 146.2 ± 1.06 ms; SDT: 166.3 ± 2.38 ms; SDT + insulin: 149.2 ± 1.83 ms). Retinal flat-mounts of SDT rats showed venous dilation and meandering vascular networks. Furthermore, acellular capillaries were observed in the retinal trypsin digestion. Insulin treatment prevented these ocular abnormalities in SDT rats. Conclusions: These findings indicate that ocular complications of SDT rats are caused by hyperglycaemia. The features of SDT rats indicate their usefulness for the future study of diabetic retinopathy.
- Published
- 2006
29. Parathyroid Hormone (1-34) Improves Bone Mineral Density and Glucose Metabolism in Spontaneously Diabetic Torii-Leprfa Rats
- Author
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Takeshi Ohta, Shuichi Kimura, Mutsuyoshi Matsushita, Tomohiko Sasase, and Eimei Sato
- Subjects
Blood Glucose ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Bone density ,medicine.medical_treatment ,Blood sugar ,Parathyroid hormone ,Blood serum ,Bone Density ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,medicine ,Animals ,Bone mineral ,General Veterinary ,biology ,business.industry ,musculoskeletal, neural, and ocular physiology ,Insulin ,Rats, Inbred Strains ,musculoskeletal system ,medicine.disease ,Rats ,Glucose ,Endocrinology ,Parathyroid Hormone ,Osteocalcin ,biology.protein ,business - Abstract
The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a model of obese type 2 diabetes, shows obesity, hyperglycaemia and low bone mineral density (BMD). The objective of this study is to evaluate the effects of parathyroid hormone (1-34) [PTH(1-34)] on BMD and glucose metabolism in the SDT-fa/fa rat. SDT-fa/fa rats showed obesity with hyperglycaemia and decreased serum osteocalcin levels and the tibial BMD. A 4-week treatment of PTH(1-34) (20 µg/kg/day) increased the serum osteocalcin levels and the tibial BMD, and decreased the serum glucose levels without changing the serum insulin levels. These findings indicate that PTH(1-34) improved not only BMD but also glucose metabolism in SDT-fa/fa rats. This study suggests that PTH(1-34) is a novel agent for the treatment of diabetic osteoporosis.
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- 2012
30. JTE-522 selectively inhibits cyclooxygenase-2-derived prostaglandin production in inflammatory tissues
- Author
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H. Tazaki, Hiroyuki Iwamura, Korekiyo Wakitani, and Mutsuyoshi Matsushita
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Male ,Immunology ,Prostaglandin ,Inflammation ,Pharmacology ,Carrageenan ,Dinoprostone ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,In vivo ,medicine ,Gastric mucosa ,Animals ,Edema ,Cyclooxygenase Inhibitors ,Oxazoles ,Whole blood ,Gastrointestinal tract ,Cyclooxygenase 2 Inhibitors ,biology ,Foot ,business.industry ,Benzenesulfonates ,Rats ,Isoenzymes ,Thromboxane B2 ,medicine.anatomical_structure ,chemistry ,Cyclooxygenase 2 ,Gastric Mucosa ,Prostaglandin-Endoperoxide Synthases ,Macrophages, Peritoneal ,Prostaglandins ,biology.protein ,Cyclooxygenase ,medicine.symptom ,business - Abstract
Objective and Design: To investigate the effect of JTE-522, a selective cyclooxygenase (COX)-2 inhibitor, on prostaglandin (PG) production and COX expression in rats.¶Subjects: Male rats (4-8 weeks old) were used for in vivo experiments, while for in vitro assay, rat peritoneal macrophages were used.¶Treatment: JTE-522 (1-100mg/kg) and indomethacin (0.03-10mg/kg) were administered orally. JTE-522 and reference compounds (0.01-10 μM) were subjected to COX expression.¶Results: JTE-522 inhibited the development of carrageenin-induced paw edema and PGE2 production in inflammatory paws at a dose of 10mg/kg. On the other hand, JTE-522 (1-100 mg/kg) did not affect A23187-stimulated thromboxane B2 release from whole blood or the PGE2 level in gastric mucosa. JTE-522 did not suppress lipopolysaccharide-induced COX-2 expression in peritoneal macrophages.¶Conclusion: These results indicate that JTE-522 selectively inhibits PG production mediated by COX-2 in inflammatory tissues. JTE-522 may thus represent a novel type of anti-inflammatory drug without adverse effects on the gastrointestinal tract.
- Published
- 2000
31. Profile of JTE-522 as a Human Cyclooxygenase-2 Inhibitor
- Author
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Toyomichi Nanayama, Michiko Masaki, Korekiyo Wakitani, and Mutsuyoshi Matsushita
- Subjects
Lipopolysaccharides ,Time Factors ,Pharmacology ,Peripheral blood mononuclear cell ,Dinoprostone ,chemistry.chemical_compound ,medicine ,Humans ,Cyclooxygenase Inhibitors ,Platelet ,Prostaglandin E2 ,Oxazoles ,IC50 ,Cyclooxygenase 2 Inhibitors ,biology ,Benzenesulfonates ,Membrane Proteins ,Enzyme assay ,Isoenzymes ,Thromboxane B2 ,chemistry ,Mechanism of action ,Cyclooxygenase 2 ,Prostaglandin-Endoperoxide Synthases ,Cyclooxygenase 1 ,Leukocytes, Mononuclear ,biology.protein ,Cyclooxygenase ,medicine.symptom ,medicine.drug - Abstract
Inhibitory activity and the mechanism of action of JTE-522 (4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamid e), a novel selective cyclooxygenase (COX)-2 inhibitor, on human COX-1 and COX-2 were investigated and compared with those of reference compounds. In an enzyme assay, JTE-522 inhibited yeast-expressed human recombinant COX-2 with an IC50 value of 0.085 microM. In contrast, JTE-522 did not inhibit human COX-1 prepared from human platelets at concentrations up to 100 microM. In a cell-based assay, JTE-522 diminished lipopolysaccharide-induced prostaglandin E2 production in human peripheral blood mononuclear cells (COX-2) (IC50 value = 15.1 nM). On the other hand, JTE-522 was less potent at inhibiting calcium ionophore-induced thromboxane B2 production in washed human platelets (COX-1) (IC50 value = 6210 nM). JTE-522 showed highly selective inhibition of human COX-2, and its activity was more selective than that of other COX-2 inhibitors (NS-398 and SC-58635). Human recombinant COX-2 activity was attenuated by JTE-522 in a dose-dependent and time-dependent manner. In contrast, the inhibitory activity of JTE-522 on human COX-1 was not affected by preincubation time. COX-2 inhibition by JTE-522 could not be recovered by gel filtration. These results indicate that JTE-522 is a highly selective, time-dependent and irreversible inhibitor of human COX-2.
- Published
- 1998
32. Pharmacological profile of JTE-522, a novel prostaglandin H synthase-2 inhibitor, in rats
- Author
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Mutsuyoshi Matsushita, Y. Yagi, Michiko Masaki, T. Tanaka, and Korekiyo Wakitani
- Subjects
Male ,Indomethacin ,Immunology ,Administration, Oral ,Arthritis ,Pharmacology ,Carrageenan ,Rats, Sprague-Dawley ,In vivo ,Edema ,Animals ,Medicine ,Cyclooxygenase Inhibitors ,Antipyretic ,Rats, Wistar ,Oxazoles ,IC50 ,ED50 ,Gastrointestinal tract ,Cyclooxygenase 2 Inhibitors ,Dose-Response Relationship, Drug ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Benzenesulfonates ,Membrane Proteins ,medicine.disease ,Arthritis, Experimental ,Rats ,Isoenzymes ,Disease Models, Animal ,Cyclooxygenase 2 ,Hyperalgesia ,Prostaglandin-Endoperoxide Synthases ,Rats, Inbred Lew ,Cyclooxygenase 1 ,medicine.symptom ,business ,medicine.drug - Abstract
Objective and Design: The antinociceptive, antipyretic, and anti-inflammatory effects of JTE-522, a novel selective prostaglandin H synthase (PGHS)-2 inhibitor, were examined in rats.¶Materials: Sheep seminal vesicle PGHS-1 and placenta PGHS-2 were used for in vitro assay, while for in vivo experiments, male rats (4–8 weeks old) were used.¶Treatment: JTE-522 and reference compounds (0.01–100 μM) were subjected to enzyme assay. JTE-522 (0.3–30 mg/kg) and indomethacin (0.3–10 mg/kg) were administered orally.¶Results: JTE-522 inhibited PGHS-2 (IC50: 0.64 μM) without affecting PGHS-1 activity at 100 μM. In rats with yeast-induced hyperalgesia, JTE-522 showed a dose-dependent antinociceptive effect (ED50: 4.4 mg/kg). In rats with yeast-induced pyrexia, JTE-522 significantly reversed the pyrexic response (ED50: 3.9 mg/kg). Orally administered JTE-522 dose-dependently inhibited carrageenin-induced rat paw edema (ED30: 4.7 mg/kg). In rats with adjuvant-induced arthritis, JTE-522 showed a significant inhibitory effect at daily doses of 0.3–3 mg/kg. JTE-522 did not cause severe gastric lesions at oral doses up to 300 mg/kg.¶Conclusions: Our results indicate that the selective PGHS-2 inhibitor JTE-522 may represent a novel type of anti-inflammatory drug without adverse effects on the gastrointestinal tract. JTE-522 may thus be a promising agent for treating both acute inflammatory diseases and chronic inflammatory diseases such as rheumatoid arthritis.
- Published
- 1997
33. Orally administered selective TRPV1 antagonist, JTS-653, attenuates chronic pain refractory to non-steroidal anti-inflammatory drugs in rats and mice including post-herpetic pain
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Yoshihiro Kitagawa, Masahiro Sakata, Kenji Usui, Mutsuyoshi Matsushita, Yuji Hamada, Isao Tamai, and Masashi Wada
- Subjects
Male ,Pyridines ,TRPV1 ,Administration, Oral ,Neuralgia, Postherpetic ,Pain ,TRPV Cation Channels ,Severity of Illness Index ,Rats, Sprague-Dawley ,Transient receptor potential channel ,Mice ,Refractory ,medicine ,Animals ,Molecular Targeted Therapy ,Pharmacology ,Analgesics ,business.industry ,lcsh:RM1-950 ,Anti-Inflammatory Agents, Non-Steroidal ,Chronic pain ,Antagonist ,medicine.disease ,Motor coordination ,Benzoxazines ,Rats ,Disease Models, Animal ,lcsh:Therapeutics. Pharmacology ,Nociception ,Non steroidal anti inflammatory ,Anesthesia ,Chronic Disease ,Molecular Medicine ,business - Abstract
Chronic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) is a major problem and drugs for such pain are needed. Many studies suggest that transient receptor potential vanilloid type 1 (TRPV1) is associated with NSAID-refractory chronic pain. Therefore, we investigated the involvement of TRPV1 in NSAID-refractory chronic pain using experimental models for NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. The selective TRPV1 antagonist JTS-653 {(3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide} reversed mechanical hyperalgesia on day 7 after injection of complete-Freund-adjuvant into the hindpaw in rats at 0.3 mg/kg, whereas indomethacin showed no effect. JTS-653 reduced chronic pain at 0.3 mg/kg in herpes simplex virus-1–inoculated mice that has been reported as NSAID-refractory pain. JTS-653 partially attenuated mechanical hyperalgesia in the L5 spinal nerve ligation model in rats at 0.3 mg/kg, whereas indomethacin showed no effect. Both JTS-653 and indomethacin reduced formalin-induced pain in the second phase, whereas they showed no effect in the first phase. JTS-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. These findings demonstrate the TRPV1 involvement in NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. TRPV1 antagonists would be useful for the treatment of NSAID-refractory chronic pain. Keywords:: transient receptor potential vanilloid type 1 (TRPV1), non-steroidal anti-inflammatory drug (NSAID), chronic pain, post-herpetic pain, herpes simplex virus-1 (HSV-1)
- Published
- 2013
34. JTE-852, a novel spleen tyrosine kinase inhibitor, blocks antigen-induced allergic reactions in rats.
- Author
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Toshinobu KATO, Takeshi OHTA, Hidenori IWASAKI, Hatsue KOBAYASHI, Akira MATSUO, Takahiro HATA, and Mutsuyoshi MATSUSHITA
- Subjects
PROTEIN-tyrosine kinase inhibitors ,ALLERGY in animals ,ALLERGY treatment ,ANTIGENS ,ANTIALLERGIC agents - Abstract
Conventional clinical treatments for allergy management remain suboptimal; new, orally available medications that improve a wide range of allergic signs have been desired. We previously demonstrated that JTE-852, a novel spleen tyrosine kinase inhibitor, potently and simultaneously suppresses secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by immunoglobulin E-crosslinking. In the present study, we investigated the effects of JTE-852 in four rat models (sneezing, rhinorrhea, airway constriction, and airway inflammation) as representatives of allergy models. Rats were sensitized and challenged with antigen. Allergic reactions developed after challenge were detected. JTE-852 and current anti-allergic drugs (ketotifen, pranlukast, and prednisolone) were administered orally before challenge. JTE-852 showed significant blocking effects on antigen-induced allergic reactions in all models, indicating that JTE-852 in oral dosage form would improve a wide range of allergic signs. The current anti-allergic drugs, on the other hand, failed to display significant suppression in several models. Because JTE-852 suppresses the secretion of all three groups of allergic mediators from mast cells, it would be capable of targeting signs that current drugs cannot sufficiently relieve. We anticipate JTE-852 to be a promising new anti-allergic drug that is potentially more effective than conventional drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
35. Ferric citrate hydrate, a new phosphate binder, prevents the complications of secondary hyperparathyroidism and vascular calcification
- Author
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Atsuhiro Uemura, Minako Tanimoto, Ken-ichi Miyamoto, Akio Iida, Yusuke Kemmochi, Mutsuyoshi Matsushita, Akira Matsuo, Kochi Kakimoto, Yuichi Shinozaki, and Takayuki Mimura
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,chemistry.chemical_element ,Ferric Compounds ,Phosphates ,Parathyroid Glands ,Rats, Sprague-Dawley ,Hyperphosphatemia ,Ectopic calcification ,Internal medicine ,medicine ,Animals ,Vascular Calcification ,Aorta ,Calcium metabolism ,Hyperparathyroidism ,business.industry ,Phosphorus ,medicine.disease ,Phosphate binder ,Rats ,Endocrinology ,chemistry ,Biochemistry ,Nephrology ,Secondary hyperparathyroidism ,Calcium ,Hyperparathyroidism, Secondary ,business ,Calcification - Abstract
Background/Aims: Ferric citrate hydrate (JTT-751) is being developed as a treatment for hyperphosphatemia in chronic kidney disease patients, and shows serum phosphorus-reducing effects on hyperphosphatemia in hemodialysis patients. We examined whether JTT-751 could reduce phosphorus absorption in normal rats and prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in chronic renal failure (CRF) rats. Methods: Normal rats were fed a diet containing 0.3, 1 or 3% JTT-751 for 7 days. The effects of JTT-751 on phosphorus absorption were evaluated with fecal and urinary phosphorus excretion. Next, a CRF model simulating hyperphosphatemia was induced by feeding rats a 0.75% adenine diet. After 21 days of starting the adenine diet feeding, 1 or 3% JTT-751 was administered for 35 days by dietary admixture. The serum phosphorus levels and mineral parameters were measured. Calcification in the aorta was examined biochemically and histopathologically. Hyperparathyroidism and bone abnormalities were evaluated by histopathological analysis of the parathyroid and femur, respectively. Results: In normal rats, JTT-751 increased fecal phosphorus excretion and reduced phosphorus absorption and urinary phosphorus excretion. In CRF rats, JTT-751 reduced serum phosphorus levels, the calcium-phosphorus product and calcium content in the aorta. Serum intact parathyroid hormone levels and the incidence and severity of parathyroid hyperplasia were also decreased. JTT-751 reduced femoral bone fibrosis, porosity and osteoid formation. Conclusions: JTT-751 could bind with phosphate in the gastrointestinal tract, increase fecal phosphorus excretion and reduce phosphorus absorption. JTT-751 could prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in rats.
- Published
- 2012
36. Effect of JTP-2942, a novel thyrotropin-releasing hormone analogue, on pentobarbital-induced anesthesia in rats
- Author
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Kunio Iwata, Mutsuyoshi Matsushita, Atsushi Hamada, Katsuo Toide, and Fumihiko Yonemori
- Subjects
Male ,medicine.medical_specialty ,Pentobarbital ,medicine.medical_treatment ,Peptide hormone ,Choline ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Thyrotropin-Releasing Hormone Analogue ,Anesthesia ,Rats, Wistar ,Antidote ,Thyrotropin-Releasing Hormone ,Brain Chemistry ,Pharmacology ,business.industry ,Acetylcholine ,Rats ,Endocrinology ,Analeptic ,chemistry ,Anesthetic ,business ,medicine.drug - Abstract
The effects of a novel thyrotropin-releasing hormone (TRH) analogue, Nα-((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)- L -histidyl- l -prolinamide monohydrate (JTP-2942), on pentobarbital-induced anesthesia in rats were investigated and compared with those of TRH. Intravenous administration of both JTP-2942 and TRH caused a dose-dependent decrease in the recovery time from pentobarbital-induced anesthesia. The minimum effective doses of JTP-2942 and TRH were respectively 0.03 and 1 mg/kg. The effect of JTP-2942 was antagonized by intraperitoneal scopolamine (0.5 mg/kg). Intraperitoneal JTP-2942 (1 mg/kg) caused an increase of acetylcholine release and a decrease of choline release in the frontal cortex and hippocampus of pentobarbital-treated rats. In addition, JTP-2942 ameliorated the decrease of hemicholinium-3-sensitive high-affinity choline uptake and the increase of acetylcholine in these brain regions. However, JTP-2942 had no effect on choline acetyltransferase activity or the choline content, which were also not changed by pentobarbital. Our results indicate that the effect of JTP-2942 on pentobarbital-induced anesthesia was about 30 times more potent than that of TRH, and suggest that JTP-2942 may act by accelerating acetylcholine turnover.
- Published
- 1995
37. JTS-653 blocks afferent nerve firing and attenuates bladder overactivity without affecting normal voiding function
- Author
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Mikio Hayashi, Mariko Maekawa, Tomokazu Kanehisa, Kenji Usui, Atsuko Miyai, Akira Matsuo, Masahiro Sakata, Mutsuyoshi Matsushita, Yoshihiro Kitagawa, and Masashi Wada
- Subjects
Contraction (grammar) ,Carbachol ,Pyridines ,Urology ,Urinary Bladder ,TRPV1 ,Resiniferatoxin ,TRPV Cation Channels ,Urination ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,medicine ,Animals ,Neurons, Afferent ,Urinary bladder ,medicine.diagnostic_test ,business.industry ,Urinary Bladder, Overactive ,Antagonist ,Cystometry ,Benzoxazines ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Administration, Intravesical ,chemistry ,Capsaicin ,Anesthesia ,Female ,business ,medicine.drug - Abstract
We evaluated the role of TRPV1 in bladder overactivity based on afferent nerve firing and urodynamic parameters using the selective TRPV1 antagonist JTS-653.We evaluated the effects of JTS-653 on the increased pelvic nerve discharge and intravesical pressure induced by intravesical infusion of 100 μM capsaicin in anesthetized rats. The effects of JTS-653 on the urodynamic parameters of bladder overactivity induced by intravesical infusion of 30 nM resiniferatoxin or 0.2% acetic acid, or on normal bladder activity were evaluated by cystometry in conscious rats. The effects of JTS-653 on carbachol induced contraction were investigated using bladder muscle strips.JTS-653 significantly suppressed the capsaicin induced increase in nerve discharge and intravesical pressure. Intravesical infusion of resiniferatoxin or acetic acid decreased the intercontraction interval and voided volume. JTS-653 significantly increased the intercontraction interval and voided volume in rats with resiniferatoxin or acetic acid induced bladder overactivity without affecting maximal voiding pressure. The antimuscarinic agent propiverine significantly decreased maximal voiding pressure but did not affect the intercontraction interval or voided volume in rats with acetic acid induced bladder overactivity. In normal rats JTS-653 showed no significant effects on the intercontraction interval, voided volume or maximal voiding pressure. JTS-653 did not affect carbachol induced contraction of the bladder muscle.Our findings suggest that TRPV1 is involved in bladder overactivity via afferent nerve activation but it is not associated with normal voiding function. A TRPV1 antagonist would be a useful drug for bladder overactivity with a different pharmacological profile than antimuscarinic agents.
- Published
- 2012
38. Diabetic peripheral neuropathy in Spontaneously Diabetic Torii-Lepr(fa) (SDT fatty) rats
- Author
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Takayuki, Yamaguchi, Tomohiko, Sasase, Yasuko, Mera, Daisuke, Tomimoto, Hironobu, Tadaki, Yusuke, Kemmochi, Takeshi, Ohta, Eimei, Sato, and Mutsuyoshi, Matsushita
- Subjects
Blood Glucose ,Male ,Motor Neurons ,Pioglitazone ,Body Weight ,Neural Conduction ,Rats ,Rats, Zucker ,Rats, Sprague-Dawley ,Disease Models, Animal ,Diabetes Mellitus, Type 2 ,Diabetic Neuropathies ,Sural Nerve ,Animals ,Insulin ,Thiazolidinediones - Abstract
Spontaneously Diabetic Torii (SDT) rat is a hereditary model of diabetes. Although the SDT rat shows severe diabetic complications, the onset of hyperglycemia is late. SDT fatty rat, established by introducing the fa allele of the Zucker fatty rat to SDT rat, develops diabetes much faster than SDT rat. In the present study, diabetic peripheral neuropathy (DPN) was evaluated to show the further usefulness of this animal model. Motor nerve conduction velocity (MNCV) was delayed, and the number of sural nerve fibers was decreased in SDT fatty rat. Treatment of pioglitazone lowered blood glucose level and prevented delay of MNCV in SDT fatty rats. SDT fatty rat is a useful animal model for studies of DPN in type 2 diabetes.
- Published
- 2012
39. Pharmacological characterization of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel transient receptor potential vanilloid 1 antagonist
- Author
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Yoshihiro, Kitagawa, Atsuko, Miyai, Kenji, Usui, Yuji, Hamada, Katsuya, Deai, Masashi, Wada, Yoshihisa, Koga, Masahiro, Sakata, Mikio, Hayashi, Makoto, Tominaga, and Mutsuyoshi, Matsushita
- Subjects
Male ,Pyridines ,TRPV Cation Channels ,Carrageenan ,Benzoxazines ,Body Temperature ,Rats ,Rats, Sprague-Dawley ,HEK293 Cells ,Hyperalgesia ,Animals ,Humans ,Central Nervous System Stimulants ,Capsaicin - Abstract
Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel TRPV1 antagonist. JTS-653 displaced [(3)H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with pA(2) values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC(50) values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC(50) values of 1.4 nM. JTS-653 showed weak or no inhibitory effects on other TRP channels, receptors, and enzymes. JTS-653 significantly prevented capsaicin-induced mechanical hyperalgesia at 1 mg/kg p.o. and attenuated carrageenan-induced mechanical hyperalgesia at 0.3 mg/kg p.o. JTS-653 significantly attenuated carrageenan-induced thermal hyperalgesia at 0.1 mg/kg p.o. and fully reversed at 0.3 mg/kg p.o. without affecting the volume of the carrageenan-treated paw. JTS-653 showed a transient increase of body temperature at 0.3 mg/kg p.o. These results indicated that JTS-653 is a highly potent and selective TRPV1 antagonist in vitro and in vivo and suggested that JTS-653 is one of the most potent TRPV1 antagonists. The profiles of JTS-653, high potency in vivo and transient hyperthermia, seem to be associated with polymodal inhibition of TRPV1 activation.
- Published
- 2012
40. Effects of ovariectomy on bone metabolism and bone mineral density in spontaneously diabetic Torii-Lepr(fa) rats
- Author
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Tomohiko Sasase, Mutsuyoshi Matsushita, Takeshi Ohta, and Shuichi Kimura
- Subjects
Blood Glucose ,Deoxypyridinoline ,medicine.medical_specialty ,Ovariectomy ,Osteocalcin ,Type 2 diabetes ,Bone resorption ,Bone remodeling ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Bone Density ,Diabetes mellitus ,Internal medicine ,Hyperlipidemia ,medicine ,Animals ,Insulin ,Tibia ,Obesity ,Amino Acids ,Bone mineral ,Lumbar Vertebrae ,General Veterinary ,business.industry ,Body Weight ,Estrogens ,Rats, Inbred Strains ,medicine.disease ,Rats ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Osteoporosis ,Female ,business ,Biomarkers - Abstract
The Spontaneously Diabetic Torii-Lepr(fa) (SDT- fa/fa) rat is a new model of obese type 2 diabetes. The female SDT-fa/fa rat shows obesity, hyperglycemia and hyperlipidemia from a young age. However, it is not known whether diabetes and estrogen deficiency can lead to bone abnormalities in the female SDT-fa/fa rat. The objective of the present study was to investigate the effects of ovariectomy (OVX) on bone metabolism and bone mineral density (BMD) in the female SDT-fa/fa rat. Female Sprague-Dawley rats were used as control animals. The BMDs of the whole tibia and fifth lumbar (L5) vertebral body were analyzed at 30 weeks after OVX. Serum osteocalcin, a bone formation marker, and urine deoxypyridinoline (DPD), a bone resorption marker, were sequentially analyzed before and at 5, 15 and 30 weeks after OVX. Serum osteocalcin and urine DPD levels were lower in SDT-fa/fa rats than in control rats before OVX. Both serum osteocalcin and urine DPD levels were elevated in control rats 5-30 weeks after OVX, but only the urine DPD levels were elevated in SDT-fa/fa rats 5-30 weeks after OVX. SDT-fa/fa rats showed a decrease in the BMDs of the whole tibia and L5 vertebral body compared with control rats. OVX decreased the BMDs of the whole tibia and L5 vertebral body in control rats, but not in SDT-fa/fa rats. These data suggest that estrogen deficiency is not a risk factor for bone loss in type 2 diabetes mellitus.
- Published
- 2011
41. Characteristics of bone turnover, bone mass and bone strength in Spontaneously Diabetic Torii-Lepr fa rats
- Author
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Eimei Sato, Shuichi Kimura, Mutsuyoshi Matsushita, Tomohiko Sasase, and Takeshi Ohta
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Deoxypyridinoline ,Bone density ,Endocrinology, Diabetes and Metabolism ,Osteocalcin ,Bone remodeling ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Endocrinology ,Imaging, Three-Dimensional ,Bone Density ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Orthopedics and Sports Medicine ,Femur ,Tibia ,Amino Acids ,Homocysteine ,Bone mineral ,Calcium metabolism ,Chemistry ,Body Weight ,General Medicine ,Organ Size ,medicine.disease ,Rats ,Radiography ,Diabetes Mellitus, Type 2 ,Receptors, Leptin ,Calcium ,Bone Remodeling - Abstract
The Spontaneously Diabetic Torii-Lepr (fa) (SDT-fa/fa) rat is a new model of obese type 2 diabetes. The SDT-fa/fa rat shows obesity and hyperglycemia at a young age compared to the Spontaneously Diabetic Torii (SDT-+/+) rat; however, bone abnormalities in the SDT-fa/fa rat have not been investigated. The objective of the present study was to investigate the effects of obese type 2 diabetes on bone turnover, bone mass, and bone strength in the SDT-fa/fa rat. Sprague-Dawley rats were used as control animals, and SDT-+/+ rats were used as non-obese type 2 diabetic rats. Serum osteocalcin and urine deoxypyridinoline levels were decreased in SDT-fa/fa rats compared to control rats at a young age. SDT-fa/fa rats showed decreases in bone mineral density and bone mineral content of the whole tibia, and shortening of the tibia and femur compared to control and SDT-+/+ rats. Deterioration in bone geometrical properties of the femur midshaft such as cortical thickness and minimum moment of inertia, was observed in SDT-fa/fa rats compared to control and SDT-+/+ rats. Furthermore, trabecular bone volume of the distal femur was decreased in SDT-fa/fa rats compared to control rats. These negative effects on bone in SDT-fa/fa rats caused severe decreases in maximum load, stiffness, and energy absorption of the femur. In addition, serum levels of homocysteine, a candidate for bone fragility markers, were elevated in SDT-fa/fa rats compared to control and SDT-+/+ rats. In conclusion, the SDT-fa/fa rat may be a useful model to investigate bone abnormalities in obese type 2 diabetes.
- Published
- 2011
42. Pathophysiological analysis of female Spontaneously Diabetic Torii fatty rats
- Author
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Tomohiko Sasase, Taku Masuyama, Hisayo Morinaga, Katsuhiro Miyajima, Masami Shinohara, Makoto Kakutani, Mutsuyoshi Matsushita, Yoshiaki Katsuda, Takeshi Ohta, Yukihito Ishii, Takahiro Hata, and Nobuhisa Ueda
- Subjects
medicine.medical_specialty ,Blood lipids ,Renal function ,General Biochemistry, Genetics and Molecular Biology ,Diabetes Mellitus, Experimental ,Eating ,Islets of Langerhans ,Internal medicine ,Diabetes mellitus ,Hyperlipidemia ,medicine ,Hyperinsulinemia ,Animals ,General Veterinary ,business.industry ,Pancreatic islets ,Body Weight ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Rats, Inbred Strains ,General Medicine ,Organ Size ,medicine.disease ,Pathophysiology ,Rats ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Disease Progression ,Animal Science and Zoology ,Female ,business - Abstract
Obesity, hyperglycemia, hyperlipidemia, and diabetes-associated complications appear at younger ages (6-8 weeks) in the male Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat than in the male original SDT (SDT-+/+) rat. However, the incidence and progression of diabetes mellitus and diabetic complications in the female SDT-fa/fa rat have not been reported in detail. In the present study, the pathophysiological features of the female SDT-fa/fa rat were examined, and compared with those of the female SDT-+/+ rat. Female SDT-fa/fa rats showed hyperphagia, obesity, hyperglycemia, and hyperlipidemia from 5 or 6 weeks of age, and hyperinsulinemia was observed from 5 to 12 weeks. Pathological changes pancreatic islets were observed from 8 weeks. Renal function parameters, such as urine volume and urinary protein, increased from 16 weeks, and pathological findings in the renal tubule, and cataracts were also observed from 16 weeks. Increases of visceral and subcutaneous fats were obvious during the observation period. In pair-feeding with SDT-+/+ rats, SDT-fa/fa rats showed improved hyperglycemia and hypertriglycemia, but hypercholesterolemia was not entirely improved during the study period. Female SDT-fa/fa rats showed diabetes mellitus and diabetes-associated complications at young ages, and fat accumulation was remarkable. Suppression of hyperphagia in SDT-fa/fa rats was effective at improving hyperglycemia and hypertriglycemia. In conclusion, the female SDT-fa/fa rat has the potential to become an important animal model of type 2 diabetes mellitus with obesity, especially for women, for which few models currently exist.
- Published
- 2010
43. Protein kinase C beta inhibitor prevents diabetic peripheral neuropathy, but not histopathological abnormalities of retina in Spontaneously Diabetic Torii rat
- Author
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T. Abe, Katsuhiro Miyajima, Masami Shinohara, Tomohiko Sasase, Takeshi Ohta, Mutsuyoshi Matsushita, Akihiro Kakehashi, and Hisayo Morinaga
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Neural Conduction ,Protein Kinase C beta ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Endocrinology ,Diabetic Neuropathies ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,Medicine ,Animals ,Pyrroles ,Protein Kinase C ,Retina ,Hypoalgesia ,Diabetic Retinopathy ,business.industry ,Retinal ,Diabetic retinopathy ,medicine.disease ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Peripheral neuropathy ,chemistry ,Indans ,business ,Optic disc - Abstract
Spontaneously Diabetic Torii (SDT) rat shows severe ocular complications such as tractional retinal detachment. In the present study, effect of protein kinase C beta (PKCbeta) inhibitor JTT-010 was evaluated to clarify the involvement of PKCbeta in complications of SDT rat. SDT rats were administered JTT-010 (10 or 50 mg/kg/day) for 48 weeks. SDT rats showed delayed oscillatory potentials in electroretinogram. Delayed motor nerve conduction velocity, decreased coefficients of variation of R-R intervals in electrocardiogram and thermal hypoalgesia were also observed. These functional disorders were prevented by administration of JTT-010. Abnormal retinal vascular was formed and the optic disc was protruded in SDT rat; however, JTT-010 did not prevent these hyperglycaemia-induced retinal abnormalities. These findings indicate that PKCbeta is intimately involved in diabetic complications; however, it seems that other factor(s) are primary contributors to histopathological abnormalities in retina. Therefore, PKCbeta inhibitors require concurrent administration of antihyperglycaemic drugs to achieve maximum effect on diabetic complications.
- Published
- 2009
44. Effect of Food Restriction on Adipose Tissue in Spontaneously Diabetic Torii Fatty Rats
- Author
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Yukihito Ishii, Masatoshi Ueda, Mutsuyoshi Matsushita, Kenichi Matsui, Tomohiko Sasase, Katsuhiro Miyajima, Hisayo Morinaga, Takeshi Ohta, Makoto Ito, and Sumiaki Fukuda
- Subjects
Male ,medicine.medical_specialty ,lcsh:Internal medicine ,Article Subject ,lcsh:Specialties of internal medicine ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,lcsh:Medicine ,Type 2 diabetes ,Mesenteric fat ,Biology ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Rats, Mutant Strains ,Cell size ,Acetyltransferases ,lcsh:RC581-951 ,Internal medicine ,Adipocytes ,medicine ,Animals ,Obesity ,RNA, Messenger ,lcsh:RC31-1245 ,Caloric Restriction ,Cell Size ,DNA Primers ,Lipoprotein lipase ,Glucose Transporter Type 4 ,lcsh:RC648-665 ,Base Sequence ,Tumor Necrosis Factor-alpha ,lcsh:R ,General Medicine ,medicine.disease ,Rats ,Rats, Zucker ,Food restriction ,Disease Models, Animal ,Lipoprotein Lipase ,Glucose ,Endocrinology ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Tumor necrosis factor alpha ,Oxidation-Reduction ,Research Article - Abstract
Spontaneously Diabetic Torii-fa/fa(SDT fatty) rat is a new model of obese type 2 diabetes. SDT fatty rat exhibits obesity associated with hyperphagia. In this study, SDT fatty rats were subjected to pair-feeding with SDT-+/+ (SDT) rats from 6 to 22 weeks of age. The ratio of visceral fat weight to subcutaneous fat weight (V/S) decreased at 12 weeks of age in the pair-feeding rats. The intraperitoneal fat weight such as epididymal and retroperitoneal fat weight decreased, whereas mesenteric fat weight had no change. Cell size of the epididymal fat in the pair-feeding rats tended to decrease. Glucose oxidation level in epididymal fat in the pair-feeding rats at 12 weeks of age was recovered to a similar level with that in SDT rats. These results indicated that SDT fatty rat is a useful model to evaluate the functional or the morphological features in adipose tissue and develop a novel drug for antiobesity.
- Published
- 2009
45. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling
- Author
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Yasuharu Numata, Akihiko Kitoh, Yoshiki Miyachi, Teruki Dainichi, Gyohei Egawa, Yasuo Yamamoto, Kenji Kabashima, Atsushi Otsuka, Tetsuya Honda, Wataru Amano, Yukari Kimoto, Hayato Kunugi, Saeko Nakajima, Mutsuyoshi Matsushita, and Atsuo Tanimoto
- Subjects
Keratinocytes ,STAT3 Transcription Factor ,Transplantation, Heterologous ,Immunology ,Mice, Nude ,Human skin ,Filaggrin Proteins ,Dermatitis, Atopic ,Immunocompromised Host ,Mice ,Intermediate Filament Proteins ,medicine ,Animals ,Humans ,Immunology and Allergy ,RNA, Small Interfering ,STAT3 ,Protein Kinase Inhibitors ,Janus kinase inhibitor ,STAT6 ,Skin, Artificial ,Interleukin-13 ,integumentary system ,biology ,Activator (genetics) ,Cell Differentiation ,Skin Transplantation ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Expression Regulation ,STAT protein ,biology.protein ,Interleukin-4 ,STAT6 Transcription Factor ,Janus kinase ,Keratinocyte ,Signal Transduction - Abstract
Background Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which skin barrier function is disrupted in patients with AD remains unclear. Objectives Taking into account the fact that the T H 2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. Methods We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. Results IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. Conclusion STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
- Published
- 2015
46. Hereditary postprandial hypertriglyceridemic rabbit exhibits insulin resistance and central obesity: a novel model of metabolic syndrome
- Author
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Tsunekata Ito, Hitonobu Tomoike, Yasuko Mera, Mutsuyoshi Matsushita, Takashi Kawai, and Kazuo Ohwada
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Blood Pressure ,Biology ,Intra-Abdominal Fat ,chemistry.chemical_compound ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Insulin ,Genetic Predisposition to Disease ,Obesity ,Pancreatic hormone ,Triglycerides ,Hypertriglyceridemia ,Metabolic Syndrome ,Glucose tolerance test ,Triglyceride ,medicine.diagnostic_test ,Glucose Tolerance Test ,medicine.disease ,Postprandial Period ,Disease Models, Animal ,Postprandial ,Endocrinology ,Cholesterol ,chemistry ,Rabbits ,Metabolic syndrome ,Insulin Resistance ,Cardiology and Cardiovascular Medicine - Abstract
Objective— We have established a hereditary postprandial hypertriglyceridemic (PHT) rabbit. The present study was designed to define whether this rabbit model represents both insulin resistance and central obesity. Methods and Results— Body weight, abdominal circumference, visceral fat weight, and glucose tolerance were compared between PHT and Japanese white (JW) rabbit. Plasma levels of triglycerides (TG), total cholesterol (TC), glucose, and insulin were measured before and after feeding. Abdominal circumference of PHT rabbit was larger than that of JW rabbit, with no difference in body mass index. Visceral fat accumulation was noted as obvious in mesenterium, retroperitoneal space, and epididymal area. Plasma TG and TC levels were high preprandially and markedly increased postprandially in PHT rabbit compared with JW rabbit. Although plasma glucose levels were comparable in both groups, plasma insulin levels were elevated in PHT rabbit. Glucose tolerance tests indicated that plasma insulin levels in PHT rabbit were consistently higher than in JW rabbit. A positive correlation was observed between plasma insulin levels and visceral fat weight in PHT rabbit. Conclusions— PHT rabbit shows insulin resistance along with central obesity. PHT rabbit will serve as a model for elucidating genetic predisposition and pathophysiology in metabolic syndrome.
- Published
- 2006
47. JTP-426467 acts as a selective antagonist for peroxisome proliferator-activated receptor gamma in vitro and in vivo
- Author
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T. Shibata, Makoto Ito, Mutsuyoshi Matsushita, J. Nishiu, Makoto Kakutani, M. Shindo, and Y. Ishida
- Subjects
Agonist ,Blood Glucose ,Leptin ,Male ,medicine.medical_specialty ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Peroxisome proliferator-activated receptor ,Biology ,Weight Gain ,Rosiglitazone ,chemistry.chemical_compound ,Mice ,Endocrinology ,In vivo ,Genes, Reporter ,Adipocyte ,Internal medicine ,Internal Medicine ,medicine ,Adipocytes ,Animals ,Humans ,Hypoglycemic Agents ,Obesity ,RNA, Messenger ,Receptor ,Cells, Cultured ,chemistry.chemical_classification ,Reporter gene ,Benzoxazoles ,Adipogenesis ,Dose-Response Relationship, Drug ,Antagonist ,Cell Differentiation ,PPAR gamma ,chemistry ,Gene Expression Regulation ,Thiazolidinediones ,Anti-Obesity Agents ,HeLa Cells - Abstract
Aim JTP-426467 was identified as a result of screening in search of selective antagonist for peroxisome proliferator-activated receptor gamma (PPARgamma). We examined whether JTP-426467 functioned as a PPARgamma antagonist in vitro and in vivo and investigated physiological effects of JTP-426467. Methods The effect of JTP-426467 as a PPARgamma antagonist was studied in a cell-based reporter assay and an adipocyte differentiation assay. Target mRNA expression levels were determined by branched DNA (bDNA) assay. To examine the effects as a PPARgamma antagonist in vivo, a competitive study between JTP-426467 and BRL49653 (rosiglitazone), a PPARgamma agonist, was performed using KK-Ay mice. The effects of JTP-426467 alone after administration to KK-Ay mice were also explored. JTP-426467 antagonized PPARgamma activity in a reporter assay system, but not PPARalpha. Results JTP-426467 inhibited the expression of hormone-sensitive lipase (HSL) mRNA, an adipocyte-abundant gene, but not PPARgamma itself or cyclophilin mRNA (as constitutive mRNA), and also suppressed triglyceride accumulation in differentiated stromal vascular fraction cells (SVFs). JTP-426467 antagonized PPARgamma agonistic action by BRL49653 in KK-Ay mice on high-fat diet, in terms of plasma glucose, body weight gain and interscapular brown adipose tissue (IBAT) weight. JTP-426467 alone inhibited body weight gain and decreased plasma leptin level in KK-Ay mice. Conclusions JTP-426467 acted as a pure and potent PPARgamma antagonist in vitro. Interestingly, JTP-426467 completely antagonized the effects of PPARgamma agonist BRL49653 in an obese diabetic model. JTP-426467 may be a useful tool for the study of PPARgamma in biological and physiological function.
- Published
- 2006
48. Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCbeta-selective inhibitors
- Author
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Tomoyuki Ikemoto, Masahiro Tanaka, Katsutaka Yasue, Minoru Ubukata, Tomohiko Sasase, Shoichi Sagawa, Yasunori Hase, Jun-Ichi Hoshi, Mitsuru Takahashi, Fumito Shimoma, Nobuhisa Ueda, Mutsuyoshi Matsushita, and Takashi Inaba
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Biological Availability ,Biochemistry ,Chemical synthesis ,Diabetes Mellitus, Experimental ,Maleimides ,chemistry.chemical_compound ,Structure-Activity Relationship ,Oral administration ,Drug Discovery ,Protein Kinase C beta ,Animals ,Molecular Biology ,Maleimide ,Protein kinase C ,Protein Kinase C ,Indole test ,chemistry.chemical_classification ,Diabetic Retinopathy ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Bioavailability ,Rats ,Enzyme ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route.
- Published
- 2006
49. Cholesteryl ester transfer protein promotes the formation of cholesterol-rich remnant like lipoprotein particles in human plasma
- Author
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Tomohiko Sasase, Atsuko Miyai, Takamitsu Nakano, Mutsuyoshi Matsushita, Noboru Furukawa, Katsuyuki Nakajima, and Hiroshi Okamoto
- Subjects
Male ,food.ingredient ,Lipoproteins ,Clinical Biochemistry ,Sterol O-acyltransferase ,Dithionitrobenzoic Acid ,In Vitro Techniques ,Biochemistry ,Lecithin ,Phosphatidylcholine-Sterol O-Acyltransferase ,chemistry.chemical_compound ,food ,Cholesterylester transfer protein ,Humans ,Sulfhydryl Compounds ,Enzyme Inhibitors ,CETP inhibitor ,Triglycerides ,biology ,Triglyceride ,Cholesterol ,Anticholesteremic Agents ,Biochemistry (medical) ,Antibodies, Monoclonal ,Esters ,General Medicine ,Molecular biology ,Amides ,Recombinant Proteins ,Cholesterol Ester Transfer Proteins ,carbohydrates (lipids) ,chemistry ,biology.protein ,Cholesteryl ester ,lipids (amino acids, peptides, and proteins) ,Female ,Lipoprotein - Abstract
Background Cholesteryl ester transfer protein (CETP) is suggested to be involved in the cholesterol level in remnant like lipoprotein particles (RLP), but there is no direct evidence that CETP increases cholesterol-rich RLP in plasma. Methods Human plasma was incubated with or without HDL containing [ 3 H]-labeled cholesteryl ester ([ 3 H]CE), recombinant CETP or CETP inhibitors at 37 °C in vitro . Results The RLP–cholesterol (RLP–C) level increased time-dependently and the amount of RLP–C increase ( Δ RLP–C) by the incubation was positively correlated with triglyceride (TG) level in plasma ( r = 0.597, P = 0.0070). [ 3 H]CE in HDL was transferred to RLP fraction under 37 °C incubation, and the amount of [ 3 H]CE transferred to RLP correlated significantly with Δ RLP–C in plasma ( r = 0.611, P = 0.0156). Human recombinant CETP enhanced the RLP–C increase, while CETP inhibitor JTT-705 and anti-human CETP monoclonal antibody inhibited both the RLP–C increase and [ 3 H]CE transfer to RLP. On the other hand, an inhibition of lecithin: cholesterol acyltransferase (LCAT) did not affect the RLP–C increase. In triglyceride-rich lipoproteins (TRL) fraction, JTT-705 inhibited [ 3 H]CE transfer to RLP more strongly than that to non-RLP. Conclusions CETP promotes the formation of cholesterol-rich RLP through the transfer of CE from HDL to TRL and CETP inhibitors are useful to reduce RLP–C.
- Published
- 2006
50. Novel protein kinase C-beta isoform selective inhibitor JTT-010 ameliorates both hyper- and hypoalgesia in streptozotocin- induced diabetic rats
- Author
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Kenji Sakoda, H. Yamada, Makoto Ito, N. Imagawa, T. Abe, Tomohiko Sasase, Mutsuyoshi Matsushita, Michiru Tanaka, and Shoichi Sagawa
- Subjects
Male ,medicine.medical_specialty ,Diabetic neuropathy ,Endocrinology, Diabetes and Metabolism ,Neural Conduction ,Nerve conduction velocity ,Diabetes Mellitus, Experimental ,Hypesthesia ,Rats, Sprague-Dawley ,Endocrinology ,Diabetic Neuropathies ,Internal medicine ,Protein Kinase C beta ,Internal Medicine ,medicine ,Animals ,Pyrroles ,Protein kinase C ,Protein Kinase C ,Hypoalgesia ,business.industry ,medicine.disease ,Streptozotocin ,Sciatic Nerve ,Rats ,Nociception ,Hyperalgesia ,Anesthesia ,Indans ,Sciatic nerve ,medicine.symptom ,business ,medicine.drug - Abstract
Aim: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-β is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-β isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined. Methods: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests. Results: JTT-010 inhibited PKC-βI and -βII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3–3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher. Conclusions: These observations suggest that PKC-β contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-β inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.
- Published
- 2005
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