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Research Projects |
[Diabetes Mellitus] |
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Diabetes Mellitus is characterized by loss of insulin-producing beta-cell of the islets of Langerhans in the pancreas, even in type 2 diabetes. In type 2 diabetes, simultaneous stimulation with high blood glucose and free fatty acid to beta-cells induces the phenomenon designated "glucolipotoxicity" and results in apoptosis of the beta-cells and decreased islet mass. We have been studying about the molecular mechanisms of glucolipotoxicity of the beta-cells using the techniques of cell biology and molecular biology and are conducing the translational research aimed protection and recovery of the islet function. Also several clinical trials using ghrelin, orexigenic peptide, against diabetic complications are now on-going.
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| 1 |
Ueno H, Yamaguchi H, Mizuta M, Nakazato M.: The role of PYY in feeding regulation. Regul Pept, 145: 12-16, 2008
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| 2 |
Saitoh Y, Chun-Ping C, Noma K, Ueno H, Mizuta M, Nakazato M.: Pioglitazone attenuates fatty acid-induced oxidative stress and apoptosis in pancreatic beta-cells. Diabetes Obes Metab, 10: 564-573, 2008
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| 3 |
Saitoh Y, Liu R, Ueno H, Mizuta M, Nakazato M.: Oral pioglitazone administration increases food intake through ghrelin-independent pathway in Zucker fatty rat. Diabetes Res Clin Pract, 77: 351-356, 2007
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| 4 |
Ueno H, Shiiya T, Mizuta M, Mondal MS, Nakazato M.: Plasma ghrelin concentrations in different clinical stages of diabetic complications and glycemic control in Japanese diabetics. Endocrine J, 54: 895-902, 2007
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| 5 |
Ueno H, Yamaguchi H, Nakazato M.: Ghrelin: A gastric peptide that regulates food intake and energy homeostasis. Regul Pept, 126: 11-19, 2005
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| 6 |
Osawa H, Nakazato M, Date Y, Kita H, Ohnishi H, Ueno H, Shiiya T, Satoh K, Ishino Y, Sugano K.: Impaired production of gastric ghrelin in chronic gastritis associated with Helicobacter pylori. J Clin Endocrinol Metab, 90: 10-16, 2005
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| 7 |
Liu R, Mizuta M, Matsukura S.: The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. J Pharmacol Exp Ther, 310: 52-58, 2004
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| 8 |
Liu R, Mizuta M, Matsukura S.: Long-term oral nicotine administration reduces insulin resisitance in obese rats. Eur J Pharmacol, 458: 227-234, 2003
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| 9 |
Liu RH, Mizuta M, Kurose T, Matsukura S.: Early events involved in the development of insuiln resistance in Zucker fatty rat. Int J Obesity, 26: 318-326, 2002
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| 10 |
Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S.: Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab, 87: 240-244, 2002
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[Endocrinology]
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Peptide
hormones or neuropeptides function as cell-to-cell signaling molecules
to mediate a variety of physiological phenomena. We have been working
on functional analysis of biologically active peptides, especially
in the field of feeding regulation and energy homeostasis. Our group
has established biochemical, genetical, anatomical and pharmacological
techniques to clarify the functional roles of bioactive peptides
in vivo. The ongoing research projects are as follows. |
| 1 |
Molecular
and biochemical research on development of obesity. Quantum leaps
in our understanding of the mechanisms involved in energy homeostasis
have resulted from the recent identification of neuronal circuits
that control food intake. A large array of hypothalamic neuropeptides
participates in the central regulation of feeding and energy expenditure.
We undertook a systematic approach to elucidate the functional roles
of neuropeptides in appetite regulation and energy homeostasis.
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| 2 |
Analysis
of anorectic effect of nicotine in neural circuitry. Nicotine, the
major agent in tobacco, suppresses food intake, but the signaling
pathway of nicotineﾕs anorectic effects has not elucidated in vivo.
We have been studying the neuronal pathway using midbrain-transected
rats and saporin-DBH treated rats to dennervate between the hypothalamus
and the medulla. |
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Selected Publications; |
| 1 |
Nakazato
M, Kawagoe T, Shimbara T, Toshinai K, Date Y, Mondal MS, Kangawa
K, Matsuo H, and Matsukura S.: Ghrelin: a novel peptide hormone
involved in the regulation of growth hormone secretion and energy
balance. Endocrine J, in press |
| 2 |
Mondal
MS, Toshinai K, Ueno H, Koshinaka K, and Nakazato M.: Characterization
of obestatin in rat and human stomach and plasma, and its lack of
effect on feeding behavior in rodents. J Endocrinol, in press |
| 3 |
Ueno H, Shiiya T, Mizuta M, Mondal MS, and Nakazato M.: Plasma ghrelin
concentrations in different clinical stages of diabetic complications
and glycemic control in Japanese diabetics. Endocrine J, 54: 895-902
, 2007 |
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4 |
Mondal MS, Yamaguchi H, Date Y, Kawagoe T, Tsuruta T, Kageyama H,
Kawamura Y, Shioda S, Shimomura Y, Mori M, Nakazato M .: Neuropeptide
W is present in antral G cells of rat, mouse, and human stomach.
J Endocrinol 188: 49-57, 2006 |
| 5 |
Toshinai
K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y,
Mondal MS, Shimbara T, Kawagoe T, Murakami N, Miyazato M, Kangawa
K, and Nakazato M.: Des-acyl ghrelin induces food intake by a mechanism
independent of the growth hormone secretagogue receptor. Endocrinology,
147: 2306-14, 2006 |
| 6 |
Sawada H, Yamaguchi H, Shimbara T, Toshinai K, Mondal MS, Date Y,
Murakami N, Katafuchi T, Minamino N, Nunoi H, and Nakazato M.: Central
effects of CRSP-1 on energy homeostasis in rats. Endocrinology,
147: 2043-50, 2006 |
| 7 |
Mondal
MS, Yamaguchi H, Date Y, TsurutaT, Kageyama H, Shimomura Y, Mori
M, Nakazato M: Neuropeptide W is present in antral G cells of rat,
mouse,and human stomach. J Endocrinol, 188: 49-57, 2006 |
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[Respirology] |
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We
have conducted molecular-biological analysis on natural immunity
and cytokine network to clarify pathophysiological mechanisms of
respiratory diseases; and evaluated the quantification, localization,
and biosynthesis of defensins family, antibacterial and cytotoxic
peptides, to elucidate its significance in the pathophysiology of
pulmonary diseases. We showed the relationship between innate and
acquired immunity in infectious diseases and interstitial lung diseases.
We are performing translational research using bioactive substances
such as ghrelin. Ghrelin, a hormone produced in the stomach, functions
as an energy regulator to enhance appetite. Other than this function,
ghrelin is expected to serve as a new therapeutic agent for cachexic
patients with chronic respiratory diseases due to its various functions
such as anti-inflammatory activity. To improve exercise tolerance
in COPD patients, we conducted a clinical trial using ghrelin and
rehabilitation. We also discovered a new physiological function
of ghrelin in this clinical trial. We will emphasize the importance
of the both researches, ﾒ from bench to bed ﾓandﾒ from bed to benchﾓ
in a study of respiratory diseases.
As fundamental researches of lung cancer, we analyzed a cancer-causing
mechanism using a knockout mouse to clarify a significance of PTEN,
one of the major cancer suppressor genes. This investigation will
be useful to develop a new treatment for lung cancer in the future.
Finally, we look forward to the active participation of many young
scientists who are interested in molecular analysis and clinical
research. Together we hope to develop new treatments for refractory
respiratory diseases using bioactive substances. |
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Selected Publications; |
| 1 |
Kodama T, Ashitani J, Matsumoto N, Kangawa K, and Nakazato M.: Ghrelin
treatment suppresses neutropfil-dominant inflammation in airways
of patients with chronic respiratory infection. Pulm Pharmacol Ther,
in press |
| 2 |
Ashitani JI, Kyoraku Y, Yanagi S, Matsumoto N, and Nakazato M.:
Elevated levels of beta-D-glucan in bronchoalveolar lavage fluid
in patients with farmer's lung in Miyazaki, Japan. Respiration,
74: 69-75, 2007 |
| 3 |
Ashitani
J, Matsumoto N, and Nakazato M.: Elevated alpha-defensin levels
in plasma of patients with pulmonary sarcoidosis. Respirology, 12:
339-345, 2007 |
| 4 |
Ashitani J, Matsumoto N, and Nakazato M.: Elevated levels of antimicrobial
peptides in bronchoalveolar lavage fluid in patients with chronic
eosinophilic pneumonia. Respiration, 74: 69-75, 2007 |
| 5 |
Iiboshi
H, Ashitani J, Katoh S, Sano A, Matsumoto N, Mukae H, and Nakazato
M.: Long-term treatment with theophylline reduces neutrophils, interleukin-8
and tumor necrosis factor-_ in the sputum of patients with chronic
obstructive pulmonary disease. Pulm Pharmacol Ther, 20: 46-51, 2007 |
| 6 |
Yanagi S, Kishimoto H, Kawahara K, Sasaki T, Sasaki M, Nishio M,
Yajima N, Hamada K, Horie Y, Kubo H, Mak TW, Nakano T, Nakazato
M, and Suzuki A.: Pten controls lung morphogenesis, bronchioalveolar
stem cells, and onset of lung adenocarcinomas. J Clin Invest, 117:
2929-2940, 2007 |
| 7 |
Yanagi S, Ashitani J, Imai K, Kyoraku Y, Sano A, Matsumoto N, Nakazato
M. Significance of human b defensins in epithelial lining fluid
of patients with chronic lower respiratory tract infections. Clinical
Microbiology and Infection, 13: 63-69, 2007 |
| 8 |
Iiboshi H, Ashitani J, Katoh S, Sano A, Matsumoto N, Mukae H, Nakazato
M: Long-term Treatment with Theophylline Reduces Neutrophils, Interleukin-8
and Tumor Necrosis Factor-a in the Sputum of Patients with Chronic
Obstructive Pulmonary Disease. Pulm Pharmacol Ther, 20: 46-51, 2007
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Ishimoto
H, Mukae H, Date Y, Shimbara T, Mondal M S, Ashitani J, Hiratsuka
T, Kubo S, Kohno S, Nakazato M: Identification of hBD-3 in Respiratory
Tract and Serum and its Increase in Pneumonia. Eur Resp J, 27: 253-260,
2006 |
| 10 |
Yanagi
S, Ashitani J, Ishimoto H, Date Y, Mukae H, Chino N, Nakazato M:
Isolation of human- Defensin-4 in Lung Tissue and Its Increase in
Lower Respiratory Tract Infection. Respir Res, 6: 130, 2005 |
| 11 |
Ashitani
J, Mukae H, Arimura Y, Sana A, Tokojima M, Nakazato M: High concentrations
of _-defensins in plasma and bronchoalveolar lavage fluid of patients
with acute respiratory distress syndrome. Life Sciences, 75: 1123-1134,
2004 |
| 12 |
Hiratsuka
T, Mukae H, Iiboshi H, Ashitani J, Nabeshima K, Minematsu T, Cnino
N, Ihi T, Kohno S, Nakazato M: Increased concentrations of human
_-defensins in plasma and bronchoalveolar lavage fluid of patients
with diffuse panbronchiolitis. Thorax, 58: 425-430, 2003 |
| 13 |
Katoh
S, Matsumoto N, Kawakita K, Tominaga A, Kincade PW, Matsukura S.
A role for CD44 in an antigen-induced murine model of pulmonary
eosinophilia. J Clin Invest, 111: 1563-1570, 2003 |
| 14 |
Ashitani J, Mukae H, Hiratsuka T, Nakazato M, Kumamoto K, Matsukura
S : Elevated levels of _-defensins in plasma and bronchoalveolar
lavage fluid of patients with active pulmonary tuberculosis, Chest,
; 121: 519-526, 2002 |
| 15 |
Mukae H, Iiboshi H, Nakazato M, Hiratsuka T, Tokojima M, Abe K,
Ashitani J, Kadota J, Matsukura S, Kohno S: Raised plasma concentrations
of _-defensins in patients with idiopathic pulmonary fibrosis, Thorax,
57: 623-628, 2002 |
| 16 |
Matsumoto
N, Mukae H, Nakamura-Uchiyama F, Ashitani J, Abe K, Katoh S, Kohno
S, Nawa Y, Matsukura S: Elevated levels of thymus and activation-regulated
chemokine (TARC) in pleural effusion samples from patients infested
with Paragonimus westermani. Clin Exp Immunol, 130: 314-318, 2002
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