Kazunori Fujino

Publications (14)61.71 Total impact

• Article: Haematopoietic cells produce BDNF and regulate appetite upon migration to the hypothalamus.

  Hiroshi Urabe, Hideto Kojima, Lawrence Chan, Tomoya Terashima, Nobuhiro Ogawa, Miwako Katagi, Kazunori Fujino, Asako Kumagai, Hiromichi Kawai, Akihiro Asakawa, Akio Inui, Hitoshi Yasuda, Yutaka Eguchi, Kazuhiro Oka, Hiroshi Maegawa, Atsunori Kashiwagi, Hiroshi Kimura
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  ABSTRACT: Brain-derived neurotrophic factor (BDNF) suppresses food intake by acting on neurons in the hypothalamus. Here we show that BDNF-producing haematopoietic cells control appetite and energy balance by migrating to the hypothalamic paraventricular nucleus. These haematopoietic-derived paraventricular nucleus cells produce microglial markers and make direct contacts with neurons in response to feeding status. Mice with congenital BDNF deficiency, specifically in haematopoietic cells, develop hyperphagia, obesity and insulin resistance. These abnormalities are ameliorated by bone marrow transplantation with wild-type bone marrow cells. Furthermore, when injected into the third ventricle, wild-type bone marrow mononuclear cells home to the paraventricular nucleus and reverse the hyperphagia of BDNF-deficient mice. Our results suggest a novel mechanism of feeding control based on the production of BDNF by haematopoietic cells and highlight a potential new therapeutic route for the treatment of obesity.
  Nature Communications 02/2013; 4:1526. · 7.40 Impact Factor
• Article: Ghrelin family of peptides and gut motility.

  Akihiro Asakawa, Koji Ataka, Kazunori Fujino, Chih-Yen Chen, Ikuo Kato, Mineko Fujimiya, Akio Inui
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  ABSTRACT: Acyl ghrelin, des-acyl ghrelin, and obestatin are three peptides isolated from the gastrointestinal tract and encoded by the same preproghrelin gene. Three ghrelin gene products participate in modulating appetite, adipogenesis, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. We have investigated the effects of ghrelin family of peptides on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats by manometric method. Intracerebroventricular (ICV) and intravenous (IV) administration of acyl ghrelin induced fasted motor activity in the duodenum in fed rats. ICV and IV administration of des-acyl ghrelin disrupted fasted motor activity in the antrum. Changes in gastric motility induced by IV administration of des-acyl ghrelin were antagonized by ICV administration of a corticotropin-releasing factor (CRF) 2 receptor antagonist. IV administration of obestatin decreased the percentage motor index in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats. ICV administration of CRF 1 and 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Ghrelin gene products regulate feeding-associated gastroduodenal motility. Stomach may regulate various functions including gastrointestinal motility via acyl ghrelin, des-acyl ghrelin and obestatin as an endocrine organ. Increasing knowledge of the effects of ghrelin family of peptides on gastrointestinal motility could lead to innovative new therapies for functional gastrointestinal disorders.
  Journal of Gastroenterology and Hepatology 04/2011; 26 Suppl 3:73-4. · 2.87 Impact Factor
• Article: Homing of the bone marrow-derived interstitial cells of Cajal is decreased in diabetic mouse intestine.

  Yimin Li, Hideto Kojima, Kazunori Fujino, Kazuhiro Matsumura, Miwako Katagi, Hiroshi Urabe, Lawrence Chan, Yutaka Eguchi, Linghui Zhao, Hiroshi Kimura
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  ABSTRACT: Interstitial cells of Cajal (ICCs), which express c-Kit receptor tyrosine kinase (KIT), play an important role in gastrointestinal motility. Loss of ICCs likely contributes to diabetic gastrointestinal motility disorder, however, the mechanism of attrition remains unknown. Here, we test the hypothesis that the bone marrow-derived progenitors are an important source of intestinal ICCs and that decreased homing of these progenitors in diabetes contributes to ICC diminution. Wild type mice were X-ray irradiated, transplanted with bone marrow (BMT) from green fluorescence protein (GFP)-transgenic (TG)-mice and subsequently made diabetic by streptozotocin (STZ) injection. Intestinal homing of GFP-positive bone marrow-derived cells was examined 2 or 5 months after STZ treatment. In the BMT-mice, we found many GFP-positive bone marrow-derived cells (BMDCs) in most parts of the intestinal area, the number of BMDCs was significantly decreased in diabetic mice compared with nondiabetic controls. As a representative area, we further examined the myenteric plexus of the proximal small intestine, and found that the cell numbers of ICCs marked by c-Kit-positive immunoreactivity were decreased by more than 40% in diabetic versus nondiabetic mice. Furthermore, numbers of c-Kit+/GFP+ and c-Kit+/GFP- cells were similar in nondiabetic mice, and decreased by 45.8% and 42.0%, respectively, in diabetic mice. These results suggest that the decreased homing from the bone marrow is a major cause of ICC loss in the intestine in diabetes mellitus.
  Journal of Gastroenterology and Hepatology 01/2011; 26(6):1072-8. · 2.87 Impact Factor
• Article: Parathyroid hormone-related protein has an anorexigenic activity via activation of hypothalamic urocortins 2 and 3.

  Akihiro Asakawa, Mineko Fujimiya, Akira Niijima, Kazunori Fujino, Noriko Kodama, Yuki Sato, Ikuo Kato, Hiroaki Nanba, Alessandro Laviano, Michael M Meguid, Akio Inui
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  ABSTRACT: Cancer cachexia is reported to be a major cause of cancer-related death. Since the pathogenesis is not entirely understood, only few effective therapies have been established. Since myriad tumors produce parathyroid hormone-related protein (PTHrP), plasma concentrations of PTHrP are increased in cancer cachexia. We measured the food intake, gastric emptying, conditioned taste aversion (CTA), and gene expression of hypothalamic neuropeptides in mice after administering PTHrP intraperitoneally. We administered PTHrP intravenously in rats and examined the gastroduodenal motility and vagal nerve activities. We also examined whether chronic administration of PTHrP influenced the food intake and body weight. Peripherally administered PTHrP induced negative energy balance by decreasing the food intake and gastric emptying; however, it did not induce CTA. The mechanism involved the activation of hypothalamic urocortins 2 and 3 through vagal afferent pathways and the suppression of gastroduodenal motor activity. The continuous infusion of PTHrP reduced the food intake and body weight gain with a concomitant decrease in the fat and skeletal muscle. Our findings suggest that PTHrP influences the food intake and body weight; therefore, PTHrP can be considered as a therapeutic target for cancer cachexia.
  Psychoneuroendocrinology 02/2010; 35(8):1178-86. · 5.81 Impact Factor
• Article: A surviving case of mitochondrial cardiomyopathy diagnosed from the symptoms of multiple organ dysfunction syndrome.

  Yasuyuki Tsujita, Takeo Kunitomo, Masanori Fujii, Satoshi Furukawa, Hideki Otsuki, Kazunori Fujino, Tetsu Hamamoto, Takahisa Tabata, Kazuhiro Matsumura, Teiji Sasaki, Takao Saotome, Hiromichi Kawai, Tetsuya Matsumoto, Kengo Maeda, Minoru Horie, Yutaka Eguchi
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  ABSTRACT: A 49-year-old female cardiomyopathic patient with heart, hepatic, and renal failure and lactic acidosis was transferred to the intensive care unit without a unifying diagnosis. She was of short stature (145 cm tall), had difficulty in hearing, a past history of complete atrioventricular block, and had received a permanent pacemaker. She had been diagnosed and treated as dilated cardiomyopathy by her primary doctor. Treatment in the intensive care unit for 21 days including plasma exchange, continuous hemodiafiltration, artificial ventilation, and administration of catecholamine, carperitide, and a large amount of coenzyme Q10 (210 mg/day) improved the symptoms. Genetic analysis using mitochondrial DNA from leukocytes and sternocleidomastoid muscle revealed a 3243A>G mutation in the mitochondrial tRNA(Leu (UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The patient recovered through intensive care and could be discharged from hospital without any sequelae. This case was mitochondrial cardiomyopathy diagnosed from the symptoms of multiple organ dysfunction syndrome. Cardiomyopathy due to the mutation of mitochondrial DNA is not a common disease. However, it should be considered as a possible cause of heart failure.
  International journal of cardiology 08/2008; 128(1):e43-5. · 7.08 Impact Factor
• Article: Transient receptor potential vanilloid 1 antagonist, capsazepine, improves survival in a rat hemorrhagic shock model.

  Hiroya Akabori, Hiroshi Yamamoto, Hiroshi Tsuchihashi, Tsuyoshi Mori, Kazunori Fujino, Tomoharu Shimizu, Yoshihiro Endo, Tohru Tani
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  ABSTRACT: To evaluate the role of transient receptor potential vanilloid 1 (TRPV1) in a rat hemorrhagic shock (HS) model using the TRPV1 antagonist, capsazepine (CPZ). TRPV1, distributed within the sensory nerve, plays a role in the regulation of cardiovascular functions. TRPV1 may be involved in the cardiovascular responses to HS. Male rats were anesthetized and HS was induced with the mean arterial pressure (MAP) at 30 mm Hg for 90 minutes. CPZ (5.0 micromol/kg) was administered at 30 minutes after the shock induction, and the 24-hour survival rates were assessed. The MAP, heart rate, and shed blood volume (SBV) were recorded throughout the experiment. Arterial blood gas analysis and the plasma catecholamines levels were measured before and after HS. Double-immunohistochemistry for Fos and tyrosine hydroxylase (TH) was performed in the rostral ventrolateral medulla (RVLM) of the brain. CPZ significantly improved the 24-hour survival rates, which was accompanied by the increase in the MAP and the SBV, a decrease of the plasma catecholamines levels, and attenuation of the severe metabolic acidosis. Furthermore, CPZ reduced the percentage of double-labeled neurons for Fos and TH in the RVLM of the rat brain. TRPV1 may be involved in the regulation of the cardiovascular responses to HS, at least in part, by recruiting catecholaminergic neurons in the RVLM. CPZ appears to induce metabolic compensations, which may be potentially useful in HS.
  Annals of Surgery 07/2007; 245(6):964-70. · 7.49 Impact Factor
• Article: Wood creosote prevents CRF-induced motility via 5-HT3 receptors in proximal and 5-HT4 receptors in distal colon in rats.

  Koji Ataka, Tomoo Kuge, Kazunori Fujino, Toku Takahashi, Mineko Fujimiya
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  ABSTRACT: Wood creosote has been used as an herbal medicine against acute diarrhea caused by food poisoning and has an inhibitory effect on colonic motility and enterotoxin-induced ion secretion. Since no previous studies have examined the effects of wood creosote on stress-induced alteration of colonic motility, we examined the effects on the colonic motility altered by intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF), which is a key mediator in responses to stress. We recorded motor activity in proximal and distal colon of unrestrained conscious rats via two manometory catheters. The frequencies of phase III-like contraction and the % motor indices in both proximal and distal colon were measured. At the same time the number of fecal pellets excreted was counted. I.c.v. injection of CRF increased the motor activity in both proximal and distal colon, and these effects were completely antagonized by i.c.v. injection of a selective CRF type 1 antagonist but not by a CRF type 2 antagonist. Changes in colonic motility induced by CRF were reversed by intravenously administered wood creosote. Intraluminal administration of the 5-HT(3) receptor antagonist granisetron, or the 5-HT(4) receptor antagonist SB 204070 blocked the increase in colonic motility induced by i.c.v. injection of CRF. Wood creosote prevented the increase in colonic motility induced by the 5-HT(3) receptor agonist SR57227A in the proximal colon, while it prevented the increase in colonic motility induced by the 5-HT(4) receptor agonist RS67506 in the distal colon. These results indicate that wood creosote prevents the increase in colonic motility induced by CRF via 5-HT(3) receptors in the proximal colon, and via 5-HT(4) receptors in the distal colon, suggesting that wood creosote might be useful to treat stress-induced diarrhea.
  Autonomic Neuroscience 06/2007; 133(2):136-45. · 1.86 Impact Factor
• Article: Peptide YY3-36 and pancreatic polypeptide suppress food intake.

  Akihiro Asakawa, Masaharu Uemoto, Naohiko Ueno, Miwako Katagi, Mineko Fujimiya, Kazunori Fujino, Noriko Kodama, Hiroaki Nanba, Ruka Sakamaki, Naotaka Shinfuku, Michael M Meguid, Akio Inui
  Journal of Gastroenterology and Hepatology 10/2006; 21(9):1501-2. · 2.87 Impact Factor
• Article: Peptide YY3‐36 and pancreatic polypeptide suppress food intake

  Akihiro Asakawa, Masaharu Uemoto, Naohiko Ueno, Miwako Katagi, Mineko Fujimiya, Kazunori Fujino, Noriko Kodama, Hiroaki Nanba, Ruka Sakamaki, Naotaka Shinfuku, Michael M Meguid, Akio Inui
  Journal of Gastroenterology and Hepatology 07/2006; 21(9):1501 - 1502. · 2.87 Impact Factor
• Article: A case of severe acute pancreatitis treated with CTR-001 direct hemoperfusion for cytokine apheresis.

  Takao Saotome, Yoshihiro Endo, Teiji Sasaki, Takahisa Tabata, Tetsu Hamamoto, Kazunori Fujino, Akira Andoh, Yutaka Eguchi, Tohru Tani, Yoshihide Fujiyama
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  ABSTRACT: Severe acute pancreatitis is a clinical entity that can develop into multiple organ failure (MOF), and still has a poor prognosis. It is generally agreed that excessive humoral mediators such as pro-inflammatory cytokines play important roles in the pathogenesis of organ failure in patients with severe acute pancreatitis (SAP). Furthermore, it has been reported that continuous hemodiafiltration (CHDF) can remove the excess humoral mediators during the hypercytokinemic state of systemic inflammatory response syndrome (SIRS). We experienced a case of severe acute pancreatitis induced by alcohol abuse, on whom we performed cytokine apheresis. The patient was a 46 year-old male. He received 14 cytokine apheresis procedures, for about 4 hours in each session, using a CTR-001 direct hemoperfusion (DHP) cartridge. His serum levels of pro-inflammatory cytokines such as interleukin-6 (IL-6; 1649.1+/-667.1-1257.1+/-489.4 pg/mL, P=0.013) decreased significantly after the CTR-001 procedures. However tumor necrosis factor-alpha (TNF-alpha) (26.2+/-1.7-24.3+/-1.9 pg/mL, P=0.087), IL-1beta (6.1+/-2.9-3.49+/-1.1 pg/mL, P=0.477), IL-8 (192.5+/-33.4-229.5+/-51.8 pg/mL, P=0.754) and IL-10 (14.4+/-2.7-14.0+/-1.9 pg/mL, P=0.726) did not decrease statistically. Therefore, we conclude that in this case, cytokine apheresis using a CTR-001 cartridge was effective for reducing the pro-inflammatory cytokines during severe acute pancreatitis.
  Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 09/2005; 9(4):367-71. · 1.39 Impact Factor
• Article: Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats.

  Chih-Yen Chen, Akio Inui, Akihiro Asakawa, Kazunori Fujino, Ikuo Kato, Chih-Chuan Chen, Naohiko Ueno, Mineko Fujimiya
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  ABSTRACT: Although it has been shown that des-acyl ghrelin decreases food intake and gastric emptying, no previous studies have examined the effects of des-acyl ghrelin on physiologic fed and fasted motor activity in the gastrointestinal tract. We examined the effects of intraperitoneal (IP) administration of des-acyl ghrelin on food intake and the effects of intracerebroventricular (ICV) or intravenous (IV) administration of des-acyl ghrelin on gastroduodenal motility using freely moving conscious rat models. The brain nuclei responding to these effects were examined by c- fos immunohistochemistry of the brain sections. IP injection of des-acyl ghrelin decreased food intake, and this effect was not altered by capsaicin treatment. IP injection of des-acyl ghrelin enhanced c- fos expression in the arcuate and paraventricular nucleus but not in the nucleus of the solitary tract. Both ICV and IV injection of des-acyl ghrelin disrupted fasted motor activity in the antrum but not in the duodenum. Changes in gastric motility induced by IV injection of des-acyl ghrelin were completely antagonized by ICV injection of a selective corticotropin-releasing factor (CRF) 2 receptor antagonist; however, the CRF 1 receptor antagonist had no effects. The results suggest that des-acyl ghrelin decreases food intake and disrupts the fasted motor activity of the antrum in freely moving conscious rats. Peripheral des-acyl ghrelin may induce this function by direct activation of brain receptor by crossing the blood-brain barrier but not by the activation of vagal afferent pathways. In the brain, CRF 2 receptor, but not CRF 1 receptor, is involved in this action.
  Gastroenterology 08/2005; 129(1):8-25. · 11.68 Impact Factor
• Article: Inhibition of the vanilloid receptor subtype-1 attenuates TNBS-colitis.

  Kazunori Fujino, Yoji Takami, Sebastian G de la Fuente, Kirk A Ludwig, Christopher R Mantyh
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  ABSTRACT: Primary sensory neurons are important in regard to the initiation and propagation of intestinal inflammation. The vanilloid receptor subtype-1 (VR-1) is a cation channel located on the sensory nerves that, when stimulated, release proinflammatory peptides. Previous reports have indicated that inhibition of VR-1 with capsazepine (CPZ), a VR-1 antagonist, attenuates dextran sodium sulfate (DSS) colitis in rats. DSS-induced colitis resembles ulcerative colitis with regard to its pathologic features. In this study, we examined the effect of CPZ on trinitrobenzene sulfonic acid (TNBS)-induced colitis, an experimental model of intestinal inflammation that most closely resembles the histologic and microscopic features of Crohn's disease. Colitis was induced by administering a single enema of 100 mg/kg TNBS in 50% ethanol via catheter to lightly anesthetized rats. Subsets of rats were treated with either 1 micromol/kg/ml of CPZ or CPZ-vehicle via enema for 6 days. Seven days after TNBS administration, rats were sacrificed and inflammation was assessed using a validated macroscopic damage score (MDS) and by measuring myeloperoxidase (MPO) activity. In addition, histologic examination was performed. TNBS administration resulted in reproducible chronic erosive lesions extending into the muscularis propria and extensive recruitment of neutrophils in the distal colon. MDS and MPO scores were considerably elevated in the TNBS colons when compared with the TNBS vehicle animals. TNBS rats treated with CPZ enemas exhibited a substantial reduction in MDS and MPO scores and demonstrated dramatically improved pathologic findings. Topical CPZ resulted in considerable attenuation of TNBS-induced colitis. These results support the role of VR-1 and sensory neurons with regard to intestinal inflammation.
  Journal of Gastrointestinal Surgery 12/2004; 8(7):842-7; discussion 847-8. · 2.83 Impact Factor
• Article: [Ghrelin and gut motility].

  Akihiro Asakawa, Akio Inui, Mineko Fujimiya, Kazunori Fujino, Akira Niijima
  Nippon rinsho. Japanese journal of clinical medicine 10/2004; 62 Suppl 9:365-8.
• Article: Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats.

  Kazunori Fujino, Akio Inui, Akihiro Asakawa, Naoki Kihara, Masaki Fujimura, Mineko Fujimiya
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  ABSTRACT: Ghrelin is a newly discovered orexigenic peptide originating from the stomach. However, its action in regulating the fed and fasted motor activity of the digestive tract is not fully understood. In the present study, we examined the effects of intracerebroventricular (I.C.V.) and intravenous (I.V.) injection of ghrelin on the physiological fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats. I.C.V. and I.V. injection of ghrelin induced fasted motor activity in the duodenum in normal fed rats, while I.V. injection of ghrelin induced fasted motor activity in both the stomach and duodenum in vagotomized rats. The effects of I.C.V. and I.V. injected ghrelin were blocked by growth hormone secretagogue receptor (GHS-R) antagonist given by the same route and also blocked by immunoneutralization of neuropeptide Y (NPY) in the brain. The effects of I.V. injected ghrelin were not altered by I.C.V. injection of GHS-R antagonist in vagotomized rats. Injection of GHS-R antagonist blocked the fasted motor activity in both the stomach and duodenum in vagotomized rats but did not affect the fasted motor activity in normal rats. Low intragastric pH inhibited the effect of ghrelin. The present results indicate that ghrelin is involved in regulation of fasted motor activity in the stomach and duodenum. Peripheral ghrelin may induce the fasted motor activity by activating the NPY neurons in the brain, probably through ghrelin receptors on vagal afferent neurons. Once the brain mechanism is eliminated by truncal vagotomy, ghrelin might be primarily involved in the regulation of fasted motor activity through ghrelin receptors on the stomach and duodenum. The action of ghrelin to induce fasted motor activity is strongly affected by intragastric pH; low pH inhibits the action.
  The Journal of Physiology 08/2003; 550(Pt 1):227-40. · 4.72 Impact Factor