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Murakami, Manabu ; Nemoto, Takayuki ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Ono, Kyoichi ; Watanabe, Hiroyuki ; Hirota, Kazuyoshi ; Ohba, Takayoshi
概要:
Aims: The purpose of the current study was to evaluate the significance of the endothelin system in catecholamine release and synthesis in the adrenal gland.Main Methods: Primary cultures of isolated bovine adrenal medullary cells
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were prepared. Gene expression, intracellular calcium changes, epinephrine release, and other factors were investigated.Key findings: Expression of endothelin receptors in the rat adrenal gland was confirmed. Intravenous infusion of endothelin-1 (1.0 nmol) increased blood pressure (systolic and diastolic). Endothelin-1 stimulated intracellular calcium changes, resulting in increased nuclear factor of T cell (NFAT) activity and epinephrine release from cultured adrenal medullary cells. Furthermore, endothelin-1 increased catecholamine synthesis and caused hypertrophic changes in the cell size.Significance: Our findings indicate involvement of the endothelin system in the sympathetic regulation of the adrenalmedulla.
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Shintaku, Tomohiro ; Ohba, Takayoshi ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Hirota, Kazuyoshi ; Ono, Kyoichi ; Mariya, Yasushi ; Imaizumi, Tadaatsu ; Sawamura, Daisuke ; Murakami, Manabu
概要:
General anesthesia is important for pharmacological studies in laboratory animals. Although a number of transgenic anima
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ls have been reported, basic analyses concerning mouse ECG and heart rate variability（ HRV） have not been rigorously examined.
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Shintaku, Tomohiro ; Ohba, Takayoshi ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Hirota, Kazuyoshi ; Ono, Kyoichi ; Mariya, Yasushi ; Imaizumi, Tadaatsu ; Sawamura, Daisuke ; Murakami, Manabu
概要:
We compared the effects of inhalation anesthesia（ 2% isoflurane）, intraperitoneal injection of pentobarbital anesthesia
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（50 mg/kg）, and a combination anesthetic consisting of medetomidine, midazolam and butorphanol （MMB） on electrocardiograms in mice. Using either isoflurane inhalation anesthesia or pentobarbital anesthesia, heart rate （HR） was in the acceptable range （ca. 450-500 bpm）. In contrast, MMB anesthesia decreased HR significantly. Importantly, MMB anesthesia responded minimally to propranolol （β-blocker）, suggesting that MMB anesthesia affects sympathetic tonus and is not suitable for evaluation of the cardiovascular or sympathetic system. We confirmed that modified MMB, with a decreased dose of medetomidine from the original protocol（ an α2 agonist）, was associated with a HR of 400 bpm and a diminished response to propranolol. Our present results illustrate the importance of using an appropriate form of anesthesia suitable for experimental pharmacological studies.
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Onda, Kaoru ; Yoshida, Hidemi ; Hayakari, Ryo ; Xing, Fei ; Wang, Lian ; Matsumiya, Tomoh ; Kawaguchi, Shogo ; Murakami, Manabu ; Imaizumi, Tadaatsu
概要:
Dysregulation of iron homeostasis in brain causes various neurodegenerative disorders. In fact, high concentration of ir
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on is present in brains of patients with Alzheimer’s disease. It was previously reported that CXCL8 protects human neurons from amyloid-β-induced neurotoxicity and that astrocytes have the potential to play important roles in Alzheimer’s disease. In the present study, we examined the effect of desferrioxamine, an iron chelator, on the expression of CXCL8 in U373MG human astrocytoma cells used as a model of astrocytes. Treatment of the cells with desferrioxamine induced the expression of CXCL8. Pretreatment of the cells with FeSO4 counteracted the positive effect of desferrioxamine on CXCL8 production, suggesting that the effect of desferrioxamine was due to iron chelation. RNA interference experiments showed that HIF-1α was not involved in desferrioxamine-induced CXCL8 expression. We conclude that desferrioxamine induces CXCL8 in astrocytes and the chelation of iron may be a new therapeutic strategy for Alzheimer’s disease.
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| 5.
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Chong, Han ; Ogata, Yoshiki ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Watanabe, Hiroyuki ; Imaizumi, Tadaatsu ; Hirota, Kazuyoshi ; Ono, Kyoichi ; Ohba, Takayoshi ; Murakami, Manabu
概要:
Transgenic mice experiments have become increasingly popular to research human inherited disease.However, a number of Ja
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panese researchers have difficulty with the selection of anesthesia, after the classificationof ketamine, probably the most used anesthesia, as a narcotic drug in 2006. Therefore, we compared the effects ofinhalation anesthesia （2% of isoflurane, sevoflurane and enflurane） and intraperitoneal pentobarbital anesthesia （50mg/kg） on the electrocardiogram（ ECG） and blood oxygen saturation（ SPO2） of mice. With inhalation anesthesia, theheart rate（ HR） and SPO2 were within an acceptable range. In contrast, the HR significantly decreased after initiationof pentobarbital anesthesia, and gradually returned to a low rate. Importantly, pentobarbital anesthesia significantlylowered SPO2, and heart rate variability analysis showed unstable beat-to-beat intervals during pentobarbitalanesthesia, suggesting that inhalation anesthesia is more suitable for evaluation of cardiorespiratory responsesthan pentobarbital anesthesia. During anesthesia, propranolol, a ????-adrenergic blocker, significantly decreased heartrate. Atropine, a parasympathetic blocker, also significantly increased heart rate. Our data suggest that inhalation anesthesia is suitable for cardiorespiratory analysis in mice.
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| 6.
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Nozaki, Shuhei ; Ogata, Yoshiki ; Yonekura, Manabu ; Han, Chong ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Hirota, Kazuyoshi ; Matsuzaki, Yasushi ; Tomita, Hirofumi ; Imaizumi, Tadaatsu ; Itagaki, Shirou ; Sawamura, Daisuke ; Murakami, Manabu
概要:
We analyzed the effects of halothane as an inhalational anesthetic agent on electrocardiogram （ECG）parameters in C57/BL6
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mice. Following induction of anesthesia using 2% halothane, the ECGs showed a regularpattern and the heart rate （HR） was within an acceptable range （~500 bpm）. The HR decreased with increasinghalothane concentration in a concentration-dependent fashion. The frequency domain analysis showed that the high-frequency （HF） component decreased and the lowfrequency（LF） component increased in a concentration-dependent fashion. Therefore, the LF/HF ratio increasedwith increasing halothane concentration, suggesting effects on the autonomic nervous system. We analyzed the pharmacological response to sympathetic blockade with propranolol, a typical adrenergicβ-blocker, under halothane anesthesia. Propranolol administration resulted in a decreased HR; interestingly,intraperitoneal injection of propranolol （120 μg/kg body weight） resulted in arrhythmia （sick sinus syndrome）during anesthesia with 3% halothane. Our results indicate the importance of selecting a suitable anesthetic agent for C57/BL6 mice in pharmacological studies
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| 7.
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Ogata, Yoshiki ; Yonekura, Manabu ; Yamaki, Rouichi ; Han, Chong ; Fujiwara, Tomonori ; Seya, Kazuhiko ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Imaizumi, Tadaatsu ; Hirota, Kazuyoshi ; Tomita, Hirofumi ; Murakami, Manabu
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We examined the effects of enflurane anesthesia on the mouse cardiac autonomic nervous system usingelectrocardiogram（ EC
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G） analysis. Enflurane had a lower effect on heart rate（ HR） compared to isoflurane, which ismore widely used in small animal studies. Under anesthesia with 3 or 4% of enflurane, administration of propranololhad a significant effect on HR. Enflurane increased R-R interval length in a dose-dependent fashion, and the R-Rinterval became unstable at high concentrations. Although HR decreased with high doses of enflurane, we observednormal sinus rhythm and no arrhythmia. These results suggest that the effect of enflurane anesthesia is acceptableeven though the drug can lead to cardiac instability. No remarkable changes were observed in HR frequency. These results suggest that enflurane anesthesia may be suitable for cardiac autonomic nervous system analysis.
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| 8.
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Han, Chong ; Inaba, Wataru ; Yonekura, Manabu ; Ogata, Yoshiki ; Ohba, Takayoshi ; Kushikata, Tetsuya ; Niwa, Hidetoshi ; Yanagisawa, Teruyuki ; Tomita, Hirofumi ; Itagaki, Shirou ; Hirota, Kazuyoshi ; Akai, Hiroaki ; Mizukami, Hiroki ; Murakami, Manabu
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Persistent hyperglycemia is implicated in the pathogenesis of chronic diabetic complications, such asneuropathy. Theref
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ore, we investigated Electrocardiogram（ ECG）-related changes, including various ECG parametersand heart rate variability, and neuropathic changes in diabetic Goto-Kakizaki （GK） rats, a spontaneous model fortype 2 diabetes. GK rats （50 weeks old） showed increased plasma glucose and decreased R-R interval variability,which was likely due to diabetic polyneuropathy in the autonomic nervous system. Interestingly, GK rats showed adecreased baroreflex compared with control Wistar rats. Furthermore, GK rats showed limited fluctuation changesin beat-to-beat dynamics. In the frequency domain analysis, the low-frequency component was similar but the highfrequencycomponent was significantly decreased in GK rats, suggesting decreased parasympathetic nerve regulationand conserved sympathetic nerve regulation. In addition, GK rats showed a limited response to high-dose atropine, amuscarinic receptor antagonist, indicating modified parasympathetic nerve regulation in GK rats. Our data stronglysuggests that GK rat could be a nice animal model for chronic cardiovascular disease related to diabetic neuropathy.
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| 9.
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Murakami, Manabu ; Murakami, Agnieszka A ; Ohba, Takayoshi
概要:
We analyzed transient and stable eukaryotic gene expression using internal ribosome entry site （IRES）and green fluoresce
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nt protein （GFP）-S65T （IRES-GFP） expression systems. The IRES-containing vector enablessimple construction of a plasmid and easy detection of transfected cells, as well as an estimation of the levels of thegene of interest. This system is useful for measuring changes in the intracellular calcium concentration using thefluorescent calcium indicator Fura-2 AM, although subcellular localization of the protein of interest is not detectable.Importantly, the IRES-GFP plasmid showed delayed expression and an approximate 40% reduction in fluorescenceintensity, which suggests that usage of IRES-containing expression system might cause under-estimation of desiredgene. Although this technique has some disadvantages, the IRES-containing vector is simple and straightforward for gene expression analysis, comparing with co-expression procedure of multiple plasmids.
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| 10.
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Imaizumi, Tadaatsu ; Yano, Chikashi ; Numata, Akiko ; Tsugawa, Koji ; Hayakari, Ryo ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Watanabe, Shojiro ; Tsuruga, Kazushi ; Kawaguchi, Shogo ; Murakami, Manabu ; Tanaka, Hiroshi
概要:
Activation of Toll-like receptor 3 (TLR3) signaling followed by type I interferon (IFN) expression is crucial in antivir
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al and "pseudoviral" immune reactions in renal mesangial cells (MCs). These reactions are probably involved in the pathogenesis of chronic kidney disease (CKD). However, the role of IFN-induced 35-kDa protein 35 (IFI35), a type I IFN-dependent transcript, in glomerular inflammation is unclear. Here, we aimed to investigate the expression and the role of IFI35 in IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 and IFN-β/melanoma differentiation-associated gene 5 (MDA5)/CXCL10 axes in MCs.<br />We treated human MCs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, then analysed the IFI35 expression by reverse transcription-polymerase chain reaction and western blotting. To examine the regulation of IFI35 expression, we subjected MCs to RNA interference (siRNA) against IFN-β, RIG-I, and MDA5.<br />Activation of TLR3 by poly IC induces the IFI35 expression in MCs. siRNA against IFN-β inhibited poly IC-induced IFI35 expression. Knockdown of IFI35 resulted in a decrease of poly IC-induced RIG-I and MDA5 protein as well as decreased CCL5 and CXCL10 mRNA and protein expression. However, it did not affect the expression of none of phosphorylated signal transducers or activator of transcription (STAT) 1 protein, or RIG-I and MDA5 in mRNA levels.<br />Regional expression of IFI35 and its dysregulation may be involved in the pathogenesis of glomerular inflammation in CKD.
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