巻号一覧
90 巻 (2002)
- 4 号 p. 295-
- 3 号 p. 205-
- 2 号 p. 101-
- 1 号 p. 1-
90 巻, 3 号
選択された号の論文の15件中1～15を表示しています
- |<
- <
- 1
- >
- >|
Forum Minireview
-
Mizuo Miyazaki専門分野: Infomation Science
2002 年 90 巻 3 号 p. 205
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーPDF形式でダウンロード (41K) -
Masatoshi Nakajima, Noriyuki Naya専門分野: Infomation Science
2002 年 90 巻 3 号 p. 206-209
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーChymase, a chymotrypsin-like serine protease, has not only alternative angiotensin II-generating activity but also various activities involving inflammatory responses. However, little is known of its contribution to physiological functions. Therefore, chymase inhibitors are thought to be potentially useful as tools for elucidating the physiological functions of chymase and therapeutic agents. Within the last five years, many patents on non-peptide chymase inhibitors have been published. We developed a potent non-peptide chymase inhibitor BCEAB (4-[1-{[bis-(4-methyl-phenyl)-methy]-carbamoyl}-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid) and examined its effect on inflamed tissue remodeling and fibrosis using a hamster sponge implant model. BCEAB has high inhibitory activity against human chymase but not against angiotensin-converting enzyme, elastase and tryptase. In the hamster sponge implant model, oral administration of BCEAB for 15 days dose-dependently suppressed both the dry weight of granuloma tissues in the sponge discs and the amounts of hydroxyproline in the tissues gradually increased during the experimental period. These results suggest that chymase, at least in part, participates in the growth of granuloma tissues of inflammatory regions by stimulating fibroblast growth and extracellular matrix collagen deposition. Chymase inhibitors for oral administration, such as BCEAB, might be useful for clarifying the pathophysiological roles of chymase in vivo.
抄録全体を表示PDF形式でダウンロード (152K) -
Takeo Suzuki, Hiroki Kaki, Shinichi Naya, Soji Murayama, Akira Tatsui, ...専門分野: Infomation Science
2002 年 90 巻 3 号 p. 210-213
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーHuman chymase is a mast cell-derived serine proteinase, which is a non-angiotensin converting enzyme angiotensin II-generating enzyme. It appears to participate in various diseases, but it is unclear whether chymase plays major roles in physiological and pathophysiological functions in vivo. To obtain information on the physiological and pathophysiological functions of chymase and to search for diseases in which chymase participates, in the present study, we aimed at producing recombinant human chymase in large quantities and at developing an ELISA system using anti-human chymase antibodies. A recombinant human chymase was produced by a silkworm-baculovirus expression system. The recombinant chymase in active form was efficiently purified from larval hemolymph using cation-exchange and heparin column chromatography. This recombinant enzyme was enzymatically identical with native human chymase. On the other hand, the stability of the recombinant enzyme in cultured medium for mammalian cells at 37°C was very high as compared with the stability of the native enzyme; 20% of the activity was maintained 120 h after addition of medium. These results indicated that the recombinant enzyme could also utilize in vitro and in vivo assay systems. We obtained several anti-chymase monoclonal antibodies by using the recombinant human chymase as antigen. These antibodies were used to construct an ELISA system for measuring the chymase concentration in blood. As a result of preliminary examination using this ELISA system, it was shown that the chymase concentration in each serum from hypertensive patients is significantly higher than in normal serum. The ELISA system will be applicable for clinical diagnosis and in vivo evaluation systems for chymase-targeting drugs.
抄録全体を表示PDF形式でダウンロード (171K) -
Teruaki Imada, Naruyasu Komorita, Fujio Kobayashi, Koji Naito, Tsutomu ...専門分野: Infomation Science
2002 年 90 巻 3 号 p. 214-217
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーA novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may have a therapeutic potential in the treatment of AD. We found that Y-40613 (2-[5-amino-2-(4-fluorophenyl)-1,6-dihydro-6-oxo-1-pyrimidinyl]-N-{1-[(5-methoxycarbonyl-2-benzoxazolyl)carbonyl]-2-phenylethyl}acetamide) dose-dependently suppressed the scratching response in a mouse pruritus model, with inhibitory efficacy enhanced by combination with conventional drugs, suggesting that chymase contributes to the development of pruritus by a unique mechanism or mechanisms. In fact, chymase injected in the model induced the scratching response. In vitro IgE production from mouse B cells was increased by purified rat chymase and suppressed by Y-40613. Increased serum IgE observed in Brown Norway rats injected with mercury chloride was suppressed by Y-40613. Furthermore, Y-40613 lowered ear thickness as well as serum IgE level in a mouse contact dermatitis model. Taken together, these findings suggest that the specific chymase inhibitor Y-40613 may ameliorate symptoms of AD through the dual inhibition of the chymase-dependent IgE production pathway and itching sensation.
抄録全体を表示PDF形式でダウンロード (200K) -
Yoshikazu Sukenaga, Keiichi Kamoshita, Shinji Takai, Mizuo Miyazaki専門分野: Infomation Science
2002 年 90 巻 3 号 p. 218-222
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーChymase leading to tissue remodeling is expected to be a potent pharmaceutical target. Its functions in vivo are still unclear, because of lack of orally available inhibitors. Recently, however, the chymase inhibitor NK3201 (2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl] acetamide) was demonstrated to have oral activity against neointimal hyperplasia in dog models (Takai S. et al., Life Sci 69, 1725 – 1732 (2001)). In this review, by showing the efficacy of NK3201 in some hamster models, chymase functions in vivo are summarized, and the potency of this chymase inhibitor is introduced. In vitro study, NK3201 showed potent chymase specific inhibitory activity, and Dixon plot analysis indicated competitive inhibition. Oral administration of NK3201 into normal rats resulted in rapid spread over every tissue except the brain, and sufficient activity to inhibit tissue chymase was detected even after 24 h. In passive cutaneous anaphylaxis, myocardial infarction and bleomycin-induced pulmonary fibrosis models, orally administered NK3201 showed potent inhibition of inflammatory response, tissue angiotensin II formation, and fibrosis, respectively. These data suggest that chymase has a vital role in tissue remodeling through promotion of the inflammatory response, tissue angiotensin II and tissue fibrosis. Our recent data indicated chymase participation in bladder fibrosis, like interstitial cystitis. Therefore, the orally active chymase inhibitor NK3201 may have protective effects on tissue remodeling in several diseases.
抄録全体を表示PDF形式でダウンロード (278K) -
Shinji Takai, Mizuo Miyazaki専門分野: Infomation Science
2002 年 90 巻 3 号 p. 223-227
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーIn vascular tissues, angiotensin II is potentially cleaved from angiotensin I by chymase and angiotensin-converting enzyme (ACE). In the normal state, vascular ACE regulates local angiotensin II formation and plays a crucial role in the regulation of blood pressure, whereas chymase is stored in mast cells and has no enzymatic activity. Chymase is activated immediately upon its release into the extracellular matrix in vascular tissues after mast cells have been activated by stimuli such as vessel injury by grafting or a balloon catheter. In dog grafted veins, chymase activity is increased, and the vascular proliferation is suppressed by either a chymase inhibitor or an angiotensin II receptor blocker. After balloon injury in dog vessels, chymase activity is significantly increased in the injured artery, and a chymase inhibitor is effective in preventing the vascular proliferation, but an ACE inhibitor is ineffective. Chymase plays an important role in the development of vascular proliferation via the induction of local angiotensin II formation in injured vessels.
抄録全体を表示PDF形式でダウンロード (140K)
Full Papers
-
Shigeki Miyamoto, Bing-Mei Zhu, Kazunori Kamiya, Yoshinobu Nagasawa, K ...専門分野: Infomation Science
2002 年 90 巻 3 号 p. 229-235
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーKB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate) has been used as a pharmacological tool to block the Ca2+ influx-mode of the Na+/Ca2+ exchanger, which is thought to contribute to ischemia/reperfusion and digitalis arrhythmias. We examined effects of KB-R7943 on ischemia/reperfusion arrhythmias in beagle dogs anesthetized with sodium pentobarbital. Lead II ECG and BP were measured. KB-R7943 or the solvent (10% DMSO) was injected i.v. as a bolus, and 5 min later, the left anterior descending coronary artery was occluded for 30 min followed by reperfusion. KB-R7943 at 5 or 10 mg/kg increased BP without changing ECG parameters including the heart rate. Although 5 mg/kg KB-R7943 deceased the number of arrhythmic beats during the ischemic period, mortality due to ischemia/reperfusion was not decreased by KB-R7943 (5 and 10 mg/kg). KB-R7943 at 5 mg/kg also did not suppress the ouabain-induced arrhythmias. These negative results suggest that Na+/Ca2+ exchange inhibition may not be a useful strategy of suppressing arrhythmias.
抄録全体を表示PDF形式でダウンロード (378K) -
Yujiang Wang, Mie Ohtsuka-Isoya, Ping Shao, Seizaburo Sakamoto, Hisash ...専門分野: Infomation Science
2002 年 90 巻 3 号 p. 236-246
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーExcessive glucocorticoids induce osteoporosis. However, there is some controversy regarding the mechanism of action, and even the endpoint result. The present study was carried out to obtain further insight into the action of glucocorticoids on bone formation and resorption in rats. Growing rats were injected subcutaneously with methylprednisolone (mPSL) at doses of 0, 2.5, 5, 10 or 20 mg/kg per day for 4 weeks. Bone mineral density (BMD), enchondral and periosteal bone formation, collagen synthetic activities of osteoblasts, numbers of osteoblasts and osteoclasts, and serum markers to assess bone turnover were determined. Administration of mPSL dose-dependently increased the BMD in the tibial metaphysis, while it dose-dependently decreased the BMD in the diaphysis. Both enchondral and periosteal bone formation were decreased in a dose-dependent fashion. The incorporation and secretion of 3H-proline by osteoblasts were both decreased in trabecular and cortical bones. The number of osteoclasts, together with the number of osteoblasts, in the tibial metaphysis was drastically decreased. Serum alkaline phosphatase and osteocalcin were decreased at higher doses. These results support the recent notion that glucocorticoids inhibit both bone formation and resorption. In addition, BMD as an endpoint result might differ from site to site in bone due to a different balance between bone formation and resorption.
抄録全体を表示PDF形式でダウンロード (822K) -
Shinichiro Haze, Keiko Sakai, Yoko Gozu専門分野: Infomation Science
2002 年 90 巻 3 号 p. 247-253
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーWe investigated the effects of fragrance inhalation on sympathetic activity in normal adult subjects using both power spectral analysis of blood pressure fluctuations and measurement of plasma catecholamine levels. Fragrance inhalation of essential oils, such as pepper oil, estragon oil, fennel oil or grapefruit oil, resulted in 1.5- to 2.5-fold increase in relative sympathetic activity, representing low frequency amplitude of systolic blood pressure (SBP-LF amplitude), compared with inhalation of an odorless solvent, triethyl citrate (P<0.05, each). In contrast, fragrance inhalation of rose oil or patchouli oil caused a 40% decrease in relative sympathetic activity (P<0.01, each). Fragrance inhalation of pepper oil induced a 1.7-fold increase in plasma adrenaline concentration compared with the resting state (P = 0.06), while fragrance inhalation of rose oil caused a 30% decrease in adrenaline concentration (P<0.01). Our results indicate that fragrance inhalation of essential oils may modulate sympathetic activity in normal adults.
抄録全体を表示PDF形式でダウンロード (197K) -
Chihiro Tohda, Noriaki Matsumoto, Kun Zou, Meselhy R. Meselhy, Katsuko ...専門分野: Infomation Science
2002 年 90 巻 3 号 p. 254-262
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーExtension of axons and dendrites in neurons may compensate for and repair damaged neuronal networks in the dementia brain. To find out drugs capable of regenerating the neuronal network, we focused on several herbal drugs belonging to the genus Panax, kinds of Ginseng, and investigated neurite outgrowth activity of their extracts and compounds. We found that the methanol extracts of Ginseng (root of P. ginseng), Notoginseng (root of P. notoginseng) and Ye-Sanchi in Chinese (rhizome of a relative to P. vietnamensis) increased neurite outgrowth in SK-N-SH cells. The protopanaxadiol-type saponins, ginsenosides Rb1 and Rb3, and notoginsenosides R4 and Fa isolated from Ye-Sanchi extract extended neurites, while protopanaxatriol-, ocotillol- and oleanane-type saponins had no effect on the neurite outgrowth. The percentage of cells with multipolar neurites and number of varicosities were intensely high in cells treated with the methanol extract of Ye-Sanchi as well as ginsenosides Rb1 and Rb3, and notoginsenosides R4 and Fa. Both phosphorylated NF-H-expressing neurites and MAP2-expressing ones were extended by treatment with those saponins and the extract. Especially, longer neurites were mainly positive for phosphorylated NF-H. These results suggest that protopanaxadiol-type saponins enhance axonal and dendritic formation activity.
抄録全体を表示PDF形式でダウンロード (387K) -
Miyako Takata, Naoto Burioka, Shigehiro Ohdo, Hiroshi Takane, Hideyuki ...専門分野: Infomation Science
2002 年 90 巻 3 号 p. 263-269
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーThe mammalian circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and in most peripheral tissues. Clock genes drive the biological clock. However, circadian expression variations of the human clock genes are still unclear. In this study, we analyzed the daily variations of mPer2 and mClock mRNA expression in both the mouse SCN and liver to evaluate the central and peripheral alterations in the rodent clock genes. We also examined whether there are the daily variations of the clock genes hPer2 and hClock in human peripheral blood mononuclear cells (PBMCs). The daily variation of mClock and mPer2 mRNA expression in mouse SCN and liver were determined at ZT2, ZT6, ZT10, ZT14, ZT18 or ZT22. We isolated PBMCs from 9 healthy volunteers at 9:00 and 21:00 and examined the expression of hPer2 and hClock mRNA by RT-PCR analysis. The animals exhibited a robust daily rhythm in the RNA levels of mPer2 in the SCN and liver (P<0.01, respectively). In humans, hPer2 mRNA expression also had daily variation, and the hPer2 mRNA levels at 9:00 were significantly larger than those at 21:00 (P<0.01). While, the Clock mRNA in both mice and humans exhibited no daily variation. These findings suggest that the variation in hPer2 mRNA expression may be useful for assessing human peripheral circadian systems.
抄録全体を表示PDF形式でダウンロード (223K) -
Takehiko Maeda, Shiroh Kishioka, Norihiro Inoue, Norifumi Shimizu, Yoh ...専門分野: Infomation Science
2002 年 90 巻 3 号 p. 270-275
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーThis paper is the first report of a genetic index for morphine withdrawal in infant rats. We examined the effects of naloxone (2 mg/kg) on c-fos mRNA levels in brains of infant and adult rats following repeated treatment with morphine (20 mg/kg, once daily for 5 days). One hour after a single administration of naloxone (naloxone challenge), an increase in c-fos mRNA was observed in the olfactory bulb, hypothalamus and medulla oblongata of infant rats, and in the olfactory bulb and hypothalamus, but not in the medulla oblongata of adult rats. The c-fos mRNA levels returned to control levels 6 h after the naloxone challenge. The increase in c-fos mRNA levels was followed by body weight loss in both infant and adult rats. When MK-801, a non-competitive N-methyl-D -aspartate (NMDA) receptor antagonist, was co-administered along with morphine, it inhibited the naloxone-induced increases in c-fos mRNA levels in infant rats following repeated morphine administration. These results suggest that physical dependence develops in infant rats following repeated morphine administration and that the increment of c-fos mRNA levels is a useful indicator for naloxone-precipitated morphine withdrawal in infant as well as in adult rats.
抄録全体を表示PDF形式でダウンロード (189K) -
De Cheng Ren, Guan Hua Du, Jun Tian Zhang専門分野: Infomation Science
2002 年 90 巻 3 号 p. 276-280
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーThe effect of the water-soluble extract (WSE) of Salvia miltiorrhiza on neutrophil-endothelial cell adhesion was investigated. Cell adhesion was evaluated by testing neutrophil myeloperoxidase activity: expression of adhesion molecules in human umbilical vein endothelial cells (HUVEC) was measured by ELISA: the neutrophil activation rate induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was tested by the method of nitroblue tetrazolium (NBT) reduction. The results showed that the adhesion rate of neutrophils to unstimulated HUVEC was very low. TNFα (50 – 800 U/ml) increased the adhesion of neutrophils to TNFα-stimulated HUVEC in a concentration- and time-dependent manner. The WSE of Salvia miltiorrhiza (0.01 – 1 mg/ml) dose-dependently inhibited the adhesion of neutrophils. The inhibitory rate of the WSE of Salvia miltiorrhiza at 0.01, 0.1 and 1 mg/ml was 6.2%, 17.0% and 28.0%, respectively. fMLP (10−9 – 10−5 M) increased the activation rate of neutrophils concentration-dependently. The WSE of Salvia miltiorrhiza also concentration-dependently inhibited the adhesion of fMLP-activated neutrophils to HUVEC. The inhibitory rate of the WSE of Salvia miltiorrhiza at 0.001, 0.01 and 0.1 mg/ml was 5.3%, 26.3% and 28.9%, respectively. Moreover, TNFα upregulated expression of adhesion molecule E-selectin, ICAM-1 and VCAM-1. The WSE of Salvia miltiorrhiza had an inhibitory effect on TNF α-induced expression of these molecules. These results indicated that the WSE of Salvia miltiorrhiza inhibited neutrophil-endothelial adhesion. The action mechanism of the WSE of Salvia miltiorrhiza was partly related to suppressing the expression of adhesion molecules.
抄録全体を表示PDF形式でダウンロード (136K) -
Hitoshi Kontani, Chisato Shiraoya専門分野: Infomation Science
2002 年 90 巻 3 号 p. 281-290
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーWe simultaneously recorded the prostatic contractile and urethral pressure responses to electrical stimulation (ES) of the hypogastric nerves (HGNs) or phenylephrine in anesthetized rats and studied the effects of tamsulosin on these responses. At 0.01 and 0.1 mg/kg, i.v., tamsulosin inhibited the prostatic responses to ES of the HGNs in a dose-dependent manner, while at 1 μg/kg, i.v., it reduced the response to phenylephrine (0.01 mg/kg, i.v.) to about 26% of the nonantagonized level. These inhibitory effects on prostatic responses were maintained for 60 min. Tamsulosin exerted an inhibitory effect on the urethral response to ES of the HGNs at 0.01 mg/kg, i.v. but not at 0.1 mg/kg, i.v. At 1 μg/kg, i.v., tamsulosin also reduced the urethral response to phenylephrine to about 46% of the nonantagonized level; this effect was maintained for 60 min. Furthermore, tamsulosin was found to exert a stronger inhibitory effect on the prostatic response than on the urethral response induced by sympathetic nerve activation. Our findings suggest that rat urethral sympathetic nerve terminals may contain prejunctional α1 adrenoceptors that modulate the release of norepinephrine.
抄録全体を表示PDF形式でダウンロード (504K)
Short Communication
-
Chin-San Liu, Ching-Shan Tsai専門分野: Infomation Science
2002 年 90 巻 3 号 p. 291-294
発行日: 2002年
公開日: 2002/11/23
ジャーナル フリーNull genotype of glutathione S-transferase class μ (GSTM1(−)) and the plasma level of malondialdehyde (MDA) were determined in normal subjects, epileptics with good seizure control and epileptics with intractable seizure. The frequency of GSTM1(−) of the epileptics with intractable seizure was significantly higher than that of the group with good seizure control and that of the normal subjects. The average plasma level of MDA of the patients with GSTM1(−) genotype was higher than that of the subjects with GSTM1(+) in either the normal or epileptic group. Thus, the GSTM1(−) genotype may be one of the genetic factors involved in the response to anticonvulsant therapy.
抄録全体を表示PDF形式でダウンロード (120K)
- |<
- <
- 1
- >
- >|