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91.
Yoshihiro Mitsuhashi Yuichi Sugiyama Shogo Ozawa Takashi Nitanai Kunihiro Sasahara Kan-Ichi Nakamura Miroru Tanaka Takuzo Nishimura Makoto Inaba Tomowo Kobayashi 《Cancer chemotherapy and pharmacology》1990,27(1):20-26
Summary Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Loglog plots of body weight (W; kg) vs total plasma clearance (CLtot, p; ml/min) and steady-state distribution volume (Vd, ss; 1) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was >97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CLtot,p=50.6 W0.957; Bd, ss=1.29 W1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CLu
tot,p and Vd,u
ss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CLu
tot,p=71.7 W0.891; Bd,u
ss=1.82 W0.966) were also high (r0.991). The extrapolated values vs those observed in a 70-kg human were the following: CLu
tot,p, 3,160 vs 2,290 ml/min; Vd,u
ss, 110 vs 1061. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation. 相似文献
92.
Objectives It is likely that genetic factors play a role in the etiology of chronic sinusitis, and airway inflammation is an important pathological feature in chronic sinusitis. We hypothesized that individuals with greater inflammatory responses may be more likely to acquire the disease. Polymorphisms of the tumor necrosis factor (TNF) genes have been described, and certain inflammatory diseases are reportedly associated with certain alleles of TNF genes. The purpose of this study is to examine whether there is an association between some alleles of TNF genes and chronic sinusitis. Study Design Thirty‐eight Japanese patients with intractable chronic sinusitis were selected on the basis of the following criteria: 1) persistent mucous or mucopurulent nasal discharge and/or postnasal dripping for longer than 3 years and 2) opacification in bilateral maxillary sinuses and ethmoid cells on plain radiographic films. Methods Both tumor necrosis factor‐α (TNF‐α) and tumor necrosis factor‐β (TNF‐β) gene polymorphisms were analyzed by polymerase chain reaction (PCR) with restriction fragment length polymorphisms in these patients and 35 healthy control subjects. Results A significantly higher frequency (P < .05) of TNFB*2 allele of TNF‐β gene polymorphism was observed in patients with chronic sinusitis (74%) compared with control subjects (56%). There was no association between alleles of TNF‐α and chronic sinusitis. Conclusion We concluded that TNF‐β gene polymorphism may form a component of the genetic predisposition to chronic sinusitis in Japanese patients. 相似文献
93.
Akitaka Yamasaki Kumiko Maruyama-Takahashi Kento Nishida Shogo Okazaki Kouki Okita Yasutoshi Akiyama Hideaki Suzuki Yuichi Endo Kazue Masuko Takashi Masuko Yoshihisa Tomioka 《Genes to cells : devoted to molecular & cellular mechanisms》2023,28(5):374-382
Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be caused by cancer heterogeneity and persistent HER phosphorylation, often reduces overall therapeutic effects. We herein showed that a newly discovered molecular complex between CD98 and HER2 affected HER function and cancer cell growth. The immunoprecipitation of the HER2 or HER3 protein from lysates of SKBR3 breast cancer (BrCa) cells revealed the HER2-CD98 or HER3-CD98 complex. The knockdown of CD98 by small interfering RNAs inhibited the phosphorylation of HER2 in SKBR3 cells. A bispecific antibody (BsAb) that recognized the HER2 and CD98 proteins was constructed from a humanized anti-HER2 (SER4) IgG and an anti-CD98 (HBJ127) single chain variable fragment, and this BsAb significantly inhibited the cell growth of SKBR3 cells. Prior to the inhibition of AKT phosphorylation, BsAb inhibited the phosphorylation of HER2, however, significant inhibition of HER2 phosphorylation was not observed in anti-HER2 pertuzumab, trastuzumab, SER4 or anti-CD98 HBJ127 in SKBR3 cells. The dual targeting of HER2 and CD98 has potential as a new therapeutic strategy for BrCa. 相似文献
94.
Kazuharu Arakawa Tetsuro Hirose Toshifumi Inada Takuhiro Ito Toshie Kai Masaaki Oyama Yukihide Tomari Takao Yoda Shinichi Nakagawa 《Genes to cells : devoted to molecular & cellular mechanisms》2023,28(8):539-552
A long-standing assumption in molecular biology posits that the conservation of protein and nucleic acid sequences emphasizes the functional significance of biomolecules. These conserved sequences fold into distinct secondary and tertiary structures, enable highly specific molecular interactions, and regulate complex yet organized molecular processes within living cells. However, recent evidence suggests that biomolecules can also function through primary sequence regions that lack conservation across species or gene families. These regions typically do not form rigid structures, and their inherent flexibility is critical for their functional roles. This review examines the emerging roles and molecular mechanisms of “nondomain biomolecules,” whose functions are not easily predicted due to the absence of conserved functional domains. We propose the hypothesis that both domain- and nondomain-type molecules work together to enable flexible and efficient molecular processes within the highly crowded intracellular environment. 相似文献
95.
Mitsuhiro Fukao Yuichi Hattori Morio Kanno Ichiro Sakuma Akira Kitabatake 《British journal of pharmacology》1997,120(7):1328-1334
- The aim of the present study was to identify the sources of Ca2+ contributing to acetylcholine (ACh)-induced release of endothelium-derived hyperpolarizing factor (EDHF) from endothelial cells of rat mesenteric artery and to assess the pathway involved. The changes in membrane potentials of smooth muscles by ACh measured with the microelectrode technique were evaluated as a marker for EDHF release.
- ACh elicited membrane hyperpolarization of smooth muscle cells in an endothelium-dependent manner. The hyperpolarizing response was not affected by treatment with 10 μM indomethacin, 300 μM NG-nitro-L-arginine or 10 μM oxyhaemoglobin, thereby indicating that the hyperpolarization is not mediated by prostanoids or nitric oxide but is presumably by EDHF.
- In the presence of extracellular Ca2+, 1 μM ACh generated a hyperpolarization composed of the transient and sustained components. By contrast, in Ca2+-free medium, ACh produced only transient hyperpolarization.
- Pretreatment with 100 nM thapsigargin and 3 μM cyclopiazonic acid, endoplasmic reticulum Ca2+-ATPase inhibitors, completely abolished ACh-induced hyperpolarization. Pretreatment with 20 mM caffeine also markedly attenuated ACh-induced hyperpolarization. However, the overall pattern and peak amplitude of hyperpolarization were unaffected by pretreatment with 1 μM ryanodine.
- In the presence of 5 mM Ni2+ or 3 mM Mn2+, the hyperpolarizing response to ACh was transient, and the sustained component of hyperpolarization was not observed. On the other hand, 1 μM nifedipine had no effect on ACh-induced hyperpolarization.
- ACh-induced hyperpolarization was nearly completely eliminated by 500 nM U-73122 or 200 μM 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, inhibitors of phospholipase C, but was unchanged by 500 nM U-73343, an inactive form of U-73122. Pretreatment with 20 nM staurosporine, an inhibitor of protein kinase C, did not modify ACh-induced hyperpolarization.
- These results indicate that the ACh-induced release of EDHF from endothelial cells of rat mesenteric artery is possibly initiated by Ca2+ release from inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ pool as a consequence of stimulation of phospholipid hydrolysis due to phospholipase C activation, and maintained by Ca2+ influx via a Ni2+- and Mn2+-sensitive pathway distinct from L-type Ca2+ channels. The Ca2+-influx mechanism seems to be activated following IP3-induced depletion of the pool.
96.
Jun Hatazawa Hiroshi Itoh Eku Shimosegawa Iwao Kanno Matsutaroh Murakami Shuichi Miura Hidehiro Iida Toshio Okudera Atsushi Inugami Toshihide Ogawa Hideaki Fujita Yuichi Satoh Ken Nagata Yutaka Hirata Kazuo Uemura 《Annals of nuclear medicine》1994,8(3):213-217
We studied the brain uptake of amino acid in a patient with acute cerebral infarction with L-[2-(F-18)] fluorophenylalanine and positron emission tomography. The increased accumulation of the ligand was specifically found in the peri-infarct area where oxygen metabolism was still maintained but decreased later in the 72-day follow-up period. The kinetic analysis revealed that increased accumulation was not due to increased transport from the blood to the brain but to delayed washout from the brain to the blood. Although the mechanism is still unknown, abnormally high accumulation of L-[F-18]fluorophenylalanine may predict delayed neuronal changes after ischemic insults of the brain. 相似文献
97.
Niho N Tamura T Toyoda K Uneyama C Shibutani M Hirose M 《Kokuritsu Iyakuhin Shokuhin Eisei Kenkyūjo hōkoku = Bulletin of National Institute of Health Sciences》1999,(117):129-134
A subchronic toxicity study of chitin, a natural structural component of crustacean shells, was performed in F344 rats by feeding of the powdered diet containing 5%, 1.7%, 0.6%, 0.2%, and 0% concentrations of the substance. Each group consisted of 10 males and 10 females. All animals survived until the end of the experiment. There were no changes indicating obvious toxicity of chitin in the clinical signs, body weight, food intake, hematology, serum biochemistry, or histopathological findings, except a slight decrease in body weight gain in the 5% chitin-treated males. Although the mechanism is unclear, the suppression of body weight gain may be due to the slight decrease in caloric content of the food in the 5% chitin-treated animals, a change unrelated to toxicity. Thus, there was no obvious toxicity of chitin in F344 rats at concentrations up to 5% in the diet for 13 weeks. 相似文献
98.
99.
A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy 总被引:23,自引:0,他引:23
Hirose S Iwata H Akiyoshi H Kobayashi K Ito M Wada K Kaneko S Mitsudome A 《Neurology》1999,53(8):1749-1753
OBJECTIVE: To identify the mutation responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a nonwhite family. BACKGROUND: ADNFLE is newly recognized as an entity of idiopathic partial epilepsy. Recently, two different mutations of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) gene were identified in a white family as a cause of ADNFLE. METHODS: Four affected and three unaffected individuals in three generations of a Japanese family with ADNFLE, and 100 unrelated healthy Japanese volunteers were studied. Clinical features and EEG findings in affected individuals were consistent with those of ADNFLE reported in white families with ADNFLE. Mutations within the CHRNA4 gene were screened for using single-strand conformation polymorphism analysis (SSCA) and were determined by direct sequencing. The mutation identified was sought in volunteers by the amplification refractory mutation system. RESULTS: A C-to-T exchange (C755T) was found in exon 5 of the CHRNA4 gene on one allele of affected individuals. C755T segregated in affected individuals and was not found in 200 alleles obtained from the volunteers. C755T replaced serine 252 (Ser252) in the second membrane-spanning domain (M2) of CHRNA4 with a leucine. Ser252 is conserved characteristically in the alpha-subunit of acetylcholine receptor and is considered to play an important role in channel function. CONCLUSION: C755T is a novel missense mutation of the CHRNA4 gene causing autosomal dominant nocturnal frontal lobe epilepsy in this Japanese family. 相似文献
100.