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Biomedical subjects

Ken-ichi Yoshida

Publications and source records attributed to Ken-ichi Yoshida.

At least 37 records · Page 2Linked to original sources
PubMed2004

Carbon monoxide protects against cardiac ischemia--reperfusion injury in vivo via MAPK and Akt--eNOS pathways.

BACKGROUND: Carbon monoxide (CO) is postulated to protect tissues against several types of injuries. We investigated the role of CO in amelioration of cardiac ischemia-reperfusion injury in vivo and the mechanisms involved in it. METHODS AND RESULTS: Rats inhaled CO (250 ppm, 500 ppm, or 1000 ppm) for 24 hours in a chamber after myocardial ischemia-reperfusion induced by occluding the left anterior descending coronary artery for 30 minutes. Pre-exposure to 1000 ppm of CO significantly reduced the ratio of infarct areas to risk areas and suppressed the migration of macrophages and monocytes into infarct areas, and the expression of tumor necrosis factor (TNF)-alpha in the heart; however, 250 ppm, 500 ppm of CO, or low barometric pressure hypoxia (0.5 atm) did not affect them. Exposure to 1000 ppm CO resulted in the activation of p38 mitogen-activated protein kinase (p38MAPK), protein kinase Balpha(Akt), endothelial nitric oxide synthase (eNOS), and cyclic guanosine monophosphate (cGMP) in the myocardium. Inhibition of p38MAPK, PI3kinase, NO, and soluble guanylate cyclase with SB203580, wortmannin, N(G)-nitro-L-arginine methyl ester (L-NAME), and methylene blue, respectively, attenuated the cytoprotection by CO. CONCLUSIONS: CO has beneficial effects on cardiac ischemia-reperfusion injury; this effect is mediated by p38MAPK pathway and Akt-eNOS pathway, including production of cGMP.

Animals↗
PubMed2004

MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety.

Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.

Acrylates↗
PubMed2004

MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 3: Optimization of potency in the pyridopyrimidine series through the application of a pharmacophore model.

The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.

Bacterial Outer Membrane Proteins↗
PubMed2004

A brief regional ischemic-reperfusion enhances propofol-induced depression in left ventricular function of in situ rat hearts.

BACKGROUND: Propofol is short-acting intravenous general anesthetics that reduces cardiovascular hemodynamics. The effects of propofol on intrinsic myocardial contractility, however, remain debatable. The aim of the current study was to test the hypothesis that inhibitory effects of propofol on left ventricular (LV) contractility and mechanical work capability of in situ ejecting rat hearts are attenuated after a brief regional ischemia and reperfusion. METHODS: The authors obtained steady-state LV pressure-volume loops and intermittently obtained LV end-systolic pressure-volume relation and evaluated effects of propofol on LV function by end-systolic pressure (ESPmLVV), systolic pressure-volume area (PVAmLVV) at midrange LV volume (mLVV). RESULTS: Propofol (5.2 +/- 0.3 approximately 11.1 +/- 3.7 microg.ml) significantly decreased ESP0.08 to 78 +/- 12% approximately 64 +/- 13% of prepropofol and PVA0.08 to 76 +/- 13%approximately 63 +/- 16% of prepropofol in normal hearts, whereas propofol at a lower concentration (4.1 +/- 1.0 microg/ml) did not. Although brief ischemic-reperfusion per se did not affect LV function, propofol after that, even at a lower concentration (4.1 +/- 1.0 microg/ml), significantly decreased ESP0.08 to 70 +/- 27% of prepropofol and PVA0.08 to 68 +/- 33% of prepropofol. Pretreatment with a protein kinase C (PKC) inhibitor, bisindolylmaleimide reduced the propofol (4.1 +/- 1.0 microg/ml)-induced greater decreases in ESP0.08 and PVA0.08 after brief ischemic-reperfusion to 94 +/- 33% and 92 +/- 39% of prepropofol. In the propofol-infused hearts after brief ischemic-reperfusion, protein kinase C-epsilon translocation to the nucleus-myofibril fraction was found. CONCLUSION: In contrast to the study hypothesis, brief ischemic-reperfusion enhanced the inhibitory effects of propofol on LV systolic function; this enhancement is attributable to activation of protein kinase C.

Anesthetics, Intravenous↗
PubMed2004

Down-regulation of connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat hearts in vivo.

Connexin 43 (Cx43), a primary component of gap junctions, contributes to intercellular electrochemical communication. Cx43 undergoes dephosphorylation in early ischemia. We examined whether Cx43 is degraded in association with dephosphorylation during early myocardial ischemia and whether ischemic preconditioning (IP) affects the degradation after rat coronary artery occlusion. Male Sprague-Dawley rats underwent coronary artery occlusion for 1, 2, or 3 hours, or for 1 hour following treatment either with a calcineurin inhibitor (cyclosporine A), proteasome inhibitor (PSI), or lysosomal inhibitor (E64c), or following IP alone or after protein kinase C (PKC) inhibitor (chelerythrine) pretreatment. The IP was afforded by three cycles of 3 minute ischemia and 5 minute reperfusion. A large portion of the phosphorylated Cx43 (pCx43) in the membrane fraction was dephosphorylated, while a small portion was degraded at 1 hour of ischemia. The effects of the inhibitors were dephosphorylation and degradation by calcineurin and proteasome/lysosome, respectively. IP suppressed the decrease in pCx43 and increase in dCx43, while only the former was inhibited by the PKC inhibitor chelerythrine. The Cx43 mRNA level was reduced at 3 hours, but not at 1 hour of ischemia, irrespective of IP. We believe that Cx43 is dephosphorylated and degraded in early ischemia, whereas Cx43 transcription was suppressed at a later phase of ischemia.

Alkaloids↗
PubMed2003

MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds.

Problems of low solubility, high serum protein binding, and lack of efficacy in vivo in first generation MexAB-OprM specific efflux pump inhibitors were addressed. Through the use of pharmacophore modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements were arrayed gave second generation leads with greatly improved physical properties and activity in the potentiation of antibacterial quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo.

Animals↗
PubMed2003

Hypothermia attenuates delayed cortical cell death and ROS generation following CO inhalation.

Carbon monoxide (CO) is the most popular cause of poisoning. The bilateral basal ganglia lesion characterizes the delayed neuronal cell death (DCD). We demonstrated there were both apoptosis and necrosis in the cortex, basal ganglia and hippocampus in a case of human CO accident. To elucidate the mechanism of DCD after CO inhalation, histological studies on the rat brain were conducted. Rats were ventilated with nitrous oxide (sham group), 10% O(2) (hypoxia group) or 1005 ppm CO (CO group) for 90 min, while the pericranial temperature was controlled at either 32, 37, or 39 degrees C during CO inhalation. After reoxygenation for 30 min, the rats were allowed to recover for 48 h. The ratio of eosinophilic and HNE-positive neurons in the cortex were higher in the CO group than in the hypoxia group at 37 degrees C, while the PaO(2) was much lower in the hypoxia than in the CO group. The damage was alleviated in the hypothermia (32 degrees C) as compared with normothermia, while the hyperthermia (39 degrees C) did not significantly increased it. CO inhalation injures neuron by reactive oxygen species (ROS), independent of hypoxia, as can be concluded from the histological comparison of DCD with HNE immunoreactivity.

Aldehydes↗
PubMed2003

The mechanism of alphaB-crystallin gene expression by proteasome inhibition.

The mechanism of small heat shock protein/alphaB-crystallin gene expression by proteasome inhibition was investigated. Expression of alphaB-crystallin was induced efficiently only by proteasome inhibition and not by heat shock while expression of HSP27 was induced efficiently by both proteasome inhibition and heat shock. The promoter of the alphaB-crystallin gene contains two conserved heat shock elements, one located between -397 and -374 and the other between -57 and -37, relative to the transcription start site. Electrophoretic mobility shift assay (EMSA) revealed that proteasome inhibition induces binding of heat shock factors to both heat shock elements in the alphaB-crystallin gene promoter. However, a transient transfection assay using deletion constructs of the alphaB-crystallin gene promoter showed that the region between -373 and -58 plays an important role in promoter activity. These results indicate the presence of differential response mechanisms of alphaB-crystallin gene expression to proteasome inhibition and heat shock, and that the activation of heat shock elements is not sufficient for the efficient induction of the alphaB-crystallin gene by proteasome inhibition.

Acetylcysteine↗
PubMed2003

DNA microarray analysis of Bacillus subtilis sigma factors of extracytoplasmic function family.

Target gene candidates of the seven extracytoplasmic function (ECF) sigma factors of Bacillus subtilis have been surveyed using DNA microarray analysis of mRNA extracted from cells grown in Luria-Bertani broth, in which an ECF sigma factor gene was placed under the control of the spac promoter on multicopy plasmid pDG148 and overexpressed. The number of target candidates for each of the sigma factors varied greatly, and a total of 278 genes were selected. Interestingly, the above target gene candidates shared only one gene out of 94 target genes of the general stress sigma B that have been reported in the literature thus far. Furthermore, lacZ-fusion experiments based on the results of DNA microarray analysis indicated that each ECF sigma factor directs transcription of its own operon, with the exception of sigZ. The DNA microarray data collected in this study are available at the KEGG Expression Database web site (http://www.genome.ad.jp/kegg/expression/).

Bacillus subtilis↗
PubMed2003

Identification of additional TnrA-regulated genes of Bacillus subtilis associated with a TnrA box.

Bacillus subtilis TnrA is a global regulator that responds to the availability of nitrogen sources and both activates and represses many genes during nitrogen-limited growth. In order to obtain a holistic view of the gene regulation depending on TnrA, we performed a genome-wide screening for TnrA-regulated genes associated with a TnrA box. A combination of DNA microarray hybridization and a genome-wide search for TnrA boxes allowed us to find 36 TnrA-regulated transcription units associated with a putative TnrA box. Gel retardation assaying, using probes carrying at least one putative TnrA box and the deletion derivatives of each box, indicated that 17 out of 36 transcription units were likely TnrA targets associated with the TnrA boxes, two of which (nasA and nasBCDEF) possessed a common TnrA box. The sequences of these TnrA boxes contained a consensus one, TGTNANAWWWTMTNACA. The TnrA targets detected in this study were nrgAB, pucJKLM, glnQHMP, nasDEF, oppABCDF, nasA, nasBCDEF and ywrD for positive regulation, and gltAB, pel, ywdIJK, yycCB, yttA, yxkC, ywlFG, yodF and alsT for negative regulation, nrgAB and gltAB being well-studied TnrA targets. It was unexpected that the negatively regulated TnrA targets were as many as the positively regulated targets. The physiological role of the TnrA regulon is discussed.

Amino Acid Motifs↗
PubMed2003

Organization and expression of the Bacillus subtilis sigY operon.

We investigated the organization and expression of the Bacillus subtilis sigY operon, the first gene of which codes for sigmaY, a member of the extracytoplasmic function (ECF) family of sigma factors. The sigY operon, comprising six genes (sigY, yxlC, D, E, F, and G), was induced upon nitrogen starvation; it was continuously transcribed from the 31st base upstream of sigY to a neighboring convergent gene, yxlH, resulting in a 4.2-kb mRNA. The expression of the sigY operon was also positively autoregulated through sigmaY, suggesting that its transcription is likely to be directed by sigmaY. Deletion analysis of the sigY promoter, which was localized by primer extension, revealed the promoter region of sigY with the "-10" and "-35" sequences of CGTC and TGAACG, respectively. The latter sequence was distinct from those recognized by sigmaW, sigmaX, and sigmaM. The sigmaY-directed transcription of sigY was under negative regulation involving YxlD. sigY disruption affected sporulation induced by nitrogen starvation, but sigY induction upon nitrogen starvation was not associated with the sporulation process. The organization and function of the sigY operon are significantly conserved in several microorganisms living in adverse living environments.

Amino Acid Sequence↗
PubMed2003

Angiotensin II dependent testicular fibrosis and effects on spermatogenesis after vasectomy in the rat.

PURPOSE: Vasectomy induces testicular interstitial fibrosis in time dependent fashion and inhibits spermatogenesis. We investigated the contribution of angiotensin II (Ang II) to the development of interstitial fibrosis after vasectomy. MATERIALS AND METHODS: Bilateral vasectomy was performed in 8-week-old Wistar rats and the testes were harvested 1 to 24 weeks after vasectomy. Interstitial fibrosis was evaluated by Masson's trichrome staining. Western blotting and immunohistochemistry were done to examine the expressions of heat shock protein 47 (HSP47), HNE (4-hydroxy-2,3-nonenal) and transforming growth factor-beta1 (TGF-beta1). The antioxidative agent N-acetylcysteine (NAC), the Ang II type 1 receptor antagonist losartan or the Ang converting enzyme inhibitor enalapril was given orally for 24 weeks to vasectomized rats. Spermatogenesis was evaluated by testicular weight and the percent of haploid cells was analyzed by flow cytometry. RESULTS: Vasectomy significantly increased interstitial fibrosis (more than 8 weeks) and induced the expression of HSP47, HNE modified protein and TGF-beta1. TGF-beta1 and HSP47 immunoreactivity was localized to Leydig cells and fibroblasts. NAC or losartan but not enalapril inhibited the expression of these molecules induced by vasectomy. Increased interstitial fibrosis and impaired spermatogenesis were partially abrogated by NAC or losartan administration. CONCLUSIONS: There is Ang II type 1 receptor dependent fibrosis after vasectomy. Oxidative condition is considered to trigger and promote these fibrogenic processes. Ang II contributes to the regulation of intratesticular autocrine or paracrine functions after vasectomy.

Acetylcysteine↗
PubMed2003

A Japanese case of familial Mediterranean fever with family history demonstrating a mutation in MEFV.

We describe a 17-year-old woman with a family history of FMF who suffered from recurrent fever accompanied by pains in the left chest and abdomen. During a five-year period she experienced attacks about once every six months. The metaraminol provocative test was positive. Genomic DNA extracted from peripheral blood lymphocytes from both her and her parents were analyzed by polymerase chain reaction (PCR), followed by cycle sequencing. We detected a mutation (ATG to ATA) in codon 694 in exon 10 of the FMF gene, MEFV, that resulted in a substitution of isoleucine for methionine (M6941) in both her and her father. This is the first Japanese case of FMF with a mutation in MEFV identified in the family history.

Adolescent↗
PubMed2003

Molecular mechanism of emotional stress-induced and catecholamine-induced heart attack.

Emotional or physical stress triggers 'tako-tsubo' cardiomyopathy or 'transient left ventricular apical ballooning', but the pathogenesis is unclear. In response to the immobilization stress of rats, a useful model of emotional stress, rapid activation of p44/p42 mitogen-activated protein kinase was observed in the heart, followed by a transient upregulation of immediate early genes in the smooth muscle cells of coronary arteries, the endothelial cells and the myocardium. Heat shock protein 70 was induced in the aortic and coronary arterial smooth muscle cells and in the myocardium. Natriuretic peptide genes were also upregulated in the myocardium. Sequential gene expression can be considered as an adaptive response to emotional stress. Blocking of both alpha-adrenoceptors and beta-adrenoceptors eliminated the upregulation of immediate early genes induced by stress, while alpha-agonists and beta-agonists upregulated immediate early genes in the perfused heart. Activation of alpha-adrenoceptors and beta-adrenoceptors is the primary trigger of emotional stress-induced molecular changes in the heart.

Animals↗
PubMed2003

Two fatal cases involving concurrent use of methamphetamine and morphine.

We report on two cases of simultaneous administration of methamphetamine (MAP) and morphine (MOR) with hyperthermia. The blood levels of MAP and MOR were toxic and putatively lethal, respectively, although hyperthermia is a known cause of intoxication due to MAP rather than MOR. In Japan, MAP is the most predominant cause of drug intoxication. The presented cases suggest that MOR may exert synergistic effect on hyperthermia due to the MAP intoxication, together with experimental findings.

Adult↗
PubMed2002

Detection of the calcium antagonist nicardipine and its metabolites by gas chromatography-mass spectrometry.

An 89-year-old male patient, hospitalized with Parkinson's syndrome, suddenly died shortly after an intravenous drug injection. The conditions indicated that an overdose of nicardipine (1.3 mg/(mlkg)) may be given to the patient. At the autopsy, no pathological changes were noted. With a capillary gas chromatograph with mass spectrometer (GC-MS), nicardipine (4.97 microg/ml) and its pyridine metabolite (M-5, 5.0 microg/ml) were detected in the heart blood of the deceased. This result indicated that an overdose of intravenous nicardipine caused a sudden death of a patient in a poor condition.

Aged↗