Emerging drugs--molecular mechanisms of action of Asian medicines.
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Animals↗
Biomedical subjects
T Satoh
Publications and source records attributed to T Satoh.
Increased plasma levels of adrenomedullin in patients with pulmonary hypertension.
Adrenomedullin, a potent hypotensive peptide, reduces blood pressure and pulmonary vascular resistance, and increases pulmonary blood flow. The mRNA for adrenomedullin and its receptor is highly expressed in the lung, suggesting a regulatory role for adrenomedullin in the pulmonary circulation. To investigate the clinical significance of adrenomedullin in patients with pulmonary hypertension, we studied the relationship between plasma levels of adrenomedullin and pulmonary haemodynamics. Venous, arterial and pulmonary arterial blood samples were obtained during cardiac catheterization and plasma levels of adrenomedullin were measured by specific radioimmunoassay in 33 consecutive patients with severe pulmonary hypertension (12 cases of primary pulmonary hypertension, 21 with chronic thromboembolic pulmonary hypertension; age 49+/-16 years, mean pulmonary arterial pressure 50+/-15mmHg). In addition, plasma levels of adrenomedullin were measured before and after acute nitric oxide inhalation. The changes in plasma adrenomedullin during the follow-up period of 10.3+/-4.3 months were also evaluated (n=5). Sixty-two healthy subjects served as the control group. Adrenomedullin was measured in an antecubital vein in the controls. Plasma levels of adrenomedullin were significantly higher in the patients with pulmonary hypertension than in the control subjects (10.1+/-8.7 versus 4.9+/-1.1pmol/l, P<0.01). Plasma levels of adrenomedullin, expressed as their natural logarithm, were significantly correlated with mean right atrial pressure (r=0.71, P<0.01), stroke volume (r=-0.63, P<0.01), total pulmonary resistance (r=0.60, P<0.01), mean pulmonary arterial pressure (r=0.37, P<0.05), and the natural logarithm of plasma atrial natriuretic peptide (r=0. 63, P<0.01). Plasma levels of adrenomedullin did not change significantly after nitric oxide inhalation, but significantly increased in association with the elevation of the total pulmonary resistance during the long-term follow-up period. These results suggest that plasma levels of adrenomedullin increase in proportion to the extent of pulmonary hypertension.
Administration, Inhalation↗
Serial MRI of extrapontine myelinolysis of the basal ganglia: a case report.
We study a patient with extrapontine myelinolysis (EPM), without central pontine myelinolysis (CPM), who exhibited changes in abnormalities observed with MRI. MRI in the acute stage of the bilateral basal ganglia showed a high signal intensity on T2-weighted images, and a low signal on T1-weighted images. The low signal on T1-weighted images of the lesion in the acute stage changed to a high signal in the subacute stage. This change may reflect the involvement of microhemorrhagic lesions caused by vascular endothelial injury associated with EPM. We propose that vascular endothelial injury due to rapid osmotic change and subsequent demyelination is involved in the patho-etiology of EPM.
Adult↗
Effect of rat glicentin on intestinal adaptation in small intestine-resected rats.
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Acclimatization↗
Genomic organization and promoter function of the mouse uncoupling protein 2 (UCP2) gene.
We cloned and characterized the mouse uncoupling protein 2 (UCP2) gene and its promoter region. The gene spans approximately 6.3 kb and contains eight exons and seven introns. Two short exons are located in the 5' untranslated region, and each of the remaining exons encodes one of the transmembrane domains. 3'-RACE analysis showed that a polyadenylation signal 257 bp downstream from the stop codon was functional. Primer extension analysis indicated a single transcriptional start site 369 bp upstream from the translational start site. The promoter region lacks both TATA and CAAT boxes but is GC-rich. A construct containing 1250 bp of the promoter region showed significant activity in all 6 cell lines examined, and the region between -160 and -678 bp exhibited strong positive regulatory activity. These features of the UCP2 gene are different from those of the UCP1 gene and may contribute to its ubiquitous expression.
Amino Acid Sequence↗
cDNA cloning and genomic organization of peroxisome proliferator-inducible long-chain acyl-CoA hydrolase from rat liver cytosol.
The cDNA for a peroxisome proliferator-inducible long-chain acyl-CoA hydrolase from rat liver cytosol, referred to as rLACH2, was isolated and its genomic structure was determined. The cDNA encoded a 419-amino-acid polypeptide with a calculated molecular weight of 46,011. Sequence analysis identified an active-site serine motif (Gly-x-Ser-x-Gly) common to carboxylesterases and lipases. When expressed in Escherichia coli, the cDNA directed expression of a protein immunoreactive to an anti-rLACH2 antibody with a molecular mass of 47 kDa, identical to that of purified rLACH2. Northern blot analysis showed marked induction of rLACH2 mRNA in the liver after feeding rats with di(2-ethylhexyl)phthalate, a peroxisome proliferator. The rLACH2 gene spanned about 19 kb and comprised 3 exons, the intron/exon boundaries of which were consistent with the donor/acceptor splice rule. A putative peroxisome proliferator response element (AGGTCATGGTTCA) was identified in the 5'-flanking region, suggesting the involvement of peroxisome proliferator-activated receptors in the regulation of rLACH2 gene expression.
Amino Acid Sequence↗
Imaging of the super high affinity binding sites for [3H]Ro15-4513 in rat hippocampus: comparison between in vitro and in vivo binding.
The super high affinity binding sites for [3H]Ro15-4513, a partial inverse agonist of central benzodiazepine receptors, were analyzed in rat hippocampus both in vivo and in vitro. An ultra high sensitive method of autoradiography with an imaging plate system was employed for quantitative analysis of [3H]Ro15-4513 binding. In in vitro binding, the super high affinity binding sites in the hippocampus were observed when the [3H]Ro15-4513 concentration was below 0.5 nM. In vivo, the super high affinity binding sites were only found when the injected dose of Ro15-4513 was below 3.6 microg/kg and almost disappeared when the dose was increased to 10 microg/kg. These results both in vivo and in vitro indicate that there is a significant discrepancy between actual free ligand concentration in vivo and in vitro, and that concentrations in intact brain may be much lower than previously thought.
Affinity Labels↗
Involvement of Ras in Bruton's tyrosine kinase-mediated JNK activation.
Defects in Bruton's tyrosine kinase (Btk) result in B cell immunodeficiencies in humans and mice. Recent studies showed that Btk is required for maximal activation of JNK, a family of stress-activated protein kinases, induced by several extracellular stimuli including interleukin (IL)-3. On the other hand, IL-3-induced JNK activation is dependent on Ras. In the present study we have investigated whether Ras is involved in Btk-mediated JNK activation in BaF3 mouse pro-B cells. Overexpression of wild-type Btk protein in these cells enhanced JNK activation upon IL-3 stimulation, whereas expression of kinase-dead Btk partially suppressed JNK activation. Induced expression of the dominant negative Ras(N17) in the cells overexpressing wild-type Btk suppressed JNK activation. Importantly, overexpression of Btk enhanced the level of the GTP-bound, active form of Ras in response to IL-3 stimulation. Btk overexpression also increased the Shc-Grb2 association induced by IL-3 stimulation. Expression of either N17Ras or V12Ras did not impose any effects on Btk kinase activity. These data collectively indicate that Ras plays a role of an intermediary signaling protein in Btk-mediated JNK activation induced by the IL-3 signaling pathway.
Adaptor Proteins, Signal Transducing↗
Serial processing of the somesthetic information revealed by different effects of stimulus rate on the somatosensory-evoked potentials and magnetic fields.
In order to evaluate information processing in the somatosensory cortex, the effect of two different stimulus rates was investigated by simultaneously recording somatosensory-evoked potentials (SEPs) and magnetic fields (SEFs) in nine healthy adults. During electric stimulation of the median nerve at the wrist, SEFs were recorded with the helmet-shaped whole-head coverage magnetometer array with 122 first-order planar gradiometers while SEPs were simultaneously recorded from seven scalp positions. Interstimulus intervals (ISIs) of 0.9 s and 4 s were compared. In all subjects, N20 as well as its magnetic counterpart, N20m, was clearly demonstrated over the contralateral somatosensory area. Subsequent deflections around 80-200 ms did not make any clear peak and were smaller than those at 20-60 ms (P30m, P40m, N50m and P60m). After 200 ms, SEFs were negligible, whereas SEPs had larger amplitude than those of shorter latencies, constituting a peak around 250 ms (P250). Both SEF and SEP deflections later than 40 ms were decreased in responses at the shorter ISI; this diminution was most prominent for P250. Therefore, it is concluded that the tangential currents in the somatosensory cortex (area 3b) mainly contribute to responses during the first 200 ms after the stimulus, whereas the radially oriented currents (most likely in the crown of the postcentral gyrus) take over for subsequent information processing.
Adult↗
Platinum catalysts for the high-yield oxidation of methane to a methanol derivative
Platinum catalysts are reported for the direct, low-temperature, oxidative conversion of methane to a methanol derivative at greater than 70 percent one-pass yield based on methane. The catalysts are platinum complexes derived from the bidiazine ligand family that are stable, active, and selective for the oxidation of a carbon-hydrogen bond of methane to produce methyl esters. Mechanistic studies show that platinum(II) is the most active oxidation state of platinum for reaction with methane, and are consistent with reaction proceeding through carbon-hydrogen bond activation of methane to generate a platinum-methyl intermediate that is oxidized to generate the methyl ester product.
Journal Article↗
Role of metal-ligand coordination in the folding pathway of zinc finger peptides.
In the zinc fingers of TFIIIA family, two cysteines near the N-terminus and two histidines near the C-terminus are conserved for each finger unit. A cooperative binding of these residues to a Zn(II) ion is essential for the formation of the finger structure consisting of an anti-parallel beta-sheet and an alpha-helix. In order to reveal the folding pathway of the zinc finger, we have investigated, by Raman spectroscopy, the relationship between Zn(II)-ligand binding and conformational change of a 27-mer peptide representing the third finger of mouse transcription factor Zif268. In the absence of Zn(II), the peptide assumes a beta-sheet-rich structure. Upon addition of Zn(II), cysteines preferentially bind to Zn(II) prior to the metal coordination of histidines. Both the Zn(II)-cysteine and Zn(II)-histidine binding induce a partial secondary structure transition from beta-sheet to alpha-helix. Exchange of the ligand amino acid residues, i.e., cysteines to histidines and vice versa, produces a striking effect on the folding of the peptide. The beta-sheet-->alpha-helix transition is induced only by the Zn(II)-cysteine binding and the ligand exchanged peptide is not capable of folding into the finger structure. The present results demonstrate the importance of the ligand arrangement in the folding of zinc finger.
Animals↗
Identification of the major allergens in wheat flour responsible for baker's asthma.
Baker's asthma, a typical occupational allergic disease, is a serious problem in the food industries. In this study, purification and identification of major allergens recognized by IgEs in sera of allergic patients were performed. Major immunoreactive proteins were purified from the albumin fraction by gel filtration on a Toyopearl HW-50 column followed by reverse-phase HPLC. The N-terminal amino acid sequences and molecular masses measured by MS indicated that the major immunoreactive proteins are members of the alpha-amylase inhibitor family, 0.19 and 0.28. Significant leukotriene release by each purified protein was observed in cell-associated stimulation tests, suggesting in vivo activity of these antigens. Carbohydrate analyses of major allergens indicated that they are monoglycosylated but not N-glycosylated in spite of the presence of a potential N-glycosylation site. Recombinant 0.19 expressed in Escherichia coli showed the same reactivity with IgE as native wheat 0.19 in Western blotting and ELISA using methyl vinyl ether maleic anhydride co-polymer as an immobilizing reagent, suggesting that the allergenic epitopes are located in the peptide portions.
Allergens↗
A novel subtype of G-protein-coupled receptor kinase, GRK7, in teleost cone photoreceptors.
Two kinds of retinal cDNA fragments (OIGRK-R and -C) encoding the putative G-protein-coupled receptor kinases (GRKs) were isolated from medaka, Oryzias latipes. OIGRK-R appears to be closely related to the rhodopsin kinase (RK) found in the outer segments of mammalian photoreceptors, but the deduced amino acid sequence of OIGRK-C shows less than 50% identity to those of GRKs known to date, suggesting that OIGRK-C is a novel GRK subtype (GRK7). The mRNA of OIGRK-R is detectable in rods, and that of OIGRK-C is found in all four types of cone photoreceptor. The C-terminal of OIGRK-R has a consensus sequence for farnesylation, whereas, surprisingly, OIGRK-C has a consensus sequence for geranylgeranylation. Our result are consistent with the concept that lower vertebrates have rod- and cone-specific opsin kinases.
Amino Acid Sequence↗
Synthesis of a new class of camptothecin derivatives, the long-chain fatty acid esters of 10-hydroxycamptothecin, as a potent prodrug candidate, and their in vitro metabolic conversion by carboxylesterases.
Five (20S)-10-hydroxycamptothecin derivatives carrying the long-chain fatty acid esters were prepared for the development of a new class of prodrug-type agents. In vitro experiments using three kinds of purified carboxylesterase isozymes from the liver microsomes of rat, pig, and human demonstrated that these derivatives were efficiently metabolized by enzymes compared with CPT-11.
Animals↗
A new class of highly potent farnesyl diphosphate-competitive inhibitors of farnesyltransferase.
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3T3 Cells↗
Serum neopterin, beta2-microglobulin, soluble interleukin-2 receptors, and immunoglobulin levels in healthy adolescents.
Serum biomarkers, such as neopterin, beta2-microglobulin (B2M), and soluble interleukin-2 receptors (sIL-2R), are elevated in viral infections, including HIV-1 infection, and in inflammatory conditions, autoimmune disease, and malignancies. For many of these conditions, serum levels correlate with disease activity. Application of these biomarkers in adolescents is limited by a lack of information on the range and determinants of variability (age, sex, race) for serum levels of these important molecules in this age group. To address this question, we analyzed serum samples from a well-characterized heterogeneous population of 111 healthy adolescents. White children had significantly higher serum levels of sIL-2R and IgM and lower levels of IgG (P </= 0.001) than black children. Boys had higher sIL-2R and B2M levels (P < 0.005) and lower IgM levels (P < 0.05) than girls. No significant age effect on B2M or neopterin level was observed over the age range of 12-19 years included in this analysis. However, stratification by race showed that serum sIL-2R level was significantly associated with age among whites, but not among blacks. Values of these biomarkers in this population are compared with age-stratified values in the previously analyzed 20- to 69-year-old population from whose households the adolescent subjects were recruited.
Adolescent↗
Lack of survival benefit of extended lymph node dissection for ductal adenocarcinoma of the head of the pancreas: retrospective multi-institutional analysis in Japan.
It has not been established that extended lymph node resection is necessary for ductal adenocarcinoma of the head of the pancreas. According to the general rules for the study of pancreatic cancer, a multiinstitutional, retrospective clinical study was undertaken to investigate the efficiency of extended lymph node dissection for this malignancy. Altogether 501 patients underwent resection of the pancreas between 1991 and 1994 at 77 medical facilities; the surgical procedures, staging, lymph node dissection, curability, and survival rate were analyzed retrospectively. Eighteen of the patients died within 30 postoperative days, leaving 483 patients to be studied. The resection was curative microscopically in 94 patients, resulting in a 3-year survival of 29%. Macroscopically curative resection resulted in a 3-year survival of 14%; noncurative resection produced a 3-year survival of 6%. Although extended lymph node dissection was performed on 38 patients in stage I, 42 patients in stage II, 206 patients in stage III, and 1 patient in stage IV, there was no improvement in survival when the results were compared to those seen after standard or palliative lymph node dissection. The extent of lymph node dissection has not affected the prognosis for ductal adenocarcinoma of the head of the pancreas at any stage of the course of the disease. Excessive lymph node dissection in advanced cases does not necessarily lead to a favorable prognosis. The patients who undergo a radical operation with an adequate lymph node dissection have longer survivals.
Adult↗
Comparative analysis of CD80 and CD86 on human Langerhans cells: expression and function.
Although both CD80 (B7-1) and CD86 (B7-2/B70) have been recently identified in cultured human Langerhans cells (LC), little is known of the role and regulatory properties of CD80 and CD86 on human LC. We present here the results of a study comparing the expression and function of CD80 and CD86 in human LC using the T-helper type-1 cytokines IL-2 and interferon gamma (IFN)-gamma, and the T-helper type-2 cytokines IL-10, IL-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). Freshly isolated human LC expressed little CD80 and CD86 in vitro, but the expression of both molecules was rapidly induced during a 72-h incubation with cytokines and the expression of CD86 occurred much earlier and more strongly than that of CD80. The expression of both CD80 and CD86 was upregulated by GM-CSF and downregulated by IL-10, and the expression of CD86, but not that of CD80, was upregulated by both IL-4 and IFN-gamma. Finally, pretreatment of LC with GM-CSF and IFN-gamma, but not with IL-4, enhanced the alloreactive T-cell proliferation induced by the LC, and IL-10 pretreatment of LC decreased their capacity for alloreaction. These results indicate that the expression of both CD80 and CD86 on human LC may be regulated by these cytokines (IL-2, IL-4, GM-CSF, IFN-gamma and IL-10) secreted from helper T cells infiltrating into the inflammatory microenvironment.
Antigen Presentation↗