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Biomedical subjects

M Adachi

Publications and source records attributed to M Adachi.

At least 91 records · Page 5Linked to original sources
PubMed2001

Development of a stereoselective practical synthetic route to indolmycin, a candidate anti-H. pylori agent.

A stereoselective practical synthetic route to indolmycin is described. The route is composed of the regioselective coupling of indolyl magnesium halide with a trans-epoxy ester, diastereoselective oxazolone ring formation with guanidine and amine exchange reaction with methylamine. In the coupling step, use of dichloromethane as co-solvent and conversion of the resulting hydroxy ester to the hydroxy acid for purification, make this process efficient and practical. The oxazolone ring is formed in good yield without epimerization at the C5 position by treatment with guanidine and potassium tert-butoxide in tert-butanol at room temperature. In the final step, the amino group is efficiently converted to the methylamino group in aqueous methylamine solution at 5 degrees C. After examination of the route with racemates, indolmycin was synthesized stereoselectively in 22% total yield from optically active trans-epoxy ester. This route was applied to the preparation of the metabolites of indolmycin.

Amines↗
PubMed2001

The novel monoclonal antibody MH8-4 inhibiting cell motility recognizes integrin alpha 3: inverse of its expression withmetastases in colon cancer.

The molecular basis of cell motility is obviously highly complex and is considered to be controlled by a number of molecular systems including cell adhesion molecules, their receptors, cytoskeletal components, a junctional unit connecting cytoskeletal components and membrane receptors, and various peptide growth factors. The possible involvement of proteins at the cell surface in controlling cell motility has been systematically investigated. Previously, we have addressed this question using functional monoclonal antibodies (MAbs), which inhibit cell motility as probes. In order to further identify cell surface molecules involved in metastasis of gastrointestinal tumors, the present study utilized an approach based on the selection of a colon cancer cell line RPMI4788, which showed high motility out of a large number of human gastrointestinal tumor cell lines. MAb MH8-4 was established after immunization of mice with RPMI4788 and selected on the basis of inhibition of RPMI4788 cell migration in a transwell penetration assay. MH8-4 inhibited the phagokinetic tract motility of various cancer cell lines. A cDNA cloning revealed that MH8-4 recognized a specific protein structure, integrin alpha 3. In order to determine whether these experimental results are of relevance with respect to actual human gastrointestinal tumors, we investigated integrin alpha 3 expression in 40 colon cancers with distant metastases. Our immunohistochemical study showed that in almost 27.5% of the cases, the metastatic tumors had lower integrin alpha 3 levels than their corresponding primary tumors. Moreover, there were no primary tumors with lower integrin alpha 3 expression than their corresponding metastatic tumors. Our data suggest that low integrin alpha 3 expression may be associated with the metastatic potential of certain colon cancers.

Antibodies, Monoclonal↗
PubMed2001

Interleukin-10 relieves the inhibitory effects of interferon-gamma on normal human lung fibroblasts.

Interleukin-10 (IL-10) is an important cytokine that suppresses the production of cytokines and chemokines by immune cells. IL-10 has been suggested to be involved in chronic inflammatory responses including the remodeling process in the lung. We investigated the effects of IL-10 on proliferation, extracellular matrix and cytokine production in normal human lung fibroblasts (NHLF). Human IL-10 (hIL-10) complementary DNA (cDNA) was transfected into NHLF using an adenoviral vector. No significant changes were observed in proliferation, fibronectin or procollagen type I production in the NHLF transfected with hIL-10 cDNA. Interferon (IFN)-gamma significantly inhibited cell proliferation and extracellular matrix production in a dose-dependent manner. Transfection of hIL-10 cDNA significantly relieved the suppressive effects of IFN-gamma in NHLF. Transforming growth factor (TGF)-beta production was not significantly affected by either transfection of hIL-10 cDNA or the addition of IFN-gamma. The relief of the suppressive function of IFN-gamma by IL-10 suggested that IL-10 is indirectly involved in the remodeling process in the lung interstitium.

Adenoviridae↗
PubMed2001

[Epidural blood patch for the treatment of intracranial hypotension due to cerebrospinal fluid leakage after thoracic spine surgery].

We report a case of a 44-year-old woman successfully treated by an epidural blood patch for intracranial hypotension due to cerebrospinal fluid (CSF) leakage into the thoracic cavity after thoracic spine surgery. The patient was admitted to our hospital with the complaint of postural headaches. She had received anterior thoracic instrumentation for thoracic disc herniation four months earlier. Lumbar puncture demonstrated low CSF pressure, and Gd-enhanced MR images displayed diffuse dural enhancement. Accordingly, she was diagnosed as having intracranial hypotension. 111In-DTPA cisternography revealed a CSF leakage into the left thoracic cavity, possibly caused by dural laceration during thoracic spine surgery. To avoid the risk of direct surgery, we performed epidural blood patch; 3 ml of autologous blood was injected into the epidural cavity. Postoperatively postural headaches immediately disappeared. MRI taken one year later revealed disappearance of diffuse dural enhancement, and 111In-DTPA cisternography revealed no CSF fluid leaks. Epidural blood patch seems to be a choice of treatment for CSF leak after spinal surgery.

Adult↗
PubMed2001

[Leukotriene modifiers].

Cysteinyl leukotriene (CysLT) C4, D4, and E4 play key roles in asthma. CysLTs are newly generated after cellular activation and are produced by eosinophils, mast cells, alveolar macrophages, and neutrophils. Pharmacological actions of CysLTs include potent bronchoconstriction, increased microvascular leakage and mucus secretion, chemoattraction of eosinophils, acceleration of eosinophil apoptosis, and proliferation of human airway smooth muscle. Recent studies demonstrated that CysLT1 receptors are distributed on CD34+ stem cells, eosinophils, monocytes, macrophages, basophils, and B cells in addition to airway smooth muscle. Because of these wide variety of distribution, Cys LTs may have another important roles in airway inflammation. CysLT1 receptor antagonist is widely used and found to be beneficial for the chronic management of asthma especially to symptomatic patients who had already been treated with moderate to high doses of inhaled corticosteroids and also to mild to moderate steroid-naive asthmatic patients.

Acetates↗
PubMed2001

[Thromboxane A2 synthase inhibitor and receptor antagonist].

Thromboxane A2 (TxA2) plays an important role in asthma. TxA2 are newly generated after cellular activation and are produced by not only platelets but also eosinophils, basophils, alveolar macrophages, and neutrophils. Pharmacological actions of TxA2 include potent bronchoconstriction, increased microvascular leakage, impairment of mucociliary clearance, and induction of airway hyperresponsiveness. Recent study demonstrated that TxA2 receptor antagonist decreased the number of eosinophils in bronchial biopsy specimens, suggesting that this type of agent possesses anti-inflammatory actions in asthma. Furthermore, addition of TxA2 synthase inhibitor significantly increased the PEF values in the persistent asthmatic patients despite the treatment with moderate-dose of inhaled corticosteroids. Therefore, these results suggest that TxA2 synthase inhibitor and receptor antagonist are useful for the treatment with symptomatic patients who had already been treated with inhaled corticosteroids.

Asthma↗
PubMed2001

[Combination treatment with inhaled corticosteroid/long-acting beta 2-adrenergic bronchodilator in the treatment of asthma].

Several classes of medications are used in the treatment of bronchial asthma. Inhaled corticosteroids are the most potent and effective anti-inflammatory agents. The addition of a long-acting beta 2-adrenergic bronchodilator to inhaled corticosteroids for the treatment of asthma has been shown to improve pulmonary function. Combining an inhaled corticosteroid, fluticasone propionate with a long-acting beta 2-adrenergic bronchodilator, salmeterol in a single inhaler permits treatment of both the inflammatory and bronchoconstrictive components of asthma. Combination treatment with fluticasone and salmeterol improves symptoms and lung function, reduces supplemental use of short-acting beta 2-adrenergic bronchodilator. The combination therapy provides better asthma control and may simplify the management of asthma.

Administration, Inhalation↗
PubMed2000

p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation.

The stress-responsive p38 MAPK, when activated by genotoxic stresses such as UV radiation, enhances p53 activity by phosphorylation and leads to cell cycle arrest or apoptosis. Here we report that a member of the protein phosphatase type 2C family, Wip1, has a role in down-regulating p38-p53 signaling during the recovery phase of the damaged cells. Wip1 was originally identified as a gene whose expression is induced following gamma or UV radiation in a p53-dependent manner. We found that Wip1 is also inducible by other environmental stresses, such as anisomycin, H(2)O(2) and methyl methane sulfonate. UV-induction of Wip1 requires p38 activity in addition to the wild-type p53. Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue. Furthermore, Wip1 expression attenuates UV-induced p53 phosphorylation at Ser33 and Ser46, residues previously reported to be phosphorylated by p38. Wip1 expression also suppresses both p53-mediated transcription and apoptosis in response to UV radiation. These results suggest that p53-dependent expression of Wip1 mediates a negative feedback regulation of p38-p53 signaling and contributes to suppression of the UV-induced apoptosis.

Animals↗
PubMed2000

Suppression of pulmonary metastasis using adenovirally motility related protein-1 (MRP-1/CD9) gene delivery.

Previously we showed that MRP-1/CD9 might prevent tumor metastasis by suppression of cell motility and invasion of tissue barriers. The present study explored the possibility of preventing metastasis of mouse melanoma BL6 by expression of MRP-1/CD9 through gene transfer. A replication-deficient adenovirus vector was used for the in vivo transfer of MRP-1/CD9 cDNA. Intratumor injection of an adenovirus vector (rAd-MRP-1/CD9) expressing MRP-1/CD9 resulted in a 73.7% reduction in the number of pulmonary metastases of mice and the median survival time of mice treated with rAd-MRP-1/CD9 was significantly longer than those treated with the rAd-beta-gal vector (103.2 approximately plus;8.5 days vs 71.2 approximately plus;5.2 days, P<0.001 respectively). These results support the expression of MRP-1/CD9 through gene transfer as a therapeutic strategy for preventing metastases and prolonging survival, and support the feasibility of gene transfer in a clinically relevant setting.

Adenoviridae↗
PubMed2000

Identification and characterization of a novel MAP kinase kinase kinase, MLTK.

The MAPK cascades regulate a wide variety of cellular functions, including cell proliferation, differentiation, and stress responses. Here we have identified a novel MAP kinase kinase kinase (MAPKKK), termed MLTK (for MLK-like mitogen-activated protein triple kinase), whose expression is increased by activation of the ERK/MAPK pathway. There are two alternatively spliced forms of MLTK, MLTKalpha and MLTKbeta. When overexpressed in cells, both MLTKalpha and MLTKbeta are able to activate the ERK, JNK/SAPK, p38, and ERK5 pathways. Moreover, both MLTKalpha and MLTKbeta are activated in response to osmotic shock with hyperosmolar media through autophosphorylation. Remarkably, expression of MLTKalpha, but not MLTKbeta, in Swiss 3T3 cells results in the disruption of actin stress fibers and dramatic morphological changes. A kinase-dead form of MLTKalpha does not cause these phenomena. Inhibition of the p38 pathway significantly blocks MLTKalpha-induced stress fiber disruption and morphological changes. These results suggest that MLTK is a stress-activated MAPKKK that may be involved in the regulation of actin organization.

3T3 Cells↗
PubMed2000

Screening of the Men1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors.

Hyperparathyroidism is the first manifestation in a majority of multiple endocrine neoplasia (MEN1) patients. To discriminate between sporadic and hereditary parathyroid tumors and characterize MEN1 somatic mutations, we examined MEN1 gene mutations in patients who had undergone surgery for sporadic parathyroid tumors. DNA was extracted from fresh frozen parathyroid tumor specimens from 112 patients as well as from peripheral blood leukocytes from 64 of the 112 patients. Sequence analysis was performed to examine exons 2-10 of the MEN1 gene for mutations. Loss of heterozygosity (LOH) was also examined by an analysis of codon 418 and 541, which lie within a polymorphic region of MEN1. Somatic MEN1 mutations were found in 25 of the 112 patients (22%). Two patients had two point mutations (508del33 and Y341X and 363insT and 1767delT, respectively). A total of 27 mutations were characterized, 20 of which have not been reported previously. There were 7 nonsense mutations, 10 frameshift mutations, 2 splice site deletions, 5 missense mutations, and 3 in-frame mutations. Nineteen mutations (70%) predicted truncation of the menin protein. Germ-line MEN1 mutations were found in 3 of 64 patients (5%) who had no family history of endocrine tumors associated with MEN1, and these patients were identified as MEN1 gene probands. LOH at the MEN1 locus was detected in three parathyroid tumors showing germ-line mutation. LOH was significantly frequent in parathyroid tumors with somatic MEN1 mutations (15 of 22 tumors, 68%) but not in those without germ-line or somatic MEN1 mutations (14 of 51 tumors, 28%; P = 0.0011). Our findings suggest that alterations of both alleles of the MEN1 gene may be associated not only with endocrine tumors of affected MEN1 patients but also with sporadic parathyroid tumors. Germ-line MEN1 gene analysis can distinguish heritable from nonheritable parathyroid tumors, and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumor is recommended before parathyroid surgery.

Adult↗
PubMed2000

A new assay for lipiodol in a tumor using a combination of m-chloroperbenzoic acid-mediated oxidation and the iodo-starch reaction.

Lipiodol, an iodine adduct lipid, has been used as a targeting carrier of anticancer drugs in experimental animals and humans. In most studies, the concentrations of the anticancer drugs in tissues and organs have been monitored, but not of the carrier because a simple method for measuring lipiodol in biological organs did not exist. Here we present an analytical method for the quantitative determination of lipiodol in tissue. This method is based on the measurement of iodine released from lipiodol by an oxidative reaction. The released iodine was measured spectrophotometrically by monitoring the iodo-starch reaction. Using this method, we were able to demonstrate the tumor specificity of lipiodol using rabbits bearing VX2 tumors in the liver. The present method is also expected to be applicable to human cancers, such as hepatic and colon cancer.

Animals↗
PubMed2000

Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis.

Histone deacetylase (HDAC) inhibitors can induce transcriptional activation of a number of genes and induce cellular differentiation as histone acetylation levels increase. Although these inhibitors induce apoptosis in several cell lines, the precise mechanism by which they do so remains obscure. This study shows that HDAC inhibitors, sodium butyrate and trichostatin A (TSA), abrogate interleukin (IL)-2-mediated gene expression in IL-2-dependent cells. The HDAC inhibitors readily induced apoptosis in IL-2-dependent ILT-Mat cells and BAF-B03 transfectants expressing the IL-2 receptor betac chain, whereas they induced far less apoptosis in cytokine-independent K562 cells. However, these inhibitors similarly increased acetylation levels of histones in both cells. Although histone hyperacetylation is believed to lead to transcriptional activation, the results showed an abrogation of IL-2-mediated induction of c-myc, bag-1, and LC-PTP gene expression. This observed abrogation of gene expression occurred prior to phosphatidylserine externalization, a process that occurs in early apoptotic cells. Considering the biologic role played by IL-2-mediated gene expression in cell survival, these data suggest that its abrogation may contribute to the apoptotic process induced by HDAC inhibitors. (Blood. 2000;96:1490-1495)

Animals↗