Search for η

We measured missing mass spectrum of the ^{12}C(γ,p) reaction for the first time in coincidence with potential decay products from η^{'} bound nuclei. We tagged an (η+p) pair associated with the η^{'}N→ηN process in a nucleus. After applying kinematical selections to reduce backgrounds, no signal events were observed in the bound-state region. An upper limit of the signal cross section in the opening angle cosθ_{lab}^{ηp}<-0.9 was obtained to be 2.2 nb/sr at the 90% confidence level. It is compared with theoretical cross sections, whose normalization ambiguity is suppressed by measuring a quasifree η^{'} production rate. Our results indicate a small branching fraction of the η^{'}N→ηN process and/or a shallow η^{'}-nucleus potential.

Inhibitory effect of statins on inflammatory cytokine production from human bronchial epithelial cells.

Statins are 3-hydroxy-3-methylglutaryl-co-enzyme A reductase inhibitors of cholesterol biosynthesis, and have been reported to exert pleiotropic effects on cellular signalling and cellular functions involved in inflammation. Recent reports have demonstrated that previous statin therapy reduced the risk of pneumonia or increased survival in patients with community-acquired pneumonia. However, the precise mechanisms responsible for these effects are unclear. In the present study, we examined the effects of statins on cytokine production from lipopolysaccharide (LPS)-stimulated human bronchial epithelial cells (BEAS-2B). Interleukin (IL)-6 and IL-8 mRNA expression and protein secretion in LPS-stimulated cells were inhibited significantly by the lipophilic statin pitavastatin and the hydrophilic statin pravastatin. As these inhibitory effects of statin were negated by adding mevalonate, the anti-inflammatory effects of statins appear to be exerted via the mevalonic cascade. In addition, the activation levels of Ras homologue gene family A (RhoA) in BEAS-2B cells cultured with pitavastatin were significantly lower than those without the statin. These results suggest that statins have anti-inflammatory effects by reducing cytokine production through inhibition of the mevalonic cascade followed by RhoA activation in the lung.

Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells.

Summary The macrolide antibiotics are now well known to have anti-inflammatory effects. Because dendritic cells (DCs) orchestrate immune responses, we examined the in vitro effects of clarithromycin (CAM), azithromycin (AZM) and midecamycin (MDM) on the expression of co-stimulatory molecules and production of cytokines [interleukin (IL)-10, IL-6, interferon (IFN)-gamma, IL-12p40, tumour necrosis factor (TNF)-alpha] of murine bone marrow-derived DCs by lipopolysaccharide (LPS) stimulation. A 15-membered macrolide, AZM, and a 14-membered macrolide, CAM, significantly enhanced the intensity of a co-stimulatory molecule, CD80, on DCs but not CD86 and CD40. AZM significantly increased the production of IL-10 and CAM significantly inhibited the production of IL-6 by DCs. However, a 16-membered macrolide, MDM, did not have any significant effect on these surface markers and cytokine productions. Moreover, AZM increased IL-10 and CAM decreased IL-2 productions significantly, when naive T cells derived from spleen were co-cultured with DCs treated in advance with LPS and these macrolides. These findings suggest that 14-membered and 15-membered, but not 16-membered macrolides play as anti-inflammatory agents, at least in part, through modulating the functions of DCs. However, each macrolide affects them in different ways.

Synthesis of the novel analogues of dysidiolide and their structure-activity relationship.

The novel analogues of natural cdc25A inhibitor dysidiolide were synthesized. To investigate the structure-activity relationship, the inhibitory activity to enzyme and cell cycle was examined.

[Natural organic compounds that affect to microtubule functions: syntheses and structure-activity relationships of combretastatins, curacin A and their analogs as the colchicine-site ligands on tubulin].

Microtubules (MT) are cylindrical polymers of the protein tubulin (TN) alpha, beta-heterodimer, and are known to be the main component of spindles in mitotic apparatus of eucaryotic cells. MT are also involved in many other basic and essential cell functions. There are a number of natural and synthetic compounds that interfere with MT function to cause the mitotic arrest of eucaryotic cells. Such antimitotic agents show a broad biological activity, and can be used for medicinal and agrochemical purposes. On the other hand, they are important also as the biochemical tools for understanding the dynamics of MT network. Most of such antimitotic agents, with a few exceptions, bind to beta-TN. Among them, colchicine (CLC), vinblastine and taxol have played major roles in practical uses as well as in biochemical studies of MT functions. They all bind to beta-TN but their binding sites are different. We have worked on a variety of antimitotic agents that bind to either of colchicine-site, vinblastine-site and taxol-site, in discovery, structures, biological actions and/or interactions with TN. In this paper, the results of our studies on CLC-site ligands were summarized; (1) synthetic analogs of combretastatin A-4 (CBS A-4), isolated as a cytotoxic compound produced by a species of South African tree Combretum caffrum, (2) curacin A (CU-A), a cytotoxic metabolite of a marine cyanobacteria Lyngbya majuscula, and its related compounds. Interactions of these compounds with TN were studied and structure-activity relationships of these two classes of compounds were discussed.

Separation of phosphatidylinositol 4-phosphate from a mixture with phosphatidylserine and phosphatidylinositol by Sep-Pak C18 cartridge.

A simple and efficient method for the separation of phosphatidylinositol 4-phosphate (PI 4-P) from phosphatidylinositol (PI) and phosphatidylserine (PS) is described. A mixture of PI, PI 4-P and PS was injected onto a Sep-Pak C18 cartridge. PI and PS were flushed through the cartridge with solvent 1 [methanol-chloroform (3: 1)] while PI 4-P remained in it. Then the cartridge was inverted, and PI 4-P was eluted backward with solvent 2 [chloroform-methanol-0.5 M aqueous ammonium hydroxide (9:7:2)].

[Two cases of multiple primary cancer involving the lung with old pulmonary tuberculosis].

We reported 2 relatively rare cases of multiple primary cancer including lung cancer accompanied by old pulmonary tuberculosis. Patient 1 was a 62-year-old man admitted to our hospital for further evaluation of an infiltrative shadow on chest X-ray films, and a cervical tumor noted 10 years earlier and thought to be thyroid cancer. A Transbronchial lung biopsy (TBLB) specimen disclosed poorly differentiated squamous cell carcinoma. A right upper lobectomy and thyroidectomy were performed. Histopathologic findings showed a neoplastic lesion adjacent to caseous necrosis with formation of granuloma consistent with tuberculosis. Also, the cervical tumor was considered to be a metastatic lymph node from thyroid papillary carcinoma. Patient 2 was a 73-year-old man with a 14-year history of treatment for transitional cell carcinoma of urinary bladder, who had been admitted to our hospital for further evaluation because of a nodular shadow observed on chest X-ray films. TBLB specimens disclosed adenocarcinoma. A right upper lobectomy was performed. Histopathologic findings revealed a neoplastic tumorlet in the same lobe. No detectable increases in serum TNF-alpha, IL-1 beta or IFN-gamma were observed in either patient. Phytohemagglutinin- and concanavalin-A-stimulated lymphocyte proliferation decreased in Patient 1. These findings suggested that the immunocompromised status of patients with cancer in addition to old pulmonary tuberculosis may contribute to the development of lung cancer.

Evidence that 3'-phosphorylated polyphosphoinositides are generated at the nuclear surface: use of immunostaining technique with monoclonal antibodies specific for PI 3,4-P(2).

Phosphatidylinositol (PI) 3,4-P(2) is a phosphoinositide that has been shown to be important for signal transduction in growth factor stimulation. We have produced monoclonal antibodies specific for PI 3,4-P(2), which were able to detect PI 3,4-P(2) generated in 293T cells treated with H(2)O(2), or in MKN45/BD110 cells expressing activated PI 3-kinase in immunostaining. Prolonged treatment with 0.05% Tween 20 resulted in detection of staining not only at the plasma membrane, but also at the nuclear surface, indicating that 3'-phosphorylated phosphoinositides can be generated and function in the nucleus.

Synthesis of a novel class of cdc25A inhibitors from vitamin D3.

We have developed a novel class of cdc25A inhibitors by drastic modification of the hydrophobic and hydrophilic substructures of dysidiolide. The unsaturated derivative 3b strongly inhibited cdc25A (IC50 = 7.7 microM) and caused GI arrest of HL60 cells.

Immunological function and nutritional status in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: Infection is a major complication associated with increased morbidity and mortality in patients with hepatocellular carcinoma. We compared the immunological function and nutritional status in 16 patients with hepatocellular carcinoma (13 patients had liver cirrhosis) with those of 21 normal healthy subjects. METHODOLOGY: The immunological function was assessed by chemotaxis and superoxide anion production by neutrophils, phagocytosis and killing activities of neutrophils and monocytes, absolute and relative number of peripheral blood lymphocytes, the percentage of peripheral lymphocyte subsets and serum concentrations of immunoglobulins. RESULTS: Although the phagocytic and bactericidal activities of monocytes and superoxide production of neutrophils were not different between the groups, the phagocytic and bactericidal activities of neutrophils and the percentage of natural killer cells were significantly reduced in patients with hepatocellular carcinoma. In the latter group, the prognostic nutrition index was significantly high compared with normal subjects, indicating a poor nutritional status. The phagocytic and bactericidal activities of neutrophils were low in patients with a poor nutritional status compared to those with a good nutritional status. CONCLUSIONS: Our results suggest that impaired immunological competence and undernourishment may be one of the mechanisms causing increased susceptibility of patients with hepatocellular carcinoma to infection.

Novel small molecule nonpeptide aminopeptidase n inhibitors with a cyclic imide skeleton.

A novel series of small molecule nonpeptide aminopeptidase N (APN) inhibitors with a N-phenylphthalimide or N-phenylhomophthalimide skeleton were prepared. Evaluation of their protease inhibitory activities revealed that (i) some N-phenylphthalimide analogs are potent APN inhibitors, but they are also inhibitors of another protease, dipeptidylpeptidase IV (DPP-IV), and (ii) some N-phenylhomophthalimide analogs, including 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22), are potent and specific inhibitors of APN without DPP-IV-inhibitory activity. The structure-activity relationship studies of N-phenylphthalimides and N-phenylhomophthalimides are reviewed. PIQ-22 showed potent tumor-cell invasion-inhibitory activity.

Reduced immune function and malnutrition in the elderly.

An important observation in elderly subjects is their susceptibility to infection associated with a decline in host immune function. Nutrition is also an important factor that influences host defense against infection. We, therefore, evaluated the relationship between nutritional status in 155 healthy subjects ranging in age from 20 to 99 years and various immunological parameters, including the phagocytic and bactericidal activities of neutrophils and monocytes, superoxide production and chemotaxis of neutrophils, lymphocyte subsets, blastoid transformation and serum immunoglobulins. Aging was associated with increased phagocytic activity of neutrophils but not bactericidal activity, superoxide production or chemotaxis of neutrophils. Aging was also associated with a significant decrease in the number of lymphocytes as well as a decline in mature T cells and helper/inducer T cells but with increased numbers of activated T cells, suppressor T cells and natural killer cells. In addition, blastoid transformation in response to phytohemagglutinin (PHA) and concanavalin A (Con A) was significantly reduced in aged subjects. A poor nutritional status was noted in individuals 60 years of age or older. The nutritional status did not influence neutrophil function but correlated significantly with the number of lymphocytes and degree of blastoid formation with PHA and Con A stimulation. Our results suggest that the cell-mediated immunity in elderly subjects is reduced as a result of malnutrition, and that improvement of the nutritional status may enhance the immune function, likely contributing to their successful aging.

Immunological competence and nutritional status in patients with lung cancer.

The rate of infection in patients with malignant disease is significantly higher than in patients with benign disease. To investigate whether immunological competence is impaired in patients with lung cancer, we assessed neutrophil function (chemotaxis, phagocytosis, bacterial killing activity, and superoxide production), monocyte function (phagocytosis and killing activity), lymphocyte subsets using flow cytometry, and proliferation of lymphocytes stimulated by phytohemagglutinin, concanavalin A, and pokeweed mitogen. Studies were performed on 22 untreated patients with lung cancer and 21 age-matched healthy volunteers. Nutritional status was assessed by Niederman's nutritional index. In patients with lung cancer neutrophil chemotaxis, monocyte phagocytosis and killing, proliferation of lymphocytes stimulated by phytohemagglutinin and concanavalin A, but not pokeweed mitogen, and the number of natural killer cells were significantly lower than in healthy volunteers, whereas gammadelta T cells were increased (p < 0.05). The mean score on Niederman's nutritional index was worse in patients than in healthy volunteers (p < 0.001). Our results suggest that the impaired immunological competence and undernutrition may be among the mechanisms causing increased susceptibility to infection in patients with lung cancer.

Sequence selective interaction between nucleotides and intercalators bound to water soluble dextran: an application to the affinity chromatography of dinucleotides.

The analysis of association constant between dextran coupled intercalators and nucleotides revealed the base- and sequence-selective affinity to mono- and dinucleotides in aqueous solution. Acridine bound CH-Sepharose 4B, designed as the affinity stationary phase for nucleotides, also showed base- and sequence-selective affinity.

Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: influence of substituents at the phthaloyl moiety on the activity and stereoselectivity.

The synthesis and tumor necrosis factor (TNF)-alpha production enhancing activity of substituted 3'-methylthalidomides on human leukemia cell line HL-60 stimulated with 12-O-tetradecanoyl-phorbol 13-acetate (TPA) are described. Though the introduction of an electron-donating amino group at the phthaloyl moiety of alpha-methylthalidomides enhanced the activity, substituted alpha-methylthalidomides showed decreased stereoselectivity as compared to that of non-substituted alpha-methylthalidomide. The data indicates that the TNF-alpha production enhancing activity of thalidomide derivatives depends on both the electronic-state of substituents at the fused benzene ring and the stereochemistry of the glutarimide moiety.

[Complication of infection in malnutritional status].

Recently, the therapeutic guideline has been mentioned in opportunistic infection of the compromised host, and many observations regarding complication of infection in these hosts have been reported. However, there were few reports in the relationship between infection and immune function or nutritional status. In this study, we confirmed that the nutritional status influences immune function in patients with lung cancer, hepatoma and renal failure, and that malnutrition markedly reduces their immunity. In patients after operation who where the pre-operative assessment of the nutritional status was performed an attempt to improve the nutritional status has been already made to improve their prognosis. Therefore, we emphasize that the management of the nutritional status even in hosts with many other diseases is thought to be important in protection against infection and prognosis of the disease.

[A case of pulmonary sarcoidosis with multiple cavitation and pneumothorax].

We describe a rare case of pulmonary sarcoidosis with multiple cavitation and pneumothorax. A 32-year-old woman was admitted to our hospital with a dry cough and an interstitial shadow with dense infiltrates in both upper lungs and cavitation in the right upper lung on chest roentgenogram and CT. Laboratory tests revealed an elevated level of serum lysozyme. BAL fluid demonstrated a high proportion of lymphocytes with an increased CD4/CD8 ratio, compatible with sarcoidosis. Transbronchial lung and skin biopsies showed evidence of noncaseating epithelioid-cell granuloma, and a diagnosis of sarcoidosis was made. Although pneumothorax appeared in the left lung on chest roentgenogram during clinical observation conservative treatment without corticosteroids or any other therapy for a follow-up period of 3 years resulted in improvement of her clinical condition and abnormal X-ray findings.

Isolation and structure of an antimitotic cyclic peptide, ustiloxin F: chemical interrelation with a homologous peptide, ustiloxin B.

Ustiloxin F, a microtubule inhibitor, was isolated as a minor metabolite of Ustilaginoidea virens. The structure was determined from the spectral data and by chemical interrelation to ustiloxin B through reductive removal of the sulfoxide-containing side chain of ustiloxin B to give ustiloxin F. Ustiloxin F inhibited microtubule assembly with an IC50 value of 10.3 microM.

Synthesis and anti-tubulin activity of ustiloxin D derivatives.

Ustiloxin D, produced by the rice plant pathogen Ustilaginoidea virens, exhibits potent anti-tubulin activity. In order to elucidate the effects of functional groups in ustiloxin D on its activity, several derivatives were synthesized and their anti-tubulin activities were estimated. The N,N-dimethylamino derivative and the 14-O-methyl derivative were inactive (IC50 > 50 microM). 20-Hydroxymethylated ustiloxin D showed decreased inhibitory activity compared with ustiloxin D.