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Biomedical subjects

S Omura

Publications and source records attributed to S Omura.

At least 19 recordsLinked to original sources
PubMed2003

Novel OK-432-conjugated tumor vaccines induce tumor-specific immunity against murine tongue cancer.

Priming with tumor antigens is one of the most important strategies in cancer immunotherapy. To enhance tumor antigenicity, OK-432, a streptococcal preparation, was coupled to squamous cell carcinoma (KLN-205) by means of a 0.2% glutaraldehyde method. The purpose of this study was to investigate whether OK-432-conjugated tumor vaccines could induce tumor-specific immunity. Our originally developed mouse tongue cancer model was used throughout this work for the analysis of antitumor effects. Prepared OK-432-conjugated KLN-205 vaccines were immunized 3 times to DBA/2 mice. The results showed that the KLN-205 vaccines induced cytolytic activity and strongly suppressed both KLN-205 tumor incidence and growth, and survival of the mice was improved. Moreover, the histological results showed that a greater number of lymphocytes had infiltrated around tumor cells by 24 hours after tumor inoculation in the vaccine group. These results suggest that immunizations with KLN-205 vaccines increase the antitumor effects against tongue cancer.

Animals↗
PubMed2001

Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites.

Streptomyces avermitilis is a soil bacterium that carries out not only a complex morphological differentiation but also the production of secondary metabolites, one of which, avermectin, is commercially important in human and veterinary medicine. The major interest in this genus Streptomyces is the diversity of its production of secondary metabolites as an industrial microorganism. A major factor in its prominence as a producer of the variety of secondary metabolites is its possession of several metabolic pathways for biosynthesis. Here we report sequence analysis of S. avermitilis, covering 99% of its genome. At least 8.7 million base pairs exist in the linear chromosome; this is the largest bacterial genome sequence, and it provides insights into the intrinsic diversity of the production of the secondary metabolites of Streptomyces. Twenty-five kinds of secondary metabolite gene clusters were found in the genome of S. avermitilis. Four of them are concerned with the biosyntheses of melanin pigments, in which two clusters encode tyrosinase and its cofactor, another two encode an ochronotic pigment derived from homogentiginic acid, and another polyketide-derived melanin. The gene clusters for carotenoid and siderophore biosyntheses are composed of seven and five genes, respectively. There are eight kinds of gene clusters for type-I polyketide compound biosyntheses, and two clusters are involved in the biosyntheses of type-II polyketide-derived compounds. Furthermore, a polyketide synthase that resembles phloroglucinol synthase was detected. Eight clusters are involved in the biosyntheses of peptide compounds that are synthesized by nonribosomal peptide synthetases. These secondary metabolite clusters are widely located in the genome but half of them are near both ends of the genome. The total length of these clusters occupies about 6.4% of the genome.

Base Sequence↗
PubMed2001

Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor.

[structure: see text] Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor, has been accomplished by a convergent approach. The C1-C8 and C9-C18 segments were derived efficiently from D-glucose and (S)-(-)-2-methyl-1-butanol, respectively, coupled by stereoselective Julia olefination, and converted to nafuredin.

Anthelmintics↗
PubMed2001

Glucose regulates protein catabolism in ras-transformed fibroblasts through a lysosomal-dependent proteolytic pathway.

Transformed cells are exposed to heterogeneous microenvironments, including low D-glucose (Glc) concentrations inside tumours. The regulation of protein turnover is commonly impaired in many types of transformed cells, but the role of Glc in this regulation is unknown. In the present study we demonstrate that Glc controls protein turnover in ras-transformed fibroblasts (KBALB). The regulation by Glc of protein breakdown was correlated with modifications in the levels of lysosomal cathepsins B, L and D, while autophagic sequestration and non-lysosomal proteolytic systems (m- and mu-calpains and the zeta-subunit of the proteasome) remained unaffected. Lactacystin, a selective inhibitor of the proteasome, depressed proteolysis, but did not prevent its regulation by Glc. The sole inhibition of the cysteine endopeptidases (cathepsins B and L, and calpains) by E-64d [(2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester] was also not sufficient to alter the effect of Glc on proteolysis. The Glc-dependent increase in proteolysis was, however, prevented after optimal inhibition of lysosomal cysteine and aspartic endopeptidases by methylamine. We conclude that, in transformed cells, Glc plays a critical role in the regulation of protein turnover and that the lysosomal proteolytic capacity is mainly responsible for the control of intracellular proteolysis by Glc.

3T3 Cells↗
PubMed2001

Signaling pathways leading to transcription and translation cooperatively regulate the transient increase in expression of c-Fos protein.

The mechanisms by which growth factors trigger signal transduction pathways leading to the regulation of c-Fos expression are of great interest. In this study we investigated the effect of hepatocyte growth factor (HGF/SF) and epidermal growth factor (EGF) on the expression of c-fos and its product, c-Fos, in human epithelial cell line MKN74. The expression level of c-Fos protein in HGF/SF-stimulated cells was 5--10-fold higher than that in EGF-stimulated cells, whereas the level of c-fos mRNA induced by HGF/SF was similar to that by EGF. The hyperphosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), indicative of an increased number of translation initiation complexes, was detected only in HGF/SF-induced MKN74 cells. Activation of phosphatidylinositol-3'-OH kinase and FKBP12-rapamycin associated mammalian target of rapamycin (FRAP/mTOR) was observed after the treatment with HGF/SF. Pretreatment with an inhibitor of either one, i.e. LY294002 for phosphatidylinositol-3'-OH kinase or rapamycin for FRAP/mTOR, completely inhibited 4E-BP1 phosphorylation and decreased the c-Fos synthesis induced by HGF/SF down to the level found in EGF-induced cells. These results suggest that the phosphorylation of 4E-BP1 is stimulated by HGF/SF in a manner requiring both phosphatidy-linositol-3'-OH kinase-dependent and FRAP/mTOR-dependent pathways, thereby stimulating c-fos mRNA translation. Regulation of the translation process of c-fos mRNA in addition to the immediate activation of c-fos transcription is necessary for the transient increase in the level of c-Fos protein to stimulate cell proliferation.

Cell Line↗
PubMed2001

Actinohivin, a novel anti-HIV protein from an actinomycete that inhibits syncytium formation: isolation, characterization, and biological activities.

Blocking human immunodeficiency virus (HIV) entry into target cells is an important goal of HIV and acquired immune deficiency syndrome (AIDS) therapies. We have searched for anti-HIV substances from microorganisms using a syncytium formation assay system constructed with HeLa/CD4/Lac-Z and HeLa/T-env/Tat cells. We discovered a novel anti-HIV protein that inhibits syncytium formation, designated as actinohivin, from a cultured broth of a soil isolate, actinomycete strain K97-0003. ESI mass spectrometry of actinohivin isolated from the culture filtrate showed an ion with molecular mass of 12,520.3 Da. The amino acid sequence was determined by N-terminal Edman degradation of the intact protein and peptide fragments formed by endoproteinase digestions. Actinohivin consists of a 114-amino-acid chain that exhibits internal sequence triplication. Actinohivin inhibited both T-cell and macrophage tropic syncytium formation, with IC(50) values of 60 and 700 nM, respectively, and the cytopathic effect of HIV-1(IIIB) in MT-4 cells, with IC(50) value of 230 nM.

Actinomycetales↗
PubMed2001

Effects of lowering barometric pressure on guarding behavior, heart rate and blood pressure in a rat model of neuropathic pain.

We investigated whether lowering barometric pressure by 20 mmHg (LP) aggravates the guarding behavior suggestive of spontaneous pain following sciatic nerve chronic constriction injury (CCI) in rats. Systemic blood pressure (BP) and heart rate (HR) of unrestrained rats were recorded telemetrically during LP both before and after the CCI surgery. CCI rats showed guarding posture in normopressure conditions, and LP increased the cumulative time of this behavior. Baseline BP but not HR was increased following CCI. LP increased BP and HR of the rats only before the CCI surgery. Animals after CCI surgery showed variable (BP, HR) and transient (HR) responses to LP. These results indicate that (1) LP aggravated spontaneous pain and increased BP and HR in the CCI rats, and (2) CCI surgery influenced BP and HR of rats.

Animals↗
PubMed2001

An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria.

Infections with parasitic helminths are important causes of morbidity and mortality worldwide. New drugs that are parasite specific and minimally toxic to the host are needed to counter these infections effectively. Here we report the finding of a previously unidentified compound, nafuredin, from Aspergillus niger. Nafuredin inhibits NADH-fumarate reductase (complexes I + II) activity, a unique anaerobic electron transport system in helminth mitochondria, at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep. Thus, our study indicates that mitochondrial complex I is a promising target for chemotherapy, and nafuredin is a potential lead compound as an anthelmintic isolated from microorganisms.

Administration, Oral↗
PubMed2001

Molecular cloning of actinohivin, a novel anti-HIV protein from an actinomycete, and its expression in Escherichia coli.

Syncytium-inducing variants of the HIV-1 virus are correlated with poor diagnosis and rapid disease progression. We have recently discovered a novel anti-HIV protein, referred to as actinohivin, that inhibits syncytium formation. Here we describe the cloning and sequencing of the gene encoding actinohivin from the actinomycete strain K97-0003, and its expression in Escherichia coli. The actinohivin gene was located on a 0.8-kb BamHI fragment of genomic DNA. The fragment contained an open reading frame of 480 bp, which encoded a protein of 160 amino acids with calculated molecular weight of 17492.7. The N-terminal region was found to be a typical signal peptide of prokaryotes, and actinohivin was located at amino acid positions 46-160. The actinohivin gene could be expressed in E. coli using a pET30Xa/LIC expression vector and the purified recombinant actinohivin was found to inhibit syncytium formation to a similar extent as actinohivin from its natural source.

Actinomycetales↗
PubMed2001

FK506 facilitates chemical kindling induced by pentylenetetrazole in rats.

To clarify the possible role played by calcineurin in kindling development, we examined the effects of pretreatment with FK506, a selective calcineurin inhibitor, on pentylenetetrazole (PTZ) kindling in rats. FK506 facilitated the speed of kindling induced by repeated administration of 30-mg/kg PTZ, while FK506 did not ameliorate acute seizure manifestations after a single injection of PTZ. Our results suggested that calcineurin might exert an inhibitory effect on PTZ kindling.

Animals↗
PubMed2001

Organization of biosynthetic gene cluster for avermectin in Streptomyces avermitilis: analysis of enzymatic domains in four polyketide synthases.

The analysis of the incorporation of 13C-labeled precursors into avermectins indicates that the avermectin aglycons are synthesized by head-to-tail condensation of various acyl groups, which is similar to the biosynthesis of other polyketides. Polyketide synthases (PKS) use the appropriate CoA ester as a primer and add acetate units from malonyl-CoA and propionate units from methylmalonyl-CoA to assemble the polyketides. Avermectin aglycons are formed by addition to the starter unit (2-methylbutyrate or isobutyrate) of 12 acyl condensations in the order P-A-A-A-A-P-P-A-P-A-P-A (P, propionyl; A, acetyl). Within the 90-kb gene cluster for a vermectin biosynthesis, the central 65-kb segment was found to be required for aglycon biosynthesis by phenotypic analysis of strains containing deletion or insertion mutations in this region. A complete sequence analysis of the 65-kb segment indicated that this segment encodes avermectin PKS. The avermectin PKS genes are organized into two converging blocks of ORFs. From the results of sequencing analysis, a feature of the two regions, aveA1/aveA2 and avea3/aveA4, is that they encode four kinds of large multifunctional polypeptides containing 55 domains which possess putative fatty acid synthase-like activities. The avermectin PKS (AVES 1-4) appear to contain two, three, or four modules. AVES1 and 2 contain two and four modules, respectively, whereas AVES 3 and AVES 4 each contains three modules. The 12 modules correspond to the 12 cycles required for synthesis of the avermectin aglycon.

Amino Acid Sequence↗
PubMed2001

Description of two novel species of the genus Kitasatospora Omura et al. 1982, Kitasatospora cineracea sp. nov. and Kitasatospora niigatensis sp. nov.

Five actinomycete strains, SK-3255T, SK-3406T, SK-3412, SK-3421 and OM-5023, were isolated using a novobiocin-containing agar medium from soil samples. These strains produced long spore chains on aerial mycelium and contained LL- and meso-diaminopimelic acids (DAPs) in the cell wall. On the basis of morphological and chemotaxonomic characteristics and phylogenetic analysis, these five strains were classified into the genus Kitasatospora. DNA-DNA hybridization and comparison of physiological characteristics revealed that strains SK-3255T and SK-3406T differed from known species. Strains SK-3406T, SK-3412 and SK-3421 were regarded as the same species. Strain OM-5023 was identified as Kitasatospora griseola. Therefore, two novel species are proposed, Kitasatospora cineracea sp. nov. and Kitasatospora niigatensis sp. nov., with the type strains K. cineracea SK-3255T (= IFO 16452T = JCM 10915T = NRRL B-23134T) and K. niigatensis SK-3406T (= IFO 16453T = JCM 10916T = NRRL B-24135T).

Cell Wall↗
PubMed2001

Deacetylravidomycin M, a new inhibitor of IL-4 signal transduction, produced by Streptomyces sp. WK-6326. I. Taxonomy, fermentation, isolation and biological activities.

Streptomyces sp. WK-6326, a soil isolate, was found to produce an inhibitor of interleukin (IL)-4 signal transduction. Two structurally related compounds, a novel one designated deacetylravidomycin M and the known deacetylravidomycin, were isolated from the culture broth by solvent extraction, silica gel column chromatography and HPLC. Deacetylravidomycin M inhibited IL-4-induced CD23 expression in U937 cells without any cytotoxic effect, whereas deacetylravidomycin showed no inhibitory activity.

Aminoglycosides↗