Biomedical subjects

M Terao

Publications and source records attributed to M Terao.

At least 19 recordsLinked to original sources

PubMed2004

Atypical retinoids: an expanding series of anti-leukemia and anti-cancer agents endowed with selective apoptotic activity.

Retinoid-related molecules (RRMs) are an interesting class of novel molecules endowed with remarkable and selective apoptotic activity against various leukemia and cancer cell types. ST1926 is the most promising molecule and is active in vivo on numerous experimental models of leukemia and cancer. This has led to the development of a compound that will soon undergo phase I clinical trials. Although the primary molecular targets of RRMs' apoptotic activity are still unknown, ST1926 and congeners are characterized by a peculiar mechanism of action that centers on the mitochondrion and is associated with alterations in the homeostasis of intracellular calcium.

Antineoplastic Agents↗

PubMed2001

Purification of the aldehyde oxidase homolog 1 (AOH1) protein and cloning of the AOH1 and aldehyde oxidase homolog 2 (AOH2) genes. Identification of a novel molybdo-flavoprotein gene cluster on mouse chromosome 1.

We report the cloning of the AOH1 and AOH2 genes, which encode two novel mammalian molybdo-flavoproteins. We have purified the AOH1 protein to homogeneity in its catalytically active form from mouse liver. Twenty tryptic peptides, identified or directly sequenced by mass spectrometry, confirm the primary structure of the polypeptide deduced from the AOH1 gene. The enzyme contains one molecule of FAD, one atom of molybdenum, and four atoms of iron per subunit and shows spectroscopic features similar to those of the prototypic molybdo-flavoprotein xanthine oxidoreductase. The AOH1 and AOH2 genes are 98 and 60 kilobases long, respectively, and consist of 35 coding exons. The AOH1 gene has the potential to transcribe an extra leader non-coding exon, which is located downstream of exon 26, and is transcribed in the opposite orientation relative to all the other exons. AOH1 and AOH2 map to chromosome 1 in close proximity to each other and to the aldehyde oxidase gene, forming a molybdo-flavoenzyme gene cluster. Conservation in the position of exon/intron junctions among the mouse AOH1, AOH2, aldehyde oxidase, and xanthine oxidoreductase loci indicates that these genes are derived from the duplication of an ancestral precursor.

Aldehyde Oxidoreductases↗

PubMed2001

Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RARalpha and PML-RARalpha.

The 2-phenylaminopyrimidine derivative STI571 is a selective inhibitor of c-Abl, c-kit, and platelet-derived growth factor-receptor tyrosine kinases and is presently in phase II-III clinical studies. Here, this study reports on a novel pharmacologic activity of the compound, ie, enhancement of the cyto-differentiating, growth-inhibitory, and apoptogenic actions of all-trans-retinoic acid (ATRA). Whereas STI571 is not a cytodifferentiating agent by itself, the compound interacts with ATRA and enhances the myeloid maturation program set in motion by the retinoid in the PML-RARalpha(+) acute promyelocytic leukemia NB4 and the PML-RARalpha(-) myeloblastic HL60 and U937 cell lines. In addition, STI571 relieves the cyto-differentiation block observed in the ATRA-resistant cell lines, NB4.R1, NB4.306, and NB4.007. In NB4 promyelocytes, a RARalpha agonist, but not an RXR agonist, can substitute for ATRA and interact with STI571. By contrast, STI571 is unique among c-Abl-specific tyrosine kinase inhibitors in modulating the pharmacologic activity of ATRA. In NB4 cells, enhanced cyto-differentiation results in increased up-regulation of the expression of a number of genes coding for myeloid differentiation markers, including CD11b, CD11c, and some of the components of the nicotinamide adenine dinucleotide phosphate-oxidase enzymatic complex. All this is accompanied by inhibition of c-Abl tyrosine phosphorylation and retardation of the retinoid-dependent degradation of PML-RARalpha and RARalpha. Stabilization of the 2 retinoic acid receptors is likely to be the result of augmented and accelerated inhibition of the proteasome-dependent proteolytic activity observed on ATRA treatment.

Apoptosis↗

PubMed2001

Cytodifferentiation: a novel approach to cancer treatment and prevention.

Cytodifferentiation therapy promises to control cancer growth and progression with less serious side effects than cytotoxic chemotherapy. Despite recent progress, the molecular mechanisms regulating the differentiation of many cell types are still obscure and the number of active cytodifferentiating agents is limited. Rational ways to develop these types of agents are necessary.

Animals↗

PubMed2001

Nitric oxide participates in cataract development in selenite-treated rats.

PURPOSE: The role of nitric oxide in the development of selenite-induced cataracts in rats was examined using nitric oxide synthase (NOS) inhibitors. METHODS: Subcutaneous injection of sodium selenite was used to induce cataracts in rats, with or without pretreatment with NOS inhibitors. The anterior eye segment analysis system (EAS-1000, Nidek) was used to measure lens opacity. The glutathione content of the lenses was determined by an HPLC method and the Ca2+ content by atomic absorption spectrometry. Nitrite, a stable metabolite of nitric oxide, was determined fluorometrically. NADPH-diaphorase activity staining and Western blot analysis were used to determine NOS levels. RESULTS: Administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited lens opacification in selenite-treated rats. NG-nitro-d-arginine methyl ester, an inactive enantiomer of l-NAME, had no effect. Aminoguanidine, another NOS inhibitor, also inhibited the development of cataracts in a dose-dependent manner. On the other hand, L-arginine, a substrate of NOS, accelerated the development of cataracts. Although the opacification of the lenses was apparent approximately 3 days after selenite injection, the nitrite level was increased within one day. In addition, NOS was induced in the eye within one day of selenite injection. CONCLUSIONS: The present study demonstrated that NOS inhibitors prevented the development of cataracts in selenite-treated rats. The results also suggest that nitric oxide had an important role in the development of selenite-induced cataracts.

Animals↗

PubMed2001

RAPD- and actA gene-typing of Listeria monocytogenes isolates of human listeriosis, the intestinal contents of cows and beef.

Seventy-five L. monocytogenes isolates of human listeriosis, the intestinal contents of cows and beef were divided into 5 major clusters, 17 sub-clusters and 28 minor clusters by typing using random amplification of polymorphic DNA (RAPD). According to their major RAPD category, L. monocytogenes isolates serotyped as 1/2b and 4b were distinguished from L. monocytogenes isolates of serovars 1/2a and 1/2c. Moreover serovar 4b was distinguished from serovar 1/2b by a difference in the RAPD sub-cluster category. All L. monocytogenes were found to possess either actA gene Type I or II, and only one actA gene type was detected in each RAPD minor cluster. actA gene Type II was observed in 32.0%, 38.5% and 18.9% of isolates from humans, cows and beef, respectively, and was detected more frequently in serovar 4b (46.9%) than in serovars 1/2a (22.2%), 1/2b (7.7%) and 1/2c (0.0%). Twenty (80%) of 25 human isolates fell within three minor RAPD types (II-d (16%), V-p-1 (36%), V-p-2 (28%)). Two isolates from humans and beef were found to have the same RAPD type (Type IV-k-1), actA gene type (Type I) and serovar (1/2b). Our results suggest that only a few genotypes of L. monocytogenes are predominant in human listeriosis in Japan, although the human isolates were collected over a broad span of time and a wide geographical range. Our results also suggest that RAPD-, actA gene- and sero-typing can be useful for epidemiological analysis.

Animals↗

PubMed2001

Therapeutic effects of azathioprine in combination with low-dose prednisolone in patients with intractable autoimmune hepatitis type 1.

This study evaluated the effects of azathioprine in combination with low-dose prednisolone in the management of patients with intractable autoimmune hepatitis. Thirteen patients with intractable autoimmune hepatitis who had an incomplete or arrested response to conventional prednisolone therapy, or who relapsed during prednisolone maintenance therapy were additionally administered 50 or 100 mg/day of azathioprine in combination with prednisolone. This regimen reliably induced complete remission in 12 of 13 patients, and these 12 remained in remission during the follow-up period with maintenance therapy of 50 mg/day of azathioprine in combination with 5 mg/day of prednisolone. The findings of the current study indicate that the azathioprine and low-dose prednisolone combined therapy may offer a satisfactory alternative therapy for patients with intractable autoimmune hepatitis who have an incomplete or arrested response to conventional prednisolone therapy, or who relapse during prednisolone maintenance therapy.

Adult↗

PubMed2001

[Effects of lumbar sympathetic ganglion block in a patient with acquired lymphangioma].

A 70-year-old woman developed lymphangioma following surgery for cervical cancer and subsequent radiotherapy. The operation was performed 12 years ago, and a swelling of lower extremities was recognized 8 years ago. Her lower extremities became greatly edematous, and leakage of lymph to the groin was observed. We performed bilateral lumbar sympathetic ganglion block. After the block, lymphedema was relieved dramatically, and the leakage of the lymph to the groin was gradually reduced. We conclude that lumbar sympathetic ganglion block may be very effective in some patients with acquired lymphangioma.

Aged↗

PubMed2000

Cloning of the cDNAs coding for two novel molybdo-flavoproteins showing high similarity with aldehyde oxidase and xanthine oxidoreductase.

The cDNAs coding for two novel mouse molybdo-flavoproteins, AOH1 and AOH2 (aldehyde oxidase homolog 1 and 2), were isolated. The AOH1 and AOH2 cDNAs code for polypeptides of 1336 amino acids. The two proteins have similar primary structure and show striking amino acid identity with aldehyde oxidase and xanthine oxidoreductase, two other molybdo-flavoenzymes. AOH1 and AOH2 contain consensus sequences for a molybdopterin-binding site and two distinct 2Fe-2S redox centers. In its native conformation, AOH1 has a molecular weight consistent with a homotetrameric structure. Transfection of the AOH1 and AOH2 cDNAs results in the production of proteins with phenanthridine but not hypoxanthine oxidizing activity. Furthermore, the AOH1 protein has benzaldehyde oxidizing activity with electrophoretic characteristics identical to those of a previously identified aldehyde oxidase isoenzyme (Holmes, R. S. (1979) Biochem. Genet. 17, 517-528). The AOH1 transcript is expressed in the hepatocytes of the adult and fetal liver and in spermatogonia. In liver, the AOH1 protein is synthesized in a gender-specific fashion. The expression of AOH2 is limited to keratinized epithelia and the basal layer of the epidermis and hair folliculi. The selective cell and tissue distribution of AOH1 and AOH2 mRNAs is consistent with the localization of the respective protein products.

Aldehyde Oxidase↗

PubMed2000

Prevalence and contamination levels of Listeria monocytogenes in retail foods in Japan.

Retail foods in Japan were surveyed for the presence and contamination levels of L. monocytogenes. It was isolated from 12.2, 20.6, 37.0 and 25.0% of 41 minced beef, 34 minced pork, 46 minced chicken and 16 minced pork-beef mixture samples, respectively. MPN values were higher than 100/g in five (10.9%) minced chicken samples, but lower than 100/g in all minced beef, pork and pork-beef mixture samples. The organism was also isolated from 5.4% of the 92 smoked salmon samples at MPN values lower than 10/g, and from 3.3% of 213 ready-to-eat raw seafood samples at MPN values from lower than 0.3 to higher than 100/g. None of the 285 vegetable samples were contaminated with L. monocytogenes. These findings indicate that ready-to-eat raw seafoods are relatively high risk among the foods surveyed in this study.

Animals↗

PubMed2000

Isolation and characterization of an acute promyelocytic leukemia cell line selectively resistant to the novel antileukemic and apoptogenic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid.

6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) is a novel compound that represents the prototype of a new class of synthetic retinoids with apoptogenic properties in acute promyelocytic leukemia (APL) and other types of leukemia. In this article, using SCID mice xenografted with APL-derived NB4 cells, we demonstrate that CD437 has significant antileukemic activity in vivo. In addition, we report on the isolation and characterization of an APL cell line (NB4.437r) resistant to CD437. The cell line retains expression of PML-RARalpha and is approximately 33-fold more resistant than the parental counterpart to the apoptogenic effects of the retinoid. Resistance is relatively specific to CD437 and structural congeners because the NB4.437r cell line is still sensitive to various types of apoptogenic compounds. The CD437-resistant cell line maintains sensitivity to the antiproliferative and apoptotic action of all-trans-retinoic acid, AM580, and fenretinide, though it shows partial resistance to the cytodifferentiating effects of the first 2 compounds. Resistance to CD437 lays upstream of the CD437-induced release of cytochrome c from the mitochondria and the activation of caspase-3, -7, -8, and -9. Furthermore, NB4.437r cells are deficient in the CD437-dependent activation of nuclear NFkb and AP1-binding activities and in the phosphorylation of the protein kinase Akt. In the case of AP1, deficient assembly of the complex is not caused by the lack of activation of the Jun N-terminal kinase (JNK) family of kinases. The novel cell line will be useful in the elucidation of the molecular mechanisms underlying the apoptogenic action of CD437 and structurally related retinoids. (Blood. 2000;95:2672-2682)

Animals↗

PubMed2000

Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases.

In the NB4 model of acute promyelocytic leukemia (APL), ATRA, 9-cis retinoic acid (9-cis RA), the pan-RAR and RARalpha-selective agonists, TTNPB and AM580, induce growth inhibition, granulocytic differentiation and apoptosis. By contrast, two RXR agonists, a RARbeta agonist and an anti-AP1 retinoid have very limited activity, ATRA- and AM580-dependent effects are completely inhibited by RAR antagonistic blockade, while 9-cis RA-induced cell-growth-inhibition and apoptosis are equally inhibited by RAR and RXR antagonists. ATRA, 9-cis RA and AM580 cause upregulation of the mRNAs coding for pro-caspase-1, -7, -8, and -9, which, however, results in increased synthesis of only pro-caspase-1 and -7 proteins. These phenomena are associated with activation of pro-caspase-6, -7 and -8, cytochrome c release from the mitochondria, inversion of Bcl-2/Bax ratio and degradation of PML-RARalpha. Caspase activation is fundamental for retinoid-induced apoptosis, which is suppressed by the caspase-inhibitor z-VAD.

Alitretinoin↗

PubMed2000

Comparative study of superoxide dismutase in normal and hereditary cataract (UPL) rats.

In the present study, the levels of SOD activity and Cu, Zn-SOD mRNA in the brain, kidney, liver and eye of normal and Upjohn Pharmaceutics Limited (UPL) rats, a new hereditary cataract model derived from Sprague-Dawley rats, were measured. Although the levels of SOD activity in the eye and brain of UPL rats were significantly decreased compared with those of normal rats 3 and 5 weeks after birth, the levels of SOD activities in the kidney and liver were the same in both groups. The levels of Cu, Zn-SOD mRNA in kidney and liver of UPL rats were the same as those of normal controls. The level of Cu, Zn-SOD mRNA in the brain of normal rats 5 weeks after birth was about twofold greater than that of UPL, and that in the eye of UPL rats 3 weeks after birth was significantly decreased compared with that of normal controls. The sequences of cDNA encoding Cu, Zn-SOD and the sequences of the regulatory region of the Cu, Zn-SOD gene were confirmed to be the same in normal and UPL rats. These results indicated that the decreases in levels of SOD activity and Cu, Zn-SOD mRNA in the brain and eye of UPL rat were not due to mutation of the genomic Cu, Zn-SOD gene in UPL rats or differences in the sequence of the regulatory region of the Cu, Zn-SOD gene between normal and UPL rats.

Animals↗

PubMed2000

Effects of lipid composition on the transcorneal penetration of liposomes containing disulfiram, a potential anti-cataract agent, in the rabbit.

We previously demonstrated that topical treatment with disulfiram (DSF) prevented the development of cataracts in sodium selenite-injected rat pups. In biological systems, DSF is rapidly reduced to diethyldithiocarbamate (DDC), a potent antioxidant. In this study, we investigated the effect of altering the lipid composition of liposomes containing DSF on the transcorneal transit of DDC. Liposomes containing DSF were prepared with various molar ratios of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and cetylpyridinum chloride (CPC) by reverse-phase evaporation. Liposomes with a DMPC to DPPC molar ratio of 5:5, examined by differential scanning calorimetry, had the highest enthalpy of transition and the presence of one molar ratio of CPC further enhanced the enthalpy value. The addition of bovine serum albumin or a homogenate of rabbit cornea to the incubation buffer resulted in the release of DDC, but not DSF from the liposomes. The amount of DDC present in the aqueous humor of rabbit eyes following topical administration increased with increase in DMPC to DPPC ratios and was also enhanced by the addition of CPC to the liposomes. The results of this study suggest that liposome formulations are effective for transcorneal drug delivery of anticataract agents such as DSF. DSF in liposomes consisting of DMPC, DPPC, and CPC with a molar ratio of 8:2:1 may be a potential drug formulation for the prevention and/or treatment of cataracts.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2000

Preparation and in vivo ocular absorption studies of disulfiram solid dispersion.

Disulfiram, a dimer of diethyldithiocarbamate (DDC) which is a strong radical scavenger, is known to prevent cataract development. However, disulfiram is hardly absorbed from the cornea and its bioavailability is extremely low. In this study, we attempted to prepare disulfiram solid dispersion for the improvement of ocular bioavailability. Solid dispersions of disulfiram were prepared by either an evaporation method or a spray-drying method, using polyvinylpyrrolidone (PVP) as a carrier. Preparations were analyzed by scanning electron microscopy, powder X-ray diffractometry and differential scanning calorimetry, and confirmed to be a solid dispersion. The particle size of the solid dispersion prepared by the spray-drying method was smaller than the preparation by the evaporation method (spray-drying: 3.3+/-0.04 microm, evaporation: 34.3+/-18.0 microm). An in vivo ocular absorption experiment was conducted by instilling solid dispersions to rabbit eye and measuring the DDC in the aqueous humor. After instillation of disulfiram and PVP physical mixture, DDC was not detected in the aqueous humor. On the other hand, DDC appeared in the aqueous humor after the instillation of a solid dispersion. Maximal concentration and the area under the aqueous humor concentration-time curve were greater in the solid dispersion prepared by the spray-drying method than the preparation by the evaporation method. Disulfiram solid dispersion, especially prepared by the spray-drying method, improved ocular bioavailability.

Absorption↗

PubMed1999

The mouse aldehyde oxidase gene: molecular cloning, chromosomal mapping and functional characterization of the 5'-flanking region.

In this article, we report on the chromosome mapping and molecular cloning of the genetic locus encoding the mouse molybdo-iron/sulfur-flavoprotein aldehyde oxidase. The aldehyde oxidase locus maps to mouse chromosome 1 band C1-C2, as determined by fluorescence in situ hybridization experiments conducted on metaphase chromosomes. The gene is approximately 83 kb long and consists of 35 exons. The exon/intron boundaries are perfectly conserved relative to the corresponding human homolog and almost completely conserved relative to the mouse xanthine oxidoreductase gene. This further supports the concept that the aldehyde oxidase and xanthine oxidoreductase loci evolved from the same ancestral precursor by a gene duplication event. The position of a major transcription start site was defined by primer extension and RNase mapping analysis. The 5'-flanking region of the mouse aldehyde oxidase gene contains a functional and orientation-dependent promoter as well as several putative binding sites for known cell-specific and general transcription factors. Deletion analysis of the 5'-flanking region defines an approximately 470 bp DNA stretch which is necessary and sufficient for the transcription of the mouse aldehyde oxidase gene.

Aldehyde Oxidase↗

PubMed1999

Molecular cloning of the cDNA coding for mouse aldehyde oxidase: tissue distribution and regulation in vivo by testosterone.

The cDNA coding for mouse aldehyde oxidase (AO), a molybdoflavoprotein, has been isolated and characterized. The cDNA is 4347 nt long and consists of an open reading frame predicting a polypeptide of 1333 amino acid residues, with 5' and 3' untranslated regions of 13 and 335 nt respectively. The apparent molecular mass of the translation product in vitro derived from the corresponding cRNA is consistent with that of the monomeric subunit of the AO holoenzyme. The cDNA codes for a catalytically active form of AO, as demonstrated by transient transfection experiments conducted in the HC11 mouse mammary epithelial cell line. The deduced primary structure of the AO protein contains consensus sequences for two distinct 2Fe-2S redox centres and a molybdopterin-binding site. The amino acid sequence of the mouse AO has a high degree of similarity with the human and bovine counterparts, and a significant degree of relatedness to AO proteins of plant origin. Northern blot and in situ hybridization analyses demonstrate that hepatocytes, cardiocytes, lung endothelial or epithelial cells and oesophagus epithelial cells express high levels of AO mRNA. In the various tissues and organs considered, the level of AO mRNA expression is not strictly correlated with the amount of the corresponding protein, suggesting that the synthesis of the AO enzyme is under translational or post-translational control. In addition, we observed sex-related regulation of AO protein synthesis. In the liver of male animals, despite similar amounts of AO mRNA, the levels of the AO enzyme and corresponding polypeptide are significantly higher than those in female animals. Treatment of female mice with testosterone increases the amounts of AO mRNA and of the relative translation product to levels similar to those in male animals.

Aldehyde Oxidase↗

PubMed1999

The novel synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) causes apoptosis in acute promyelocytic leukemia cells through rapid activation of caspases.

The synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which was originally developed as an retinoic acid receptor (RAR)-gamma agonist, induces rapid apoptosis in all-trans retinoic acid (ATRA)-sensitive and ATRA-resistant clones of the NB4 cell line, a widely used experimental model of acute promyelocytic leukemia (APL). In addition, the compound is apoptogenic in primary cultures of freshly isolated APL blasts obtained from a newly diagnosed case and an ATRA-resistant relapsed patient. NB4 cells in the S-phase of the cycle are most sensitive to CD437-triggered apoptosis. CD437-dependent apoptosis does not require de novo protein synthesis and activation of RAR-gamma or any of the other nuclear retinoic acid receptors. The process is preceded by rapid activation of a caspase-like enzymatic activity capable of cleaving the fluorogenic DEVD but not the fluorogenic YVAD tetrapeptide. Increased caspase activity correlates with caspase-3 and caspase-7 activation. Inhibition of caspases by z-VAD suppresses the nuclear DNA degradation observed in NB4 cells treated with CD437, as well as the degradation of pro-caspase-3 and pro-caspase-7. CD437-dependent activation of caspases is preceded by release of cytochrome c from the mitochondria into the cytosol of treated cells. Leakage of cytochrome c lays upstream of caspase activation, because the phenomenon is left unaffected by pretreatment of NB4 cells with z-VAD. Treatment of APL cells with CD437 is associated with a caspase-dependent degradation of promyelocytic leukemia-RAR-alpha, which can be completely inhibited by z-VAD.

Amino Acid Chloromethyl Ketones↗