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Biomedical subjects

K Shudo

Publications and source records attributed to K Shudo.

At least 73 records · Page 4Linked to original sources
PubMed1996

[Retinoid antagonists].

Retinoids, retinoic acid and its bioisosters, regulate many biological functions such as cell differentiation, proliferation and embryonic development in vertebrates, through binding to and activating their specific nuclear receptors. There are two classes of nuclear receptors for retinoids, retinoic acid receptors (RAR alpha, beta, gamma) and retinoid X receptors (RXR alpha, beta, gamma). Several retinoid antagonists, which bind to but not activate RARs, have been reported. Among them, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10-pentamethylbenzo[e]naphtho [2,3-b][1,4]diazepin-13-yl)benzoic acid (LE135, 20) is a RAR beta-selective retinoid antagonist. Structure-activity relationships of LE135 (20) showed that the naphthalenyl analogs [LE540 (21) and LE550 (22)] are more potent retinoid antagonists in HL-60 assay. Contrary to the antagonistic activity of LE135 (20), an isomer of LE135 (20), 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo- [b,e][1,4]diazepin-11-yl)benzoic acid (HX600, 39) enhanced the activities of retinoids. Although the synergistic activity of HX600 (39) can be explained by the binding to RXRs and the further activation of RAR/RXR heterodimer activated by retinoid (RAR ligand), the significantly different biological character of HX600 (39) from the typical RXR-selective ligand suggested the possibility of the participation of other nuclear receptors or cofactors in the retinoid synergism.

Animals↗
PubMed1995

Identification of a major cytokinin in coconut milk.

A major cytokinin found in coconut milk was isolated by using the tobacco callus growth-promoting assay as a guide during purification. The structure of the factor was determined to be 14-O-(3-O-[beta-D-galactopyranosyl-(1-->2)-alpha-D-galactopyranosyl-(1-- >3)- alpha-L-arabinofuranosyl]-4-O-(alpha-L-arabinofuranosyl)-beta-D- galactopyranosyl)-trans-zeatin riboside [G3A2-ZR] by various NMR techniques, including heteronuclear multiple bond connectivity by 2D multiple quantum NMR (HMBC), as well as mass spectroscopy and sugar analysis. The optimum concentration of G3A2-ZR for cytokinin activity in the tobacco callus assay was estimated to be 5 x 10(-6) M, so that G3A2-ZR is one order of magnitude more potent than 1,3-diphenylurea and one order less potent than zeatin riboside. At least 20% of the cytokinin activity of coconut milk could be attributed to G3A2-ZR.

Carbohydrate Conformation↗
PubMed1995

Determination of the photoaffinity-labeled site on the ligand-binding domain of retinoic acid receptor alpha.

The ligand-binding domain of human retinoic acid receptor alpha (hRAR alpha) was photoaffinity-labeled with a fluorescent retinoid, ADAM-3, by the use of a recombinant fused protein constructed from a maltose-binding protein and the E/F-domain of hRAR alpha (MBP-RAR alpha/E), which was expressed in E. coli. The labeled site was identified as Arg-589 (this corresponds to amino acid residue 385 of hRAR alpha) or a residue in its vicinity.

Affinity Labels↗
PubMed1995

Possible involvement of retinoid-like cofactor in serum in hemin/protoporphyrin-IX-induced differentiation of human leukemia K562 cells.

Serum is generally added to media used for mammalian cell culture and for investigation of in vitro cell differentiation induction. Erythroid differentiation of human leukemia cell line K562 is induced by hemin or protoporphyrin IX in the presence of fetal bovine serum (FBS). Addition to the medium of retinoids enhanced the differentiation, and addition of retinoid antagonists suppressed the differentiation. Making the added FBS retinoid-free, i.e., treatment of the serum with charcoal, also reduced the efficiency of the cell differentiation induced by hemin or protoporphyrin IX. These facts suggest that retinoids or retinoid-like cofactor(s) in serum are necessary for hemin/protoporphyrin-IX-induced erythroid differentiation of K562 cells.

Cell Differentiation↗
PubMed1995

Correlation of differentiation-inducing activity of retinoids on human leukemia cell lines HL-60 and NB4.

Retinoids, including all-trans-retinoic acid, its isomers, and fifty synthetic retinoids (retinobenzoic acids), were tested for differentiation-inducing activity on human leukemia cell lines HL-60 and NB4. A good linear correlation, with an r value of 0.91, between the ED50 values for the differentiation-inducing activity towards HL-60 cells and that towards NB4 cells was found.

Cell Differentiation↗
PubMed1995

Modulation of normal mammary epithelial cell proliferation, morphogenesis, and functional differentiation by retinoids: a comparison of the retinobenzoic acid derivative RE80 with retinoic acid.

The ability of retinoids to modulate the proliferation as well as the morphological and functional differentiation of normal mammary epithelial cells isolated from pubescent female virgin rats was evaluated in serum-free primary culture. The retinobenzoic acid derivative RE80, present continuously or for only a limited time in culture, inhibited proliferation with an IC50 of less than 10(-10) M. In contrast, all-trans-retinoic acid (RA) inhibited proliferation with an IC50 of approximately 10(-8) M. In addition to effects on proliferation, RE80 and RA stimulated end bud colonies to differentiate to lobular alveolar colonies, inhibited alveolar budding, and suppressed the outgrowth of squamous colonies. Both retinoids also markedly stimulated functional differentiation, as assessed by accumulation of the major milk protein casein, and stimulated the synthesis of a approximately 73- to 74-kilodalton protein identified as a member of the transferrin family. Moreover, both retinoids stimulated cell death in the differentiated cell population. RE80 was approximately 100-fold more potent than RA for all of these effects. These data suggest that several mechanisms may contribute to the chemopreventive and/or therapeutic efficacy of retinoids in breast cancer, including inhibition of proliferation, stimulation of cell death, and/or induction of differentiation.

Animals↗
PubMed1995

Interaction of retinoids with steroid and peptide hormones in modulating morphological and functional differentiation of normal rat mammary epithelial cells.

The interaction of the retinoid RE80 with the lactogenic and mammogenic regulators of mammary gland development was investigated using a mammary epithelial cell (MEC) primary culture model in which cells from young virgin rats were cultured within a reconstituted basement membrane using defined serum-free medium. RE80 (10(-10) M) was able to substitute completely for epidermal growth factor and partially for hydrocortisone in stimulating both morphological and functional (casein accumulation) differentiation of the MEC. In contrast, the requirement of PRL for both differentiation processes was absolute. Furthermore, RE80 was found to abrogate the inhibitory effect of progesterone on casein accumulation and to act as an antiprogestin in terms of morphological effects. Under optimal medium conditions, RE80 also inhibited cell proliferation. This inhibition did not require epidermal growth factor, hydrocortisone, progesterone, or PRL, but, unexpectedly, was enhanced in medium deficient in or lacking hydrocortisone. Additionally, RE80 induced the death of differentiated MEC, an effect that was found to require hydrocortisone. These results suggest that retinoids may modulate transcription of the casein gene family, either directly by activation of the binding of retinoic acid receptors to the casein promoter or indirectly by modulation of the effects of other hormones. The antiproliferative effect of retinoid may also be direct or indirect by virtue of down-regulation of the receptors for one of the mitogenic hormones, possibly progesterone.

Animals↗
PubMed1995

Synergists for retinoid in cellular differentiation of human promyelocytic leukemia cells HL-60.

4-[5H-2,3-(2,5-Dimethyl-2,5-hexano)-5-methyldibenzo[b, e]diazepin-11-yl]benzoic acid (4) enhanced the differentiation-inducing activity of retinoic acid (1) and of a synthetic retinoid Am80 (2) toward human promyelocytic leukemia cells HL-60, although 4 alone did not induce differentiation. The synergistic effect of 4 on the activities of retinoids was also seen in suppression of proliferation of HL-60 cells.

Cell Differentiation↗
PubMed1995

[Chemistry of benzoxazinoids produced by plants as phytoalexin].

2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one and its desmethoxy derivative (DIMBOA and DIBOA) are major phytoalexins produced by rye, wheat, zea maize and related monocotyledoneae plants. These compounds elicit a wide variety of biological activities including antifungal and mutagenic activities. Structure-activity relationships of these compounds and their derivatives (benzoxazinoids), and the reactivity of benzoxazinoids with nucleophiles are discussed in relation to the molecular mechanism of their biological activity. The electrophilic reaction mechanism of benzoxazinoids and substituent effects of namely 7-methoxy and 2-hydroxy groups are also discussed.

Antifungal Agents↗
PubMed1995

Differentiation and tumor response to retinobenzoic acid RE-80 in a malignant conversion model.

The synthetic retinobenzoic acid RE-80 was evaluated for its potential as an inductor of tumor cell differentiation and as a chemopreventive agent. A minimally toxic dose of RE-80 in vitro produced morphologic changes typical differentiation in epidermal tumor cell colonies. Indirect immunofluorescence indicated induction of a differentiation-associated keratin of internal stratified epithelia, K13, and inhibition of the differentiation-associated epidermal keratin K1. Cultured cells were skin-grafted to athymic nu/nu mice to evaluate RE-80 effects on early stage malignant progression in vivo. When tumors had grown to 3 to 4 mm in diameter, mice were treated by intraperitoneal injection with RE-80 (67 micrograms, 170 mmol, i.p., two times per week) or vehicle (100 microliters 20% ethanol). Papillomas (benign) and moderately differentiated squamous cell carcinomas were reduced in volume about 4-fold by RE-80 treatment. Larger, poorly differentiated squamous cell carcinomas were unaffected. RE-80 resulted in a lower proportion of proliferative cells (detectable by bromodeoxyuridine incorporation) and a higher proportion of moderately to well differentiated tumors after 40 days of treatment compared with control tumors, which were mainly poorly differentiated squamous cell carcinomas. K13 induction in vitro was correlated with response to retinoid in vivo. Induction of differentiation may be mechanism of the response to RE-80 in vivo since carcinoma cells expressing K13 did not incorporate bromodeoxyuridine and were on a terminal pathway.

Animals↗
PubMed1995

A direct role of transcription factor E2F in c-myc gene expression during granulocytic and macrophage-like differentiation of HL60 cells.

The transcription factor E2F is known to play an important role in cell cycle progression through interaction with retinoblastoma protein. HL60 cells are able to differentiate into a granulocytic lineage by prolonged exposure to retinoids and into a macrophage-like lineage by exposure to tumor promoter 12-O-tetradecanoylphorbol 13-acetate, with a rapid decrease of c-myc gene expression. In this study, we assessed the changes of the E2F-binding pattern to the P2 promoter region of the c-myc gene during differentiation into both lineages. The observed changes of the E2F-binding pattern were a decrease of free E2F and an appearance of retinoblastoma protein-containing E2F complexes in both lineages. The effects of the anti-c-myc antibody and the recombinant c-Myc protein on the E2F-binding patterns suggest that the c-Myc protein is not involved directly in these changes. These changes also led the suppression of transcriptional initiation from the P2 promoter. The results indicate that, in the course of HL60 cell differentiation, E2F plays a direct role in the transcriptional control of the c-myc gene through interaction with the retinoblastoma protein. A potential role for the c-Myc protein is discussed in relation to an existing state of E2F and E2F-RB complexes in the HL60 cells.

Base Sequence↗
PubMed1995

Synthesis of oligopeptides as polynucleotide analogs.

Several dipeptides which have a nucleic acid base in their side chains were designed as water-soluble nucleotide analogs. Amino acids having a uracil or adenine moiety in the gamma-position were synthesized and were connected with another amino acid (spacer) to afford dipeptides. The oligopeptides were prepared from the dipeptides as monomer units. Although all the oligopeptides having uracil moieties examined were water-soluble as expected, these exhibited no hypochromic effect with poly A or poly dA. Contrary, the oligopeptides with adenines exhibited large hypochromicity (ca. 30%) base-specifically with poly dT or poly U.

Molecular Structure↗
PubMed1994

Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid.

BACKGROUND: Retinoic acid (RA) plays a fundamental role in diverse cellular activities. Cellular RA binding proteins (CRABPs) are thought to act by modulating the amount of RA available to nuclear RA receptors. CRABPs and cellular retinol-binding proteins (CRBPs) share a unique fold of two orthogonal beta-sheets that encapsulate their ligands. It has been suggested that a trio of residues are the prime determinants defining the high specificity of CRBPs and CRABPs for their physiological ligands. RESULTS: Bovine/murine CRABP I and human CRABP II have been crystallized in complex with their natural ligand, all-trans-RA. Human CRABP II has also been crystallized in complex with a synthetic retinoid, 'compound 19'. Their structures have been determined and refined at resolutions of 2.9 A, 1.8 A and 2.2 A, respectively. CONCLUSIONS: The retinoid-binding site in CRABPs differs significantly from that observed in CRBP. Structural changes in three juxtaposed areas of the protein create a new, displaced binding site for RA. The carboxylate of the ligand interacts with the expected trio of residues (Arg132, Tyr134 and Arg111; CRABP II numbering). The RA ligand is almost flat with the beta-ionone ring showing a significant deviation (-33 degrees) from a cis conformation relative to the isoprene tail. The edge atoms of the beta-ionone ring are accessible to solvent in a suitable orientation for presentation to metabolizing enzymes. The bulkier synthetic retinoid causes small conformational changes in the protein structure.

Amino Acid Sequence↗
PubMed1994

Retinobenzoic acids. 6. Retinoid antagonists with a heterocyclic ring.

Several candidate retinoid antagonists were designed on the basis of the ligand superfamily concept and synthesized. Retinoidal activities of these benzimidazole and benzodiazepine derivatives were examined by assay of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. The parent benzimidazole derivative, 4-(5,6,7,8-tetrahydro-5,5,8,8- tetramethylnaphth-[2,3-d]imidazol-2-yl)benzoic acid (7a), and related compounds with a small alkyl group instead of the hydrogen on the nitrogen (1N) atom of the imidazole ring exhibited retinoidal activity, and the potency strongly depended on the bulkiness of the substituent. The compounds having a phenyl or benzyl group on the nitrogen lacked differentiation-inducing activity on HL-60 cells and acted as antagonists to the potent retinoid 4-[(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (Am80). Among the compounds possessing a seven-membered heterocyclic ring as a linking group, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10- pentamethylbenzo[e]- naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid (16) also exhibited the antagonistic activity. The binding abilities of these compounds to retinoic acid receptors alpha and beta were consistent with their potency for the inhibition of HL-60 cell differentiation induced by the retinoid Am80.

Benzimidazoles↗
PubMed1994

Chiral discrimination of enantiomeric 2'-deoxythymidine 5'-triphosphate by HIV-1 reverse transcriptase and eukaryotic DNA polymerases.

Inhibitory effects of 2'-deoxy-L-thymidine 5'-triphosphate (L-dTTP), the enantiomer of the natural substrate D-dTTP, on the activity of mammalian DNA polymerases alpha, beta and gamma, Escherichia coli DNA polymerase I and human immunodeficiency virus 1 (HIV-1) reverse transcriptase were examined. When poly(rA)n-oligo(dT)12-18 was used as the template-primer, L-dTTP showed remarkable inhibitory effect on HIV-1 reverse transcriptase in competitive fashion with respect to the substrate dTTP. In contrast, L-dTTP did not inhibit DNA polymerases alpha and was slightly inhibitory to DNA polymerase beta. These results suggest that the nuclear DNA polymerases alpha and beta showed high specificity for the substrate with the natural configuration of the sugar moiety, D-dTTP, exhibiting little or no ability to recognize L-dTTP, whereas HIV-1 reverse transcriptase essentially lacked the ability to differentiate the D- and L-sugar moieties.

Animals↗
PubMed1994

Enhancement of human papillomavirus type 18 gene expression in HeLa cells by 12-O-tetradecanoylphorbol-13-acetate, 3 beta,5 alpha-dihydroxycholestan-6-one, and cholesterol.

Human papillomavirus type 18 (HPV18) is involved in the genesis of cervical cancer through expression of its viral oncoprotein in infected cells. A tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), was found to increase the level of HPV18 transcripts in an HPV18-harboring cervical cancer cell line, HeLa. A similar increase in HPV18 expression was also observed on treatment of the cells with an oxygenated cholesterol, 3 beta,5 alpha-dihydroxycholestan-6-one (yakkasterone). The effects on HPV18 expression elicited by TPA and yakkasterone were repressed by a protein kinase inhibitor, staurosporine. Treatment of the cells with cholesterol under serum-free conditions also resulted in an apparent increase of HPV18 expression.

Alkaloids↗
PubMed1994

Synthesis and biological activity of carboxyphenylquinolines and related compounds as new potent retinoids. Retinobenzoic acids. VII.

A series of new quinoline, quinolone, and quinazolinedione derivatives was synthesized and tested for retinoid activity in the human promyelocytic cell line HL-60 differentiation assay. All the quinoline compounds exhibited significant activity, depending on the substituent on the heterocycle. However, the quinolone and quinazolinedione derivatives were poor inducers of the differentiation of the HL-60 cells, the activity depending strongly on the polarity of the molecule.

Benzoates↗