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Biomedical subjects

K Shudo

Publications and source records attributed to K Shudo.

At least 19 recordsLinked to original sources
PubMed1997

Inhibition of IL-1-induced IL-6 production by synthetic retinoids.

The effects of retinoids and retinoid antagonists on IL-6 production in MC3T3-E1 cells were investigated. None of the synthetic retinoids examined stimulated IL-6 production, but all of them strongly inhibited IL-6 production induced by mouse IL-1 alpha. Their inhibitory activities correlated well with their differentiation-inducing activities in HL-60 assay or their binding affinities to nuclear retinoic acid receptors (RARs). Among three retinoid antagonists, two weak antagonists exhibited similar inhibition of mouse IL-1 alpha-induced IL-6 production, whereas a potent retinoid antagonist, 4-(13H-10,11,12,13-tetrahydro-10,10,13,13,15-pentamethyl-dinaph tho[2,3-b] [1,2-e]diazepin-7-yl)benzoic acid (LE540, 14), enhanced IL-6 production under the same conditions.

3T3 Cells↗
PubMed1997

Photoaffinity labeling of tumor promoter-binding protein (CN-TPBP) and preparation of affinity sorbent gels.

Cytosolic-nuclear tumor promoter-specific binding protein (CN-TPBP) was photoaffinity-labeled with a specific ligand, 3beta,5alpha-dihydroxycholestan-6-one (YS-64). Analysis by ODS-HPLC of peptide fragments obtained from the labeled CN-TPBP by trypsinization indicated the existence of a single specifically labeled site. Affinity gels for the purification of CN-TPBP were then prepared. As ligands for the affinity gels, 12-O-tetradecanoylphorbol 13-acetate (TPA), a typical phorbol-type tumor promoter, and benzolactam-V8-310 (BL-V8-310), a structural/biological mimic of teleocidin-class tumor promoters, were adopted. The use of these gels afforded a protein that showed a single band of 58 kDa on SDS-PAGE.

Affinity Labels↗
PubMed1996

Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects serum immunoglobulin subclass levels.

Retinoids affect many biological processes such as cell proliferation, differentiation and morphogenesis, but their effects on arthritic patients and animal models of arthritis are controversial. We tested the effect of a novel synthetic retinoic acid, Am-80 (4-[(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid), on type-II collagen (CII)-induced arthritis (CIA) in rats. Am-80 markedly suppressed the incidence of arthritis, hindpaw swelling and bone destruction. In contrast, 13-cis-retinoic acid (13-cis-RA) hardly inhibited these CIA symptoms. Moreover, Am-80, but not 13-cis-RA, strongly reduced the serum level of anti-CII antibody and differentially affected the levels of immunoglobulin (Ig) subclasses in vivo: IgG1 and IgG2a levels were decreased, while IgA level was increased without any change in the IgM level. These findings indicate that Am-80 may be one of the lead retinoic acids of a new class of anti-inflammatory agents.

Animals↗
PubMed1996

Chemistry of biologically active benzoxazinoids.

2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) and its desmethoxy derivative (DIBOA) are major allelochemicals produced by corn, wheat, rye and related monocotyledons. These benzoxazinone derivatives have a wide variety of biological actions, including antifungal and mutagenic activities. Structure-activity relationships of these compounds and their derivatives (benzoxazinoids), the reactivity of benzoxazinoids with nucleophiles, and the substituent effects of the 7-methoxy and 2-hydroxy groups are discussed in relation to the molecular mechanisms of the biological activities.

Oxazines↗
PubMed1996

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

Retinoids, including all-trans-retinoic acid (ATRA), its isomers, and fifty synthetic retinoids (retinobenzoic acids), were tested for differentiation-inducing activity on human leukemia cell lines HL-60 and NB4. Binding activity of typical retinoids to nuclear retinoic acid receptors (RARs) was also investigated. A good linear correlation between the ED50 values of differentiation-inducing activity towards HL-60 cells and those towards NB4 cells was found. Binding activities of retinoids to RAR alpha and RAR beta also correlated well to the differentiation-inducing activities.

Benzoates↗
PubMed1996

Location of two photoaffinity-labeled sites on the ligand-binding domain of retinoic acid receptor alpha.

Retinoic acid receptors (RARs) consist of six domain structures. The C-terminal region (D/E/F-domains) is involved in ligand binding, dimerization, and ligand-dependent transactivation. Structural information about RARs is required for understanding its complex function. A photoreactive retinoid denoted as ADAM-3, which was designed as the result of comparison of two fluorescent retinoids (DAM-3 and DAM-15), was synthesized and used for photoaffinity labeling of recombinant protein MBP-RAR alpha/E. The photoaffinity-labeled site was determined by an endoprotease combination method which utilizes four endoproteinases in a two-phase digestion procedure. Two major labeled fragments were detected in each digestion, and the results of two-phase digestion allowed identification of the labeled residues as being located within residues 492-510 and 585-594, which correspond to 288-306 and 381-390 in human RAR alpha, respectively.

Affinity Labels↗
PubMed1996

Novel aromatic urea derivatives with DNA-binding ability.

Several aromatic urea derivatives were designed and synthesized as DNA-targeting agents. N,N'-Dimethyl-N,N'-bis[(4-amidylphenyl)aminocarbonyl]-2,6-di aminopyridine (1) and 1,3-bis[5-(glycylamino)pyrid-2-yl]urea (3) showed remarkable DNA-binding abilities as determined by ultrafiltration assay using calf thymus DNA, their potencies being equal to and half that of netropsin, respectively. Compound 1 inhibited the proliferation of both L1210 cells and KB cells with similar IC50 values to netropsin.

Animals↗
PubMed1996

meso-DNAs with homopurine sequences: analysis of their interaction with natural DNAs.

Two homopurine sequences of meso-DNAs (DNAs having an alternating sequence of 2-deoxy-L-ribose and 2-deoxy-D-ribose in their sugar moieties), d(LADG)5 and d(LGDA)5, were prepared. Both d(LADG)5 and d(LGDA)5 interacted with the corresponding complementary natural DNAs, d(DCDT)5 and d(DTDC)5, respectively. In the interactions, pH-dependent duplex/triplex selectivity was observed, i.e., meso-d(Pu)10 formed a duplex at pH 7.5 and a triplex at pH 5.0 with the complementary D-d(Py)10. The meso-d(Pu)10/D-d(Py)10 complex showed a CD spectrum similar in shape to that of the natural complex, suggesting that meso/natural complexes form right-handed helices. At pH 7.5, ethidium bromide intercalated into both d(LADG)5/d(DCDT)5 and d(LGDA)5/d(DTDC)5 duplexes. A clear difference between d(LADG)5/d(DCDT)5 and d(LGDA)5/d(DTDC)5 was observed at pH 5.0. Addition of ethidium bromide did not affect the formed d(LADG)5/d(DCDT)5 triplex, and ethidium bromide did not intercalate into the triplex. On the other hand, d(LGDA)5 did not form a triplex with d(DTDC)5 in the presence of ethidium bromide even at pH 5.0, but it formed a duplex. Ethidium bromide intercalated into the duplex at pH 5.0.

Circular Dichroism↗
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↗