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Hiroyuki Kagechika

Publications and source records attributed to Hiroyuki Kagechika.

36 records · Page 2Linked to original sources
PubMed2004

Design and synthesis of cyclic urea compounds: a pharmacological study for retinoidal activity.

Retinoids are natural and synthetic analogues of all-trans retinoic acid (ATRA). Cancer and other serious hyperproliferative diseases are attractive therapeutic targets for retinoids. We report here the design and synthesis of novel cyclic urea compounds with retinoidal activity. YR105 exhibited potent differentiation-inducing ability toward human promyelocytic leukemia HL-60 cells at the concentration of 10(-9)M: its potency was almost equal to that of the native ligand, all-trans retinoic acid.

HL-60 Cells↗
PubMed2004

A novel melatonin derivative modulates sleep-wake cycle in rats.

The aim of this study was to evaluate, in comparison with melatonin (MLT), the effects of a novel 2-melatonin derivative, having a 2-trifluoromethyl group (MLTD) on the sleep-wake cycle in freely behaving rats. Doses of MLTD (100, 300 and 500 nmol/100 microl saline) or MLT (500 nmol/100 microl saline) replaced the i.c.v. infusion of saline during the diurnal infusion period (7:00-17:00). Diurnal infusion of MLTD significantly (P < 0.05) increased NREM sleep at doses of 300 and 500 nmol during the second 4-h time interval of the light period and the lowest dose showed delayed effects on NREM sleep in the third 4-h time interval. However, REM sleep was only increased significantly at the dose of 500 nmol. The infusion of MLT did not have effects on REM sleep but significantly increased NREM sleep. These findings support the notion that MLTD diurnal infusion into the third ventricle produces soporific effects dose-dependently and more potently than MLT. Thus, MLTD may play an important role in studies of sleep.

Animals↗
PubMed2004

The endocrine disruptors nonylphenol and octylphenol exert direct effects on T cells to suppress Th1 development and enhance Th2 development.

Some endocrine disrupting chemicals (EDCs) have been evidenced to affect cytokine production and lymphocyte proliferation. However, it is unknown whether EDCs disturb Th1/Th2 development. We chose alkylphenols that have been widely used as plastic additives and surfactants, and some of them are recognized as xenoestrogens. We examined whether they exert direct effects on T cells to suppress or enhance Th1/Th2 development. We used two experimental systems with isolated T cells in vitro. In one system, isolated CD4+CD8+ thymocytes differentiated into Th1 and Th2 by two transient stimulations and cytokine treatment. In the second system, purified naïve CD4+ T cells from DO11.10 T cell receptor-transgenic and RAG-2-deficient mice differentiate into Th1 and Th2 by the treatment with cytokines and antibodies to CD3 and CD28. In both systems, 1-10 microM of p-n-nonylphenol suppressed Th1 development and enhanced Th2 development, whereas estrogen by itself failed to affect Th1/Th2 development. p-n-Octylphenol elicited similar effects, but 4-nonylphenol and p-t-octylphenol elicited much weaker effects. p-n-Dodecylphenol or p-n-octylbenzene failed to affect Th1/Th2 development. Thus, the length and branching of the alkyl side chain appeared to affect the activity. Although some alkylphenols have been suggested to have a weak affinity to retinoic acid receptors (RAR) or progesterone receptor (PRGR), antagonists of RAR, PRGR, glucocorticoid receptor (GCR), or retinoid X receptors (RXR) failed to inhibit the activity. These results suggest that p-n-nonylphenol and p-n-octylphenol directly suppress Th1 development and enhance Th2 development through mechanisms independent of estrogen receptors, RAR, RXR, PRGR, and GCR.

Animals↗
PubMed2004

Retinoic acid imprints gut-homing specificity on T cells.

For a preferential homing of T cells to the gut, expression of the integrin alpha4beta7 and the chemokine receptor CCR9 is essential and is induced by antigenic stimulation with dendritic cells from the gut-associated lymphoid organs. Here, we show that the vitamin A (retinol) metabolite, retinoic acid, enhances the expression of alpha4beta7 and CCR9 on T cells upon activation and imprints them with the gut tropism. Dendritic cells from the gut-associated lymphoid organs produced retinoic acid from retinol. The enhanced alpha4beta7 expression on T cells by antigenic stimulation with these dendritic cells was suppressed by the retinal dehydrogenase inhibitor citral and the retinoic acid receptor antagonist LE135. Accordingly, vitamin A deficiency caused a reduction in alpha4beta7(+) memory/activated T cells in lymphoid organs and a depletion of T cells from the intestinal lamina propria. These findings revealed a novel role for retinoic acid in the imprinting of gut-homing specificity on T cells.

Animals↗
PubMed2004

Alteration in the cellular response to retinoic acid of a human acute promyelocytic leukemia cell line, UF-1, carrying a patient-derived mutant PML-RARalpha chimeric gene.

Cellular response to all-trans retinoic acid (ATRA) of acute promyelocytic leukemia (APL) with patient-derived mutant PML-retinoic acid receptor-alpha (PML-RARalpha) was investigated using an APL cell line, UF-1, carrying Arg611Trp mutation in PML-RARalpha. Although the mutant protein showed a decreased ligand-dependent transcriptional activity and retained a dominant-negative effect on normal RARalpha, UF-1 cells underwent growth inhibition, maturation and apoptosis in response to ATRA at 1 microM, but not < or = 100 nM, after 4 days of treatment with ATRA. Moreover, in the presence of 1 microM ATRA, approximately 50% of UF-1 cells expressing annexin V, an early-apoptotic marker, was negative for CD11b and showed immature morphology. These findings suggest that UF-1 cells, despite expressing mutant PML-RARalpha protein, can be induced by ATRA to undergo differentiation and apoptosis through RA-inducible mechanism(s), in which a proportion of apoptosis may occur independent of terminal differentiation. This unique cell line may be useful for investigating the pathogenesis of ATRA resistance and the mechanism of ATRA-induced apoptosis in APL.

Apoptosis↗
PubMed2003

Utility of boron clusters for drug design. Relation between estrogen receptor binding affinity and hydrophobicity of phenols bearing various types of carboranyl groups.

High binding affinity for estrogen receptor and the appearance of estrogenic activity require a phenolic ring and an appropriate hydrophobic group adjacent to the phenolic ring. A quantitative structure-activity relationship analysis based on the values of logP and the pK(a) of the phenolic group showed that the hydrophobicity of these compounds is highly correlated to the estrogen receptor alpha (ERalpha)-binding affinity. These results should be useful for application of these spherical boron clusters (dicarba-closo-dodecaboranes; carboranes) as hydrophobic pharmacophores in drug design, as well as for microscopic analysis of ER-ligand interactions.

Boron Compounds↗
PubMed2003

Absolute helical arrangement of sulfonamide in the crystal.

[reaction: see text] 1,2-Bis(N-benzenesulfonyl-N-methylamino)benzene (2), which has no fixed asymmetric element, was crystallized from ethyl acetate as chiral crystals belonging to space group P4(1)2(1)2 (No. 92) or P4(3)2(1)2 (No. 96). The array of molecules built by the CH-pi interaction along the c-axis forms an enantiomeric helical superstructure in each individual crystal. The absolute configurations of the chiral crystals of 2 were determined by X-ray crystal structure analysis using the Flack parameter method. The solid-state CD spectra of the chiral crystals in KBr were mirror images. The equilibrium between the two enantiomers in solution is fast during crystallization at ambient temperature, and the energy barrier (DeltaG()) is estimated to be 11.7 +/- 0.3 kcal/mol (233 K).

Journal Article↗
PubMed2003

Amide conformational switching induced by protonation of aromatic substituent.

[reaction: see text] Introduction of an electron-withdrawing group on the aromatic ring of N-methylacetanilide decreased the ratio of the cis conformer, and the ratio correlates well with the Hammett sigma values of the substituents. These steric properties can be applied to achieve amide conformational switching by protonation at the aromatic substituent of 4-[bis(dimethylamino)]-N-methylacetanilide or N-[p-(dimethylamino)phenyl]-N-phenylacetamide.

Journal Article↗
PubMed2003

Effects of retinoid ligands on RIP140: molecular interaction with retinoid receptors and biological activity.

Receptor interacting protein 140 (RIP140) interacts with retinoic acid receptor (RAR) and retinoid X receptor (RXR) constitutively, but hormone binding enhances this interaction. The ligand-independent interaction is mediated by the amino and central regions of RIP140 which contain a total of nine copies of the LXXLL motif, whereas the agonist-induced interaction is mediated by its carboxyl terminus which contains a novel motif (1063-1076, LTKTNPILYYMLQK). The ligand-independent interaction could be enhanced slightly by agonists, whereas the ligand-dependent interaction was strictly agonist dependent for both RAR and RXR. In the context of heterodimers, ligand occupancy of RXR played a more dominant role for both molecular interaction and biological activity of RIP140. Competition and mutation studies demonstrated an essential role for (1067)Asn and (1073)Met for a ligand-dependent interaction. A model was proposed to address the constitutive and agonist-dependent interaction of RIP140 with RAR/RXR.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors.

The vitamin A metabolite, retinoic acid (RA), affects Th1 and Th2 development. The effect is partly exerted through the modulation of antigen-presenting cell functions, but it remains unclear whether RA directly exerts its effect on T cells to influence Th1/Th2 development. To clarify this problem, we used two experimental systems with isolated T cells in vitro. In one system, isolated CD4+CD8+ thymocytes differentiated into Th1 and Th2 by two transient stimulations with defined combinations of ionomycin and phorbol myristate acetate followed by treatment with IL-2 and IL-4 and/or IL-12. In the second system, functional differentiation was induced in purified naive CD4 T cells from DO-11.10 TCR-transgenic and RAG-2-deficient mice with cytokines and antibodies to CD3 and CD28. In both systems, all-trans-RA at > or = 1 nM concentrations suppressed Th1 development, but enhanced Th2 development. 9-cis-RA elicited similar effects. The optimal enhancement of Th2 development in the second system, however, was achieved with a delayed addition of RA. The presence of RA during the initial stimulation period often suppressed Th2 development. The RA receptor (RAR) antagonists, LE540 and LE135, but not the retinoic X receptor (RXR) antagonist, PA452, inhibited the effect of RA on Th1/Th2 development. Accordingly, the RAR agonists, Am80 and Tp80, but not the RXR agonists, HX600 and TZ335, mimicked the effect of RA. The RXR agonists enhanced the effect of the RAR agonists only slightly, if at all. These results indicate that, via RAR, RA directly suppresses Th1 development and directly enhances Th2 development with its timely addition.

Alitretinoin↗
PubMed2003

Effect of synthetic retinoid, TAC-101, on experimental autoimmune disease.

The effect of 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid (TAC-101), one of the synthetic retinoids, on collagen-induced arthritis (CIA) in mice and experimental autoimmune encephalomyelitis (EAE) in rats was studied. TAC-101 at doses of 5 and 20 mg/kg clearly inhibited the development of CIA in terms of the swelling of fore- and hind-limbs and bone destruction in knee joints. TAC-101 also suppressed the production of anti-type II collagen (CII) IgG antibody and delayed-type hypersensitivity (DTH) against CII. In addition, TAC-101 delayed the onset and development of EAE but did not affect the maximum symptom of EAE in rats. The elevation of serum antimyelin basic protein (MBP) antibody and DTH to MBP on day 13 clearly suppressed by TAC-101 in EAE rats. Moreover, TAC-101 inhibited the IL-1beta-induced PGE(2) production by MG-63 cells, human osteoblast-like cells, through the suppression of cyclooxygenase II mRNA expression. These findings suggest that TAC-101 inhibits CIA in mice and EAE in rats due to the suppression of immune response to auto-antigen and the production of PGE(2).

Animals↗
PubMed2003

Cyclooxygenase inhibitors derived from thalidomide.

Several N-3,5-dimethylphenylphthalimide analogs possessing more potent cyclooxygenase-inhibiting activity than that of aspirin were prepared during structural development studies based on thalidomide. Substituent effects on the activity were investigated.

Cyclooxygenase 1↗
PubMed2003

Clinically potential subclasses of retinoid synergists revealed by gene expression profiling.

Retinoids have chemopreventive and therapeutic potency in oncology and dermatology, although their application is restricted by many undesirable side effects. For the development of more effective and less toxic retinoids, gene expression analyses using DNA microarrays have the potential to supplement conventional screening methods, which are based on the changes in cell morphology and/or function. In this study, we applied the class prediction algorithm, which was used in the molecular phenotyping of tumors, for the classification of synthetic retinoids (Am80 and Tp80) and retinoid synergists (HX630, TZ335, and PA024) as all-trans retinoic acid-like, 9-cis retinoic acid-like, and control-like classes. By analyzing the effects of all-trans retinoic acid and 9-cis retinoic acid on the gene expressions in a human promyelocytic leukemia cell line, HL60, we successfully selected 50 marker genes whose expression pattern could distinguish these classes. Moreover, the classification revealed the existence of two subclasses among the retinoid synergists used with Am80. Close inspection of the DNA microarray analyses indicated that these two subclasses had different effects on the apoptosis of HL60 cells, and this was confirmed by in vivo experiments. These results indicate that the retinoidal activity of Am80, which has already been used in clinical trials, could be modulated differently by the two classes of retinoid synergists. Thus, these two subclasses of retinoid synergists have the potency to widen the usage of Am80. Our analyses demonstrated that the gene expression profiling could provide important information for developing useful retinoid synergists by compensating conventional screening methods.

Alitretinoin↗
PubMed2002

Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions.

Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.

2-Naphthylamine↗
PubMed2002

Krüppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling.

We recently isolated a Krüppel-like zinc-finger transcription factor 5 (KLF5; also known as BTEB2 and IKLF), which is markedly induced in activated vascular smooth-muscle cells and fibroblasts. Here we describe our analysis of the in vivo function of KLF5 using heterozygous KLF5-knockout mice (Klf5(+/-)). In response to external stress, Klf5(+/-) mice showed diminished levels of arterial-wall thickening, angiogenesis, cardiac hypertrophy and interstitial fibrosis. Also, angiotensin II induced expression of KLF5, which in turn activated platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta (TGF-beta) expression. In addition, we determined that KLF5 interacted with the retinoic-acid receptor (RAR), that synthetic RAR ligands modulated KLF5 transcriptional activity, and that in vivo administration of RAR ligands affected stress responses in the cardiovascular system in a KLF5-dependent manner. KLF5 thus seems to be a key element linking external stress and cardiovascular remodeling.

Angiotensin II↗
PubMed2002

Effect of natural and synthetic retinoids on the proliferation and differentiation of three canine melanoma cell lines.

The effect of two natural retinoids and synthetic retinoids with or without retinoid synergists on the proliferation and differentiation of 3 melanoma cell lines were investigated in vitro. No retinoids showed significant growth inhibitory effect on these cell lines when used alone, however, cell differentiation and significant growth inhibition were observed when treated with a combination of retinoids and a retinoid synergist. This study may suggest that, though the cells showed low susceptibilities when retinoids were treated alone, the combination of retinoids and a retinoid synergist may be effective to control the growth of canine melanoma cell lines.

Animals↗
PubMed2002

Novel synthetic retinoids and separation of the pleiotropic retinoidal activities.

Retinoids, all-trans-retinoic acid (1a) and its analogs, act as specific modulators of cellular differentiation and proliferation, through binding to and activating specific nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Retinoids have chemotherapeutic roles in dermatology and oncology, but their usefulness is restricted by the high toxicity of retinoic acid and its hydrophobic analogs. We have developed various retinoidal benzoic acid derivatives, and named them retinobenzoic acids. Among them, aromatic amides such as Am80 (7) and Am580 (8) have superior pharmacological characteristics, including RAR subtype selectivity. Structural modification based on the ligand superfamily concept afforded several types of RAR antagonists, benzimidazole derivatives, BIPh (41) and BIBn (42), and dibenzodiazepine derivatives, LE135 (46) and LE540 (47). LE135 (46) is a unique antagonist with RARbeta-selectivity. During investigations on the structure-activity relationships of retinobenzoic acids, several retinoid synergists (RXRs agonists), such as HX600 (49), DA113 (55h) and TZ335 (57), have been found. These compounds are expected to modulate other nuclear receptors which form heterodimers with RXRs, besides retinoids. Further, we found some RXRs antagonists, HX531 (60) and HX603 (61), which inhibit the activation of both RXR homodimers and RXR RAR heterodimers. In this review, we describe our investigations on these structurally and biologically unique retinoids and retinoid-regulatory compounds.

Animals↗