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1.
FEBS Open Bio ; 7(3): 391-396, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28286734

RESUMO

Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

2.
J Nutr Biochem ; 42: 7-16, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28103535

RESUMO

(-)-Epigallocatechin gallate (EGCG), a green tea catechin, acts as a synergist with various anticancer drugs, including retinoids. Am80 is a synthetic retinoid with a different structure from all-trans-retinoic acid: Am80 is now clinically utilized as a new drug for relapsed and intractable acute promyelocytic leukemia patients. Our experiments showed that the combination of EGCG and Am80 synergistically induced both apoptosis in human lung cancer cell line PC-9 and up-regulated expressions of growth arrest and DNA damage-inducible gene 153 (GADD153), death receptor 5, and p21waf1 genes in the cells. To understand the mechanisms of synergistic anticancer activity of the combination, we gave special attention to the lysine acetylation of proteins. Proteomic analysis using nanoLC-ESI-MS/MS revealed that PC-9 cells treated with the combination contained 331 acetylated proteins, while nontreated cells contained 553 acetylated proteins, and 59 acetylated proteins were found in both groups. Among them, the combination increased acetylated-p53 and acetylated-α-tubulin through reduction of histone deacetylase (HDAC) activity in cytosol fraction, although the levels of acetylation in histones H3 or H4 did not change, and the combination reduced protein levels of HDAC4, -5 and -6 by 20% to 80%. Moreover, we found that a specific inhibitor of HDAC4 and -5 strongly induced p21waf1 gene expression, and that of HDAC6 induced both GADD153 and p21waf1 gene expression, which resulted in apoptosis. All results demonstrate that EGCG in combination with Am80 changes levels of acetylation in nonhistone proteins via down-regulation of HDAC4, -5 and -6 and stimulates apoptotic induction.


Assuntos
Benzoatos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Catequina/análogos & derivados , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Tetra-Hidronaftalenos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Catequina/farmacologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Histona Desacetilases/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Chá/química , Fator de Transcrição CHOP/genética
3.
EMBO Mol Med ; 8(11): 1340-1359, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27737899

RESUMO

Neutrophils generated by granulocyte colony-stimulating factor (GCSF) are functionally immature and, consequently, cannot effectively reduce infection and infection-related mortality in cancer chemotherapy-induced neutropenia (CCIN). Am80, a retinoic acid (RA) agonist that enhances granulocytic differentiation by selectively activating transcription factor RA receptor alpha (RARα), alternatively promotes RA-target gene expression. We found that in normal and malignant primary human hematopoietic specimens, Am80-GCSF combination coordinated proliferation with differentiation to develop complement receptor-3 (CR3)-dependent neutrophil innate immunity, through altering transcription of RA-target genes RARß2, C/EBPε, CD66, CD11b, and CD18 This led to generation of functional neutrophils capable of fighting infection, whereas neutralizing neutrophil innate immunity with anti-CD18 antibody abolished neutrophil bactericidal activities induced by Am80-GCSF Further, Am80-GCSF synergy was evaluated using six different dose-schedule-infection mouse CCIN models. The data demonstrated that during "emergency" granulopoiesis in CCIN mice undergoing transient systemic intravenous bacterial infection, Am80 effect on differentiating granulocytic precursors synergized with GCSF-dependent myeloid expansion, resulting in large amounts of functional neutrophils that reduced infection. Importantly, extensive survival tests covering a full cycle of mouse CCIN with perpetual systemic intravenous bacterial infection proved that without causing myeloid overexpansion, Am80-GCSF generated sufficient numbers of functional neutrophils that significantly reduced infection-related mortality in CCIN mice. These findings reveal a differential mechanism for generating functional neutrophils to reduce CCIN-associated infection and mortality, providing a rationale for future therapeutic approaches.


Assuntos
Antineoplásicos/efeitos adversos , Bacteriemia/imunologia , Benzoatos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Neutropenia/terapia , Neutrófilos/imunologia , Tetra-Hidronaftalenos/administração & dosagem , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos , Neutropenia/induzido quimicamente , Neutrófilos/fisiologia , Análise de Sobrevida
4.
Neurochem Res ; 41(11): 2848-2858, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27401255

RESUMO

Inhibition of pro-inflammatory functions of microglia has been considered a promising strategy to prevent pathogenic events in the central nervous system under neurodegenerative conditions. Here we examined potential inhibitory effects of nuclear receptor ligands on lipopolysaccharide (LPS)-induced inflammatory responses in microglial BV-2 cells. We demonstrate that a vitamin D receptor agonist 1,25-dihydroxyvitamin D3 (VD3) and a retinoid X receptor agonist HX630 affect LPS-induced expression of pro-inflammatory factors. Specifically, both VD3 and HX630 inhibited expression of mRNAs encoding inducible nitric oxide synthase (iNOS) and IL-6, whereas expression of IL-1ß mRNA was inhibited only by VD3. The inhibitory effect of VD3 and HX630 on expression of iNOS and IL-6 mRNAs was additive. Effect of VD3 and HX630 was also observed for inhibition of iNOS protein expression and nitric oxide production. Moreover, VD3 and HX630 inhibited LPS-induced activation of extracellular signal-regulated kinase (ERK) and nuclear translocation of nuclear factor κB (NF-κB). PD98059, an inhibitor of ERK kinase, attenuated LPS-induced nuclear translocation of NF-κB and induction of mRNAs for iNOS, IL-1ß and IL-6. These results indicate that VD3 can inhibit production of several pro-inflammatory molecules from microglia, and that suppression of ERK activation is at least in part involved in the anti-inflammatory effect of VD3.


Assuntos
Colecalciferol/metabolismo , Citocinas/biossíntese , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/biossíntese , Animais , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
Int Immunopharmacol ; 38: 367-76, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27351827

RESUMO

Accumulating lines of evidence suggest that retinoic acid receptor agonists such as Am80 exerts anti-inflammatory actions in the central nervous system, although detailed mechanisms of the action remain largely unknown. Our previous findings suggest that Am80 provides therapeutic effect on intracerebral hemorrhage in mice via suppression of expression of chemokine (C-X-C motif) ligand 2 (CXCL2). Here we investigated the mechanisms of inhibitory action of Am80 on expression of CXCL2 and other pro-inflammatory factors in microglial BV-2 cells. Pretreatment with Am80 markedly suppressed lipopolysaccharide (LPS)-induced expression of CXCL2 mRNA and release of CXCL2 protein. Am80 had no effect on LPS-induced activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. On the other hand, Am80 prevented LPS-induced nuclear translocation of p65 subunit of NF-κB complex. In addition, total expression levels of p65 and IκBα proteins, as well as of mRNAs encoding p65 and IκBα, were lowered by Am80. Dependence of CXCL2 expression on NF-κB was confirmed by the effect of an NF-κB inhibitor caffeic acid phenethyl ester that abolished LPS-induced CXCL2 expression. Caffeic acid phenethyl ester also abolished LPS-induced expression of inducible nitric oxide synthase, interleukin-1ß and tumor necrosis factor α, which may be relevant to the inhibitory effect of Am80 on expression of these pro-inflammatory factors. We additionally found that Am80 attenuated LPS-induced up-regulation of CD14, a co-receptor for Toll-like receptor 4 (TLR4). These results suggest that inhibitory effect on TLR4 signaling mediated by NF-κB pathway underlies the anti-inflammatory action of retinoic acid receptor agonists in microglia.


Assuntos
Anti-Inflamatórios/farmacologia , Benzoatos/farmacologia , Quimiocina CXCL2/metabolismo , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Receptores do Ácido Retinoico/antagonistas & inibidores , Tetra-Hidronaftalenos/farmacologia , Animais , Linhagem Celular , Quimiocina CXCL2/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Microglia/fisiologia , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Curr Alzheimer Res ; 13(11): 1277-1289, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27335034

RESUMO

Retinoic acid, the bioactive metabolite of beta-carotene or vitamin A, plays a pleiotropic, multifunctional role in vertebrate development. Studies in rodents revealed that a diet deficient in vitamin A results in a complex neonatal syndrome (the VAD syndrome), manifested in many organs. In humans, the function of retinoic acid (RA) extends into adulthood, where it has important roles in fertility, vision, and suppression of neoplastic growth. In recent years, it has also been suggested that retinoic acid might potentially act as a therapeutically relevant drug in attenuating or even preventing neurodegenerative diseases such as Alzheimer's disease (AD). Here, we report that VAD leads to an increase in A-beta peptide levels while only minor effects were observed on expression levels of the amyloid precursor protein (APP) processing proteinases in wild type mice. In line with these findings, rescue of hypovitaminosis reduced A-beta amount to baseline and induced sApp-alpha secretion in combination with an increase of alpha-secretase Adam10. By comparing retinoic acid treatment starting from a full nutrition status and a "VAD" situation in human neuroblastoma cells, we show that while intensities of differential gene expression were higher in replenished cells, a large overlap in AD-related, regulated genes was observed. Our data suggest that hypovitaminosis A can contribute to onset or progression of AD by increasing synthesis of A-beta peptides and that several AD-related genes such as ADAM10 or BDNF are regulated by retinoic acid. We suggest that dietary supplementation with retinoic acid derivatives is likely to have a beneficial effect on AD-pathology in individuals with hypovitaminosis and patients with normal vitamin A status.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Deficiência de Vitamina A/metabolismo , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Acitretina/química , Acitretina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Ceratolíticos/farmacologia , Camundongos , Neuroblastoma/metabolismo , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Presenilina-2/metabolismo , Ratos Wistar , Tretinoína/química , Tretinoína/metabolismo , Tretinoína/farmacologia
7.
J Invest Dermatol ; 136(2): 387-398, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26967475

RESUMO

Tamibarotene (Am80) is a synthetic retinoid that modulates the pathologic processes of various autoimmune and inflammatory diseases and their animal models. We here investigated the therapeutic potential of Am80 against systemic sclerosis using its animal models. Am80 significantly attenuated dermal and hypodermal fibrosis in bleomycin (BLM)-treated mice and tight skin 1 mice, respectively. Consistently, Am80 significantly suppressed the expression of various molecules related to tissue fibrosis, including transforming growth factor-ß1, connective tissue growth factor, IL-4, IL-10, IL-13, IL-17A, tumor necrosis factor-α, IFN-γ, and monocyte chemotactic protein 1 in the lesional skin of BLM-treated mice. Furthermore, Am80 decreased the proportion of effector T cells, while increasing that of naïve T cells among CD4+ T cells in the draining lymph nodes of BLM-treated mice. Moreover, a series of BLM-induced pathologic events, including endothelial-to-mesenchymal transition; ICAM-1 expression in endothelial cells; the infiltration of macrophages, mast cells, and lymphocytes; and M2 macrophage differentiation, were attenuated by Am80. Importantly, Am80 directly reversed the profibrotic phenotype of transforming growth factor-ß1-treated dermal fibroblasts, suppressed ICAM-1 expression in endothelial cells, and promoted M1 macrophage differentiation in vitro. Collectively, Am80 inhibits the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a candidate for therapeutic drugs against dermal fibrosis of systemic sclerosis.


Assuntos
Benzoatos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Escleroderma Sistêmico/tratamento farmacológico , Tetra-Hidronaftalenos/farmacologia , Animais , Bleomicina/farmacologia , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose/induzido quimicamente , Fibrose/tratamento farmacológico , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/patologia , Sensibilidade e Especificidade , Fator de Necrose Tumoral alfa/metabolismo
8.
J Pharmacol Sci ; 129(2): 119-26, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26422672

RESUMO

We have previously shown that retinoic acid receptor (RAR) stimulation by an agonist Am80 recruits nitric oxide-dependent signaling via increased expression of neuronal nitric oxide synthase (nNOS) in rat midbrain slice cultures. Using neuroblastoma SH-SY5Y cells, here we investigated the mechanisms of RAR-induced nNOS expression, together with relationship between nNOS expression and neurite outgrowth. Am80 promoted neurite outgrowth, which was attenuated by inhibitors of phosphoinositide 3-kinase (PI3K; LY294002), c-Jun N-terminal kinase (JNK; SP600125) and p38 mitogen-activated protein kinase (p38 MAPK; SB203580). A selective nNOS inhibitor 3-bromo-nitroindazole also suppressed Am80-induced neurite outgrowth. Am80-induced increase in nNOS protein expression was attenuated by LY294002, SP600125 and SB203580, whereas increase in nNOS mRNA expression was attenuated only by LY294002. Am80-induced activation of JNK and p38 MAPK was blocked by LY294002, suggesting that these kinases acted downstream of PI3K. We also confirmed that DAX1, a nuclear receptor reported to regulate nNOS expression, was up-regulated in response to Am80. siRNA-mediated knockdown of DAX1 abrogated Am80-induced nNOS expression and neurite outgrowth. These results reveal for the first time that nNOS expression is crucial for RAR-mediated neurite outgrowth, and that non-genomic signaling such as JNK and p38 MAPK is involved in RAR-mediated nNOS expression.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação Enzimológica da Expressão Gênica/genética , Expressão Gênica/genética , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Neuritos/fisiologia , Neuroblastoma , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Receptores do Ácido Retinoico/fisiologia , Animais , Benzoatos/farmacologia , Cromonas/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Morfolinas/farmacologia , Ratos , Tetra-Hidronaftalenos/farmacologia , Células Tumorais Cultivadas
9.
J Comput Aided Mol Des ; 29(10): 975-88, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26384496

RESUMO

Retinoid X receptors (RXRs) are ligand-controlled transcription factors which heterodimerize with other nuclear receptors to regulate gene transcriptions associated with crucial biological events. 9-cis retinoic acid (9cRA), which transactivates RXRs, is believed to be an endogenous RXR ligand. All-trans retinoic acid (ATRA) is a natural ligand for retinoic acid receptors (RARs), which heterodimerize with RXRs. Although the concentration of 9cRA in tissues is very low, ATRA is relatively abundant and some reports show that ATRA activates RXRs. We computationally studied the possibility of ATRA binding to RXRs using two different docking methods with our developed programs to assess the binding affinities of naturally occurring retinoids. The simulations showed good correlations to the reported binding affinities of these molecules for RXRs and RARs.


Assuntos
Simulação de Acoplamento Molecular , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides/metabolismo , Tretinoína/metabolismo , Alitretinoína , Sequência de Aminoácidos , Animais , Sítios de Ligação , Humanos , Isotretinoína/química , Isotretinoína/metabolismo , Ligantes , Camundongos , Dados de Sequência Molecular , Conformação Proteica , Estrutura Terciária de Proteína , Receptores do Ácido Retinoico/química , Reprodutibilidade dos Testes , Receptores X de Retinoides/química , Tretinoína/química
10.
FASEB J ; 29(2): 671-83, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25389133

RESUMO

Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic ß-cells of adult mice. atRA signaling was ablated in ß-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-α mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in ß-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge. Glucose-stimulated insulin secretion was also impaired in islets isolated from mice expressing RARdn. Among genes that are atRA responsive, Glut2 and Gck mRNA levels were decreased in isolated islets from RARdn-expressing mice. Histologic analyses of RARdn-expressing pancreata revealed a decrease in ß-cell mass and insulin per ß-cell 1 mo after induction of the RARdn. Our results indicate that atRA signaling mediated by RARs is required in the adult pancreas for maintaining both ß-cell function and mass, and provide insights into molecular mechanisms underlying these actions.


Assuntos
Glicemia/metabolismo , Células Secretoras de Insulina/citologia , Insulina/metabolismo , Receptores do Ácido Retinoico/metabolismo , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Genótipo , Homeostase , Insulina/sangue , Secreção de Insulina , Integrases/metabolismo , Ilhotas Pancreáticas/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Receptor alfa de Ácido Retinoico , Transdução de Sinais , Tretinoína/metabolismo
11.
Clin Exp Ophthalmol ; 43(6): 558-67, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24612001

RESUMO

BACKGROUND: To determine whether all-trans retinoic acid or a synthetic retinoic acid receptor-α/ß-specific agonist, Am80, can reduce the degree of experimental autoimmune optic neuritis in mice with experimental autoimmune encephalomyelitis. METHODS: Optic neuritis was induced in C57BL/6 mice by immunizing them with myelin oligodendrocyte glycoprotein35-55 . All-trans retinoic acid (350 µg/mouse/time point) or Am80 (5 mg/kg/time point) was administered every other day from day 0 to day 20. The degree of experimental autoimmune encephalomyelitis was scored and histopathological analysis of the optic neuritis was performed on day 22 after the immunization. In vivo-primed draining lymph node cells obtained from vehicle-treated or all-trans retinoic acid-treated mice were stimulated with myelin oligodendrocyte glycoprotein35-55 , and the culture supernatant was collected for assays of interferon-γ and interleukin-17. RESULTS: All-trans retinoic acid treatment significantly reduced the clinical score of experimental autoimmune encephalomyelitis and the severity of the optic neuritis by histopathological analysis. The production of interferon-γ and interleukin-17 was significantly reduced in all-trans retinoic acid-treated mice compared with vehicle-treated mice. Am80 treatment also significantly decreased the severity of the optic neuritis in mice with experimental autoimmune encephalomyelitis. CONCLUSIONS: These findings demonstrate that all-trans retinoic acid and Am80 treatment were able to reduce the severity of optic neuritis in mice with experimental autoimmune encephalomyelitis. Activation of retinoic acid receptor-α/ß may be a molecular target for the treatment of autoimmune optic neuritis induced by Th1 or Th17-dominated immune responses.


Assuntos
Benzoatos/uso terapêutico , Encefalomielite Autoimune Experimental/prevenção & controle , Neurite Autoimune Experimental/prevenção & controle , Neurite Óptica/prevenção & controle , Receptores do Ácido Retinoico/metabolismo , Tetra-Hidronaftalenos/uso terapêutico , Animais , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Citometria de Fluxo , Injeções Intraperitoneais , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurite Autoimune Experimental/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neurite Óptica/metabolismo , Receptores do Ácido Retinoico/agonistas , Receptor alfa de Ácido Retinoico , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Tretinoína/uso terapêutico
12.
J Control Release ; 196: 154-60, 2014 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-25312542

RESUMO

Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease, which causes widespread and irreversible alveoli collapse. Nevertheless, there is no effective drug therapy that regenerates lung tissue or prevents the progression of COPD and clinical management of patients remains mostly supportive. The aim of this study was to evaluate whether Am80 is useful as a novel pulmonary emphysema therapeutic drug. In this study, we treated the human alveolar epithelial stem cells with Am80 to clarify the differentiation-inducing mechanism and administrated Am80 transpulmonarily into elastase-induced COPD model mice to evaluate the effect of Am80 on pulmonary emphysema. First, we accordingly investigated whether Am80 had a differentiation-inducing effect on human alveolar epithelial stem cells, Am80 induced differentiation of human alveolar epithelial stem cells to alveolar type I and II cells dose dependently, and the proportion of differentiated into type I and type II alveolar epithelial cells as a result of treatment with 10 µM of Am80 for 7 days was approximately 20%. Second, we attempted to identify the major factor involved in the differentiation-inducing effect of human alveolar epithelial stem cells induced by Am80 using microarray analysis. In a microarray analysis, WNT1, lectin, SLIT, chordin, ck12, ck11, and neurexin3 showed the largest variation in the Am80-treated group compared with the controls. In quantitative polymerase-chain-reaction assay, Am80 resulted in significant reduction in the WNT1 expression ratio whereas increase in the neurexin3 expression ratio. We evaluated the repairs effect for collapsed alveoli by Am80 of pulmonary administration. In untreated and Am80-treated mice the average CT value at 2 days was, respectively, -506 and -439 and there was a significant difference. Likewise, the assessment of the distance between alveolar walls, Lm, confirmed that there was a significant difference between control (68.0±3.8 µm) and Am80-treated group (46.8±1.8 µm). These indicated that treatment with Am80 caused a reversal of lung tissue damage in elastase-induced COPD model mouse. Those results suggested that Am80 were effective as novel COPD therapeutic compounds.


Assuntos
Benzoatos/administração & dosagem , Benzoatos/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Regeneração/efeitos dos fármacos , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Humanos , Camundongos , Elastase Pancreática , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/patologia , Receptores do Ácido Retinoico/metabolismo , Células-Tronco/efeitos dos fármacos
13.
Biol Pharm Bull ; 37(11): 1816-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25212662

RESUMO

Pregabalin, (S)-3-isobutyl-γ-aminobutyric acid (GABA), is a widely used adjuvant therapy for patients with neuropathic pain, which is defined as chronic pain caused by lesions or diseases of the somatosensory nervous system. However, dizziness and somnolence (sleepiness) are common dose-limiting side effects, probably due to excessive sedative effects on higher centers of the central nervous system (CNS) which are involved in the anticonvulsant and analgesic actions of pregabalin. We speculated that transdermal delivery would minimize centrally mediated side effects. To test this idea, we evaluated the analgesic effects of pregabalin delivered through the transdermal route in animal models of neuropathic pain. Transdermally administered pregabalin increased the pain thresholds in response to mechanical stimuli in a partial sciatic nerve ligation model in rats and a spinal nerve ligation model in mice, and surprisingly also in normal animals. It is noteworthy that simple transdermal application of an aqueous solution of pregabalin is effective. This could be a useful treatment option to avoid or minimize the CNS-mediated side effects of orally administered pregabalin.


Assuntos
Analgésicos/administração & dosagem , Neuralgia/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Administração Cutânea , Animais , Sistema Nervoso Central , Tontura/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Hiperalgesia/tratamento farmacológico , Ligadura , Masculino , Camundongos Endogâmicos ICR , Pregabalina , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/cirurgia , Soluções , Nervos Espinhais/cirurgia , Ácido gama-Aminobutírico/administração & dosagem
14.
J Alzheimers Dis ; 42(2): 587-605, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24916544

RESUMO

Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-ß (Aß) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)α,ß agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-ß protein precursor 23 (AßPP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in AßPP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble Aß peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble Aß peptide in 8.5-month-old AßPP23 mice requires co-activation of RARα,ß and RXRs. RARα-positive microglia accumulated Aß plaques in the AßPP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125I-labeled oligomeric Aß1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to Aß clearance in Am80/HX630-treated AßPP23 mice. Am80/HX630 also increased IL-4Rα expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated AßPP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric Aß peptides by restoring impaired IL-4 signaling in AßPP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/uso terapêutico , Benzazepinas/uso terapêutico , Benzoatos/uso terapêutico , Tetra-Hidronaftalenos/uso terapêutico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Recém-Nascidos , Benzazepinas/química , Benzazepinas/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Insulisina/genética , Insulisina/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mutação/genética , Ratos , Ratos Wistar , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides/agonistas , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia , Fatores de Tempo
15.
ACS Chem Neurosci ; 5(7): 525-32, 2014 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-24738473

RESUMO

Neuropathic pain is a chronic condition resulting from neuronal damage. Pregabalin, the (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), is widely used to treat neuropathic pain, despite the occurrence of central nervous system (CNS)-related side effects such as dizziness and somnolence. Here we describe the pharmacology of novel GABA derivatives containing silicon-carbon bonds, silagaba compounds. Silagaba131, 132, and 161 showed pregabalin-like analgesic activities in animal models of neuropathic pain, but in contrast to pregabalin they did not impair neuromuscular coordination in rotarod tests. Pharmacokinetic studies showed that brain exposure to silagaba compounds was lower than that to pregabalin. Surprisingly, despite their potent analgesic action in vivo, silagaba compounds showed only weak binding to α2-δ protein. These compounds may be useful to study mechanisms of neuropathic pain. Our results also indicate that silagaba132 and 161 are candidates for orally effective treatment of neuropathic pain without CNS-related side effects.


Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Compostos de Organossilício/farmacologia , Ácido gama-Aminobutírico/análogos & derivados , Administração Oral , Analgésicos/efeitos adversos , Analgésicos/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Neuralgia/fisiopatologia , Compostos de Organossilício/efeitos adversos , Compostos de Organossilício/farmacocinética , Limiar da Dor/efeitos dos fármacos , Pregabalina , Desempenho Psicomotor/efeitos dos fármacos , Ensaio Radioligante , Ratos Sprague-Dawley , Ratos Wistar , Teste de Desempenho do Rota-Rod , Tato , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/farmacologia
16.
Chem Pharm Bull (Tokyo) ; 62(3): 254-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24583779

RESUMO

Selective ligands for retinoic acid receptors (RARs) and for retinoid X receptors (RXRs) are required for both biological studies and therapeutic purposes. We have synthesized a series of diarylamines incorporating hexahydrophenalene or octahydrobenzoheptalene as a hydrophobic moiety and examined their activities towards RARs and RXRs. Most of these compounds showed agonistic activity towards RXRs, but were inactive towards RARs. These RXR-specific ligands showed synergistic activity in RARα,ß ligand-induced terminal differentiation of leukemia cell line HL-60.


Assuntos
Aminas/química , Aminas/farmacologia , Fenalenos/química , Fenalenos/farmacologia , Receptores X de Retinoides/agonistas , Aminas/síntese química , Animais , Benzocicloeptenos/química , Células COS , Diferenciação Celular/efeitos dos fármacos , Chlorocebus aethiops , Sinergismo Farmacológico , Células HL-60 , Humanos , Fenalenos/síntese química , Relação Estrutura-Atividade
17.
J Neurosci Res ; 92(8): 1024-34, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24659080

RESUMO

We previously demonstrated that a synthetic retinoic acid receptor agonist, Am80, attenuated intracerebral hemorrhage (ICH)-induced neuropathological changes and neurological dysfunction. Because inflammatory events are among the prominent features of ICH pathology that are affected by Am80, this study investigated the potential involvement of proinflammatory cytokines/chemokines in the effect of Am80 on ICH. ICH induced by collagenase injection into mouse striatum caused prominent upregulation of mRNAs for interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, CXCL1, CXCL2, and CCL3. We found that dexamethasone (DEX) and Am80 differently modulated the increase in expression of these cytokines/chemokines; TNF-α expression was attenuated only by DEX, whereas CXCL2 expression was attenuated only by Am80. Expression of IL-1ß and IL-6 was inhibited both by DEX and Am80. Neurological assessments revealed that Am80, but not DEX, significantly alleviated motor dysfunction of mice after ICH. From these results, we suspected that CXCL2 might be critically involved in determining the extent of motor dysfunction. Indeed, magnetic resonance imaging-based classification of ICH in individual mice revealed that invasion of hematoma into the internal capsule, which has been shown to cause severe neurological disabilities, was associated with higher levels of CXCL2 expression than ICH without internal capsule invasion. Moreover, a CXCR1/2 antagonist reparixin ameliorated neurological deficits after ICH. Overall, suppression of CXCL2 expression may contribute to the beneficial effect of Am80 as a therapeutic agent for ICH, and interruption of CXCL2 signaling may provide a promising target for ICH therapy.


Assuntos
Benzoatos/farmacologia , Hemorragia Cerebral/tratamento farmacológico , Quimiocina CXCL2/metabolismo , Fármacos Neuroprotetores/farmacologia , Tetra-Hidronaftalenos/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Benzoatos/uso terapêutico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Quimiocina CXCL2/genética , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tetra-Hidronaftalenos/uso terapêutico
18.
Eur J Med Chem ; 69: 262-77, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24044938

RESUMO

Oxazolidinones bearing a seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane heterocycle substituted with an amide or urea functionality as the C-ring and having a [1,2,3]triazole, a thiocarbamate, an isoxazole-3-ylamino, or a thioacetamide C-5 side chain unit on the A-ring instead of the typical acetamide were synthesized and their in vitro antibacterial activities towards various pathogens were evaluated. Several derivatives exhibited potent in vitro antibacterial activity toward not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. The in vivo therapeutic effects of amide 11a and ureas 16e, 17a were 2- to 3-fold greater than that of linezolid in a systemic mouse infection model treated by intravenous administration. Furthermore, compounds 11a and 17a showed lower monoamine oxidase (MAO)-inhibitory activity than our previously reported potent oxazolidinone antibacterials 3a and 3b.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Oxazepinas/química , Oxazolidinonas/farmacologia , Tiocarbamatos/química , Amidas/química , Antibacterianos/síntese química , Antibacterianos/química , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Monoaminoxidase/análise , Monoaminoxidase/metabolismo , Oxazolidinonas/síntese química , Oxazolidinonas/química , Relação Estrutura-Atividade , Ureia/química
19.
PLoS One ; 8(9): e75445, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24066181

RESUMO

Firefly luciferase (Luc) is widely used as a reporter enzyme in cell-based assays for gene expression. A novel aromatic carboxylic acid, F-53, reported here for the first time, substantially inhibited the enzymatic activity of Luc in a Luc reporter screening. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and tandem mass spectrometry (MS/MS) analyses showed that F-53 modifies Luc at lysine-529 via amidation of the F-53 carboxyl group. The lysine-529 residue of Luc, which plays a regulatory catalytic role, can be acetylated. Luc also has a long-chain fatty acyl-CoA synthase activity. An in vitro assay that involved both recombinant Luc and mouse liver microsomes identified F-53-CoA as the reactive form produced from F-53. However, whereas the inhibitory effect of F-53 is observed in Hela cells that transiently expressed Luc, it is not observed in an in vitro assay that involves recombinant Luc alone. Therefore, insights into the activities of certain mammalian transferases can be translated to better understand the acylation by F-53. The insights from this study about the novel inhibitory modification mechanism might help not only to avoid misinterpretation of the results of Luc-based reporter screening assays but also to explain the pharmacological and toxicological effects of carboxylic acid-containing drugs.


Assuntos
Ácidos Carboxílicos/farmacologia , Luciferases/metabolismo , Acilação/efeitos dos fármacos , Animais , Células COS , Linhagem Celular , Humanos , Luciferases/química , Lisina/metabolismo , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Chem Pharm Bull (Tokyo) ; 61(8): 846-52, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23902867

RESUMO

Compound 1 (IT-M-07000) was previously reported as a candidate prodrug of Am80 (Tamibarotene; used to treat acute promyelocytic leukemia), and shown to be efficiently metabolized to Am80 via ß-oxidation. Here, we describe in detail the synthesis of 1, together with another tetradeuterated candidate prodrug, IT-YA-00616 (2), as well as two congeners, and several metabolic intermediates of 1 previously detected in mouse plasma.


Assuntos
Benzoatos/metabolismo , Fenilpropionatos/síntese química , Pró-Fármacos/síntese química , Receptores do Ácido Retinoico/agonistas , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/metabolismo , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Oxirredução , Fenilpropionatos/metabolismo , Pró-Fármacos/metabolismo
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