RESUMEN
GPRC5A is the first member of a new class of orphan receptors coupled to G proteins, which also includes GPRC5B, GPRC5C, and GPRC5D. Since its cloning and identification in the 1990s, substantial progress has been made in understanding the possible functions of this receptor. GPRC5A has been implicated in a variety of cellular events, such as cytoskeleton reorganization, cell proliferation, cell cycle regulation, migration, and survival. It appears to be a central player in different pathological processes, including tumorigenesis, inflammation, immune response, and tissue damage. The levels of GPRC5A expression differ depending on the type of cancer, with increased expression in colon, pancreas, and prostate cancers; decreased expression in lung cancer; and varied results in breast cancer. In this review, we discuss the early discovery of GPRC5A as a phorbol ester-induced gene and later as a retinoic acid-induced gene, its regulation, and its participation in important canonical pathways related to numerous types of tumors and inflammatory processes. GPRC5A represents a potential new target for cancer, inflammation, and immunity therapies.
Asunto(s)
Neoplasias Pulmonares , Receptores de Ácido Retinoico , Masculino , Humanos , Ésteres del Forbol , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Pulmonares/patología , Inflamación , TretinoinaRESUMEN
Retinoic acid (RA) is a fundamental vitamin A metabolite involved in regulating immune responses through the nuclear RA receptor (RAR) and retinoid X receptor. While performing experiments using THP-1 cells as a model for Mycobacterium tuberculosis infection, we observed that serum-supplemented cultures displayed high levels of baseline RAR activation in the presence of live, but not heat-killed, bacteria, suggesting that M. tuberculosis robustly induces the endogenous RAR pathway. Using in vitro and in vivo models, we have further explored the role of endogenous RAR activity in M. tuberculosis infection through pharmacological inhibition of RARs. We found that M. tuberculosis induces classical RA response element genes such as CD38 and DHRS3 in both THP-1 cells and human primary CD14+ monocytes via a RAR-dependent pathway. M. tuberculosis-stimulated RAR activation was observed with conditioned media and required nonproteinaceous factor(s) present in FBS. Importantly, RAR blockade by (4-[(E)-2-[5,5-dimethyl-8-(2-phenylethynyl)-6H-naphthalen-2-yl]ethenyl]benzoic acid), a specific pan-RAR inverse agonist, in a low-dose murine model of tuberculosis significantly reduced SIGLEC-F+CD64+CD11c+high alveolar macrophages in the lungs, which correlated with 2× reduction in tissue mycobacterial burden. These results suggest that the endogenous RAR activation axis contributes to M. tuberculosis infection both in vitro and in vivo and reveal an opportunity for further investigation of new antituberculosis therapies.
Asunto(s)
Mycobacterium tuberculosis , Receptores de Ácido Retinoico , Ratones , Humanos , Animales , Receptores de Ácido Retinoico/metabolismo , Mycobacterium tuberculosis/metabolismo , Agonismo Inverso de Drogas , Tretinoina/farmacología , Receptores X RetinoideRESUMEN
Eosinophils participate in the immune response against many pathogens, including viruses. Since mouse eosinophils are susceptible to influenza A virus infection and possess antiviral activity, we evaluated the expression of sialic acid residues in human eosinophils and their response against influenza virus in vitro. We demonstrated that human eosinophils express α2,6- and α2,3-linked sialic acid, and drastically reduced influenza virus titer. After influenza virus exposure, eosinophils upregulated retinoic acid-inducible gene I (RIG-I) mRNA expression, but no other pattern recognition receptors. Finally, high concentrations of interleukin-8 (IL-8) were found in influenza virus-exposed eosinophil cultures. These data suggest that human eosinophils possess antiviral activity and may play a role in the innate immune response to influenza virus.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Humana , Eosinófilos , Humanos , Interleucina-8 , Receptores de Ácido RetinoicoRESUMEN
Infection with high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer (CC), but viral infection alone does not guarantee the development of this malignancy. Indeed, deficiencies of dietary micronutrients could favor cervical cancer development in individuals that harbor HR-HPV infections. The status of retinoid levels, natural and synthetic derivatives of vitamin A, is important in maintaining cellular differentiation of the cervical epithelium. Moreover, many studies show a link between deficient intake of retinoids or alteration of the retinoid receptors and CC development. In spite of this, the effect of vitamin A deficiency (VAD) in presence of HR-HPV oncoproteins on cervical carcinogenesis in vivo has not been reported. Transgenic mice expressing E6 or E7 oncoproteins (K14E6 or K14E7 mice, respectively) were used to evaluate the possible role of VAD in the development of malignant cervical lesions. The survival of the mice in VAD condition was studied, and histopathological analysis and immunohistochemical detection of molecular cancer markers such as the tumor suppressor retinoic acid receptor beta (RARß), proliferating cell nuclear antigen (PCNA), cleaved caspase 3, and the tumor suppressor protein p16INK4A (inhibitor of CDK4) were performed. Our results show that K14E6/VAD mice showed moderate cervical dysplasia; notably, K14E7/VAD mice developed severe cervical dysplasia and cervical in situ carcinoma at an early age. VAD synergizes with HPV16E7 oncoprotein expression favoring cervical carcinogenesis in vivo.
Asunto(s)
Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/patología , Neoplasias del Cuello Uterino/patología , Deficiencia de Vitamina A/complicaciones , Animales , Cuello del Útero/metabolismo , Cuello del Útero/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Ratones , Ratones Transgénicos , Proteínas E7 de Papillomavirus/metabolismo , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/virología , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Neoplasias del Cuello Uterino/complicaciones , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/virología , Deficiencia de Vitamina A/genética , Deficiencia de Vitamina A/metabolismo , Deficiencia de Vitamina A/patologíaRESUMEN
Retinoic acid, a metabolite of vitamin A, acts through either genomic or nongenomic actions. The genomic action of retinoids exerts effects on gene transcription through interaction with retinoid receptors such as retinoic acid receptors (RARα, ß, and γ) and retinoid X receptors (RXRα, ß, and γ) that are primarily concentrated in the amygdala, pre-frontal cortex, and hippocampal areas in the brain. In response to retinoid binding, RAR/RXR heterodimers undergo major conformational changes and orchestrate the transcription of specific gene networks. Previous experimental studies have reported that retinoic acid exerts an antiepileptogenic effect through diverse mechanisms, including the modulation of gap junctions, neurotransmitters, long-term potentiation, calcium channels and some genes. To our knowledge, there are no previous or current clinical trials evaluating the use of retinoic acid for seizure control.
Asunto(s)
Tretinoina/farmacología , Humanos , Receptores de Ácido Retinoico , RetinoidesRESUMEN
During mating, males provide not only the spermatozoa to fertilize the oocyte but also other stimuli that are essential for initiating and maintaining the reproductive programme in females. In the mammalian oviduct, mating regulates sperm storage, egg transport, fertilization, early embryonic development, and oestradiol metabolism. However, the main molecules underlying these processes are poorly understood. Using microarray analyses, we identified 58 genes that were either induced or repressed by mating in the endosalpinx at 3 h post-stimulus. RT-qPCR confirmed that mating downregulated the expression of the Oas1h and Prim1 genes and upregulated the expression of the Ceacam1, Chad, Chst10, Slc5a3 and Slc26a4 genes. The functional category 'cell-to-cell signalling and interaction' was over-represented in this gene list. Network modelling identified TNF and all-trans retinoic acid (RA) as upstream regulators of the mating-induced transcriptional response, which was confirmed by intraoviductal injection of TNF or RA in unmated rats. It partially mimicked the transcriptional effect of mating in the rat endosalpinx. Furthermore, mating decreased RA levels in oviductal fluid, and RA-receptor-gamma (RARG) exhibited a nuclear location in oviductal epithelium in both unmated and mated rats, indicating RA-RARG transcriptional activity. In conclusion, the early transcriptional response regulated by mating in the rat endosalpinx is mediated by TNF and RA. These signalling molecules regulate a cohort of genes involved in 'cell-to-cell signalling and interactions' and merit further studies to understand the specific processes activated in the endosalpinx to sustain the events that occur in the mammalian oviduct early after mating.
Asunto(s)
Oviductos/metabolismo , Conducta Sexual Animal/fisiología , Transcriptoma , Tretinoina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Femenino , Regulación de la Expresión Génica , Masculino , Membrana Mucosa/metabolismo , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/metabolismo , Receptor de Ácido Retinoico gammaRESUMEN
PURPOSE: Retinoids have proved to be effective for hematologic malignancies treatment but till nowadays, their use as single agent for the solid tumor's management is still controversial. All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, exerts non-genomic interactions with different members of the protein kinase C (PKC) family, recognized modulators of different tumor progression pathways. To determine whether a group of patients could become benefited employing a retinoid therapy, in this study we have evaluated whether PKCα expression (a poor prognosis marker in breast cancer) could sensitizes mammary cells to ATRA treatment. METHODS: PKCα overexpression was achieved by stable transfection and confirmed by western blot. Transfected PKC functionality was determined by nuclear translocation-induction and confocal microscopy. In vitro proliferation was evaluated by cell counting and cell cycle distribution was analyzed by flow cytometry. In vivo studies were performed to evaluate orthotopic tumor growth and experimental lung colonization. Retinoic acid response elements (RARE) and AP1 sites-dependent activity was studied by gene reporter assays and retinoic acid receptors (RARs) were measured by RT-qPCR. RESULTS: Our findings suggest that high PKCα levels improve the differentiation response to ATRA in a RAR signaling-dependent manner. Moreover, RARß expression appears to be critical to induce ATRA sensitization, throughout AP1 trans-repression. CONCLUSION: Here we propose that retinoids could lead a highly personalized anticancer treatment, bringing benefits to patients with aggressive breast tumors resulting from high PKCα expression but, an adequate expression of the RARß receptor is required to ensure the effect on this process.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Proteína Quinasa C-alfa/genética , Receptores de Ácido Retinoico/genética , Tretinoina/farmacología , Animales , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Diferenciación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Xenoinjertos , Humanos , Células MCF-7 , Ratones , Retinoides/farmacología , Transducción de Señal/efectos de los fármacos , Vitamina A/genéticaRESUMEN
The peroxisome proliferator-activated receptor (PPAR) ß/δ has an important role in multiple inflammatory conditions, including obesity, hypertension, cancer, cardiovascular disease, diabetes mellitus, and autoimmune diseases. PPARß/δ forms a heterodimer with the retinoic acid receptor and binds to peroxisome proliferator response elements to initiate transcription of its target genes. PPARß/δ is also able to suppress the activities of several transcription factors, including nuclear factor κB, and activator protein 1, thus regulating anti-inflammatory cellular responses and playing a protective role in several diseases. Recent studies have shown that nutritional compounds, including nutrients and bioactive compounds, can regulate PPARß/δ expression. This review discusses key nutritional compounds that are known to modulate PPARß/δ and are likely to affect human health.
Asunto(s)
Dieta , Inflamación/metabolismo , PPAR delta/metabolismo , PPAR-beta/metabolismo , Animales , Curcumina/farmacología , Flavonoides/farmacología , Humanos , Inflamación/dietoterapia , FN-kappa B/metabolismo , PPAR delta/efectos de los fármacos , PPAR-beta/efectos de los fármacos , Fitoquímicos/farmacología , Polifenoles/farmacología , Receptores de Ácido Retinoico/metabolismo , Vitamina A/farmacologíaRESUMEN
Cellular retinoic acid-binding protein 2 (CRABP2) delivers all-trans retinoic acid (atRA) to retinoic acid receptors (RARs), allowing for the activation of specific gene transcription. The structural similarities between free and atRA-bound CRABP2 raise the questions of how atRA binding occurs and how the atRA:CRABP2 complex is recognized by downstream binding partners. Thus, to gain insights into these questions, we conducted a detailed atRA-CRABP2 interaction study using nuclear magnetic resonance spectroscopy. The data showed that free CRABP2 displays widespread intermediate-time scale dynamics that is effectively suppressed upon atRA binding. This effect is mirrored by the fast-time scale dynamics of CRABP2. Unexpectedly, CRABP2 rigidification in response to atRA binding leads to the stabilization of a homodimerization interface, which encompasses residues located on helix α2 and the ßC-ßD loop as well as residues on strands ßI-ßA and the ßH-ßI loop. Critically, this rigidification also affects CRABP2's nuclear localization signal and RAR-binding motif, suggesting that the loss of conformational entropy upon atRA binding may be the key for the diverse cellular functions of CRABP2.
Asunto(s)
Multimerización de Proteína , Receptores de Ácido Retinoico/química , Receptores de Ácido Retinoico/metabolismo , Tretinoina/química , Tretinoina/metabolismo , Núcleo Celular/metabolismo , Cristalización , Entropía , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Ligandos , Espectroscopía de Resonancia Magnética , Unión Proteica , Estructura Secundaria de Proteína , Receptores de Ácido Retinoico/genéticaRESUMEN
Background: All-trans retinoic acid (ATRA), a vitamin A-derived active metabolite, exerts important functions in hair biology. Previous studies indicated that excess ATRA hampered hair follicle morphogenesis and cyclic regeneration in adulthood, but other studies stated that ATRA promoted hair growth. Dermal papilla (DP), a cluster of specialized fibroblasts, plays pivotal roles in controlling development and regeneration of hair follicle. Several lines of evidence indicated that DP might be the target cells of ATRA in the hair follicle. To confirm this hypothesis, the present study was performed to explore the biological effects of ATRA on goat dermal papilla cells (DPCs) and clarify the roles of ATRA in hair biology. Results: Our experimental results indicated that key signaling transducers of ATRA were dynamically expressed in distinct stages of goat cashmere growth cycle, and high-dose ATRA treatment (10-5 M) significantly impaired the viability of goat DPCs and lowered the ratio of proliferating cells. Otherwise, goat DPCs were stimulated to enter apoptosis and their cell cycle progression was severely blocked by ATRA. Moreover, the expression of fibroblast growth factor 7 (Fgf7), one of the potent hair growth stimulators secreted by DPCs, was transcriptionally repressed following ATRA treatment. Conclusion: DPCs are the targets of ATRA in the hair follicle, and ATRA negatively regulates hair growth by the targeted suppression of cell viability and growth factor expression of goat DPCs. Through these observations, we offer a new mechanistic insight into the roles of ATRA in hair biology.
Asunto(s)
Animales , Tretinoina/farmacología , Cabras , Folículo Piloso/efectos de los fármacos , Regeneración , Técnicas In Vitro , Inmunohistoquímica , Receptores de Ácido Retinoico , Folículo Piloso/citología , Folículo Piloso/crecimiento & desarrollo , Proliferación Celular/efectos de los fármacos , Factor 7 de Crecimiento de Fibroblastos/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Retinoic acid receptors (RAR) and retinoid X receptors (RXR) are ligand-mediated transcription factors that synchronize intricate signaling networks in metazoans. Dimer formation between these two nuclear receptors mediates the recruitment of co-regulatory complexes coordinating the progression of signaling cascades during developmental and regenerative events. In the present study we identified and characterized the receptors for retinoic acid in the sea cucumber Holothuria glaberrima; a model system capable of regenerative organogenesis during adulthood. Molecular characterizations revealed the presence of three isoforms of RAR and two of RXR as a consequence of alternative splicing events. Various analyses including: primary structure sequencing, phylogenetic analysis, protein domain prediction, and multiple sequence alignment further confirmed their identity. Semiquantitative reverse transcription PCR analysis of each receptor isoform herein identified showed that the retinoid receptors are expressed in all tissues sampled: the mesenteries, respiratory trees, muscles, gonads, and the digestive tract. During regenerative organogenesis two of the receptors (RAR-L and RXR-T) showed differential expression in the posterior segment while RAR-S is differentially expressed in the anterior segment of the intestine. This work presents the first description of the components relaying the signaling for retinoic acid within this model system.
Asunto(s)
Perfilación de la Expresión Génica , Holothuria/fisiología , Intestinos/fisiología , Receptores de Ácido Retinoico/metabolismo , Empalme Alternativo , Animales , Biología Computacional , Mapeo Contig , ADN Complementario/metabolismo , Regulación de la Expresión Génica , Holothuria/genética , Sistemas de Lectura Abierta , Filogenia , Regeneración , Receptores X Retinoide/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Transducción de SeñalRESUMEN
BACKGROUND: Nephroblastoma or Wilms tumor is the most frequent kidney cancer in children and accounts for 98% of kidney tumors in this age group. Despite favorable prognosis, a subgroup of these patients progresses to recurrence and death. The retinoic acid (RA) pathway plays a role in the chemoprevention and treatment of tumors due to its effects on cell differentiation and its antiproliferative, anti-oxidant, and pro-apoptotic activities. Reports describe abnormal cellular retinoic acid-binding protein 2 (CRABP2) expression in neoplasms and its correlation with prognostic factors and clinical and pathological characteristics. The aim of this study was to evaluate the immunohistochemical expression of retinoic acid receptor alpha (RARA) and CRABP2 in paraffin-embedded samples of nephroblastomas via semiquantitative and quantitative analyses and to correlate this expression with prognostic factors. METHODS: Seventy-seven cases of nephroblastomas were selected from pediatric oncology services. The respective medical records and surgical specimens were reviewed. Three representative tumor samples and one non-tumor renal tissue sample were selected for the preparation of tissue microarrays (TMA). The Allred scoring system was used for semiquantitative immunohistochemical analyses, whereas a morphometric analysis of the stained area was employed for quantitative evaluation. The nonparametric Mann-Whitney test was used for comparisons between two groups, while the nonparametric Kruskal-Wallis test was used to compare three or more groups. RESULTS: Immunopositivity for RARA and CRABP2 was observed in both the nucleus and cytoplasm. All histological components of the nephroblastoma (blastema, epithelium, and stroma) were positive for both markers. RARA, based on semiquantitative analyses, and CRABP2, bases on quantitative analyses, exhibited increased immunohistochemical expression in patients with metastasis, with p values of 0.0247 and 0.0128, respectively. These findings were similar to the results of the quantitative analysis of RARA expression, showing greater immunopositivity in tumor samples of patients subjected to pre-surgical chemotherapy. No significant correlation was found with the other variables studied, such as disease stage, anaplasia, risk group, histological type, nodal involvement, and clinical evolution. CONCLUSIONS: Semiquantitative and quantitative analyses of the markers RARA and CRABP2 indicate their potential as biomarkers for tumor progression and their participation in nephroblastoma tumorigenesis.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Renales/patología , Receptores de Ácido Retinoico/biosíntesis , Receptor alfa de Ácido Retinoico/biosíntesis , Tumor de Wilms/patología , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
Cellular retinoic acid-binding protein 2 (CRABP2) has been detected in several organs during embryonic development. Recent studies have demonstrated that CRABP2 plays important roles in the retinoic acid, ß-catenin and Notch signaling pathways, as well as in the interaction between epithelial and mesenchymal cells, which are important for human dental pulp stem cells (hDPSCs) and tooth development. In the present study, the expression of CRABP2 during mouse molar development and the role of CRABP2 in hDPSC odontoblastic differentiation were evaluated. CRABP2 was gradually decreased during the development of the first maxillary molar, which exhibited the same trend as the expression of CRABP2 during the odontoblastic induction of hDPSCs. CRABP2 knockdown inhibited the proliferative ability of hDPSCs, while it enhanced odontoblastic differentiation via promoting mineralization nodule formation and upregulating the activity of alkaline phosphatase and the expression of mineralization-related genes. The present study uncovered a novel function of CRABP2 in hDPSCs. Our data suggest that CRABP2 may act as a regulator during the proliferation and differentiation of hDPSCs.
Asunto(s)
Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Pulpa Dental/citología , Odontoblastos/fisiología , Receptores de Ácido Retinoico/fisiología , Células Madre/fisiología , Fosfatasa Alcalina , Análisis de Varianza , Animales , Antraquinonas , Western Blotting , Comunicación Celular , Células Cultivadas , Colorantes , Regulación hacia Abajo/fisiología , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Receptores de Ácido Retinoico/análisis , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
Neuroblastoma (NB) is the most common extracranial solid childhood tumor accounting for around 15% of pediatric cancer deaths and most probably originates from a failure in the development of embryonic neural crest cells. Retinoids can inhibit the proliferation and stimulate differentiation of NB cells. In addition, epigenetic events involving changes in chromatin structure and DNA methylation can mediate the effects of retinoids; hence, the scope of this study is to investigate the use of retinoids and epigenetic drugs in NB cell lines. Here, we demonstrate that the combination of retinoid all trans-retinoic acid (ATRA) with inhibitors of either histone deacetylases (HDACs) or DNA methyltransferase is more effective in impairing the proliferation of human SH-SY5Y and SK-N-BE(2) NB cells than any drug given alone. Treatments also induced differential changes on the messenger RNA (mRNA) expression of retinoid receptor subtypes and reduced the protein content of c-Myc, the neuronal markers NeuN and ß-3 tubulin, and the oncoprotein Bmi1. These results suggest that the combination of retinoids with epigenetic modulators is more effective in reducing NB growth than treatment with single drugs.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Neuroblastoma/metabolismo , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Línea Celular Tumoral , Proliferación Celular/fisiología , Epigénesis Genética/fisiología , Inhibidores de Histona Desacetilasas/administración & dosificación , Humanos , Esteroides/administración & dosificación , Tretinoina/administración & dosificación , Tretinoina/análogos & derivadosRESUMEN
The aim of this study was the characterization of transcriptional regulatory pathways mediated by retinoic acid (RA) in Senegalese sole larvae. For this purpose, pre-metamorphic larvae were treated with a low concentration of DEAB, an inhibitor of RALDH enzyme, until the end of metamorphosis. No differences in growth, eye migration or survival were observed. Nevertheless, gene expression analysis revealed a total of 20 transcripts differentially expressed during larval development and only six related with DEAB treatments directly involved in RA metabolism and actions (rdh10a, aldh1a2, crbp1, igf2r, rarg and cyp26a1) to adapt to a low-RA environment. In a second experiment, post-metamorphic larvae were exposed to the all-trans RA (atRA) observing an opposite regulation for those genes involved in RA synthesis and degradation (rdh10a, aldh1a2, crbp1 and cyp26a1) as well as other related with thyroid- (dio2) and IGF-axes (igfbp1, igf2r and igfbp5) to balance RA levels. In a third experiment, DEAB-pretreated post-metamorphic larvae were exposed to atRA and TTNPB (a specific RAR agonist). Both drugs down-regulated rdh10a and aldh1a2 and up-regulated cyp26a1 expression demonstrating their important role in RA homeostasis. Moreover, five retinoic receptors that mediate RA actions, the thyroid receptor thrb, and five IGF binding proteins changed differentially their expression. Overall, this study demonstrates that exogenous RA modulates the expression of some genes involved in the RA synthesis, degradation and cellular transport through RAR-mediated regulatory pathways establishing a negative feedback regulatory mechanism necessary to balance endogenous RA levels and gradients.
Asunto(s)
Peces Planos/genética , Peces Planos/metabolismo , Regulación de la Expresión Génica , Larva/genética , Larva/metabolismo , Tretinoina/metabolismo , Animales , Benzoatos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Larva/crecimiento & desarrollo , Metamorfosis Biológica/efectos de los fármacos , Metamorfosis Biológica/genética , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Retinoides/farmacología , p-Aminoazobenceno/análogos & derivados , p-Aminoazobenceno/farmacologíaRESUMEN
Abstract: Cellular retinoic acid-binding protein 2 (CRABP2) has been detected in several organs during embryonic development. Recent studies have demonstrated that CRABP2 plays important roles in the retinoic acid, β-catenin and Notch signaling pathways, as well as in the interaction between epithelial and mesenchymal cells, which are important for human dental pulp stem cells (hDPSCs) and tooth development. In the present study, the expression of CRABP2 during mouse molar development and the role of CRABP2 in hDPSC odontoblastic differentiation were evaluated. CRABP2 was gradually decreased during the development of the first maxillary molar, which exhibited the same trend as the expression of CRABP2 during the odontoblastic induction of hDPSCs. CRABP2 knockdown inhibited the proliferative ability of hDPSCs, while it enhanced odontoblastic differentiation via promoting mineralization nodule formation and upregulating the activity of alkaline phosphatase and the expression of mineralization-related genes. The present study uncovered a novel function of CRABP2 in hDPSCs. Our data suggest that CRABP2 may act as a regulator during the proliferation and differentiation of hDPSCs.
Asunto(s)
Humanos , Animales , Masculino , Femenino , Células Madre/fisiología , Diferenciación Celular/fisiología , Receptores de Ácido Retinoico/fisiología , Pulpa Dental/citología , Proliferación Celular/fisiología , Odontoblastos/fisiología , Valores de Referencia , Factores de Tiempo , Inmunohistoquímica , Regulación hacia Abajo/fisiología , Comunicación Celular , Células Cultivadas , Western Blotting , Análisis de Varianza , Antraquinonas , Receptores de Ácido Retinoico/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Colorantes , Fosfatasa Alcalina , Ratones Endogámicos C57BLRESUMEN
During development and through adulthood, differentiation of diverse cell types is controlled by specific genetic and molecular programs for which transcription factors are master regulators of gene expression. Here, we present an overview of the role of nuclear receptors and their selective pharmacological modulators in oligodendrocytes linage, their role in myelination and remyelination and their potential use as a therapeutic strategy for demyelinating diseases. We discuss several aspects of nuclear receptors including: (1) the biochemistry of nuclear receptors superfamily; (2) their role on stem cells physiology, focusing in differentiation and cell removal; (3) the role of nuclear receptor in the oligodendrocytes cell linage, from oligodendrocyte progenitors cells to mature myelinating cells; and (4) the therapeutics opportunities of nuclear receptors for specific demyelinating diseases.
Asunto(s)
Adrenoleucodistrofia/genética , Enfermedad de Alzheimer/genética , Oligodendroglía/metabolismo , Receptores de Ácido Retinoico/genética , Células Madre/metabolismo , Adrenoleucodistrofia/tratamiento farmacológico , Adrenoleucodistrofia/metabolismo , Adrenoleucodistrofia/patología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Factores de Transcripción COUP/agonistas , Factores de Transcripción COUP/genética , Factores de Transcripción COUP/metabolismo , Diferenciación Celular , Linaje de la Célula , Drogas en Investigación/uso terapéutico , Regulación de la Expresión Génica , Humanos , Receptores X del Hígado/agonistas , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Oligodendroglía/efectos de los fármacos , Oligodendroglía/patología , Receptores Nucleares Huérfanos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Células Madre/efectos de los fármacos , Células Madre/patologíaRESUMEN
BACKGROUND: Transcription factors such as retinoic acid receptor alpha (RARα) and beta (RARß) and Yin Yang 1 (YY1) are associated with the progression of non-small cell lung cancer (NSCLC). In particular, a lack of RARß expression is associated with NSCLC development. The aim of this study was to analyze the expression of RARα, RARß and YY1 and their relationship with prognosis in patients with advanced NSCLC. METHODS: The expression of RARα, RARß and YY1 was assessed by immunohistochemistry and quantitative computerized image software. RESULTS: Eighty-five patients treated with platinum-based chemotherapy were included in the analysis. The mean and standard deviation of the nuclear expression of RARα, RARß and YY1 were 184.5 ± 124.4, 18 ± 27 and 16.6 ± 20.5, respectively. The nuclear expression of RARß was associated with the nuclear expression of YY1 (R 2 = 0.28; p value < 0.0001). Patients with high nuclear expression of YY1 were likely to be non-smokers (61.9 vs 40.5 %). Median progression-free survival (PFS) was 5.9 months (3.48-8.28). Low expression of RARα was independently associated with worse PFS following chemotherapy (10.3 vs 5.46 months p = 0.040). Median overall survival (OS) was 15.6 months (4.5-26.7), and lower nuclear expression of RARß was independently associated with shorter OS (27.5 vs 8.7 months; p = 0.037). CONCLUSION: Our study suggests that the loss of RARs is associated with a worse prognosis and these receptors could be a potential molecular target for NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Cisplatino/uso terapéutico , Neoplasias Pulmonares , Receptores de Ácido Retinoico , Receptor alfa de Ácido Retinoico , Factor de Transcripción YY1 , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Diagnóstico por Computador , Supervivencia sin Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Factores de Transcripción , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
Breast cancer is the most common malignancy in women, with metastases being the cause of death in 98%. In previous works we have demonstrated that retinoic acid (RA), the main retinoic acid receptor (RAR) ligand, is involved in the metastatic process by inhibiting migration through a reduced expression of the specific migration-related proteins Moesin, c-Src, and FAK. At present, our hypothesis is that RA also acts for short periods in a non-genomic action to cooperate with motility reduction and morphology of breast cancer cells. Here we identify that the administration of 10(-6) M RA (10-20 min) induces the activation of the migration-related proteins Moesin, FAK, and Paxillin in T-47D breast cancer cells. The phosphorylation exerted by the selective agonists for RARα and RARß, on Moesin, FAK, and Paxillin was comparable to the activation exerted by RA. The RARγ agonist only led to a weak activation, suggesting the involvement of RARα and RARß in this pathway. We then treated the cells with different inhibitors that are involved in cell signaling to regulate the mechanisms of cell motility. RA failed to activate Moesin, FAK, and Paxillin in cells treated with Src inhibitor (PP2) and PI3K inhibitor (WM), suggesting the participation of Src-PI3K in this pathway. Treatment with 10(-6) M RA for 20 min significantly decreased cell adhesion. However, when cells were treated with 10(-6) M RA and FAK inhibitor, the RA did not significantly inhibit adhesion, suggesting a role of FAK in the adhesion inhibited by RA. By immunofluorescence and immunoblotting analysis we demonstrated that RA induced nuclear FAK translocation leading to a reduced cellular adhesion. These findings provide new information on the actions of RA for short periods. RA participates in cell adhesion and subsequent migration, modulating the relocation and activation of proteins involved in cell migration.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Núcleo Celular/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Proteínas de Microfilamentos/metabolismo , Paxillin/metabolismo , Tretinoina/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Femenino , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas del Choque Térmico HSP72 , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Transporte de Proteínas/efectos de los fármacos , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/agonistas , Receptor alfa de Ácido Retinoico/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
The effects of lutein and conjugated linoleic acid (CLA) on growth performance and immune response of broiler chickens were evaluated in the presence and absence of Salmonella lipopolysaccharide (LPS) immune challenge. Cobb chicks (360; 1 to 22 d of age) were used in a 3 × 2 factorial arrangement of CLA (0, 1, and 2%) and lutein (0 and 50 mg/kg) dietary levels. At d 8 and 15, birds were injected with BSA to assess IgY production. At d 20, birds were injected with LPS. Samples of liver, spleen, and duodenum were collected at 3 and 16 h post-LPS challenge for RT-qPCR analysis of RXRα, RXRγ, PPARα, PPARγ, TLR-4, IL-1ß, IL-2, IL-10, and IL-12 gene expression. CLA decreased BW, BW gain (BWG), and G:F from d 1 to 20, but these effects were reversed when lutein was included in the 1% CLA diet (P < 0.001). The production of IgY anti-BSA increased following a 2% CLA supplementation (P < 0.01). LPS increased the liver:BW ratio at 3 h post-injection (P < 0.001) and decreased BWG at 3, 16, and 40 h (P < 0.001). Lutein decreased plasmatic nitric oxide levels (P < 0.01). LPS downregulated PPARα mRNA in the duodenum (P = 0.02) and liver (P = 0.04), and PPARγ (P = 0.01) and RXRα (P = 0.08) in the spleen; these effects were not reversed by CLA or lutein as initially hypothesized. Although LPS upregulated IL-1ß (P = 0.02) and IL-12 (P = 0.07) expression, lutein downregulated these pro-inflammatory cytokines in the liver (P = 0.03 and P = 0.07, respectively). Lutein decreased splenic (P = 0.09) but increased hepatic (P = 0.06) TLR-4 mRNA. A dietary CLA supplementation of 2% increased hepatic RXRα (P = 0.10). In conclusion, CLA decreased broiler chicken growth performance, but lutein could prevent this negative effect (depending on CLA dose). Lutein had an anti-inflammatory effect, and a 2% CLA supplementation improved the humoral immune response.