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1.
BMC Cancer ; 22(1): 1101, 2022 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-36303119

RESUMEN

BACKGROUND: Postoperative chemoradiotherapy (CRT) is a standard therapy for patients with high-risk factors for head and neck squamous cell carcinoma, including positive margin and extra-nodal extension (ENE). However, the prognostic impact of the number of pathological metastatic lymph nodes (pLNs) in hypopharyngeal carcinoma (HPC) is unclear. Thus, this study aimed to investigate postoperative prognostic factors for locally advanced hypopharyngeal squamous cell carcinoma (LA-HPSCC) with a focus on the number of pLNs. METHODS: We retrospectively analyzed medical records of 99 consecutive patients with LA-HPSCC who underwent total pharyngo-laryngo-esophagectomy (TPLE) and bilateral neck dissection (ND) between December 2002 and May 2019. RESULTS: The median follow-up time for all censored patients was 63.2 months. The median overall survival (OS) was 101.0 months (95% confidence interval [CI] 48.1-134.9). patients had pLNs ≥ 3. Forty-six (45.5%) patients were diagnosed with ENE. Twenty (20.2%) patients received postoperative CRT. The multivariate analysis revealed that pLNs ≥ 3 (median OS: 163.2 vs. 31.8 months, hazard ratio [HR] 2.39, 95% CI 1.16-4.94, p < 0.01) and ENE (median OS: 161.0 vs. 26.3 months, HR 4.60, 95% CI 2.26-9.36, p < 0.01) were significantly associated with poor prognosis and that postoperative CRT (HR 0.34, 95% CI 0.16-0.72, p < 0.01) was significantly associated with better prognosis. The cumulative incidence of distant metastasis was higher in patients with pLNs ≥ 3 than in those with pLNs < 3 (p < 0.01). CONCLUSION: pLNs ≥ 3 and ENE were significant poor prognostic factors for patients with LA-HPSCC who underwent TPLE and bilateral ND.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Hipofaríngeas , Humanos , Neoplasias Hipofaríngeas/cirugía , Neoplasias Hipofaríngeas/patología , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/patología , Estadificación de Neoplasias
2.
J Periodontal Res ; 57(5): 1056-1069, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35989621

RESUMEN

BACKGROUND AND OBJECTIVES: The potential role of the transcription factor Differentiated embryo-chondrocyte 2 (Dec2) in the progression of inflammatory diseases such as periodontitis has been unclear. Here, the effect of Dec2 on the expression of RANKL and on osteoclastogenesis was determined. MATERIAL AND METHODS: Wild-type (WT) and Dec2 knockout (KO) mice as a model for periodontitis were used to assess alveolar bone resorption by microcomputed tomography (CT). Western blot, flow cytometry, quantitative real-time PCR, and immunohistochemical analyses were utilized to detect inflammation and osteoclasts. Luciferase reporter and Chromatin immunoprecipitation (ChIP) assays examined the interaction between Dec2 and RANKL. RESULTS: Micro-CT showed that the alveolar bone resorption of Dec2KO mice was more severe than WT mice after treatment with P. gingivalis. Immunohistochemistry and Tartrate-resistant acid phosphatase staining showed active osteoclast differentiation in Dec2KO mice. There was an increase in CD11b+ F4/80+ and CD4+ RANKL+ T cells in Dec2KO mice treated with P. gingivalis. Moreover, inflammatory and immune markers were expressed at significantly higher levels in gingival mononuclear cells in Dec2KO mice. Furthermore, luciferase reporter and ChIP assays confirmed the direct binding of Dec2 protein to the RANKL gene. CONCLUSION: Dec2 has an immune regulation ability that modulates P. gingivalis-induced periodontitis via RANKL.


Asunto(s)
Pérdida de Hueso Alveolar , Resorción Ósea , Periodontitis , Factores de Transcripción/metabolismo , Pérdida de Hueso Alveolar/diagnóstico por imagen , Animales , Ratones , Ratones Noqueados , Osteoclastos , Periodontitis/diagnóstico por imagen , Periodontitis/metabolismo , Ligando RANK/metabolismo , Microtomografía por Rayos X
3.
Int J Mol Sci ; 23(2)2022 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-35055148

RESUMEN

Sodium fluoride (NaF) is widely used in clinical dentistry. However, the administration of high or low concentrations of NaF has various functions in different tissues. Understanding the mechanisms of the different effects of NaF will help to optimize its use in clinical applications. Studies of NaF and epithelial cells, osteoblasts, osteoclasts, and periodontal cells have suggested the significant roles of fluoride treatment. In this review, we summarize recent studies on the biphasic functions of NaF that are related to both soft and hard periodontal tissues, multiple diseases, and clinical dentistry.


Asunto(s)
Inserción Epitelial/citología , Osteoblastos/citología , Osteoclastos/citología , Fluoruro de Sodio/administración & dosificación , Odontología , Relación Dosis-Respuesta a Droga , Inserción Epitelial/efectos de los fármacos , Inserción Epitelial/metabolismo , Humanos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Transducción de Señal/efectos de los fármacos , Fluoruro de Sodio/farmacología
4.
J Periodontal Res ; 56(3): 492-500, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33641180

RESUMEN

BACKGROUND AND OBJECTIVES: Periodontal pathogens initiate various diseases and induce inflammatory host responses. The activation of inflammasomes triggers caspase-1 and interleukin (IL)-1ß-mediated pyroptosis via gasdermin D (GSDMD). Differentiated embryo chondrocyte 2 (Dec2) is a transcription repressor that controls the expression of genes involved in innate immune and inflammatory responses. However, the effects of Dec2 on inflammasome-induced pyroptosis in periodontal tissues remain elusive. This study aimed to characterize the activation of Dec2 inflammasomes that contribute to P. gingivalis lipopolysaccharide (LPS)-induced pyroptosis and its functional and regulatory importance in periodontal inflammation. MATERIALS AND METHODS: Human gingival fibroblasts (HGFs) and human periodontal ligament fibroblasts (HPDLFs) were stimulated with P. gingivalis LPS in vitro. An experimental periodontitis mouse model (wild-type (WT) and Dec2KO) was established to profile periodontal pyroptosis. RESULTS: The results demonstrate that P. gingivalis LPS activates caspase-1, caspase-11, and NF-κB in HGFs and in HPDLFs. siRNA knockdown of Dec2 stimulated the induction and further upregulated LPS-induced pyroptosis in HGFs and HPDLFs, resulting in the release of IL-1ß. Further, a deficiency of Dec2 alleviated periodontal pyroptosis via the transcriptional induction of GSDMD. In addition, P. gingivalis-induced IL-1ß expression and Dec2-deficient mice subsequently increased the inflammatory effect of P. gingivalis in HGFs and in HPDLFs, confirming the importance of Dec2 in the activation of inflammasomes and the regulation of pyroptosis. CONCLUSION: Our results demonstrate that Dec2 alleviates periodontal pyroptosis by regulating the expression of NF-κB, caspase-1 and GSDMD, suggesting that Dec2 is a crucial component of inflammasome activation and subsequent pyroptosis.


Asunto(s)
Inflamasomas , Piroptosis , Animales , Caspasa 1 , Células Cultivadas , Inflamación , Interleucina-1beta , Péptidos y Proteínas de Señalización Intracelular , Ratones , Proteínas de Unión a Fosfato
5.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-34638690

RESUMEN

Periodontal inflammation is a common inflammatory disease associated with chronic inflammation that can ultimately lead to alveolar attachment loss and bone destruction. Understanding autophagy and pyroptosis has suggested their significant roles in inflammation. In recent years, studies of differentiated embryo-chondrocyte expressed genes 1 and 2 (Dec1 and Dec2) have shown that they play important functions in autophagy and in pyroptosis, which contribute to the onset of periodontal inflammation. In this review, we summarize recent studies on the roles of clock genes, including Dec1 and Dec2, that are related to periodontal inflammation and other diseases.


Asunto(s)
Autofagia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Regulación de la Expresión Génica , Proteínas de Homeodominio/biosíntesis , Periodontitis/metabolismo , Piroptosis , Animales , Humanos , Inflamación/metabolismo , Inflamación/patología , Periodontitis/patología
6.
Biochem Biophys Res Commun ; 532(4): 513-519, 2020 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-32896382

RESUMEN

Cardiac inflammation and fibrosis triggered by left ventricular pressure overload are the major causes of heart dysfunction. Differentiated embryonic chondrocyte gene 1 (Dec1) is a basic helix-loop-helix transcription factor that is comprehensively involved in inflammation and tissue fibrosis, but its role in cardiac hypertrophy remains unclear. This study explored the effects of Dec1 on cardiac fibrosis, inflammation, and apoptosis in hypertrophic conditions. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in wild-type (WT) mice and in Dec1 knock out (KO) mice for 4 weeks. Using the TAC mouse model, prominent differences in cardiac hypertrophy at the morphological, functional, and molecular levels were delineated by Masson's Trichrome and TUNEL staining, immunohistochemistry, RT-PCR and Western Blot. DNA microarray and microRNA (miRNA) array analyses were carried out to identify gene and miRNA expression patterns. Dec1KO mice exhibited a more severe hypertrophic heart, whereas WT mice showed a more pronounced perivascular fibrosis after TAC at 4 weeks. The Dec1 deficiency promoted M2 phenotype macrophages. Dec1KO TAC mice showed fewer apoptotic cells than WT TAC mice. APEX1, WNT16, FGF10 and MMP-10 were differentially expressed according to DNA microarray analysis and expression levels of those genes and the corresponding miRNAs (miR-295, miR-200 b, miR-130a, miR-92a) showed the same trends. Furthermore, luciferase reporter assay confirmed that FGF10 is the direct target gene of miR-130. In conclusion, a Dec1 deficiency protects the heart from perivascular fibrosis, regulates M1/M2 macrophage polarization and reduces cell apoptosis, which may provide a novel insight for the treatment of cardiac hypertrophy.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Cardiomegalia/genética , Proteínas de Homeodominio/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Modelos Animales de Enfermedad , Expresión Génica , Proteínas de Homeodominio/genética , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , MicroARNs/metabolismo , Miocarditis/genética , Miocardio/citología , Miocardio/patología
7.
Am J Pathol ; 189(4): 773-783, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30664860

RESUMEN

Smad3 has circadian expression; however, whether Smad3 affects the expression of clock genes is poorly understood. Here, we investigated the regulatory mechanisms between Smad3 and the clock genes Dec1, Dec2, and Per1. In Smad3 knockout mice, the amplitude of locomotor activity was decreased, and Dec1 expression was decreased in the suprachiasmatic nucleus, liver, kidney, and tongue compared with control mice. Conversely, Dec2 and Per1 expression was increased compared with that of control mice. In Smad3 knockout mice, immunohistochemical staining revealed that Dec1 expression decreased, whereas Dec2 and Per1 expression increased in the endothelial cells of the kidney and liver. In NIH3T3 cells, Smad3 overexpression increased Dec1 expression, but decreased Dec2 and Per1 expression. In a wound-healing experiment that used Smad3 knockout mice, Dec1 expression decreased in the basal cells of squamous epithelium, promoting wound healing of the mucosa. Finally, the migration and proliferation of Smad3 knockdown squamous carcinoma cells was suppressed by Dec1 overexpression but was promoted by Dec2 overexpression. Dec1 overexpression decreased E-cadherin and proliferating cell nuclear antigen expression, whereas these expression levels were increased by Dec2 overexpression. These results suggest Smad3 is relevant to circadian rhythm and regulates cell migration and proliferation through Dec1, Dec2, and Per1 expression.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Movimiento Celular , Proliferación Celular , Células Epiteliales/citología , Proteínas de Homeodominio/metabolismo , Proteínas Circadianas Period/metabolismo , Proteína smad3/fisiología , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Células Cultivadas , Ritmo Circadiano , Células Epiteliales/metabolismo , Femenino , Regulación de la Expresión Génica , Proteínas de Homeodominio/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células 3T3 NIH , Proteínas Circadianas Period/genética , Factores de Transcripción/genética
8.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-31597354

RESUMEN

Cardiac fibrosis is a major cause of cardiac dysfunction in hypertrophic hearts. Differentiated embryonic chondrocyte gene 1 (Dec1), a basic helix-loop-helix transcription factor, has circadian expression in the heart; however, its role in cardiac diseases remains unknown. Therefore, using Dec1 knock-out (Dec1KO) and wild-type (WT) mice, we evaluated cardiac function and morphology at one and four weeks after transverse aortic constriction (TAC) or sham surgery. We found that Dec1KO mice retained cardiac function until four weeks after TAC. Dec1KO mice also revealed more severely hypertrophic hearts than WT mice at four weeks after TAC, whereas no significant change was observed at one week. An increase in Dec1 expression was found in myocardial and stromal cells of TAC-treated WT mice. In addition, Dec1 circadian expression was disrupted in the heart of TAC-treated WT mice. Cardiac perivascular fibrosis was suppressed in TAC-treated Dec1KO mice, with positive immunostaining of S100 calcium binding protein A4 (S100A4), alpha smooth muscle actin (αSMA), transforming growth factor beta 1 (TGFß1), phosphorylation of Smad family member 3 (pSmad3), tumor necrosis factor alpha (TNFα), and cyclin-interacting protein 1 (p21). Furthermore, Dec1 expression was increased in myocardial hypertrophy and myocardial infarction of autopsy cases. Taken together, our results indicate that Dec1 deficiency suppresses cardiac fibrosis, preserving cardiac function in hypertrophic hearts. We suggest that Dec1 could be a new therapeutic target in cardiac fibrosis.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Obstrucción del Flujo Ventricular Externo/complicaciones , Animales , Biomarcadores , Cardiomegalia/diagnóstico , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Cardiomiopatías/diagnóstico , Modelos Animales de Enfermedad , Ecocardiografía , Fibrosis , Expresión Génica , Pruebas de Función Cardíaca , Proteínas de Homeodominio , Masculino , Ratones , Ratones Noqueados , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/etiología , Infarto del Miocardio/metabolismo , Obstrucción del Flujo Ventricular Externo/diagnóstico , Remodelación Ventricular
9.
Int J Mol Sci ; 19(3)2018 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-29518061

RESUMEN

The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 (Bhlhe40/Stra13/Sharp2), Dec2 (Bhlhe41/Sharp1), and Bmal1 (Mop3/Arntl) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1, Dec2, and Bmal1 in coordinating the circadian and metabolic pathways.


Asunto(s)
Factores de Transcripción ARNTL/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Relojes Circadianos , Metabolismo Energético , Factores de Transcripción ARNTL/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Humanos
10.
Biochem Biophys Res Commun ; 485(1): 209-214, 2017 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-28192118

RESUMEN

PRG4 is one of the downstream molecules of the myxoid liposarcoma (MLS)-specific fusion oncoproteins TLS-CHOP and EWS-CHOP. Exogenous PRG4 expression increases the tumorigenicity of cells injected in nude mice. The molecular functions of PRG4 in tumorigenesis and/or tumor progression of MLS cells, however, still remain unclear. In this report, we demonstrated that siRNA-mediated knockdown of PRG4 suppressed the growth of the MLS-derived cell lines 1955/91 and 2645/94. In addition, PRG4 knockdown promoted adipocytic differentiation in 1955/91 cells. Thus, PRG4 may play essential roles in MLS cell growth and have potential as a therapeutic target. On the other hand, our previous study has revealed that TLS-CHOP suppresses expression of an anti-tumor cytokine IL-24, contributing to tumor cell survival. In this study, we found that double knockdown of PRG4 and IL-24 did not inhibit MLS cell growth, and single knockdown of PRG4 remarkably increased IL-24 expression. These results suggest that the growth inhibitory effect of PRG4 knockdown is caused by induction of IL-24 expression, and PRG4 may contribute to maintain MLS cell growth through repression of IL-24 expression.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Interleucinas/genética , Liposarcoma Mixoide/genética , Proteoglicanos/genética , Adipogénesis , Línea Celular Tumoral , Proliferación Celular , Humanos , Liposarcoma Mixoide/patología , Interferencia de ARN , ARN Interferente Pequeño/genética
11.
Histochem Cell Biol ; 148(6): 617-624, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28721450

RESUMEN

Bmal1, a clock gene, is associated with depression, hypertrophy, metabolic syndrome and diabetes. Smad3, which is involved in the TGF-ß signaling pathway, plays an important role in the regulation of tumor progression, fibrosis, obesity and diabetes. Our previous report showed that Smad3 has circadian expression in mouse livers. In the current study, we focused on the heart, especially on the myocardial stromal fibroblasts because the roles of Bmal1 and Smad3 in this tissue are poorly understood. Bmal1 and Smad3 have circadian expression in mouse hearts, and their circadian expression patterns were similar. Bmal1 expression decreased in the hearts of whole-body Smad3 knockout mice, whereas Smad3 expression had little effect on heart-specific Bmal1 knockout mice. Both Smad3 knockout and heart-specific Bmal1 knockout mice showed increases in p21, S100A4, CD206 and TNF-α expression in the myocardial stromal fibroblasts and macrophage compared to control mice. We also examined Smad3, Bmal1 and Dec1 expression in human tissue from old myocardial infarctions. Expression of Smad3, Bmal1 and Dec1 decreased in the stromal fibroblasts of tissue from old myocardial infarctions compared to control cases. On the other hand, p21, S100A4 and TNF-α increased in the stromal fibroblasts of tissue from old myocardial infarctions. Furthermore, expression of Smad3, Bmal1 and Dec1 decreased in TNF-α treated-NIH3T3 cells but expression of p21 and S100A4 increased. This new evidence suggests that Smad3 and Bmal1 regulate p21 and S100A4 expression in myocardial stromal fibroblasts through TNF-α.


Asunto(s)
Factores de Transcripción ARNTL/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Fibroblastos/metabolismo , Proteína de Unión al Calcio S100A4/genética , Proteína smad3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factores de Transcripción ARNTL/deficiencia , Factores de Transcripción ARNTL/genética , Animales , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fibroblastos/citología , Humanos , Macrófagos/citología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/metabolismo , Miocardio/citología , Miocardio/metabolismo , Células 3T3 NIH , Proteína de Unión al Calcio S100A4/metabolismo , Proteína smad3/deficiencia , Proteína smad3/genética
12.
Biochem Biophys Res Commun ; 467(4): 711-6, 2015 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-26498531

RESUMEN

Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) is one of the clock genes that show a circadian rhythm in various tissues. AMP-activated protein kinase (AMPK) activity plays important roles in the metabolic process and in cell death induced by glucose depletion. Recent reports have shown that AMPK activity exhibited a circadian rhythm. However, little is known regarding the regulatory mechanisms involved in the circadian rhythm of AMPK activity. The aim of this study is to investigate whether there is a direct correlation between DEC1 expression and AMPK activity. DEC1 protein and AMPK activity showed a circadian rhythm in the mouse liver with different peak levels. Knocking down DEC1 expression increased AMPK activity, whereas overexpression of DEC1 decreased it. Overexpressing the DEC1 basic mutants had little effect on the AMPK activity. DEC1 bound to the E-box of the LKB1 promoter, decreased LKB1 activity and total protein levels. There was an inverse relationship between DEC1 expression and AMPK activity. Our results suggest that DEC1 negatively regulates AMPK activity via LKB1.


Asunto(s)
Adenilato Quinasa/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Proteínas de Homeodominio/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Animales , Línea Celular , Ritmo Circadiano , Humanos , Hígado/enzimología , Hígado/metabolismo , Hígado/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/genética
13.
Biochem Biophys Res Commun ; 456(3): 721-6, 2015 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-25514040

RESUMEN

A representative phenotype of patients with tricho-rhino-phalangeal syndrome (TRPS) is sparse hair. To understand the developmental defects of these patient's hair follicles, we analyzed the development of hair follicles histologically and biochemically using Trps1 deficient (KO) mice. First, we compared the numbers of primary hair follicles in wild-type (WT) and KO embryos at different developmental stages. No differences were observed in the E14.5 skins of WT and KO mice. However, at later time points, KO fetal skin failed to properly develop secondary hair follicles, and the number of secondary hair follicles present in E18.5 KO skin was approximately half compared to that of WT skin. Sonic hedgehog expression was significantly decreased in E17.5 KO skin, whereas no changes were observed in Eda/Edar expression in E14.5 or E17.5 skins. In addition, Noggin expression was significantly decreased in E14.5 and E17.5 KO skin compared to WT skin. In parallel with the suppression of Noggin expression, BMP signaling was promoted in the epidermal cells of KO skins compared to WT skins as determined by immunohistochemistry for phosphorylated Smad1/5/8. The reduced number of secondary hair follicles was restored in skin graft cultures treated with a Noggin and BMP inhibitor. Furthermore, decreased cell proliferation, and increased apoptosis in KO skin was rescued by Noggin treatment. Taken together, we conclude that hair follicle development in Trps1 KO embryos is impaired directly or indirectly by decreased Noggin expression.


Asunto(s)
Proteínas Portadoras/biosíntesis , Dedos/anomalías , Factores de Transcripción GATA/fisiología , Enfermedades del Cabello/genética , Folículo Piloso/embriología , Síndrome de Langer-Giedion/genética , Nariz/anomalías , Animales , Apoptosis , Proteínas Portadoras/genética , Proteínas Portadoras/farmacología , Proliferación Celular , Femenino , Factores de Transcripción GATA/genética , Folículo Piloso/citología , Folículo Piloso/efectos de los fármacos , Humanos , Ratones , Ratones Noqueados , Morfogénesis/genética , Proteínas Represoras
14.
Biochem Biophys Res Commun ; 455(3-4): 390-5, 2014 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-25446074

RESUMEN

Differentiated embryo chondrocyte 2 (DEC2/Sharp-1/Bhlhe41), a basic helix-loop-helix (bHLH) transcription factor, has been shown to regulate the transcription of target genes by binding to their E-box elements. We identified a possible DEC2-response element (consensus E-box: CACGTG) in the promoter region of Twist1. Forced expression of DEC2 significantly repressed Twist1 promoter activity under normoxia and under hypoxia as assessed by a luciferase reporter assay. In addition, over-expression of DEC2 repressed Twist1 mRNA expression assessed by quantitative real-time PCR. Site-directed mutagenesis studies showed that mutagenesis of the consensus E-box sequence eliminated the ability of DEC2 to reduce the Twist1 promoter activity. Chromatin immunoprecipitation (ChIP) assays confirmed that the DEC2-mediated repression is primarily achieved by binding to the E-box in the Twist1 promoter. Knockdown of DEC2 by siRNA significantly attenuated the repression of Twist1 expression. DEC2 and Twist1 exhibit inversed protein expression patterns during development of mouse tongue embryo tissue. Given the fact that DEC2 protein is emerging as an important regulator in a vast array of cellular events, including cell differentiation, maturation of lymphocytes and the molecular clock, our study elucidates an important mechanism by which DEC2 regulates cellular function by modulating the expression of Twist1.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación de la Expresión Génica , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Animales , Secuencia de Bases , Diferenciación Celular , Línea Celular Tumoral , Células HEK293 , Humanos , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Regiones Promotoras Genéticas , Unión Proteica , ARN Interferente Pequeño/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Lengua/embriología , Factores de Transcripción/metabolismo
15.
Exp Mol Pathol ; 97(3): 458-64, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25303897

RESUMEN

Arterial medial calcification is a major complication in patients with chronic kidney disease and diabetes. It has been hypothesized that a high concentration of inorganic phosphate (Pi) induces calcification in vascular smooth muscle cells (vSMCs). However, the role of transforming growth factor-ß (TGF-ß)/Smad3 signaling in Pi-induced vascular calcification remains controversial. The aim of this study was to investigate the possible involvement of Smad3 in Pi-induced vascular calcification. We compared the degree of Pi-induced vSMC calcification between vSMCs isolated from wild-type (Smad3(+/+)) and Smad3-deficient (Smad3(-/-)) mice. We found that vSMCs from Smad3(+/+) mice had less calcium (Ca) than those from Smad3(-/-) mice when they were exposed to high concentrations of Pi and Ca (Pi+Ca). The phosphorylation of Smad3 was induced in Smad3(+/+) vSMCs by exposure to Pi+Ca. The concentration of extracellular pyrophosphate (ePPi) was lower in Smad3(-/-) vSMCs than in Smad3(+/+) vSMCs and was significantly increased in Smad3(+/+) vSMCs by treatment with TGF-ß1. Also, the addition of a small amount of PPi to culture medium significantly decreased the deposition of Ca in both Smad3(+/+) and Smad3(-/-) vSMCs. Ectonucleotide phosphatase/phosphodiesterase1 (Enpp1) was decreased at the mRNA, protein, and enzymatic activity levels in Smad3(-/-) vSMCs compared with Smad3(+/+) vSMCs. A ChIP assay showed that phosphorylated Smad3 directly binds to the Enpp1 gene. Furthermore, the calcification of aortic segments was attenuated by treatment with TGF-ß1 only in Smad3(+/+) mice. Taken together, we conclude that Pi-induced vSMC calcification is suppressed by Smad3 via an increase in ePPi.


Asunto(s)
Músculo Liso Vascular/patología , Transducción de Señal/fisiología , Proteína smad3/metabolismo , Calcificación Vascular/metabolismo , Animales , Western Blotting , Inmunoprecipitación de Cromatina , Difosfatos/metabolismo , Masculino , Ratones , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Crecimiento Transformador beta1/metabolismo , Calcificación Vascular/patología
16.
BMC Mol Cell Biol ; 25(1): 1, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38166556

RESUMEN

Chronic alcohol exposure increases liver damage such as lipid accumulation and hepatitis, resulting in hepatic cirrhosis. Chronic alcohol intake is known to disturb circadian rhythms in humans and animals. DEC1, a basic helix-loop-helix transcription factor, plays an important role in the circadian rhythm, inflammation, immune responses, and tumor progression. We have previously shown that Dec1 deficiency inhibits stresses such as periodontal inflammation and perivascular fibrosis of the heart. However, the significance of Dec1 deficiency in chronic alcohol consumption remains unclear. In the present study, we investigated whether the biological stress caused by chronic alcohol intake is inhibited in Dec1 knockout mice. We treated control and Dec1 knockout mice for three months by providing free access to 10% alcohol. The Dec1 knockout mice consumed more alcohol than control mice, however, we observed severe hepatic lipid accumulation and circadian rhythm disturbance in control mice. In contrast, Dec1 knockout mice exhibited little effect on these outcomes. We also investigated the expression of peroxisome proliferator-activated receptors (PPARs) and AMP-activated protein kinase (AMPK), which are involved in the regulation of fatty acid metabolism. Immunohistochemical analysis revealed increases of phosphorylation AMPK and PPARa but decreases PPARg in Dec1 knockout mice compared to that in control mice. This indicates a molecular basis for the inhibition of hepatic lipid accumulation in alcohol-treated Dec1 knockout mice. These results suggest a novel function of Dec1 in alcohol-induced hepatic lipid accumulation and circadian rhythm disorders.


Asunto(s)
Trastornos Cronobiológicos , Proteínas de Homeodominio , Humanos , Ratones , Animales , Proteínas de Homeodominio/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Hígado/metabolismo , Etanol/metabolismo , Ratones Noqueados , Inflamación/metabolismo , Trastornos Cronobiológicos/metabolismo , Lípidos
17.
Head Neck ; 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38406918

RESUMEN

BACKGROUND: This study aimed to examine treatment outcomes and postoperative complications associated with salvage skull base surgery following radical proton beam therapy (PBT). METHODS: Nine patients who underwent salvage skull base surgery following curative PBT as the initial treatment at our institution between September 2002 and May 2023 were retrospectively reviewed. RESULTS: The cohort comprised four males and five females with a mean age of 48.1 years. The average proton dose administered during initial therapy was 68.5 Gy (relative biological effectiveness). Among the salvage surgeries, eight were anterior skull base surgeries, and one was an anterior middle skull base surgery. No local recurrences or perioperative deaths were observed. Postoperative complications occurred in three patients (33.3%), all experiencing surgical site infections, with one also having cerebrospinal fluid leakage. CONCLUSION: The study demonstrates that salvage skull base surgery after PBT effectively achieves local control and safety in patients with recurrent sinonasal malignancies.

18.
Histol Histopathol ; 38(2): 165-170, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35876434

RESUMEN

Becker muscular dystrophy (BMD) is a hereditary disease characterized by dystrophin deletion that consequently induces muscle weakness, cardiac hypertrophy and cardiac failure; These conditions are similar to those in Duchenne muscular dystrophy. The circadian rhythm is a physiological phenomenon that is predominantly regulated by the transcription and translation of clock genes. Bmal1 (Brain and muscle Arnt-like protein 1) is one of the core clock genes, and its deficiency disturbs the circadian rhythm, results in cardiac hypertrophy and cardiac failure. Dystrophin expression under diurnal conditions and in Bmal1 deficiency is yet to be elucidated. In this study, we analyzed the heart and lungs sampled during a BMD autopsy. Macroscopical examination revealed a large heart and dilated cardiomyopathy. Microscopical examination revealed an undulated structure, as well as the degeneration, and necrosis of myocardial cells. We also analyzed dystrophin expression in tissues obtained from human autopsies and mice. In human autopsy cases, dystrophin expression was lower in the heart with BMD compared that in the heart with non-BMD hypertrophy. In the heart and muscle of control mice, dystrophin expression was higher at ZT0 than at ZT12. The dystrophin expression was found to be lower in heart-specific Bmal1 knockout mice compared to that in the control mice. Hence, our study indicated that BMD was closely associated with cardiac hypertrophy and cardiac failure, while dystrophin had a diurnal expression pattern in control mice that was regulated by Bmal1.


Asunto(s)
Cardiomiopatía Dilatada , Distrofina , Insuficiencia Cardíaca , Distrofia Muscular de Duchenne , Animales , Humanos , Ratones , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Distrofina/genética , Distrofia Muscular de Duchenne/patología , Miocitos Cardíacos/metabolismo , Ratones Noqueados
19.
Int Arch Otorhinolaryngol ; 27(4): e551-e558, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37876683

RESUMEN

Introduction Oral carcinoma has been reported at a substantial proportion in patients who never smoke and never drink. However, the proportion may vary by subsite and ethnicity. Objective We aimed to determine the clinicopathological features of buccal squamous cell carcinoma (SCC) in a Japanese population. Methods We retrospectively analyzed the records of patients diagnosed with buccal SCC at our institution from September 2002 to November 2015. We reviewed the gender, age, tumor status, treatment, smoking, alcohol drinking, multiple primary cancers, and prognosis of the patients. The overall and cause-specific survival rates were calculated, and the effects of clinicopathological variables were assessed by univariate analysis. Furthermore, the cause of death was evaluated. Results Among the 63 patients (men: 38; women: 25) included in the present study, 29 (46.0%) never smoked or drank. Women were almost 5 years older than men ( p = 0.014). The number of women in the group who never smoked or drank was disproportionately higher than that of those in the smoker or drinker groups ( p < 0.001). In total, 29 patients (46.0%) had 59 multiple primary cancers, including 26 oral cancers. Surgeries and radiotherapy were performed in 57 (90.5%) and 6 (9.5%) cases, respectively. The 5-year overall survival and disease-specific survival rates were 74.6 and 78.8%, respectively. Conclusion Our study confirms that buccal SCC may develop in older adult Japanese patients, especially in women who have never smoked or drank. These patients could be at risk for second primary malignancy.

20.
Mol Pharmacol ; 81(5): 739-47, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22355045

RESUMEN

Differentiated embryo chondrocyte-2 (DEC2), also known as bHLHE41 or Sharp1, is a pleiotropic transcription repressor that controls the expression of genes involved in cellular differentiation, hypoxia responses, apoptosis, and circadian rhythm regulation. Although a previous study demonstrated that DEC2 participates in the circadian control of hepatic metabolism by regulating the expression of cytochrome P450, the molecular mechanism is not fully understood. We reported previously that brief exposure of HepG2 cells to 50% serum resulted in 24-h oscillation in the expression of CYP3A4 as well as circadian clock genes. In this study, we found that the expression of CYP2D6, a major drug-metabolizing enzyme in humans, also exhibited a significant oscillation in serum-shocked HepG2 cells. DEC2 interacted with CCAAT/enhancer-binding protein (C/EBPα), accompanied by formation of a complex with histone deacetylase-1, which suppressed the transcriptional activity of C/EBPα to induce the expression of CYP2D6. The oscillation in the protein levels of DEC2 in serum-shocked HepG2 cells was nearly antiphase to that in the mRNA levels of CYP2D6. Transfection of cells with small interfering RNA against DEC2 decreased the amplitude of CYP2D6 mRNA oscillation in serum-shocked cells. These results suggest that DEC2 periodically represses the promoter activity of CYP2D6, resulting in its circadian expression in serum-shocked cells. DEC2 seems to constitute a molecular link through which output components from the circadian clock are associated with the time-dependent expression of hepatic drug-metabolizing enzyme.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Proteína alfa Potenciadora de Unión a CCAAT/fisiología , Ritmo Circadiano , Citocromo P-450 CYP2D6/genética , Proteínas CLOCK/fisiología , Células Hep G2 , Factor Nuclear 4 del Hepatocito/fisiología , Humanos , ARN Mensajero/análisis , Suero , Factores de Tiempo
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