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1.
Histochem Cell Biol ; 139(1): 109-18, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23052835

RESUMEN

Odontogenesis consists of a series of consecutive tooth morphogenesis stages, in which apoptosis is involved to eliminate the unnecessary cells. Autophagy, a lysosome or endosome-mediated self-degradation process, is indicated to participate in embryogenesis and tissue morphogenesis associated with apoptosis. This study hypothesized that autophagy may be involved and associated with apoptosis in odontogenesis. The transcripts of autophagy-related genes (Atg5, Atg7, and Atg12) were positively detected in tooth germs at embryonic day (E) 14.5 and postnatal day (P) 5.5 by quantitative real-time PCR. The protein expression of Atg5-Atg12 conjugate and lipidation of LC3 (microtubule-associated protein 1 light chain 3, autophagic marker) were revealed in the developing tooth germs by western blot. Meanwhile, LC3 was immunolocalized in the enamel organ and dental papilla at embryonic stages (E13.5-E18.5), especially stage E14.5 cervical loop and the PEK that facing the mesenchyme. At postnatal stages (P1.5-P15.5), besides the dental epithelium cells, LC3 was detected in the differentiating and differentiated odontoblasts, dental follicle cells, and Hertwig's epithelium root sheath cells. Moreover, double-immunofluorescence analysis revealed the partial colocalization of LC3 and TUNEL signal in the E14.5 PEK that facing the mesenchyme, the E16.5 stratum intermedium and outer enamel epithelium, the P5.5 stratum intermedium and stellate reticulum. Nevertheless, LC3 was also found in non-apoptotic cells. Furthermore, the transmission electron microscopic images revealed the presence of autophagy, as well as the partial colocalization of autophagic vacuoles and apoptotic nuclei during tooth development. Our findings imply the developmental appearance of autophagy and its partial colocalization with apoptosis during odontogenesis.


Asunto(s)
Autofagia , Diente Molar/embriología , Odontogénesis , Germen Dentario , Animales , Apoptosis , Autofagia/genética , Proteína 12 Relacionada con la Autofagia , Proteína 5 Relacionada con la Autofagia , Proteína 7 Relacionada con la Autofagia , Western Blotting , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones , Ratones Endogámicos ICR , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Diente Molar/metabolismo , Diente Molar/ultraestructura , Proteínas/genética , Proteínas/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Germen Dentario/metabolismo , Germen Dentario/ultraestructura
2.
Apoptosis ; 15(7): 850-63, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20386985

RESUMEN

Quercetin, one of the most common natural flavonoids, has been reported to possess significant anti-tumor activities both in vitro and in vivo. The present study was to investigate the effects of quercetin on growth and apoptosis in human salivary adenoid cystic carcinoma (ACC). The result from MTT assay showed that quercetin decreased cell viability of both low metastatic cell line ACC-2 and high metastatic cell line ACC-M in a concentration- and time-dependent manner. Moreover, treatment with quercetin resulted in significantly increased apoptosis in ACC cells. Our data also revealed that the apoptosis induced by quercetin treatment was through a mitochondria-dependent pathway which showed close correlation with the down-regulation of the PI3K/Akt/IKK-alpha/NF-kappaB pathway. Most importantly, quercetin significantly prevented in vivo growth of ACC xenografts in nude mice, accompanied by induction of tumor cell apoptosis, suppression of NF-kappaB nuclear translocation, as well as down-regulation of Akt and IKK-alpha activation. In addition, we explored the clinical significance of the PI3K/Akt/IKK-alpha/NF-kappaB signaling axis in ACC by immunohistochemical analysis of tissue specimens followed by the clustering analyses. We determined that the PI3K/Akt/IKK-alpha/NF-kappaB pathway is ubiquitously activated in ACC and plays an essential role in the evasion of apoptosis. Taken together, the results from our study implicated that quercetin would be a promising chemotherapeutic agent against ACC through its function of down-regulating the PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway.


Asunto(s)
Antineoplásicos/toxicidad , Apoptosis , Carcinoma Adenoide Quístico/metabolismo , Quercetina/toxicidad , Neoplasias de las Glándulas Salivales/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Carcinoma Adenoide Quístico/enzimología , Carcinoma Adenoide Quístico/patología , Caspasas/metabolismo , Línea Celular Tumoral , Citocromos c/metabolismo , Activación Enzimática , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias de las Glándulas Salivales/enzimología , Neoplasias de las Glándulas Salivales/patología , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Biomed Res Int ; 2019: 8528719, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30949512

RESUMEN

AIM: Cyclophilin A (CypA)/CD147 signaling plays critical roles in the regulation of inflammation and bone metabolism. This study aimed to investigate the participation of CypA/CD147 in mice periapical lesions progression and its relationship with bone resorption. METHODOLOGY: Periapical lesions were induced by pulp exposure in the first lower molars of 40 C57BL/6J mice. The mice were sacrificed on days 0, 7, 14, 21, 28, 35, 42, and 49. Mandibles were harvested for X-ray imaging, microcomputed tomography scanning, histologic observation, immunohistochemistry, enzyme histochemistry, and double immunofluorescence analysis. Western blot was employed to further detect the related molecular signaling pathways in LPS-stimulated RAW 264.7 cells treated with CypA inhibitor. RESULTS: The volume and area of the periapical lesions increased from day 0 to day 35 and remained comparably stable until day 49. Immunohistochemistry demonstrated that the CypA expression levels also increased from day 0 to day 35 and decreased until day 49, similar to CD147 expression (R 2 = 0.4423, P < 0.05), osteoclast number (R 2 = 0.5101, P < 0.01), and the expression of osteoclastogenesis-related matrix metalloproteinase 9 (MMP-9) (R 2 = 0.4715, P < 0.05). Serial sections further confirmed the colocalization of CypA and CD147 on osteoclasts with immunohistochemistry. And the distribution of CypA-positive or CD147-positive cells was positively correlated with the dynamics of MMP-9-positive cells by using immunofluorescence analysis. Furthermore, CD147 and MMP-9 expression in RAW 264.7 cells were both downregulated with CypA inhibitor treatment (P < 0.05). CONCLUSIONS: The present study reveals the positive correlation of CypA/CD147 signaling and osteoclast-related MMP-9 expression in mice inflammatory periapical lesions progression. Therefore, intervention of CypA/CD147 signaling could probably provide a potential therapeutic target for attenuating inflammatory bone resorption.


Asunto(s)
Pérdida de Hueso Alveolar/metabolismo , Basigina/metabolismo , Ciclofilina A/metabolismo , Regulación Enzimológica de la Expresión Génica , Metaloproteinasa 9 de la Matriz/biosíntesis , Diente Molar/metabolismo , Transducción de Señal , Pérdida de Hueso Alveolar/inducido químicamente , Pérdida de Hueso Alveolar/patología , Animales , Lipopolisacáridos/toxicidad , Masculino , Ratones , Diente Molar/patología , Células RAW 264.7
4.
Toxicol Sci ; 157(1): 100-111, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28184909

RESUMEN

2-hydroxyethyl methacrylate (HEMA) is the major resin monomer that is released from incomplete polymerized dental restorative and adhesive biomaterials during dental therapy. Autophagy and apoptosis are biologically connected and the relationship between autophagy and apoptosis is complex under various circumstances. This study aimed to determine whether autophagy is activated by HEMA and further explore the function of autophagy during the HEMA-induced apoptosis of dental mesenchymal cells (DMCs). We exposed DMCs to different concentrations of HEMA. Cell viability showed a time- and concentration-dependent decrease when exposed to HEMA. We showed that HEMA exposure increased autophagic vacuoles and the expression of autophagic biomarkers (Beclin1, Atg5 and LC3). Pre-incubated with autophagy inhibitors (3-methyladenine and chloroquine) significantly prevented HEMA-induced apoptosis. Interestingly, HEMA initiated nuclear factor-κB (NF-κB) expression and nuclear translocation, whereas the NF-κB inhibitor (Bay 11-7082) markedly suppressed HEMA-induced autophagic activation and apoptosis. As is consistent with the in vitro results, HEMA treatment resulted in dental pulp tissue toxicity and activation of typical autophagic vacuoles in the tooth slice organ culture model ex vivo. In summary, we demonstrated that NF-κB signaling functioned upstream of HEMA-inducecd autophagy in DMCs and that the activation of NF-κB-autophagy axis was responsible for HEMA-induced apoptosis. Our findings provide novel insights into the mechanisms of resin monomer-mediated dental pulp damage during dental treatment, highlighting the activation of NF-κB-autophagy axis as an important mechanism of HEMA-mediated apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Metacrilatos/toxicidad , Diente/citología , Adolescente , Adulto , Beclina-1/metabolismo , Células Cultivadas , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , FN-kappa B/metabolismo , Adulto Joven
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