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INTRODUCTION: The mechanosensitive ion channel, Piezo1, is responsible for transducing mechanical stimuli into intracellular biochemical signals and has been identified within periodontal ligament cells (PDLCs). Nonetheless, the precise biologic function of Piezo1 in the regulation of alveolar bone remodeling by PDLCs during compressive forces remains unclear. Therefore, this study focused on elucidating the role of the Piezo1 channel in alveolar bone remodeling and uncovering its underlying mechanisms. METHODS: PDLCs were subjected to compressive force and Piezo1 inhibitors. Piezo1 and ß-catenin expressions were quantified by quantitative reverse transcription polymerase chain reaction and Western blot. The intracellular calcium concentration was measured using Fluo-8 AM staining. The osteogenic and osteoclastic activities were assessed using alkaline phosphatase staining, enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and Western blot. In vivo, orthodontic tooth movement was used to determine the effects of Piezo1 on alveolar bone remodeling. RESULTS: Piezo1 and activated ß-catenin expressions were upregulated under compressive force. Piezo1 inhibition reduced ß-catenin activation, osteogenic differentiation, and osteoclastic activities. ß-catenin knockdown reversed the increased osteogenic differentiation but had little impact on osteoclastic activities. In vivo, Piezo1 inhibition led to decreased tooth movement distance, accompanied by reduced ß-catenin activation and expression of osteogenic and osteoclastic markers on the compression side. CONCLUSIONS: The Piezo1 channel is a key mechanotransduction component of PDLCs that senses compressive force and activates ß-catenin to regulate alveolar bone remodeling.
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Osteogénesis , beta Catenina , Humanos , beta Catenina/metabolismo , Células Cultivadas , Mecanotransducción Celular , Ligamento Periodontal , Remodelación Ósea/fisiología , Diferenciación Celular/fisiologíaRESUMEN
Nickel-catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, their use in asymmetric synthesis remains challenging because of the difficulty in controlling stereo- and regioselectivity. Herein, we report the first nickel-catalyzed asymmetric synthesis of N-N atropisomers by the denitrogenative transannulation of benzotriazones with alkynes. A broad range of N-N atropisomers was obtained with excellent regio- and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel-catalyzed reaction mechanism and enantioselectivity control.
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Inherently chiral calix[4]arenes are an excellent structural scaffold for enantioselective synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic enantioselective synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade enantioselective cyclization and oxidation reactions. The three-component reaction features a broad substrate scope (33â examples), high efficiency (up to 90 % yield), and excellent enantioselectivity (>95 % ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties.
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Adenosine monophosphate-activated protein kinase (AMPK) plays pivotal roles in metabolic diseases including type 2 diabetes. However, the specific role of AMPK for orthodontic tooth movement in type 2 diabetes is unclear. In this study, a diabetic rat model was established through dietary manipulation and streptozocin injection. Examinations were conducted to select qualified type 2 diabetic rats. Then, an orthodontic device was applied to these rats for 0, 3, 7, or 14 days. The distance of orthodontic tooth movement and parameters of alveolar bone were analyzed by micro-computed tomography. Periodontal osteoclastic activity, inflammatory status, and AMPK activity were measured via histological analyses. Next, we repeated the establishment of diabetic rats to investigate whether change of AMPK activity was associated with orthodontic tooth movement under type 2 diabetes. The results showed that diabetic rats exhibited an exacerbated alveolar bone resorption, overactive inflammation, and decreased periodontal AMPK activity during orthodontic tooth movement. Injection of the AMPK agonist alleviated type 2 diabetes-induced periodontal inflammation and alveolar bone resorption, thus normalizing distance of orthodontic tooth movement. Our study indicates that type 2 diabetes decreases periodontal AMPK activity, leading to excessive inflammation elevating osteoclast formation and alveolar bone resorption, which could be reversed by AMPK activation.
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Pérdida de Hueso Alveolar , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratas , Animales , Diabetes Mellitus Tipo 2/complicaciones , Técnicas de Movimiento Dental/métodos , Microtomografía por Rayos X , Proteínas Quinasas Activadas por AMP , Pérdida de Hueso Alveolar/diagnóstico por imagen , Inflamación , Ligamento PeriodontalRESUMEN
OBJECTIVE: The aim of this study was to investigate the role of ephrinB2-EphB4 signalling in alveolar bone remodelling on the tension side during orthodontic tooth movement (OTM). MATERIALS AND METHODS: An OTM model was established on sixty 8-week-old male Wistar rats. They were randomly divided into the experimental group and the control group. The animals in the experimental group were administrated with subcutaneous injection of EphB4 inhibitor NVP-BHG712 every other day, whereas the control group received only the vehicle. Samples containing the maxillary first molar and the surrounding bone were collected after 0, 3, 7, 14 and 21 days of tooth movement. RESULTS: EphrinB2-EphB4 signalling was actively expressed on the tension side during tooth movement. Micro-CT analysis showed the distance of tooth movement in the experimental group was significantly greater than that of the control group (P < .05) with significantly increased trabecular separation (Tb. Sp) and decreased trabecular number (Tb. N) from day 14 to day 21. The number of osteoclasts significantly increased in the experimental group compared with the control group after 3 and 7 days of tooth movement (P < .05). The expressions of alkaline phosphatase (ALP) and osteopontin (OPN) were significantly reduced by inhibition of EphB4 (P < .05). CONCLUSION: The inhibition of EphB4 suppressed bone formation and enhanced bone resorption activities on the tension side of tooth movement. The ephrinB2-EphB4 signalling might play an important role in alveolar bone remodelling during OTM.
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Efrina-B2 , Técnicas de Movimiento Dental , Animales , Masculino , Ratas , Remodelación Ósea , Efrina-B2/metabolismo , Osteoclastos/metabolismo , Ratas Wistar , Efrinas/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVE: This study aims to clarify the effects of diabetes mellitus (DM) on inflammatory profile during orthodontic tooth movement (OTM) and explore potential mechanisms. METHODS: OTM models were established in healthy (Ctrl) and DM rats for 0, 3, 7 or 14 days. The tooth movement distance and bone structural parameters were analyzed through micro-CT. The bone resorption activity and periodontal inflammation status were evaluated through histological staining. RNA sequencing was performed to detect differentially expressed genes in force loading-treated periodontal ligament fibroblasts (PDLFs) with or without high glucose. The differential expression of inflammatory genes associated with NOD-like receptor family pyrin domain containing 3 (NLRP3) between groups was tested in vitro and in vivo. RESULTS: DM caused remarkable reduction of alveolar bone height and density around the moved tooth, corresponding with the higher bone resorption activity and inflammatory scores of DM group. For force loading-treated PDLFs, high glucose induced the activation of inflammatory pathways, including NLRP3. Elevated expression of NLRP3 and cascade molecules (Caspase-1, GSDMD, and IL-1ß) were validated by RT-qPCR, Western blot, and immunohistochemistry staining. CONCLUSIONS: DM alters the inflammatory status of periodontium and affects tissue reconstruction during OTM. NLRP3 inflammasome may involve in diabetes-induced periodontal changes.
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OBJECTIVES: The aim of this study was to investigate cementocyte mechanotransduction during excessive orthodontic intrusive force-induced root resorption and the role of S1P signaling in this process. MATERIALS AND METHODS: Fifty-four 12-week-old male Wistar rats were randomly divided into 3 groups: control group (Control), intrusive stress application group (Stress), and intrusive stress together with S1PR2-specific antagonist injection group (Stress + JTE). A rat molar intrusion model was established on animals in the Stress and the Stress + JTE groups. The animals in the Stress + JTE group received daily intraperitoneal (i.p.) injection of S1PR2 antagonist JTE-013, while the Control and Stress groups received only the vehicle. Histomorphometric, immunohistochemical, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses were performed after euthanizing of the rats. RESULTS: Root resorption was promoted in the Stress group with increased volumes of resorption pits and amounts of molar intrusion compared with the Control group. The expression levels of cementogenic- and cementoclastic-related factors were affected under excessive intrusive force. Immunohistochemical staining and qRT-PCR analysis showed promoted S1P signaling activities during molar intrusion. Western blot analysis indicated decreased nuclear translocation of ß-catenin under excessive intrusive force. Through the administration of JTE-013, S1P signaling activity was suppressed and excessive intrusive force-induced root resorption was reversed. The regulation of S1P signaling could also influence the nuclear translocation of ß-catenin and the expressions of cementogenic- and cementoclastic-related factors. CONCLUSIONS: Root resorption was promoted under excessive orthodontic intrusive force due to the disruption of cementum homeostasis. S1P signaling pathway might play an important role in cementocyte mechanotransduction in this process. CLINICAL RELEVANCE: The S1P signaling might be a promising therapeutic target for novel therapeutic approaches to prevent external root resorption caused by excessive orthodontic intrusive force.
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Resorción Radicular , Animales , Lisofosfolípidos , Masculino , Mecanotransducción Celular , Diente Molar , Ratas , Ratas Wistar , Transducción de Señal , Esfingosina/análogos & derivados , Técnicas de Movimiento DentalRESUMEN
As a self-protective mechanism for cells to obtain energy by degrading their own structures or substances, autophagy widely occurs in basic physiological process of all kinds of eukaryotic cells. In recent years, studies have shown that autophagy can be induced through a variety of mechanical transduction pathways when various tissues and cells are exposed to different types of mechanical stress, and cells and tissues involved can thus regulate cell metabolic functions and participate in the pathological process of a variety of diseases. The stress receptors on the cell membrane and the multiple signaling pathways and cytoskeletons have been shown to play an important role in this process. At present, due to the difficulties in the establishment of the stress loading model and the limitations in the research methods concerned, the specific mechanical transduction mechanisms of autophagy induced by mechanical stress is not clear. Therefore, more reliable in vitro and in vivo models and more advanced research methodology are needed to investigate the mechanical transduction process of autophagy induced by mechanical stress, and to promote ultimately progress in the understanding of autophagy-related diseases and their treatments. This article reviewed the regulatory role of mechanical stress on autophagy in physiological and disease processes and the signal transduction process related to autophagy induced by mechanical stress.
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Autofagia , Mecanotransducción Celular , Transducción de Señal , Estrés MecánicoRESUMEN
Inhibition of matrix metalloproteinases-2 (MMP-2) activation renders cardioprotection from ischemia/reperfusion (I/R) injury; however, the signaling pathways involved have not been fully understood. Intermittent hypobaric hypoxia (IHH) has been shown to enhance myocardial tolerance to I/R injury via triggering intrinsic adaptive responses. Here we investigated whether IHH protects the heart against I/R injury via the regulation of MMP-2 and how the MMP-2 is regulated. IHH (Po2 = 84 mmHg, 4-h/day, 4 wk) improved postischemic myocardial contractile performance, lactate dehydrogenase (LDH) release, and infarct size in isolated perfused rat hearts. Moreover, IHH reversed I/R-induced MMP-2 activation and release, disorders in the levels of MMP-2 regulators, peroxynitrite (ONOO(-)) and tissue inhibitor of metalloproteinase-4 (TIMP-4), and loss of the MMP-2 targets α-actinin and troponin I. This protection was mimicked, but not augmented, by a MMP inhibitor doxycycline and lost by the α1-adrenoceptor (AR) antagonist prazosin. Furthermore, IHH increased myocardial α1A-AR and α1B-AR density but not α1D-AR after I/R. Concomitantly, IHH further enhanced the translocation of PKC epsilon (PKCε) and decreased the release of mitochondrial cytochrome c due to I/R via the activation of α1B-AR but not α1A-AR or α1D-AR. IHH-conferred cardioprotection in the postischemic contractile function, LDH release, MMP-2 activation, and nitrotyrosine as well as TIMP-4 contents were mimicked but not additive by α1-AR stimulation with phenylephrine and were abolished by an α1B-AR antagonist chloroethylclonidine and a PKCε inhibitor PKCε V1-2. These findings demonstrate that IHH exerts cardioprotection through attenuating excess ONOO(-) biosynthesis and TIMP-4 loss and sequential MMP-2 activation via the activation of α1B-AR/PKCε pathway.
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Hipoxia/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Daño por Reperfusión/metabolismo , Actinina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Doxiciclina/farmacología , Masculino , Prazosina/farmacología , Proteína Quinasa C-epsilon/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Inhibidor Tisular de Metaloproteinasa-4RESUMEN
Scaffold protein AF4/FMR2 family member 4 (AFF4) has been found to play a role in osteogenic commitment of stem cells. However, function of AFF4 in human periodontal ligament stem cells (hPDLSCs) has not been studied yet. This present study aims to investigate the biological effect of AFF4 on osteogenic differentiation of hPDLSCs and potential mechanistic pathway. First, AFF4 expression profile was evaluated in conditions of periodontitis and osteogenic differentiation of hPDLSCs by immunohistochemical staining, western blot and qRT-PCR. Next, si-RNA mediated knockdown and lentiviral transduction mediated overexpression of AFF4 were adopted to explore impact of AFF4 on osteogenic capacity of hPDLSCs. Then, possible mechanistic pathway was identified. At last, pharmacological agonist of autophagy, rapamycin, was utilized to affirm the role of autophagy in AFF4-regulated osteogenesis of hPDLSCs. First, AFF4 expressions were significantly lower in inflamed periodontal tissues and lipopolysaccharides-treated hPDLSCs than controls, and were up-regulated during osteogenic differentiation of hPDLSCs. Next, osteogenic potential of hPDLSCs was impaired by AFF4 knockdown and potentiated by AFF4 overexpression. Moreover, AFF4 was found to positively regulate autophagic activity in hPDLSCs. At last, rapamycin treatment was shown to be able to partly restore AFF4 knockdown-suppressed osteogenic differentiation. Our study demonstrates that AFF4 regulates osteogenic potential of hPDLSCs via targeting autophagic activity. The involvement of AFF4 in periodontal homeostasis was identified for the first time.
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Osteogénesis , Ligamento Periodontal , Humanos , Homólogo de la Proteína 1 Relacionada con la Autofagia , Diferenciación Celular , Células Cultivadas , Péptidos y Proteínas de Señalización Intracelular , Sirolimus/farmacología , Células Madre , Serina-Treonina Quinasas TOR , Factores de Transcripción , Factores de Elongación TranscripcionalRESUMEN
Periodontitis is a chronic inflammatory disease that affects about 45 %-50 % of adults worldwide, but the efficacy of current clinical therapies is unsatisfactory due to the complicated periodontal immune microenvironment. Thus, developing drugs that can regulate innate immune cells (e.g., macrophages) is a potent strategy to treat periodontitis. Here, we report that phloretin, a food plant-derived natural compound, is sufficient to alleviate periodontitis through immune regulation. In vivo, phloretin treatment could significantly reduce alveolar bone resorption and periodontal inflammation in mouse periodontitis models. In vitro, phloretin could suppress proinflammatory (M1-like) polarization and cytokine release in macrophages induced by LPS. Mechanistically, the immune regulatory role of phloretin in macrophages may be due to its metabolic regulation effect. Phloretin might restore the balance of M1/M2 macrophage transition in periodontitis by inhibiting HIF-1α-mediated glycolysis and PI3k/Akt pathways, thereby reducing the proinflammatory effect and immune disorder caused by over-activated M1 macrophages. Together, this study highlights that natural compound, such as phloretin, can restore periodontal immune homeostasis by metabolic regulation of macrophages, which may provide novel insight into the treatment of periodontitis.
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Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide marine metabolite, has been reported could inhibit HDAC1/2/3 through its thiol monomer. Inspired by the disuflide bond structure of this marine natural product, we designed and synthesized a series of PsA analogues, in which the disulfide bond of PsA was replaced with diselenide bond or cyclic disulfide/diselenide/selenenylsulfide motifs. We also studied the HDAC inhibition, cell growth inhibition, and apoptosis induction of these PsA analogues. The results showed that, all the synthetic diselenide analogues and cyclic selenenyl sulfide compounds exhibited better antiproferative activity than their counterpart of disulfide analogues. Among the prepared analogues, diselenide analogue P-503 and P-116 significantly increased the ability of inhibiting HDAC6 and induced apoptosis and G2/M cell cycle arrest. However, cyclic selenenylsulfides analogues P-111 lost its HDAC inhibitory ability and exhibited no effect on cell cycle and apoptosis, indicating that the anti-proliferative mechanism of cyclic selenenylsulfides analogues has changed.
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Apoptosis , Proliferación Celular , Disulfuros , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Disulfuros/química , Disulfuros/farmacología , Disulfuros/síntesis química , Humanos , Apoptosis/efectos de los fármacos , Histona Desacetilasas/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Tirosina/análogos & derivadosRESUMEN
Regenerating periodontal defects in osteoporosis patients presents a significant clinical challenge. Unlike the relatively straightforward regeneration of homogeneous bone tissue, periodontal regeneration requires the intricate reconstruction of the cementum-periodontal ligament-alveolar bone interface. Strontium (Sr)-doped biomaterials have been extensively utilized in bone tissue engineering due to their remarkable pro-osteogenic attributes. However, their application in periodontal tissue regeneration has been scarcely explored. In this study, we synthesized an innovative injectable Sr-BGN/GNM scaffold by integrating Sr-doped bioactive glass nanospheres (Sr-BGNs) into the nanofiber architecture of gelatin nanofiber microspheres (GNMs). This design, mimicking the natural bone extracellular matrix (ECM), enhanced the scaffold's mechanical properties and effectively controlled the sustained release of Sr ions (Sr2+), thereby promoting the proliferation, osteogenic differentiation, and ECM secretion of PDLSCs and BMSCs, as well as enhancing vascularization in endothelial cells. In vivo experiments further indicated that the Sr-BGNs/GNMs significantly promoted osteogenesis and angiogenesis. Moreover, the scaffold's tunable degradation kinetics optimized the prolonged release and pro-regenerative effects of Sr2+ in vivo, matching the pace of periodontal regeneration and thereby facilitating the regeneration of functional periodontal tissues under osteoporotic conditions. Therefore, Sr-BGNs/GNMs emerge as a promising candidate for advancing periodontal regeneration strategies.
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Matriz Extracelular , Microesferas , Nanofibras , Osteoporosis , Estroncio , Estroncio/química , Estroncio/farmacología , Nanofibras/química , Osteoporosis/tratamiento farmacológico , Humanos , Matriz Extracelular/química , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Animales , Osteogénesis/efectos de los fármacos , Andamios del Tejido/química , Diferenciación Celular/efectos de los fármacos , Ingeniería de Tejidos , Proliferación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Regeneración/efectos de los fármacosRESUMEN
Orthodontic tooth movement (OTM) is a highly coordinated biomechanical response to orthodontic forces with active remodelling of alveolar bone but minor root resorption. Such antiresorptive properties of root relate to cementocyte mineralization, the mechanisms of which remain largely unknown. This study used the microarray analysis to explore long non-coding ribonucleic acids involved in stress-induced cementocyte mineralization. Gain- and loss-of-function experiments, including Alkaline phosphatase (ALP) activity and Alizarin Red S staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence analyses of mineralization-associated factors, were conducted to verify long non-coding ribonucleic acids taurine-upregulated gene 1 (LncTUG1) regulation in stress-induced cementocyte mineralization, via targeting the Toll-like receptor 4 (TLR4)/SphK1 axis. The luciferase reporter assays, chromatin immunoprecipitation assays, RNA pull-down, RNA immunoprecipitation, and co-localization assays were performed to elucidate the interactions between LncTUG1, PU.1, and TLR4. Our findings indicated that LncTUG1 overexpression attenuated stress-induced cementocyte mineralization, while blocking the TLR4/SphK1 axis reversed the inhibitory effect of LncTUG1 on stress-induced cementocyte mineralization. The in vivo findings also confirmed the involvement of TLR4/SphK1 signalling in cementocyte mineralization during OTM. Mechanistically, LncTUG1 bound with PU.1 subsequently enhanced TLR4 promotor activity and thus transcriptionally elevated the expression of TLR4. In conclusion, our data revealed a critical role of LncTUG1 in regulating stress-induced cementocyte mineralization via PU.1/TLR4/SphK1 signalling, which might provide further insights for developing novel therapeutic strategies that could protect roots from resorption during OTM.
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Proteínas Proto-Oncogénicas , ARN Largo no Codificante , Transducción de Señal , Receptor Toll-Like 4 , Transactivadores , Receptor Toll-Like 4/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Ratones , Transactivadores/metabolismo , Transactivadores/genética , Cemento Dental/metabolismo , Calcificación Fisiológica/genética , Técnicas de Movimiento DentalRESUMEN
Growth performance and carcass traits may be retarded by low nutrient density diets. Organic chromium propionate (CrProp) can improve growth, carcass traits, and meat quality in farmed lambs, white broilers, and fish. Limited data regarding CrProp's impacts on yellow-feathered broilers are available. Eight hundred yellow-feathered male broilers (1-day old) were randomly allocated to 4 dietary groups and reared for 56 d. The trial was a 2 (dietary nutrient density) ×2 (CrProp) factorial arrangement with 4 diets: regular nutrient diet and low nutrient density (LND, reduction in metabolizable energy by 81 kcal and crude protein by 0.43%) diet supplemented with or without 200 mg/kg CrProp. Broilers were euthanized at d 56 after blood collection. The results indicated that the LND diet led to greater average daily feed intake (ADFI) from d 1 to 42 and feed conversion ratio (FCR) from d 22 to 42 (P < 0.05). Supplementation of CrProp improved body weight (BW) from d 1 to 56, average daily gain (ADG), and FCR during d 1 to 42 but reduced ADFI during d 1 to 21, as well as lowered abdominal fat percentage (P < 0.05). Supplementation with CrProp to regular and LND diets reduced ADFI but improved FCR from d 1 to 21 (P < 0.05). The LND diet lowered total antioxidant capacity (T-AOC) concentration and total superoxide dismutase (T-SOD) activity in the jejunal mucosa. CrProp elevated T-AOC levels and glutathione peroxidase activity (GSH-Px, P < 0.05). Dietary CrProp upregulated (P < 0.05) the expression of fatty acid transporter (FABP1) gene and peptide transporter (Pept1) gene. CrProp administration increased jejunal FABP1 expression and lowered cooking loss of breast meat (P < 0.05) in the LND group while reducing shear force (P = 0.009) of broilers treated by regular diet. In summary, CrProp administration to the LND diet can improve growth performance in the starter period and meat quality on d 56, possibly through upregulated nutrient transporter gene expression in the jejunum and enhanced antioxidant capability.
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Antioxidantes , Pollos , Propionatos , Animales , Masculino , Ovinos , Antioxidantes/metabolismo , Suplementos Dietéticos , Dieta/veterinaria , Carne/análisis , Alimentación Animal/análisis , Fenómenos Fisiológicos Nutricionales de los AnimalesRESUMEN
Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for the treatment of OIRR. Parathyroid hormone (PTH) might be a potential therapeutic agent for OIRR, but its effects still lack direct evidence, and the underlying mechanisms remain unclear. This study aims to explore the potential involvement of long noncoding RNAs (lncRNAs) in mediating the anabolic effects of intermittent PTH and contributing to cementum repair, as identifying lncRNA-disease associations can provide valuable insights for disease diagnosis and treatment. Here, we showed that intermittent PTH regulates cell proliferation and mineralization in immortalized murine cementoblast OCCM-30 via the regulation of the Wnt pathway. In vivo, daily administration of PTH is sufficient to accelerate root regeneration by locally inhibiting Wnt/ß-catenin signaling. Through RNA microarray analysis, lncRNA LITTIP (LGR6 intergenic transcript under intermittent PTH) is identified as a key regulator of cementogenesis under intermittent PTH. Chromatin isolation by RNA purification (ChIRP) and RNA immunoprecipitation (RIP) assays revealed that LITTIP binds to mRNA of leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and heterogeneous nuclear ribonucleoprotein K (HnRNPK) protein. Further co-transfection experiments confirmed that LITTIP plays a structural role in the formation of the LITTIP/Lgr6/HnRNPK complex. Moreover, LITTIP is able to promote the expression of LGR6 via the RNA-binding protein HnRNPK. Collectively, our results indicate that the intermittent PTH administration accelerates root regeneration via inhibiting Wnt pathway. The lncRNA LITTIP is identified to negatively regulate cementogenesis, which activates Wnt/ß-catenin signaling via high expression of LGR6 promoted by HnRNPK.
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Cementogénesis , ARN Largo no Codificante , Ratones , Animales , Vía de Señalización Wnt , beta Catenina/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , ARN Largo no Codificante/genética , Hormona Paratiroidea , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Periodontitis is a periodontal inflammatory condition that results from disrupted periodontal host-microbe homeostasis, manifested by the destruction of tooth-supporting structures, especially inflammatory alveolar bone loss. Osteoporosis is characterized by systemic deterioration of bone mass and microarchitecture. The roles of many systemic factors have been identified in the pathogenesis of osteoporosis, including endocrine change, metabolic disorders, health-impaired behaviors and mental stress. The prevalence rate of osteoporotic fracture is in sustained elevation in the past decades. Recent studies suggest that individuals with concomitant osteoporosis are more vulnerable to periodontal impairment. Current reviews of worse periodontal status in the context of osteoporosis are limited, mainly centering on the impacts of menopausal and diabetic osteoporosis on periodontitis. Herein, this review article makes an effort to provide a comprehensive view of the relationship between osteoporosis and periodontitis, with a focus on clarifying how those risk factors in osteoporotic populations modify the alveolar bone homeostasis in the periodontitis niche.
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Pérdida de Hueso Alveolar , Osteoporosis , Enfermedades Periodontales , Periodontitis , Humanos , Densidad Ósea , Osteoporosis/complicaciones , Periodontitis/complicaciones , Pérdida de Hueso Alveolar/complicaciones , Factores de RiesgoRESUMEN
Enterprises need intellectual property rights to protect their core knowledge, and technological diversification is an important strategic measure for enterprises to improve innovation performance. From the perspective of external resource acquisition, this study explores the mechanism of external knowledge acquisition capability (internal absorptive capability and external relational learning) on firm's technological diversification. It considers the impact of firm's innovation capability and external environmental uncertainty. The survey data of 258 Chinese pharmaceutical companies were obtained through questionnaire surveys, and various theoretical hypotheses were validated using regression analysis methods. The results show that internal absorptive capacity, external relational learning, and their interaction have a significant positive impact on technological diversification; the innovation capacity and the uncertainty of the external environment also affect enterprises' technological diversification.
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BACKGROUND: To date, therapeutic approaches for cementum regeneration are limited and outcomes remain unpredictable. A significant barrier to improve therapies for cementum regeneration is that the cementocyte and its intracellular signal transduction mechanisms remain poorly understood. This study aims to elucidate the regulatory mechanism of Wnt pathway in cementogenesis. METHODS: The effects of canonical Wnt signaling were compared in vitro using immortalized murine cementocyte cell line IDG-CM6 and osteocyte cell line IDG-SW3 by quantitative real-time polymerase chain reaction, Western blot, confocal microscopy, alkaline phosphatase (ALP) assay, and Alizarin red S staining. In vivo, histological changes of cementum and bone formation were examined in transgenic mice in which constitutive activation of ß-catenin is driven by Dmp1 promoter. RESULTS: Expression of components of the Wnt/ß-catenin pathway were much greater in the IDG-SW3 cells compared with the IDG-CM6 cells resulting in much lower expression of Sost/sclerostin in the IDG-SW3 cells. In the IDG-CM6 cells, low dose Wnt3a (20 ng/ml) had a modest effect while high dose (200 ng/ml) inhibited runt-related transcription factor 2, osterix, ALP, and osteopontin in contrast to the IDG-SW3 cells where high dose Wnt3a dramatically increased mRNA expression of these same markers. However, high Wnt3a significantly increased mRNA for components of Wnt/ß-catenin signaling pathway in both IDG-CM6 and IDG-SW3 cells. In vivo, constitutive activation of ß-catenin in the Dmp1-lineage cells in mice leads to bone hyperplasia and cementum hypoplasia. CONCLUSION: These findings indicate that Wnt signaling has distinct and different effects on the regulation of long bone as compared with cementum.
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Cementogénesis , Vía de Señalización Wnt , Ratones , Animales , Osteogénesis , beta Catenina/genética , beta Catenina/metabolismo , beta Catenina/farmacología , Diferenciación Celular , Fosfatasa Alcalina/metabolismo , ARN MensajeroRESUMEN
Construction safety standards (CSS) have knowledge characteristics, but few studies have introduced knowledge graphs (KG) as a tool into CSS management. In order to improve CSS knowledge management, this paper first analyzed the knowledge structure of 218 standards and obtained three knowledge levels of CSS. Second, a concept layer was designed which consisted of five levels of concepts and eight types of relationships. Third, an entity layer containing 147 entities was constructed via entity identification, attribute extraction and entity extraction. Finally, 177 nodes and 11 types of attributes were collected and the construction of a knowledge graph of construction safety standard (KGCSS) was completed using knowledge storage. Furthermore, we implemented knowledge inference and obtained CSS planning, i.e., the list of standard work plans used to guide the development and revision of CSS. In addition, we conducted CSS knowledge retrieval; a process which supports interrogative input. The construction of KGCSS thus facilitates the analysis, querying, and sharing of safety standards knowledge.