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1.
Methods Mol Biol ; 2763: 395-401, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38347429

RESUMO

Saliva is crucial to maintaining oral health and facilitating chewing, swallowing, and speech functions. Decreased saliva secretion, known as hyposalivation, impairs these functions and increases the risk of dental caries and other infectious diseases in the oral cavity.Saliva exhibits various rheological properties, with mucin being a factor in determining these properties. Alterations in these properties can also affect the sensation of dry mouth. In this article, we focus on the spinnbarkeit of saliva using the Neva Meter instrument and provide a methodology for fully understanding the appropriate conditions for its use.


Assuntos
Cárie Dentária , Xerostomia , Humanos , Saliva , Reologia
2.
Dev Biol ; 509: 1-10, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38311164

RESUMO

Saliva is vital to oral health, fulfilling multiple functions in the oral cavity. Three pairs of major salivary glands and hundreds of minor salivary glands contribute to saliva production. The secretory acinar cells within these glands include two distinct populations. Serous acinar cells secrete a watery saliva containing enzymes, while mucous acinar cells secrete a more viscous fluid containing highly glycosylated mucins. Despite their shared developmental origins, the parotid gland (PG) is comprised of only serous acinar cells, while the sublingual gland (SLG) contains predominantly mucous acinar cells. The instructive signals that govern the identity of serous versus mucous acinar cell phenotypes are not yet known. The homeobox transcription factor Nkx2.3 is uniquely expressed in the SLG. Disruption of the Nkx2.3 gene was reported to delay the maturation of SLG mucous acinar cells. To examine whether Nkx2.3 plays a role in directing the mucous cell phenotype, we analyzed SLG from Nkx2.3-/- mice using RNAseq, immunostaining and proteomic analysis of saliva. Our results indicate that Nkx2.3, most likely in concert with other transcription factors uniquely expressed in the SLG, is a key regulator of the molecular program that specifies the identity of mucous acinar cells.


Assuntos
Proteômica , Fatores de Transcrição , Camundongos , Animais , Fatores de Transcrição/genética , Glândulas Salivares , Glândula Sublingual , Glândula Parótida , Proteínas de Homeodomínio/genética
3.
Int J Oral Maxillofac Implants ; 38(3): 516-522, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37279219

RESUMO

PURPOSE: Although immediate-loading implant (ILI) treatment is a general treatment strategy for fully edentulous maxillae, long-term evidence is required. The purpose of this study was to evaluate the long-term clinical results of, and risk factors for, ILI treatment in fully edentulous maxillae. MATERIALS AND METHODS: ILI treatments of maxillae using 526 implants in 117 patients were reviewed retrospectively. The longest and mean observation periods were 15 years and 9.2 years, respectively. Kaplan-Meier survival curve analysis, log-rank tests, and multilevel mixed-effects parametric survival analysis were used for statistical analyses. RESULTS: Overall, 38 of 526 implants failed in 23 patients, and the estimated 15-year cumulative implant-level and patient-level survival rates were 90.7% and 73.7%, respectively. The cumulative implant survival rate was significantly higher in female patients than in male patients. Sex, implant length, and implant diameter were significantly associated with implant survival. CONCLUSION: ILI treatment of completely edentulous maxillae demonstrated viable long-term clinical outcomes. Male sex, shorter implant length, and narrow implant diameter negatively affected implant survival. Int J Oral Maxillofac Implants 2023;38:516-522. doi: 10.11607/jomi.10310.


Assuntos
Implantes Dentários , Carga Imediata em Implante Dentário , Arcada Edêntula , Boca Edêntula , Humanos , Masculino , Feminino , Estudos Retrospectivos , Análise Multinível , Maxila/cirurgia , Carga Imediata em Implante Dentário/métodos , Arcada Edêntula/cirurgia , Boca Edêntula/cirurgia , Prótese Dentária Fixada por Implante , Falha de Restauração Dentária , Seguimentos , Resultado do Tratamento
4.
J Prosthodont Res ; 2023 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-37211410

RESUMO

PURPOSE: This study aimed to investigate the effects of chronic kidney disease (CKD) on the structural and mechanical properties of the maxillary and mandibular cortical bone. METHODS: The maxillary and mandibular cortical bones from CKD model rats were used in this study. CKD-induced histological, structural, and micro-mechanical alterations were assessed using histological analyses, micro-computed tomography (CT), bone mineral density (BMD) measurements, and nanoindentation tests. RESULTS: Histological analyses indicated that CKD caused an increase in the number of osteoclasts and a decrease in the number of osteocytes in the maxilla. Micro-CT analysis revealed that CKD induced a void volume/cortical volume (%) increase, which was more remarkable in the maxilla than in the mandible. CKD also significantly decreased the BMD in the maxilla. In the nanoindentation stress-strain curve, the elastic-plastic transition point and loss modulus were lower in the CKD group than that in the control group in the maxilla, suggesting that CKD increased micro fragility of the maxillary bone. CONCLUSIONS: CKD affected bone turnover in the maxillary cortical bone. Furthermore, the maxillary histological and structural properties were compromised, and micro-mechanical properties, including the elastic-plastic transition point and loss modulus, were altered by CKD.

5.
Int J Implant Dent ; 8(1): 50, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36316516

RESUMO

PURPOSE: The purpose of this study was to investigate serum undercarboxylated osteocalcin (ucOC) levels in partially edentulous patients scheduled to receive implant treatment and determine the association between ucOC levels, vegetable intake, vitamin K, dietary fiber intake, and functional tooth number in the posterior region (p-FTN). METHODS: A total of 46 patients (20 male and 26 female, 61.9 ± 12.7 years old) were included. The association among serum ucOC levels, vegetable intake, vitamin K and dietary fiber intake was assessed using Spearman's rank correlation coefficient and binary logistic regression analysis. RESULTS: In total, 35% of patients (16/46 subjects) showed an abnormally high ucOC level (≧ 4.5 ng/mL). p-FTN showed a weak positive correlation with vegetable intake, vitamin K and dietary fiber intake (r = 0.28, 0.21, and 0.14, respectively) and a significant negative correlation with ucOC levels (r = - 0.51). Multivariate analysis demonstrated that p-FTN as well as vitamin K intake showed a significant negative association with serum ucOC levels. CONCLUSIONS: More than one-third of patients showed abnormally high ucOC levels. p-FTN showed a negative association with serum ucOC levels, which indicated the possibility that oral status affected bone quality.


Assuntos
Estado Nutricional , Vitamina K , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Osteocalcina , Osso e Ossos , Fibras na Dieta
6.
J Prosthodont Res ; 66(4): 582-588, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34924491

RESUMO

PURPOSE: The present study was performed to examine the mandibular deformation during mouth opening in edentulous patients, treated with an implant-supported fixed prosthesis using strain gauges, and identify factors affecting deformation. METHODS: Twenty patients with a fully edentulous mandible who received either 4 or ≥6 implants were included. The distal-most implants were placed mesial to the mental foramen (premolar region) in patients with 4 implants and distal to the mental foramen (molar region) in patients with ≥6 implants. Mandibular deformation during mouth opening was measured using strain gauges in two directions: anteroposterior direction and lateral direction between the distal-most implants on the left and right sides (arch width). The mandibular anatomy was evaluated using computed tomography. RESULTS: Arch width reduction between the left and right implants during mouth opening ranged from 47.38 to 512.80 µm; the range of deformation was 0.12 to 15.14 µm in the anteroposterior direction. Furthermore, a significant positive correlation was noted between arch width reduction in the premolar region and the ratio between the symphyseal bone height and width (P = 0.0003, r = 0.72). CONCLUSION: The reduction in arch width was higher in the molar region than in the premolar region during mouth opening. Moreover, the reduction could be high in the mandibular symphyseal bone because of its greater height and lesser width. The ratio between the symphyseal bone height and width is defined as the mandibular deformation index (MDI) and is used to predict the rate of mandibular bone deformation.


Assuntos
Implantes Dentários , Arcada Edêntula , Boca Edêntula , Implantação Dentária Endóssea/métodos , Implantes Dentários/efeitos adversos , Prótese Dentária Fixada por Implante/efeitos adversos , Humanos , Arcada Edêntula/cirurgia , Mandíbula/cirurgia
7.
J Mech Behav Biomed Mater ; 120: 104571, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34029943

RESUMO

The loss of bone quantity and quality in postmenopausal female patients can be a problem for dental treatment. A sufficient intake of nutrients such as calcium, magnesium, and vitamins D and K is likely correlated with the mechanical properties of bone. In particular, vitamin K2, also called menaquinone (MK), inhibits bone loss in postmenopausal women. Here we demonstrate the microstructural and mechanical properties of bone recovery in ovariectomized (OVX) rats during MK-7 administration. Bilateral ovariectomy and a sham operation were performed on 14-week-old female SPF Wistar rats. MK-4 and -7 were orally administered at 30 mg/kg daily for 12 weeks. The femur was used for the 3-point bending test and microstructural analysis of the cancellous bone by micro-CT, and the mandibular cortical bone for the evaluation of mechanical properties on a nanoscale. Micro-computed tomography revealed irregular trabecular architecture, hollow marrow cavities, and sparse trabecular bone in the femurs of the OVX group. Trabecular bone structure analysis showed that the MK-7 group had greater bone volume per tissue volume (BV/TV) and a higher trabecular number than the OVX group. The bulk-scale 3-point bending test did not allow the mechanical properties between OVX and OVX/MK7 groups to be discerned, yet at the smallest level, the elastic-plastic transition point of the nanoindentation stress-strain curve of the mandibular cortical bone was higher in the MK-7 group than in the OVX group. These findings suggest that MK-7 enables bone microstructural and mechanical recovery in the OVX model.


Assuntos
Densidade Óssea , Animais , Feminino , Humanos , Ovariectomia , Ratos , Ratos Wistar , Vitamina K 2/análogos & derivados , Vitamina K 2/farmacologia , Microtomografia por Raio-X
8.
Sci Rep ; 11(1): 8950, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33903607

RESUMO

Reconstruction of a critical-sized osseous defect is challenging in maxillofacial surgery. Despite novel treatments and advances in supportive therapies, severe complications including infection, nonunion, and malunion can still occur. Here, we aimed to assess the use of a beta-tricalcium phosphate (ß-TCP) scaffold loaded with high mobility group box-1 protein (HMGB-1) as a novel critical-sized bone defect treatment in rabbits. The study was performed on 15 specific pathogen-free New Zealand rabbits divided into three groups: Group A had an osseous defect filled with a ß-TCP scaffold loaded with phosphate-buffered saline (PBS) (100 µL/scaffold), the defect in group B was filled with recombinant human bone morphogenetic protein 2 (rhBMP-2) (10 µg/100 µL), and the defect in group C was loaded with HMGB-1 (10 µg/100 µL). Micro-computed tomography (CT) examination demonstrated that group C (HMGB-1) showed the highest new bone volume ratio, with a mean value of 66.5%, followed by the group B (rhBMP-2) (31.0%), and group A (Control) (7.1%). Histological examination of the HMGB-1 treated group showed a vast area covered by lamellar and woven bone surrounding the ß-TCP granule remnants. These results suggest that HMGB-1 could be an effective alternative molecule for bone regeneration in critical-sized mandibular bone defects.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Proteína HMGB1/farmacologia , Mandíbula/metabolismo , Traumatismos Mandibulares/tratamento farmacológico , Animais , Fosfatos de Cálcio/farmacologia , Humanos , Masculino , Mandíbula/patologia , Traumatismos Mandibulares/mortalidade , Traumatismos Mandibulares/patologia , Coelhos
9.
J Prosthodont Res ; 65(2): 219-224, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32938854

RESUMO

PURPOSE: In this study, we aimed to investigate the effect of glucose metabolism on bone healing after tooth extraction in an osteoporosis rat model administered zoledronic acid (ZA) and dexamethasone (DX). METHODS: In total, 24 male Wistar rats (4 weeks old) were randomly assigned to four groups: Control (subcutaneous physiological saline), ZD (subcutaneous ZA and DX twice a week), Ins+ZD (subcutaneous insulin followed by ZD treatment), and Met+ZD (oral metformin followed by ZD treatment). Blood was collected every two weeks . Two weeks after treatment initiation, the first molar tooth on the right maxilla was extracted from all rats. Four weeks later, the rats were sacrificed, and bone healing was assessed. Maxillae samples were fixed and scanned using micro-computed tomography for quantifying areas of bone defects. Hematoxylin-eosin and tartrate-resistant acid phosphatase (TRAP) staining were performed to evaluate bone apoptosis and osteoclast number. RESULTS: In all experimental groups, body weight was statistically lower than that in the Control group, with no changes observed in uncarboxylated osteocalcin concentrations. The radiological analysis revealed that insulin or metformin administration improved healing in the tooth extraction socket (p < 0.01). Histological examination revealed that the osteonecrosis area was reduced in the Ins+ZD and Met+ZD groups (p < 0.01). TRAP staining presented increased osteoclast numbers in the ZD group when compared with that observed in the Control. CONCLUSIONS: Tooth extraction with long-term ZA and DX administration inhibited bone remodeling and induced bisphosphonate-related osteonecrosis of the jaw-like lesions. Metformin exerted protective effects ag ainst osteonecrosis of the jaw.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Metformina , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Difosfonatos , Imidazóis , Masculino , Ratos , Ratos Wistar , Extração Dentária , Microtomografia por Raio-X
10.
J Cell Physiol ; 235(11): 8533-8545, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32329061

RESUMO

The widely expressed Anoctamin 6 (Ano6) supports different Ca2+ -dependent functions, but little is known about its role in salivary glands. Mouse submandibular gland (SMG) acinar cells exhibited a robust regulatory volume decrease (RVD) following cell swelling that was reduced approximately 70% in Ano6-/- mice. Ca2+ -free conditions nearly eliminated the RVD response suggesting that Ano6 is an obligatory component of the cell volume-activated, Ca2+ -dependent RVD pathway in salivary gland acinar cells. Ex vivo agonist-stimulated secretion of water and ions was unaffected by Ano6 disruption under both isotonic and hypotonic conditions suggesting that Ano6 does not play a major role in fluid and electrolyte secretion. In contrast, the total amount of ß-adrenergic-dependent protein secretion by the SMG was significantly reduced in Ano6-/- mice. Closer inspection of these latter results revealed that protein secretion was affected only in the female SMG by Ano6 disruption. These results indicate that Ano6 modulates the RVD response and protein secretion by salivary gland acinar cells.


Assuntos
Células Acinares/metabolismo , Anoctaminas/metabolismo , Tamanho Celular , Proteínas de Transferência de Fosfolipídeos/metabolismo , Saliva/metabolismo , Animais , Anoctamina-1/metabolismo , Canais de Cloreto/metabolismo , Cloretos/metabolismo , Camundongos Knockout , Glândulas Salivares , Glândula Submandibular/metabolismo
11.
J Prosthodont Res ; 64(2): 217-223, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31852608

RESUMO

PURPOSE: We assessed the effects of hyperglycaemia induced by streptozotocin (STZ) on peri-implantitis developing after implant osseointegration. METHODS: Thirty-six male Wistar rats (4 weeks old) were used. We placed titanium implants 4 weeks after extraction of the maxillary first molars. Healing abutments were attached 4 weeks later. After osseointegration was confirmed, the rats were divided into control, hyperglycaemia (STZ), and STZ with insulin (STZ+INS) groups. Hyperglycaemia was induced by a single injection of 50mg/kg STZ. Silk ligatures were placed on only the right sides (i.e. ligature sides), not on the left sides. Peri-implant tissues extracted at 4 weeks post-ligation were analysed both radiologically (via micro-computed tomography) and histologically (via toluidine blue staining). Total RNA was also extracted and analysed by quantitative PCR to detect TNF-α, IL-1ß and the receptor of advanced glycation end products (RAGE). Additionally, advanced glycation end products (AGEs) were measured by ELISA. RESULTS: Radiological and histological analyses showed that bone loss on the non-ligature sides was significantly greater in the STZ than the control group. However, on the ligature sides, bone loss was greater than on the non-ligature sides, and no significant difference was evident among the three groups. The levels of mRNAs encoding TNF-α, IL-1ß, RAGE, and AGEs on the ligature sides were significantly upregulated (all P<0.05) in the STZ compared to the control group. CONCLUSIONS: Although hyperglycaemia could be associated with bone loss around implants with increased AGE production and RAGE expression, hyperglycaemia does not become a triggering factor of ligature induced peri-implantitis.


Assuntos
Perda do Osso Alveolar , Implantes Dentários , Hiperglicemia , Peri-Implantite , Animais , Masculino , Osseointegração , Ratos , Ratos Wistar , Microtomografia por Raio-X
12.
J Biol Chem ; 295(5): 1411-1425, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31882545

RESUMO

The importance of the microbiome in health and its disruption in disease is continuing to be elucidated. However, the multitude of host and environmental factors that influence the microbiome are still largely unknown. Here, we examined UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 3 (Galnt3)-deficient mice, which serve as a model for the disease hyperphosphatemic familial tumoral calcinosis (HFTC). In HFTC, loss of GALNT3 activity in the bone is thought to lead to altered glycosylation of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23), resulting in hyperphosphatemia and subdermal calcified tumors. However, GALNT3 is expressed in other tissues in addition to bone, suggesting that systemic loss could result in other pathologies. Using semiquantitative real-time PCR, we found that Galnt3 is the major O-glycosyltransferase expressed in the secretory cells of salivary glands. Additionally, 16S rRNA gene sequencing revealed that the loss of Galnt3 resulted in changes in the structure, composition, and stability of the oral microbiome. Moreover, we identified the major secreted salivary mucin, Muc10, as an in vivo substrate of Galnt3. Given that mucins and their O-glycans are known to interact with various microbes, our results suggest that loss of Galnt3 decreases glycosylation of Muc10, which alters the composition and stability of the oral microbiome. Considering that oral findings have been documented in HFTC patients, our study suggests that investigating GALNT3-mediated changes in the oral microbiome may be warranted.


Assuntos
Calcinose/metabolismo , Calcinose/microbiologia , Hiperostose Cortical Congênita/metabolismo , Hiperostose Cortical Congênita/microbiologia , Hiperfosfatemia/metabolismo , Hiperfosfatemia/microbiologia , Microbiota/genética , N-Acetilgalactosaminiltransferases/metabolismo , Glândulas Salivares/metabolismo , Animais , Calcinose/genética , Feminino , Fator de Crescimento de Fibroblastos 23 , Glicosilação , Glicosiltransferases/metabolismo , Hiperostose Cortical Congênita/genética , Hiperfosfatemia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/química , Mucinas/metabolismo , N-Acetilgalactosaminiltransferases/genética , Polissacarídeos/metabolismo , RNA Ribossômico 16S/genética
13.
Physiol Rep ; 7(23): e14232, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31833218

RESUMO

Slc4a11, a member of the Slc4 HCO3- transporter family, has a wide tissue distribution. In mouse salivary glands, the expression of Slc4a11 mRNA was more than eightfold greater than the other nine members of the Slc4 gene family. The Slc4a11 protein displayed a diffuse subcellular distribution in both the acinar and duct cells of mouse submandibular glands (SMG). Slc4a11 disruption induced a significant increase in the Na+ and Cl- concentrations of stimulated SMG saliva, whereas it did not affect the fluid secretion rate in response to either ß-adrenergic or cholinergic receptor stimulation. Heterologous expressed mouse Slc4a11 acted as a H+ /OH- transporter that was uncoupled of Na+ or Cl- movement, and this activity was blocked by ethyl-isopropyl amiloride (EIPA) but not 4,4'-Diisothiocyanato-2,2'-stilbenedisulfonic acid (DIDS). Slc4a11 disruption revealed that Slc4a11 does not play a major role in intracellular pH regulation in mouse salivary gland cells. In contrast, NaCl reabsorption was impaired in the SMG saliva of female compared to male Slc4a11 null mice, which correlated with the loss of duct cells and a decrease in expression of the duct-cell-specific transcription factor Ascl3. Together, our results suggest that Slc4a11 expression regulates the number of ducts cells in the mouse SMG and consequently NaCl reabsorption.


Assuntos
Absorção Fisiológica , Proteínas de Transporte de Ânions/metabolismo , Prótons , Cloreto de Sódio/metabolismo , Glândula Submandibular/metabolismo , Simportadores/metabolismo , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia , Amilorida/análogos & derivados , Amilorida/farmacologia , Animais , Proteínas de Transporte de Ânions/antagonistas & inibidores , Proteínas de Transporte de Ânions/genética , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Glândula Submandibular/citologia , Simportadores/antagonistas & inibidores , Simportadores/genética
14.
Am J Physiol Cell Physiol ; 317(6): C1153-C1160, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532720

RESUMO

The nonselective anion exchanger Slc26a6, also known as putative anion transporter 1 and chloride/formate exchanger, is thought to play a major role in HCO3- transport in exocrine glands. In this study, Slc26a6 null mice were used to explore the function of Slc26a6 in the exocrine pancreas. Slc26a6 primarily localized to the apical membrane of pancreatic exocrine acinar cells. The volume of stimulated juice secretion by the ex vivo pancreas was significantly reduced ~35% in Slc26a6-/- mice, but no changes occurred in the gross structure or gland weights of Slc26a6 null mice. The secretion of pancreatic juice by Slc26a6+/+ mice was dependent on HCO3- while, in contrast, fluid secretion by Slc26a6-/- mice was independent of HCO3-, suggesting that Slc26a6 mediates the HCO3--dependent component of fluid secretion. Consistent with these observations, disruption of Slc26a6 also significantly reduced HCO3- secretion by the pancreas ~35%. Taken together, these results demonstrate that the apical Slc26a6 anion exchanger in acinar cells is involved in HCO3--dependent fluid secretion but that another major HCO3--independent pathway is the primary driver of the fluid secretion process in the mouse pancreas.


Assuntos
Células Acinares/metabolismo , Antiporters/genética , Bicarbonatos/metabolismo , Líquidos Corporais/metabolismo , Pâncreas Exócrino/metabolismo , Transportadores de Sulfato/genética , Células Acinares/citologia , Animais , Anoctamina-1/genética , Anoctamina-1/metabolismo , Antiporters/deficiência , Aquaporina 5/genética , Aquaporina 5/metabolismo , Peso Corporal , Linhagem Celular , Membrana Celular/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Transporte de Íons , Masculino , Camundongos , Camundongos Knockout , Técnicas de Cultura de Órgãos , Tamanho do Órgão , Pâncreas Exócrino/citologia , Membro 2 da Família 12 de Carreador de Soluto/genética , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Transportadores de Sulfato/deficiência
15.
Proc Natl Acad Sci U S A ; 116(37): 18684-18690, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451647

RESUMO

Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic ß cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured ß cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by ß-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in ß cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M3/efeitos dos fármacos , Acetilcolina/metabolismo , Adulto , Regulação Alostérica/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular Tumoral , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , Pessoa de Meia-Idade , Agonistas Muscarínicos/uso terapêutico , Obesidade/sangue , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Cultura Primária de Células , Estudo de Prova de Conceito , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Adulto Jovem
16.
J Mech Behav Biomed Mater ; 98: 20-25, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31176091

RESUMO

Initial intimate apposition between implant fixtures and host bone at the surgical site is a critical factor for osseointegration of dental implants. The advanced glycation end products accumulated in the jaw bone could lead to potential failure of a dental implant during the initial integration stage, because of the inferior bone mechanical property associated with the abnormal collagen cross-linking at the material level. Here, we demonstrate the lowered creep deformation resistance and reduced dimensional recovery of jaw bone in line with high levels of pentosidine accumulation in the bone matrix which likely correlate with the pentosidine level in blood plasma. Peripheral blood samples and cortical bone samples at the surgical site were obtained from patients scheduled for dental implants in the mandible. The pentosidine levels in blood plasma were assessed. Subsequently, the relative pentosidine levels and the mechanical properties of the jaw bone were quantified by Raman microspectroscopy and nanoindentation, respectively. The nanoindentation tests revealed less creep deformation resistance and reduced time-dependent dimensional recovery of bone samples with the increase in the relative pentosidine level in the bone matrix. Higher tan δ values at the various frequencies during the dynamic indentation tests also suggested that viscoelasticity is associated with the relative intensity of pentosidine in the jaw bone matrix. We found a positive correlation between the pentosidine levels in blood plasma and the bone matrix, which in turn reduced the mechanical property of the jaw bone at the material level. Increased creep and reduced dimensional recovery of the jaw bone may diminish the mechanical interlocking of dental implants during the initial integration stage. Given the likely correlation between the plasma pentosidine level and the mechanical properties of bone, measurement of the plasma pentosidine level could serve as a new index to assess jaw bone matrix quality in advance of implant surgery.


Assuntos
Arginina/análogos & derivados , Arcada Osseodentária/metabolismo , Lisina/análogos & derivados , Teste de Materiais , Fenômenos Mecânicos , Nanotecnologia , Arginina/metabolismo , Fenômenos Biomecânicos , Humanos , Arcada Osseodentária/fisiologia , Lisina/metabolismo
17.
FEBS Open Bio ; 9(5): 947-958, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30998297

RESUMO

Transcriptional profiling identified 933 sexually dimorphic genes out of the 14 371 protein-coding genes expressed in the three major murine salivary glands: parotid, sublingual, and submandibular. Most (89%) sex-specific genes were enriched in a single gland, while only 0.5% of the sexually dimorphic genes were enriched in all glands. The sublingual gland displayed a strong male sex bias (94% of sex-enriched genes), while a sex preference was not obvious in the parotid or submandibular glands. A subset of transcription factor genes was correlated with the expression of gland-specific, sex-enriched genes. Higher expression of Cftr chloride and Scnn1 sodium channels in the male submandibular correlated with greater NaCl reabsorption. In conclusion, adult salivary glands display sex- and gland-specific differences in gene expression that reflect their unique functional properties.


Assuntos
Glândula Parótida/metabolismo , Glândula Sublingual/metabolismo , Glândula Submandibular/metabolismo , Transcriptoma , Animais , Feminino , Masculino , Camundongos , Caracteres Sexuais
18.
J Prosthodont Res ; 63(4): 411-414, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31006561

RESUMO

PURPOSE: This study investigated changes in food and nutrient intake after implant-supported fixed prosthesis treatment in patients with partial edentulous posterior regions. METHODS: This study included 30 patients who received implant treatment with fixed prostheses in the posterior region. Food and nutrient intake was evaluated using a brief self-administered diet history questionnaire at baseline and post-implant treatment, and the results were statistically analyzed. RESULTS: Treatment with implant-supported fixed prostheses in patients with posterior edentulous conditions tended to increase the amounts of soy products and vegetables consumed: in particular, intake of carrot and squash was significantly increased. The total energy, protein, lipid, and carbohydrate intakes were comparable between baseline and post-implant treatment. On the other hand, the vegetable protein, α-carotene, daidzein, and genistein intakes were significantly increased, and dietary fiber and ß-carotene intakes tended to be increased in patients with implant-supported fixed prostheses. CONCLUSIONS: Implant-supported fixed prostheses in patients with posterior edentulous conditions affected food intake, resulting in improved nutrient intake.


Assuntos
Implantes Dentários , Arcada Edêntula , Boca Edêntula , Prótese Dentária Fixada por Implante , Falha de Restauração Dentária , Seguimentos , Humanos , Nutrientes
19.
Int J Implant Dent ; 5(1): 7, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30911853

RESUMO

BACKGROUND: The aim of this study was to evaluate the plaque removal efficacies of electric toothbrushes and electric dental floss compared with conventional manual toothbrushing in cleaning the fitting surface of an All-on-4™ concept (Nobel Biocare, Zürich-Flughafen, Switzerland) implant-supported fixed dental prosthesis (FDP). METHODS: Nine patients with maxillary edentulous arches participated in the study. We investigated two electric-powered brushes (Sonicare Diamond Clean®, Koninklijke Philips N.V., Amsterdam, the Netherlands [SD group], and the Oral-B Professional Care Smart Series 5000®, Braun GmbH, Kronberg, Germany [OralB group]) and one electric dental floss unit (Air Floss®, Koninklijke Philips N.V. [AF group]). A manual toothbrush (Tuft24® MS, OralCare Inc., Tokyo, Japan) was used by the control group. The fitting surface of the FDP was stained to allow visualization of the entire accumulated plaque area. Both the buccal and palatal portions of the plaque area were assessed before and after brushing to evaluate each instrument's plaque removal rate using a crossover study design. Two-week washout periods were employed between each evaluation. RESULTS: The plaque removal rates were 53.5 ± 8.5%, 70.9 ± 6.5%, 75.4 ± 6.3%, and 74.4 ± 4.2% for the control, AF, OralB, and SD groups, respectively. When participants were divided into two groups based on their plaque removal rates with a manual toothbrush (poor brushing and good brushing), the poor brushing group showed significant improvement in the plaque removal rate when using electric-powered toothbrushes. The plaque removal rates for the buccal area were significantly higher for the OralB and SD groups than for the manual brushing group (control group), with rates of 52.8 ± 7.9%, 70.1 ± 7.3%, 77.7 ± 6.5%, and 79.5 ± 3.7% for the control, AF, OralB, and SD groups, respectively. The plaque removal rates in the palatal area were consistently lower than those in the buccal area for each of the three electric instruments. CONCLUSIONS: The results suggest that patients who are not adept at manual toothbrushing may potentially improve their removal of plaque from the fitting surfaces of FDPs by using electric toothbrushes.

20.
J Cell Physiol ; 234(9): 16376-16388, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30767201

RESUMO

The HCO3 - secretion mechanism in salivary glands is unclear but is thought to rely on the co-ordinated activity of multiple ion transport proteins including members of the Slc4 family of bicarbonate transporters. Slc4a7 was immunolocalized to the apical membrane of mouse submandibular duct cells. In contrast, Slc4a7 was not detected in acinar cells, and correspondingly, Slc4a7 disruption did not affect fluid secretion in response to cholinergic or ß-adrenergic stimulation in the submandibular gland (SMG). Much of the Na + -dependent intracellular pH (pH i ) regulation in SMG duct cells was insensitive to 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid, S0859, and to the removal of extracellular HCO 3 - . Consistent with these latter observations, the Slc4a7 null mutation had no impact on HCO 3 - secretion nor on pH i regulation in duct cells. Taken together, our results revealed that Slc4a7 targets to the apical membrane of mouse SMG duct cells where it contributes little if any to pH i regulation or stimulated HCO 3 - secretion.

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