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1.
Int J Oral Sci ; 15(1): 53, 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38052774

ABSTRACT

Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg-1 of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3-7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities.


Subject(s)
Familial Hypophosphatemic Rickets , Humans , Male , Mice , Animals , Familial Hypophosphatemic Rickets/drug therapy , Familial Hypophosphatemic Rickets/metabolism , Familial Hypophosphatemic Rickets/pathology , Fibroblast Growth Factor-23 , Retrospective Studies , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Bone and Bones/metabolism , Phosphates/metabolism , Phosphates/therapeutic use
2.
Front Physiol ; 14: 1102751, 2023.
Article in English | MEDLINE | ID: mdl-36776964

ABSTRACT

Fibroblast growth factor 23 (FGF23), a hormone, mainly produced by osteocytes, regulates phosphate and vitamin D metabolism. By contrast, 1,25-dihydroxyvitamin D3, the active form of vitamin D, has been shown to enhance FGF23 production. While it is likely that osteocytes are heterogenous in terms of gene expression profiles, specific subpopulations of Fgf23-expressing osteocytes have not been identified. Single-cell RNA sequencing (scRNA-seq) technology can characterize the transcriptome of an individual cell. Recently, scRNA-seq has been used for bone tissue analysis. However, owing to technical difficulties associated with isolation of osteocytes, studies using scRNA-seq analysis to characterize FGF23-producing osteocytes are lacking. In this study, we characterized osteocytes secreting FGF23 from murine femurs in response to calcitriol (1,25-dihydroxyvitamin D3) using scRNA-seq. We first detected Dmp1, Mepe, and Phex expression in murine osteocytes by in situ hybridization and used these as marker genes of osteocytes. After decalcification, enzyme digestion, and removal of CD45+ cells, femoral bone cells were subjected to scRNA-seq. We identified cell clusters containing osteocytes using marker gene expression. While Fgf23 expression was observed in some osteocytes isolated from femurs of calcitriol-injected mice, no Fgf23 expression was detected in untreated mice. In addition, the expression of several genes which are known to be changed after 1,25-dihydroxyvitamin D3 treatment such as Ccnd2, Fn1, Igfbp7, Pdgfa, and Timp1 was also affected by calcitriol treatment in Fgf23-expressing osteocytes, but not in those lacking Fgf23 expression, even after calcitriol administration. Furthermore, box-and-whisker plots indicated that Fgf23 expression was observed in osteocytes with higher expression levels of the Fam20c, Dmp1, and Phex genes, whose inactivating mutations have been shown to cause FGF23-related hypophosphatemic diseases. These results indicate that osteocytes are heterogeneous with respect to their responsiveness to 1,25-dihydroxyvitamin D3, and sensitivity to 1,25-dihydroxyvitamin D3 is one of the characteristics of osteocytes with Fgf23 expression. It is likely that there is a subpopulation of osteocytes expressing several genes, including Fgf23, involved in phosphate metabolism.

3.
Acta Crystallogr C Struct Chem ; 77(Pt 6): 286-290, 2021 Jun 01.
Article in English | MEDLINE | ID: mdl-34089252

ABSTRACT

A novel Ruddlesden-Popper-related compound, Gd3Ba2Fe4O12, was discovered and its crystal structure was determined via single-crystal X-ray diffraction. The structure has an ordered structure of octahedra and pyramids along the c axis. Gd3Ba2Fe4O12 belongs to the tetragonal system P42/ncm, with a = 5.59040 (10) Šand c = 35.1899 (10) Å. The A-site ions in the Ruddlesden-Popper structure, i.e. Gd3+ and Ba2+, exhibit an ordering along the c axis. The perfect oxygen deficiency is accommodated at the GdO layers in the proper Ruddlesden-Popper structure. Using the bond-valence-sum method, the Fe ions in the FeO6 octahedra and FeO5 pyramids represent valence states of +3 and +2.5, respectively, demonstrating a two-dimensional charge disproportionation. The corner-sharing FeO6 octahedra and FeO5 pyramids are tilted in opposite directions, with the neighbours around one axis of the simple perovskite configuration, which, using Glazer's notation, can be represented as a-b0c0/b0a-c0. In the perovskite blocks, the facing FeO5 pyramids across the Gd layer rotate in the same sense, which is a unique rotation feature related to oxygen deficiency.

4.
Nat Prod Commun ; 11(8): 1171-1173, 2016 Aug.
Article in English | MEDLINE | ID: mdl-30725584

ABSTRACT

There are many varieties of tea (Camellia sinensis) obtained by different processing methods. In Japan, sencha tea has been used to brew beverages f6r centuries, and tencha leaves are used to make powdered green tea, matcha, which is used as an important food additive to impart the odor of green tea. We investigated the differences between the odors of sencha and tencha and their aroma profiles. We used our new technique to evaluate the odor of green tea, based on the theory that the aroma characteristics of materials arise from the interactions of groups of compounds with similar structures. Hexane extracts from sencha and tencha leaves were analyzed by gas chromatography-olfactometry. We detected several important compounds for tencha. The hexane extracts were separated by distillation, and groups of compounds with different boiling points were obtained. We investigated the group of high-boiling point constituents, which had a matcha-like odor and consisted of a group of odor constituents common to sencha and tencha. Tencha had a characteristic seaweed-like odor, and the low-boiling point constituents caused the differences in the tencha and sencha odors.


Subject(s)
Camellia sinensis/chemistry , Odorants/analysis , Plant Extracts/chemistry , Plant Leaves/chemistry , Tea/chemistry
5.
Life Sci ; 88(17-18): 798-802, 2011 Apr 25.
Article in English | MEDLINE | ID: mdl-21362430

ABSTRACT

AIMS: Insulinoma-associated protein 2ß (IA-2ß) is considered to play a significant role in regulated secretion. Recent studies have shown that the mouse brain expresses three major isoforms of IA-2ß, named IA-2ß60, IA-2ß64, and IA-2ß71. In this study, we analyzed the tissue-, cell- and organelle-specific distributions of IA-2ß isoforms in mice. MAIN METHODS: To localize IA-2ß expression in mouse tissues and cells, western blot and immunohistochemical analyses were carried out. The subcellular distribution of IA-2ß isoforms was assessed by sedimentation of mouse brain homogenates in a discontinuous sucrose density gradient. KEY FINDINGS: IA-2ß60 was abundant in the cerebrum, cerebellum, medulla oblongata, pancreas, adrenal gland, and pituitary, and in the muscular and mucosal layers of the digestive organs. In contrast, the expression of IA-2ß64 and IA-2ß71 was restricted to the cerebrum, cerebellum, medulla oblongata, and pituitary, and the muscular layers of the digestive organs. Immunohistochemical analysis of mouse pancreatic islets revealed that pancreatic beta cells expressed IA-2ß60 exclusively, whereas alpha and delta cells expressed all three isoforms. By the sedimentation of mouse brain homogenates, it was shown that IA-2ß64 and IA-2ß71 were co-localized with IA-2 on secretory granules, but were absent from synaptic vesicles (SVs). On the other hand, IA-2ß60 was co-localized with synaptophisin on SVs, but was absent from secretory granules. SIGNIFICANCE: The tissue-, cell- and organelle-specific distributions of IA-2ß isoforms suggest that IA-2ß60 has a role in secretion from SVs, whereas IA-2ß64 and IA-2ß71 are involved in secretion from secretory granules.


Subject(s)
Receptor-Like Protein Tyrosine Phosphatases, Class 8/metabolism , Adrenal Glands/metabolism , Animals , Blotting, Western , Cerebellum/metabolism , Cerebrum/metabolism , Medulla Oblongata/metabolism , Mice , Muscle, Smooth/metabolism , Pancreas/metabolism , Pituitary Gland/metabolism , Protein Isoforms/metabolism , Subcellular Fractions/metabolism
6.
Int J Mol Med ; 24(1): 23-7, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19513530

ABSTRACT

Insulinoma-associated protein 2 (IA-2) is the major autoantigen that contributes to the pathogenesis of type 1 diabetes (T1D). IA-2-deficient (IA-2-/-) mice showed impaired insulin secretion after intraperitoneal injection of glucose as well as elevated glucose level in a glucose tolerance test. Despite the fact that 70% of newly diagnosed T1D patients have an antibody against IA-2, the role of IA-2 in the pathogenesis of T1D is largely unknown. In this study, the sensitivity to diabetes induced by streptozotocin (STZ) of IA-2-/- mice was compared with that of wild-type (WT) mice. STZ injection to IA-2-/- mice caused significant elevation of blood glucose and depressed insulin concentration in the pancreas. Furthermore, abnormal ultrastructure in the beta cells of the IA-2-/- mice was revealed by electron microscopy, showing a decreased number of insulin containing vesicles and dilation of the ER-Golgi complex. These results demonstrated that IA-2-/- mice had higher sensitivity to STZ, suggesting a role of IA-2 not only in the secretion but also in the production of insulin.


Subject(s)
Autoantigens/physiology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/metabolism , Receptor-Like Protein Tyrosine Phosphatases, Class 8/physiology , Streptozocin , Animals , Autoantigens/genetics , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Insulin/blood , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/ultrastructure , Male , Mice , Mice, Knockout , Receptor-Like Protein Tyrosine Phosphatases, Class 8/genetics
7.
Neurosci Lett ; 446(1): 11-5, 2008 Nov 28.
Article in English | MEDLINE | ID: mdl-18809465

ABSTRACT

The neuroprotective function of prion protein (PrP) was revealed first by the fact that reintroduction of the mouse prion protein gene (Prnp) into a mouse Prnp(-/-) neuronal cell line, HpL3-4, could prevent apoptosis induced by serum deprivation. In the present study, the anti-apoptotic activities of mouse, hamster, and bovine PrP were compared by expressing mouse PrP (MoPrP), hamster PrP (HaPrP), and bovine PrP (BoPrP) in HpL3-4 cells, respectively. Morphological analysis and DNA fragmentation assays demonstrated that HpL3-4 cells expressing HaPrP, BoPrP, and empty vector (EM) showed the typical features of apoptosis with DNA laddering and apoptotic bodies after serum deprivation, whereas HpL3-4 cells expressing MoPrP showed decreased levels of apoptosis in comparison. The levels of histone-associated DNA fragments (mono- and oligonucleosomes) in the cytosol fractions of the cells correlated with the levels of DNA laddering. These results indicate a species-specific anti-apoptotic function of PrP exists, suggesting that the interaction of the mouse PrP with mouse host factors is required for its anti-apoptotic activity.


Subject(s)
Apoptosis/physiology , Neurons/metabolism , Prions/physiology , Animals , Apoptosis/drug effects , Apoptosis/genetics , Blotting, Western , Cattle , Cell Line , Cricetinae , Culture Media, Serum-Free , DNA Fragmentation/drug effects , Mice , Mice, Knockout , Neurons/cytology , Polymerase Chain Reaction , Prions/genetics , Prions/metabolism , Species Specificity , Statistics as Topic , Transfection/methods
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