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1.
Diabetes Care ; 43(10): 2519-2527, 2020 10.
Article in English | MEDLINE | ID: mdl-32694214

ABSTRACT

OBJECTIVE: To examine the mechanisms responsible for improved glycemia with combined sodium-glucose cotransporter 2 inhibitor (SGLT2i) plus dipeptidyl peptidase 4 inhibitor therapy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Fifty-six patients (HbA1c 8.9 ± 0.2% [74 ± 2 mmol/mol]) were randomized to dapagliflozin (DAPA) 10 mg, DAPA/saxagliptin (SAXA) 10/5 mg, or placebo (PCB) for 16 weeks. Basal endogenous glucose production (EGP) (3-3H-glucose), urinary glucose excretion, glucose/lipid oxidation, HbA1c, and substrate/hormone levels were determined before treatment (Pre-Tx) and after treatment (Post-Tx). RESULTS: At week 16, HbA1c decrease was greater (P < 0.05) in DAPA/SAXA (-2.0 ± 0.3%) vs. DAPA (-1.4 ± 0.2%) and greater than PCB (0.2 ± 0.2%). Day 1 of drug administration, EGP (∼2.40 mg/kg/min) decreased by -0.44 ± 0.09 mg/kg/min in PCB (P < 0.05) but only by -0.21 ± 0.02 mg/kg/min in DAPA and DAPA/SAXA (P < 0.05 vs. PCB). At week 16, EGP increased to 2.67 ± 0.09 mg/kg/min (DAPA) and 2.61 ± 0.08 mg/kg/min (DAPA/SAXA), despite reductions in fasting plasma glucose by 47 and 77 mg/dL, respectively, and no changes in PCB. Baseline plasma free fatty acids rose by 40 µmol/L with DAPA but declined by -110 with PCB and -90 µmol/L with DAPA/SAXA (P < 0.05, Pre-Tx vs. Post-Tx). In DAPA, carbohydrate oxidation rates decreased from 1.1 ± 0.1 to 0.7 ± 0.1 mg/kg/min, whereas lipid oxidation rates increased from 0.6 ± 0.1 to 0.8 ± 0.1 mg/kg/min (P < 0.01). In DAPA/SAXA, the shift in carbohydrate (1.1 ± 0.1 to 0.9 ± 0.1 mg/kg/min) and lipid (0.6 ± 0.1 to 0.7 ± 0.1 mg/kg/min) oxidation was attenuated (P < 0.05). CONCLUSIONS: The addition of SAXA to DAPA resulted in superior glycemic control compared with DAPA monotherapy partly because of increased glucose utilization and oxidation. Although the decrease in insulin/glucagon ratio was prevented by SAXA, EGP paradoxical elevation persisted, indicating that other factors mediate EGP changes in response to SGLT2i-induced glucosuria.


Subject(s)
Adamantane/analogs & derivatives , Benzhydryl Compounds/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/administration & dosage , Glucose/metabolism , Glucosides/administration & dosage , Adamantane/administration & dosage , Adamantane/adverse effects , Adult , Benzhydryl Compounds/adverse effects , Blood Glucose/drug effects , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Dipeptides/adverse effects , Double-Blind Method , Drug Therapy, Combination , Energy Metabolism/drug effects , Female , Glucosides/adverse effects , Glycated Hemoglobin/drug effects , Glycated Hemoglobin/metabolism , Glycosuria/urine , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Kinetics , Male , Middle Aged , Oxidation-Reduction/drug effects
2.
Nat Commun ; 10(1): 4720, 2019 10 17.
Article in English | MEDLINE | ID: mdl-31624249

ABSTRACT

Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.


Subject(s)
Adipose Tissue/metabolism , Genes, Tumor Suppressor , Insulin Resistance/genetics , Liver/metabolism , Membrane Proteins/genetics , Adipogenesis/genetics , Animals , Diet, High-Fat , Gene Expression Profiling/methods , Gluconeogenesis/genetics , Humans , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Organ Specificity/genetics
4.
Hum Mol Genet ; 27(10): 1794-1808, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29547888

ABSTRACT

The TMEM127 tumor suppressor gene encodes a transmembrane protein of unknown function mutated in pheochromocytomas and, rarely, in renal cancers. Tumors with inactivating TMEM127 mutations have increased mTORC1 signaling by undefined mechanisms. Here we report that TMEM127 interacts with the lysosome-anchored complex comprised of Rag GTPases, the LAMTOR pentamer (or 'ragulator') and vATPase, which controls amino acid-mediated mTORC1 activation. We found that under nutrient-rich conditions TMEM127 expression reduces mTORC1 recruitment to Rags. In addition, TMEM127 interacts with LAMTOR in an amino acid-dependent manner and decreases the LAMTOR1-vATPase association, while TMEM127-vATPase binding requires intact lysosomal acidification but is amino acid independent. Conversely, both murine and human cells lacking TMEM127 accumulate LAMTOR proteins in the lysosome. Consistent with these findings, pheochromocytomas with TMEM127 mutations have increased levels of LAMTOR proteins. These results suggest that TMEM127 interactions with ragulator and vATPase at the lysosome contribute to restrain mTORC1 signaling in response to amino acids, thus explaining the increased mTORC1 activation seen in TMEM127-deficient tumors.


Subject(s)
Adrenal Gland Neoplasms/genetics , Carrier Proteins/genetics , Membrane Proteins/genetics , Pheochromocytoma/genetics , Adrenal Gland Neoplasms/metabolism , Adrenal Gland Neoplasms/pathology , Amino Acids/genetics , Animals , Gene Expression Regulation , Genes, Tumor Suppressor , Humans , Intracellular Signaling Peptides and Proteins , Lysosomes/genetics , Lysosomes/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mice , Multiprotein Complexes/genetics , Mutation , Pheochromocytoma/metabolism , Pheochromocytoma/pathology , Signal Transduction
5.
Inorg Chem ; 57(5): 2381-2385, 2018 Mar 05.
Article in English | MEDLINE | ID: mdl-29457720

ABSTRACT

Anion- and solvent-induced single-crystal-to-single-crystal transformation within an iron(II) triazole system has been generated from {[Fe(TPPT)2Cl2]·CHCl3} n (1a) to [Fe(TPPT)(C2O4)0.5Cl(H2O)] n (1b). Luminescence studies indicated that the resultant 1b can be considered as a promising luminescent probe for CrO42- and cyano molecules.

7.
Clin Cancer Res ; 22(9): 2301-10, 2016 05 01.
Article in English | MEDLINE | ID: mdl-26700204

ABSTRACT

PURPOSE: Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. EXPERIMENTAL DESIGN: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was subjected to microarray-based transcription, protein expression, and histone methylation analysis by Western blotting or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. RESULTS: We detected mutations in chromatin-remodeling genes, including histone-methyltransferases, histone-demethylases, and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes, mutations were also detected in the validation group. In addition, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. CONCLUSIONS: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes. Clin Cancer Res; 22(9); 2301-10. ©2015 AACR.


Subject(s)
Chromatin Assembly and Disassembly/genetics , Chromatin/genetics , Germ-Line Mutation/genetics , Paraganglioma/genetics , Pheochromocytoma/genetics , Adolescent , Adrenal Gland Neoplasms/genetics , Adult , Aged , Carcinoma, Neuroendocrine/genetics , Child , Exome/genetics , Female , Giant Cell Tumor of Bone/genetics , Histone Demethylases/genetics , Histone Methyltransferases , Histone-Lysine N-Methyltransferase/genetics , Histones/genetics , Humans , Male , Middle Aged , Thyroid Neoplasms/genetics , Young Adult , c-Mer Tyrosine Kinase/genetics
8.
Nat Commun ; 6: 7768, 2015 Jul 16.
Article in English | MEDLINE | ID: mdl-26178471

ABSTRACT

Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α-KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.


Subject(s)
Alcohol Oxidoreductases/genetics , Dioxygenases/metabolism , Gene Expression Regulation, Neoplastic , Isocitrate Dehydrogenase/genetics , Ketoglutaric Acids/metabolism , Lymphoma, Large B-Cell, Diffuse/genetics , Blotting, Western , Cell Line, Tumor , DNA Methylation/genetics , Epigenesis, Genetic , HEK293 Cells , Histones/metabolism , Humans , Hydroxylation/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Isocitrate Dehydrogenase/metabolism , Methylation , Real-Time Polymerase Chain Reaction
9.
Endocr Relat Cancer ; 20(3): 349-59, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23533246

ABSTRACT

Pheochromocytomas and paragangliomas are highly vascular tumors of the autonomic nervous system. Germline mutations, including those in hypoxia-related genes, occur in one third of the cases, but somatic mutations are infrequent in these tumors. Using exome sequencing of six paired constitutive and tumor DNA from sporadic pheochromocytomas and paragangliomas, we identified a somatic mutation in the HIF2A (EPAS1) gene. Screening of an additional 239 pheochromocytomas/paragangliomas uncovered three other HIF2A variants in sporadic (4/167, 2.3%) but not in hereditary tumors or controls. Three of the mutations involved proline 531, one of the two residues that controls HIF2α stability by hydroxylation. The fourth mutation, on Ser71, was adjacent to the DNA binding domain. No mutations were detected in the homologous regions of the HIF1A gene in 132 tumors. Mutant HIF2A tumors had increased expression of HIF2α target genes, suggesting an activating effect of the mutations. Ectopically expressed HIF2α mutants in HEK293, renal cell carcinoma 786-0, or rat pheochromocytoma PC12 cell lines showed increased stability, resistance to VHL-mediated degradation, target induction, and reduced chromaffin cell differentiation. Furthermore, mice injected with cells expressing mutant HIF2A developed tumors, and those with Pro531Thr and Pro531Ser mutations had shorter latency than tumors from mice with wild-type HIF2A. Our results support a direct oncogenic role for HIF2A in human neoplasia and strengthen the link between hypoxic pathways and pheochromocytomas and paragangliomas.


Subject(s)
Adrenal Gland Neoplasms/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Paraganglioma/genetics , Pheochromocytoma/genetics , Adrenal Gland Neoplasms/pathology , Aged , Animals , Child , Female , HEK293 Cells , Humans , Male , Mice , Mice, Nude , Middle Aged , Mutation , PC12 Cells , Paraganglioma/pathology , Pheochromocytoma/pathology , Rats , Tumor Burden
10.
Aging Cell ; 10(3): 493-505, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21385310

ABSTRACT

In a previous study, we reported that a deficiency in MnSOD activity (approximately 80% reduction) targeted to type IIB skeletal muscle fibers was sufficient to elevate oxidative stress and to reduce muscle function in young adult mice (TnIFastCreSod2(fl/fl) mice). In this study, we used TnIFastCreSod2(fl/fl) mice to examine the effect of elevated oxidative stress on mitochondrial function and to test the hypothesis that elevated oxidative stress and decreased mitochondrial function over the lifespan of the TnIFastCreSod2(fl/fl) mice would be sufficient to accelerate muscle atrophy associated with aging. We found that mitochondrial function is reduced in both young and old TnIFastCreSod2(fl/fl) mice, when compared with control mice. Complex II activity is reduced by 47% in young and by approximately 90% in old TnIFastCreSod2(fl/fl) mice, and was found to be associated with reduced levels of the catalytic subunits for complex II, SDHA and SDHB. Complex II-linked mitochondrial respiration is reduced by approximately 70% in young TnIFastCreSod2(fl/fl) mice. Complex II-linked mitochondrial Adenosine-Tri-Phosphate (ATP) production is reduced by 39% in young and was found to be almost completely absent in old TnIFastCreSod2(fl/fl) mice. Furthermore, in old TnIFastCreSod2(fl/fl) mice, aconitase activity is almost completely abolished; mitochondrial superoxide release remains > 2-fold elevated; and oxidative damage (measured as F(2) - isoprostanes) is increased by 30% relative to age-matched controls. These data show that despite elevated skeletal muscle-specific mitochondrial oxidative stress, oxidative damage, and complex II-linked mitochondrial dysfunction, age-related muscle atrophy was not accelerated in old TnIFastCreSod2(fl/fl) mice, suggesting mitochondrial oxidative stress may not be causal for age-related muscle atrophy.


Subject(s)
Aging , Mitochondria, Muscle/enzymology , Muscle, Skeletal/enzymology , Muscular Atrophy/metabolism , Superoxide Dismutase , Aconitate Hydratase/metabolism , Adenosine Triphosphate/biosynthesis , Animals , F2-Isoprostanes/analysis , Isoenzymes/metabolism , Mice , Mice, Transgenic , Muscle, Skeletal/cytology , Muscular Atrophy/genetics , Muscular Atrophy/pathology , Oxidation-Reduction , Oxidative Stress , Succinate Dehydrogenase/metabolism , Superoxide Dismutase/deficiency , Superoxide Dismutase/genetics , Superoxides/analysis
11.
JAMA ; 304(23): 2611-9, 2010 Dec 15.
Article in English | MEDLINE | ID: mdl-21156949

ABSTRACT

CONTEXT: Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. OBJECTIVES: To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. DESIGN, SETTING, AND PARTICIPANTS: We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. MAIN OUTCOME MEASURES: The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. RESULTS: We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. CONCLUSIONS: Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.


Subject(s)
Adrenal Gland Neoplasms/genetics , Germ-Line Mutation , Membrane Proteins/genetics , Paraganglioma/genetics , Pheochromocytoma/genetics , Adolescent , Adrenal Gland Neoplasms/metabolism , Adult , Age of Onset , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Membrane Proteins/metabolism , Microscopy, Confocal , Middle Aged , Paraganglioma/metabolism , Pheochromocytoma/metabolism , Polymerase Chain Reaction , Sequence Analysis, DNA
12.
Nat Genet ; 42(3): 229-33, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20154675

ABSTRACT

Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary. However, the molecular basis of the majority of these tumors is unknown. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations and, similarly, show hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Accordingly, in vitro gain-of-function and loss-of-function analyses indicate that TMEM127 is a negative regulator of mTOR. TMEM127 dynamically associates with the endomembrane system and colocalizes with perinuclear (activated) mTOR, suggesting a subcompartmental-specific effect. Our studies identify TMEM127 as a tumor suppressor gene and validate the power of hereditary tumors to elucidate cancer pathogenesis.


Subject(s)
Adrenal Gland Neoplasms/genetics , Germ-Line Mutation , Membrane Proteins/genetics , Pheochromocytoma/genetics , Adult , Aged , Cells, Cultured , Cohort Studies , DNA Mutational Analysis , Family , Genetic Predisposition to Disease , Germ-Line Mutation/physiology , Humans , Middle Aged , Polymorphism, Single Nucleotide/physiology
13.
Zhonghua Yi Xue Za Zhi ; 89(42): 2958-62, 2009 Nov 17.
Article in Chinese | MEDLINE | ID: mdl-20137703

ABSTRACT

OBJECTIVE: To investigate whether the polymorphism of osteoprotegerin (OPG) gene is associated with the change of BMD (bone mineral density) after alendronate therapy in postmenopausal women with osteoporosis and determine the correlation between genotypes and therapeutic effect. METHODS: Eighty postmenopausal osteoporotic patients were recruited with an average age of (64.2 +/- 7.7) years old. Every patient took oral alendronate (Fosamax) 70 mg weekly and Caltrate 600 mg daily for 12 months. At pre- and post-treatment, BMD was measured at lumbar spine 2 - 4 and hip sites. PCR-RFLP was performed for three polymorphisms at the promoter site of OPG gene (A163G, T245G and T950C). RESULTS: One-year therapy was accomplished in 67 patients. Patients with G allele (genotype AG and GG) of site A163G, the baseline BMD of vertebral L2-4, inter-troche and total hip were lower than genotype AA [(0.732 +/- 0.113) g/cm(2) vs (0.819 +/- 0.157) g/cm(2), (0.775 +/- 0.101) g/cm(2) vs (0.843 +/- 0.124) g/cm(2) and (0.667 +/- 0.105) g/cm(2) vs (0.725 +/- 0.091) g/cm(2)]. Patients with G allele (genotype TG and GG) of site T245G, baseline BMD of vertebral L2-4, inter-troche and total hip were lower than genotype TT [(0.723 +/- 0.111) g/cm(2) vs (0.819 +/- 0.155) g/cm(2), (0.776 +/- 0.102) g/cm(2) vs (0.840 +/- 0.124) g/cm(2) and (0.670 +/- 0.109) g/cm(2) vs (0.721 +/- 0.091) g/cm(2)]. After one-year therapy, at site A163G, the percentage of BMD change at inter-troche was higher in genotype AA than in genotypes AG and GG [2.50 (3.47)% vs 0.88% (3.47%)%, P = 0.014]. While at site T245G, the percentage of BMD change at inter-troche and total hip were higher in genotype TT than in genotype TG and GG 2.50% (3.47%) vs 0.61% (3.31%), P = 0.011; 2.72% (2.68%) vs 0.89 (3.01%), P = 0.046]. CONCLUSION: The G allele of sites A163G and T245G may be the risk allele of postmenopausal osteoporosis. Furthermore, patients with genotypes AA (A163G) and (T245G) show a better therapeutic effect to alendronate.


Subject(s)
Bone Density , Osteoporosis, Postmenopausal/genetics , Osteoporosis, Postmenopausal/metabolism , Osteoprotegerin/genetics , Aged , Alendronate/therapeutic use , Alleles , Female , Genotype , Humans , Middle Aged , Osteoporosis, Postmenopausal/drug therapy , Osteoprotegerin/therapeutic use , Polymorphism, Genetic
14.
Acta Pharmacol Sin ; 29(12): 1493-8, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19026169

ABSTRACT

AIM: Osteoclastic activity is mainly assessed by measurement of urinary markers (eg C-terminal cross-linked telopeptides of type I collagen, N-terminal crosslinked telopeptides of type I collagen, etc), the levels of which could often be affected by renal clearance. Recently, serum tartrate-resistant acid phosphatase 5b (TRACP5b) has been used as an alternative serum marker to evaluate osteoclastic activity. We investigated the age-related changes of TRACP5b level and its association with bone mineral density (BMD) in Chinese women. METHODS: Seven-hundred and twenty-two Chinese mainland women aged 20-79 years were recruited in the study. Serum TRACP5b level was measured using immunoassay to evaluate the state of bone resorption. Bone mineral density (BMD) (g/cm2) at lumbar spine 1-4 and proximal femur were measured by duelenergy X-ray absorptiometry. RESULTS: The serum TRACP5b level reached a bottom value in premenopausal women aged 30-39, gradually increased in women aged 40-49, rapidly rose in women aged 50-59, and culminated with a maximum value in women aged 60-69 before a slow drop in women aged 70- 79. The average level of TRACP5b was significantly higher in postmenopausal women [(3.29+/-1.07) U/L] than in premenopausal women ([1.70+/-0.59] U/L). The levels of TRACP5b were inversely correlated with BMD at all measured sites (P<0.001). Furthermore, the level of TRACP5b was obviously higher in women with osteoporosis and osteopenia than those with normal bone mass (P<0.001). CONCLUSION: We have established the reference values of serum TRACP5b in Chinese mainland women, and found that postmenopausal women had higher TRACP5b concentration than younger women. The results showed that serum TRACP5b was a sensitive and useful parameter for the evaluation of age-related changes of bone absorption.


Subject(s)
Acid Phosphatase/blood , Aging/blood , Biomarkers/blood , Bone Density , Isoenzymes/blood , Absorptiometry, Photon , Adult , Aged , Bone Diseases, Metabolic/blood , Bone Resorption/metabolism , China , Female , Humans , Middle Aged , Osteoporosis, Postmenopausal/blood , Osteoporosis, Postmenopausal/diagnosis , Postmenopause/blood , Tartrate-Resistant Acid Phosphatase , Young Adult
15.
Hum Genet ; 124(3): 279-85, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18726616

ABSTRACT

Recently, the KIF1B beta gene on 1p36, a region commonly deleted in neural crest cancers, was found to be a proapoptotic factor for sympathetic precursors. KIF1B beta mutations were detected in pheochromocytomas and neuroblastomas, two sympathetic lineage tumors, suggesting a role for this gene in cancer. Here, we studied five individuals from a three-generation cancer-prone family with a KIF1B beta germline variant and seven of their tumors, both of neural crest and nonneural origin. Genetic studies including sequencing, copy number analysis and fluorescence in situ-hybridization (FISH) showed retention of both KIF1B beta alleles in all neural crest-derived tumors in this family, consistent with haploinsufficiency or methylation of the wild-type allele. In contrast, the lung adenocarcinoma from one mutation carrier had somatic loss of the wild-type allele in agreement with a classical two-hit inactivation. Global transcription analysis of KIF1B beta mutant pheochromocytomas revealed that these tumors are transcriptionally related to pheochromocytomas with RET and NF1 mutations but independent from SDH- and VHL-associated tumors. Furthermore, KIF1B beta-mutant tumors are uniquely enriched for pathways related to glutamate metabolism and the oxidative stress response. Our data start to delineate the signals that are disrupted by KIF1B beta dysfunction in pheochromocytomas and suggest that loss of this gene may also be permissive to the development of nonneural crest malignancies. This may imply the existence of a tissue-specific gene dosage requirement for its tumorigenesis.


Subject(s)
Adenocarcinoma/genetics , Chromosomes, Human, Pair 1 , Germ-Line Mutation , Kinesins/genetics , Lung Neoplasms/genetics , Nervous System Neoplasms/metabolism , Neurons/metabolism , Pheochromocytoma/genetics , Adult , Family Health , Female , Heterozygote , Humans , Kinesins/physiology , Male , Middle Aged
16.
Zhonghua Yi Xue Za Zhi ; 87(12): 808-11, 2007 Mar 27.
Article in Chinese | MEDLINE | ID: mdl-17565860

ABSTRACT

OBJECTIVE: To develop a simple screening tool for low bone mass of postmenopausal women. METHODS: 405 postmenopausal women in Shanghai who visited the department of osteoporosis consecutively, aged 62.8 +/- 8.0 (47 approximately 90), underwent questionnaire survey on the risk factors of osteoporosis and fracture. Dual energy X-ray absorptiometry (DXA) was conducted on the left or right femoral neck to measure the bone mineral density (BMD) to identify osteoporosis (T-score

Subject(s)
Absorptiometry, Photon/methods , Bone Density , Femur Neck/diagnostic imaging , Surveys and Questionnaires , Aged , Aged, 80 and over , China , Female , Femur Neck/metabolism , Humans , Mass Screening/methods , Middle Aged , Osteoporosis, Postmenopausal/metabolism , Osteoporosis, Postmenopausal/prevention & control , Regression Analysis , Reproducibility of Results
17.
Acta Pharmacol Sin ; 28(2): 287-95, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17241533

ABSTRACT

AIM: To assess the contribution of single nucleotide polymorphisms (SNP) and haplotypes in the peroxisome proliferators-activated receptor-gamma co-activator-1 (PPARGC1) and adiponectin genes to normal bone mineral density (BMD) variation in healthy Chinese women and men. METHODS: We performed population-based (ANOVA) and family-based (quantitative trait locus transmission disequilibrium test) association studies of PPARGC1 and adiponectin genes. SNP in the 2 genes were genotyped. BMD was measured using dual-energy X-ray absorptiometry in the lumbar spine and hip in 401 nuclear families with a total of 1260 subjects, including 458 premenopausal women, 20-40 years of age; 401 postmenopausal women (mothers), 43-74 years of age; and 401 men (fathers), 49-76 years of age. RESULTS: Significant within-family association was found between the Thr394Thr polymorphism in the PPGAGC1 gene and peak BMD in the femoral neck (P=0.026). Subsequent permutations were in agreement with this significant within-family association result (P=0.016), but Thr394Thr SNP only accounted for 0.7% of the variation in femoral neck peak BMD. However, no significant within-family association was detected between each SNP in the adiponectin gene and peak BMD. Although no significant association was found between BMD and SNP in the PPARGC1 and adiponectin genes in both men and postmenopausal women, haplotype 2 (T-T) in the adiponectin gene was associated with lumbar spine BMD in postmenopausal women (P=0.019). CONCLUSION: Our findings suggest that Thr394Thr SNP in the PPARGC1 gene was associated with peak BMD in the femoral neck in Chinese women. Confirmation of our results is needed in other populations and with more functional markers within and flanking the PPARGC1 or adiponectin genes region.


Subject(s)
Adiponectin/genetics , Bone Density , Haplotypes , Nuclear Family , Polymorphism, Single Nucleotide , Transcription Factors/genetics , Adult , Aged , Female , Gene Frequency , Humans , Linkage Disequilibrium , Male , Middle Aged
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 23(4): 397-401, 2006 Aug.
Article in Chinese | MEDLINE | ID: mdl-16883525

ABSTRACT

OBJECTIVE: To investigate the association of polymorphisms of start codon (Fok I site) and CDX2 binding site in vitamin D receptor gene (VDR) concerned with the effect of calcium supplementation on bone mineral density (BMD) and bone turnover markers of postmenopausal women. METHODS: Two hundreds unrelated postmenopausal women of Han ethnicity in Shanghai were randomly divided into 2 groups of 100 women: high calcium group (1000 mg element calcium and 400 units of vitamin D were given daily for 12 months) and low calcium group (300 mg element calcium and 300 units of vitamin D were given daily for 12 months). BMD and bone turnover markers were measured at baseline and 12 months after calcium supplementation. VDR gene Fok I and CDX2 polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific multiplex PCR, respectively. RESULTS: One hundred and seventy-one women completed 12-month study period. The frequency of VDR Fok I genotypes was 48.0 % for Ff, 31.0 % for FF, and 21.0 % for ff, and the frequency of CDX2 genotypes was 56.7 % for AG, 25.7% for GG, and 17.6% for AA. The frequencies distribution of Fok I and CDX2 alleles in the entire population or in two subgroups all followed the Hardy-Weinberg equilibrium. No significant difference of baseline BMD and bone turnover markers in Fok I genotypes or CDX2 genotypes was observed in the entire population or in two subgroups. Moreover, regardless of calcium supplementation given for 12 months, no significant association was found between Fok I or CDX2 polymorphisms and the endpoint values or percentage changes of any BMD and bone turnover markers in either high calcium group or low calcium group. CONCLUSION: There is no significant relationship between VDR gene Fok I or CDX2 polymorphisms and the effect of high or low doses calcium supplementation on BMD and bone turnover markers in Shanghai postmenopausal women of Han ethnicity.


Subject(s)
Bone Density/drug effects , Calcium, Dietary/therapeutic use , Codon, Initiator/genetics , Polymorphism, Genetic/genetics , Receptors, Calcitriol/genetics , Aged , Bone and Bones/drug effects , Bone and Bones/metabolism , Calcium, Dietary/administration & dosage , Dietary Supplements , Drug Therapy, Combination , Female , Gene Frequency , Genotype , Humans , Middle Aged , Osteoporosis, Postmenopausal/prevention & control , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Postmenopause/drug effects , Vitamin D/administration & dosage , Vitamin D/therapeutic use , Vitamins/administration & dosage , Vitamins/therapeutic use
19.
Acta Pharmacol Sin ; 27(9): 1231-7, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16923345

ABSTRACT

AIM: To construct an A20 expression vector under the control of mouse osteocalcin promoter (OC-A20), and investigate osteoblastic MC3T3-E1 cell line, which stably overexpresses A20 protein prevented tumor necrosis factor (TNF)-alpha-induced apoptosis. METHODS: OC-A20 vector was constructed by fusing a fragment of the mouse osteocalcin gene-2 promoter with human A20 complementary DNA. Then the mouse MC3T3-E1 cell line, stably transfected by A20, was established. The expression of A20 mRNA and A20 protein in the cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. To determine the specificity of A20 expression in osteoblast, the mouse osteoblastic MC3T3-E1 cell line and mouse embryo fibroblast NIH3T3 cell line were transiently transfected with OC-A20. The anti-apoptotic role of A20 in MC3T3-E1 cells was determined by Flow cytometric analysis (FACS), terminal dUTP nick endo-labeling (TUNEL) and DNA gel electrophoresis analysis (DNA Ladder), respectively. RESULTS: Weak A20 expression was found in MC3T3-E1 cells with the primers of mouse A20. A20 mRNA and A20 protein expression were identified in MC3T3-E1 cells transfected with OC-A20 using RT-PCR and Western blot analysis. Only A20 mRNA expression was found in MC3T3-E1 cell after MC3T3-E1 cells and NIH3T3 cells were transient transfected with OC-A20. A decrease obviously occurred in the rate of apoptosis in the OC-A20 group compared with the empty vector (pcDNA3) group by FACS (P< 0.001). A significant increase in TUNEL positive staining was found in the pcDNA group compared with OC-A20 group (P< 0.001). Simultaneously, similar effects were demonstrated in DNA gel electrophoresis analysis. CONCLUSION: We constructed an osteoblast-specific expression vector that expressed A20 protein in MC3T3-E1 cells and confirmed that A20 protects osteoblast against TNF-alpha-induced apoptosis.


Subject(s)
Apoptosis , Nuclear Proteins/biosynthesis , Osteocalcin/genetics , Tumor Necrosis Factor-alpha/pharmacology , 3T3 Cells , Animals , DNA, Complementary/genetics , DNA-Binding Proteins , Genetic Vectors , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/physiology , Mice , NIH 3T3 Cells , Nuclear Proteins/genetics , Nuclear Proteins/physiology , Promoter Regions, Genetic , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Transfection , Tumor Necrosis Factor alpha-Induced Protein 3
20.
Asian J Androl ; 8(4): 419-27, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16763717

ABSTRACT

AIM: To establish bone mineral density (BMD) reference database in healthy Chinese men of Han ethnicity, and to estimate the prevalence of osteoporosis in the population. METHODS: The BMD in the lumbar spine 1-4 (L1-4) and proximal femur was measured using dual energy X-ray absorptiometry in a total of 1 385 healthy Chinese men of Han ethnicity aged 20-89 years old in Shanghai. RESULTS: The highly significant negative correlation between age and BMD at any sites of proximal femur was found in the studied population, wheras no correlation between age and BMD at lumbar spine was observed. The peak BMD of the lumbar spine and any sites of hip in Chinese men was defined as the mean BMD for the subjects aged 20-89 years. According to World Health Organization (WHO) criteria, the BMD cut-off values for osteoporosis of the L1-4, total hip, femoral neck, trochanter and intertrochanter in Chinese men are 0.719, 0.638, 0.575, 0.437 and 0.725 g/cm(2), respectively. Using the current Chinese reference data, the prevalence of osteoporosis at the L1-4, total hip, femoral neck, trochanter and intertrochanter is 5.4%, 3.8%, 6.3%, 1.8% and 2.8% in 1 084 men aged 50 years or older, respectively. However, using a database for US non-Hispanic white men (NHANES III), the prevalence of osteoporosis or osteopenia at any sites of the hip was significantly higher than that while using the current Chinese reference data. CONCLUSION: The BMD reference database was established in healthy Chinese men of Han ethnicity, and will facilitate more accurate diagnosis of osteoporosis in Chinese men.


Subject(s)
Bone Density , Femur/diagnostic imaging , Spine/diagnostic imaging , Absorptiometry, Photon , Adult , Aged , Aged, 80 and over , China/epidemiology , Humans , Male , Middle Aged , Osteoporosis/diagnostic imaging , Osteoporosis/epidemiology , Prevalence , Reference Values
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