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1.
Plant Physiol ; 187(1): 174-186, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34618134

RESUMO

Chloroplasts play an indispensable role in the arms race between plant viruses and hosts. Chloroplast proteins are often recruited by plant viruses to support viral replication and movement. However, the mechanism by which chloroplast proteins regulate potyvirus infection remains largely unknown. In this study, we observed that Nicotiana benthamiana ribosomal protein large subunit 1 (NbRPL1), a chloroplast ribosomal protein, localized to the chloroplasts via its N-terminal 61 amino acids (transit peptide), and interacted with tobacco vein banding mosaic virus (TVBMV) nuclear inclusion protein b (NIb), an RNA-dependent RNA polymerase. Upon TVBMV infection, NbRPL1 was recruited into the 6K2-induced viral replication complexes in chloroplasts. Silencing of NbRPL1 expression reduced TVBMV replication. NbRPL1 competed with NbBeclin1 to bind NIb, and reduced the NbBeclin1-mediated degradation of NIb. Therefore, our results suggest that NbRPL1 interacts with NIb in the chloroplasts, reduces NbBeclin1-mediated NIb degradation, and enhances TVBMV infection.

2.
Dalton Trans ; 50(42): 15267-15273, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34632996

RESUMO

In this work, organic supramolecular linkers involving cucubit[6]urils CB[6] and N,N'-hexamethylene-bis(pyrazinyl hexafluorophosphate) (BPHF@CB[6]) were utilized to assemble dodenuclear silver chalcogenolate clusters into three one-dimensional (1D) materials under different synthesis conditions. These three crystal structures of CB[6]-based sliver cluster-organic rotaxane frameworks were well resolved, and their emission properties were investigated systematically. This construction strategy involving organic supramolecular linkers gives a new methodology for cluster-assembled materials with intriguing structural and functional properties.

3.
Cell Death Dis ; 12(9): 799, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404767

RESUMO

Lactate dehydrogenase A (LDHA), a critical component of the glycolytic pathway, relates to the development of various cancers, including thyroid cancer. However, the regulatory mechanism of LDHA inhibition and the physiological significance of the LDHA inhibitors in papillary thyroid cancer (PTC) are unknown. Long non-coding RNA (lncRNA) plays a vital role in tumor growth and progression. Here, we identified a novel lncRNA LINC00671 negatively correlated with LDHA, downregulating LDHA expression and predicting good clinical outcome in thyroid cancer. Moreover, hypoxia inhibits LINC00671 expression and activates LDHA expression largely through transcriptional factor STAT3. STAT3/LINC00671/LDHA axis regulates thyroid cancer glycolysis, growth, and lung metastasis both in vitro and in vivo. In thyroid cancer patients, LINC00671 expression is negatively correlated with LDHA and STAT3 expression. Our work established STAT3/LINC00671/LDHA as a critical axis to regulate PTC growth and progression. Inhibition of LDHA or STAT3 or supplement of LINC00671 could be potential therapeutic strategies in thyroid cancer.

4.
Phytopathology ; 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34191551

RESUMO

Potyviral Coat protein (CP) is involved in the replication and movement of potyviruses. However, little information is available on the roles of CP-coding sequence in potyviral infection. Here, we introduced synonymous substitutions to the codon c574g575c576 coding conserved residue arginine at position 192 (R192) of tobacco vein banding mosaic virus (TVBMV) CP. Substitution of the codon c574g575c576 to a574g575a576 or a574g575g576, but not c574g575a576, c574g575t576, or c574g575g576, reduced the replication, cell-to-cell movement, and accumulation of TVBMV in Nicotiana benthamiana plants, suggesting that c574 was critical for replication of TVBMV. Nucleotides 531 to 576 of the TVBMV CP-coding sequence were predicted to form a stem-loop structure, in which four consecutive c-g base pairs (C576-G531, c532-g575, c574-g533, and C534-G573) were located at the stem. Synonymous substitutions of R178-codon c532g533c534 to A532G533A534 and A532G533G534, but not c532g533a534, c532g533t534, or c532g533g534, reduced the replication levels, cell-to-cell, and systemic movement of TVBMV, suggesting that c532 was critical for TVBMV replication. Synonymous substitutions disrupting base pairs C576-G531 and C534-G573 did not affect viral accumulation. After three serial passage inoculation, the accumulation of spontaneous mutant viruses was restored and codons A532G533A534, A532G533G534, a574g575a576, or a574g575g576 of mutants was separately changed to C532G533A534, C532G533G534, C574g575a576, or C574g575g576. Synonymous mutation of R178 and R192 also reduced viral accumulation in N. tabacum plants. Therefore, we concluded that the two consecutive c532-g575 and c574-g533 base pairs played critical roles in TVBMV replication via maintaining the stability of stem-loop structure formed by nucleotides 531 to 576 of CP-coding sequence.

5.
Mol Plant Microbe Interact ; 34(6): 658-668, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33534601

RESUMO

Potyviruses move to neighboring cells in the form of virus particles or a coat protein (CP)-containing ribonucleoprotein complex. However, the precise roles of RNA-binding residues in potyviral CP in viral cell-to-cell movement remain to be elucidated. In this study, we predicted the three-dimensional model of tobacco vein banding mosaic virus (TVBMV)-encoded CP and found nine residues presumably located in the CP RNA-binding pocket. Substitutions of the two basic residues at positions 192 and 225 (R192 and K225) with either alanine, cysteine, or glutamic acid abolished TVBMV cell-to-cell and systemic movement in Nicotiana benthamiana plants. These substitutions also reduced the replication of the mutant viruses. Results from the electrophoretic mobility shift assay showed that the RNA-binding activity of mutant CPs derived from R192 or K225 substitutions was significantly lower than that of wild-type CP. Analysis of purified virus particles showed that mutant viruses with R192 or K225 substitutions formed RNA-free virus-like particles. Mutations of R192 and K225 did not change the CP plasmodesmata localization. The wild-type TVBMV CP could rescue the deficient cell-to-cell movement of mutant viruses. Moreover, deletion of any of the other seven residues also abolished TVBMV cell-to-cell movement and reduced the CP RNA-binding activity. The corresponding nine residues in watermelon mosaic virus CP were also found to play essential roles in virus cell-to-cell movement. In conclusion, residues R192 and K225 in the CP RNA-binding pocket are critical for viral RNA binding and affect both virus replication and cell-to-cell movement.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Assuntos
Proteínas do Capsídeo , Tabaco , Proteínas do Capsídeo/genética , Potyvirus , RNA Viral/genética , Tabaco/genética , Replicação Viral
6.
Food Chem ; 335: 127602, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32739807

RESUMO

Bioactive phenolics primarily contribute to versatile health benefits of pigeon pea. For the first time, an UPLC-QqQ-MS/MS method was developed for the quantitative analysis of eleven bioactive phenolic compounds in pigeon pea natural resources (seeds, leaves, and roots) and in vitro cultures (calli and hairy roots). The proposed method could be achieved within 6 min of running time, and displayed the satisfactory linearity, sensitivity, precision, accuracy, and stability. According to analytical results, the distribution of eleven target compounds in different organs of pigeon pea was clarified. Also, it was surprisingly found that pigeon pea in vitro cultures exhibited superiority in contents of genistin and cajaninstilbene acid as compared with natural resources. Overall, the present work provided a rapid and sensitive analysis approach, which could be useful not only for quality control of pigeon pea natural resources, but also for applicability and safety evaluation of pigeon pea in vitro cultures.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ervilhas/química , Fenóis/análise , Espectrometria de Massas em Tandem/métodos , Medicamentos de Ervas Chinesas/química , Folhas de Planta/química , Controle de Qualidade , Reprodutibilidade dos Testes , Sementes/química
7.
Nanoscale Res Lett ; 15(1): 211, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170390

RESUMO

A 13.5 kV 4H-SiC PiN rectifier with a considerable active area of 0.1 cm2 is fabricated in this paper. Charge-field-modulated junction termination extension (CFM-JTE) has been proposed for satisfying the requirement of ultra-high reverse voltage, which enlarges the JTE dose tolerance window, making it approximately 2.8 times that of the conventional two-zone JTE. Besides, the CFM-JTE can be implemented through the conventional two-zone JTE process. The measured forward current is up to 100 A @ VF = 5.2 V in the absence of carrier lifetime enhancement technology. The CFM-JTE structure accomplishes 96% of the theoretical breakdown voltage of the parallel plane junction with a relatively small terminal area of 400 µm, which contributes to achieving the Baliga's figure of merit of 58.8 GW/cm2.

8.
Front Plant Sci ; 11: 1279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973838

RESUMO

Cross-protection is a promising measure to control plant viral diseases. Reverse genetics had been recently adopted to generate attenuated mutants that have potential in cross-protection. But studies on the variability of the progeny viruses of the attenuated mutants are scarce. Sugarcane mosaic virus (SCMV; genus Potyvirus, family Potyviridae) is the prevalent virus inducing maize dwarf mosaic disease in China. Here, we showed that the substitution of arginine with isoleucine in the FRNK motif at position 184 of helper component-proteinase (HC-Pro) abolished its RNA silencing suppression (RSS) activity, drastically reduced the virulence and accumulation level of SCMV, and impaired the synergism between SCMV and maize chlorotic mottle virus. The attenuated mutant could protect maize plants from a severe infection of SCMV. However, a spontaneous mutation of glycine at position 440 to arginine in HC-Pro rescued the virulence and synergism with maize chlorotic mottle virus of SCMV and the RSS activity of HC-Pro. Similar results were obtained with tobacco vein banding mosaic virus and watermelon mosaic virus. These results provide novel evidence for the complementary mutation of potyviruses in maintaining the HC-Pro RSS activity and potyviral virulence and remind us of evaluating the potential risk of attenuated mutants thoroughly before applying for the control of plant viral diseases via cross-protection.

9.
J Pharm Biomed Anal ; 189: 113456, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32653816

RESUMO

Taxus species are highly concerned due to the presence of anticancer taxoids (especially paclitaxel) and health beneficial flavonoids. For the first time, an UHPLC-MS/MS method was developed for the simultaneous determination of seven taxoids and seven flavonoids in twigs and leaves of three Taxus species. The satisfactory separation of fourteen target compounds was achieved within 5 min of running time on an Agilent ZORBAX Eclipse Plus C18 column (50 mm × 2.1 mm I.D., 1.8 µm) using an acetonitrile-water gradient elution program. Mass transitions of all analytes in selected reaction monitoring acquisition mode were systematically optimized for obtaining the highest signal intensities. Regression equations of all analytes exhibited excellent linearities with coefficients higher than 0.9990, and the lowest limits of quantification of all analytes ranged from 0.01 to 1.66 ng/mL. The intra- and inter-day precisions (relative standard deviations) of all analytes were less than 4.17% for retention time and less than 7.42% for peak area, and the spiking standard recoveries of all analytes ranged from 96.85%-104.77%. By the aid of the proposed method, the distribution of fourteen target compounds in twigs and leaves of Taxus chinensis, Taxus cuspidata, and Taxus media was clearly figured out. Overall, the present work provided a rapid and valid UHPLC-MS/MS approach, which could not only be useful for quality control and applicability assessment of twigs and leaves of the three Taxus species in pharmaceutical and nutraceutical industries, but also offer a good reference for the systematic analysis of taxoids and flavonoids in other Taxus species.


Assuntos
Espectrometria de Massas em Tandem , Taxus , Cromatografia Líquida de Alta Pressão , Flavonoides , Folhas de Planta/química , Reprodutibilidade dos Testes , Taxoides
10.
J Agric Food Chem ; 68(31): 8350-8361, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32672956

RESUMO

Phenolic compounds in pigeon pea possess various biological properties beneficial to human health. In this study, pigeon pea hairy root cultures (PPHRCs) were developed as an effective in vitro platform for the production of phenolic compounds. A high-productive hairy root line was screened and characterized, and its culture conditions were optimized in terms of biomass productivity and phenolic yield. The comparative profiling of 10 phenolic compounds in PPHRCs and pigeon pea natural resources (seeds, leaves, and roots) was achieved by ultra-high-performance liquid chromatography-tandem mass spectrometry analysis. The total phenolic yield in PPHRCs (3278.44 µg/g) was much higher than those in seeds (68.86 µg/g) and roots (846.03 µg/g), and comparable to leaves (3379.49 µg/g). Notably, PPHRCs exhibited superiority in the yield of the most important health-promoting compound cajaninstilbene acid (2996.23 µg/g) against natural resources (4.42-2293.31 µg/g). Overall, PPHRCs could serve as promising potential alternative sources for the production of phenolic compounds with nutraceutical/medicinal values.


Assuntos
Cajanus/metabolismo , Fenóis/química , Extratos Vegetais/química , Raízes de Plantas/química , Raízes de Plantas/crescimento & desenvolvimento , Antioxidantes/química , Antioxidantes/metabolismo , Cajanus/química , Cajanus/crescimento & desenvolvimento , Técnicas de Cultura de Células , Fenóis/metabolismo , Extratos Vegetais/metabolismo , Raízes de Plantas/metabolismo , Sementes/química , Sementes/metabolismo
11.
Oral Dis ; 25(7): 1759-1768, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357246

RESUMO

OBJECTIVES: To detect whether early growth response 1 (EGR1) in peripheral blood leucocytes (PBLs) indicates temporomandibular joint (TMJ) osteoarthritis (OA) lesions. MATERIALS AND METHODS: Egr1 mRNA expression levels in PBLs were detected in eight malocclusion patients without temporomandibular disorder (TMD) signs and 16 malocclusion patients with clinical TMD signs with (eight) or without (eight) imaging signs of TMJ OA. Twelve 6-week-old rats were randomized to a control group and a unilateral anterior crossbite (UAC) group and were sampled at 4 weeks. The Egr1 mRNA expression levels in PBLs and protein expression levels in different orofacial tissues were measured. RESULTS: Patients with TMD signs with/without TMJ OA diagnosis showed lower Egr1 mRNA expression levels in PBLs than patients without TMD signs. The lower Egr1 mRNA expression was also found in the PBLs of UAC rats, which were induced to exhibit early histo-morphological signs of TMJ OA lesions. In subchondral bone of UAC rats, EGR1 protein expression was decreased, co-localization of EGR1 with osterix or dentin matrix protein-1 was identified, and the number of EGR1 and osterix double-positive cells was reduced (all p < .05). CONCLUSION: Egr1 reduction in PBLs potentially indicates subchondral bone OA lesions at an early stage.


Assuntos
Cartilagem Articular , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Côndilo Mandibular , Osteoartrite , Transtornos da Articulação Temporomandibular/etiologia , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Má Oclusão/complicações , RNA Mensageiro , Distribuição Aleatória , Ratos , Articulação Temporomandibular , Transtornos da Articulação Temporomandibular/metabolismo , Tomografia Computadorizada por Raios X , Fatores de Transcrição/análise
12.
J Oral Rehabil ; 46(9): 820-827, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31046158

RESUMO

Biomarkers of temporomandibular joint (TMJ) osteoarthritis (OA) remain unknown. The objective was to detect whether molecular biomarkers from peripheral blood leucocytes (PBLs) engage in TMJ OA lesions. Thirty-four six-week-old Sprague Dawley rats were used. The top upregulated gene ontology categories and gene-fold changes in PBLs were detected by a microarray analysis comparing rats that received 20-week unilateral anterior crossbite (UAC) treatment with age-matched controls (n = 4). Twenty weeks of UAC treatment had been reported to induce TMJ OA-like lesions. The other twenty-four rats were randomly placed in the UAC and control groups at 12- and 20-week time points (n = 6). The mRNA expression levels of the selected biomarkers derived from the microarray analysis and their protein expression in the alveolar bone and TMJ were detected. The microarray analysis indicated that the three most highly involved genes in PBLs were Egr1, Ephx1 and Il10, which were confirmed by real-time PCR detection. The increased protein expression levels of the three detected molecules were demonstrated in cartilage and subchondral bone (P < 0.05), and increased levels of EPHX1 were reported in discs (P < 0.05); however, increased levels were not present in the alveolar bone. Immunohistochemistry revealed the increased distribution of EGR1-positive, EXPH1-positive and IL10-positive cells predominantly in the osteochondral interface, with EXPH1 also present in TMJ discs. In conclusion, the increased mRNA expression of Egr1, Ephx1 and Il10 in PBLs may serve as potential biomarkers for developed osteoarthritic lesions relating to osteochondral interface hardness changes induced by dental biomechanical stimulation.


Assuntos
Cartilagem Articular , Transtornos da Articulação Temporomandibular , Animais , Côndilo Mandibular , Ratos , Ratos Sprague-Dawley , Articulação Temporomandibular
13.
Adv Biosyst ; 3(5): e1900006, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-32627411

RESUMO

The application of ascorbate (vitamin C) for cancer therapy was first proposed in the 1970s and has shown promising results in recent clinical trials. Pharmacological doses of ascorbate selectively induce cell death in different types of cancer cells through the generation of H2 O2. However, some cancer cells are resistant to ascorbate. So increasing the sensitivity of resistant cancer cells to ascorbate has attracted considerable attention. Till now, a few attempts in nanomaterials have been made to improve the effect of ascorbate. In this study, a simple ferritin caged copper nanoparticle (Fn-Cu) significantly improves the susceptibility of ascorbate-resistant cancer cells to pharmacological ascorbate via selective inhibition of catalase activity in cancer cells, while having negligible cytotoxicity to normal cells. Remarkably, combination of Fn-Cu with a lower dose of ascorbate significantly inhibits ascorbate-resistant tumor growth and metastasis in vivo. These data demonstrate Fn-Cu has the therapeutic potential by enhancing the effect of ascorbate in cancer therapy.


Assuntos
Antineoplásicos , Ácido Ascórbico , Ferritinas , Nanopartículas , Neoplasias Experimentais , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ácido Ascórbico/química , Ácido Ascórbico/farmacologia , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Ferritinas/química , Ferritinas/farmacologia , Células HEK293 , Humanos , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia
14.
Clin Chim Acta ; 489: 21-28, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30408480

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. OI patients of autosomal recessive inheritance are extremely rare, of which OI type XIII is attributable to mutation in BMP1 gene. CASE REPORT: Here, we detect the pathogenic mutations and analyze their relation to the phenotypes in a Chinese family with OI using next-generation sequencing (NGS) and Sanger sequencing. We also evaluate the efficacy of alendronate treatment in the patient with OI type XIII. The clinical phenotypes of the patient included recurrent fractures, muscle weakness, bone deformity, macrocephaly and elbow contractures, but no blue sclera or dentinogenesis imperfecta. High-resolution peripheral quantitative computed tomography revealed high bone mineral density and bone volume, but reduced trabecular numbers, increased porosity and comprised strength in this patient. Novel heterozygous mutations of c.1324G > T (p.Asp442Tyr) and c.148 + 1G > A in BMP1 gene were found in the proband, which would affect the CUB2 domain and the prodomain of mutant proteins. The parents were heterozygous carriers for the two mutations respectively, but with normal phenotype. CONCLUSIONS: We report for the first time that the novel pathogenic mutations in BMP1 can lead to the extremely rare OI type XIII, which exhibit unique characters of high bone mass, but with impaired bone microstructure and comprised bone strength. Alendronate is beneficial in increasing bone mineral density and decreasing bone resorption biomarkers, but concerns still remain whether it can reduce fracture incidence in this rare type of OI.


Assuntos
Proteína Morfogenética Óssea 1/genética , Mutação , Osteogênese Imperfeita/genética , Adolescente , Seguimentos , Heterozigoto , Humanos , Masculino , Fenótipo
15.
J Cancer Res Ther ; 14(Supplement): S427-S432, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29970701

RESUMO

Objective: Sunitinib/sorafenib (SU/SO), dendritic cells (DCs), or DC-cytokine-induced killer (CIK) could significantly prolong progression-free survival (PFS), 3-year overall survival (OS), or 5-year OS for patients with metastatic renal cell carcinoma (mRCC). We retrospectively analyzed the clinical efficacy between SU/SO combined with DC-CIK and SU/SO monotherapy in treating renal cell carcinoma (RCC) patients with metastasis after radical nephrectomy. Materials and Methods: All patients (n = 34) with postoperative mRCC in our hospital from January 2009 to January 2014 were received either SU/SO monotherapy (Group 1, n = 15) or in combination with DC-CIK (Group 2, n = 19). A retrospective study was based on the primary endpoint (PFS) and secondary endpoint (OS). Results: At a median follow-up of 19.5 months, in Group 2, as compared with in Group 1, the median PFS was significantly longer (28.0 vs. 11.0 months, P = 0.03). Moreover, the 3-year OS was higher (57.1% vs. 28.6%). The cases of progressive diseases (PDs) and deaths were less in Group 2 than that in Group 1 (PD: 8 vs. 9, deaths: 3 vs. 5); however, the cases of stable diseases were more (11 vs. 6). In addition, the 3-year OS was higher in SU + DC-CIK group than that in SO + DC-CIK group (63.36% vs. 50%). There was no significant difference for PFS between SO + DC-CIK group and SU single agent group. Conclusions: SU/SO with DC-CIK could significantly prolong the median PFS, improve the 3-year OS rate, prolong the 3-year OS. It is likely to be a new approach for mRCC after radical nephrectomy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Células Matadoras Induzidas por Citocinas/imunologia , Células Dendríticas/imunologia , Imunoterapia Adotiva , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Terapia Combinada , Células Matadoras Induzidas por Citocinas/metabolismo , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia Adotiva/métodos , Indóis/administração & dosagem , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Cuidados Pós-Operatórios , Pirróis/administração & dosagem , Estudos Retrospectivos , Sorafenibe , Sunitinibe , Análise de Sobrevida , Resultado do Tratamento
16.
Clin Chim Acta ; 478: 216-221, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29104038

RESUMO

BACKGROUNDS: SERPINF1 mutations caused deficiency of pigment epithelium-derived factor (PEDF) and would lead to osteogenesis imperfecta (OI) type VI. However, serum PEDF levels were unclear in Chinese OI patients who had clear molecular diagnosis. OBJECTIVE: To assess PEDF levels in different genotypes of OI, to evaluate the influencing factors of PEDF in Chinese OI patients with clear molecular diagnosis. METHODS: Known candidate genes of OI were examined by a targeted next generation sequence. Serum PEDF levels were measured by ELISA in 6 OI patients with SERPINF1 mutations, 6 carriers of one copy of the SERPINF1 mutation, 88 OI patients with COL1A1, CLO1A2, IFITM5 and other pathogenic mutations of OI and 24 healthy controls. We compared the differences in serum PEDF levels among different OI patients and normal controls. RESULTS: Serum PEDF levels were extremely low in OI patients with SERPINF1 mutations (0.66±1.60µg/ml) than in OI patients with other pathogenic mutations (4.88±1.43-7.07±2.43µg/ml), carriers of one copy of SERPINF1 mutation (4.94±2.35µg/ml), and normal controls (7.29±2.31µg/m) (P<0.001). No significant differences in serum PEDF concentrations were found among patients with OI type I, III or IV, and between patients with or without bisphosphonate treatment. Serum PEDF level was positively correlated with Z-score of weight (r=0.310, P=0.004), BMI (r=0.253, P=0.020) and alanine aminotransferase (r=0.291, P=0.007). CONCLUSIONS: Extremely low level of PEDF was demonstrated as a specific, convenient, and inexpensive diagnostic biomarker for OI patients with SERPINF1 mutations, but it could not provide information regarding the clinical severity of OI and the efficacy of bisphosphonates treatment.


Assuntos
Proteínas do Olho/sangue , Mutação , Fatores de Crescimento Neural/sangue , Osteogênese Imperfeita/genética , Serpinas/sangue , Adulto , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Estudos de Casos e Controles , Difosfonatos/uso terapêutico , Proteínas do Olho/genética , Humanos , Fatores de Crescimento Neural/deficiência , Fatores de Crescimento Neural/genética , Osteogênese Imperfeita/sangue , Osteogênese Imperfeita/classificação , Serpinas/deficiência , Serpinas/genética , Adulto Jovem
17.
Clin Chim Acta ; 468: 39-45, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28192073

RESUMO

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive autonomic and sensory neuropathy. CIPA is associated with various mutations in NTRK1. CASES: Two unrelated Chinese patients presented separately with symptoms of insensitivity to pain, inability to sweat, repeated painless fractures, and Charcot arthropathy were recruited. Both of them were clinically diagnosed with CIPA. Increased serum bone resorption marker (ß-CTX) levels and decreased BMD were observed in both patients. X-ray films revealed enlarged bony calli in the fracture sites, Charcot arthropathy, and bilateral lower limb osteomyelitis. Sanger sequencing demonstrated compound heterozygous mutations in NTRK1 for proband 1 (IVS7-33T>A in intron 7 and c. 2281C>T in exon 17) and for proband 2 (IVS7-33T>A in intron 7 and c.1652delA in exon 14), of which the variation in exon 14 in NTRK1 was a novel mutation. CONCLUSIONS: We report the detailed phenotypes, as well as both recurrent and novel mutations in NTRK1 in 2 Chinese patients with CIPA. The genetic findings of our study expand the gene mutation spectrum of CIPA.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neuropatias Hereditárias Sensoriais e Autônomas/enzimologia , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Mutação , Receptor trkA/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Receptor trkA/química , Adulto Jovem
18.
Calcif Tissue Int ; 100(1): 55-66, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27796462

RESUMO

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection of SERPINF1 mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations in SERPINF1 gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271_279dup, p.Ala91_Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283 + 1G > T, splicing site) and exon 5 (c.498_499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202_1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G > A, p.Gly62Ser) and in-frame insertion (c.271_279dup, p.Ala91_Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T + ?, p.Gln133X + ?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.


Assuntos
Proteínas do Olho/genética , Fraturas Ósseas/genética , Predisposição Genética para Doença/genética , Mutação/genética , Fatores de Crescimento Neural/genética , Osteogênese Imperfeita/genética , Serpinas/genética , Adolescente , Densidade Óssea/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Fenótipo
19.
J Hum Genet ; 62(2): 205-211, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27762305

RESUMO

Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by decreased bone mass and increased fracture risk. The majority of OI cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. OI cases of autosomal recessive inheritance are rare, and OI type XI is attributable to mutation of the FKBP10 gene. Here, we used next-generation sequencing and Sanger sequencing to detect mutations in FKBP10 and to analyze their relation to the phenotypes of OI type XI in three Chinese patients. We also evaluated the efficacy of zoledronic acid treatment in these patients. Two of the affected patients had novel compound heterozygous mutations, one patient with c.343C>T (p.R115X) in exon 2 and c.1085delC (p.A362fsX1) in exon 7, and the other patient with c.879C>G (p.Y293X) in exon 5 and c.918-3C>G in intron 5. In the third proband, we identified a homozygous single base-pair duplication, c.831dupC (p.G278RfsX95) in exon 5. In conclusion, we report for the first time that these novel pathogenic mutations of FKBP10 can lead to the extremely rare type XI OI without contractures, which expands the genotypic spectrum of OI. The phenotypes of these patients are similar to patients with types III or IV OI, and zoledronic acid is effective in increasing BMD, inhibiting bone resorption biomarkers and reducing fractures of these patients.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Fraturas Ósseas/prevenção & controle , Imidazóis/uso terapêutico , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Proteínas de Ligação a Tacrolimo/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Reabsorção Óssea/prevenção & controle , Criança , Pré-Escolar , China/epidemiologia , Colágeno Tipo I/genética , Feminino , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Proteínas de Membrana/genética , Análise de Sequência de DNA , Adulto Jovem , Ácido Zoledrônico
20.
Chin Med Sci J ; 31(1): 8-16, 2016 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-28031082

RESUMO

Objective To investigate the relationship between geranylgeranyl pyrophosphate synthase (GGPPS) gene polymorphisms and bone response to alendronate in Chinese osteoporotic women.Methods A total of 639 postmenopausal women with osteoporosis or osteopenia were included and randomly received treatment of low dose (70 mg per two weeks) or standard dose (70 mg weekly) of alendronate for one year. The six tag single nucleotide polymorphisms of GGPPS gene were identified. Bone mineral density (BMD), serum cross-linked C-telopeptide of type I collagen (ß-CTX), and total alkaline phosphatase (ALP) were measured before and after treatment. GGPPS gene polymorphisms and the changes of BMD and bone turnover markers after treatment were analyzed.Results rs10925503 polymorphism of GGPPS gene was correlated to serum ß-CTX levels at baseline, and patients with TT genotype had significantly higher serum ß-CTX level than those with TC or CC genotype (all P<0.05). No correlation was found between polymorphisms of GGPPS gene and serum total ALP levels, as well as BMD at baseline. After 12 months of treatment, lumbar spine and hip BMD increased and serum bone turnover markers decreased significantly (P<0.01), and without obvious differences between the low dose and standard dose groups (all P>0.05). However, GGPPS gene polymorphisms were uncorrelated to percentage changes of BMD, serum total ALP, and ß-CTX levels (all P>0.05).Conclusion GGPPS gene polymorphisms are correlated to osteoclasts activity, but all tag single nucleotide polymorphisms of GGPPS gene have no influence on the skeletal response to alendronate treatment.


Assuntos
Polimorfismo Genético , Alendronato , Grupo com Ancestrais do Continente Asiático , Biomarcadores , Densidade Óssea , Feminino , Geranil-Geranildifosfato Geranil-Geraniltransferase , Humanos , Osteoporose Pós-Menopausa , Fenótipo
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