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1.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 490-494, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816659

RESUMO

Objective: To investigate the effects of RPA1 silencing on the invasion, migration and cell cycle of human nasopharyngeal carcinoma CNE-2R cells. Methods: shRNA technology was used to construct CNE-2R cell lines with RPA1 low-expression, which were verified by RT-PCR and Western blotting. The following assays were performed using the three 3 groups: control group(CNE-2),negative control group(NC-shRNA) and RPA1 down-regulation group(RPA1-shRNA). The effects of RPA silence on the proliferation, invasion, migration, and cell cycle of CNE-2R cells were detected using Cell Counting Kit-8, clone formation experiment, Transwell, scratch test and flow cytometry, respectively. The expressions of Chk2, p-Chk2, Cdc 25c and p-cdc25c were tested by Western blot assay. Results: The expressions of RPA1 mRNA and protein in the RPA1-shRNA group were lower than those in the CNE-2 and NC-shRNA groups significantly (P<0.01 and 0.05). Compared with CNE-2 and NC-shRNA groups, the abilities of proliferation, invasion and migration of RPA1-shRNA group were decreased and the cell cycle in the RPA1-shRNA group was blocked in the G2/M phase (P<0.01). The expressions of Chk2 and Cdc25c in RPA1-shRNA group cells were lower than those in CNE-2R and NC-shRNA group cells (P<0.05), while the expressions of p-Chk2 and p-cdc25c were higher than those in the other groups (P<0.05). Conclusion: After RPA1 silenced, the proliferation and migration of radio resistant human nasopharyngeal carcinoma CNE-2R cells was inhibited, resulting in cell cycle arrested in the G2/M phase.


Assuntos
Neoplasias Nasofaríngeas , Apoptose , Ciclo Celular , Divisão Celular , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 529-533, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816667

RESUMO

Objective: To compare the changes in the number of circulating endothelial progenitor cells and hypoxia-inducible factors in patients with type 2 diabetes at different altitudes, and to provide a basis for the research and treatment of type 2 diabetes vascular complications. Methods: Selected Type 2 diabetes patients who were diagnosed in a low altitude area of 386 m (Xianyang City) and a high altitude area of 1 520 m (Lanzhou) (25 persons/29 persons) and healthy persons (20 persons/20 persons) were selected. An automatic biochemical analyzer was used to detect the indexes of blood lipids, blood glucose, and glycosylated hemoglobin of the two groups of people, and the concentration of Hypoxia inducible factor-1α (HIF-1α) was detected by enzyme-linked immunosorbent assay (ELISA). The number of circulating endothelial progenitor cells (EPCs) in peripheral blood was determined by a cytometer. Results: No matter in low or high altitude areas, the number of circulating EPCs in the diabetes group was lower than that in the healthy group (P<0.01). The levels of body mass index (BMI), waist to hip ratio (WHR), triglyceride (TG), fasting blood glucose (FBG) and glycosylated hemoglobin (HbAlc) were increased (P<0.05). Compared with the low-altitude group, the expression levels of HIF-1α in diabetic patients at high-altitude and healthy people were increased significantly (P<0.05), while the number of circulating EPCs was decreased significantly (P<0.05), and the number of circulating EPCs in healthy people or the patients with type 2 diabetes without vascular complications was higher than that of patients with type 2 diabetes with vascular complications (P<0.05). Conclusion: With the increase in altitude, the expression level of HIF-1α in type 2 diabetes mellitus(T2DM)patients is increased, and the number of circulating EPCs is decreased, which is closely related to the degree of vascular disease. Therefore, it is possible through transplantation of EPCs for high altitude T2DM patients to achieve the prevention and improvement of diabetic vascular complications.


Assuntos
Diabetes Mellitus Tipo 2 , Células Progenitoras Endoteliais , Altitude , Hemoglobina A Glicada , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia
4.
Cell Death Discov ; 7(1): 282, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635641

RESUMO

The fatality rate of non-small cell lung cancer (NSCLC) has been high due to the existence of cancer stem cells (CSCs). Non-muscle myosin heavy chain 9 (MYH9) can promote the progression of various tumors, but its effect on the stem cell-like characteristics of lung cancer cells (LCCs) has not been clarified. Our research found that the stemness characteristics of LCCs were significantly enhanced by the overexpression of MYH9, and the knockout of MYH9 had the opposite effects. The in vivo with inhibitor blebbistatin further confirmed the effect of MYH9 on the stem cell-like behavior of LCCs. Furthermore, western blotting showed that the expression level of CSCs markers (CD44, SOX2, Nanog, CD133, and OCT4) was also regulated by MYH9. Mechanistic studies have shown that MYH9 regulates stem cell-like features of LCCs by regulating the mTOR signaling pathway, which was supported by sphere formation experiments after LCCs were treated with inhibitors Rapamycin and CHIR-99021. Importantly, high expression of MYH9 in lung cancer is positively correlated with poor clinical prognosis and is an independent risk factor for patients with NSCLC.

5.
J Tradit Chin Med ; 41(5): 826-832, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34708642

RESUMO

OBJECTIVE: To describe a protocol to assess the effects of Traditional Chinese Medicine (TCM) on patients with coronary heart disease (CHD) showing symptoms of phlegm-heat-stasis symptom pattern. METHODS: This is a single-blind randomized controlled trial that will be conducted in the First Teaching Hospital of Tianjin University of TCM and 60 patients with CHD showing phlegm-heat-stasis symptom pattern will be included. Patients will be randomly divided into either a treatment group (Qingre Huatan formulae + Western Medicine) or to a control group (conventional Western Medicine only) for 7-14 d. Primary patient outcomes will be vascular endothelial function and quality of life. Measurement data will be expressed as mean ± standard deviation using t-test analysis or repeated-measure variance analysis. Enumeration data will be expressed by cases and percentages, using χ2 analysis, and rank sum test will be used for ranked data. RESULTS: This study further verified the effectiveness and safety of Qingre Huatan formulae for the phlegm-heat-stasis syndrome pattern of CHD on the basis of previous studies on the characteristics of syndromes and medication rules. DISCUSSION: Phlegm-heat-stasis symptom pattern has become a common manifestation in CHD. Standardized Western medications together with TCM have been extensively used in China and have developed into a comprehensive treatment model. Our trial will help formulate recommendations for symptom maintenance and provide clinical evidence for the application of TCM for patients with CHD showing phlegm-heat-stasis symptom pattern.

6.
Front Pharmacol ; 12: 668407, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335247

RESUMO

Coronavirus disease 2019 (COVID-19) is an emergent infectious pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is highly contagious and pathogenic. COVID-19 has rapidly swept across the world since it was first discovered in December 2019 and has drawn significant attention worldwide. During the early stages of the outbreak in China, traditional Chinese medicines (TCMs) were involved in the whole treatment process. As an indispensable part of TCM, Chinese patent medicines (CPMs) played an irreplaceable role in the prevention and treatment of this epidemic. Their use has achieved remarkable therapeutic efficacy during the period of medical observation and clinical treatment of mild, moderate, severe, and critical cases and during convalescence. In order to better propagate and make full use of the benefits of TCM in the treatment of COVID-19, this review will summarize the potential target of SARS-CoV-2 as well as the theoretical basis and clinical efficacy of recommended 22 CPMs by the National Health Commission and the Administration of TCM and local provinces or cities in the treatment of COVID-19. Additionally, the study will further analyze the drug composition, potential active ingredients, potential targets, regulated signaling pathways, and possible mechanisms for COVID-19 through anti-inflammatory and immunoregulation, antiviral, improve lung injury, antipyretic and organ protection to provide meaningful information about the clinical application of CPMs.

7.
Phytochemistry ; 190: 112850, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34217042

RESUMO

The phytochemical assessment of Cinnamomum migao H. W. Li fruits illustrated the isolation and identification of ten undescribed guaiane-type sesquiterpenoids "miganoids A-J″ and one undescribed sesquiterpene "7(S)-(hydroxypropanyl)-3-methyl-2-(4-oxopentyl) cyclohex-2-en-1-one". The extensive analysis of HRESIMS, 1D NMR, 2D NMR, experimental circular dichroism (ECD), and calculated (ECD) analysis entirely corroborated the configuration and confirmation of these isolated compounds. Moreover, the anti-inflammatory properties of the reported compounds were established by determining the LPS induced nitric oxide production. In the current study, miganoid C is testified the most active compound with about 89% NO inhibition. Additionally, miganoids C, E, and G also exhibited moderate inhibitory effects against the pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6). The IC50 values for miganoid C and miganoid G were determined as 19.4 and 14.5 µΜ against TNF-α mRNA, respectively.


Assuntos
Cinnamomum , Sesquiterpenos , Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Óxido Nítrico , Sesquiterpenos/farmacologia , Sesquiterpenos de Guaiano
8.
Front Cell Dev Biol ; 9: 659260, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34164393

RESUMO

Background: Focusing on antiangiogenesis may provide promising choices for treatment of gastric cancer (GC). This study aimed to investigate the mechanistic role of BCAT1 in the pathogenesis of GC, particularly in angiogenesis. Methods: Bioinformatics and clinical samples analysis were used to investigate the expression and potential mechanism of BCAT1 in GC. BGC823 cells with BCAT1 overexpression or silencing were induced by lentiviral transduction. Cell phenotypes and angiogenesis were evaluated. The relevant proteins were quantized by Western blotting, immunohistochemistry, or immunofluorescence. Xenograft models were constructed to confirm the role of BCAT1 in vivo. Results: BCAT1 was overexpressed in GC patients and associated with lower survival. BCAT1 expression was correlated with proliferation-, invasion-, or angiogenesis-related markers expression and pathways. Silencing BCAT1 expression suppressed cell viability, colony formation, cycle progression, invasion, and angiogenesis of BGC823 cells, as well as the tumor growth of xenograft models, whereas overexpressing BCAT1 had the opposite results both in vitro and in vivo. Bioinformatics analysis and Western blotting demonstrated that BCAT1 activated the PI3K/AKT/mTOR pathway. The addition of LY294002 reversed the tumor growth induced by BCAT1 overexpression, further verifying this mechanism. Conclusion: BCAT1 might act as an oncogene by facilitating proliferation, invasion, and angiogenesis through activation of the PI3K/AKT/mTOR pathway. This finding could aid the optimization of antiangiogenesis strategies.

9.
Stem Cell Res Ther ; 12(1): 119, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579362

RESUMO

BACKGROUND: Tumor-associated antigens (TAAs) can be targeted in cancer therapy. We previously identified a monoclonal antibody (mAb) 12C7, which presented anti-tumor activity in lung cancer stem cells (LCSCs). Here, we aimed to identify the target antigen for 12C7 and confirm its role in LCSCs. METHODS: Immunofluorescence was used for antigen localization. After targeted antigen purification by electrophoresis and immunoblot, the antigen was identified by LC-MALDI-TOF/TOF mass spectrometry, immunofluorescence, and immunoprecipitation. The overexpression or silence of ENO1 was induced by lentiviral transduction. Self-renewal, growth, and invasion of LCSCs were evaluated by sphere formation, colony formation, and invasion assay, respectively. High-throughput transcriptome sequencing (RNA-seq) and bioinformatics analysis were performed to analyze downstream targets and pathways of targeted antigen. RESULTS: Targeted antigen showed a surface antigen expression pattern, and the 43-55 kDa protein band was identified as α-enolase (ENO1). Self-renewal, growth, and invasion abilities of LCSCs were remarkably inhibited by ENO1 downregulation, while enhanced by ENO1 upregulation. RNA-seq and bioinformatics analysis eventually screened 4 self-renewal-related and 6 invasion-related differentially expressed genes. GSEA analysis and qRT-PCR verified that ENO1 regulated self-renewal, invasion-related genes, and pathways. KEGG pathway analysis and immunoblot demonstrated that ENO1 inactivated AMPK pathway and activated mTOR pathway in LCSCs. CONCLUSIONS: ENO1 is identified as a targeted antigen of mAb 12C7 and plays a pivotal role in facilitating self-renewal, growth, and invasion of LCSCs. These findings provide a potent therapeutic target for the stem cell therapy for lung cancer and have potential to improve the anti-tumor activity of 12C7.


Assuntos
Neoplasias , Fosfopiruvato Hidratase , Proteínas Quinases Ativadas por AMP , Anticorpos Monoclonais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Pulmão , Células-Tronco Neoplásicas , Fenótipo , Fosfopiruvato Hidratase/genética , Serina-Treonina Quinases TOR/genética
10.
Cell Death Dis ; 11(10): 870, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067426

RESUMO

Recent studies have demonstrated that gastric cancer stem cells (CSCs) are a rare sub-group of gastric cancer (GC) cells and have an important role in promoting the tumor growth and progression of GC. In the present study, we demonstrated that the glycolytic enzyme Enolase 1 (ENO1) was involved in the regulation of the stem cell-like characteristics of GC cells, as compared to the parental cell lines PAMC-82 and SNU16, the expression of ENO1 in spheroids markedly increased. We then observed that ENO1 could enhance stem cell-like characteristics, including self-renewal capacity, cell invasion and migration, chemoresistance, and even the tumorigenicity of GC cells. ENO1 is known as an enzyme that is involved in glycolysis, but our results showed that ENO1 could markedly promote the glycolytic activity of cells. Furthermore, inhibiting glycolysis activity using 2-deoxy-D-glucose treatment significantly reduced the stemness of GC cells. Therefore, ENO1 could improve the stemness of CSCs by enhancing the cells' glycolysis. Subsequently, to further confirm our results, we found that the inhibition of ENO1 using AP-III-a4 (ENOblock) could reduce the stemness of GC cells to a similar extent as the knockdown of ENO1 by shRNA. Finally, increased expression of ENO1 was related to poor prognosis in GC patients. Taken together, our results demonstrated that ENO1 is a significant biomarker associated with the stemness of GC cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicólise/fisiologia , Células-Tronco Neoplásicas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Glicólise/genética , Humanos , Fosfopiruvato Hidratase/genética , Estômago/patologia , Neoplasias Gástricas/patologia
11.
Ann Rheum Dis ; 79(11): 1460-1467, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32737104

RESUMO

OBJECTIVES AND METHODS: With 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them. RESULTS: Lower eBMD were observed in patients with PsA than in controls in both model0 (ß-coefficient=-0.014, p=0.0006) and model1 (ß-coefficient=-0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (ß-coefficient=-0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture. CONCLUSIONS: The effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.


Assuntos
Antirreumáticos/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose/epidemiologia , Psoríase/complicações , Psoríase/tratamento farmacológico , Humanos , Análise da Randomização Mendeliana
12.
Huan Jing Ke Xue ; 41(6): 2898-2907, 2020 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608807

RESUMO

Plants modify the soil microenvironment through root exudation. It is important to study the dynamic changes of soil ecosystem from the perspective of root-soil-microbe interactions after vegetation restoration in the riparian zone of the Three Gorges Reservoir (TGR). The rhizosphere and bulk soils of Cynodon dactylon, Hemarthria altissima, Taxodium distichum, and Salix matsudana were collected from the vegetation restoration demonstration base of Ruxi River to explore the differences in nutrient contents and enzyme activities between the rhizosphere and bulk soils. At the same time, the diversity of the bacterial community in the rhizosphere and bulk soils was also investigated using the high throughput sequencing method, with the aim to clarify the growth adaptabilities and nutritional utilization strategies within a more precise rhizosphere range. The results showed that ① Suitable plants enhanced the transformation efficiency of rhizosphere nutrients in different ways to improve their adaptability to the soil environment in the TGR. Compared with bulk soil, root activities had significant effects on nutrient contents in the rhizosphere. Among them, SOC, AN, TN, and AP were enriched significantly to a certain degree, while the changes of potassium were not consistent in different plant species. ② In the process of vegetation restoration, the deposition of litter and root secretion indirectly regulated soil enzyme activity. Invertase, urease, and acid phosphatase, all exhibited positive rhizosphere effects (R/S>1) in these four suitable plant species. However, considering the differences in root structure and physiological characteristics between herbaceous and woody plants, the rhizosphere effect of these three enzymes in four plants was different. ③ The results of high-throughput sequencing showed that there was no significant difference in bacterial community diversity between the rhizosphere and bulk soil of four suitable plant species in the TGR. In addition, Proteobacteria, Acidobacteria, Chloroflexi, Actinobacteria, Bacteroidetes, Planctomycetes, Cyanobacteria, Firmicutes, Nitrospirae, Gemmatimonadetes, WS3, and Crenarchaeota were the twelve most abundant bacterial phyla in the rhizosphere and bulk soils, serving the ecological functions of nutrition absorption and disease suppression. Their colonization was found to be beneficial to the stress resistance of plants growing in harsh riparian ecosystems in the TGR.


Assuntos
Ecossistema , Solo , Nutrientes , Raízes de Plantas , Plantas , Rizosfera , Microbiologia do Solo
13.
Korean J Parasitol ; 58(2): 153-159, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32418384

RESUMO

The chigger mite Leptotrombidium sialkotense is one of the 6 main vectors of scrub typhus in China. Before present study, L. sialkotense was found in some parts of Hunan province, China with a narrow geographical distribution. During field investigation 2016-2017, we found L. sialkotense in Jingha, southern Yunnan, China. Of 15 small mammal host species, L. sialkotense were collected from 6 species of the hosts. Rattus brunneusculus was a dominant host of L. sialkotense, from which 98.3% of the mites were collected. The chigger mite showed a relatively high infestation prevalence (PM=11.7%) and mean abundance (MA=0.5) in comparison with the rest 5 host species. These results reveal a certain host specificity of L. sialkotense to a rat R. brunneusculus. The mite L. sialkotense showed an aggregated distribution on the host (P<0.05). A positive correlation observed between L. sialkotense and the body length of hosts. There was a positive interspecific association between L. sialkotense and 2 other dominant vectors, L. deliense and L. scutellare.


Assuntos
Vetores de Doenças , Tifo por Ácaros/parasitologia , Trombiculidae , Animais , China/epidemiologia , Interações Hospedeiro-Parasita , Ratos , Tifo por Ácaros/epidemiologia
14.
Parkinsonism Relat Disord ; 73: 1-2, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32151945

RESUMO

We screened the RFC1 intronic AAGGG repeat expansions in late-onset ataxia cases, MSA patients and controls. The data suggested that no biallelic repeat expansion carrier was found in our cohort and the heterozygous intronic AAGGG repeat expansions may not lead to an increased risk of late-onset ataxia or MSA.


Assuntos
Ataxia Cerebelar/genética , Expansão das Repetições de DNA , Atrofia de Múltiplos Sistemas/genética , Proteína de Replicação C/genética , Adulto , Idade de Início , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Mil Med Res ; 7(1): 7, 2020 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-32111253

RESUMO

Methodological quality (risk of bias) assessment is an important step before study initiation usage. Therefore, accurately judging study type is the first priority, and the choosing proper tool is also important. In this review, we introduced methodological quality assessment tools for randomized controlled trial (including individual and cluster), animal study, non-randomized interventional studies (including follow-up study, controlled before-and-after study, before-after/ pre-post study, uncontrolled longitudinal study, interrupted time series study), cohort study, case-control study, cross-sectional study (including analytical and descriptive), observational case series and case reports, comparative effectiveness research, diagnostic study, health economic evaluation, prediction study (including predictor finding study, prediction model impact study, prognostic prediction model study), qualitative study, outcome measurement instruments (including patient - reported outcome measure development, content validity, structural validity, internal consistency, cross-cultural validity/ measurement invariance, reliability, measurement error, criterion validity, hypotheses testing for construct validity, and responsiveness), systematic review and meta-analysis, and clinical practice guideline. The readers of our review can distinguish the types of medical studies and choose appropriate tools. In one word, comprehensively mastering relevant knowledge and implementing more practices are basic requirements for correctly assessing the methodological quality.


Assuntos
Viés , Psicometria/normas , Projetos de Pesquisa/normas , Pesquisa/classificação , Animais , Humanos , Psicometria/instrumentação , Psicometria/métodos , Reprodutibilidade dos Testes , Pesquisa/instrumentação , Projetos de Pesquisa/estatística & dados numéricos
16.
Front Neurol ; 10: 1094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749756

RESUMO

Background: Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is the most common type of autosomal dominant ataxia. Like other neurodegenerative diseases, is characterized by the dysfunction of the protein quality control (PQC) system. The carboxyl terminus of the Hsp70-interacting protein (CHIP), an important component of PQC, participates in the clearance of misfolded proteins to maintain cellular homeostasis. While no cure for SCA3 exists, the disease progresses slowly. Thus, the identification of biomarkers that indicate the severity and prognosis of this disease would be valuable. Methods: In this exploratory case-control study, we quantitatively evaluated the concentrations of CHIP in the sera of 80 patients with SCA3 and 80 age and sex-matched controls, using the enzyme-linked immunosorbent assay (ELISA). CHIP levels in the cerebrospinal fluid (CSF) donated by six patients and six healthy volunteers, who were matched for sex and age were also measured. All the baseline data were collected, and the patients underwent clinical evaluation. The correlations between CHIP levels and several clinical measurements were analyzed. Results: The serum CHIP level in the SCA3 group was (80.93 ± 28.68) ng/mL, which was significantly higher than those in the control group [(40.37 ± 18.55) ng/mL]. Similar results were observed for the CSF [(164.59 ± 42.99) ng/mL and (37.47 ± 7.85) ng/mL, respectively]. CSF CHIP levels were significantly higher than the serum CHIP levels in the SCA3 group but not in the control group. The Dunn-Bonferroni post-hoc for Kruskal-Wallis test revealed no significant difference between the serum and CSF of the patients and the control group. Multivariate linear regression showed that serum CHIP levels correlated positively with disease severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Moreover, we found that serum CHIP levels were moderately correlated with age in healthy controls. Conclusion: The present study determined that CHIP levels increased significantly in the serum and CSF of patients with SCA3 and that serum CHIP levels were corelated with disease severity. Thus, CHIP is a promising biomarker for SCA3.

17.
Aging Dis ; 10(4): 908-914, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31440394

RESUMO

Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) mutations are responsible for autosomal dominant early-onset Alzheimer's disease (AD-EOAD). To analyze the phenotypes and genotypes of EOAD patients, we performed comprehensive clinical assessments as well as mutation screening of PSEN1, PSEN2, and exons 16 and 17 of APP by Sanger sequencing in the three Chinese EOAD families. We identified two novel mutations of PSEN1 (Y256N and H214R) in samples from these families, and a de novo mutation of PSEN1 (G206V) in a patient with very early-onset sporadic Alzheimer's disease. A combination of bioinformatics tools based on evolutionary, structural and computational methods predicted that the mutations were all deleterious. These findings suggest that PSEN1 Y256N, H214R, and G206V need to be considered as potential causative mutations in EOAD patients. Further functional studies are needed to evaluate the roles of these mutations in the pathogenesis of AD.

18.
Neuromuscul Disord ; 29(7): 549-553, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31255525

RESUMO

Limb-girdle myasthenia with tubular aggregates, a subtype of congenital myasthenic syndrome, is an extremely rare autosomal recessive genetic disease characterized by prominent limb-girdle weakness and good response to acetylcholinesterase inhibitor therapy. Herein, we reported two novel mutations of GFPT1 gene in a Chinese pedigree. Two siblings presented with fatigue, weakness of limb-girdle and decrement of the muscle action potential with repetitive nerve stimulation. Thus, myasthenia gravis was initially suspected, but anti-AChR antibodies were negative. Two novel missense mutations (p.Lys154Asn and p.Asn363Ser) in GFPT1 were identified through genetic testing conducted on 167 well-established genes associated with muscular diseases by targeted high throughput sequencing. Both mutations have not been recorded in the dsSNP database, Exome Aggregation Consortium database and 1000 Genomes Project database. The mutation sites were co-segregated with the phenotype and conserved between the different species. The mutations were not found in the 200 unrelated normal controls. Muscle biopsies revealed tubular aggregates, in accordance with previous reports with GFPT1 mutations. Subsequently, dramatic improvement in strength occurred following anti-cholinesterase therapy. Our study will be helpful for the diagnosis and treatment for Limb-girdle myasthenia with tubular aggregates.


Assuntos
Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação de Sentido Incorreto/genética , Miopatias Congênitas Estruturais/genética , Potenciais de Ação , Animais , Inibidores da Colinesterase/uso terapêutico , Bases de Dados Genéticas , Estimulação Elétrica , Feminino , Testes Genéticos , Humanos , Masculino , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/patologia , Miopatias Congênitas Estruturais/tratamento farmacológico , Miopatias Congênitas Estruturais/patologia , Linhagem , Polimorfismo de Nucleotídeo Único , Brometo de Piridostigmina/uso terapêutico , Adulto Jovem
19.
Front Mol Neurosci ; 12: 159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316347

RESUMO

Spinocerebellar ataxia 3, also known as Machado-Joseph disease (SCA3/MJD), is a rare autosomal-dominant neurodegenerative disease caused by an abnormal expansion of CAG repeats in the ATXN3 gene. In the present study, we performed a global metabolomic analysis to identify pathogenic biochemical pathways and novel biomarkers implicated in SCA3 patients. Metabolic profiling of serum samples from 13 preclinical SCA3 patients, 13 symptomatic SCA3 patients, and 15 healthy controls were mapped using ultra-high-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry techniques. The symptomatic SCA3 patients showed a metabolic profile significantly distinct from those of the preclinical SCA3 patients and healthy controls. The principal differential metabolites were involved in the amino acid (AA) metabolism and fatty acid metabolism pathways. In addition, four candidate serum biomarkers, FFA 16:1 (palmitoleic acid), FFA 18:3 (linolenic acid), L-Proline and L-Tryptophan, were selected to discriminate between symptomatic SCA3 patients and healthy controls by receiver operator curve analysis with an area under the curve of 0.979. Our study demonstrates that symptomatic SCA3 patients present distinct metabolic profiles with perturbed AA metabolism and fatty acid metabolism, and FFA 16:1, FFA 18:3, L-Proline and L-Tryptophan are identified as potential disease biomarkers.

20.
J Neurol ; 266(7): 1796-1800, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31041581

RESUMO

BACKGROUND: Recently, rs2421947 in DNM3 (dynamin 3) was reported as a genetic modifier of age at onset (AAO) of LRRK2 G2019S-related Parkinson's disease (PD) in a genome-wide association study in Arab-Berber population. Rs356219 in SNCA (α-synuclein) was also reported to regulate the AAO of LRRK2-related PD in European populations, and GAK (Cyclin G-associated kinase) rs1524282 was reported to be associated with an increased PD risk with an interaction with SNCA rs356219. G2019S variant is rare in Asian populations, whereas two other Asian-specific LRRK2 variants, G2385R and R1628P, are more frequent with a twofold increased risk of PD. METHODS: In this study, we investigated whether rs2421947, rs356219 and rs1524282 modified AAO in LRRK2-related PD patients in Han Chinese population. We screened LRRK2 G2385R and R1628P variants in 732 PD patients and 1992 healthy controls, and genotyped DNM3 rs2421947, SNCA rs356219 and GAK rs1524282 among the LRRK2 carriers. RESULTS: The SNCA rs356219-G allele was found to increase the risk of PD in LRRK2 carriers (OR 1.50, 95%CI 1.08-2.01, P = 0.016), and the AAO of AG + GG genotypes was 4 years earlier than AA genotype (P = 0.006). Nonetheless, no similar association was found in DNM3 rs2421947 and GAK rs1524282. CONCLUSIONS: Our results show that SNCA but not DNM3 or GAK is associated with AAO of LRRK2-PD patients in Chinese population.


Assuntos
Dinamina III/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , alfa-Sinucleína/genética , Idade de Início , Idoso , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Vigilância da População
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