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1.
Biosens Bioelectron ; 176: 112954, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33412428

RESUMO

CRISPR/Cas system have drawn increasing attention in accurate and sensitive nucleic acids detection. Herein, we reported a novel Cas12a-based electrochemiluminescence biosensor for target amplification-free human papilloma virus subtype (HPV-16) DNA detection. During this detection process, Cas12a employed its two-part recognition mechanism to improve the specificity and trans-cleavage capability to achieve signal amplification, while L-Methionine stabilized gold nanoclusters (Met-AuNCs) were served as high-efficiency ECL emitters to achieve ECL signal transition. Given the unique combination of Cas12a with ECL technique, the detection limit was determined as 0.48 pM and the whole detection could be completed within 70 min. We also validated the practical application of the proposed biosensor by using undiluted human blood samples, which gives impetus to the design of new generations of CRISPR/Cas detection system beyond the traditional ones with ultimate applications in sensing analysis and diagnostic technologies.

2.
Math Biosci Eng ; 17(4): 3240-3251, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987527

RESUMO

A stochastic two-species competition system with saturation effect and distributed delays is formulated, in which two coupling noise sources are incorporated and every noise source has effect on two species' intrinsic growth rates in nonlinear form. By transforming the two-dimensional system with weak kernel into an equivalent four-dimensional system, sufficient conditions for extinction of two species and the existence of a stationary distribution of the positive solutions to the system are obtained. Our main results show that the two coupling noises play a significant role on the long time behavior of system.

3.
Biomed Environ Sci ; 33(8): 573-582, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32933609

RESUMO

Objective: To investigate the relationship between human cytomegalovirus (HCMV) infection and peripheral blood CD14 +CD16 + monocytes in the pathogenesis of coronary heart disease (CHD), and to elucidate the mechanism of pathogenesis in CHD by analyzing the correlation between infection, inflammation, and CHD, to provide a basis for the prevention, evaluation, and treatment of the disease. Methods: In total, 192 patients with CHD were divided into three groups: latent CHD, angina pectoris, and myocardial infarction. HCMV-IgM and -IgG antibodies were assessed using ELISA; CD14 +CD16 + monocytes were counted using a five-type automated hematology analyzer; mononuclear cells were assessed using fluorescence-activated cell sorting; and an automatic biochemical analyzer was used to measure the levels of triglyceride, cholesterol, high- and low-density lipoprotein cholesterols, lipoprotein, hs-CRp and Hcy. Results: The positive rates of HCMV-IgM and -IgG were significantly higher in the CHD groups than in the control group. HCMV infection affects lipid metabolism to promote immune and inflammatory responses. Conclusion: HCMV infection has a specific correlation with the occurrence and development of CHD. The expression of CD14 +CD16 + mononuclear cells in the CHD group was increased accordingly and correlated with acute HCMV infection. Thus, HCMV antibody as well as peripheral blood CD14 +CD16 + mononuclear cells can be used to monitor the occurrence and development of CHD.


Assuntos
Angina Pectoris/epidemiologia , Doença das Coronárias/epidemiologia , Infecções por Citomegalovirus/complicações , Citomegalovirus/fisiologia , Inflamação/epidemiologia , Infarto do Miocárdio/epidemiologia , Angina Pectoris/virologia , China/epidemiologia , Doença das Coronárias/virologia , Humanos , Incidência , Inflamação/etiologia , Contagem de Leucócitos , Monócitos/metabolismo , Infarto do Miocárdio/virologia
4.
World J Psychiatry ; 10(6): 125-138, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32742946

RESUMO

A spectrum of neuropsychiatric disorders is a common complication from stroke. Neuropsychiatric disorders after stroke have negative effects on functional recovery, increasing the rate of mortality and disability of stroke survivors. Given the vital significance of maintaining physical and mental health in stroke patients, neuropsychiatric issues after stroke have raised concerns by clinicians and researchers. This mini-review focuses on the most common non-cognitive functional neuropsychiatric disorders seen after stroke, including depressive disorders, anxiety disorders, post-traumatic stress disorder, psychosis, and psychotic disorders. For each condition, the clinical performance, epidemiology, identification of the therapeutic implication, and strategies are reviewed and discussed; the main opinions and perspectives presented here are based on the latest controlled studies, meta-analysis, or updated systematic reviews. In the absence of data from controlled studies, consensus recommendations were provided accordingly.

5.
Obes Surg ; 30(1): 279-289, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605365

RESUMO

BACKGROUND: Duodenal-jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction. Increasing evidence has demonstrated that brain insulin signaling plays an important role in the pathophysiology of type 2 diabetes. This study explores whether the antidiabetic effect of DJB is involved in brain insulin signaling activation and brain glucose utilization. METHODS: A diabetic rat model was established by high-fat and high-glucose diet. DJB or sham surgery was performed in diabetic rats. 18F-FDG PET scanning was used to detect glucose uptake in different organs, particularly in the brain. The levels of glucose transporters, glucose utilization-related proteins (HK1 and PFK2), insulin, and insulin signaling pathway-related proteins (InsR, IRS1/2, PI3K, and p-Akt) in the brain tissues were evaluated and analyzed. RESULTS: The results showed that DJB significantly improved basal glycemic parameters and reversed the decreasing glucose uptake in the brains of type 2 diabetic rats. DJB significantly increased not only the expression levels of brain insulin, IRS1/2, PI3K, and p-Akt but also the levels of the glucose utilization enzymes HK1 and PFK2 in the brain. CONCLUSION: These results indicate that enhanced brain insulin signaling transduction and brain glucose utilization play important roles in the antidiabetic effect of DJB.


Assuntos
Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Duodeno/cirurgia , Derivação Gástrica/métodos , Glucose/metabolismo , Insulina/metabolismo , Jejuno/cirurgia , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/cirurgia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Duodeno/patologia , Resistência à Insulina/fisiologia , Jejuno/patologia , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Resultado do Tratamento , Perda de Peso
6.
J Phys Chem A ; 124(1): 82-89, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31815471

RESUMO

A new terbium (III) luminescent compound {[Tb2(PDC)2(ox)(H2O)4](H2O)2}n was synthesized by the self-assembly of Tb3+ ions with 3,5-pyridinedicarboxylate (PDC) and oxalate (ox) ligands and characterized by fluorescence spectroscopy and single-crystal X-ray diffraction. The density functional theory (DFT) and high-level correlated ab initio wave function methods with Spin-Orbit Coupling correction (CASSCF/SO and CAS-NEVPT2/SOC) were successfully applied to predict the absorption and emission spectra of this strongly correlated lanthanide system in excellent agreement with the experimental results.

7.
Aging Dis ; 10(6): 1199-1206, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788332

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective impairment of upper and lower motor neurons. We aimed to investigate the genetic spectrum and variability in Chinese patients with ALS. A total of 24 familial ALS (FALS) and 21 early-onset sporadic ALS (SALS) of Chinese ancestry were enrolled. Targeted next-generation sequencing (NGS) was performed in the probands, followed by verification by Sanger sequencing and co-segregation analysis. Clinical features of patients with pathogenic or likely pathogenic variants were present. The mutation frequency of ALS-related genes was then analyzed in Chinese population. In this cohort, 17 known mutations (9 SOD1, 5 FUS, 2 TARDBP and one SETX) were identified in 14 FALS and 6 early-onset SALS. Moreover, 7 novel variants (SOD1 c.112G>C, OPTN c.811C>T, ERBB4 c.965T>A, DCTN1 c.1915C>T, NEFH c.2602G>A, NEK1 c.3622G>A, and TAF15 c.1535G>A) were identified. In southeastern Chinese FALS, the mutation frequency of SOD1, FUS, and TARDBP was 52.9%, 8.8%, 8.8% respectively. In early-onset SALS, FUS mutations were the most common (22.6%). In Chinese ALS cases, p.H47R is most frequent SOD1 mutations, while p.R521 is most common FUS mutation and p.M337V is most common TARDBP mutation. Our results revealed that mutations in SOD1, FUS and TARDBP are the most common cause of Chinese FALS, while FUS mutations are the most common cause of early-onset SALS. The genetic spectrum is different between Chinese ALS and Caucasian ALS.

8.
Aging Dis ; 10(5): 1003-1011, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31595198

RESUMO

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG triplet repeats expansion in exon 1 of the Huntingtin gene (HTT). In China, HD is considered to have a low prevalence. The goal of this study was to describe the clinical characteristic and genetic profiles of HD in a Chinese cohort. A total of 322 individuals with expanded CAG repeats were consecutively recruited from the neurologic clinics of three medical centers in Southeastern China between 2008 and 2018. Among them, 80 were pre-symptomatic mutation carriers and 242 were symptomatic patients. The mean age at onset (AAO), defined here as the age at motor symptom onset, of the 242 manifest HD individuals was 40.3 ± 11.9 years and the mean CAG repeat length was 46.1 ± 7.5 in the group of symptomatic patients. Initial symptoms were abnormal movements in 88.8% of the patients with psychiatric symptoms in 6.2%, cognitive impairment in 3.3% and others in 1.7%. The AAO of motor was negatively correlated with the CAG repeat length in an exponential regression analysis (R 2 = 0.74, P<0.001). Analysis of 46 parent-child pairs showed that the CAG repeat length was longer in the offspring group (45.8 ±7.6) than in the parent group (43.8 ±3.0) (p=0.005). Overall, this study provides clinical and genetic profiles in a cohort of Chinese patients with HD, which should contribute to a better understanding of this disorder.

9.
Transl Neurodegener ; 8: 19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31289639

RESUMO

Background: Although many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population. Methods: In this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants. Results: We identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in SPG11, two (p.T55 M, p.S308 T) in AP5Z1, one (p.S242 N) in ALDH18A1, one (p.D597fs) in GBA2, and one (p.Q486X) in ATP13A2 in 8 index patients and their family members. Mutations in ALDH18A1, AP5Z1, CAPN1 and ATP13A2 genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in ALDH18A1 decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in AP5Z1 induced lysosomal dysfunction. Conclusion: Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

10.
J Cell Mol Med ; 23(8): 4991-5005, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31207106

RESUMO

Melanoma is one of the most malignant skin tumours with constantly increasing incidence worldwide. Previous studies have demonstrated that microRNA-374 (miR-374) is a novel biomarker for cancer therapy. Therefore, this study explores whether miR-374 targeting tyrosinase (TYR) affects melanoma and its underlying mechanism. We constructed subcutaneous melanoma models to carry out the following experiments. The cells were transfected with a series of miR-374 mimics, miR-374 inhibitors or siRNA against TYR. Dual luciferase reporter gene assay was used for the verification of the targeting relationship between miR-374 and TYR. Reverse transcription quantitative polymerase chain reaction and western blot analysis were conducted to determine the expression of miR-374, TYR, ß-catenin, B-cell leukaemia 2 (Bcl-2), Bcl-2 associated X protein (Bax), Low-density lipoprotein receptor-related protein 6 (LRP6), Leucine-rich repeat G protein-coupled receptor 5 (LGR5) and CyclinD1. Cell proliferation, migration, invasion, cell cycle distribution and apoptosis were evaluated using cell counting kit-8 assay, scratch test, transwell assay and flow cytometry respectively. TYR was proved as a putative target of miR-374 as the evidenced by the result. It was observed that up-regulated miR-374 or down-regulated TYR increased expression of Bax and decreased expressions of TYR, ß-catenin, LRP6, Bcl-2, CyclinD1 and LGR5, along with diminished cell proliferation, migration, invasion and enhanced apoptosis. Meanwhile, cells with miR-374 inhibitors showed an opposite trend. These findings indicated that up-regulated miR-374 could inhibit the expression of TYR to suppress cell proliferation, migration, invasion and promote cell apoptosis in melanoma cells by inhibiting the Wnt signalling pathway.


Assuntos
Melanoma/metabolismo , MicroRNAs/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Nus , MicroRNAs/genética , Monofenol Mono-Oxigenase/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Transplante Heterólogo , Via de Sinalização Wnt/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
11.
Math Biosci Eng ; 16(4): 2371-2390, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31137218

RESUMO

This study adopted the uniform interpolation method to obtain five gradation types (labeled A, B, C, D, and E, from "coarse-grained" to "fine-grained" types) based on the skeleton dense structure and cement-stabilized macadam (CSM) aggregate gradation range recommended by current specifications. The optimum water content of the CSM exhibited a linear increase with gradation, whereas the maximum dry density exhibited a variation that can be described by a quadratic curve, for which the peak maximum dry density was near the maximum dry density of the Type B gradation. In the CSM structure, the skeleton void effect of the coarse-grained aggregate, the filling effect of the fine-grained aggregate, and the cementation effect of the cement and aggregate exhibited corresponding fluctuations. The ability to resist temperature shrinkage deformation was reduced. Additionally, the optimum values of the compressive strength and compression rebound modulus of the CSM plotted near the curve of the Type D gradation.


Assuntos
Materiais de Construção , Polienos/química , Algoritmos , Força Compressiva , Engenharia/métodos , Teste de Materiais , Estresse Mecânico , Temperatura , Água
12.
J Clin Med ; 9(1)2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31906103

RESUMO

Atrial fibrillation (AF) is responsible for significant morbidity and mortality in patients with heart failure (HF). Modern pacemakers provide an index of intrathoracic fluid status (OptiVol fluid index-OVFI) by measuring daily intrathoracic impedance. This study aimed to determine whether OVFI is associated with increased atrial tachycardia/fibrillation (AT/AF) events in patients with a preserved ejection fraction (EF). We retrospectively reviewed data from patients with Medtronic Advisa pacemakers between 2012 and 2014 in our hospital. The association and temporal relationship between OVFI and AT/AF events were determined. A total of 150 patients with 211 follow-up visits (mean 1.4 visits per patient) were evaluated. The device-detected AT/AF prevalence was 47%. Device-measured OVFI ≥ 20 Ω-days was significantly associated with the onset of AT/AF ≥ 4 h. OVFI threshold crossing preceded AT/AF events in 55.1% of cases, followed by AT/AF events in only 18.7%. Fluid overload represented by OVFI may trigger AT/AF episodes in patients with a preserved EF more often than that previously reported in patients with a reduced EF. Our findings support the view that worsening pulmonary congestion is associated with increased AT/AF frequency and suggests that fluid overload could trigger and perpetuate AT/AF events in patients with a preserved EF.

13.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 34(2): 154-158, 2018 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-29926681

RESUMO

OBJECTIVES: Investigate the influence of benazepril and amlodipine on the expression of secretin (PZ) and somatostatin (SS) in spontaneously hypertensive rats (SHR). METHODS: Forty-five SHRs (14 weeks old, male) were randomly assigned into 3 groups (n=15):SHR group, Benazepril group (which was given benazepril 0.90 mg·kg-1·d-1) and Amlodipine group (SHRs were given amlodipine 0.45 mg· kg-1·d-1), taking WistarKyoto(WKY) as normal control (n=15), meanwhile, rats in SHR group and WKY group were given the same volume of distilled water. After 8 weeks of intervention, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was detected by enzyme-linked immunoassay and RT-PCR. RESULTS: After 8 weeks of intervention, compared with the WKY group, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was increased significantly in SHR group (P<0. 05). Compared with SHR group, the expression of PZ in duodenum and SS in sinuses ventriculi was decreased significantly in Benazepril group and Amlodipine group (P<0.05). Compared with Benazepril group, in Amlodipine group the expression of PZ mRNA in duodenum and SS mRNA in sinuses ventriculi was decreased more significantly (P<0.05). CONCLUSIONS: The regulation disorder of PZ in duodenum and SS in sinuses ventriculi exists in SHR. The antihypertensive effect of benazepril and amlodipine may be realized by regulating the expression of PZ and SS, while the regulation of amlodipine is more obvious than benazepril.


Assuntos
Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Benzazepinas/farmacologia , Hipertensão/tratamento farmacológico , Secretina/metabolismo , Somatostatina/metabolismo , Animais , Pressão Sanguínea , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
14.
J Mol Med (Berl) ; 96(7): 701-712, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29934652

RESUMO

Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative diseases characterized by progressive weakness and spasticity of lower limbs. To clarify the genetic spectrum and improve the diagnosis of HSP patients, targeted next-generation sequencing (NGS) was applied to detect the culprit genes in 55 Chinese HSP pedigrees. The classification of novel variants was based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Patients remaining negative following targeted NGS were further screened for gross deletions/duplications by multiplex ligation-dependent probe amplification (MLPA). We made a genetic diagnosis in 61.8% (34/55) of families and identified 33 mutations, including 14 known mutations and 19 novel mutations. Of them, one was de novo mutation (NIPA1: c.316G>A). SPAST mutations (22/39, 56.4%) are the most common in Chinese AD-HSP followed by ATL1 (4/39, 10.3%). Moreover, we identified the third BSCL2 mutation (c.1309G>C) related to HSP by further functional studies and first reported the KIF1A mutation (c.304G>A) in China. Our findings broaden the genetic spectrum of HSP and improve the diagnosis of HSP patients. These results demonstrate the efficiency of targeted NGS to make a more rapid and precise diagnosis in patients with clinically suspected HSP. KEY MESSAGES: We made a genetic diagnosis in 61.8% of families and identified 33 mutations. SPAST mutations are the most common in Chinese AD-HSP followed by ATL1. Our findings broaden the genetic spectrum and improve the diagnosis of HSP.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Idoso , Alelos , Substituição de Aminoácidos , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , China , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Espastina/genética , Adulto Jovem
16.
Water Sci Technol ; 77(5-6): 1483-1492, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29595151

RESUMO

This study developed a partial nitrification (PN) and anaerobic ammonia oxidation (Anammox) process for treating high-ammonia wastewater using an innovative biofilm system in which ammonia oxidizing bacteria grew on fluidized Kaldnes (K1) carriers and Anammox bacteria grew on fixed acryl resin carriers. The airlift loop biofilm reactor (ALBR) was stably operated for more than 4 months under the following conditions: 35 ± 2 °C, pH 7.5-8.0 and dissolved oxygen (DO) of 0.5-3.5 mg/L. The results showed that the total nitrogen removal efficiency reached a maximum of 75% and the total nitrogen removal loading rate was above 0.4 kg/(d·m3). DO was the most efficient control parameter in the mixed biofilm system, and values below 1.5 mg/L were observed in the riser zone for the PN reaction, while values below 0.8 mg/L were observed in the downer zone for the Anammox reaction. Scanning electron microscopy and Fluorescence In Situ Hybridization images showed that most of the nitrifying bacteria were distributed on the K1 carriers and most of the Anammox bacteria were distributed within the acryl resin carriers. Therefore, the results indicate that the proposed combined biofilm system is easy to operate and efficient for the treatment of high-ammonia wastewater.


Assuntos
Amônia/metabolismo , Biofilmes , Reatores Biológicos/microbiologia , Nitrogênio/metabolismo , Águas Residuárias/química , Amônia/química , Bactérias/genética , Bactérias/metabolismo , Desnitrificação , Hibridização in Situ Fluorescente , Microscopia Eletrônica de Varredura , Nitrificação , Nitrogênio/química , Oxirredução , Eliminação de Resíduos Líquidos/métodos , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo
17.
Int Immunopharmacol ; 52: 44-50, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28858725

RESUMO

3BNC117, which was discovered in 2011, is a broadly neutralizing antibody (bNAb) and specifically neutralizes the human immunodeficiency virus type-1 (HIV-1) by targeting the CD4-binding site. This is the first comprehensive review that focuses on the role of 3BNC117 in the prevention of HIV-1 and acquired immune deficiency syndrome (AIDS). Briefly, 3BNC117 neutralizes many HIV/SHIV strains in vitro, blocks HIV-1 acquisition in animal models via a pre-exposure prophylaxis, alleviates HIV-1-associated viremia via a post-exposure therapeutic effect, prevents the establishment of latent HIV-1 reservoirs, and induces both humoral and cellular anti-HIV immune responses in vivo. The outcomes of Phase I and Phase IIa clinical trials in 2015 and 2016 showed the safety, tolerability, and therapeutic efficacy of 3BNC117 in HIV-1-infected human individuals. Nevertheless, anti-3BNC117 antibodies and HIV-1 strains resistant to 3BNC117 pose clinical challenges to immunotherapy with 3BNC117, so potential strategies for optimizing the potency of 3BNC117 are suggested here. Predictably, HIV-1 prevention and AIDS treatment will benefit from combinational immunotherapies with 3BNC117 and other pharmaceuticals (bNAbs, antiretroviral medicines, viral inducers, etc.) in the near future.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/terapia , HIV-1/fisiologia , Imunoterapia/métodos , Animais , Anticorpos Monoclonais Humanizados , Anticorpos Amplamente Neutralizantes , Ensaios Clínicos como Assunto , Terapia Combinada , Infecções por HIV/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Carga Viral
18.
Hum Mutat ; 38(11): 1569-1578, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28776325

RESUMO

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln), in two Chinese CMT families with consanguineous histories. Further functional studies were performed to characterize the biological effects of these variants. Cell culture transfection studies showed that mutant NDRG1 carrying p.Leu146Pro, p.Arg148*, or p.Arg234Gln variant degraded faster than wild-type NDRG1, resulting in lower protein levels. Live cell confocal microscopy and coimmunoprecipitation analysis indicated that these variants did not disrupt the interaction between NDRG1 and Rab4a protein. However, NDRG1-knockdown cells expressing mutant NDRG1 displayed enlarged Rab4a-positive compartments. Moreover, mutant NDRG1 could not enhance the uptake of DiI-LDL or increase the fraction of low-density lipoprotein receptor on the cell surface. Taken together, our study described two missense mutations in NDRG1 and emphasized the important role of NDRG1 in intracellular protein trafficking.


Assuntos
Proteínas de Ciclo Celular/genética , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Estudos de Associação Genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação de Sentido Incorreto , Doença de Refsum/diagnóstico , Doença de Refsum/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Proteínas de Ciclo Celular/metabolismo , Doença de Charcot-Marie-Tooth/metabolismo , Feminino , Duplicação Gênica , Técnicas de Silenciamento de Genes , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Fenótipo , Ligação Proteica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Doença de Refsum/metabolismo , Análise de Sequência de DNA , Deleção de Sequência , Adulto Jovem , Proteínas rab4 de Ligação ao GTP/metabolismo
19.
Biosci Rep ; 37(5)2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-28724603

RESUMO

The study aims to evaluate the effects of miR-136 on the proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) of melanoma cells by targetting premelanosome protein (PMEL) through the Wnt signaling pathway. After establishment of melanoma mouse models, melanoma (model group) and normal tissues (normal group) were collected. Immunohistochemistry was performed to determine PMEL protein concentration. Mouse melanoma cells were assigned into control, blank, negative control (NC), miR-136 mimics, miR-136 inhibitors, siRNA-PMEL, and miR-136 inhibitors + siRNA-PMEL, LiC1 (Wnt signaling pathway activator), and siRNA-PMEL+ LiCl groups. MTT, Scratch test, Transwell assay, and flow cytometry were performed to measure cell proliferation, migration, invasion, and apoptosis. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to evaluate miR-136, PMEL, ß-catenin, Wnt3a, Bcl-2, Bax, Caspase, E-cadherin, and N-cadherin expressions. PMEL is highly expressed in melanoma tissues. MiR-136, Bax, Caspase, and E-cadherin expressions decreased in the model group, whereas PMEL, ß-catenin, Bcl-2, Wnt3a, and N-cadherin expressions increased. Bax, Caspase, and E-cadherin expressions increased in the miR-136 mimics and siRNA-PMEL groups, whereas the expressions decreased in the miR-136 inhibitors group and LiC1 group. PMEL, ß-catenin, Bcl-2, Wnt3a, and N-cadherin expressions, cell proliferation, migration, and invasion decreased, and the apoptosis rate inceased in the miR-136 mimics and siRNA-PMEL groups; whereas the tendencies were opposite to those in the miR-136 inhibitors group and LiC1 group. In the siRNA-PMEL+ LiCl group, PMEL expression decreased. These findings indicated that overexpression of miR-136 inhibits melanoma cell EMT, proliferation, migration, invasion, and promotes apoptosis by targetting PMEL through down-regulation of the Wnt signaling pathway.


Assuntos
Transição Epitelial-Mesenquimal , Melanoma/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Via de Sinalização Wnt , Antígeno gp100 de Melanoma/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Masculino , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , MicroRNAs/metabolismo , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Antígeno gp100 de Melanoma/metabolismo
20.
Tumour Biol ; 39(5): 1010428317701632, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28466784

RESUMO

Long non-coding RNAs have recently emerged as important regulators in the pathogenesis and progression of cancers. The long non-coding RNA urothelial carcinoma-associated 1 is reportedly upregulated and functions as an oncogene in some tumors. However, the role of urothelial carcinoma-associated 1 in renal cell carcinoma is not well elucidated so far. In this study, we found that urothelial carcinoma-associated 1 was overexpressed in renal cell carcinoma tissues compared with the adjacent normal tissues, and higher urothelial carcinoma-associated 1 expression levels were positively associated with advanced tumor stage and poor survival time in renal cell carcinoma patients. Further studies showed that knockdown of urothelial carcinoma-associated 1 suppressed renal cell carcinoma cell proliferation and S-phase cell number in vitro. Moreover, urothelial carcinoma-associated 1 was found to be associated with enhancer of zeste homolog 2, which suppressed p21 expression through histone methylation (H3K27me3) on p21 promoter. We also showed that knockdown of urothelial carcinoma-associated 1 increased the p21 protein expression through regulating enhancer of zeste homolog 2. In addition, bioinformatics analysis and dual-luciferase reporter assays confirmed that miR-495 was a target of urothelial carcinoma-associated 1 in renal cell carcinoma, and urothelial carcinoma-associated 1 promoted cell proliferation by negatively regulating miR-495. These findings illuminated that urothelial carcinoma-associated 1 promoted renal cell carcinoma progression through enhancer of zeste homolog 2 and interacted with miR-495. Overall, overexpression of urothelial carcinoma-associated 1 functions as an oncogene in renal cell carcinoma that may offer a novel therapeutic target for renal cell carcinoma patients.


Assuntos
Carcinoma de Células Renais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , MicroRNAs/biossíntese , RNA Longo não Codificante/genética , Adulto , Idoso , Apoptose/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
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