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1.
CNS Neurosci Ther ; 25(12): 1353-1362, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31793209

RESUMO

AIMS: Microglia and infiltrated macrophages play important roles in inflammatory processes after ischemic stroke. Modulating microglia/macrophage polarization from pro-inflammatory phenotype to anti-inflammatory state has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. Melatonin has been shown to be neuroprotective in experimental stroke models. However, the effect of melatonin on microglia polarization after stroke and underlying mechanisms remain unknown. METHODS: In vivo, cerebral ischemia was induced by distal middle cerebral artery occlusion (dMCAO) in C57BL/6J mice. Melatonin was injected intraperitoneally (20 mg/kg) at 0 and 24 hours after ischemia. In vitro, the microglial cell line BV2 was stimulated to the pro-inflammatory state with conditioned media (CM) collected from oxygen-glucose deprivation (OGD) challenged neuronal cell line Neuro-2a (N2a). Real-time PCR was utilized to detect the mRNA expression of microglia phenotype markers. Activation of signal transducer and activator of transcription 3 (STAT3) pathway was determined by Western blot of phosphorylated STAT3 (pSTAT3). A neuron-microglia co-culture system was used to determine whether melatonin can inhibit the neurotoxic effect of pro-inflammatory microglia to post-OGD neurons. RESULTS: Melatonin treatment reduced brain infarct and improved neurological functions 3 days after dMCAO, which was accompanied by decreased expression of pro-inflammatory markers and increased expression of anti-inflammatory markers in the ischemic brain. In vitro studies confirmed that melatonin directly inhibited the pro-inflammatory responses in BV2 cells upon exposure to OGD neuron CM. The microglia possessing pro-inflammatory phenotype exacerbated post-OGD N2a cells death, whereas melatonin reduced such neurotoxic effect. Further, melatonin enhanced the otherwise inhibited pSTAT3 expression in BV2 cells treated with OGD neuron CM. STAT3 blockade significantly reduced the effect of melatonin on microglial phenotype shift. CONCLUSION: Melatonin treatment ameliorates brain damage at least partially through shifting microglia phenotype from pro-inflammatory to anti-inflammatory polarity in a STAT3-dependent manner.

2.
BMC Bioinformatics ; 20(Suppl 25): 691, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31874619

RESUMO

BACKGROUND: The association between BIN1 rs744373 variant and Alzheimer's disease (AD) had been identified by genome-wide association studies (GWASs) as well as candidate gene studies in Caucasian populations. But in East Asian populations, both positive and negative results had been identified by association studies. Considering the smaller sample sizes of the studies in East Asian, we believe that the results did not have enough statistical power. RESULTS: We conducted a meta-analysis with 71,168 samples (22,395 AD cases and 48,773 controls, from 37 studies of 19 articles). Based on the additive model, we observed significant genetic heterogeneities in pooled populations as well as Caucasians and East Asians. We identified a significant association between rs744373 polymorphism with AD in pooled populations (P = 5 × 10- 07, odds ratio (OR) = 1.12, and 95% confidence interval (CI) 1.07-1.17) and in Caucasian populations (P = 3.38 × 10- 08, OR = 1.16, 95% CI 1.10-1.22). But in the East Asian populations, the association was not identified (P = 0.393, OR = 1.057, and 95% CI 0.95-1.15). Besides, the regression analysis suggested no significant publication bias. The results for sensitivity analysis as well as meta-analysis under the dominant model and recessive model remained consistent, which demonstrated the reliability of our finding. CONCLUSIONS: The large-scale meta-analysis highlighted the significant association between rs744373 polymorphism and AD risk in Caucasian populations but not in the East Asian populations.

3.
Oncol Res ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753063

RESUMO

Long non-coding RNA CRNDE (CRNDE) recently emerged as a carcinogenic promoter in various cancers including medulloblastoma. However, the functions and molecular mechanisms of CRNDE to the acquired drug resistance of medulloblastoma are still unclear. The transcript levels of CRNDE were examined in four medulloblastoma cell lines exposed to cisplatin treatment and IC50 values were calculated. Effects of CRNDE knockdown or miR-29c-3p overexpression on cell viability, colony formation, apoptosis, migration and invasion were assessed using the CCK-8, colony formation assay, flow cytometry, and transwell assays, respectively. RNA pull-down and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular interactions between CRNDE and miR-29c-3p involved in medulloblastoma cells. The in vivo role of CRNDE knockdown or miR-29c-3p overexpression on tumor growth and apoptosis was evaluated in a xenograft mouse model of human medulloblastoma. The transcript levels of lncRNA CRNDE were significantly higher in cisplatin treated tumor cells with higher IC50 values. Depletion of CRNDE inhibited tumor cell proliferation and colony formation, induced cell apoptosis, and suppressed migration and invasion in medulloblastoma cells. Moreover, overexpression of miR-29c-3p inhibited tumor cell proliferation and colony formation, migration and invasion, and enhanced apoptosis and chemosensitivity to cisplatin. In addition, CRNDE was found to be act as miR-29c-3p sponge. Furthermore, in vivo experiments showed the CRNDE/miR-29c-3p interactions involved in medulloblastoma. Our study demonstrates that CRNDE acts as a critical mediator of proliferation, apoptosis, migration, invasion and resistance to chemotherapeutics via binding to and negatively regulating miR-29c-3p in medulloblastoma cells. These results provide novel molecular targets for treatment of medulloblastoma.

4.
Front Genet ; 10: 519, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354783

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease. APOE is the strong genetic risk factor of AD. The existing genome-wide association studies have identified many single nucleotide polymorphisms (SNPs) with minor effects on AD risk and the polygenic risk score (PRS) is presented to combine the effect of these SNPs. On the other hand, the volumes of various brain regions in AD patients have significant changes compared to that in normal individuals. Ch4 brain region containing at least 90% cholinergic neurons is the most extensive and conspicuous in the basal forebrain. Here, we investigated the relationship between the combined effect of AD-associated SNPs and Ch4 volume using the PRS approach. Our results showed that Ch4 volume in AD patients is significantly different from that in normal control subjects (p-value < 2.2 × 10-16). AD PRS, is not associated with the Ch4 volume in AD patients, excluding the APOE region (p-value = 0.264) and including the APOE region (p-value = 0.213). However, AD best-fit PRS, excluding the APOE region, is associated with Ch4 volume in normal control subjects (p-value = 0.015). AD PRS based on 8070 SNPs could explain 3.35% variance of Ch4 volume. In addition, the p-value of AD PRS model in normal control subjects, including the APOE region, is 0.006. AD PRS based on 8079 SNPs could explain 4.23% variance of Ch4 volume. In conclusion, PRS based on AD-associated SNPs is significantly related to Ch4 volume in normal subjects but not in patients.

5.
Zhongguo Zhong Yao Za Zhi ; 44(3): 495-499, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30989914

RESUMO

Twelve alkaloids were isolated from the bulbs of Fritillaria yuminensis by column chromatography over silica gel, ODS, and Sephadex LH-20, as well as RP-HPLC. Their structures were identified mainly by NMR and MS analyses as yubeinine(1), imperialine(2), delavinone(3), tortifoline(4), hupehenizioiside(5), imperialine-ß-D-glucoside(6), kuroyurinidine(7), pengbeisine A(8), walujewine A(9), peimisine-3-O-ß-D-glucopyranoside(10), solanidine-3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside(11), and solanidine-3-O-α-L-rhamnopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→4)]-ß-D-glucopyranoside(12). Compounds 4-12 were obtained from F. yuminensis for the first time.


Assuntos
Alcaloides/análise , Fritillaria/química , Raízes de Plantas/química , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Fitoquímicos/análise
6.
J Cell Physiol ; 234(11): 20118-20127, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30953359

RESUMO

This study aims to determine the feasibility of using oligodeoxynucleotides with unmethylated cytosine-guanine dinucleotide sequences (CpG ODN) as an immunity protection strategy for a mouse model of acute respiratory distress syndrome (ARDS). This is a prospective laboratory animal investigation. Twenty-week-old BALB/c mice in Animal research laboratory were randomized into groups. An ARDS model was induced in mice using lipopolysaccharides (LPSs). CpG ODN was intranasally and transrectally immunized before or after the 3rd and 7th days of establishing the ARDS model. Mice were euthanized on Day 7 after the second immunization. Then, retroorbital bleeding was carried out and the chest was rapidly opened to collect the trachea and tissues from both lungs for testing. CpG ODN significantly improved the pathologic impairment in mice lung, especially after the intranasal administration of 50 µg. This resulted in the least severe lung tissue injury. Furthermore, interleukin-6 (IL-6) and IL-8 concentrations were lower, which was second to mice treated with the rectal administration of 20 µg CpG ODN. In contrast, the nasal and rectal administration of CpG ODN in BALB/c mice before LPS immunization did not appear to exhibit any significant protective effects. The intranasal administration of CpG ODN may be a potential treatment approach to ARDS. More studies are needed to further determine the protective mechanism of CpG ODN.

7.
Exp Ther Med ; 17(4): 2632-2640, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30906455

RESUMO

Hepatic ischemia/reperfusion (IR) injury is a critical contraindication of hepatobiliary surgery and results in severe liver damage. It is imperative to identify underlying pathophysiological mechanisms. In the current study, a rat model of liver IR was established to explore the mechanisms of sevoflurane during surgical intervention on IR. The detection of cytokines was performed using ELISA and reverse transcription-quantitative polymerase chain reaction and western blot assays were used to detect mRNA and protein expression levels, respectively. The target protein of microRNA (miR)-9-5p was identified by in vitro luciferase reporter assay. Cell apoptosis was detected by Annexin-V/propidium iodide and TUNEL staining assays. The results demonstrated that sevoflurane exerted protective effect against liver IR. Sevoflurane administration ameliorated a cytokine storm by decreasing serum levels of interleukin (IL)-1 and -6 and tumor necrosis factor (TNF)-α, and improved liver function was determined. IR-induced damage was mediated by an increase in transcription factor p65 expression and activation of the nuclear factor (NF)-κB signaling pathway, which were suppressed by sevoflurane treatment. In situ analysis predicted that NFKB3, encoding for p65, may be targeted by miR-9-5p and the hypothesis was verified by in vitro reporter assays using wild type and mutant sequences of the NFKB3 3'-untranslated region. Furthermore, pretreatment of hepatic tissue with a miR-9-5p mimic inhibited IR-associated injury as suggested by the decrease in the Suzuki score and decreased serum levels of TNF-α, IL-1 and IL-6. The results indicated that sevoflurane protected the liver from IR injury by increasing miR-9-5p expression and miR-9-5p may be a potential treatment target in IR.

8.
Gastroenterology ; 156(6): 1890-1904.e16, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30711627

RESUMO

BACKGROUND & AIMS: Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors. METHODS: We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines. RESULTS: B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4+ T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal-regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3-positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth. CONCLUSIONS: Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4+ T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells.


Assuntos
Carcinoma Hepatocelular/genética , Epigênese Genética , Imunoglobulina G/metabolismo , Neoplasias Hepáticas/genética , Macrófagos/metabolismo , Plasmócitos/metabolismo , Adulto , Idoso , Animais , Antimetabólitos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Quimiocina CCL20/metabolismo , Quimiocina CXCL10/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Decitabina/farmacologia , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Indóis/farmacologia , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Fígado/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Contagem de Linfócitos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Fenótipo , Plasmócitos/imunologia , Piridonas/farmacologia , Receptores CXCR3/metabolismo , Receptores Fc/metabolismo , Transdução de Sinais , Transcriptoma
9.
Int J Oncol ; 54(2): 455-466, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30431078

RESUMO

Chronic lymphocytic leukemia (CLL) is one of the most often diagnosed hematological malignant tumors in the Western world and a type of inert B­cell lymphoma that commonly attacks the elderly. Small ubiquitin related modifier (SUMO)­specific protease 2 (SENP2) can act as a suppressor in various types of cancer by regulating the stability of ß­catenin to affect the Notch signaling pathway; however, it has a low expression level in CLL cells. In this study, we firstly used western blot analysis and RT­qPCR to detect the protein and mRNA expression levels of SENP2 in the peripheral blood of patients with CLL and healthy volunteers. Secondly, we overexpressed or knocked down the expression of SENP2 in CLL cells and then determined the cell invasive and chemotactic ability in a Transwell assay and chemotaxis assay. We examined the sensitivity of the cells to cytarabine and dexamethasone via a CCK­8 assay and determined the cell apoptotic condition and the expression of the Notch signaling pathway using flow cytometry and western blot analysis. The results demonstrated that the patients with CLL had relatively low expression levels of SENP2. The overexpression of SENP2 in the CLL cells decreased their invasive and proliferative ability, as well as their chemotactic response and enhanced their sensitivity to cytarabine and dexamethasone, while it promoted cell apoptosis. The silencing of SENP2 in the CLL cells generally produced the opposite results. We thus hypothesized that the overexpression of SENP2 downregulated ß­catenin expression, thus inhibiting the Notch signaling pathway in CLL cells. Moreover, the nuclear factor (NF)­κB signaling pathway was also regulated by the overexpression of SENP2. On the whole, the findings of this study indicate tha SENP2 can act as a tumor suppressor in CLL cells, and may thus prove to be a novel target for CLL treatment in clinical practice.


Assuntos
Cisteína Endopeptidases/genética , Leucemia Linfocítica Crônica de Células B/genética , NF-kappa B/genética , Receptores Notch/genética , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/antagonistas & inibidores , RNA Mensageiro/genética , Receptores Notch/antagonistas & inibidores , Transdução de Sinais , beta Catenina/genética
10.
Fitoterapia ; 131: 112-118, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30336193

RESUMO

Three new isosteroidal alkaloids, frititorines A-C (1-3), were isolated from the bulbs of Fritillaria tortifolia, together with ten known ones (4-13). Their structures were elucidated by extensive spectroscopic analyses, chemical methods, and single-crystal X-ray crystallographic analysis. Compound 1 is the first 5ß-cevanine alkaloid with a cis A/B ring junction from the Fritillaria genus. Compound 2 is the first example of glycosylated isosteroidal alkaloid N-oxide. Compound 1 showed significant relaxant effect on Ach-induced tracheal contraction with pA2 and EC50 values equivalent to those of aminophylline.


Assuntos
Alcaloides/isolamento & purificação , Fritillaria/química , Raízes de Plantas/química , Traqueia/efeitos dos fármacos , Animais , China , Técnicas In Vitro , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Ratos Sprague-Dawley
11.
J Mol Neurosci ; 66(1): 37-43, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30088171

RESUMO

Genetic association studies have identified significant association between the GAB2 rs2373115 variant and Alzheimer's disease (AD). However, it is unknown whether rs2373115 affects the regulation of nearby genes. Here, we evaluate the potential effect of rs2373115 on gene expression using multiple eQTL (expression quantitative trait loci) datasets from human brain tissues from the Mayo Clinic brain expression genome-wide association study (eGWAS), the UK Brain Expression Consortium (UKBEC), the Genotype-Tissue Expression (GTEx) project, and the Brain xQTL Serve. Our findings indicate that the rs2373115 C allele is associated with increased NARS2 expression, and both reduced and increased GAB2 expression in human tissues. Using a large-scale AD case-control expression dataset, we found increased GAB2 expression and reduced NARS2 expression in AD cases compared with controls. We believe that our findings provide important information regarding the rs2373115 variant and expression of nearby genes with respect to AD risk.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Aspartato-tRNA Ligase/genética , Encéfalo/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alelos , Aspartato-tRNA Ligase/metabolismo , Estudos de Casos e Controles , Humanos
12.
Neural Regen Res ; 13(10): 1685-1692, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30136678

RESUMO

Spinal cord injury (SCI) from trauma or disease severely impairs sensory and motor function. Neurorehabilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing damaged connections in the central nervous system. An increasing number of preclinical studies suggest that melatonin may be useful for the treatment of SCI. Melatonin is an indolamine that is primarily secreted by the pineal gland and known to be regulated by photoperiodicity. However, it is also a versatile hormone with antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. Here, we review the neuroprotective properties of melatonin and the potential mechanisms by which it might be beneficial in the treatment of SCI. We also describe therapies that combine melatonin with exercise, oxytetracycline, and dexamethasone to attenuate the secondary injury after SCI and limit potential side effects. Finally, we discuss how injury at different spinal levels may differentially affect the secretion of melatonin.

13.
Life Sci ; 203: 315-322, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29730170

RESUMO

A growing number of studies reported that rosiglitazone (a PPARgamma agonist) could ameliorate the painful state and prevent stress-induced depression. However, whether rosiglitazone can prevent pain-induced depression is unclear. This study aimed to explore the antidepressant effects of rosiglitazone in L5 spinal nerve transection (SNT) induced neuropathic pain rats. In addition, AMPK inhibitor (Compound C) and autophagic antagonist (3-methyladenine, 3-MA) were applied to investigate the underlying therapeutic mechanisms. L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors were detected by paw pressure threshold test (PPT), open-field test (OFT), forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT). Rosiglitazone could ameliorate L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors and the effect could be reversed by Compound C or 3-MA. Compared with the sham group, the levels of BDNF, AMPK, Beclin-1 and LC3B in rats hippocampus significantly decreased in L5 SNT group. On the contrary, rosiglitazone administration significantly up-regulated the levels of AMPK, BDNF, Beclin-1 and LC3B in rats hippocampus. Compared with sham group, the levels of TNF-α, IL-1ß, superoxide dismutase (SOD) and malondialdehyde (MDA) in rat hippocampus significantly increased in L5 SNT group. Besides, rosiglitazone administration significantly decreased the levels of TNF-α, IL-1ß, SOD and MDA in hippocampus. Compared with rosiglitazone group, 3-MA administration, but not Compound C administration, significantly increased the levels of TNF-α, IL-1ß, SOD and MDA in hippocampus. In conclusion, rosiglitazone can counteract down-regulation of AMPK and BDNF induced by L5 SNT rats in hippocampus, and activate autophagic pathway. These effects may contribute to the antidepressant effect of rosiglitazone on the rats with depression induced by L5 SNT.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Neuralgia/complicações , Tiazolidinedionas/farmacologia , Animais , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Elevação dos Membros Posteriores , Hipoglicemiantes/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Rosiglitazona , Estresse Psicológico
14.
J Alzheimers Dis ; 61(3): 1077-1088, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29332039

RESUMO

Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer's disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Receptor EphA1/sangue , Receptor EphA1/genética , Estudos de Casos e Controles , China , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Medição de Risco
15.
Neurol Sci ; 38(7): 1255-1262, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28429084

RESUMO

In 2006, a candidate gene study reported death-associated protein kinase 1 (DAPK1) rs4878104 variant to be significantly associated with Alzheimer's disease (AD) risk. However, the following studies showed inconsistent association results. Here, we conducted an updated analysis to investigate the potential association between rs4878104 and AD using a total of 60,751 samples (20,161 AD cases and 40,590 controls). In the pooled population, the results based on the allele and genotype genetic models show that rs4878104 variant is not significantly associated with AD risk. Interestingly, we identified rs4878104 variant to be significantly associated with AD risk in American population and Chinese population in subgroup analysis. Using multiple large-scale expression quantitative trait loci datasets, we further found that rs4878104 T allele could significantly regulate increased DAPK1 expression in European population. These findings suggest that rs4878104 may contribute AD susceptibility by modifying DAPK1 expression in European population.


Assuntos
Doença de Alzheimer/genética , Proteínas Quinases Associadas com Morte Celular/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Proteínas Reguladoras de Apoptose/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Risco
16.
Mol Med Rep ; 15(5): 2537-2545, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28447742

RESUMO

Fracture healing involves the coordinated actions of multiple cytokines. Bone morphogenetic protein 9 (BMP9) is an important factor in bone formation. The present study aimed to investigate the osteogenic potential of bone marrow stem cells (BMSCs) in response to adenoviral (Ad)BMP9, and the early fracture repair properties of AdBMP9 in surgically­created fractures in osteoporotic rats. Alkaline phosphatase (ALP) activity was assayed and matrix mineralization was examined by Alizarin Red S staining. mRNA and protein expression levels of BMP9, runt­related transcription factor 2 (RUNX2) and type 1 collagen (COL­1) were detected in vitro and in vivo. Femoral bone mineral density was assessed for osteoporosis in ovariectomized rats. An open femora fracture was subsequently created, and gelatin sponges containing AdBMP9 were implanted. The femora were harvested for radiographical, micro­computed tomography, biomechanical and histological analysis 4 weeks later. BMP9 successfully increased ALP activity and induced mineralized nodule formation in BMSCs. BMP9 in gelatin sponges demonstrated marked effects on microstructural parameters and the biomechanical strength of bone callus. In addition, it upregulated the expression levels of RUNX2 and COL­1. AdBMP9 in gelatin sponges significantly mediated callus formation, and increased bone mass and strength in osteoporotic rats with femora fractures. The results of the present study suggested that BMP9 enhanced callus formation and maintained early mechanical stability during fracture healing in osteoporotic rats, implicating it as a potential novel therapeutic target for fracture healing.


Assuntos
Calo Ósseo/metabolismo , Fraturas do Fêmur/metabolismo , Consolidação da Fratura , Fator 2 de Diferenciação de Crescimento/biossíntese , Osteoporose/metabolismo , Adenoviridae , Animais , Calo Ósseo/patologia , Feminino , Fraturas do Fêmur/genética , Fraturas do Fêmur/patologia , Fator 2 de Diferenciação de Crescimento/genética , Osteoporose/genética , Osteoporose/patologia , Ratos , Ratos Sprague-Dawley , Transdução Genética
17.
Am J Sports Med ; 45(6): 1349-1358, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28298055

RESUMO

BACKGROUND: Moderate graft pretensioning in anterior cruciate ligament (ACL) reconstruction is paramount to restore knee stability and normalize knee kinematics. However, little is known about the effect of graft pretensioning on graft-to-bone healing after ACL reconstruction. HYPOTHESIS: Moderate graft pretensioning will improve bone formation within the bone tunnel after ACL reconstruction, resulting in superior load to failure. STUDY DESIGN: Controlled laboratory study. METHODS: 67 male Sprague-Dawley rats underwent unilateral ACL reconstruction with a flexor digitorum longus tendon autograft. The graft was subjected to pretensioning forces of 0 N, 5 N, or 10 N. Custom-made external fixators were used for knee immobilization postoperatively. Rats were euthanized for biomechanical load-to-failure testing (n = 45) and micro-computed tomography (µCT) examination (n = 22) at 3 and 6 weeks after surgery. Three regions of each femoral and tibial bone tunnel (aperture, middle, and tunnel exit) were chosen for measurement of tunnel diameter and new bone formation. RESULTS: Biomechanical tests revealed significantly higher load-to-failure in the 5-N graft pretensioned group compared with the 0- and 10-N groups at 3 weeks (8.58 ± 2.67 N vs 3.96 ± 1.83 N and 4.46 ± 2.62 N, respectively) and 6 weeks (16.56 ± 3.50 N vs 10.82 ± 1.97 N and 7.35 ± 2.85 N, respectively) after surgery ( P < .05). The mean bone tunnel diameters at each of the 3 regions were significantly smaller in the 5-N group, at both the femoral and tibial tunnel sites, than in the 0- and 10-N groups ( P < .05). At 3 and 6 weeks postoperatively, the bone mineral density, bone volume fraction, and connectivity density around the aperture and middle regions of the tibial bone tunnels were all significantly higher in the 5-N group compared with the 0- and 10-N groups ( P < .05). In the aperture and middle regions of the femoral bone tunnels, pretensioning at either 5 or 10 N resulted in increased bone formation compared with the nonpretensioned group at 3 weeks postoperatively. No differences were found in bone formation between any of the 3 femoral tunnel regions at 6 weeks. CONCLUSION: Graft pretensioning can stimulate new bone formation and improve tendon-to-bone tunnel healing after ACL reconstruction. CLINICAL RELEVANCE: Optimal graft pretensioning force in ACL reconstruction can improve bone tunnel healing. Further study is necessary to understand the mechanisms underlying the effect of graft pretensioning on healing at the bone-tunnel interface.


Assuntos
Reconstrução do Ligamento Cruzado Anterior/métodos , Fêmur/fisiologia , Osteogênese , Tendões/transplante , Tíbia/fisiologia , Animais , Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/cirurgia , Fenômenos Biomecânicos , Densidade Óssea , Fixadores Externos , Fêmur/cirurgia , Imobilização/métodos , Masculino , Modelos Animais , Ratos , Ratos Sprague-Dawley , Tíbia/cirurgia , Transplante Autólogo , Cicatrização , Microtomografia por Raio-X
18.
J Neurol Sci ; 375: 18-22, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28320126

RESUMO

A genome-wide association study identified GAB2 rs2373115 to be associated with Alzheimer's disease (AD) risk in European population. However, inconsistent results are reported in East Asian population. Here, we performed an updated analysis using 65,704 samples including 20,982 AD cases and 44,722 controls. First, we investigated the GAB2 rs2373115 variant in Asian population using 3974 AD cases and 7568 controls. To further evaluate the effect of rs2373115 in different populations, we selected 17,008 AD cases and 37,154 controls in European population. We used three genetic models, and found no significant heterogeneity in Asian population. A fixed effect model analysis showed no significant association between rs2373115 and AD in Asian population. There was no significant heterogeneity in the pooled East Asian and European populations. The fixed effect model analysis again showed no significant association between rs2373115 and AD in these pooled populations. Taken together, these findings suggest that GAB2 rs2373115 may contribute to AD susceptibility only in European population but not in East Asian population.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Doença de Alzheimer/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Bases de Dados Bibliográficas/estatística & dados numéricos , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metanálise como Assunto
19.
J Shoulder Elbow Surg ; 26(4): 580-588, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27887870

RESUMO

BACKGROUND: Bone marrow aspirate has been used in recent years to augment tendon-to-bone healing, including in rotator cuff repair. However, the healing mechanism in cell-based therapy has not been elucidated in detail. METHODS: Sixteen athymic nude rats were randomly allocated to 2 groups: experimental (human mesenchymal stem cells in fibrin glue carrier) and control (fibrin glue only). Animals were sacrificed at 2 and 4 weeks. Immunohistochemical staining was performed to evaluate Indian hedgehog (Ihh) signaling and SOX9 signaling in the healing enthesis. Macrophages were identified using CD68 and CD163 staining, and proliferating cells were identified using proliferating cell nuclear antigen staining. RESULTS: More organized and stronger staining for collagen II and a higher abundance of SOX9+ cells were observed at the enthesis in the experimental group at 2 weeks. There was significantly higher Gli1 and Patched1 expression in the experimental group at the enthesis at 2 weeks and higher numbers of Ihh+ cells in the enthesis of the experimental group vs control at both 2 weeks and 4 weeks postoperatively. There were more CD68+ cells localized to the tendon midsubstance at 2 weeks compared with 4 weeks, and there was a higher level of CD163 staining in the tendon midsubstance in the experimental group than in the control group at 4 weeks. CONCLUSION: Stem cell application had a positive effect on fibrocartilage formation at the healing rotator cuff repair site. Both SOX9 and Ihh signaling appear to play an important role in the healing process.


Assuntos
Proteínas Hedgehog/metabolismo , Células-Tronco Mesenquimais/metabolismo , Manguito Rotador/metabolismo , Transdução de Sinais , Animais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Contagem de Células , Colágeno Tipo II/metabolismo , Fibrocartilagem , Humanos , Macrófagos/química , Masculino , Transplante de Células-Tronco Mesenquimais , Receptor Patched-1/metabolismo , Ratos , Ratos Nus , Ratos Sprague-Dawley , Receptores de Superfície Celular/análise , Fatores de Transcrição SOX9/metabolismo , Transplante Heterólogo , Cicatrização , Proteína GLI1 em Dedos de Zinco/metabolismo
20.
BMC Infect Dis ; 16: 347, 2016 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-27450277

RESUMO

BACKGROUND: Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment. METHODS: To assess drug interactions between the HIV integrase strand transfer inhibitor dolutegravir (DTG) and DCV, subjects were randomized into 1 of 2 sequences in an open-label, 3-period, crossover study. Subjects received either DTG 50 mg once daily or DCV 60 mg once daily for 5 days in periods 1 and 2 and DTG 50 mg plus DCV 60 mg once daily for 5 days in period 3, with no washout between periods 2 and 3. Between periods 1 and 2, there was a washout period of at least 7 days. RESULTS: The geometric least-squares mean ratios (90 % confidence intervals) of DCV area under the concentration-time curve over a dosing interval (AUC0-τ), maximum observed concentration (Cmax), and concentration at the end of the dosing interval (Cτ) were 0.978 (0.831-1.15), 1.03 (0.843-1.25), and 1.06 (0.876-1.29), respectively, when DCV was administered with DTG compared with DCV alone. Compared with DTG alone, coadministration of DTG with DCV increased DTG AUC0-τ, Cmax, and Cτ by approximately 33, 29, and 45 %, respectively. CONCLUSIONS: DCV plasma exposure was not meaningfully affected by DTG. Coadministration of DTG with DCV resulted in slight increases in DTG AUC0-τ, Cmax, and Cτ. Accumulated safety and tolerability data in humans receiving DTG to date suggests this effect is not considered clinically significant. DTG and DCV can be coadministered without dose adjustment. TRIAL REGISTRATION: Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.


Assuntos
Antivirais/farmacocinética , Área Sob a Curva , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Imidazóis/farmacocinética , Adolescente , Adulto , Idoso , Antivirais/sangue , Estudos Cross-Over , Esquema de Medicação , Interações de Medicamentos , Feminino , Inibidores de Integrase de HIV/sangue , Inibidores de Integrase de HIV/farmacocinética , Voluntários Saudáveis , Compostos Heterocíclicos com 3 Anéis/sangue , Humanos , Imidazóis/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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