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1.
Artigo em Inglês | MEDLINE | ID: mdl-32006489

RESUMO

PURPOSE: The application of bio-resorbable plates in craniomaxillofacial surgery is increasing because of the advantage of avoiding secondary surgery. This study aimed to evaluate the effects of osteosynthesis with prebent bio-resorbable plates for treating zygomaticomaxillary complex (ZMC) fractures. MATERIALS AND METHODS: We implemented a prospective case series composed of patients with ZMC fractures who underwent treatment at the School of Stomatology at China Medical University. Bio-resorbable plates were used for fracture fixation. The fractures were stabilized with bio-resorbable plates prebent on a 3-dimensionally printed skull model with the fractures reduced using virtual simulation. The primary outcome variable was the stability rate of reduced bone segments. Other study variables were mouth opening, occlusion, paresthesia or anesthesia in the infraorbital nerve region (PAIN), and diplopia. Outcome variables were determined by calculating stability rates of reduced bone segments, resolution rates of postoperative restricted mouth opening, malocclusion, PAIN, and diplopia. RESULTS: The sample was composed of 11 patients recruited between November 2016 and September 2018. All surgical procedures were successful, with no severe complications. The stability rate of reduced bone segments from different mechanical buttress regions was 100%. Satisfactory postoperative stability of bio-resorbable plates was obtained in all cases. The resolution rates of postoperative restricted mouth opening and malocclusion were 75% and 100%, respectively. PAIN and diplopia symptoms resolved in 50% and 100% of cases, respectively. CONCLUSIONS: The results suggest that osteosynthesis with bio-resorbable plates prebent on a 3-dimensionally printed skull model, designed by virtual simulation, works well for patients with ZMC fractures. Future studies should focus on the broader applications of these findings in the practice of oral and maxillofacial surgery.

2.
Exp Cell Res ; 386(2): 111741, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759968

RESUMO

Survivin is a newly identified tumour-associated antigen and has been demonstrated to be an excellent target for immunotherapy in several cancers, but its role in hepatocellular carcinoma treatment is still unknown. In this study, survivin-derived peptide-specific cytotoxic T lymphocytes (CTLs) from peripheral blood mononuclear cells of healthy donors were induced by multiple stimulations with HLA-A2- restricted survivin peptide-pulsed T2 cells. The induced CTLs exhibited specific lysis of T2 cells pulsed with the peptide and HLA-A2+ hepatocellular carcinoma cells expressing survivin, while HLA-A2+ hepatocellular carcinoma cell lines that did not express survivin were not recognized by the CTLs. These results suggest that the survivin peptide epitope could be a potential target of specific immunotherapy for HLA-A2+ patients with hepatocellular carcinoma.

3.
J Sci Food Agric ; 100(1): 325-334, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31584699

RESUMO

BACKGROUND: Meat fraud and adulteration incidents occur frequently in almost all regions of the globe, especially with the increase in the world's population. To ensure the authenticity of meat products, we developed a 10-plex xMAP assay to simultaneously detect ten animal materials: bovine, caprine, poultry, swine, donkey, deer, horse, dog, fox and mink. RESULTS: This method was investigated by analyzing DNA extracts from raw muscle, muscle mixtures, meat products and animal feeds. Our results indicated that the species of interest can be identified, differentiated and detected down to 1 g kg-1 in binary mixtures or 0.01-0.001 ng of genomic DNA from specific species. Testing of 125 commercial samples showed a 97.4% coincidence rate with the method used in routine testing in our lab. CONCLUSION: These results indicated that the method established in this study could detect ten animal materials simultaneously within 3 h, which provides a new, useful tool for animal ingredient analysis in meat products and animal feeds. © 2019 Society of Chemical Industry.


Assuntos
DNA Mitocondrial/genética , Contaminação de Alimentos/análise , Produtos da Carne/análise , Técnicas de Amplificação de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Ração Animal/análise , Animais , Bovinos , Cervos , Cães , Raposas , Cabras , Cavalos , Vison , Técnicas de Amplificação de Ácido Nucleico/instrumentação , Aves Domésticas , Suínos
4.
Sci Rep ; 9(1): 15857, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676833

RESUMO

HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral genes, including vpr. Antiretroviral therapy ameliorates HIVAN without eradicating HIV from the kidneys and the mechanism by which it protects kidneys is poorly understood. Since HIV protease inhibitors have "off target" cellular effects, we studied whether darunavir, the most commonly prescribed protease inhibitor, protects kidneys from HIV-induced injury via mechanisms independent of HIV protease and viral replication. Renal epithelial cells were transduced with lentiviruses encoding HIV (lacking protease and reverse transcriptase), Vpr, or vector control. Darunavir attenuated HIV and Vpr-induced activation of Stat3, Src, Erk, and cytokines, which are critical for HIVAN pathogenesis. We then studied HIV-transgenic mice, which develop HIVAN in the absence of HIV protease or reverse transcriptase. Mice were treated with darunavir, zidovudine, darunavir + zidovudine, or control. Darunavir and darunavir + zidovudine reduced albuminuria and histologic kidney injury and normalized expression of dysregulated proteins. RNA-seq analyses demonstrated that darunavir suppressed HIV-induced upregulation of immune response genes in human kidney cells. These data demonstrate that darunavir protects against HIV-induced renal injury via mechanisms that are independent of inhibition of HIV protease.

5.
Biol Reprod ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31616914

RESUMO

Pentachloronitrobenzene (PCNB) is an organochlorine fungicide widely used for crop production and has become an environmental concern. Little is known about the effect of PCNB on ovarian steroidogenesis and follicular development. We found that PCNB stimulated Star expression and progesterone production in cultured rat granulosa cells in a dose-dependent manner. PCNB activated MAPK3/1 (ERK1/2), thus inhibition of either PKA or MAPK3/1 signalling pathway significantly attenuated progesterone biosynthesis caused by PCNB, suggesting that PCNB induced progesterone production by activating the cAMP/PKA and MAPK3/1 signalling pathways. Further investigation demonstrated that PCNB induced Star expression and altered MAPK3/1 signalling in ovary tissues of immature SD rats treated with PCNB at the dose of 100, 200 or 300 mg/kg by daily gavage for 7 days, while serum progesterone level was dose-dependently decreased. We demonstrated that PCNB exposure accelerated the recruitment of primordial follicles into the growing follicle pool in ovary tissues, accompanied by increased levels of AMH in both ovary tissues and serum. Taken together, our data demonstrate for the first time that PCNB stimulated Star expression, altered MAPK3/1 signalling and progesterone production in vivo and in vitro, and accelerated follicular development with a concomitant increase in AMH in ovary tissues and serum. Our findings provide novel insight into the toxicity of PCNB to animal ovary function.

6.
J Transl Med ; 17(1): 277, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434567

RESUMO

Following publication of the original article [1], the authors reported errors in Fig. 5. The ROS picture of low dose Marine intervention group in Fig. 5d was used incorrectly, which was caused by the error of the storage path of the picture in the experiment. It was not discovered in time due to the approximation of the two graphs. In addition, the label of middle dose Marine intervention group in Fig. 5a was omitted.

7.
Clin Sci (Lond) ; 133(12): 1281-1295, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31171573

RESUMO

GDF1 plays an important role in left-right patterning and genetic mutations in the coding region of GDF1 are associated with congenital heart disease (CHD). However, the genetic variation in the promoter of GDF1 with sporadic CHD and its expression regulation is little known. The association of the genetic variation in GDF1 promoter with CHD was examined in two case-control studies, including 1084 cases and 1198 controls in the first study and 582 cases and 615 controls in the second study. We identified one single nucleotide polymorphism (SNP) rs181317402 and two novel genetic mutations located in the promoter region of GDF1. Analysis of combined samples revealed a significant association in genotype and allele frequencies of rs181317402 T/G polymorphism between CHD cases in overall or ventricular septal defects or Tetralogy of Fallot and the control group. rs181317402 allele G polymorphism was significantly associated with a decreased risk of CHD. Furthermore, luciferase assay, chromatin immunoprecipitation and DNA pulldown assay indicated that Nkx2.5 transactivated the expression of GDF1 by binding to the promoter of GDF1. Luciferase activity assay showed that rs181317402 allele G significantly increased the basal and Nkx2.5-mediated activity of GDF1 promoter, while the two genetic mutations had the opposite effect. rs181317402 TG genotype was associated with significantly increased mRNA level of GDF1 compared with TT genotype in 18 CHD individuals. Our results demonstrate for the first time that Nkx2.5 acts upstream of GDF1 and the genetic variants in GDF1 promoter may confer genetic susceptibility to sporadic CHD potentially by altering its expression.

8.
Biomed Res Int ; 2019: 7343957, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31111065

RESUMO

Biocompatible scaffolding materials play an important role in bone tissue engineering. This study sought to develop and characterize a nano-hydroxyapatite (nHA)/collagen I (ColI)/multi-walled carbon nanotube (MWCNT) composite scaffold loaded with recombinant bone morphogenetic protein-9 (BMP-9) for bone tissue engineering by in vitro and in vivo experiments. The composite nHA/ColI/MWCNT scaffolds were fabricated at various concentrations of MWCNTs (0.5, 1, and 1.5% wt) by blending and freeze drying. The porosity, swelling rate, water absorption rate, mechanical properties, and biocompatibility of scaffolds were measured. After loading with BMP-9, bone marrow mesenchymal stem cells (BMMSCs) were seeded to evaluate their characteristics in vitro and in a critical sized defect in Sprague-Dawley rats in vivo. It was shown that the 1% MWCNT group was the most suitable for bone tissue engineering. Our results demonstrated that scaffolds loaded with BMP-9 promoted differentiation of BMMSCs into osteoblasts in vitro and induced more bone formation in vivo. To conclude, nHA/ColI/MWCNT scaffolds loaded with BMP-9 possess high biocompatibility and osteogenesis and are a good candidate for use in bone tissue engineering.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Osso e Ossos , Colágeno Tipo I/farmacologia , Fator 2 de Diferenciação de Crescimento/metabolismo , Fator 2 de Diferenciação de Crescimento/farmacologia , Engenharia Tecidual , Animais , Materiais Biocompatíveis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Durapatita/farmacologia , Liofilização , Células-Tronco Mesenquimais , Nanoestruturas , Osteoblastos , Osteogênese/efeitos dos fármacos , Porosidade , Ratos , Ratos Sprague-Dawley , Tecidos Suporte
9.
Appl Microbiol Biotechnol ; 103(11): 4575-4584, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31001745

RESUMO

The identification of animal species in feed and feedstuffs is important for detecting contamination and fraudulent replacement of animal components that might cause health and economic problems. A novel multiplex assay, based on xMAP technology and the generic detection of closely related species, was developed for the simultaneous differential detection of avian, fish, and ruminant DNA in products. Universal primers and probes specific to avian, fish, or ruminant species were designed to target a conserved mitochondrial DNA sequence in the 12S ribosomal RNA gene (rRNA). The assay specificity was validated using samples of 27 target and 10 nontarget animal species. The limits of detection of the purified DNA were determined to be 0.2 pg/µL-0.1 ng/µL by testing the meat samples of six species and four feedstuffs. The detection sensitivity of the experimental mixtures was demonstrated to be 0.01% (weight percentage). The assay's suitability for practical application was evaluated by testing feed samples; unlabeled animal ingredients were detected in 32% of the 56 samples. The assay differentially detected the three targeted categories of animal species in less than 2 h, reflecting improvements in speed and efficiency. Based on these results, this novel multiplex xMAP assay provides a reliable and highly efficient technology for the routine detection of animal species in feed and other products for which this information is needed.


Assuntos
Ração Animal/análise , DNA/isolamento & purificação , Contaminação de Alimentos , Hibridização de Ácido Nucleico/métodos , Reação em Cadeia da Polimerase/métodos , Animais , Aves , DNA/genética , Primers do DNA/genética , Peixes , Sondas de Oligonucleotídeos/genética , RNA Ribossômico/genética , Ruminantes , Sensibilidade e Especificidade
10.
Ther Clin Risk Manag ; 15: 293-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858709

RESUMO

Background: Given the increasing use of immune checkpoint inhibitors (ICIs), a concomitant rise in adverse events is inevitable. In a recent Phase III trial of ICIs versus placebo, we found the staggering difference of incidence of fatal adverse events (FAEs). Hence, we should determine the risk of FAEs in ICIs. Objective: To address the risks of FAEs associated with each ICI regimen, we performed a systematic review and meta-analysis of clinical trials with the Food and Drug Administration-approved ICI regimens in patients with advanced solid tumors. Methods: Literature searching was based on PubMed before April 15, 2018. The numbers of FAEs in both study group and placebo group were collected. We assessed the risk of fatal adverse reactions associated with ICIs on Pooled Peto OR and associated 95% CI. Results: Twelve trials were identified. OR value of FADs in all ICIs was 2.32 (95% CI: 1.33, 4.05; P=0.003). The incidence of FAE in ICI in all included studies were up to 3.2%. OR value of clinical trials of prostate cancer was 3.71 (95% CI: 1.12, 12.26; P=0.03). Among the ICI cohorts, the common FAEs were gastrointestinal toxicity (n=12, 25%), pulmonary toxicity (n=10, 20%), cardiac toxicity (n=5, 10%), and hepatic toxicity (n=5, 10%). Conclusion: The cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors have a significantly higher risk of FAE (P=0.01), whereas programmed cell death protein 1 (PD-1) inhibitors were not. The most common CTLA-4-related FAE was gastrointestinal toxicity, and the most common PD-1-related FAE was pulmonary toxicity. Moreover, we have shown that ipilimumab has significant dose-dependent lethal toxicity.

11.
J Cell Mol Med ; 23(4): 2731-2743, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30770623

RESUMO

Lipid metabolism disorders lead to vascular endothelial injury. Matrine is an alkaloid that has been used to improve obesity and diabetes and for the treatment of hepatitis B. However, its effect on lipid metabolism disorders and vascular injury is unclear. Here, we investigated the effect of matrine on high-fat diet fed mice and oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs). Computational virtual docking analyses, phosphoinositide 3-kinase (PI3K) and protein kinase C-α (PKCα) inhibitors were used to localize matrine in vascular injuries. The results showed that matrine-treated mice were more resistant to abnormal lipid metabolism and inflammation than vehicle-treated mice and exhibited significantly alleviated ox-LDL-stimulated dysfunction of HUVECs, restored diminished nitric oxide release, decreased reactive oxygen species generation and increased expression phosphorylation of AKT-Ser473 and endothelial nitric oxide synthase (eNOS)-Ser1177. Matrine not only up-regulates eNOS-Ser1177 but also down-regulates eNOS-Thr495, a PKCα-controlled negative regulator of eNOS. Using computational virtual docking analyses and biochemical assays, matrine was also shown to influence eNOS/NO via PKCα inhibition. Moreover, the protective effects of matrine were significantly abolished by the simultaneous application of PKCα and the PI3K inhibitor. Matrine may thus be potentially employed as a novel therapeutic strategy against high-fat diet-induced vascular injury.

12.
J Transl Med ; 16(1): 319, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458883

RESUMO

BACKGROUND: Endoplasmic reticulum (ER) stress, which can promote lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Calcium (Ca2+) homeostasis is considered to play a key role in ER stress. Matrine (Mat) has been applied for the treatment of hepatitis B, but its effect on NAFLD is still unknown, and there is no unified view of Mat on the regulation of ER stress in the previous literature. METHODS: The pharmacological effects were studied in high-fat-diet or methionine-choline-deficient diet induced C57BL/6J mice models and in palmitic acid (PA) induced L02 human liver cell model. Calcium fluorescence experiments, computational virtual docking analysis and biochemical assays were used in identifying the locus of Mat. RESULTS: The results showed that Mat-treated mice were more resistant to steatosis in the liver than vehicle-treated mice and that Mat significantly reduced hepatic inflammation, lipid peroxides. The beneficial effect of Mat was associated with suppressing ER stress and restoring mitochondrial dysfunction. Additionally, Mat decreased the PA-induced lipid accumulation, ER stress and cytosolic calcium level ([Ca2+]c) in hepatocyte cell lines in low and middle dose. However, the high dose Mat did not show satisfactory results in cell model. Calcium fluorescence experiments showed that Mat was able to regulate [Ca2+]c. By computational virtual docking analysis and biochemical assays, Mat was shown to influence [Ca2+]c via direct inhibition of SERCA. CONCLUSIONS: The results showed that the bi-directional regulation of Mat to endoplasmic reticulum at different doses was based on the inhibition of SERCA. In addition, the results also provide a theoretical basis for Mat as a potential therapeutic strategy in NAFLD/NASH.


Assuntos
Alcaloides/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/patologia , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Quinolizinas/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Citosol/metabolismo , Dieta Hiperlipídica , Homeostase/efeitos dos fármacos , Humanos , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Ácido Palmítico , Espécies Reativas de Oxigênio/metabolismo
13.
Food Funct ; 9(11): 5880-5890, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30374490

RESUMO

Dry citrus peel (Chenpi) is not only consumed as a dietary supplement, but also used for the treatment of respiratory diseases. Pinelliae Rhizoma Praeparatum (Banxia) is always used with Chenpi for the treatment of respiratory diseases, but ß-sitosterol, the main active component in Banxia, as a food additive, shows no respiratory system activity. In the present study, the pharmacokinetic characters showed that the absorption of the active components of Chenpi was accelerated under pathological conditions combined with Banxia. Although the bioavailability of active components did not significantly change, the distribution of active components in tissues increased, particularly in the target organ. These results are consistent with the combination of Chenpi with ß-sitosterol. Furthermore, the pharmacodynamics result also indicated that Chenpi combined with Banxia or ß-sitosterol was able to ameliorate histopathologic damage and decrease the levels of inflammatory factors. The results suggest that pharmacokinetic interactions improve the pharmacological activity of Chenpi in respiratory diseases.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Citrus/química , Pinellia/química , Extratos Vegetais/farmacologia , Extratos Vegetais/farmacocinética , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Frutas/química , Lipopolissacarídeos , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sitosteroides/farmacologia
14.
Electrophoresis ; 39(24): 3156-3170, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30194859

RESUMO

In this paper, we numerically investigated a multifunctional AC electrothermal (ACET) micropump embedded with an asymmetric spiral microelectrode pair in a cylindrical microchannel for simultaneous pumping and mixing in high-conductivity fluids, which makes the pump useful for biofluid applications. When an AC signal was applied to the asymmetric spiral electrode pair, the vortices induced on the electrode surfaces with centerlines along the corresponding spiral electrode length exhibit a spiral distribution, and the net flow in the cylindrical microchannel is generated by the ACET effect. The vorticity field distribution can explain the mechanism of simultaneous pumping and mixing. Because the vorticity field is inclined against the microchannel direction, vortices on top of the spiral electrodes can affect the ACET flow in the following two aspects at the same time: one is pumping the flow in the microchannel direction, and the other is mixing the samples by stirring the flow. We also determined that the geometric ratios of the electrode width to the gap or slant angle of the spiral electrodes can feasibly be used to control the relative strength of the pumping and mixing capabilities, and we achieved an optimal design that gives both desirable pumping and mixing efficiencies. This study shows that the spiral ACET micropump design can rapidly drive the high-conductivity fluids and efficiently mix samples simultaneously. The numerical simulation of the spiral ACET micropump is of significant importance for practical, chemical and biological applications, and feasible fabrication techiniques should be experimentally investigated in future studies.


Assuntos
Biotecnologia/instrumentação , Microeletrodos , Técnicas Analíticas Microfluídicas/instrumentação , Simulação por Computador , Desenho de Equipamento , Temperatura Ambiente
15.
DNA Cell Biol ; 37(2): 109-116, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29298094

RESUMO

miR-138 modulates cardiac morphogenesis in zebrafish. We explored whether a genetic polymorphism in miR-138 might contribute to the occurrence of sporadic congenital heart disease (CHD) and the potential mechanism. We performed a case-control study consisting of 857 CHD cases and 938 non-CHD controls by genotyping miR-138 in a Chinese population. Two SNPs, including rare rs139365823 located in the pre-miR-138 sequence and rs76987351 located in the pri-miR-138 sequence, were identified by sequencing miR-138. The results demonstrated that the genotypes and allele frequencies of the rs139365823 minor allele A were significantly associated with the increased risk of CHD cases overall or in the Tetralogy of Fallot (TOF) subtype, but not with the rs76987351 A/G allele. Real-time PCR data showed that the rs139365823 minor allele A significantly increased the expression of mature miR-138, whereas the rs76987351 minor allele A had the opposite effect. As TOF is caused by severe outflow tract (OFT) development and an alignment defect, we identified Dvl2, involved in OFT development, as a direct target of miR-138. Further, the rs139365823 minor allele A enhanced the miR-138-mediated inhibitory regulation of Dvl2. Taken together, our results demonstrated for the first time that the functional variant rs139365823 in pre-miR-138 altered the expression of mature miR-138 and its inhibitory effect on target genes and conferred the risk for CHD in the population studied here.


Assuntos
Cardiopatias Congênitas/genética , MicroRNAs/genética , Estudos de Casos e Controles , Criança , China , Proteínas Desgrenhadas/genética , Proteínas Desgrenhadas/metabolismo , Feminino , Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único , Interferência de RNA , Fatores de Risco
16.
Cell Res ; 28(1): 48-68, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29076503

RESUMO

The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity. ASD-like symptoms were recapitulated in mice by overexpressing UBE3A in the prefrontal cortex or by administration of an ALDH1A antagonist, whereas RA supplements significantly alleviated excessive UBE3A dosage-induced ASD-like phenotypes. By identifying reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, our findings introduce a new vista of ASD etiology and facilitate a mode of therapeutic development against this increasingly prevalent disease.


Assuntos
Transtorno do Espectro Autista/metabolismo , Neurônios/metabolismo , Retinal Desidrogenase/metabolismo , Tretinoína/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Pré-Escolar , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Plasticidade Neuronal , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
17.
Chem Biol Interact ; 278: 162-169, 2017 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-28987327

RESUMO

Deltamethrin (DLT) is effective against a broad spectrum of insects. Exposure to DLT has been demonstrated to cause oxidative stress. However, the mechanism of oxidative stress induced by DLT is little known. Groups of rats were gavaged with DLT once daily for 7 days at six dosages: 0, 2, 5, 10, 20, 40 mg/kg. The intensity of neurotoxicity and liver dysfunction caused by DLT were significantly increased in a dose-dependent manner. We found that DLT caused the increase of cytosolic superoxide in tissues. Western blot analysis showed that both the expression of p66shc and Ser36 phosphorylated p66shc, which were involved in ROS generation, were increased in tissues treated with DLT. Further investigation showed that DLT treatment resulted in the increase of intracellular ROS accompanied with elevated p66shc expression in different cell lines. And treatment of cells with DLT induced p66shc phosphorylation at Ser36 and the translocation of p66shc from cytoplasm to mitochondria. Moreover, the overexpression of wildtype p66shc caused the increase of DLT-mediated ROS level in SH-SY5Y cells, but cells overexpressing p66shcSer36Ala mutant plasmid had the opposite effect. And p66shc suppression by siRNA blunted DLT-mediated ROS generation. Taken together, our findings indicated p66shc mediated DLT-induced oxidative stress, which may be partly responsible for toxic effects.


Assuntos
Nitrilos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Piretrinas/toxicidade , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Microscopia Confocal , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/antagonistas & inibidores , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética
18.
Genet Test Mol Biomarkers ; 21(5): 312-315, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28346832

RESUMO

AIMS: TCF21 knockout mice display cardiac defects, including ventricular septal defects (VSDs). Functional rs12190287 polymorphisms located within the 3' untranslated region (3'-UTR) of TCF21 were associated with a risk of coronary heart disease in the European and Eastern populations. However, whether rs12190287 polymorphisms in the TCF21-3'UTR confer predisposition to congenital heart disease (CHD) is unclear. METHODS: A case-control study was designed consisting of 781 nonsyndromic VSD patients and 867 non-CHD control subjects. The genotype frequency of rs12190287 polymorphisms was determined by real-time polymerase chain reaction. RESULTS: There were significant differences in the genotype and allele frequencies of rs12190287 between the cases and controls in a Chinese population. Allele G of rs12190287 was significantly associated with an increased risk of VSD in a Chinese population. CONCLUSIONS: Our results demonstrate that rs12190287 polymorphisms confer predisposition to VSDs in the Chinese population studied here.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Comunicação Interventricular/genética , Regiões 3' não Traduzidas , Adolescente , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Doença da Artéria Coronariana/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Cardiopatias Congênitas/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
19.
J Am Soc Nephrol ; 28(6): 1729-1740, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28028135

RESUMO

Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function.


Assuntos
Lesão Renal Aguda/classificação , Lesão Renal Aguda/genética , Transcriptoma , Animais , Feminino , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL
20.
Cell Discov ; 2: 16009, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27462456

RESUMO

In mammalian cells, DNA methylation critically regulates gene expression and thus has pivotal roles in myriad of physiological and pathological processes. Here we report a novel method for targeted DNA demethylation using the widely used clustered regularly interspaced short palindromic repeat (CRISPR)-Cas system. Initially, modified single guide RNAs (sgRNAs) (sgRNA2.0) were constructed by inserting two copies of bacteriophage MS2 RNA elements into the conventional sgRNAs, which would facilitate the tethering of the Tet1 catalytic domain (Tet-CD), in fusion with dCas9 or MS2 coat proteins, to the targeted gene loci. Subsequently, such system was shown to significantly upregulate transcription of the target genes, including RANKL, MAGEB2 or MMP2, which was in close correlation to DNA demethylation of their neighboring CpGs in the promoters. In addition, the dCas9/sgRNA2.0-directed demethylation system appeared to afford efficient demethylation of the target genes with tenuous off-target effects. Applications of this system would not only help us understand mechanistically how DNA methylation might regulate gene expression in specific contexts, but also enable control of gene expression and functionality with potential clinical benefits.

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