RESUMO
Neutrophils, the most abundant and efficient defenders against pathogens, exert opposing functions across cancer types. However, given their short half-life, it remains challenging to explore how neutrophils adopt specific fates in cancer. Here, we generated and integrated single-cell neutrophil transcriptomes from 17 cancer types (225 samples from 143 patients). Neutrophils exhibited extraordinary complexity, with 10 distinct states including inflammation, angiogenesis, and antigen presentation. Notably, the antigen-presenting program was associated with favorable survival in most cancers and could be evoked by leucine metabolism and subsequent histone H3K27ac modification. These neutrophils could further invoke both (neo)antigen-specific and antigen-independent T cell responses. Neutrophil delivery or a leucine diet fine-tuned the immune balance to enhance anti-PD-1 therapy in various murine cancer models. In summary, these data not only indicate the neutrophil divergence across cancers but also suggest therapeutic opportunities such as antigen-presenting neutrophil delivery.
Assuntos
Apresentação de Antígeno , Neoplasias , Neutrófilos , Animais , Humanos , Camundongos , Antígenos de Neoplasias , Leucina/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Neutrófilos/metabolismo , Linfócitos T , Análise da Expressão Gênica de Célula ÚnicaRESUMO
Circular RNAs (circRNAs) produced from back-splicing of exons of pre-mRNAs are widely expressed, but current understanding of their functions is limited. These RNAs are stable in general and are thought to have unique structural conformations distinct from their linear RNA cognates. Here, we show that endogenous circRNAs tend to form 16-26 bp imperfect RNA duplexes and act as inhibitors of double-stranded RNA (dsRNA)-activated protein kinase (PKR) related to innate immunity. Upon poly(I:C) stimulation or viral infection, circRNAs are globally degraded by RNase L, a process required for PKR activation in early cellular innate immune responses. Augmented PKR phosphorylation and circRNA reduction are found in peripheral blood mononuclear cells (PBMCs) derived from patients with autoimmune disease systemic lupus erythematosus (SLE). Importantly, overexpression of the dsRNA-containing circRNA in PBMCs or T cells derived from SLE can alleviate the aberrant PKR activation cascade, thus providing a connection between circRNAs and SLE.
Assuntos
RNA Circular/metabolismo , RNA Circular/fisiologia , eIF-2 Quinase/metabolismo , Adolescente , Adulto , Doenças Autoimunes/genética , Linhagem Celular , Endorribonucleases/metabolismo , Feminino , Humanos , Imunidade Inata/genética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/genética , Pessoa de Meia-Idade , Fosforilação , RNA/metabolismo , Splicing de RNA/genética , Estabilidade de RNA/fisiologia , RNA Circular/genética , RNA de Cadeia Dupla/metabolismo , Viroses/metabolismo , eIF-2 Quinase/imunologiaRESUMO
Exon back-splicing-generated circular RNAs, as a group, can suppress double-stranded RNA (dsRNA)-activated protein kinase R (PKR) in cells. We have sought to synthesize immunogenicity-free, short dsRNA-containing RNA circles as PKR inhibitors. Here, we report that RNA circles synthesized by permuted self-splicing thymidylate synthase (td) introns from T4 bacteriophage or by Anabaena pre-tRNA group I intron could induce an immune response. Autocatalytic splicing introduces â¼74 nt td or â¼186 nt Anabaena extraneous fragments that can distort the folding status of original circular RNAs or form structures themselves to provoke innate immune responses. In contrast, synthesized RNA circles produced by T4 RNA ligase without extraneous fragments exhibit minimized immunogenicity. Importantly, directly ligated circular RNAs that form short dsRNA regions efficiently suppress PKR activation 103- to 106-fold higher than reported chemical compounds C16 and 2-AP, highlighting the future use of circular RNAs as potent inhibitors for diseases related to PKR overreaction.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , RNA Circular/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Células A549 , Bacteriófago T4/enzimologia , Bacteriófago T4/genética , Células HEK293 , Células HeLa , Humanos , Imunidade Inata/efeitos dos fármacos , Íntrons , Conformação de Ácido Nucleico , Inibidores de Proteínas Quinases/imunologia , RNA Ligase (ATP)/genética , RNA Ligase (ATP)/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Circular/genética , RNA Circular/imunologia , Timidilato Sintase/genética , Timidilato Sintase/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , eIF-2 Quinase/metabolismoRESUMO
AIMS: Experiments confirmed that circular RNAs contributed to the pathogenesis of diabetic foot ulcers (DFUs). CircHIPK3 was upregulated in type 2 diabetes mellitus (T2DM), but its role in DFU remained unknown. Our study aimed to investigate the regulatory functions of exosomal circHIPK3 and its potential mechanisms in DFU. METHODS: Exosomal size and distribution, marker proteins, and circHIPK3 levels were evaluated by transmission electron microscope, ExoView R200, western blot, and qRT-PCR. Flow cytometry, MTT, Wound healing assays, and tube formation assays were used to assess the roles of exosomal circHIPK3 in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs). The relationships between Nrf2/VEGFA/circHIPK3 and miR-20b-5p, and between Nrf2 and VEGFA were determined by luciferase reporter assay and RNA immunoprecipitation. We used cell and mice models to investigate the mechanisms of exosomal circHIPK3 under diabetic conditions. RESULTS: CircHIPK3 was significantly upregulated in exo-circHIPK3 rather than exo-vector. Exo-circHIPK3 remarkably inhibited cell apoptosis but promoted cell proliferation, migration, and tube formation in HG-treated HUVECs. Luciferase reporter and RIP assays showed that miR-20b-5p targeted and inhibited Nrf2 and VEGFA, and circHIPK3 acted as a ceRNA of miR-20b-5p to inhibit the binding to its downstream genes Nrf2 and VEGFA. Mechanistically, circHIPK3 promoted cell proliferation, migration, and angiogenesis via downregulating miR-20b-5p to upregulate Nrf2 and VEGFA. However, the overexpressed miR-20b-5p could abolish the promoting effects of circHIPK3 overexpression on cell proliferation, migration, and tube formation under HG conditions. CONCLUSION: UCMSCs-derived exosomal circHIPK3 protected HG-treated HUVECs via miR-20b-5p/Nrf2/VEGFA axis. The exosomal circHIPK3 might be a therapeutic candidate to treat DFU.
Assuntos
Diabetes Mellitus Tipo 2 , MicroRNAs , Humanos , Camundongos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proliferação de Células/genética , Fator A de Crescimento do Endotélio VascularRESUMO
Circular RNAs are produced from back-splicing of exons of precursor mRNAs (pre-mRNAs). The sequences of exons in circular RNAs are identical to their linear cognate mRNAs, but the circular format may confer constraints on their folding and conformation, leading to potentially different functions from their linear RNA cognates. Here, we describe experimental and computational steps that optimize the selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) to probe circular RNA secondary structure at single-nucleotide resolution in living cells.
Assuntos
RNA Circular , RNA , Conformação de Ácido Nucleico , RNA/química , Precursores de RNA , Splicing de RNA/genética , RNA Circular/genéticaRESUMO
Two new xanthones, calmemxanthone A (1) and calmemxanthone B (2), along with eleven known compounds were isolated from the dried twigs of Calophyllum membranaceum Gardn. et Champ. The structures of compounds 1 and 2 were established by analysis of spectra and mass spectrometry data. The absolute configuration of compound 1 was confirmed by electronic circular dichroism (ECD) spectral analysis. The anti-inflammation action of these compounds were evaluated on lipopolysaccharide (LPS)-induced inflammatory damage to human endometrial stromal cells (HESCs), and the structure-activities of 1-13 were also discussed. Compound 10 presented the anti-inflammation action with an IC50 value of 20.3â µM, that might be relevant to the regulation of NF-κB signaling pathway via the suppression of TRIF, IKKα, and IκBα.
Assuntos
Calophyllum , Células-Tronco Embrionárias Humanas , Xantonas , Anti-Inflamatórios/farmacologia , Calophyllum/química , Humanos , Estrutura Molecular , Xantonas/química , Xantonas/farmacologiaRESUMO
Objective To explore the associations of obstructive sleep apnea(OSA) and gender with estimated glomerular filtration rate(eGFR) in hypertensive populations.Methods From February 2005 to August 2010,2064 hypertensive patients who were treated in the Department of Hypertension Center underwent overnight polysomnographic monitoring.According to the apnea-hypopnea index(AHI),they were assigned into an hypertension combined with OSA group and a hypertension group.The clinical characteristics and sleep monitoring indicators were compared between different genders and between the two groups.Multivariate Logistic regression was employed to analyze the influencing factors of eGFR.Results Among the 2064 hypertensive patients,there were 1537 males(including 1221 patients with OSA) and 527 females(including 350 patients with OSA).The males had higher prevalence of OSA(χ2=36.631,P<0.001) and diastolic blood pressure(Z=-7.776,P<0.001) and lower eGFR(Z=-3.010,P=0.003) than the females.The males had higher AHI(Z=-8.727,P<0.001),apnea index(Z=-9.252,P<0.001),hypopnea index(HI)(Z=-4.868,P<0.001) than the females,and the lowest oxygen saturation(t=-3.325,P=0.001) was significantly lower in males than in females.The hypertension combined with OSA group showed lower eGFR than the hypertension group(Z=-27.434,P<0.001;Z=-18.762,P<0.001).HI was negatively correlated with eGFR in the male population(r=-0.006,P=0.017),and AHI and HI were negatively correlated eGFR in females(r=-0.108,P=0.013;r=-0.094,P=0.032).After adjustment,Logistic regression showed that OSA and oxygen desaturation index 4 were the risk factors for the reduction of eGFR in hypertensive patients in males and females,respectively(OR=1.383,95%CI=1.010-1.905,P=0.045;OR=1.013,95%CI=1.002-1.024,P=0.021).Conclusion OSA lowers the eGFR of hypertensive patients,and OSA and oxygen desaturation index are the risk factors for the decrease in eGFR in male and female hypertensive patients,respectively.
Assuntos
Hipertensão , Apneia Obstrutiva do Sono , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Masculino , Oxigênio , Polissonografia , Apneia Obstrutiva do Sono/complicaçõesRESUMO
Seven new triterpenoids including two cycloartanes (1-2), a lanostane (3), a tirucallane (4), a dammarane (5), an ursane (6), and an oleanane (7), along with nineteen known triterpenoids (8-26), have been obtained from the roots of Euphorbia fischeriana. Their structures were established by NMR, HRESIMS, single-crystal X-ray diffraction analysis, Mosher's method, NMR calculations, ECD analysis, and comparison with structurally related known analogues. Among them, compounds 1 and 8 were a pair of cycloartane-type triterpenoids epimers. Our bioassays have established that compounds 1-5 and 10 displayed moderate cytotoxic effects, and the structure-activity relationships of cycloartane-type triterpenoids (CTTs) were further examined. Notably, some triterpenoids displayed moderate inhibitory effects against AChE by an in vitro screened experiment. Triterpenoid 7 (Euphorfistrine G, ETG) displayed the potent inhibitory effect with IC50 = 2.45 and Ki = 2.30 µM (inhibition kinetic). And, in silico docking analyses have been performed to investigate the inhibitory mechanism of compound 7.
Assuntos
Acetilcolinesterase/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Colinesterase/farmacologia , Euphorbia/química , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Thorea hispida exclusively inhabits freshwater environments and is characterized by a triphasic life history. In this study, the organelle genomes and transcriptomes of different life history stages of T. hispida were examined using next generation sequencing. The chloroplast and mitochondrial genomes of the chantransia stage were 175,747 and 25,411 bp in length, respectively. The chantransia stage was highly similar to the gametophyte stage based on comparisons of organelle genomes and phylogenetic reconstruction. Transcriptomic comparisons of two stages found that ribosome-related genes were the most up-regulated in the gametophyte stage of T. hispida. Seven meiosis-specific genes, including SPO11 initiator of meiotic double-stranded breaks(spo11), meiotic nuclear divisions 1(mnd1), RAD51 recombinase(rad51), mutS homolog 4(msh4), mutS homolog 5(msh5), REC8 meiotic recombination protein(rec8), and DNA helicase Mer3(mer3), were differentially regulated between the two life history stages. The organelle genomes and transcriptomes from T. hispida provided in this study will be valuable for future studies of freshwater red algae.
Assuntos
Água Doce , Rodófitas/fisiologia , Transcriptoma , Filogenia , Reação em Cadeia da Polimerase em Tempo Real , Rodófitas/genéticaRESUMO
Objective To explore the mechanism of obstructive sleep apnea(OSA) by assessing the association between human TWIK-related acid-sensitive K + channel-1(TASK-1) gene and OSA. Methods A total of 164 patients with severe OSA and 171 patients without OSA were recruited from the Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region,China,from April to December 2016.Two single nucleotide polymorphisms(rs1275988 and rs2586886) in the TASK-1 gene were selected and genotyped using a Kompetitive Allele Specific PCR genotyping system. Results In patients with blood potassium <3.95 mmol/L,the distribution of rs1275988 alleles(G vs.A)(χ 2=4.474,P=0.034) and recessive model(GG+GA vs.AA)(χ 2=4.327,P=0.038) showed significant differences between severe and non-OSA groups.The distribution of rs2586886 alleles(G vs.A)(χ 2=6.345,P=0.012) and dominant model(AA+GA vs.GA)(χ 2=4.431,P=0.035) showed significant differences between severe and non-OSA groups.The Logistic regression analysis showed that the GG genotype was a risk factor for OSA patients with blood potassium <3.95 mmol/L(OR=7.854,95% CI:1.710-36.000,P=0.008;OR=8.849,95% CI:1.816-43.117,P=0.007). Conclusions Both the GG genotypes of rs1275988 and rs2586886 in the TASK-1 gene may be potential risk factors in severe OSA patients with blood potassium <3.95 mmol/L.Serum potassium>3.95 mmol/L in patients with TASK-1 GG genotype may be conducive to reducing the incidence of severe OSA.
Assuntos
Proteínas do Tecido Nervoso/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Apneia Obstrutiva do Sono/genética , Alelos , Estudos de Casos e Controles , China , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Potássio/sangue , Fatores de RiscoRESUMO
Fibronectin (FN) is a high-molecular-weight extracellular matrix protein that contains the RGDS motif, which is required to bind to integrins. Synthetic RGDS peptides have been reported to compete with FN to bind to the cell surface and inhibit the function of FN. Here, we identified that synthetic RGDS peptides significantly inhibit human enterovirus 71 (EV71) infection in cell cultures. In addition, mice treated with RGDS peptides and infected with EV71 had a significantly higher survival rate and a lower viral load than the control group. Because RGDS peptides affect the function of FN, we questioned whether FN may play a role in virus infection. Our study indicates that overexpression of FN enhanced EV71 infection. In contrast, knockout of FN significantly reduced viral yield and decreased the viral binding to host cells. Furthermore, EV71 entry, rather than intracellular viral replication, was blocked by FN inhibitor pretreatment. Next, we found that FN could interact with the EV71 capsid protein VP1, and further truncated-mutation assays indicated that the D2 domain of FN could interact with the N-terminal fragment of VP1. Taken together, our results demonstrate that the host factor FN binds to EV71 particles and facilitates EV71 entry, providing a potential therapy target for EV71 infection.IMPORTANCE Hand, foot, and mouth disease outbreaks have occurred frequently in recent years, sometimes causing severe neurological complications and even death in infants and young children worldwide. Unfortunately, no effective antiviral drugs are available for human enterovirus 71 (EV71), one of the viruses that cause hand, foot, and mouth disease. The infection process and the host factors involved remain unknown, although several receptors have been identified. In this study, we found that the host factor fibronectin (FN) facilitated EV71 replication by interacting with EV71 particles and further mediated their entry. The RGDS peptide, an FN inhibitor, significantly inhibited EV71 replication in both RD cells and mice. In conclusion, our research identified a new host factor involved in EV71 infection, providing a new potential antiviral target for EV71 treatment.
Assuntos
Enterovirus Humano A/metabolismo , Infecções por Enterovirus/patologia , Fibronectinas/metabolismo , Internalização do Vírus , Animais , Sistemas CRISPR-Cas , Linhagem Celular , Enterovirus Humano A/genética , Infecções por Enterovirus/virologia , Fibronectinas/genética , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Replicação Viral/fisiologiaRESUMO
BACKGROUND A growing body of evidence suggests that systemic lupus erythematosus (SLE) may result in reversible cognitive dysfunction. Vitamin D is considered important for neurons. The therapeutic effect of vitamin D was evaluated in a rat model of SLE. MATERIAL AND METHODS There were 20 male MRL/lpr mice randomly divided into the SLE model group and the vitamin D group, in addition, 10 male C57BL 6J mice were used as the control (CON) group. Vitamin D was administered intraperitoneally (2 µg/kg) for 4 weeks. After 4 weeks of continuing intervention, we tested the cognitive function using the Morris water maze. The expression of vitamin D receptor (VDR), amyloid-ß, caspase-3, and Bcl-2 were detected by western blot analysis. RESULTS In the present study, we observed that vitamin D treatment alleviated neurobehavioral deficits in the mice with SLE. At the molecular levels, administration of vitamin D activated the expression of VDR and reduced the number of dead cells in the CA1 region of the hippocampus as well as regulated caspase-3 and Bcl-2 expression. CONCLUSIONS In conclusion, our results indicated that vitamin D played a protective role by suppressing inflammatory cytokines, thereby ultimately inhibiting the progression of apoptosis in a mouse model of SLE. Vitamin D may be promising as a protective intervention in SLE with cognitive dysfunction, and more and more experiments are warranted for its clinical testing in the near future.
Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Vitamina D/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Caspase 3/metabolismo , Citocinas/metabolismo , Hipocampo/patologia , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Tempo , Vitamina D/farmacologiaRESUMO
OBJECTIVES: To discover novel feruloyl esterases (FAEs) by the function-driven screening procedure from soil metagenome. RESULTS: A novel FAE gene bds4 was isolated from a soil metagenomic library and over-expressed in Escherichia coli. The recombinant enzyme BDS4 was purified to homogeneity with a predicted molecular weight of 38.8 kDa. BDS4 exhibited strong activity (57.05 U/mg) toward methyl ferulate under the optimum pH and temperature of 8.0 and 37°C. Based on its amino acid sequence and model substrates specificity, BDS4 was classified as a type-C FAE. The quantity of the releasing ferulic acid can be enhanced significantly in the presence of xylanase compared with BDS4 alone from de-starched wheat bran. In addition, BDS4 can also hydrolyze several phthalates such as diethyl phthalate, dimethyl phthalate and dibutyl phthalate. CONCLUSION: The current investigation discovered a novel FAE with phthalate-degrading activity and highlighted the usefulness of metagenomic approaches as a powerful tool for discovery of novel FAEs.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , DNA/isolamento & purificação , Metagenômica , Ácidos Ftálicos/metabolismo , Microbiologia do Solo , Biotransformação , Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/isolamento & purificação , Clonagem Molecular , DNA/genética , Estabilidade Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Concentração de Íons de Hidrogênio , Peso Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , TemperaturaRESUMO
There is a concern about the increasing prevalence of health problems related to the ingestion of fluoride (F-) in the developing world. Drinking water is one important source of F-, and the concentration of F- needs to be known to ensure the safety of drinking water. In this study, F- levels in drinking water were investigated across Taiyuan in Shanxi Province, China. Spatial-temporal distribution characteristics and potential associated health risks were analyzed using GIS. We collected 485 samples from shallow wells without any defluoridation treatments between 2008 and 2016. After analyzing the samples of F- content we found that mean F- levels of urban areas (0.61⯱â¯0.39â¯mgâ¯L-1), suburban areas (0.70⯱â¯0.87â¯mgâ¯L-1) and for all of Taiyuan city (0.63⯱â¯0.56â¯mgâ¯L-1) were in optimum range based on the recommendation by USEPA. However, individual locations within industrial areas (e.g. Gujiao District) had higher F- levels (1.06â¯mgâ¯L-1). A concerning result showed that 12.37% of tested locations had F- concentrations larger than 1.0â¯mgâ¯L-1. We calculated F- Health Risk Indices (HRIsF) and found that highest were associated with suburban areas, especially in the year 2009 and 2010. However, from 2008 to 2016, overall F- levels and HRIsF of the sampled groundwater in Taiyuan City showed a decreasing trend. HRIsF in suburban areas was higher than urban areas, possible due to the heavily prevalent coal mining industry in those areas. Specific policies should be formulated to address HRIsF.
Assuntos
Água Potável/química , Fluoretos/análise , Água Subterrânea/química , Poluentes Químicos da Água/análise , China/epidemiologia , Monitoramento Ambiental , Sistemas de Informação Geográfica , Humanos , Medição de Risco , Análise Espaço-Temporal , Saúde Suburbana , Saúde da População UrbanaRESUMO
OBJECTIVE: To explore the relationships of BRAF V600E and TERT promoter mutations with the clinicopathological features in papillary thyroid carcinoma (PTC). METHODS: The mutations of BRAF V600E and TERT promoters were examined by PCR-direct sequencing in tumor tissues from 326 PTC patients, while the relationships between the gene mutations and clinicopathological features were analyzed. RESULTS: BRAF V600E mutation was found in 269/326 (82.52%), and TERT promoter mutation in 11/326 (3.37%) of PTC patients. In site mutations of TERT promoter, 9 cases were C228T and 2 cases were C250T. Single factor analysis showed that BRAF V600E mutations were significantly associated with age and recurrence/distant metastasis of tumor (P < 0.05), while TERT promoter mutations were significantly associated with age, tumor size, extrathyroidal extension, T stage, AJCC stage and recurrence/distant metastasis of tumor (P < 0.05). Coexistence of BRAF V600E and TERT promoter mutations (BRAF+/TERT+) were particularly associated with age, tumor size, extrathyroidal extension, T stage and AJCC stage (P < 0.05). CONCLUSION: Coexistence of BRAF V600E and TERT promoter mutations in PTC shows more aggressive tumor behavior.
Assuntos
Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Mutação , Recidiva Local de Neoplasia , Prognóstico , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genéticaRESUMO
Accumulating evidence indicates that asiatic acid, a natural triterpene isolated from Centella asiatica, has anti-inflammatory activity. However, the anti-inflammatory effects of asiatic acid on LPS-stimulated endometrial epithelial cells and the involved molecular pathways have not been completely elucidated. In the present study, we evaluated the effects of asiatic acid on LPS-induced inflammatory response in endometrial epithelial cells. Mouse endometrial epithelial cells were treated with asiatic acid and stimulated with LPS. ELISA was performed to measure the levels of inflammatory cytokines TNF-α, IL-1ß, and PGE2. Western blot analysis was used to test the expression of PPARγ and NF-κB. The results showed that LPS-induced inflammatory mediators TNF-α, IL-1ß, NO, and PGE2 were significantly inhibited by asiatic acid. Furthermore, LPS-induced TLR4 expression and NF-κB activation were concentration-dependently suppressed by asiatic acid. In addition, asiatic acid was found to increase the expression of PPARγ in a concentration-dependently manner. The inhibition of asiatic acid on inflammatory mediators production were prevented by PPARγ inhibitor, GW9662. Taken together, these results showed that asiatic acid exhibited its anti-inflammatory effects in endometrial epithelial cells by activating PPARγ.
Assuntos
Anti-Inflamatórios/metabolismo , Células Epiteliais/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Triterpenos Pentacíclicos/metabolismo , Animais , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/fisiologia , Fatores Imunológicos/análise , Camundongos , Modelos BiológicosRESUMO
TWIK-related acid-sensitive K + channel(TASK)is an important member of the two-pore-domain potassium channels family. It is widely expressed in the central nervous system and peripheral tissues and is extremely sensitive to hypoxia and pH changes in extracellular fluid. TASK participates in regulating the expression of respiratory center and the respiratory movement and also plays certain role in sleep regulation. This article reviews the recent advances in the roles of TASK in the regulation of respiration and sleep.
Assuntos
Proteínas do Tecido Nervoso/fisiologia , Canais de Potássio de Domínios Poros em Tandem/fisiologia , Respiração , Sono , Sistema Nervoso Central , Humanos , Concentração de Íons de Hidrogênio , HipóxiaRESUMO
BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is widely used in the treatment of cervical degenerative disease; however, the variation of cervical sagittal alignment changes after ACDF has been rarely explored. The purpose of this study is to determine the relationship between changes of cervical sagittal alignment after ACDF and spino-pelvic sagittal alignment under Roussouly classification. METHODS: A cohort of 133 Chinese cervical spondylotic patients who received ACDF from 2011 to 2012 was recruited. All patients were categorized with Roussouly Classification. Lateral X-ray images of global spine were obtained, and preoperative and postoperative parameters were measured and analyzed, including C2-C7 angles (C2-C7), C0-C7 angles (C0-C7), external auditory meatus (EAM) tilt, sacral slope (SS), thoracic kyphosis (TK), lumbar lordosis (LL), spinal sacral angles (SSA), Superior adjacent inter-vertebral angle (SAIV), inferior adjacent inter-vertebral angle (IAIV) and et al. The Wilcoxon signed-rank test was used for intragroup comparisons preoperatively and at postoperative 48 months. RESULTS: Among the parameters, C2-C7 and C0-C7 showed significant increase, while EAM TK, and IAIV decreased significantly. In type I, EAM and TK decreased significantly, however SS showed a significant increase; in type II, TK showed a significant decrease, but SSA showed a significant increase; in type III, a significant increase of C0-C7 was observed with a significant decrease in EAM, nevertheless, LL, SS and SSA showed significant decreases; and in type IV, C2-C7 showed a significant increase and EAM decreased significantly. The percentage of lordotic alignment in cervical spine increased, which was presenting in type I, III and IV. Nevertheless, the amount of patients with straight cervical alignment increased in type II. CONCLUSION: The backward movement of head occurs is the compensatory mechanism in cervical sagittal alignment modifications after ACDF. The compensatory alteration of spino-pelvic sagittal alignment varied in different Roussouly type.
Assuntos
Vértebras Cervicais/diagnóstico por imagem , Discotomia/tendências , Ossos Pélvicos/diagnóstico por imagem , Fusão Vertebral/tendências , Espondilose/classificação , Espondilose/diagnóstico por imagem , Adulto , Idoso , Vértebras Cervicais/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ossos Pélvicos/cirurgia , Estudos Retrospectivos , Espondilose/cirurgia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is strongly associated with the increasing prevalence of cerebrovascular events and metabolic syndrome. A growing number of studies have shown OSAS is an independent factor for insulin resistance, glucose intolerance and type2 diabetes. However, relationship of OSAS with dysglycemia is complex and still remains poorly understood. Glucose transporter 4 (GLUT4) gene is Human and rodents' main glucose transporter sensitive to insulin, and therefore confirmation of candidate gene polymorphisms and association with OSAS is needed. Aim of our study was to assess whether GLUT4 gene polymorphisms are associated with OSAS. METHODS: Patients hospitalized at People's Hospital of Xinjiang were selected from January to December 2010. A total of 568 Han subjects who possibly exist OSAS base on a history and physical examination were completed the polysomnography, 412of whom (72.5%) were diagnosed with OSAS, and 156 individuals were confirmed without OSAS (27.5%). 96 severe OSAS patients chosen from OSAS were used for DNA sequencing in functional domain. Blood samples were collected from all subjects and genotyping was performed on DNA extracted from blood cells. RESULTS: We performed GLUT4 genome sequencing, found 4 mutated sites. And finally selected three mutated sites such as rs5415, rs4517 and rs5435, according to principle of linkage disequilibrium (r2 > 0.8) and minimum gene allele frequency > 5%. All SNPs satisfied HEW (P > 0.05). Our study demonstrated a significant association of GLUT4 SNPrs5417 allele with OSAS, compared with controls (P < 0.05). Haplotype H1 (TCC) and H3 (CCC) defined as SNPrs5415, rs4517 and rs5435 are marginally associated with OSAS (P < 0.05). Frequencies of C haplotype of rs5417 in OSAS were higher than in controls. After adjustment for confounding factors, (AC + AA) genotype significantly reduces prevalence of OSAS, compared with CC genotype. Level of awake blood oxygen and lowest blood oxygen of (AA + AC) genotype was significantly superior to those of CC genotype. CONCLUSIONS: Our study demonstrates GLUT4 gene SNPrs5417 is associated with OSAS in hypertensive population. Carriers of AA + AC have less prevalence of obstructive sleep apnea syndrome than that of CC carriers.
Assuntos
Transportador de Glucose Tipo 4/genética , Polimorfismo de Nucleotídeo Único , Apneia Obstrutiva do Sono/genética , Adulto , Estudos de Casos e Controles , China , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Teste de Tolerância a Glucose , Haplótipos , Humanos , Hipertensão/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
OBJECTIVE: To explore whether the polymorphism of suppressor of cytokine signaling-3 (SOCS-3) and dyslipidemia are correlated in Uygur females. METHODS: A total of 1379 Uygur females from Xinjiang Uygur Autonomous Region were enrolled in this study. Three single nucleotide polymorphisms (SNPs), namely rs12953258, rs4969168, and rs9914220, were analyzed after being genotyped. RESULTS: Of these three SNPs, the frequency distribution of rs12953258 sites was found to be significantly different between dyslipidemia group and normal group (P=0.032). The frequency distribution of rs12953258 sites between the high-density lipoprotein-cholesterol (HDL-C) abnormal group and normal group also showed significant difference (P=0.029). Logistic regression analysis showed that the genotype AA of rs12953258 was a risk factor for dyslipidemia among the Uygur females [CC vs. AA:OR=3.271,95%CI(1.092-9.797), P=0.034]. The genotype AA of rs12953258 might be related to the decreased high HDL-C and increased trigleceride, whereas the genotype AA coupled with abnormal body mass index (BMI) were more likely to be linked with the higher prevalence of dyslipidemia in Uygur females. CONCLUSIONS: The polymorphism of SOCS-3 is correlated to the dyslipidemia in Uygur females in Xinjiang. Carriers of Genotype AA of rs12953258 coupled with abnormal BMI are more susceptible to dyslipidemia.