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Previous studies have shown that excessive alcohol consumption is associated with poor sleep. However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits (e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population. To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization (MR) design. Observational analyses and one-sample MR (linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank (UKB). Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia. Phenotype analyses were externally validated using data from the National Health and Nutrition Examination Survey (2017-2018). Data analysis was conducted from January 2022 to October 2022. The association between alcohol consumption and six self-reported sleep traits (short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia) were analysed. This study included 383,357 UKB participants (mean [SD] age, 57.0 [8.0] years; 46% male) who consumed a mean (SD) of 9.0 (10.0) standard drinks (one standard drink equivalent to 14 g of alcohol) per week. In the observational analyses, alcohol consumption was significantly associated with all sleep traits. Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping. In linear MR analyses, a 1-SD (14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold (95% CI, 1.07-1.22) higher risk of snoring (P < 0.001), a 1.28-fold (95% CI, 1.20-1.37) higher risk of evening chronotype (P < 0.001) and a 1.24-fold (95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning (P < 0.001). Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment. The results of the two-sample MR analyses were consistent with those of the one-sample MR analyses, but with a slightly attenuated overall estimate. Our findings suggest that even low levels of alcohol consumption may affect sleep health, particularly by increasing the risk of snoring and evening chronotypes. The negative effects of alcohol consumption on sleep should be made clear to the public in order to promote public health.
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Consumo de Bebidas Alcoólicas , Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Distúrbios do Início e da Manutenção do Sono , Sono , Humanos , Análise da Randomização Mendeliana/métodos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/epidemiologia , Masculino , Reino Unido/epidemiologia , Feminino , Pessoa de Meia-Idade , Sono/genética , Sono/fisiologia , Idoso , Distúrbios do Início e da Manutenção do Sono/genética , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Ronco/genética , Ronco/epidemiologia , Adulto , Fenótipo , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Biobanco do Reino UnidoRESUMO
An efficient intermolecular annulation of indazole aldehydes with propargylic amines has been developed for the synthesis of pyrazinoindazoles under catalyst- and additive-free conditions. This straightforward methodology was found to feature a wide substrate scope, high atom economy and environmental advantages. The bioactivity results of these new pyrazino[1,2-b]indazoles showed that some of them exhibited significant antifungal activity.
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In this study, we delved into the prototypical components and metabolites of Platycodonis Radix extracts(PRE) from Tongcheng city in plasma, urine and feces of rats, and revealed its metabolic pathways and metabolic rules in vivo. The prototypical components and metabolites of PRE in rats were characterized and identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) and mass defect filter(MDF). The biological samples were analyzed by ACQUITY UPLC BEH C_(18)(2.1 mm×100 mm, 1.7 µm), with 0.1% formic acid water(A)-0.1% formic acid acetonitrile(B) as mobile phase, and the biological samples were analyzed in negative ion mode by electrospray ionization mass spectrometry(ESI-MS). Twelve prototypical saponins and twenty-seven metabolites were detected in plasma, urine and feces of rats treated with PRE by oral administration. Eleven prototypical components and nine metabolites were detected in plasma, eleven prototypical components and eight metabo-lites were detected in urine, and ten prototypical components and twenty metabolites were detected in feces. Further studies showed that the metabolic pathways of PRE in rats mainly include oxidation, reduction, acetylation, stepwise hydrolytic deglycosylation, glucuronidation and so on. This study provides a scientific basis for clarifying the pharmacological basis and mechanism of PRE from Tongcheng city.
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Medicamentos de Ervas Chinesas , Redes e Vias Metabólicas , Platycodon , Ratos Sprague-Dawley , Animais , Ratos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Masculino , Cromatografia Líquida de Alta Pressão , Platycodon/química , Fezes/química , Espectrometria de Massas por Ionização por Electrospray , Saponinas/metabolismo , ChinaRESUMO
BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder currently without satisfactory therapeutic treatments. Triggering receptors expressed on a myeloid cells-2 (Trem2) gene mutation has been reported as a powerful AD risk factor that induces Trem2 gene deletion aggravated microglia disfunction and Amyloid-ß (Aß) aggregation in the brain. The traditional Chinese medicine (TCM) formula Danggui-Shaoyao-San (DSS) has shown therapeutic effect on alleviating the symptoms of AD. However, the neuroprotective effect and underlying mechanism of DSS against AD is still far from fully understood. METHODS: Double-label immunofluorescence and Western blotting were employed to evaluate the different polarization states of mouse BV2 microglial (BV2) cells after lipopolysaccharide (LPS) or interleukin (IL)-4 treatment. Trem2 over-expression lentiviral vector and Trem2 siRNA were used respectively to evaluate the effect of Trem2 on microglia polarization via detecting the proteins expression of iNOS and arginase1 (Arg1) by Western blotting while the Aß-scavenging capacity of BV2 cells was assessed by flow cytometry. Cell counting kit-8 (CCK8) assay was performed to assess the effect of DSS on the viability of BV2 cells. Flow cytometry was used to investigate the effect of DSS on the Aß-scavenging capacity of BV2 cells treated with corresponding concentration of DSS-containing serum. Protein of Trem2 and the gene expression of the M1 or M2 phenotype in BV2 cells treated with DSS after Trem2 over-expression or silence were detected by Western blot and RT-qPCR, respectively. RESULTS: In vitro experiments. DSS exhibited anti-inflammatory and neuroprotective functions. It was found that Trem2 had an effect on inducing a shift of M1 microglia towards the M2 phenotype and enhanced the Aß-scavenging capacity of BV2 cells, further that DSS administration relieved inflammation by engulfing Aß through the activities of Trem2. Importantly, DSS treatment effectively increased the Aß-scavenging capacity of BV2 cells through accelerating the shift of M1 microglia towards an M2 phenotype via increasing Trem2 expression. CONCLUSIONS: Results demonstrated that DSS promoted the clearance of Aß through the regulation of microglia polarization via increased expression of Trem2 in BV2 cells.
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Doença de Alzheimer , Microglia , Camundongos , Animais , Inflamação/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genéticaRESUMO
A novel near-infrared (NIR) fluorescent probe (SWJT-9) was designed and synthesized for the detection of hypochlorite anion (ClO-) using a diaminomaleonitrile group as the recognition site. SWJT-9 had large Stokes shift (237 nm) and showed an excellent NIR fluorescence response to ClO- with the color change under the visible light. It showed a low detection limit (24.7 nM), high selectivity, and rapid detection (within 2 min) for ClO-. The new detection mechanism of SWJT-9 on ClO- was confirmed by 1H NMR, MS spectrum, and the density functional theory (DFT) calculations. In addition, the probe was successfully used to detect ClO- in HeLa cells.
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Corantes Fluorescentes , Ácido Hipocloroso , Humanos , Corantes Fluorescentes/química , Ácido Hipocloroso/química , Células HeLa , Esqueleto , Espectrometria de FluorescênciaRESUMO
The incidence of insomnia has been increasing in recent years. In addition, due to the impact of the COVID-19 pandemic, more and more people are experiencing a variety of insomniac problems, including having difficulty in sleep initation, waking up too early, and short sleep duration. Chronic insomnia may seriously affect patients' life and work, increase their risks of developing physical and mental illnesses, and cause crushing social and economic burdens. Sedative-hypnotics, including benzodiazepine agonists, melatonin receptor agonists, orexin receptor antagonists, and antidepressants with hypnotic effects, are widely used to treat most patients suffering from insomnia. However, there is the phenomenon of the non-medical use and abuse of sedative-hypnotic drugs, especially benzodiazepine receptor agonists. The abuse of sedative-hypnotic drugs may lead to mental and physical dependence, cognitive impairment, depression and anxiety, as well as an increased risks of falls and death. Therefore, drug regulatory authorities in China and other countries have issued relevant policies to reinforce regulation. Herein, we reviewed the prevalent use and safety of sedative-hypnotic drugs and proposed suggestions concerning their appropriate use. Both the efficacy and safety of sedative-hypnotic drugs should be carefully considered so that patients suffering from insomnia receive thorough and prompt treatment and the problem of potential abuse of sedative-hypnotic drugs is assessed in an objective and scientific manner. We also hope to provide references for the standardized clinical use of insomnia drugs.
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COVID-19 , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Pandemias , Hipnóticos e Sedativos/efeitos adversos , SonoRESUMO
The structural, electronic and vibrational properties of solid carbon dioxide phases (I, II, III, and IV) under high pressure are studied using first-principles calculations. The calculated structural parameters are in good agreement with the experimental values. The third-order Birch-Murnaghan equation of state is fitted, and the corresponding parameters are obtained. We obtained the phase boundary points of each phase and plotted the phase diagram of solid carbon dioxide. The influence of pressure on the band structure and density of states is studied. The vibrational properties of the four phases of carbon dioxide were studied in detail, and the infrared and Raman spectra of the four phases were obtained. It can be seen from the calculated spectrum that the number and frequency of vibration peaks are in good agreement with the experimental values. And, we also analyze the influence of pressure on the frequency of vibration mode.
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BACKGROUND: Although restricting food intake during labor is recommended by guidelines, intrapartum starvation has not been popular in some regions. We conducted this comparative cross-sectional study to determine the prevalence of risk stomach in non-fasted laboring women compared with fasted non-laboring women using gastric ultrasound. METHODS: Ultrasound examination of the antrum was performed in 50 term fasted non-laboring women before elective cesarean delivery and 50 laboring women allowed to eat and drink during active labor. Examinations consisted of the qualitative (antral grades, 0-3) and quantitative evaluation (antral cross-sectional area and calculated gastric volume) in the supine and right lateral decubitus (RLD) position. A risk stomach was defined as an antral grade ≥ 2 or grade 1 with gastric volume ≥ 1.5 ml· kg- 1. RESULTS: No non-laboring women had grade ≥ 2, while 34 (68%) laboring women had grade ≥ 2. Nine (18%) non-laboring and 40 (80%) laboring women presented risk stomach (P < 0.001) (risk ratio: 4.4, 95% CI 2.4-8.2). Compared with non-laboring women, laboring women had larger antral area at "empty" stomach (grade 0) (437 mm2 vs.350 mm2 in supine, 571 mm2 vs.480 mm2 in RLD, P < 0.05) and cut-off values of antral area to discriminate a risk stomach (510 mm2 vs. 453 mm2 in supine, 670 mm2 vs. 605 mm2 in RLD). CONCLUSIONS: This study confirms a higher prevalence of risk stomach presents in laboring women under a liberal eating policy, gastric ultrasound is therefore useful for this risk population if general anesthesia is required unexpectedly.
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Jejum , Conteúdo Gastrointestinal/diagnóstico por imagem , Trabalho de Parto , Ultrassonografia/métodos , Adulto , Estudos Transversais , Feminino , Humanos , Gravidez , Prevalência , Medição de Risco , Estômago/diagnóstico por imagemRESUMO
A metabolic illness known as non-alcoholic fatty liver disease (NAFLD), affects more than one-quarter of the world's population. Bile acids (BAs), as detergents involved in lipid digestion, show an abnormal metabolism in patients with NAFLD. However, BAs can affect other organs as well, such as the brain, where it has a neuroprotective effect. According to a series of studies, brain disorders may be extrahepatic manifestations of NAFLD, such as depression, changes to the cerebrovascular system, and worsening cognitive ability. Consequently, we propose that NAFLD affects the development of brain disease, through the bile acid signaling pathway. Through direct or indirect channels, BAs can send messages to the brain. Some BAs may operate directly on the central Farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) by overcoming the blood-brain barrier (BBB). Furthermore, glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor (FGF) 19 are released from the intestine FXR and GPBAR1 receptors, upon activation, both of which send signals to the brain. Inflammatory, systemic metabolic disorders in the liver and brain are regulated by the bile acid-activated receptors FXR and GPBAR1, which are potential therapeutic targets. From a bile acid viewpoint, we examine the bile acid signaling changes in NAFLD and brain disease. We also recommend the development of dual GPBAR1/FXR ligands to reduce side effects and manage NAFLD and brain disease efficiently.
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Encefalopatias , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Ácidos e Sais Biliares/metabolismo , Transdução de Sinais , Fígado/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Encefalopatias/metabolismoRESUMO
A novel two-site chemodosimeter (SWJT-4) based on fluorescein skeleton to detect diethyl chlorophosphate (DCP) was designed and synthesized. It is a turn-on fluorescent probe for DCP with good selectivity and obvious color change in aqueous solution. Interestingly, the two oxime groups of SWJT-4 as dual response sites initiated different reactions with DCP to form a cyano group and an isoxazole ring, respectively. The corresponding mechanism was confirmed by 1H NMR, MS and DFT calculation. Moreover, SWJT-4 could be used as a fluorescent test paper to detect DCP vapor.
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Corantes Fluorescentes/química , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/química , Espectrometria de Fluorescência/métodos , Cor , Química Computacional , Fluoresceína/síntese química , Fluoresceína/química , Corantes Fluorescentes/síntese química , Compostos Organofosforados/análise , Compostos Organofosforados/química , Sensibilidade e Especificidade , Água/químicaRESUMO
BACKGROUND AND OBJECTIVES: COVID-19-related quarantine and stress have likely escalated the crisis of Internet addiction. This study aimed to determine the impact of the COVID-19 pandemic on Internet use and related risk factors among the general public in China. METHODS: A large-sample cross-sectional online survey was conducted from March 24 to April 30, 2020, in China, and 20,472 participants completed the survey. We investigated the prevalence and severity of Internet addiction based on the Internet Addiction Test (IAT), and explored the risk factors related to increases in time spent on Internet use and severity of Internet addiction, as well as severe Internet addiction. RESULTS: The overall prevalence of Internet addiction was 36.7% among the general population during the pandemic, and that of severe Internet addiction was 2.8%, according to IAT scores. Time spent on recreational Internet use had significantly increased during the pandemic, and almost half of participants reported increases in the severity of Internet addiction. Risk factors for increases in time spent on Internet use and severity of Internet addiction and severe Internet addiction included having fewer social supporters, perceiving pressure and impact on mental health status due to COVID-19, and being over-engaged in playing videogames. DISCUSSION AND CONCLUSIONS: The COVID-19 pandemic adversely impacted Internet use and increased the prevalence and severity of Internet addiction among the general population in China, especially in vulnerable populations. SCIENTIFIC SIGNIFICANCE: This study provides evidence for policymakers to refine public health policies to control the pandemic and make efforts to provide population-specific prevention and interventions for people at risk of developing Internet addiction. (Am J Addict 2021;00:00-00).
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Comportamento Aditivo/psicologia , COVID-19/psicologia , Transtorno de Adição à Internet/epidemiologia , Adolescente , Adulto , Comportamento Aditivo/epidemiologia , COVID-19/epidemiologia , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Internet , Transtorno de Adição à Internet/psicologia , Masculino , Pessoa de Meia-Idade , Pandemias , Prevalência , Fatores de Risco , SARS-CoV-2 , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: The intrathecal hyperbaric bupivacaine dosage for cesarean section is difficult to predetermine. This study aimed to develop a decision-support model using a machine-learning algorithm for assessing intrathecal hyperbaric bupivacaine dose based on physical variables during cesarean section. METHODS: Term parturients presenting for elective cesarean section under spinal anaesthesia were enrolled. Spinal anesthesia was performed at the L3/4 interspace with 0.5% hyperbaric bupivacaine at dosages determined by the anesthesiologist. A spinal spread level between T4-T6 was considered the appropriate block level. We used a machine-learning algorithm to identify relevant parameters. The dataset was split into derivation (80%) and validation (20%) cohorts. A decision-support model was developed for obtaining the regression equation between optimized intrathecal 0.5% hyperbaric bupivacaine volume and physical variables. RESULTS: A total of 684 parturients were included, of whom 516 (75.44%) and 168 (24.56%) had block levels between T4 and T6, and less than T6 or higher than T4, respectively. The appropriate block level rate was 75.44%, with the mean bupivacaine volume [1.965, 95%CI (1.945,1.984)]ml. In lasso regression, based on the principle of predicting a reasonable dose of intrathecal bupivacaine with fewer physical variables, the model is "Y=0.5922+ 0.055117* X1-0.017599*X2" (Y: bupivacaine volume; X1: vertebral column length; X2: abdominal girth), with λ 0.055, MSE 0.0087, and R2 0.807. CONCLUSIONS: After applying a machine-learning algorithm, we developed a decision model with R2 0.8070 and MSE due to error 0.0087 using abdominal girth and vertebral column length for predicting the optimized intrathecal 0.5% hyperbaric bupivacaine dosage during term cesarean sections.
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Algoritmos , Anestesia Obstétrica , Raquianestesia , Bupivacaína/administração & dosagem , Técnicas de Apoio para a Decisão , Aprendizado de Máquina , Adulto , Anestésicos Locais/administração & dosagem , Cesárea , Feminino , Humanos , Gravidez , Estudos ProspectivosRESUMO
The abnormal deposition of the extracellular amyloid-ß peptide is the typical pathological hallmark of Alzheimer's disease. Strategies to reduce the amyloid-ß deposition effectively alleviate the neuronal degeneration and cognitive deficits of Alzheimer's disease. Danggui-Shaoyao-San has been considered a useful therapeutic agent known for the treatment of Alzheimer's disease. However, the mechanism of Danggui-Shaoyao-San for the treatment of Alzheimer's disease remains unclear. We investigated Danggui-Shaoyao-San's effect on amyloidosis and neuronal degeneration in an APP/PS1 mouse model. We found Danggui-Shaoyao-San alleviated the cognitive deficits in APP/PS1 mice. Additionally, Danggui-Shaoyao-San ameliorated the neuronal degeneration in these mice. Danggui-Shaoyao-San reduced the amyloidosis and amyloid-ß1-42 deposition in APP/PS1 mouse brain and down-regulated the receptor for advanced glycation end products, and up-regulated the level of low-density lipoprotein receptor-related protein-1. However, the protein expression of the ß-amyloid precursor protein, ß-Secretase and presenilin-1 (PS1) in the amyloid-ß production pathway, and the expression of neprilysin and insulin-degrading enzyme in the amyloid-ß degradation pathway were not altered. Our findings collectively suggest that Danggui-Shaoyao-San could ameliorate the amyloidosis and neuronal degeneration of Alzheimer's disease, which may be associated with its up-regulation lipoprotein receptor-related protein-1 and down-regulation of the receptor for advanced glycation end products.
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Doença de Alzheimer/tratamento farmacológico , Amiloidose/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVES: To investigate the incidence of preterm birth and risk factors for preterm birth. METHODS: A prospective cohort study was performed for the pregnant women in early pregnancy and their spouses, who underwent prenatal examination for the first time in Hunan Provincial Maternal and Child Health Care Hospital from May 2014 to December 2016 and decided to be hospitalized for delivery. A questionnaire survey was performed to collect exposure information possibly related to preterm birth. The hospital's medical record system was used for information verification and to record the pregnancy outcome. A multivariate logistic regression analysis was used to investigate the risk factors for preterm birth. RESULTS: A total of 6 764 pregnant women with complete data were included, and the incidence rate of preterm birth was 17.09%. The multivariate logistic regression analysis showed that a history of adverse pregnancy outcomes, eating areca nut before pregnancy, a history of pregnancy complications, a history of hepatitis, no folate supplementation during pregnancy, medication during pregnancy, active smoking and passive smoking during pregnancy, drinking during pregnancy, unbalanced diet during pregnancy, high-intensity physical activity during pregnancy, and natural conception after treatment of infertility or assisted conception as the way of conception were risk factors for preterm birth (P<0.05). Additionally, the pregnant women whose spouses were older, had a higher body mass index or smoked had an increased risk for preterm birth (P<0.05). A higher level of education of pregnant women or their spouses and lower gravidity were protective factors against preterm birth (P<0.05). CONCLUSIONS: There are many risk factors for preterm birth. Special attention should be paid to the life behaviors of pregnant women during pregnancy, and health education should be strengthened for pregnant women and their spouses to develop good living habits and reduce the incidence of preterm births.
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Nascimento Prematuro , Poluição por Fumaça de Tabaco , Criança , Feminino , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Estudos Prospectivos , Fatores de RiscoRESUMO
Rice (Oryza sativa L.) has two ecotypes, upland and lowland rice, that have been observed to show different tolerance levels under flooding stress. In this study, two rice cultivars, upland (Up221, flooding-intolerant) and lowland (Low88, flooding-tolerant), were initially used to study their molecular mechanisms in response to flooding germination. We observed that variations in the OsCBL10 promoter sequences in these two cultivars might contribute to this divergence in flooding tolerance. Further analysis using another eight rice cultivars revealed that the OsCBL10 promoter could be classified as either a flooding-tolerant type (T-type) or a flooding-intolerant type (I-type). The OsCBL10 T-type promoter only existed in japonica lowland cultivars, whereas the OsCBL10 I-type promoter existed in japonica upland, indica upland and indica lowland cultivars. Flooding-tolerant rice cultivars containing the OsCBL10 T-type promoter have shown lower Ca2+ flow and higher α-amylase activities in comparison to those in flooding-intolerant cultivars. Furthermore, the OsCBL10 overexpression lines were sensitive to both flooding and hypoxic treatments during rice germination with enhanced Ca2+ flow in comparison to wild-type. Subsequent findings also indicate that OsCBL10 may affect OsCIPK15 protein abundance and its downstream pathways. In summary, our results suggest that the adaptation to flooding stress during rice germination is associated with two different OsCBL10 promoters, which in turn affect OsCBL10 expression in different cultivars and negatively affect OsCIPK15 protein accumulation and its downstream cascade.
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Adaptação Fisiológica , Calcineurina/metabolismo , Cálcio/metabolismo , Oryza/genética , Regiões Promotoras Genéticas/genética , Calcineurina/genética , Ecótipo , Inundações , Variação Genética , Germinação , Oryza/fisiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Sementes/genética , Sementes/fisiologia , Especificidade da Espécie , Estresse FisiológicoRESUMO
BACKGROUND: Immune checkpoint inhibitors have been shown to promote antitumor immunity and achieve durable tumor remissions. However, certain tumors are refractory to current immunotherapy. These negative results encouraged us to uncover other therapeutic targets and strategies. PTPN2 (protein tyrosine phosphatase, non-receptor type 2) has been newly identified as an immunotherapy target. Loss of PTPN2 sensitizes the tumor to immunotherapy via IFNγ signaling. METHODS: Here, we investigated the relationship between PTPN2 mRNA levels and clinical characteristics in gliomas. RNA-seq data of a cohort of 325 patients with glioma were available from the Chinese Glioma Genome Atlas and 671 from The Cancer Genome Atlas. R language, GraphPad Prism 5, and SPSS 22.0 were used to analyze data and draw figures. RESULTS: PTPN2 transcript levels increased significantly with higher grades of glioma and in isocitrate dehydrogenase (IDH) wild-type and mesenchymal subtype gliomas. A comprehensive biological analysis was conducted, which indicated a crucial role of PTPN2 in the immune and inflammation responses in gliomas. Specifically, PTPN2 was positively associated with HCK, LCK, MHC II, and STAT1 but negatively related to IgG and interferon. Moreover, canonical correlation analysis showed a positive correlation of PTPN2 with infiltrating immune cells, such as macrophages, neutrophils, and CD8+ T cells. Clinically, higher levels of PTPN2 were associated with a worse overall survival both in patients with gliomas and glioblastomas. CONCLUSION: PTPN2 expression level was increased in glioblastomas and associated with gliomas of the IDH wild-type and mesenchymal subtype. There was a close correlation between PTPN2 and the immune response and inflammatory activity in gliomas. Our results show that PTPN2 is a promising immunotherapy target and may provide additional treatment strategies.
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Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Glioma/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , RNA Mensageiro/metabolismo , Área Sob a Curva , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Estudos de Coortes , Correlação de Dados , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Glioma/imunologia , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Macrófagos/patologia , Masculino , Mutação/genética , Neutrófilos/patologia , Proteínas Proto-Oncogênicas c-hck/metabolismo , Fator de Transcrição STAT1/metabolismoRESUMO
BACKGROUND: Pituitary adenomas (PAs) are the second most common brain tumors, and mostly are benign tumors. However, there exists subtypes of PAs refractory to common treatments, and need novel therapy. Programmed death 1 (PD-1) blockade has shown durable objective response in a variety of malignancies, and the key predictive markers for this immunotherapy were PD-L1 and CD8+ tumor-infiltrating lymphocyte (TILs) expression. To evaluate the potential immunotherapy for PAs, we investigated the expression of these two immune markers in PAs. METHODS: Immunohistochemistry (IHC) was performed to detect the expression of PD-L1 and CD8+ TILs in PAs. The ratio of positive expression of PD-L1 and CD8+ TILs was compared with chi-squared tests among different subtypes of PAs. The association between their expression profile and clinical parameters was analyzed using a chi-squared test, or Fisher's exact probability test when appropriate. RESULTS: One hundred and ninety one patients with PAs were retrospectively involved in this study, consisting of 106 non-functioning PAs (NF-PAs, 55.5%), 40 PRL-secreting PAs (PRL-PAs, 20.9%), 31 GH-secreting PAs (GH-PAs, 16.2%), 9 ACTH-secreting PAs (ACTH-PAs, 4.7%) and 5 plurihormonal adenomas (2.6%) respectively. 36.6% of them were PD-L1 positive and 86.9% were CD8+ TILs positive. The positive PD-L1 immunostaining presented more frequently in functioning PAs (58.8%), compared with that (34.3%) in nonfunctioning group (p = 0.000). Moreover, the rates of PD-L1 expression were more associated with increased blood levels of PRL, GH, ACTH and cortisol. Contrastly, positive CD8+ TILs immunostaining was only correlated with elevated blood level of GH. For the analysis of immune markers with pathological results, PD-L1 expression was associated with PRL and GH immunostaining and higher Ki-67 index. But CD8+ TILs was only correlated with PRL immunostaining. CONCLUSION: Our results showed that PD-L1 was frequently expressed in functioning PAs with association of aggressive behaviors in PAs. The immunotherapy could be a promising treatment option of PAs.
Assuntos
Adenoma/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Imunoterapia , Neoplasias Hipofisárias/imunologia , Adenoma/patologia , Adenoma/terapia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/patologia , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/terapia , Estudos Retrospectivos , Adulto JovemRESUMO
A nine-layer WS2/MoS2 heterostructure is established on a sapphire substrate after sequential growth of large-area and uniform five- and four-layer MoS2 and WS2 films by using sulfurization of predeposited 1.0 nm molybdenum (Mo) and tungsten (W), respectively. By using the results obtained from the ultraviolet photoelectron spectroscopy and the absorption spectrum measurements of the standalone MoS2 and WS2 samples, a type-II band alignment is predicated for the WS2/MoS2 heterostructure. Increasing drain currents and enhanced field-effect mobility value of the transistor fabricated on the heterostructure suggested that a channel with higher electron concentration compared with the standalone MoS2 transistor channel is obtained with electron injection from WS2 to MoS2 under thermal equilibrium. Selective 2D crystal growth with (I) blank sapphire substrate, (II) standalone MoS2, (III) WS2/MoS2 heterostructure, and (IV) standalone WS2 was demonstrated on a single sapphire substrate. The results have revealed the potential of this growth technique for practical applications.
RESUMO
Epigenetic changes are involved in learning and memory, and histone deacetylase (HDAC) inhibitors are considered potential therapeutic agents for Alzheimer's disease (AD). We previously reported that (-)-epigallocatechin-3-gallate (EGCG) acts as an HDAC inhibitor. Here, we demonstrate that EGCG reduced ß-amyloid (Aß) accumulation in vitro and rescued cognitive deterioration in senescence-accelerated mice P8 (SAMP8) via intragastric administration of low- and high-dose EGCG (5 and 15 mg/kg, respectively) for 60 days. The AD brain has decreased levels of the rate-limiting degradation enzyme of Aß, neprilysin (NEP). We found an association between EGCG-induced reduction in Aß accumulation and elevated NEP expression. Further, NEP silencing prevented the EGCG-induced Aß downregulation. Our findings suggest that EGCG might be effective for treating AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Catequina/análogos & derivados , Transtornos Cognitivos/tratamento farmacológico , Neprilisina/metabolismo , Regulação para Cima/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Células CHO , Catequina/química , Catequina/farmacologia , Proliferação de Células , Células Cultivadas , Transtornos Cognitivos/metabolismo , Cricetulus , Modelos Animais de Doenças , Camundongos , EstereoisomerismoRESUMO
In present study, an ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS)-based plant metabolomics approach was established to investigate the metabolic profiles of the leaves, main root, branch root, and rhizome of Mountain Cultivated Ginseng (MCG). The UHPLC-QTOF/MS data were subjected to principal component analysis(PCA) and orthogonal partial least squared discrimination analysis(OPLS-DA) to find the potential characteristic components of the four parts of MCG in a quick way. The four different parts could be separated into four different groups of phytochemicals according to the PCA scores. The chemical constituents in four parts of MCG were obviously different. The identities of 81 major peaks that were detected in the four parts of MCG and the potential markers were identified by comparison with the reference compounds or were tentatively assigned by matching the retention time, empirical molecular formula and fragment ions with those of the published compounds of the Panax species. This proposed analytical method is fast, accurate, and reliable for differentiating the different parts of MCG. Moreover, this study supplied a new method for the quality evaluation of other Chinese medicinal materials.