RESUMO
INTRODUCTION: There is currently no widely accepted approach to screening for pancreatic cancer (PC). We aimed to develop and validate a risk prediction model for pancreatic ductal adenocarcinoma (PDAC), the most common form of PC, across 2 health systems using electronic health records. METHODS: This retrospective cohort study consisted of patients aged 50-84 years having at least 1 clinic-based visit over a 10-year study period at Kaiser Permanente Southern California (model training, internal validation) and the Veterans Affairs (VA, external testing). Random survival forests models were built to identify the most relevant predictors from >500 variables and to predict risk of PDAC within 18 months of cohort entry. RESULTS: The Kaiser Permanente Southern California cohort consisted of 1.8 million patients (mean age 61.6) with 1,792 PDAC cases. The 18-month incidence rate of PDAC was 0.77 (95% confidence interval 0.73-0.80)/1,000 person-years. The final main model contained age, abdominal pain, weight change, HbA1c, and alanine transaminase change (c-index: mean = 0.77, SD = 0.02; calibration test: P value 0.4, SD 0.3). The final early detection model comprised the same features as those selected by the main model except for abdominal pain (c-index: 0.77 and SD 0.4; calibration test: P value 0.3 and SD 0.3). The VA testing cohort consisted of 2.7 million patients (mean age 66.1) with an 18-month incidence rate of 1.27 (1.23-1.30)/1,000 person-years. The recalibrated main and early detection models based on VA testing data sets achieved a mean c-index of 0.71 (SD 0.002) and 0.68 (SD 0.003), respectively. DISCUSSION: Using widely available parameters in electronic health records, we developed and externally validated parsimonious machine learning-based models for detection of PC. These models may be suitable for real-time clinical application.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/epidemiologia , Aprendizado de Máquina , Neoplasias PancreáticasRESUMO
BACKGROUND/OBJECTIVES: There is currently no widely accepted approach to identify patients at increased risk for sporadic pancreatic cancer (PC). We aimed to compare the performance of two machine-learning models with a regression-based model in predicting pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. METHODS: This retrospective cohort study consisted of patients 50-84 years of age enrolled in either Kaiser Permanente Southern California (KPSC, model training, internal validation) or the Veterans Affairs (VA, external testing) between 2008 and 2017. The performance of random survival forests (RSF) and eXtreme gradient boosting (XGB) models were compared to that of COX proportional hazards regression (COX). Heterogeneity of the three models were assessed. RESULTS: The KPSC and the VA cohorts consisted of 1.8 and 2.7 million patients with 1792 and 4582 incident PDAC cases within 18 months, respectively. Predictors selected into all three models included age, abdominal pain, weight change, and glycated hemoglobin (A1c). Additionally, RSF selected change in alanine transaminase (ALT), whereas the XGB and COX selected the rate of change in ALT. The COX model appeared to have lower AUC (KPSC: 0.737, 95% CI 0.710-0.764; VA: 0.706, 0.699-0.714), compared to those of RSF (KPSC: 0.767, 0.744-0.791; VA: 0.731, 0.724-0.739) and XGB (KPSC: 0.779, 0.755-0.802; VA: 0.742, 0.735-0.750). Among patients with top 5% predicted risk from all three models (N = 29,663), 117 developed PDAC, of which RSF, XGB and COX captured 84 (9 unique), 87 (4 unique), 87 (19 unique) cases, respectively. CONCLUSIONS: The three models complement each other, but each has unique contributions.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Neoplasias Pancreáticas/epidemiologia , Carcinoma Ductal Pancreático/epidemiologia , Aprendizado de Máquina , Neoplasias PancreáticasRESUMO
Drug resistance is a major impediment to the successful treatment of glioma. This study aimed to elucidate the effects and mechanisms of the long noncoding RNA membrane-associated guanylate kinase inverted-2 antisense RNA 3 (MAGI2-AS3) on temozolomide (TMZ) resistance in glioma cells. MAGI2-AS3 expression in TMZ-resistant glioblastoma (GBM) cells was analyzed using the Gene Expression Omnibus data set GSE113510 and quantitative real-time PCR (qRT-PCR). Cell viability and TMZ half-maximal inhibitory concentration values were determined using the MTT assay. Apoptosis and cell cycle distribution were evaluated using flow cytometry. The expression of multidrug resistance 1 (MDR1), ATP-binding cassette superfamily G member 2 (ABCG2), protein kinase B (Akt), and phosphorylated Akt was detected using qRT-PCR and/or western blot analysis. MAGI2-AS3 was expressed at low levels in TMZ-resistant GBM cells relative to that in their parental cells. MAGI2-AS3 re-expression alleviated TMZ resistance in TMZ-resistant GBM cells. MAGI2-AS3 overexpression also accelerated TMZ-induced apoptosis and G2/M phase arrest. Mechanistically, MAGI2-AS3 overexpression reduced MDR1 and ABCG2 expression and inhibited the Akt pathway, whereas Akt overexpression abrogated the reduction in MDR1 and ABCG2 expression induced by MAGI2-AS3. Moreover, activation of the Akt pathway inhibited the effects of MAGI2-AS3 on TMZ resistance. MAGI2-AS3 inhibited tumor growth and enhanced the suppressive effect of TMZ on glioma tumorigenesis in vivo. In conclusion, MAGI2-AS3 reverses TMZ resistance in glioma cells by inactivating the Akt pathway.
Assuntos
Glioblastoma , Glioma , MicroRNAs , RNA Longo não Codificante , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , RNA Antissenso/farmacologia , RNA Antissenso/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , MicroRNAs/genética , Resistencia a Medicamentos Antineoplásicos/genética , RNA Longo não Codificante/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Guanilato Quinases/genética , Guanilato Quinases/metabolismo , Guanilato Quinases/farmacologiaRESUMO
KIAA0101, a proliferating cell nuclear antigen (PCNA)-associated factor, is reported to be overexpressed and identified as an oncogene in several human malignancies. The purpose of this study is to determine the function and possible mechanism of KIAA0101 in glioma progression. KIAA0101 expression in glioma patients was analyzed by GSE50161 and GEPIA datasets. Kaplan-Meier survival analysis was used to evaluate the survival distributions. KIAA0101 expression in glioma cells were detected by qRT-PCR and western blot analyses. The function of KIAA0101 was investigated using MTT, flow cytometry, caspase-3 activity, and Transwell assays. Additionally, glycolytic flux was determined by measuring extracellular acidification rate (ECAR), glucose consumption, lactate production, and adenosine triphosphate (ATP) level. The changes of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway were detected by western blot analysis. Results showed that KIAA0101 was upregulated in glioma tissues and cells. High KIAA0101 expression predicted a poor prognosis in glioma patients. KIAA0101 depletion impeded cell proliferation, migration, and invasion and triggered apoptosis in glioma cells. KIAA0101 silencing reduced the ECAR, glucose consumption, lactate production, and ATP level in glioma cells, suggesting that KIAA0101 knockdown inhibited glycolysis in glioma cells. Mechanistically, KIAA0101 knockdown inhibited the PI3K/AKT/mTOR pathway. In conclusion, KIAA0101 silencing inhibited glioma progression and glycolysis by inactivating the PI3K/AKT/mTOR pathway.
Assuntos
Proteínas de Ligação a DNA , Glioma , Fosfatidilinositol 3-Quinase , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/genética , Glioma/metabolismo , Glicólise , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Isoflurane, a common volatile anesthetic, has been widely used to provide general anesthesia in operations. However, exposure to isoflurane may cause widespread neurotoxicity in the developing animal brain. Fraxetin, a natural coumarin derivative extracted from the bark of Fraxinus rhynchophylla, possesses versatile pharmacological properties including anti-oxidative, anti-inflammatory, and neuroprotective effects. However, the effect and action mechanism of fraxetin on neurotoxicity induced by isoflurane are unknown. Reactive oxygen species (ROS) generation, cell viability, lactate dehydrogenase (LDH) release, and apoptosis were estimated by 2',7'-dichlorofluorescin-diacetate (DCFH-DA) staining, MTT, LDH release, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining assays, respectively. The protein levels of light chain 3 (LC3)-I, LC3-II, p62, protein kinase B (Akt), and phosphorylated Akt (p-Akt) were detected by western blot analysis. Isoflurane induced ROS, LDH release, apoptosis, and autophagy, but inhibited the viability in HT22 cells, which were overturned by fraxetin or ROS scavenger N-acetyl-L-cysteine. Fraxetin suppressed isoflurane-induced PI3K/Akt inactivation in HT22 cells. PI3K/Akt inactivation by LY294002 resisted the effects of fraxetin on isoflurane-induced autophagy and autophagy-modulated neurotoxicity in HT22 cells. In conclusion, fraxetin suppressed ROS-dependent autophagy by activating the PI3K/Akt pathway to inhibit isoflurane-induced neurotoxicity in hippocampal neuronal cells.
Assuntos
Isoflurano , Síndromes Neurotóxicas , Animais , Apoptose , Autofagia , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Hipocampo , Isoflurano/metabolismo , Isoflurano/toxicidade , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cardamonin is a chalcone with neuroprotective activity. The aim of our study was to explore the functions and mechanism of action of cardamonin in ischemic stroke. Oxygen-glucose deprivation and reperfusion (OGD/R)-induced human brain microvascular endothelial cells (HBMECs) and middle cerebral artery occlusion (MCAO) mouse model were utilized to mimic ischemic stroke. Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide. Permeability was investigated via fluorescein isothiocyanate-dextran assay. Apoptosis was detected by TdT-Mediated dUTP Nick End Labeling staining. Hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) protein levels were measured using Western blotting. Brain injury was evaluated by 2,3,5-triphenyltetrazolium chloride staining, neurological score and brain water content. The 37 overlapping targets of ischemic stroke and cardamonin were predicted to be associated with the HIF-1/VEGFA signaling. Cardamonin alleviated OGD/R-induced viability reduction and increase of permeability and apoptosis in HBMECs. Cardamonin increased OGD/R-induced activation of the HIF-1α/VEGFA pathway. Inhibition of the HIF-1α/VEGFA signaling using inhibitor relieved the effect of cardamonin on cell viability, permeability and apoptosis in HBMECs under OGD/R. Cardamonin mitigated brain injury and promoted activation of the HIF-1α/VEGFA signaling in MCAO-treated mice. Overall, cardamonin protected against OGD/R-induced HBMEC damage and MACO-induced brain injury through activating the HIF-1α/VEGFA pathway.
Assuntos
Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Traumatismo por Reperfusão , Animais , Apoptose , Isquemia Encefálica/tratamento farmacológico , Chalconas , Células Endoteliais/metabolismo , Glucose/metabolismo , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Camundongos , Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
More than 1000 years, the Meiyu-Baiu have shaped the uniqueness of natural resources, civilization and culture in the Yangtze River Basin of China and the main islands of Japan. In recent decades, frequent rainstorms and droughts have seemingly diminished the misty features of traditional Meiyu-Baiu rainfall. However, there is still no consensus on whether their traditional nature is suspended. In this study, we quantitatively demonstrate that the Meiyu-Baiu almost completely lost their traditional features during 1961-2023, â¼80% of which can be attributed to anthropogenic warming. Furthermore, in a warmer future, the traditional Meiyu-Baiu will be more unlikely to appear. This study underscores the urgency in adapting to climate shift because destructive extremes are measurably taking the place of mild and maternal rains.
RESUMO
Background: Over the last decade, there has been growing interest in inverted classroom teaching (ICT) and its various forms within the education sector. Physiology is a core course that bridges basic and clinical medicine, and ICT in physiology has been sporadically practiced to different extents globally. However, students' and teachers' responses and feedback to ICT in physiology are diverse, and the effectiveness of a modified ICT model integrated into regular teaching practice in physiology courses is difficult to assess objectively and quantitatively. Objective: This study aimed to explore the current status and development direction of ICT in physiology in basic medical education using bibliometric visual analysis of the related literature. Methods: A bibliometric analysis of the ICT-related literature in physiology published between 2000 and 2023 was performed using CiteSpace, a bibliometric visualization tool, based on the Web of Science database. Moreover, an in-depth review was performed to summarize the application of ICT in physiology courses worldwide, along with identification of research hot spots and development trends. Results: A total of 42 studies were included for this bibliometric analysis, with the year 2013 marking the commencement of the field. University staff and doctors working at affiliated hospitals represent the core authors of this field, with several research teams forming cooperative relationships and developing research networks. The development of ICT in physiology could be divided into several stages: the introduction stage (2013-2014), extensive practice stage (2015-2019), and modification and growth stage (2020-2023). Gopalan C is the author with the highest citation count of 5 cited publications and has published 14 relevant papers since 2016, with a significant surge from 2019 to 2022. Author collaboration is generally limited in this field, and most academic work has been conducted in independent teams, with minimal cross-team communication. Authors from the United States published the highest number of papers related to ICT in physiology (18 in total, accounting for over 43% of the total papers), and their intermediary centrality was 0.24, indicating strong connections both within the country and internationally. Chinese authors ranked second, publishing 8 papers in the field, although their intermediary centrality was only 0.02, suggesting limited international influence and lower overall research quality. The topics of ICT in physiology research have been multifaceted, covering active learning, autonomous learning, student performance, teaching effect, blended teaching, and others. Conclusions: This bibliometric analysis and literature review provides a comprehensive overview of the history, development process, and future direction of the field of ICT in physiology. These findings can help to strengthen academic exchange and cooperation internationally, while promoting the diversification and effectiveness of ICT in physiology through building academic communities to jointly train emerging medical talents.
Assuntos
Bibliometria , Fisiologia , Humanos , Fisiologia/educação , Educação Médica/métodos , Ensino , Currículo/tendênciasRESUMO
BACKGROUND: Understanding the burden of aortic stenosis (AS) across diverse racial and ethnic populations is important to ensure equitable resource allocation. This study explored whether severe AS rate varies by race and ethnicity. METHODS: The rates of severe AS, stratified by race and ethnicity, were calculated among 615,038 adults with a transthoracic echocardiogram. Logistic regression analysis was performed to identify factors associated with severe AS. RESULTS: Severe AS rates ranged from 0.08% in adults < 50 years old to 3.8% in those ≥ 90 years old. Compared to non-Hispanic White and Asian American [adjusted odds ratio (aOR) = 0.47, 95% confidence interval (CI): 0.42-0.53] and non-Hispanic Black (aOR = 0.44, 95% CI: 0.39-0.50) patients were less likely to have severe AS, whereas Hispanic patients (aOR = 0.91, 95% CI: 0.87-0.98) had near similar likelihood. Age was the strongest risk factor for severe AS (compared to age < 50 years, aOR = 21.8, 95% CI: 17.8-26.6 for age 80-89 years, and aOR = 43.8, 95% 35.5-54.0 for age ≥ 90 years). Additional factors associated with severe AS included male sex (aOR = 1.38, 95% CI: 1.30-1.46) and diabetes (aOR = 1.23, 95% CI: 1.15-1.31). CONCLUSIONS: Asian American and non-Hispanic Black adults had lower rates of severe AS compared to White and Hispanic patients. The rate of severe AS progressively increases with age in all racial and ethnic groups, with higher rates in men compared with women. With a demographic shift toward an aging and more diverse population, the burden of AS is anticipated to rise. Ensuring adequate allocation of resources to meet the evolving needs of a diverse population remains a shared health care imperative.
RESUMO
Recent rapid Arctic sea ice loss was documented as combined results from anthropogenic forcing and climate system internal variability. However, the role of internal variability is not well understood. Here, we propose that the Asian-Pacific Oscillation (APO), an intrinsic atmospheric mode featuring out-of-phase variations in upper-tropospheric temperatures between Asia and the North Pacific, is one driver for autumn sea ice variability in the eastern Arctic. The positive summer APO favors warming of the mid-latitude North Atlantic sea surface temperatures. This warming persists to autumn and in turn triggers strong anticyclonic anomalies over the Barents-Kara-Laptev Seas and weak lower-tropospheric cyclonic anomalies over the East Siberian Sea, enhancing moisture transport into the eastern Arctic. Such changes consequently increase lower-tropospheric humidity, downwelling longwave radiation, and surface air temperature in the eastern Arctic, thereby melting sea ice. Hence, a recent tendency of the summer APO towards the positive phase accelerates autumn sea ice loss in the eastern Arctic.
RESUMO
The blood-brain barrier (BBB) is a remarkable and intricate barrier that controls the exchange of molecules between the bloodstream and the brain. Its role in maintaining the stability of the central nervous system cannot be overstated. Over the years, advancements in neuroscience and technology have enabled us to delve into the cellular and molecular components of the BBB, as well as its regulation. Yet, there is a scarcity of comprehensive reviews that follow a logical framework of structure-function-regulation, particularly focusing on the nuances of BBB regulation under both normal and pathological conditions. This review sets out to address this gap by taking a historical perspective on the discovery of the BBB and highlighting the major observations that led to its recognition as a distinct brain barrier. It explores the intricate cellular elements contributing to the formation of the BBB, including endothelial cells, pericytes, astrocytes, and neurons, emphasizing their collective role in upholding the integrity and functionality of the BBB. Furthermore, the review delves into the dynamic regulation of the BBB in physiological states, encompassing neural, humoral, and auto-regulatory mechanisms. By shedding light on these regulatory processes, a deeper understanding of the BBB's response to various physiological cues emerges. This review also investigates the disruption of the BBB integrity under diverse pathological conditions, such as ischemia, infection, and toxin exposure. It elucidates the underlying mechanisms that contribute to BBB dysfunction and explores potential therapeutic strategies that aim to restore the BBB integrity and function. Overall, this recapitulation provides valuable insights into the structure, functions, and regulation of the BBB. By integrating historical perspectives, cellular elements, regulatory mechanisms, and pathological implications, this review contributes to a more comprehensive understanding of the BBB and paves the way for future research and therapeutic interventions.
Assuntos
Barreira Hematoencefálica , Células Endoteliais , Encéfalo/patologia , Sistema Nervoso Central , AstrócitosRESUMO
Background: CD27 is an immunological checkpoint gene, plays a critical function inInhibition or activation of cancer immunity. The CD27/CD27L axis is its pathway of action. Therefore, our goal was to examine the predictive role of CD27 in the clinical prognosis of 33 cancer types and its functions in cancer progression, as well as explore the link between pan-cancer CD27 gene expression and immune infiltration. Methods: By comprehensive use of datasets and methods from TCGA, cBioPortal, GTEx, HPA, KM-plotter, Spearman, CellMinerTM, R packages and RT-qPCR, we delved deeper into the potential impact of the CD27 on cancer development. These include expression differences, immune infiltration, matrix infiltration, gene mutations, DNA methylation, signaling pathways, TMB, MSI, and prognosis. Also, we explored CD27 interactions with different drugs. Results: The results showed that, mutated CD27 was highly expressed in most cancers. The CD27 showed strong diagnostic value in 4 cancers and marked a positive prognosis for CESC, intracervical adenocarcinoma, HNSC, and endometrial cancer, and a poor prognosis for UVM. In addition, CD27 affects multiple immune and inflammatory signaling pathways and is positively correlated with immune cell infiltration, T cell differentiation, macrophage M1 polarization, stromal infiltration, and drug sensitivity. DNA methylation is involved in CD27 expression in cancer. Conclusion: CD27, which is mutated in cancers and appears widely highly expressed and altered tumor immune invasion and stromal invasion by affecting multiple immune-related and inflammation signaling pathways, plays a significant role in CESC, HNSC, UCEC and UVM, and may be used as a therapeutic target for related cancers.
RESUMO
The "Arctic warming-Eurasia cooling" trend has significantly affected the changes of weather patterns and climate extremes at lower latitudes and has attached huge attentions. However, this winter trend weakened from 2012 to 2021. In the same time period, subseasonal reversals between the warm Arctic-cold Eurasia (WACE) and cold Arctic-warm Eurasia (CAWE) patterns became more frequent and the subseasonal intensity of the WACE/CAWE pattern was still comparable with that from 1996 to 2011. This study highlighted the co-occurrence of this subseasonal variability and trend changes in the WACE/CAWE pattern based on long-term reanalysis datasets and Coupled Model Intercomparison Project Phase 6 simulations. The preceding sea surface temperature anomalies in the tropical Atlantic and Indian oceans had significant primary impacts on the WACE/CAWE pattern in early and late winter, respectively, which were confirmed by numerical experiments based on the Community Atmosphere Model and Atmospheric Model Intercomparison Project. Their coordination worked to effectively modulate the subseasonal phase reversal between the WACE and CAWE patterns just like what happened in the winters of 2020 and 2021. Findings of the present study imply that subseasonal changes need to be considered in the prediction of climate extremes at mid- to low latitudes.
RESUMO
Mei-yu is an important weather phenomenon in the middle-lower Yangtze River valley (YRV) region. This study investigates the changes in the characteristics of Mei-yu under global warming and the potential reasons based on observation and reanalysis data during 1961-2022. Notable increasing long-term trends are detected in the number of days without rainfall (NDWOR), the intensity of rainfall events, and the frequency and intensity of extreme precipitation events (EPEs) in the YRV region during the Mei-yu period (15 June-10 July) over past decades. The increasing trend in NDWOR is attributed to decreased relative humidity over land surface and a longer time for the air to be replenished with moisture after rainfall events in a warming climate. The increasing trends in the intensity of rainfall events and frequency/intensity of EPEs are attributed to the strengthened transient water vapor convergence and convection in the atmosphere under global warming. Furthermore, the response of Mei-yu to 2°C of global warming with respect to the pre-industrial climate is analysed using CMIP6 models. The results suggest that the NDWOR, intensity of rainfall events and frequency of EPEs will increase in the YRV region during the Mei-yu period under the 2°C warming scenario, which implies a more challenging climate risk management in the future. Overall, the intensity of rainfall events during the Mei-yu period has the most significant response to climate change in observations and projections. The model results have a relatively large uncertainty.
RESUMO
Ischemic stroke is a cerebrovascular disease which is related to brain function loss induced by cerebral ischemia. Translocator protein (TSPO) is an important regulator in inflammatory diseases, while its role in ischemic stroke remains largely unknown. This research aimed to explore the role and action mechanism of TSPO in oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuron cell damage. The differentially expressed genes in ischemic stroke were predicted using GSE140275 dataset, DisGeNet, and GeneCards databases. Differentiated SH-SY5Y cells and primary neurons were subjected to transfection, and stimulated with OGD/R or MCC950 (NLRP3 inhibitor). Proteins were detected by western blotting and ELISA. Cell apoptosis was evaluated through CCK-8, caspase-3 activity and TUNEL assays. TSPO was upregulated in ischemic stroke and in SH-SY5Y cells and primary neurons after OGD/R treatment. TSPO silencing attenuated OGD/R-induced inflammation and apoptosis by decreasing NLRP3 inflammasome activity. TSPO downregulation increased PPARγ expression and decreased HMGB1 expression in OGD/R-treated cells, which was reversed by silencing PPARγ. PPARγ knockdown abolished the effect of TSPO silence on NLRP3 inflammasome activity, inflammation, and cell apoptosis in OGD/R-treated cells, while PPARγ overexpression alleviated OGD/R-induced injury in SH-SY5Y cells. In conclusion, TSPO knockdown attenuates neuroinflammation and neural apoptosis by decreasing NLRP3 inflammasome activity through PPARγ pathway.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Neuroblastoma , Traumatismo por Reperfusão , Apoptose/genética , Isquemia Encefálica/metabolismo , Proteínas de Transporte , Glucose/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças Neuroinflamatórias , Oxigênio/metabolismo , PPAR gama/metabolismo , Receptores de GABA , Reperfusão , Traumatismo por Reperfusão/metabolismoRESUMO
North China suffers from severe haze pollution and has received widespread attentions since the winter of 2012. In addition to human activities, climate variability also plays an important role, particularly in the interannual-decadal variations in the number of haze days in North China (HDNC). Many previous studies separately explored numerous preceding climate drivers, including Arctic sea ice, Eurasia snow and soil moisture, sea surface temperature in Pacific and Atlantic and forcing of Tibetan Plateau, but lacked assessment and analysis of the joint effects. In this study, we reviewed their impacts on HDNC and associated physical mechanisms. Beyond that, the synergetic effects were newly revealed by the observations and numerical experiments with fixed emissions. The preceding signals explained approximately 66% of the interannual-decadal variations in HDNC by exciting teleconnection patterns in winter and influencing the local dispersion conditions in North China. Furthermore, some future research directions were identified, such as the subseasonal variations in HDNC, subseasonal-seasonal prediction of haze by numerical climate models, and changing relationships between HDNC and climate conditions.