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Despite significant advances in understanding the general health impacts of air pollution, the toxic effects of air pollution on cells in the human respiratory tract are still elusive. A robust, biologically relevant in vitro model for recapitulating the physiological response of the human airway is needed to obtain a thorough understanding of the molecular mechanisms of air pollutants. In this study, by using 1-nitropyrene (1-NP) as a proof-of-concept, we demonstrate the effectiveness and reliability of evaluating environmental pollutants in physiologically active human airway organoids. Multimodal imaging tools, including live cell imaging, fluorescence microscopy, and MALDI-mass spectrometry imaging (MSI), were implemented to evaluate the cytotoxicity of 1-NP for airway organoids. In addition, lipidomic alterations upon 1-NP treatment were quantitatively analyzed by nontargeted lipidomics. 1-NP exposure was found to be associated with the overproduction of reactive oxygen species (ROS), and dysregulation of lipid pathways, including the SM-Cer conversion, as well as cardiolipin in our organoids. Compared with that of cell lines, a higher tolerance of 1-NP toxicity was observed in the human airway organoids, which might reflect a more physiologically relevant response in the native airway epithelium. Collectively, we have established a novel system for evaluating and investigating molecular mechanisms of environmental pollutants in the human airways via the combinatory use of human airway organoids, multimodal imaging analysis, and MS-based analyses.
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Contaminantes Atmosféricos , Pirenos , Sistema Respiratorio , Humanos , Reproducibilidad de los Resultados , Organoides , Imagen MultimodalRESUMEN
PURPOSE: This study aims to develop an accurate and simplified scoring system based on the national early warning score (NEWS) to predict the mortality of intensive care unit (ICU) patients. METHODS: The information of patients was retrieved from the Medical Information Mart for Intensive Care (MIMIC)-III and -IV databases. The Modified National Early Warning Score (MNEWS) of the patients was calculated. The discrimination ability of the MNEWS, acute physiology and chronic health scoring system II (APACHE II), and original NEWS systems in predicting patients' mortality was evaluated using area under the receiver operating characteristic (AUROC) analysis. The DeLong test was used to estimate the receiver operating characteristic curve. The Hosmer-Lemeshow goodness-of-fit test was then applied to evaluate the calibration of the MNEWS. RESULTS: In total, 7275 ICU patients from the MIMIC-III and -IV databases were included in the derivation cohort and 1507 ICU patients from Xi'an Medical University were included in the validation cohort. In the derivation cohort, the nonsurvivors had significantly higher MNEWSs than the survivors (12.5 ± 3.4 vs 8.8 ± 3.4, P < 0.05). MNEWS and APACHE II both had a better performance than the NEWS in predicting hospital mortality and 90-day mortality. The optimal cutoff of MNEWS was 11. Patients with an MNEWS ≥ 11 had significantly shorter survival than those having an MNEWS of <11. Furthermore, MNEWS had a high calibration ability in predicting hospital mortality of ICU patients (χ2 = 6.534 and P = 0.588) by the Hosmer-Lemeshow test. This finding was confirmed in the validation cohort. CONCLUSION: MNEWS is a simple and accurate scoring system for evaluating the severity and predicting the outcomes of ICU patients.
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Puntuación de Alerta Temprana , Unidades de Cuidados Intensivos , Humanos , Cuidados Críticos , APACHE , Mortalidad Hospitalaria , Curva ROC , PronósticoRESUMEN
Autism is one of the urgent problems in neuroscience. Early research in our laboratory found that dcf1 gene-deficient mice exhibited autistic behavior. Reviewing the literature, we know that the caudate putamen (CPu) brain region is closely related to the occurrence of autism. In this study, we observed that the electrical signal in the abnormal brain region of adult mice was enhanced by using field potential detection for the corresponding brain region. We then used retrovirus markers to track neurons in the CPu brain region and found that there are neural projections in the hippocampus-CPu brain region. Therefore, we selected DREADDs (Designer receptors exclusively activated by designer drugs) to inhibit the abnormal brain region of the mouse and found, through behavioral testing, that this can inhibit the autistic behavior of mice. This research provides new evidence for the understanding of the cause of autism and has accumulated new basis for the treatment of autism. It has theoretical significance and potential application value for the understanding and treatment of autism.
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Trastorno Autístico/fisiopatología , Encéfalo/fisiopatología , Eliminación de Gen , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Animales , Conducta Animal , Electrofisiología , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Putamen/metabolismo , RetroviridaeRESUMEN
The role of microRNAs has been recently identified in chronic obstructive pulmonary disease (COPD). This study aimed to examine the role of miR-132 in the pathophysiology of COPD and to explore the underlying molecular mechanisms of miR-132 in COPD. MiR-132 and suppressor of cytokine signaling 5 (SOCS5) mRNA expression were detected by qRT-PCR. The number of CD4+ and CD8+ T cells was analyzed by flow cytometry. SOCS5 and epidermal growth factor receptor (EGFR) protein levels were determined by western blot. Interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) concentrations were measured by ELISA. MiR-132 expression was up-regulated in the serum from COPD patients and smokers compared with nonsmoker controls. The number of CD8+ T cells was significantly increased in the serum from COPD patients and smokers. MiR-132 expression was negatively correlated with FEV1/FVC%, and positively correlated with CD8+ T cells (%). MiR-132 overexpression repressed SOCS5 expression via directly targeting SOCS5 3'UTR in human monocyte-like cells (THP-1), which was confirmed by luciferase reporter assay. MiR-132 overexpression increased EGFR protein levels and the concentrations of inflammatory cytokines (IL-1ß and TNF-α) in THP-1 cells, and these effects were attenuated by enforced expression of SOCS5. Further, cigarette smoke extract (CSE) treatment up-regulated miR-132 expression, down-regulated SOCS5 expression, and increased inflammatory cytokines levels, which was attenuated by miR-132 knockdown in THP-1 cells. Consistent findings were also found in the human bronchial epithelial cells (BEAS-2B). Collectively, our data implicated that miR-132 may promote inflammation in THP-1 and BEAS-2B cells at least via targeting SOCS5 in COPD.
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MicroARNs/biosíntesis , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Proteínas Supresoras de la Señalización de Citocinas/biosíntesis , Adulto , Anciano , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/fisiopatología , Masculino , MicroARNs/genética , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Fumar/efectos adversos , Proteínas Supresoras de la Señalización de Citocinas/genética , Regulación hacia ArribaRESUMEN
Neurologic Rosai-Dorfman disease (RDD) is a rare type of non-Langerhans cell histiocytosis that affects the central nervous system. Most neurologic RDDs grow like meningiomas, have clear boundaries, and can be completely resected. However, a few RDDs are invasive and aggressive, and no effective treatment options are available because the molecular mechanisms involved remain unknown. Here, we report a case of deadly and glucocorticoid-resistant neurologic RDD and explore its possible pathogenic mechanisms via single-cell RNA sequencing. First, we identified two distinct but evolutionarily related histiocyte subpopulations (the C1Q+ and SPP1+ histiocytes) that accumulated in the biopsy sample. The expression of genes in the KRAS signaling pathway was upregulated, indicating gain-of-function of KRAS mutations. The C1Q+ and SPP1+ histiocytes were highly differentiated and arrested in the G1 phase, excluding the idea that RDD is a lympho-histio-proliferative disorder. Second, although C1Q+ histiocytes were the primary RDD cell type, SPP1+ histiocytes highly expressed several severe inflammation-related and invasive factors, such as WNT5A, IL-6, and MMP12, suggesting that SPP1+ histiocytes plays a central role in driving the progression of this disease. Third, oligodendrocytes were found to be the prominent cell type that initiates RDD via MIF and may resist glucocorticoid treatment via the MDK and PTN signaling pathways. In summary, in this case, we report a rare presentation of neurologic RDD and provided new insight into the pathogenic mechanisms of progressive neurologic RDD. This study will also offer evidence for developing precision therapies targeting this complex disease.
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Histiocitosis Sinusal , Análisis de la Célula Individual , Humanos , Masculino , Histiocitos/patología , Histiocitosis Sinusal/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína Wnt-5a/metabolismo , Proteína Wnt-5a/genética , Persona de Mediana EdadRESUMEN
Background: Sepsis is a life-threatening condition marked by a severe systemic response to infection, leading to widespread inflammation, cellular signaling disruption, and metabolic dysregulation. The role of lipid and amino acid metabolism in sepsis is not fully understood, but aberrations in this pathway could contribute to the disease's pathophysiology. Methods: To explore the potential of lipid and amino acid compounds as biomarkers for the diagnosis and prognosis of sepsis, a two-sample Mendelian Randomization (MR) study was conducted, examining the relationship between sepsis and 249 serum lipid and amino acid-related markers. Key enzymes involved in synthesis of phosphatidylcholine, including choline/ethanolamine phosphotransferase 1 (CEPT1), choline phosphotransferase 1 (CPT1), and ethanolamine phosphotransferase 1 (EPT1), were also targeted for drug-target Mendelian randomization. Results: The study found that phosphatidylcholines (OR IVW: 0.88, 95%CI: 0.80-0.96, p = 0.005) and phospholipids in medium HDL (OR IVW: 0.86, 95%CI: 0.77-0.96, p = 0.007) potentially exhibit a protective effect against sepsis nominally. However, the potential drug target of CEPT1, CPT1, and EPT1 was found to be unrelated to septic outcomes. Conclusion: Our findings suggest that increasing levels of phosphatidylcholines and medium HDL phospholipids may reduce the incidence of sepsis. This highlights the potential of lipid-based biomarkers in the diagnosis and management of sepsis, opening avenues for new therapeutic strategies.
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SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination. The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences. Molecular markers for evaluating the pathogenicity of new variants are therefore needed. By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels, six key molecules on the polyamine biosynthesis pathway including putrescine, SAM, dc-SAM, ODC1, SAMS, and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants. To validate our discovery, human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients. Using ODC1 as a proof-of-concept, differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system (RAS) and positively associated with ACE2 activity. Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern (VOCs) and was found to be correlated with each VOCs' pathogenic properties. Particularly, the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models. Our work, therefore, presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Multiómica , PutrescinaRESUMEN
Clear cell tumor of the lung is a rare and benign pulmonary tumor; only sporadic cases have been reported. Here, we report the case of a 38-year-old man with recurrent cough, blood-streaked sputum and left chest pain. A chest computed tomography scan showed a round, homogeneous pulmonary mass in the left lower lobe, which exhibited intense heterogeneous enhancement in the arterial phase and homogeneous in the delay phase after injecting a contrast agent. The patient underwent a fine-needle aspiration biopsy and was diagnosed as having a benign clear cell tumor of the lung. The clinical presentation and radiographic investigation of this tumor are summarized in this paper to recognize this rare disease. Interestingly, we found some differences with previously reported cases.
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Adenocarcinoma de Células Claras/patología , Neoplasias Pulmonares/patología , Adenocarcinoma de Células Claras/cirugía , Adulto , Biopsia con Aguja Fina , Humanos , Neoplasias Pulmonares/cirugía , Masculino , Pronóstico , Tomografía Computarizada por Rayos XRESUMEN
A serendipitous and highly efficient approach for the construction of a variety of δ-carboline derivatives was developed through base-promoted cascade ß-F-elimination/electrocyclization/Diels-Alder/retro-Diels-Alder reaction of N-2,2,2-trifluoroethylisatin ketoimine esters with alkynes in good to high yields with excellent regio-/chemoselectivity control. Moreover, a reasonable reaction pathway was proposed, which was in accordance with the prepared reaction intermediate and control experiment results. The δ-carboline product could be easily converted into a new chiral Py-box-type ligand through simple synthetic transformations. This salient strategy featured the advantages of metal-free conditions, excellent regio-/chemoselectivity, good to high yields, and outstanding substrate tolerance. Importantly, the potential application of these fascinating δ-carboline derivative products is well demonstrated in the recognition of ferric ions.
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The importance of chiral amino acids (AAs) in living organisms has been widely recognized since the discovery of endogenous d-AAs as potential biomarkers in several metabolic disorders. Chiral analysis by ion mobility spectrometry-mass spectrometry (IMS-MS) has the advantages of high speed and sensitivity but is still in its infancy. Here, an N α-(2,4-dinitro-5-fluorophenyl)-l-alaninamide (FDAA) derivatization is combined with trapped ion mobility spectrometry-mass spectrometry (TIMS-MS) for chiral AA analysis. For the first time, we demonstrate the simultaneous separation of 19 pairs of chiral proteinogenic AAs in a single fixed condition TIMS-MS run. The utility of this approach is presented for mouse brain extracts by direct-infusion TIMS-MS. The robust separation ability in complex biological samples was proven in matrix-assisted laser desorption/ionization (MALDI) TIMS mass spectrometry imaging (MSI) as well by directly depositing 19 pairs of chiral AAs on a tissue slide following on-tissue derivatization. In addition, endogenous chiral amino acids were also detected and distinguished. The developed methods show compelling application prospects in biomarker discovery and biological research.
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BACKGROUND: The novel Coronavirus Disease 2019 (COVID-19) infection broken out in Wuhan. We aimed to analyse the impact of medical support and population emigration from Wuhan on the cure rate and mortality of COVID-19 infection in China and to provide early warning on the developmental trend of the epidemic. METHODS: Data were obtained from The National Health Commission of People's Republic of China, Chinese Center for Disease Control and Prevention and The National Health Commission of People's Republic of Hubei Province. The Poisson distribution and normal approximate were used to analyse the relationship between population emigration from Wuhan and the probability of outbreaks and to predict the developmental trend of the epidemic situation. RESULTS: The outbreak were related to population emigration from Wuhan in 87% of the cities in Hubei. The result of developmental trend indicated that 95% confidence intervals of confirmed case in Xiaogan and HuangGang were 3301.678-3526.042 and 3201.189-3422.17, respectively. For province outside of Hubei, the outbreak in 76% of the provinces were related to population emigration from Wuhan. Hot spot provinces for epidemic prevention included GuangDong and HeNan. Medical support significantly improved the cure rate of patients with COVID-19 (r = 0.852, p < 0.001). CONCLUSION: Population emigration from Wuhan has a certain impact on the probability of outbreaks COVID-19 in Hubei and the whole country, medical support improved the cure rate of patients with COVID-19.
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COVID-19/terapia , COVID-19/transmisión , Viaje/estadística & datos numéricos , COVID-19/epidemiología , China/epidemiología , Humanos , SARS-CoV-2RESUMEN
OBJECTIVE: This study aims to evaluate the accuracy of the Acute Physiology and Chronic Health Evaluation (APACHE) II score on different days in predicting the mortality of critically ill patients to identify the best time point for the APACHE II score. METHODS: The demographic and clinical data are retrieved from the Medical Information Mart for Intensive Care (MIMIC)-IV dataset. APACHE II scores on days 1, 2, 3, 5, 7, 14, and 28 of hospitalization are calculated, and their performance is evaluated using the area under the receiver operating characteristic (AUROC) analysis. The cut-off for defining the high risk of mortality is determined using Youden's index. The APACHE II score on day 3 is the best time point to predict hospital mortality of ICU patients. The Hosmer-Lemeshow goodness-of-fit test is then applied to evaluate the calibration of the day 3 APACHE II score. RESULTS: We recruited 6,374 eligible subjects from the MIMIC-IV database. Day 3 is the optimal time point for obtaining the APACHE II score to predict the hospital mortality of patients. The best cut-off for day 3 APACHE II score is 17. When APACHE II score ≥17, the sensitivity for the non-survivors and survivors is 92.8 and 82.2%, respectively, and the positive predictive value (PPV) is 23.1%. When APACHE II socre <17, the specificity for non-survivors and survivors is 90.1 and 80.2%, respectively, and the negative predictive value (NPV) is 87.8%. When day-3 APACHE II is used to predict the hospital mortality, the AUROC is 0.743 (P <0.001). In the ≥17 group, the sensitivity of non-survivors and survivors is 92.2 and 81.3%, respectively, and the PPV is 30.3%. In the <17 group, the specificity of non-survivors and survivors is 100.0 and 80.2%, respectively, and the NPV is 81.6%. The Hosmer-Lemeshow test indicated day-3 APACHE II has a high predicting the hospital mortality (X 2 = 6.198, P = 0.625, consistency = 79.4%). However, the day-1 APACHE II has a poor calibration in predicting the hospital mortality rate (X 2 = 294.898, P <0.001). CONCLUSION: Day-3 APACHE II score is an optimal biomarker to predict the outcomes of ICU patients; 17 is the best cut-off for defining patients at high risk of mortality.
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The K+-Cl- co-transporter 2 (KCC2) is a neuron-specific Cl- extruder in the dorsal horn of spinal cord. The low intracellular Cl- concentration established by KCC2 is critical for GABAergic and glycinergic systems to generate synaptic inhibition. Peripheral nerve lesions have been shown to cause KCC2 dysfunction in adult spinal cord through brain-derived neurotrophic factor (BDNF) signaling, which switches the hyperpolarizing inhibitory transmission to be depolarizing and excitatory. However, the mechanisms by which BDNF impairs KCC2 function remain to be elucidated. Here we found that BDNF treatment enhanced KCC2 ubiquitination in the dorsal horn of adult mice, a post-translational modification that leads to KCC2 degradation. Our data showed that spinal BDNF application promoted KCC2 interaction with Casitas B-lineage lymphoma b (Cbl-b), one of the E3 ubiquitin ligases that are involved in the spinal processing of nociceptive information. Knockdown of Cbl-b expression decreased KCC2 ubiquitination level and attenuated the pain hypersensitivity induced by BDNF. Spared nerve injury significantly increased KCC2 ubiquitination, which could be reversed by inhibition of TrkB receptor. Our data implicated that KCC2 was one of the important pain-related substrates of Cbl-b and that ubiquitin modification contributed to BDNF-induced KCC2 hypofunction in the spinal cord.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hiperalgesia/patología , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Asta Dorsal de la Médula Espinal/patología , Simportadores/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Hiperalgesia/etiología , Masculino , Ratones , Células del Asta Posterior/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas c-cbl/genética , Transducción de Señal , Asta Dorsal de la Médula Espinal/citología , Ubiquitinación , Cotransportadores de K ClRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-ß (Aß) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aß aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients. OBJECTIVE: Our goal is to investigate the effect of Dcf1 on Aß aggregation and memory deficits in AD development. METHODS: The mouse and Drosophila AD model were used to test the expression and aggregation of Aß, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies. RESULTS: Deletion of Dcf1 resulted in decreased Aß42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aß42 AD Drosophila, the expression of Dcf1 in Aß42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aß aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice. CONCLUSION: Dcf1 causes Aß-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues.
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Péptidos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Proteínas de la Membrana/genética , Trastornos de la Memoria/genética , Proteínas del Tejido Nervioso/genética , Agregación Patológica de Proteínas/genética , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Condicionamiento Clásico/fisiología , Drosophila melanogaster , Hipocampo/patología , Humanos , Aprendizaje/fisiología , Proteínas de la Membrana/metabolismo , Memoria/fisiología , Trastornos de la Memoria/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Receptores AMPA/metabolismoRESUMEN
Glycine receptor is one of the chloride-permeable ion channels composed of combinations of four α subunits and one ß subunit. In adult spinal cord, the glycine receptor α1 subunit is crucial for the generation of inhibitory neurotransmission. The reduced glycinergic inhibition is regarded as one of the key spinal mechanisms underlying pathological pain symptoms. However, the expression and function of glycine receptors in the peripheral system are largely unknown as yet. Here we found that glycine receptor α1 subunit was prevalent in the dorsal root ganglia (DRG) neurons as well as in the sciatic nerves of adult mice. Intraganglionar or intraplantar injection of glycine receptor antagonist strychnine caused the hypersensitivity to mechanical, thermal and cold stimuli, suggesting the functional importance of peripheral glycine receptors in the control of nociceptive signal transmission. Our data showed that peripheral inflammation induced by formalin decreased the expression of glycine receptor α1 subunit on the plasma membrane of DRG neurons, which was attributed to the activation of protein kinase C signaling. Intraplantar application of glycine receptor agonist glycine or positive modulator divalent zinc ion alleviated the first-phase painful behaviors induced by formalin. These data suggested that peripheral glycine receptor might serve as an effective target for pain therapy.
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Ganglios Espinales/metabolismo , Inhibición Neural , Dolor Nociceptivo/metabolismo , Receptores de Glicina/metabolismo , Analgésicos/farmacología , Animales , Conducta Animal , Modelos Animales de Enfermedad , Formaldehído , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/fisiopatología , Glicinérgicos/farmacología , Masculino , Ratones , Actividad Motora , Inhibición Neural/efectos de los fármacos , Nocicepción , Dolor Nociceptivo/inducido químicamente , Dolor Nociceptivo/fisiopatología , Dolor Nociceptivo/prevención & control , Umbral del Dolor/efectos de los fármacos , Proteína Quinasa C/metabolismo , Receptores de Glicina/antagonistas & inhibidores , Transducción de SeñalRESUMEN
INTRODUCTION: The aim of this study was to evaluate the clinical diagnostic value of combined detection of serum ferritin (SF), carcino-embryonic antigen (CEA) and C-reactive protein (CRP) in non-small cell lung cancer (NSCLC). METHODS: The study included 70 patients with NSCLC, 50 patients with benign lung disease and 50 healthy subjects. The serum concentrations of SF, CEA and CRP were determined by ELISA. RESULTS: The results showed that the serum levels of SF, CEA and CRP in the NSCLC group were significantly higher than those of the benign lung disease group and the control group. The expression of the above three indexes in the lung cancer group III+IV was higher than that in the I+II group (P<0.05), and the expression of SF, CEA and CRP in the adenocarcinoma group was higher than that in the squamous cell carcinoma group. The difference is statistically significant (P<0.01). When the serum CEA, SF and CRP levels were used alone for diagnosis of NSCLC, CRP had the best diagnostic value. The area under the curve was 0.795. The diagnostic sensitivity and specificity were 81.8% and 66.8%, respectivelyWhen combining these three factors, the area under the curve was 0.890, and the sensitivity and specificity were 80.3% and 82.5%, respectively. The parameters above were also significantly different (all P<0.01). CONCLUSION: This study indicated that the combined detection of serum SF, CEA and CRP could improve the early diagnostic sensitivity of NSCLC, and may be used as a potential diagnostic method for NSCLC.
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BACKGROUND: Circular RNAs (circRNAs) participate in the development of human cancers by regulating multiple cell processes. CircRNA antisense to the cerebellar degeneration-related protein 1 transcript (circCDR1as) expression is dysregulated in many cancers, including non-small-cell lung cancer (NSCLC). However, the mechanism by which circCDR1as mediates the development of NSCLC remains unknown. METHODS: A total of 30 paired cancer and normal tissues were collected from patients with NSCLC. The expression levels of circCDR1as, microRNA (miR)-219a-5p and Sex determining region Y-box protein 5 (SOX5) were measured in tissues or cells by quantitative real-time polymerase chain reaction or western blot. Cell viability, apoptosis, migration and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, colony formation, flow cytometry and transwell assays, respectively. The target relationship between miR-219a-5p and circCDR1as or SOX5 was validated by dual-luciferase reporter assay. RESULTS: CircCDR1as expression was elevated in NSCLC tissues and cells in comparison to the matched controls. Interference of circCDR1as led to obvious inhibition of cell viability, migration and invasion and increase of apoptosis in NSCLC cells. MiR-219a-5p acted as a target of circCDR1as and miR-219a-5p downregulation attenuated the regulatory effect of circCDR1as silencing on NSCLC progression. Moreover, miR-219a-5p targeted SOX5 to repress the progression of NSCLC in vitro. Besides, circCDR1as knockdown reduced the expression of SOX5 by increasing miR-219a-5p level. CONCLUSION: Knockdown of circCDR1as inhibited the progression of NSCLC by decreasing cell viability, migration and invasion and increasing apoptosis by upregulating miR-219a-5p and downregulating SOX5.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , MicroARNs/genética , ARN Circular/genética , Factores de Transcripción SOXD/metabolismo , Apoptosis , Autoantígenos/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Invasividad Neoplásica , Proteínas del Tejido Nervioso/genética , Pronóstico , Factores de Transcripción SOXD/genética , Células Tumorales CultivadasRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder partly induced by dysregulation of different brain regions. Prefrontal cortex (PFC) dysregulation has been reported to associate with mental symptoms such as delusion, apathy, and depression in AD patients. However, the internal mechanisms have not yet been well-understood. This study aims to identify the potential therapeutic target genes and related pathways in PFC of AD. First, differential expression analyses were performed on transcriptome microarray of PFC between AD specimens and non-AD controls. Second, protein-protein interaction networks were constructed based on the identified differentially expressed genes to explore candidate therapeutic target genes. Finally, these candidate genes were validated through biological experiments. The enrichment analyses showed that the differentially expressed genes were significantly enriched in protein functions and pathways related to AD. Furthermore, the top ten hub genes in the protein-protein interaction network (ELAVL1, CUL3, MAPK6, FBXW11, YWHAE, YWHAZ, GRB2, CLTC, YWHAQ, and PDHA1) were proved to be directly or indirectly related to AD. Besides, six genes (PDHA1, CLTC, YWHAE, MAPK6, YWHAZ, and GRB2) of which were validated to significantly altered in AD mice by biological experiments. Importantly, the most significantly changed gene, PDHA1, was proposed for the first time that may be serve as a target gene in AD treatment. In summary, several genes and pathways that play critical roles in PFC of AD patients have been uncovered, which will provide novel insights on molecular targets for treatment and diagnostic biomarkers of AD.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Corteza Prefrontal/metabolismo , Transcriptoma/fisiología , Animales , Biología Computacional , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcriptoma/genéticaRESUMEN
Glycine receptor α1ins subunit is located at inhibitory synapses in the superficial dorsal horn of adult spinal cord and is engaged in the glycinergic inhibition of nociceptive neuronal excitability and transmission. The α1ins phosphorylation at Ser380 by extracellular signal-regulated kinase (ERK) has been shown to decrease glycinergic synaptic currents and contribute to spinal disinhibition. Here we found that peripheral inflammation induced by Complete Freund's Adjuvant increased Ser380 phosphorylation in spinal cord dorsal horn of mice, which was repressed by specific activation of adenosine A1 receptor (A1R). Protein phosphatase-1 (PP1), a ubiquitously-distributed serine/threonine phosphatase, was required for A1R to reduce Ser380 phosphorylation. Our data showed that Gßγ dimer, when released after activation of Gi protein-coupled A1R, interacted with PP1 and directed this phosphatase to α1ins, allowing for the full dephosphorylation of Ser380 residue. Sequestration of Gßγ dimer by viral expression of the C-terminal tail of ß-adrenergic receptor kinase (ßARKct) dissociated PP1 from α1ins complex, leading to robust Ser380 phosphorylation. Meanwhile, Gßγ inhibition compromised the ability of A1R to alleviate inflammatory pain. The inhibitory effect of A1R on Ser380 phosphorylation was also attributed to the inactivation of ERK in CFA mice. Our data thus identified glycine receptor α1ins subunit as an important target for adenosinergic suppression of inflammatory pain.
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Analgesia/métodos , Receptor de Adenosina A1/metabolismo , Receptores de Glicina/metabolismo , Asta Dorsal de la Médula Espinal/metabolismo , Adenosina/farmacología , Agonistas del Receptor de Adenosina A1/farmacología , Animales , Relación Dosis-Respuesta a Droga , Adyuvante de Freund/toxicidad , Células HEK293 , Humanos , Masculino , Ratones , Dolor/inducido químicamente , Dolor/metabolismo , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Asta Dorsal de la Médula Espinal/química , Asta Dorsal de la Médula Espinal/efectos de los fármacosRESUMEN
BACKGROUND: The aim of this study was to analyze the psychological status of and its influencing factors in health care workers (HCWs) during the coronavirus disease 2019 (COVID-19) outbreak so as to provide sufficient theory and scientific basis for the formulation and implementation of relevant policies and measures in improving the psychological status of HCWs. METHOD: During February 1 to February 20, 2020, 1,002 members of the HCWs from Xi'an and Wuhan completed a 12-item questionnaire regarding pressure about the COVID-19 influenza pandemic, along with the 12-item General Health Questionnaire (GHQ-12). The GHQ-12 scale was divided by three points. The positive group was scored more than 3. All data were analyzed by SPSS. RESULTS: More than half of the participants (61.1%) reported psychological distress. The HCWs have sufficient information about the COVID-19 symptoms, prognosis, treatment, infection route, and preventive measures (medians ranged from 6/9 to 8/9). Female, engaged in clinic work less than 7 years, married person, and working in Wuhan were risk factors affecting the psychological status of HCWs (P < 0.05). CONCLUSION: Psychological distress is common in HCWs during the COVID-19 outbreak. Hospitals and relevant departments should provide psychological support to HCWs, and strict infection control measures should be developed.