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The Ca(2+) modulation in the dorsal raphe nucleus (DRN) plays an important role in sleep-wake regulation. Calmodulin-dependent kinase II (CaMKII) is an important signal-transducing molecule that is activated by Ca(2+) . This study investigated the effects of intracellular Ca(2+) /CaMKII signaling in the DRN on sleep-wake states in rats. Maximum and minimum CaMKII phosphorylation was detected at Zeitgeber time 21 (ZT 21; wakefulness state) and ZT 3 (sleep state), respectively, across the light-dark rhythm in the DRN in rats. Six-hour sleep deprivation significantly reduced CaMKII phosphorylation in the DRN. Microinjection of the CAMKII activation inhibitor KN-93 (5 or 10 nmol) into the DRN suppressed wakefulness and enhanced rapid-eye-movement sleep (REMS) and non-REM sleep (NREMS). Application of a high dose of KN-93 (10 nmol) increased slow-wave sleep (SWS) time, SWS bouts, the mean duration of SWS, the percentage of SWS relative to total sleep, and delta power density during NREMS. Microinjection of CaCl2 (50 nmol) in the DRN increased CaMKII phosphorylation and decreased NREMS, SWS, and REMS. KN-93 abolished the inhibitory effects of CaCl2 on NREMS, SWS, and REMS. These data indicate a novel wake-promoting and sleep-suppressing role for the Ca(2+) /CaMKII signaling pathway in DRN neurons. We propose that the intracellular Ca(2+) /CaMKII signaling in the dorsal raphe nucleus (DRN) plays wake-promoting and sleep-suppressing role in rats. Intra-DRN application of KN-93 (CaMKII activation inhibitor) suppressed wakefulness and enhanced rapid-eye-movement sleep (REMS) and non-REMS (NREMS). Intra-DRN application of CaCl2 attenuated REMS and NREMS. We think these findings should provide a novel cellular and molecular mechanism of sleep-wake regulation.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Sono/fisiologia , Vigília/fisiologia , Animais , Benzilaminas/farmacologia , Cloreto de Cálcio/farmacologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Eletroencefalografia , Eletromiografia , Masculino , Microinjeções , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Privação do Sono , Estatísticas não Paramétricas , Sulfonamidas/farmacologia , Vigília/efeitos dos fármacosRESUMO
Necroptosis is a recently discovered necrotic cell death which is regulated by receptor interacting protein kinase 1 (RIPK1) and RIPK3 under the stimulus of death signal and can be inhibited by necrostatin-1 (Nec-1) specifically. Therefore, the aim was to investigate the role of necroptosis in a rat model of acute respiratory distress syndrome (ARDS) induced by oleic acid (OA) and assess the effect of Nec-1 on lung injury in ARDS. Our results found that RIPK1, RIPK3 and mixed lineage kinase domain-like protein (MLKL) were abundantly expressed in rat lung tissues of OA-induced ARDS. Nec-1 pretreatment improved pulmonary function and attenuated lung edema dramatically in OA-induced ARDS rats. Furthermore, Nec-1 reduced RIPK1-RIPK3 interaction and down-regulated RIPK1-RIPK3-MLKL signal pathway, and inhibited inflammatory response by reducing neutrophil infiltration and protein leakage into lung tissue in OA-induced ARDS. Collectively, our study proves the intervention of necroptosis in OA-induced ARDS. Moreover, our findings imply that Nec-1 plays an important role in the treatment of ARDS via inhibiting necroptosis and inflammation.
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Imidazóis/uso terapêutico , Indóis/uso terapêutico , Substâncias Protetoras/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar , Agregação Celular/efeitos dos fármacos , Contagem de Células , Modelos Animais de Doenças , Imidazóis/farmacologia , Imuno-Histoquímica , Indóis/farmacologia , Inflamação/patologia , Masculino , Necrose , Ácido Oleico , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Posttraumatic nightmares are a highly prevalent and distressing symptom of posttraumatic stress disorder (PTSD), but have been the subject of limited phenomenological investigations. METHODS: We utilized a communication box to establish PTSD symptoms in rats through exposure to footshock stress (FS) and psychological stress (PS). The immunohistochemical test and high-performance liquid chromatography with electrochemical detection were used to detect the activity and monoamine levels in the rats' arousal systems. RESULTS: Twenty-one days after traumatic stress, 14.17% of FS and 12.5% of PS rats exhibited startled awakening, and the same rats showed hyperfunction of the locus coeruleus/noradrenergic system and hypofunction of the perifornical nucleus/orexinergic system. Changes in serotonin levels in the dorsal raphe nucleus showed opposite trends in the FS and PS rats that were startled awake. No differences were found in other sleep/arousal systems. CONCLUSION: These results suggest that different clinically therapeutic strategies should be considered to treat different trauma-induced posttraumatic nightmares.
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Encéfalo/metabolismo , Terrores Noturnos/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estresse Psicológico/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Eletrochoque , Feminino , Pé , Imuno-Histoquímica , Neurônios/metabolismo , Norepinefrina/metabolismo , Orexinas/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Reflexo de Sobressalto/fisiologia , Serotonina/metabolismo , Sono/fisiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Vigília/fisiologiaRESUMO
The present study was aimed to investigate the role of necroptosis in the pathogenesis of acute respiratory distress syndrome (ARDS). The rat model of ARDS was induced by intravenous injection of oleic acid (OA), and observed for 4 h. The lung injury was evaluated by arterial blood gas, lung wet-dry weight ratio (W/D) and histological analyses. Simultaneously, bronchoalveolar lavage fluid (BALF) was collected for total and differential cell analysis and total protein determination. Tumor necrosis factor alpha (TNF-α) level in BALF was determined with a rat TNF-α ELISA kit. Expressions of receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL) in lung tissue were determined by Western blot and immunohistochemical staining. The interaction between RIPK1 and RIPK3 was explored by immunoprecipitation. The results showed that, compared with those in control group, total white blood cells count (WBC), polymorphonuclear percentage (PMN%), total protein concentration, TNF-α level in BALF, W/D, and the alveolar-arterial oxygen tension difference (P(A-a)O2) in OA group were significantly increased at 4 h after OA injection. Western blot and immunostaining further showed remarkably increased expressions of RIPK1, RIPK3 and MLKL in lung tissue from OA group. Additionally, immunoprecipitation results indicated an enforced interaction between RIPK1 and RIPK3 in OA group. Collectively, the TNF-α level in BALF and the RIPK1-RIPK3-MLKL signaling pathway in lung tissue were found to be upregulated and activated with the process of ARDS. These findings implicate that RIPK1/RIPK3-mediated necroptosis plays a possible role in the pathogenesis of ARDS, which may provide a new idea to develop novel drugs for the therapy of ARDS.
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Pneumopatias , Transtornos Respiratórios , Doença Aguda , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Necrose , Ácido Oleico , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores , Transdução de Sinais , Fator de Necrose Tumoral alfaRESUMO
AIM: 7-O-ethylfangchinoline (YH-200) is a bisbenzylisoquinoline derivative. The aim of this study was to investigate the antidepressant-like action and underlying mechanisms of YH-200 in mice. METHODS: Mice were treated with YH-200 (15, 30, and 60 mg/kg, ig) or tetrandrine (30 and 60 mg/kg, ig) before conducting forced swimming test (FST), tail suspension test (TST), or open field test (OFT). RESULTS: YH-200 (60 mg/kg) significantly decreased the immobility time in both FST and TST, and prolonged the latency to immobility in FST. YH-200 (60 mg/kg) was more potent than the natural bisbenzylisoquinoline alkaloid tetrandrine (60 mg/kg) in FST. Pretreatment with α1-adrenoceptor antagonist prazosin (1 mg/kg), ß-adrenoceptor antagonist propranolol (2 mg/kg), dopamine D1/D5 receptor antagonist SCH23390 (0.05 mg/kg), dopamine D2/D3 receptor antagonist haloperidol (0.2 mg/kg) or AMPA receptor antagonist NBQX (10 mg/kg) prevented the antidepressant-like action of YH-200 (60 mg/kg) in FST. In contrast, pretreatment with α2 adrenoceptor antagonist yohimbine (1 mg/kg) augmented the antidepressant-like action of YH-200 (30 mg/kg) in FST. Chronic administration of YH-200 (30 and 60 mg/kg for 14 d) did not produce drug tolerance; instead its antidepressant-like action was strengthened. Chronic administration of YH-200 did not affect the body weight of mice compared to control mice. CONCLUSION: YH-200 exerts its antidepressant-like action in mice via acting at multi-targets, including α1, α2 and ß-adrenoceptors, D1/D5 and D2 /D3 receptors, as well as AMPA receptors.
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Antidepressivos/farmacologia , Benzilisoquinolinas/farmacologia , Receptores de AMPA/metabolismo , Receptores Adrenérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Elevação dos Membros Posteriores , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
AIM: Disrupted sleep may be a prodromal symptom or a predictor of depressive disorders. In this study we investigated the relationship between depression symptoms and disrupted sleep using a novel model of stress-mimicked sleep disorders in rats. METHODS: SD rats were injected with corticosterone (10, 20 or 40 mg/kg, sc) or vehicle for 7 d. Their sleep-wake behavior was monitored through implanted EEG and EMG electrodes. Their depressive behaviors were assessed using forced swim test, open field test and sucrose preference test. RESULTS: The corticosterone-treated rats showed significantly reduced sleep time, disinhibition of rapid-eye-movement (REM) sleep and altered power spectra during non-REM sleep. All depressive behavioral tests did not show significant difference across the groups. However, individual correlation analysis revealed statistically significance: the immobility time (despair) was negatively correlated with REM sleep latency, slow wave sleep (SWS) time ratio, SWS bouts and delta power density, and it was positively correlated with REM sleep bouts and beta power density. Meanwhile, sucrose preference (anhedonia) was positively correlated with total sleep time and light sleep bouts, and it was negatively correlated with the REM sleep time ratio. CONCLUSION: In stress-mimicked rats, sleep disturbances are a predictor of depressive disorders, and certain symptoms of depression may be related to the disruption of several specific sleep parameters.
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Corticosterona/metabolismo , Depressão/etiologia , Transtornos do Sono-Vigília/etiologia , Estresse Fisiológico , Animais , Depressão/metabolismo , Depressão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Sono , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/fisiopatologiaRESUMO
BACKGROUND: Synchronous liver metastasis (SLM) is a significant contributor to morbidity in colorectal cancer (CRC). There are no effective predictive device integration algorithms to predict adverse SLM events during the diagnosis of CRC. AIM: To explore the risk factors for SLM in CRC and construct a visual prediction model based on gray-level co-occurrence matrix (GLCM) features collected from magnetic resonance imaging (MRI). METHODS: Our study retrospectively enrolled 392 patients with CRC from Yichang Central People's Hospital from January 2015 to May 2023. Patients were randomly divided into a training and validation group (3:7). The clinical parameters and GLCM features extracted from MRI were included as candidate variables. The prediction model was constructed using a generalized linear regression model, random forest model (RFM), and artificial neural network model. Receiver operating characteristic curves and decision curves were used to evaluate the prediction model. RESULTS: Among the 392 patients, 48 had SLM (12.24%). We obtained fourteen GLCM imaging data for variable screening of SLM prediction models. Inverse difference, mean sum, sum entropy, sum variance, sum of squares, energy, and difference variance were listed as candidate variables, and the prediction efficiency (area under the curve) of the subsequent RFM in the training set and internal validation set was 0.917 [95% confidence interval (95%CI): 0.866-0.968] and 0.09 (95%CI: 0.858-0.960), respectively. CONCLUSION: A predictive model combining GLCM image features with machine learning can predict SLM in CRC. This model can assist clinicians in making timely and personalized clinical decisions.
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Millions of adenosine (A) to inosine (I) RNA editing events are reported and well-studied in eukaryotes; however, many features and functions remain unclear in prokaryotes. By combining PacBio Sequel, Illumina whole-genome sequencing, and RNA Sequencing data of two Klebsiella pneumoniae strains with different virulence, a total of 13 RNA editing events are identified. The RNA editing event of badR is focused, which shows a significant difference in editing levels in the two K. pneumoniae strains and is predicted to be a transcription factor. A hard-coded Cys is mutated on DNA to simulate the effect of complete editing of badR. Transcriptome analysis identifies the cellular quorum sensing (QS) pathway as the most dramatic change, demonstrating the dynamic regulation of RNA editing on badR related to coordinated collective behavior. Indeed, a significant difference in autoinducer 2 activity and cell growth is detected when the cells reach the stationary phase. Additionally, the mutant strain shows significantly lower virulence than the WT strain in the Galleria mellonella infection model. Furthermore, RNA editing regulation of badR is highly conserved across K. pneumoniae strains. Overall, this work provides new insights into posttranscriptional regulation in bacteria.
Assuntos
Klebsiella pneumoniae , Percepção de Quorum , Virulência/genética , Klebsiella pneumoniae/genética , Percepção de Quorum/genética , Edição de RNA/genética , Sequenciamento Completo do GenomaRESUMO
A microcavity laser with linear polarization finds practical applications in metrology and biomedical imaging. Through a pulsed light excitation, the polarization characteristics of amplified spontaneous emissions (ASEs) from ten-period ZnO/Zn0.8Mg0.2O multiple quantum wells (MQWs) on a C-Plane sapphire substrate were investigated at room temperature. Unlike unpolarized spontaneous emissions, with 35 meV of energy differences between the C and AB bands, the ASE of MQWs revealed transverse-electric (TE) polarization under the edge emission configuration. The excited ASE from the surface normal of the polar ZnO/Zn0.8Mg0.2O MQWs with hexagonal symmetry revealed linear polarization under the pump of the stripe line through the focusing by using a cylindrical lens. The polarization direction of ASE is independent of the pump polarization but always perpendicular to the pump stripe, even if the cylindrical lens is rotated 90 degrees because of the gain-guiding effect.
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Fatty acid-binding protein (Fabp)-4 is a member of the FABP family. Mammalian fabp4 has been demonstrated to involve in inflammation and immunity, whereas the related data of fish fabp4 remain limited. Therefore, we further investigated the effects of fabp4 on immunity in Ctenopharyngodon idella. The fabp4 sequence spanned 405 bp was cloned first, sharing high identity to fabp4 from other fish and mammals. Fabp4 expression was the highest in the adipose tissue, followed by the heart, muscle, and liver. In vivo, lipopolysaccharide (LPS) triggered the expression of fabp4, toll-like receptor (tlr)-22, interleukin (il)-1ß, and tumor necrosis factor (tnf)-α in the kidney and spleen. In vitro, exposing C. idella CIK cells to LPS decreased their viability, and the expression of fabp4 was also increased by LPS. However, BMS309403, an inhibitor of FABP4, mitigated these effects. Furthermore, treating the cells with LPS or fabp4 overexpression plasmids resulted in reactive oxygen species (ROS) generation and upregulation of inflammatory genes expression, including tlr22, type-I interferon (ifn-1), interferon regulatory factor (irf)-7, tnfα, il-1ß, and interferon-ß promoter stimulator 1. These effects were ameliorated by preincubation with BMS309403. Moreover, incubating the cells with glutathione reduced the production of ROS and the expression of inflammatory genes that were evoked by LPS and plasmid treatments. These results showed that fabp4 acts as a pro-inflammatory molecule via elevating ROS levels, providing a novel understanding of the molecular regulation of innate immunity in teleosts.
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Carpas , Doenças dos Peixes , Animais , Carpas/genética , Carpas/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Proteínas de Peixes/metabolismo , Expressão Gênica , Imunidade Inata/genética , Estresse OxidativoRESUMO
Herein, based on the strategy of synergetic catalysis, we report a cobalt-based coordination polymer PEI6-Co. As a heterogeneous catalyst, PEI6-Co shows a selectivity of 95% and a yield of 1170 mmol g-1 for visible-light-driven CO2-to-CO conversion in a water containing system, which is almost 2.8 times that of the mononuclear cobalt catalyst CoL1 and is comparable to that of the dinuclear cobalt catalyst Co2L.
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The class II trans-activator (CIITA) is the master regulator of the major histocompatibility complex (MHC) gene expression. CIITA mutations have been previously associated with several kinds of tumors, while the role of CIITA polymorphisms (rs3087456) in laryngeal squamous cell carcinoma (LSCC) is little known. We evaluate the link between CIITA polymorphisms and the existence of LSCC in patients. This study was conducted with 200 Chinese Han patients (LSCC) and 200 healthy control subjects. The association of CIITA genetic polymorphism rs3087456 with the risk of LSCC was assessed through pyrosequencing. The CIITA expression in LSCC tumor tissue and adjacent normal tissue was detected by immunohistochemistry (IHC) staining. The relationship between the genotype of rs3087456 in controls and in clinical pathology features in LSCC were analyzed, and in-silico analysis was also used for the CIITA gene. The in-silico analysis results showed that the CIITA gene is closely related to genes such as RFX5 and RFXAP. The IHC results showed that CIITA was highly expressed in LSCC tumor tissues, compared with the corresponding adjacent normal tissues. The AG, AG + AA, and A genotypes of rs3087456 of CIITA gene notably increased the risk of LSCC compared to the controls. Our study suggests that CIITA polymorphism (rs3087456) is associated with a higher risk of developing LSCC in a Chinese cohort.
Assuntos
Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Transativadores/genética , Adulto , Povo Asiático , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Forty microsatellite loci were selected to amplify the genomic DNA of cultured stock of largemouth bass (Micropterus salmoides L.) in China. Genotypic differences of these microsatellites loci were analyzed using 2-test between the maximal weight group and minimal weight group. Sixteen microsatellites showing significantly difference (P<0.1) were used in genotyping 121 individuals, and the associations between their genotypes and growth traits were examined. Microsatellite loci of JZL60, JZL67, JZL72, JZL124, MiSaTPW76, MiSaTPW117 and MiSaTPW173 were significantly associated with body weight, body length, and body height (P < 0.05 or P < 0.01). The most favorable genotypes for growth traits were AA at JZL60, BB at JZL67, AC at JZL72, BB at MiSaTPW76 and BC at MiSaTPW117. In addition, a total of 47 alleles for the 16 loci were detected (2 approximately 5 alleles for each locus). The average effective number of alleles (Ae), observed heterozygosity (Ho), expected heterozygosity (He) and mean polymorphic information content (PIC) was 2.938, 0.515, 0.500 and 0.445, respectively, both of which indicated that the population genetic diversity was medium.
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Bass/genética , Variação Genética , Crescimento/genética , Repetições de Microssatélites , Polimorfismo Genético , Animais , Especificidade da EspécieRESUMO
OBJECTIVE: To evaluate the efficacy and safety of blood-letting therapy (BLT) in treatment of hypertension. METHODS: A comprehensive electronic and manual bibliographic searches were performed in Cochrane Central Register of Controlled Trials, Excerpt Medica Database (EMBASE), PubMed, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, and Wanfang Database to identify randomized controlled trials (RCTs) in which hypertensive patients were treated with BLT or BLT plus antihypertensive drugs (BPAD) against placebo, no treatment or antihypertensive drugs. The Cochrane Risk Assessment Tool was used to assess the methodological quality of trials. The Review Manager 5.3 software was used for meta-analysis. RESULTS: A total of 7 RCTs with 637 hypertensive patients from 1989 to 2017 were identified. Compared with antihypertensive drugs, blood pressure was significantly reduced by BLT (RR=1.21, 95% CI: 1.01 to 1.44, P=0.03; heterogeneity: P=0.06, I2=60%) and BPAD (RR=1.25, 95% CI, 1.02 to 1.53, P=0.03; heterogeneity: P= 0.01, I2=71%). Moreover, a significant improvement in Chinese medicine syndrome by BLT (RR=1.32; 95% CI: 1.14 to 1.53, P=0.0002; heterogeneity: P=0.53, I2=0%) and BPAD (RR=1.47; 95% CI: 1.06 to 2.04, P=0.02; heterogeneity: P=0.13, I2=56%) was identified. The reported adverse effects were well tolerated. CONCLUSION: Although some positive findings were identified, no definite conclusions regarding the efficacy and safety of BLT as complementary and alternative approach for treatment of hypertension could be drew due to the generally poor methodological design, significant heterogeneity, and insufficient clinical data. Further rigorously designed trials are warranted to confirm the results.
Assuntos
Sangria , Hipertensão/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Terapia Combinada , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome , Resultado do TratamentoRESUMO
Background: NLRP3 inflammasome is an inflammatory mediator. The expression of NLRP3 inflammasome is associated with the development of various tumors and is closely related to the prognosis of tumors. However, the role of NLRP3 inflammasome in laryngeal squamous cell carcinoma (LSCC) remains unclear. This study aim to investigate the influence of NLPR3 inflammasome expression in LSCC, and especially the NLRP3 inflammasome expression level and the prognosis of LSCC after surgery in a Chinese population. Methods: We used quantitative real-time PCR and immunohistochemical (IHC) staining to calculate the mRNA (20 patients, fresh tissue) and protein expression (104 patients, paraffin tissue microarray) levels of the NLRP3 inflammasome (NLRP3/IL-18/IL-1ß/ASC/caspase-1), respectively. We also analyzed the relationship between NLRP3 inflammasome expression levels and LSCC cancer tissues compared with adjacent normal tissues and the clinical features of LSCC. Kaplan-Meier survival curves of overall survival (OS) and disease-free survival (DFS) in LSCC patients were compared and analyzed under different expression levels of the NLRP3 inflammasome. Results: Our results indicated that the mRNA expression of the NLRP3 inflammasome was higher in LSCC cancer tissues compared with adjacent normal tissues (p < 0.001). The IHC staining score also demonstrated that the expression of the NLRP3 inflammasome was higher than in the adjacent normal tissues (p < 0.001). The NLRP3 inflammasome expression also exhibited a close relationship with the clinicopathological characteristics (especially the stage of LSCC) of LSCC. Univariate Cox regression analysis and multivariate Cox regression analysis revealed that both NLRP3 and IL-1ß had an increased risk of LSCC progression (p < 0.05). The Kaplan-Meier log rank test (OS and DFS) demonstrated that high expression of NLRP3/IL-18/IL-1ß/ASC was statistically different than the low expression group (p < 0.05) of LSCC patients after surgery. Conclusion: The high expression group of the NLRP3 inflammasome (NLRP3/IL-18/IL-1ß/ASC) had a poorer prognosis (OS and DFS) than the low expression group of LSCC patients 5 years after surgery. The NLRP3 inflammasome (NLRP3/IL-18/IL-1ß/ASC) may be used as an auxiliary indicator to predict LSCC patient prognosis after surgery.
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Microbioma Gastrointestinal , Lesão Pulmonar , NF-kappa B , Transdução de Sinais , Microbioma Gastrointestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Lesão Pulmonar/microbiologia , Lesão Pulmonar/metabolismo , Camundongos , Fumaça/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Lesão por Inalação de FumaçaRESUMO
Saturation and beating of coherent acoustic phonon (CAP) oscillations were observed and attributed to the screening of a built-in electric field with increasing pump power using degenerate pump-probe measurements near the exciton resonance of polar ZnO/Zn0.8Mg0.2O multiple quantum wells (MQWs). After purifying the CAP signals by using an empirical mode decomposition, we found not only that the CAP amplitude follows the trend of the band gap renormalization (BGR) and shows saturation at high pump power, but also that the CAP oscillation period coincides with that of the MQWs, consistent with the XRD and TEM results. An additional low-frequency oscillation modifying the CAP signal is revealed due to the negative change in refractive index caused by BGR as the pump power increases.
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Reactive oxygen speciesinduced cyclophilin A (CyPA) release from vascular smooth muscle cells (VSMCs) may be inhibited by simvastatin in vitro. The present study aimed to further examine the effect of simvastatin on serum CyPA levels and the basigin (CD147)extracellular signalregulated kinase (ERK) 1/2cyclin pathway during thoracic aorta remodeling. The mechanisms through which simvastatin may inhibit CyPA secretion from VSMCs were further investigated. Serum CyPA levels and the expression kinetics of CyPAassociated signaling pathways were examined following simvastatin treatment in rat thoracic aortas during hypertension. Cell lysates were prepared from middle layer of thoracic aortas at 1, 4, 8 and 12 weeks subsequent to surgery. ELISA analysis revealed that serum CyPA levels were gradually increased with the progression of thoracic aorta remodeling. Western blotting demonstrated that the expression of CD147, phosphorylatedERK1/2, cyclin D1, cyclin A, and cyclin E were increased with the progression of thoracic aorta remodeling. Simvastatin administration for 4, 8 and 12 weeks diminished all these changes, as observed in the hypertensive group. VSMCs from simvastatintreated rats secreted a decreased amount of CyPA compared with VSMCs from hypertensive rats. In addition, pretreatment with geranylgeraniol partly reversed the inhibitory effect of simvastatin on LY83583induced CyPA secretion in cultured VSMCs, whereas GGTI298 and KD025 [a selective Rhoassociated protein kinase 2 (ROCK2) inhibitor] mimicked the inhibitory effect of simvastatin. The present study demonstrated that simvastatin alleviated thoracic aorta remodeling by reducing CyPA secretion and expression of the CD147ERK1/2cyclin signaling pathway. In addition, the results of the present study demonstrated that the RhoROCK2 pathway mediated CyPA secretion from VSMCs.
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Aorta Torácica/metabolismo , Aorta Torácica/patologia , Ciclofilina A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Remodelação Vascular/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Animais , Basigina/metabolismo , Biomarcadores , Biópsia , Ciclinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , RatosRESUMO
The Ca(2+)/calmodulin-dependent protein phosphatase calcineurin (CN), a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B, plays critical functions in various cellular processes such as cardiac hypertrophy and T cell activation. It is the target of the most widely used immunosuppressants for transplantation, tacrolimus (FK506) and cyclosporin A. However, the structure of a large part of the CNA regulatory region remains to be determined, and there has been considerable debate concerning the regulation of CN activity. Here, we report the crystal structure of full-length CN (ß isoform), which revealed a novel autoinhibitory segment (AIS) in addition to the well-known autoinhibitory domain (AID). The AIS nestles in a hydrophobic intersubunit groove, which overlaps the recognition site for substrates and immunosuppressant-immunophilin complexes. Indeed, disruption of this AIS interaction results in partial stimulation of CN activity. More importantly, our biochemical studies demonstrate that calmodulin does not remove AID from the active site, but only regulates the orientation of AID with respect to the catalytic core, causing incomplete activation of CN. Our findings challenge the current model for CN activation, and provide a better understanding of molecular mechanisms of CN activity regulation.
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Calcineurina/química , Calcineurina/metabolismo , Animais , Calmodulina/metabolismo , Ativação Enzimática , Humanos , Camundongos , Modelos Moleculares , Subunidades Proteicas/químicaRESUMO
Serotonergic neurons in the dorsal raphe nucleus (DRN) are involved in the control of sleep-wake states. Our previous studies have indicated that calcium (Ca(2+)) modulation in the DRN plays an important role in rapid-eye-movement sleep (REMS) and non-REMS (NREMS) regulation during pentobarbital hypnosis. The present study investigated the effects of Ca(2+) in the DRN on sleep-wake regulation and the related neuronal mechanism in freely moving rats. Our results showed that microinjection of CaCl2 (25 or 50 nmol) in the DRN promoted wakefulness and suppressed NREMS including slow wave sleep and REMS in freely moving rats. Application of CaCl2 (25 or 50 nmol) in the DRN significantly increased serotonin in the DRN and hypothalamus, and noradrenaline in the locus coeruleus and hypothalamus. Immunohistochemistry study indicated that application of CaCl2 (25 or 50 nmol) in the DRN significantly increased c-Fos expression ratio in wake-promoting neurons including serotonergic neurons in the DRN, noradrenergic neurons in the locus coeruleus, and orxinergic neurons in the perifornical nucleus, but decreased c-Fos expression ratio of GABAergic sleep-promoting neurons in the ventrolateral preoptic nucleus. These results suggest that Ca(2+) in the DRN exert arousal effects via up-regulating serotonergic functions in the endogenous sleep-wake regulating pathways.