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Objective To investigate the effect of human platelet-rich plasma-derived exosomes(PRP-exos)on the proliferation of Schwann cell(SC)cultured in vitro. Methods PRP-exos were extracted by polymerization-precipitation combined with ultracentrifugation.The morphology of PRP-exos was observed by transmission electron microscopy,and the concentration and particle size distribution of PRP-exos were determined by nanoparticle tracking analysis.Western blotting was employed to determine the expression of the marker proteins CD63,CD81,and CD9 on exosome surface and the platelet membrane glycoprotein CD41.The SCs of rats were isolated and cultured,and the expression of the SC marker S100ß was detected by immunofluorescence staining.The fluorescently labeled PRP-exos were co-cultured with SCs in vitro for observation of their interaction.EdU assay was employed to detect the effect of PRP-exos on SC proliferation,and CCK-8 assay to detect the effects of PRP-exos at different concentrations(0,10,20,40,80,and 160 µg/ml)on SC proliferation. Results The extracted PRP-exos appeared as uniform saucer-shaped vesicles with the average particle size of(122.8±38.7)nm and the concentration of 3.5×1012 particles/ml.CD63,CD81,CD9,and CD41 were highly expressed on PRP-exos surface(P<0.001,P=0.025,P=0.004,and P=0.032).The isolated SCs expressed S100ß,and PRP-exos could be taken up by SCs.PRP-exos of 40,80,and 160 µg/ml promoted the proliferation of SCs,and that of 40 µg/ml showed the best performance(all P<0.01). Conclusions High concentrations of PRP-exos can be extracted from PRP.PRP-exos can be taken up by SCs and promote the proliferation of SCs cultured in vitro.
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Exossomos , Plasma Rico em Plaquetas , Humanos , Ratos , Animais , Exossomos/metabolismo , Células de Schwann , Técnicas de Cocultura , Proliferação de Células , Células CultivadasRESUMO
Adiponectin (APN) is the most abundant adipokine in human plasma, and has insulin-sensitizing effect. Recent studies have reported that APN plays both anti- and pro-inflammatory roles under different circumstances. However, there is a lack of convincing evidence that decipher APN's anti-inflammatory role through the known receptors and their downstream signaling pathways. In this study, we evaluated a new molecular mechanism underlying APN's anti-inflammatory roles. Our results revealed that the globular domain of adiponectin (gAdp) interacted with the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1). In vitro experiments showed that gAdp inhibited activation of the T cells via the LAIR-1, through a process that also involved downstream SHP-2. These findings indicate that LAIR-1 is a novel APN receptor, affirming APN's anti-inflammatory effect. In summary, we have identified a novel mechanism of peripheral immunoregulatory processes that provides baseline information for further studies on gAdp's role and its contribution to inflammation.
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Adiponectina/farmacologia , Anti-Inflamatórios/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Células HEK293 , Humanos , Ligantes , Receptores Imunológicos/imunologia , Linfócitos T/imunologiaRESUMO
Cancer stem cells (CSCs) play an important role in shaping the invasive cancer phenotype by contributing to tumor initiation, metastasis, relapse, and therapeutic resistance in non-small cell lung cancer (NSCLC). The Aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, which is well known for mediating the toxicity and tumorigenesis of a variety of environmental pollutants, has been extensively recognized as an important mediator in NSCLC development. Here, evidence showed that AhR was overexpressed in NSCLC tissues, and a high AhR protein level was associated with an aggressive tumor phenotype. Knockdown of AhR suppressed cell proliferation, invasion and migration, as well as CSC-like properties, while upregulation and activation of AhR enhanced CSC-like properties and increased stem cell-associated gene expression in NSCLC cells. Elevated and activated AhR leads to phosphorylation of janus kinase 2 (Jak2), as well as its downstream effector, activator of transcription 3 (STAT3), while inhibition of Jak2/STAT3 signaling by pharmacologic approach attenuates the effects of AhR-mediated NSCLC cell stemness, suggesting a role for the Jak2/STAT3 pathway in AhR-regulated NSCLC stemness. In summary, our study uncovers a transcriptional-independent mechanism of AhR through which AhR mediates NSCLC stemness via Jak2/STAT3 signaling pathway, indicating a promising target for the treatment of NSCLC.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Janus Quinase 2/genética , Neoplasias Pulmonares/genética , Células-Tronco Neoplásicas/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Fator de Transcrição STAT3/genética , Adulto , Idoso , Animais , Compostos Azo/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/metabolismo , Cinurenina/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Nitrilas , Fenótipo , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Magnetic microhelix motors are widely employed in various applications such as cargo transportation, drug delivery, toxic substance declogging, and cell manipulation, due to their unique adaptive magnetic manipulation capabilities. In this work, high-precision stereoscopic additive manufacturing techniques were used to produce customized microhelices with varying structural parameters, including different pitch numbers (2-4 pitches), sizes (0.1-0.25 mm), and taper angles (172°-180°). Their motion performance in mesoscopic tubes was systematically investigated. The magnetic microhelix motors' speed increases when circle numbers and taper angles decrease, while circle diameters increase. The magnetic microhelix motors' speed could achieve a 1500% enhancement reaching 0.16 mm s-1 in a 0.3 mm tube, with a pitch number of 3, diameter of 0.2 mm, and taper angle of 172°. Furthermore, their vessel declogging capability is confirmed in in vitro experiments.
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Structural color, renowned for its enduring vibrancy, has been extensively developed and applied in the fields of display and anticounterfeiting. However, its limitations in brightness and saturation hinder further application in these areas. Herein, we propose a pendant evaporation self-assembly method to address these challenges simultaneously. By leveraging natural convection and Marangoni flow synchronization, the self-assembly process enhances the dynamics and duration of colloidal nanoparticles, thereby enhancing the orderliness of colloidal photonic crystals. On average, this technique boosts the brightness of structural color by 20% and its saturation by 35%. Moreover, pendant evaporation self-assembly is simple and convenient to operate, making it suitable for industrial production. We anticipate that its adoption will remarkably advance the industrialization of structural color, facilitating its engineering applications across various fields, such as display technology and anticounterfeiting identification.
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OBJECTIVE: To investigate the mechanism of regulatory T cells (Treg) in heat stroke (HS)-induced acute kidney injury (AKI). METHODS: Male SPF Balb/c mice were randomly divided into control group, HS group (HS+Rat IgG), HS+PC61 group, and HS+Treg group (n = 6). The HS mice model was established by making the body temperature of the mice reach 42.7 centigrade at room temperature 39.5 centigrade with relative humidity 60% for 1 hour. In HS+PC61 group, 100 µg PC61 antibody (anti-CD25) was injected through the tail vein in consecutive 2 days before the model was established to eliminate Tregs. Mice in HS+Treg group was injected with 1×106 Treg via tail vein immediately after successful modeling. The proportion of Treg infiltrated in the kidney, serum creatinine (SCr) and histopathology, levels of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) both in the serum and kidney tissue, as well as proportion of neutrophils and macrophages located in the kidney were observed at 24 hours after HS. RESULTS: HS dampened renal function and exaggerated kidney injury, up-regulated levels of inflammatory cytokines both in local kidney and circulation, and increased infiltration of neutrophils and macrophages to the injured kidneys. The proportion of Treg (Treg/CD4+) infiltrated in kidney was significantly decreased in HS group, compared with control group [(3.40±0.46)% vs. (7.67±0.82)%, P < 0.01]. Compared with HS group, local Tregs in kidney were almost completely depleted via PC61 antibody [(0.77±0.12)% vs. (3.40±0.46)%, P < 0.01]. Depletion of Tregs could exacerbate HS-AKI, indicating by increased serum creatinine [SCr (mmol/L): 348.22±35.36 vs. 254.42±27.40, P < 0.01] and pathological injury (Paller score: 4.70±0.20 vs. 3.60±0.20, P < 0.01), incremental levels of IFN-γand TNF-α both in injured kidney and serum [serum IFN-γ (ng/L): 747.70±64.52 vs. 508.46±44.79, serum TNF-α (ng/L): 647.41±26.62 vs. 464.53±41.80, both P < 0.01], and more infiltrated neutrophils and macrophages in the injured kidney [neutrophil proportion: (6.63±0.67)% vs. (4.37±0.43)%, macrophage proportion: (38.70±1.66)% vs. (33.19±1.55)%, both P < 0.01]. On the contrast, adoptive transfer of Tregs could reverse the aforementioned effects of Treg depletion, indicating by incremental proportion of Tregs in the injured kidney [(10.58±1.19)% vs. (3.40±0.46)%, P < 0.01], decreased serum creatinine [SCr (mmol/L): 168.24±40.56 vs. 254.42±27.40, P < 0.01] and pathological injury (Paller score: 2.73±0.11 vs. 3.60±0.20, P < 0.01), reduced levels of IFN-γ and TNF-α both in injured kidney and serum [serum IFN-γ (ng/L): 262.62±22.68 vs. 508.46±44.79, serum TNF-α (ng/L): 206.41±22.58 vs. 464.53±41.80, both P < 0.01], and less infiltrated neutrophils and macrophages in the injured kidney [neutrophil proportion: (3.04±0.33)% vs. (4.37±0.43)%, macrophage proportion: (25.68±1.93)% vs. (33.19±1.55)%, both P < 0.01]. CONCLUSIONS: Treg might be involved in HS-AKI, possibly via down-regulation of pro-inflammatory cytokines and infiltration of inflammatory cells.
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Injúria Renal Aguda , Golpe de Calor , Masculino , Animais , Camundongos , Ratos , Linfócitos T Reguladores , Creatinina , Fator de Necrose Tumoral alfa , Citocinas , Interferon gamaRESUMO
Sepsis-induced encephalopathy (SAE) is a detrimental complication in patients with severe sepsis, while there is still no effective treatment. Previous studies have elucidated the neuroprotective effects of glucagon-like peptide-1 receptor (GLP-1R) agonists. However, the role of GLP-1R agonists in the pathological process of SAE is unclear. Here, we found that GLP-1R was up-regulated in the microglia of septic mice. The activation of GLP-1R with Liraglutide could inhibit endoplasmic reticulum stress (ER stress) and associated inflammatory response as well as apoptosis triggered by LPS or tunicamycin (TM) in BV2 cells. In vivo experiments confirmed the benefits of Liraglutide in the regulation of microglial activation, ER stress, inflammation, and apoptosis in the hippocampus of septic mice. Additionally, the survival rate and cognitive dysfunction of septic mice were also improved after Liraglutide administration. Mechanically, cAMP/PKA/CREB signaling is involved in the protection of ER stress-induced inflammation and apoptosis in cultured microglial cells under LPS or TM stimulations. In conclusion, we speculated that GLP-1/GLP-1R activation in microglia might be a potential therapeutic target for the treatment of SAE.
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Encefalopatia Associada a Sepse , Sepse , Camundongos , Animais , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Microglia/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Lipopolissacarídeos/toxicidade , Apoptose , Inflamação/etiologia , Inflamação/patologia , Modelos Animais de Doenças , Encefalopatia Associada a Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/etiologia , Sepse/complicações , Estresse do Retículo EndoplasmáticoAssuntos
Evolução Biológica , Fósseis , Serpentes , Animais , Argentina , Extremidades , Locomoção , Seleção Genética , Serpentes/anatomia & histologia , Serpentes/genética , Serpentes/fisiologiaRESUMO
PURPOSE: To evaluate the effects of high and low levels of PEEP on ICU patients without ARDS. METHODS: We searched public databases (including PubMed, EMBASE, Cochrane Library and Clinicaltrial.gov). The Cochrane Risk of Bias Assessment tool was used to evaluate the quality of the included studies. RESULTS: We included 2307 patients from 24 trials. Although no significant difference was found between high and low PEEP applications in in-hospital mortality (risk ratio[RR] 0.98, 95% confidence interval[CI] [0.81, 1.19], P = 0.87), high PEEP indeed decreased the incidence of ARDS, hypoxemia, and increased the level of PaO2/FIO2. In addition, although the overall results did not reveal any advantages of high PEEP in terms of secondary outcomes regarding 28-day mortality, the duration of ventilation, atelectasis, pulmonary barotrauma, hypotension, and so forth, the subgroup analysis concerning the level of low PEEP (ZEEP or not) and patient type (postoperative or medical ones) yielded different results. The TSA results suggested that more RCTs are needed. CONCLUSIONS: Although ventilation with high PEEP in ICU patients without ARDS may not reduce in-hospital mortality, the decreased incidences of ARDS and hypoxemia and the improvement in PaO2/FIO2 were found in the high PEEP arm.
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Respiração com Pressão Positiva , Síndrome do Desconforto Respiratório , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Respiração com Pressão Positiva/métodos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapiaRESUMO
Background: Acute kidney injury (AKI) is a common complication of exertional heat stroke (EHS) with a complex pathogenesis. We established a stable mouse model of EHS-related AKI (EHS-AKI). Methods: C57BL/6 male mice were divided into 6 groups: Saline Control group, Glycerol Control group, Saline + Sham heat exercise (SHE) group, Saline + Heat exercise (HE) group, Glycerol + SHE group, and Glycerol + HE group. Samples from the Saline Control group and the Glycerol Control group were taken 6 h after the intramuscular injection of saline (4 mL/kg) or glycerol (4 mL/kg) to provide a baseline for comparisons with the other 4 groups. The other 4 groups of mice started exercise 6 h after the intramuscular injection of saline or glycerol, and were sacrificed to collect samples after exercise. Finally, serum and the pathology of kidney and muscle tissues were quantified. Results: There were no differences in the creatinine (Cr), blood urea nitrogen (BUN), creatine kinase (CK), and myoglobin (MYO) levels, but the interleukin 6 (IL-6) level was more increased (P<0.05) in the Glycerol Control group than the Saline Control group at the baseline. The IL-6 levels of the Glycerol + HE group were also higher than those of the Saline + HE groups at 6 and 12 h (P<0.05). The Cr levels at 12 h and 1 day, the BUN levels at 6 h, 12 h, 1 day, and 2 days in the Glycerol+ HE group were higher than the baseline levels (P<0.05). And the renal pathological scores at 6 h, 12 h, 1 day, 2 days, or 3 days were 0.79, 1.29, 1.58, 0.85, and 0.77. However, there was only slight renal pathological injury in the Saline + HE group at 12 h, and 1 day, and the scores were 0.13, and 0.41. The CK level in each group all peaked at 6 h after exercise and higher than the baseline (P<0.05). However, there was no difference in the MYO levels of each group compared to the baseline. Conclusions: We established a stable mouse model of EHS-AKI by conducting a heat exercise after the intramuscular injection of glycerol. Our findings lay the foundation for follow-up clinical and basic research.
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The holotype of Junggarsuchus sloani, from the Shishugou Formation (early Late Jurassic) of Xinjiang, China, consists of a nearly complete skull and the anterior half of an articulated skeleton, including the pectoral girdles, nearly complete forelimbs, vertebral column, and ribs. Here, we describe its anatomy and compare it to other early diverging crocodylomorphs, based in part on CT scans of its skull and that of Dibothrosuchus elaphros from the Early Jurassic of China. Junggarsuchus shares many features with a cursorial assemblage of crocodylomorphs, informally known as "sphenosuchians," whose relationships are poorly understood. However, it also displays several derived crocodyliform features that are not found among most "sphenosuchians." Our phylogenetic analysis corroborates the hypothesis that Junggarsuchus is closer to Crocodyliformes, including living crocodylians, than are Dibothrosuchus and Sphenosuchus, but not as close to crocodyliforms as Almadasuchus and Macelognathus, and that the "Sphenosuchia" are a paraphyletic assemblage. D. elaphros and Sphenosuchus acutus are hypothesized to be more closely related to Crocodyliformes than are the remaining non-crocodyliform crocodylomorphs, which form several smaller groups but are largely unresolved.
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Fósseis , Crânio , Animais , Cabeça/anatomia & histologia , Filogenia , Crânio/anatomia & histologia , Crânio/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Sepsis is a systemic inflammatory response due to infection, resulting in organ dysfunction. Timely targeted interventions can improve prognosis. Inflammation plays a crucial role in the process of sepsis. To identify potential sepsis early, we developed and validated a nomogram model and a simple risk scoring model for predicting sepsis in critically ill patients. METHODS: The medical records of adult patients admitted to our intensive care unit (ICU) from August 2017 to December 2020 were analyzed. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%). A nomogram model was developed through multivariate logistic regression analysis. The continuous variables included in nomogram model were transformed into dichotomous variables. Then, a multivariable logistic regression analysis was performed based on these dichotomous variables, and the odds ratio (OR) for each variable was used to construct a simple risk scoring model. The receiver operating characteristic curves (ROC) were constructed, and the area under the curve (AUC) was calculated. RESULTS: A total of 2074 patients were enrolled. Finally, white blood cell (WBC), C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT) and neutrophil-to-lymphocyte ratio (NLR) were included in our models. The AUC of the nomogram model and the simple risk scoring model were 0.854 and 0.842, respectively. The prediction performance of the two models on sepsis is comparable (p = 0.1298). CONCLUSION: This study combining five commonly available inflammatory markers (WBC, CRP, IL-6, PCT and NLR) developed a nomogram model and a simple risk scoring model to predict sepsis in critically ill patients. Although the prediction performance of the two models is comparable, the simple risk scoring model may be simpler and more practical for clinicians to identify potential sepsis in critically ill patients at an early stage and strategize treatments.
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The labyrinth of the vertebrate inner ear is a sensory system that governs the perception of head rotations. Central hypotheses predict that labyrinth shape and size are related to ecological adaptations, but this is under debate and has rarely been tested outside of mammals. We analyze the evolution of labyrinth morphology and its ecological drivers in living and fossil turtles, an understudied group that underwent multiple locomotory transitions during 230 million years of evolution. We show that turtles have unexpectedly large labyrinths that evolved during the origin of aquatic habits. Turtle labyrinths are relatively larger than those of mammals, and comparable to many birds, undermining the hypothesis that labyrinth size correlates directly with agility across vertebrates. We also find that labyrinth shape variation does not correlate with ecology in turtles, undermining the widespread expectation that reptilian labyrinth shapes convey behavioral signal, and demonstrating the importance of understudied groups, like turtles.
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Orelha Interna , Tartarugas , Animais , Aves , Fósseis , Mamíferos , Filogenia , Tartarugas/anatomia & histologiaRESUMO
The deep learning gesture recognition based on surface electromyography plays an increasingly important role in human-computer interaction. In order to ensure the high accuracy of deep learning in multistate muscle action recognition and ensure that the training model can be applied in the embedded chip with small storage space, this paper presents a feature model construction and optimization method based on multichannel sEMG amplification unit. The feature model is established by using multidimensional sequential sEMG images by combining convolutional neural network and long-term memory network to solve the problem of multistate sEMG signal recognition. The experimental results show that under the same network structure, the sEMG signal with fast Fourier transform and root mean square as feature data processing has a good recognition rate, and the recognition accuracy of complex gestures is 91.40%, with the size of 1 MB. The model can still control the artificial hand accurately when the model is small and the precision is high.
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Background: Lung cancer has the highest mortality rate among cancers worldwide, with non-small cell lung cancer (NSCLC) the most common type. Increasing evidence shows that PHB2 is highly expressed in other cancer types; however, the effects of PHB2 in NSCLC are currently poorly understood. Method: PHB2 expression and its clinical relevance in NSCLC tumor tissues were analyzed using a tissue microarray. The biological role of PHB2 in NSCLC was investigated in vitro and in vivo using immunohistochemistry and immunofluorescence staining, gene expression knockdown and overexpression, cell proliferation assay, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, wound healing assay, Transwell assay, western blot analysis, qRT-PCR, coimmunoprecipitation, and mass spectrometry analysis. Results: Our major finding is that PHB2 facilitates tumorigenesis in NSCLC by interacting with and stabilizing RACK1, which further induces activation of downstream tumor-promoting effectors. PHB2 was found to be overexpressed in NSCLC tumor tissues, and its expression was correlated with clinicopathological features. Furthermore, PHB2 overexpression promoted proliferation, migration, and invasion, whereas PHB2 knockdown enhanced apoptosis in NSCLC cells. The stimulating effect of PHB2 on tumorigenesis was also verified in vivo. In addition, PHB2 interacted with RACK1 and increased its expression through posttranslational modification, which further induced activation of the Akt and FAK pathways. Conclusions: Our results reveal the effects of PHB2 on tumorigenesis and its regulation of RACK1 and RACK1-associated proteins and downstream signaling in NSCLC. We believe that the crosstalk between PHB2 and RACK1 provides us with a great opportunity to design and develop novel therapeutic strategies for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Quinase C Ativada/metabolismo , Proteínas Repressoras/metabolismo , Apoptose/genética , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , China , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas de Neoplasias/fisiologia , Proibitinas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Quinase C Ativada/fisiologia , Proteínas Repressoras/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Cluster of differentiation 226 (CD226) molecules play a crucial role in the activation of effector CD4+ T cells during the immune response process, but a cell-intrinsic function of CD226 in CD4+ T subsets is not clear. In this study, we showed that Cd226-/- mice were resistant to myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE) with highly expressed IL-10+CD4+ T cells and downregulated IL-17A+CD4+ T cells when compared with wild-type (WT) mice. Th17 cell infiltration into the central nervous system (CNS) was largely decreased in the absence of CD226 during EAE. CD226 deficiency facilitated the proliferation of regulatory T cells (Tregs), with increased numbers of Tregs observed in EAE mice, and supported the elevated induced regulatory T cell (iTregs) proliferation in vitro. The Akt and Erk signaling pathways were shown to be involved in Cd226-/- Treg proliferation and function in vivo and in vitro. These findings collectively indicate that CD226 is a key molecule regulating the Treg-mediated suppression of autoimmune responses by inhibiting Treg proliferation. Thus, the results of this study identify additional mechanisms by which CD226 regulates Treg functions in EAE and supports the potential therapeutic effects of anti-CD226 molecules on autoimmune diseases.
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Antígenos de Diferenciação de Linfócitos T/metabolismo , Proliferação de Células , Sistema Nervoso Central/enzimologia , Encefalomielite Autoimune Experimental/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ativação Linfocitária , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T Reguladores/enzimologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Células Cultivadas , Sistema Nervoso Central/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Although several evidences suggesting the vital roles that innate immunity plays in the persistence and elimination of chronic hepatitis B virus (CHB) infection, the exact mechanism is still complicated. Here, we successfully polarized monocytes derived from healthy human peripheral blood mononuclear cells (PBMCs) into M1/M2 macrophages and detected the effects of hepatitis B core antigen (HBcAg) on the polarization and function of macrophages via the Toll-like receptor (TLR) 2 signaling pathway. The results showed that HBcAg had a negligible impact on M1 polarization, while it effectively impaired M2 polarization and promoted the production of pro-inflammatory cytokines such as IL-6 and TNF-α. Additionally, HBcAg treatment increased TLR2 expression on M2 macrophages and TLR2 blockade abolished the effects of HBcAg on the impaired phenotype and pro-inflammatory cytokine productions of M2 macrophages. Signaling pathway analysis revealed that the nuclear factor κB (NF-κB) pathway, the downstream of TLR2, was upregulated upon HBcAg treatment in both M1 and M2 macrophages. Furthermore, a CD8+ T-macrophage coculture system implied that compared with PBS stimulation, HBcAg-stimulated M2 macrophages regained their ability to activate CD8+ T cells with higher secretion of IFN-γ. Finally, we found impaired expression of M2-related molecules and increased levels of pro-inflammation cytokines in M2 macrophages from CHB patients upon HBcAg stimulation. In conclusion, these results imply a favorable role of HBcAg in the establishment of a pro-inflammatory microenvironment by macrophages, which may suggest a potential therapeutic strategy of HBcAg-induced macrophage activation in CHB infection.
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Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Receptor 2 Toll-Like/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cultura de Células , Diferenciação Celular/imunologia , Técnicas de Cocultura , Citocinas/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologiaRESUMO
Macrophages are essential for wound repair after myocardial infarction (MI). CD226, a member of immunoglobulin superfamily, is expressed on inflammatory monocytes, however, the role of CD226 in infarct healing and the effect of CD226 on macrophage remain unknown. Methods: Wild type and CD226 knockout (CD226 KO) mice were subjected to permanent coronary ligation. CD226 expression, cardiac function and ventricular remodeling were evaluated. Profile of macrophages, myofibroblasts, angiogenesis and monocytes mobilization were determined. Results: CD226 expression increased in the infarcted heart, with a peak on day 7 after MI. CD226 KO attenuated infarct expansion and improved infarct healing after MI. CD226 deletion resulted in increased F4/80+ CD206+ M2 macrophages and diminished Mac-3+ iNOS+ M1 macrophages accumulation in the infarcted heart, as well as enrichment of α-smooth muscle actin positive myofibroblasts and Ki67+ CD31+ endothelial cells, leading to increased reparative collagen deposition and angiogenesis. Furthermore, CD226 deletion restrained inflammatory monocytes mobilization, as revealed by enhanced retention of Ly6Chi monocytes in the spleen associated with a decrease of Ly6Chi monocytes in the peripheral blood, whereas local proliferation of macrophage in the ischemic heart was not affected by CD226 deficiency. In vitro studies using bone marrow-derived macrophages showed that CD226 deletion potentiated M2 polarization and suppressed M1 polarization. Conclusion: CD226 expression is dramatically increased in the infarcted heart, and CD226 deletion improves post-infarction healing and cardiac function by favoring macrophage polarization towards reparative phenotype. Thus, inhibition of CD226 may represent a novel therapeutic approach to improve wound healing and cardiac function after MI.
Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Macrófagos/metabolismo , Infarto do Miocárdio/metabolismo , Remodelação Ventricular , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Células Endoteliais/metabolismo , Ativação de Macrófagos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Fenótipo , CicatrizaçãoRESUMO
Pterosaurs were a unique clade of flying reptiles that were contemporaries of dinosaurs in Mesozoic ecosystems. The Pterodactyloidea as the most species-diverse group of pterosaurs dominated the sky during Cretaceous time, but earlier phases of their evolution remain poorly known. Here, we describe a 160 Ma filter-feeding pterosaur from western Liaoning, China, representing the geologically oldest record of the Ctenochasmatidae, a group of exclusive filter feeders characterized by an elongated snout and numerous fine teeth. The new pterosaur took the lead of a major ecological transition in pterosaur evolution from fish-catching to filter-feeding adaptation, prior to the Tithonian (145-152 Ma) diversification of the Ctenochasmatidae. Our research shows that the rise of ctenochasmatid pterosaurs was followed by the burst of eco-morphological divergence of other pterodactyloid clades, which involved a wide range of feeding adaptations that considerably altered the terrestrial ecosystems of the Cretaceous world.
RESUMO
Fossils are indispensible in understanding the evolutionary origins of the modern fauna. Crown-group spadefoot toads (Anura: Pelobatoidea) are the best-known fossorial frog clade to inhabit arid environments, with species utilizing a characteristic bony spade on their foot for burrowing. Endemic to the Northern Hemisphere, they are distributed across the Holarctic except East Asia. Here we report a rare fossil of a crown-group spadefoot toad from the late Paleocene of Mongolia. The phylogenetic analysis using both morphological and molecular information recovered this Asian fossil inside the modern North American pelobatoid clade Scaphiopodidae. The presence of a spade and the phylogenetic position of the new fossil frog strongly support its burrowing behavior. The late Paleocene age and other information suggestive of a mild climate cast doubt on the conventional assertion that burrowing evolved as an adaptation to aridity in spadefoot toads. Temporally and geographically, the new fossil provides the earliest record of Scaphiopodidae worldwide, and the only member of the group in Asia. Quantitative biogeographic analysis suggests that Scaphiopodidae, despite originating in North America, dispersed into East Asia via Beringia in the Early Cenozoic. The absence of spadefoot toads in East Asia today is a result of extinction.