RESUMEN
BACKGROUND: Acute kidney injury (AKI) is a common and serious complication after cardiac surgery that significantly affects patient outcomes. Given the limited treatment options available, identifying modifiable risk factors is critical. Frailty and obesity, two heterogeneous physiological states, have significant implications for identifying and preventing AKI. Our study investigated the interplay among frailty, body composition, and AKI risk after cardiac surgery to inform patient management strategies. MATERIAL AND METHODS: This retrospective cohort study included three international cohorts. Primary analysis was conducted in adult patients who underwent cardiac surgery between 2014 and 2019 at Wuhan XX Hospital, China. We tested the generalizability of our findings with data from two independent international cohorts, the Medical Information Mart for Intensive Care IV (MIMIC-IV) and the eICU Collaborative Research Database. Frailty was assessed using a clinical lab-based frailty index (FI-LAB), while total body fat percentage (BF%) was calculated based on a formula accounting for BMI, sex, and age. Logistic regression models were used to analyze the associations between frailty, body fat, and AKI, adjusting for pertinent covariates. RESULTS: A total of 8785 patients across three international cohorts were included in the study. In the primary analysis of 3,569 patients from Wuhan XX Hospital, moderate and severe frailty were associated with an increased AKI risk after cardiac surgery. Moreover, a nonlinear relationship was observed between body fat percentage and AKI risk. When stratified by the degree of frailty, lower body fat correlated with a decreased incidence of AKI. Extended analyses using the MIMIC-IV and eICU cohorts (n=3,951 and n=1,265, respectively) validated these findings and demonstrated that a lower total BF% was associated with decreased AKI incidence. Moderation analysis revealed that the effect of frailty on AKI risk was moderated by the body fat percentage. Sensitivity analyses demonstrated results consistent with the main analyses. CONCLUSION: Higher degrees of frailty were associated with an elevated risk of AKI following cardiac surgery, and total BF% moderated this relationship. This research underscores the significance of integrating frailty and body fat assessments into routine cardiovascular care to identify high-risk patients for AKI and implement personalized interventions to improve patient outcomes.
RESUMEN
Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases, and the 5-year survival rate of patients remains unsatisfactory. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that are considered essential posttranscriptional regulators of tumorigenesis, including NSCLC. In this study, we aimed to investigate the biological role of miR-3074-5p in NSCLC cells and the underlying molecular mechanisms. We showed that miR-3074-5p expression was decreased in human NSCLC specimens and cell lines. Moreover, miR-3074-5p overexpression inhibited cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. In addition, miR-3074-5p overexpression not only suppressed tumor growth but also enhanced the antitumor effect of paclitaxel (PTX) on NSCLC cells in vitro and in vivo. A transcriptome sequencing assay revealed genes that were differentially expressed after miR-3074-5p overexpression, and among the genes whose expression levels were most significantly decreased, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) was a target of miR-3074-5p. The regulatory effect of miR-3074-5p on YWHAZ expression was verified by Western blotting and dual-luciferase reporter assays. The inhibition of A549 cell growth, migration and invasion was reversed by YWHAZ overexpression. Furthermore, we showed that PTX stimulated the expression of the YWHAZ and Hsp27 proteins and promoted the phosphorylation of Hsp27 (at S15 and S78). YWHAZ was confirmed to interact with Hsp27 in A549 cells, and downregulating YWHAZ expression promoted the degradation of the Hsp27 protein. Taken together, these results suggest that the miR-3074-5p/YWHAZ/Hsp27 axis may be a novel therapeutic target for NSCLC treatment.
Asunto(s)
Proteínas 14-3-3 , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Choque Térmico HSP27 , Neoplasias Pulmonares , MicroARNs , Paclitaxel , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas 14-3-3/metabolismo , Proteínas 14-3-3/genética , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP27/genética , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones Desnudos , Apoptosis/efectos de los fármacos , Masculino , Ratones , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Ratones Endogámicos BALB C , Femenino , Chaperonas Moleculares/metabolismo , Células A549 , Transducción de SeñalRESUMEN
Particulate matter (PM) is considered the fundamental component of atmospheric pollutants and is associated with the pathogenesis of many respiratory diseases. Fibroblast growth factor 10 (FGF10) mediates mesenchymal-epithelial signaling and has been linked with the repair process of PM-induced lung injury (PMLI). However, the pathogenic mechanism of PMLI and the specific FGF10 protective mechanism against this injury are still undetermined. PM was administered in vivo into murine airways or in vitro to human bronchial epithelial cells (HBECs), and the inflammatory response and ferroptosis-related proteins SLC7A11 and GPX4 were assessed. The present research investigates the FGF10-mediated regulation of ferroptosis in PMLI mice models in vivo and HBECs in vitro. The results showed that FGF10 pretreatment reduced PM-mediated oxidative damage and ferroptosis in vivo and in vitro. Furthermore, FGF10 pretreatment led to reduced oxidative stress, decreased secretion of inflammatory mediators, and activation of the Nrf2-dependent antioxidant signaling. Additionally, silencing of Nrf2 using siRNA in the context of FGF10 treatment attenuated the effect on ferroptosis. Altogether, both in vivo and in vitro assessments confirmed that FGF10 protects against PMLI by inhibiting ferroptosis via the Nrf2 signaling. Thus, FGF10 can be used as a novel ferroptosis suppressor and a potential treatment target in PMLI.
Asunto(s)
Ferroptosis , Factor 10 de Crecimiento de Fibroblastos , Lesión Pulmonar , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Material Particulado , Transducción de Señal , Ferroptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Material Particulado/toxicidad , Humanos , Transducción de Señal/efectos de los fármacos , Factor 10 de Crecimiento de Fibroblastos/metabolismo , Factor 10 de Crecimiento de Fibroblastos/genética , Ratones , Estrés Oxidativo/efectos de los fármacos , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Lesión Pulmonar/prevención & control , Masculino , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Línea Celular , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Modelos Animales de Enfermedad , Sistema de Transporte de Aminoácidos y+RESUMEN
Extracellular vesicles (EVs) contain the characteristics of their cell of origin and mediate cell-to-cell communication. Platelet-derived extracellular vesicles (PEVs) not only have procoagulant activity but also contain platelet-derived inflammatory factors (CD40L and mtDNA) that mediate inflammatory responses. Studies have shown that platelets are activated during storage to produce large amounts of PEVs, which may have implications for platelet transfusion therapy. Compared to platelets, PEVs have a longer storage time and greater procoagulant activity, making them an ideal alternative to platelets. This review describes the reasons and mechanisms by which PEVs may have a role in blood transfusion therapy.
What is the context?Platelet transfusion is a treatment that can be effective in preventing bleeding and reducing the amount of bleeding. However, platelet transfusion may cause some unsatisfactory effects for patients, such as adverse transfusion reactions and poor prognosis in cancer patients. These benefits and harms caused by platelet transfusion may be related to PEVs. With the prolongation of storage time during the shelf life of platelets, PEVs were continuously released and the therapeutic effect of platelet components seems to get worse.What is new?This article not only reviews the evidence for PEVs plays a role in blood transfusion therapy but also introduces the mechanism of PEVs in platelet storage lesion and the common methods of isolation and characterization of PEVs.What is the impact?It is necessary to improve the method of isolation and purification of PEVs, to increase the purity of PEVs isolation, and to further demonstrate the potential of PEVs to replace platelets. Further research into the mechanisms by which platelets and PEVs affect the prognosis of cancer patients is required.
Asunto(s)
Plaquetas , Vesículas Extracelulares , Humanos , Transfusión de Plaquetas , Transfusión SanguíneaRESUMEN
Background: Resistance restricts the long-term therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC) with positive EGFR mutations. The present study sought to identify the potential protein osteopontin (OPN) involved in EGFR-TKI resistance and examine its therapeutic mechanism in NSCLC. Methods: The expression of OPN in NSCLC tissues was evaluated by immunohistochemistry (IHC). Western blot (WB), quantitative realtime polymerase chain reaction (qRT-PCR), and immunofluorescence staining were used to analyze OPN and epithelial-mesenchymal transition (EMT)-related protein expression in the PC9 and PC9 gefitinib resistance (PC9GR) cells. Enzyme-linked immunosorbent assays (ELISAs) were used to detect the secreted OPN. Cell Counting Kit-8 (CCK-8) assays and flow cytometry were used to examine the effect of OPN on the gefitinib-induced growth and death of PC9 or PC9GR cells. Results: OPN was upregulated in the human NSCLC tissues and cells resistant to EGFR-TKIs. The overexpression of OPN inhibited EGFR-TKI-induced apoptosis and was associated with the formation of EMT. By activating the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)-EMT pathway, OPN contributed to the development of EGFR-TKI resistance. Reducing OPN expression and inhibiting PI3K/AKT signaling improved EGFR-TKI sensitivity significantly more than the use of either agent alone. Conclusions: This study showed that OPN increased EGFR-TKI resistance in NSCLC through the OPN-PI3K/AKT-EMT pathway. Our findings may provide a possible therapeutic target for overcoming EGFR-TKI resistance in this pathway.
RESUMEN
Particulate matter (PM) is a major environmental pollutant that contributes considerably to deaths worldwide. The pathogenesis of PM-induced lung injury (PILI) is far from elucidated and warrants effective intervention. An effective component of licorice, glycyrrhizin (GL), has been the subject of much research due to its anti-inflammatory and anti-oxidative capabilities. Although preventive properties of GL are well-known, the precise mechanism of GL in PILI has not yet been investigated. A mouse model of PILI was used to examine the protective effects of GL in vivo, and a human bronchial epithelial cells (HBECs) model was used in vitro. In order to determine whether GL mitigates PILI, its effects on endoplasmic reticulum (ER) stress, NLRP3 inflammasome-mediated pyroptosis and the oxidative response were examined. According to the findings, GL reduced PILI and activate anti-oxidative Nrf2/HO-1/NQO1 signaling in mice. Notably, the effect of GL on PM-induced ER stress and NLRP3 inflammasome-mediated pyroptosis was significantly attenuated by the Nrf2 inhibitor ML385. The data suggest that via the anti-oxidative Nrf2 signaling, GL may reduce oxidative stress-mediated ER stress and NLRP3 inflammasome-mediated pyroptosis. Therefore, GL may serve as a promising treatment for PILI.
Asunto(s)
Inflamasomas , Lesión Pulmonar , Humanos , Animales , Ratones , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Piroptosis , Material Particulado/toxicidad , Transducción de Señal , Estrés del Retículo Endoplásmico , NAD(P)H Deshidrogenasa (Quinona)/metabolismoRESUMEN
Background: Epicardial adipose tissue (EAT) acts as an active immune organ and plays a critical role in the pathogenesis of heart failure (HF). However, the characteristics of immune cells in EAT of HF patients have rarely been elucidated. Methods: To identify key immune cells in EAT, an integrated bioinformatics analysis was performed on public datasets. EAT samples with paired subcutaneous adipose tissue (SAT), heart, and peripheral blood samples from HF patients were collected in validation experiments. T cell receptor (TCR) repertoire was assessed by high-throughput sequencing. The phenotypic characteristics and key effector molecules of T lymphocytes in EAT were assessed by flow cytometry and histological staining. Results: Compared with SAT, EAT was enriched for immune activation-related genes and T lymphocytes. Compared with EAT from the controls, activation of T lymphocytes was more pronounced in EAT from HF patients. T lymphocytes in EAT of HF patients were enriched by highly expanded clonotypes and had greater TCR clonotype sharing with cardiac tissue relative to SAT. Experiments confirmed the abundance of IFN-γ+ effector memory T lymphocytes (TEM) in EAT of HF patients. CCL5 and GZMK were confirmed to be associated with T lymphocytes in EAT of HF patients. Conclusion: EAT of HF patients was characterized by pronounced immune activation of clonally expanded IFN-γ+ TEM and a generally higher degree of TCR clonotypes sharing with paired cardiac tissue.
Asunto(s)
Tejido Adiposo , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/patología , Grasa Subcutánea , Pericardio/patología , Receptores de Antígenos de Linfocitos TRESUMEN
Particulate matter (PM) is a major environmental contaminant that causes and worsens respiratory diseases. Fibroblast growth factor 10 (FGF10), a paracrine fibroblast growth factor that specifically stimulates repair and regeneration after injury, has been shown to protect against PM-induced lung injury. However, the underlying mechanisms are still unclear. In this study, the protective effects of FGF10 were investigated using a PM-induced lung injury mouse model in vivo and BEAS-2B cells in vitro. According to the findings, FGF10 treatment alleviated PM-induced oxidative damage and pyroptosis in vivo and in vitro. Mechanistically, FGF10 activated antioxidative Nrf2 signaling. Inhibition of PI3K signaling with LY294002 or Nrf2 signaling with ML385 revealed that FGF10-mediated lung protection was mediated by the PI3K/Akt/Nrf2 pathway. These results collectively indicate that FGF10 inhibits oxidative stress-mediated pyroptosis via the PI3K/Akt/Nrf2 pathway, suggesting a possible therapy for PM-induced lung injury.
Asunto(s)
Factor 10 de Crecimiento de Fibroblastos , Lesión Pulmonar , Material Particulado , Piroptosis , Animales , Ratones , Factor 10 de Crecimiento de Fibroblastos/genética , Factor 10 de Crecimiento de Fibroblastos/inmunología , Lesión Pulmonar/etiología , Lesión Pulmonar/genética , Lesión Pulmonar/inmunología , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo/genética , Estrés Oxidativo/inmunología , Material Particulado/toxicidad , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Piroptosis/genética , Piroptosis/inmunología , Transducción de SeñalRESUMEN
Background: Particulate matter (PM), a well-known environmental pollutant, is an independent risk factor associated with the morbidity of various respiratory diseases. Oxidative stress is an important pathophysiological mechanism related to PM exposure, which mediates redox-sensitive inflammatory signaling, leading to lung injury. Fibroblast growth factor 10 (FGF10), a paracrine fibroblast growth factor that mediates mesenchymal to epithelial signaling, participates in epithelial repair during lung injury. However, whether FGF10-mediated repair in PM-induced lung injury is related to the regulation of oxidative stress remains to be elucidated. Methods: In vivo, the C57BL/6 mice were randomly divided, with intratracheal instillation of 5 mg/kg FGF10 1 h before 4 mg/kg PM for 2 consecutive days. In vitro, the BEAS-2B cells were pretreated with 10 ng/mL FGF10 before exposed to 200 µg/mL PM. Besides, the specific Nrf2 inhibitor ML385 was adopted in vitro. The harvested lung tissues were pathologic grading scored. The state of oxidative stress was assessed with dihydroethidium (DHE) staining, malondialdehyde (MDA) activity, hydrogen peroxide (H2O2) assays and reactive oxygen species (ROS). The contents of IL-6 and IL-8 in bronchoalveolar lavage (BAL) as well as culture supernatant were quantified by ELISA. The protein levels of nuclear factor erythroid 2 related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) signaling from lung tissue as well as cell lysate were determined by Western blot. Results: In this study, recombinant FGF10 administration relieved the degree of lung injury, which is characterized by bronchitis, in a mouse model of PM exposure. In addition, reduced ROS levels, which are indicative of restrained oxidative stress, were also observed. Moreover, two redox-sensitive signaling pathways, Nrf2 and NF-κB, were found to be differentially regulated by FGF10. Using a cellular model of PM exposure, we found that the anti-inflammatory effect of FGF10 on NF-κB signaling was mediated through the regulation of oxidative stress. The anti-oxidative effect relied on the stimulation of Nrf2 signaling. Blockade of Nrf2 signaling with ML385 significantly compromised the anti-inflammatory effect of FGF10. Conclusions: These results underscore that the protective anti-oxidative effects of FGF10 in lung injury are mediated by the stimulation of Nrf2 signaling and inhibition of the NF-κB pathway.
RESUMEN
Background: Post-operative heart transplantation patients often require admission to an intensive care unit (ICU). Early prediction of the ICU length of stay (ICU-LOS) of these patients is of great significance and can guide treatment while reducing the mortality rate among patients. However, conventional linear models have tended to perform worse than non-linear models. Materials and Methods: We collected the clinical data of 365 patients from Wuhan Union Hospital who underwent heart transplantation surgery between April 2017 and August 2020. The patients were randomly divided into training data (N = 256) and test data (N = 109) groups. 84 clinical features were collected for each patient. Features were validated using the Least Absolute Shrinkage and Selection Operator (LASSO) regression's fivefold cross-validation method. We obtained Shapley Additive explanations (SHAP) values by executing package "shap" to interpret model predictions. Four machine learning models and logistic regression algorithms were developed. The area under the receiver operating characteristic curve (AUC-ROC) was used to compare the prediction performance of different models. Finally, for the convenience of clinicians, an online web-server was established and can be freely accessed via the website https://wuhanunion.shinyapps.io/PredictICUStay/. Results: In this study, 365 consecutive patients undergoing heart transplantation surgery for moderate (NYHA grade 3) or severe (NYHA grade 4) heart failure were collected in Wuhan Union Hospital from 2017 to 2020. The median age of the recipient patients was 47.2 years, while the median age of the donors was 35.58 years. 330 (90.4%) of the donor patients were men, and the average surgery duration was 260.06 min. Among this cohort, 47 (12.9%) had renal complications, 25 (6.8%) had hepatic complications, 11 (3%) had undergone chest re-exploration and 19 (5.2%) had undergone extracorporeal membrane oxygenation (ECMO). The following six important clinical features were selected using LASSO regression, and according to the result of SHAP, the rank of importance was (1) the use of extracorporeal membrane oxygenation (ECMO); (2) donor age; (3) the use of an intra-aortic balloon pump (IABP); (4) length of surgery; (5) high creatinine (Cr); and (6) the use of continuous renal replacement therapy (CRRT). The eXtreme Gradient Boosting (XGBoost) algorithm presented significantly better predictive performance (AUC-ROC = 0.88) than other models [Accuracy: 0.87; sensitivity: 0.98; specificity: 0.51; positive predictive value (PPV): 0.86; negative predictive value (NPV): 0.93]. Conclusion: Using the XGBoost classifier with heart transplantation patients can provide an accurate prediction of ICU-LOS, which will not only improve the accuracy of clinical decision-making but also contribute to the allocation and management of medical resources; it is also a real-world example of precision medicine in hospitals.
RESUMEN
Coronavirus disease 2019 (COVID-19) has caused a global pandemic impacting over 200 countries/regions and more than 200 million patients worldwide. Among the infected patients, there is a high prevalence of COVID-19-related cardiovascular injuries. However, the specific mechanisms linking cardiovascular damage and COVID-19 remain unclear. The COVID-19 pandemic also has exacerbated the mental health burden of humans. Considering the close association between neuroimmune interactions and cardiovascular disease, this review assessed the complex pathophysiological mechanisms connecting neuroimmune interactions and cardiovascular disease. It was revealed that the mental health burden might be a pivotal accomplice causing COVID-19-associated cardiovascular damage. Specifically, the proinflammatory status of patients with a terrible mood state is closely related to overdrive of the hypothalamus-pituitary-adrenal (HPA) axis, sympathovagal imbalance, and endothelial dysfunction, which lead to an increased risk of developing cardiovascular injury during COVID-19. Therefore, during the prevention and treatment of cardiovascular complications in COVID-19 patients, particular attention should be given to relieve the mental health burden of these patients.
Asunto(s)
COVID-19 , Enfermedades Cardiovasculares , COVID-19/complicaciones , Humanos , Neuroinmunomodulación , Pandemias , SARS-CoV-2RESUMEN
The spread of NDM-5-producing Escherichia coli has become a severe challenge in clinical therapy, which necessitates reliable detection and surveillance methods. However, limited information is available regarding the prevalence and dissemination of the blaNDM-5 gene in E. coli in China. Therefore, we investigated the dissemination of the blaNDM-5 gene in carbapenem-resistant E. coli isolates from different regions. A total of 1,180 carbapenem-resistant enterobacteriaceae strains were obtained from patients admitted to the 20 sentinel hospitals in 8 cities. Strains positive for blaNDM-5 were detected using the Vitek 2 compact system, 16S ribosomal RNA (rRNA) gene sequencing, polymerase chain reaction, the S1 pulsed-field gel electrophoresis assay, and Southern blot hybridization. The horizontal-transfer capability of the blaNDM gene was assessed by filter mating with a standard E. coli J53 azide-resistant strain as the recipient. Genotyping, susceptibility testing, and whole genome sequencing were performed. Seven strains of blaNDM-5-positive E. coli were detected in 1,180 clinical strains from different regions in China. The blaNDM-5-carrying strains showed resistance to multiple tested antibiotics and belonged to two widespread sequence types, sequence type (ST)167 and ST405. Antimicrobial resistance genes, including blaCTX-M, blaOXA, blaCMY, and two novel blaTEM variants (blaTEM-230 and blaTEM-231) were also identified. Southern blotting located the blaNDM-5 gene on 46 kb IncX3 plasmids in all isolates, which showed only two single nucleotide differences between EJN003 and the other strains. This study further confirms the increasing occurrence of blaNDM-5-carrying IncX3 plasmids and the dissemination of carbapenem resistance in E. coli isolates using the plasmid from different parts in China, which warrants stringent surveillance and control measures.
Asunto(s)
Farmacorresistencia Bacteriana , Infecciones por Escherichia coli , Escherichia coli , Antibacterianos/farmacología , Carbapenémicos , China/epidemiología , Farmacorresistencia Bacteriana/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Infecciones por Escherichia coli/epidemiología , Humanos , Pruebas de Sensibilidad Microbiana , Plásmidos/genética , beta-Lactamasas/genéticaRESUMEN
Mechanical stimulus is critical to cardiovascular development during embryogenesis period.The mechanoreceptors of endocardial cells and cardiac myocytes may sense mechanical signals and initiate signal transduction that induce gene expression at a cellular level,and then translate molecular-level events into tissue-level deformations,thus guiding embryo development.This review summarizes the regulatory roles of mechanical signals in the early cardiac development including the formation of heart tube,looping,valve and septal morphogenesis,ventricular development and maturation.Further,we discuss the potential mechanical transduction mechanisms of platelet endothelial cell adhesion molecule 1-vascular endothelial-cadherin-vascular endothelial growth factor receptor 2 complex,primary cilia,ion channels,and other mechanical sensors that affect some cardiac malformations.
Asunto(s)
Corazón , Mecanotransducción Celular , Animales , Corazón/embriología , Humanos , Miocitos Cardíacos/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Background: The sphingosine 1-phosphate (S1P)/S1P receptor (S1pr) 1 signaling plays an essential role in regulating vascular integrity and angiogenesis. We have previously shown that cell-surface expression of endoglin (Eng) is sustained by S1P/S1pr1 signaling in endothelial cells (ECs). However, whether S1pr1 mediates Eng signaling, or vice versa, remains unknown. Methods: S1pr1 inhibitors were used to study whether pharmacological inhibition induces basal vascular leakage in vivo. An acute respiratory distress syndrome (ARDS) model was used to study whether S1pr1 inhibition evoked greater inflammation in lungs. A S1pr1 inhibitor, a bone morphogenetic protein 9 (BMP9) blocking antibody, or lentivirus-mediated expression of soluble extracellular domain of Eng (sEng) were used to test whether blocking both S1P/S1pr1 and BMP9/Eng signaling axes would impose any interaction in retinal angiogenesis. To clarify whether S1P and BMP9 function in a linear pathway, a study of trans-endothelial electrical resistance (TEER) measurement was carried out using a mouse islet EC line MS1; time course studies were executed to exam downstream effectors of S1P and BMP9 signaling pathways in ECs; two stable MS1 cell lines were generated, one with overexpression of human S1PR1 and the other with knockdown of Eng, to validate S1pr1 and Eng were the key players for the crosstalk. Inhibitor of extracellular regulated protein kinases (ERK) was used to check whether this signaling was involved in S1P-induced cell-surface localization of Eng. Results: The present study elucidated that S1pr1 and Eng are both pivotal for angiogenesis in the postnatal mouse retina, and that the activation of S1pr1 or Eng increases vascular barrier function. Activation of S1pr1 enhanced the phosphorylation of Smad family members 1, 5, and 8 (pSmad1/5/8), while the inhibition of S1pr1 reduced the levels of pSma1/5/8 induced by BMP9 treatment. Activation or loss of Eng did not affect S1pr1 signaling. Moreover, activation of ERK was involved in promoting EC-surface expression of Eng by S1pr1. Conclusions: Our data demonstrates for the first time that there exists a linear pathway of S1pr1-Eng signaling axis in ECs, which governs vascular homeostasis. Functional BMP9/Eng signaling requires S1P/S1pr1 activation, and S1pr1 signaling acts as a vascular protection mechanism upstream of Eng.
RESUMEN
Exposure of the lungs to particulate matter (PM) leads to the development of respiratory disease and involves mechanisms such as oxydative stress, mitochondrial dysfunction and endoplasmic reticulum (ER) stress. However, there are no effective therapies to treat PM-induced lung diseases. Fibroblast growth factor 10 (FGF10) is a multifunctional growth factor mediating mesenchymal-to-epithelial signaling and displaying a significant therapeutic potential following injury. The present research aims to investigate the regulatory mechanism of FGF10 on ER stress in PM-induced lung injury. PM-induced lung injury leads to peribronchial wall thickening and marked infiltration of inflammatory cells which is associated with increased secretion of inflammatory cytokines. The results show that FGF10 treatment attenuates PM-induced lung injury in vivo and reversed ER stress protein GRP78 and CHOP levels. Moreover, comparison of human bronchial epithelial cells cultured with PM and FGF10 vs PM alone shows sustained cell proliferation and restrained secretion of inflammatory cytokines supporting FGF10's protective role. Significantly, both ERK1/2 and PI3K/AKT inhibitors largely abolished the impact of FGF10 on PM-induced ER stress. Taken together, both in vivo and in vitro experiments showed that FGF10, via the activation of ERK1/2 and PI3K/AKT signaling, protects against PM-induced lung injury through the regulation of ER stress. Therefore, FGF10 represents a potential therapy for PM-induced lung injury.
Asunto(s)
Estrés del Retículo Endoplásmico , Lesión Pulmonar , Apoptosis , Factor 10 de Crecimiento de Fibroblastos/farmacología , Factor 10 de Crecimiento de Fibroblastos/uso terapéutico , Humanos , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/tratamiento farmacológico , Material Particulado/toxicidad , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
OBJECTIVE: The aims of this retrospective study were to investigate and evaluate the safety and efficacy of three approaches for closure of secundum atrial septal defect (ASD). METHODS: In this study, we reviewed clinical data for transcatheter occlusion (TCO, n=63), transthoracic occlusion (TTO, n=55), and right anterolateral minithoracotomy (RALT, n=60) techniques used for ASD closure. We compared the safety and efficacy of the three approaches. RESULTS: ASD size in the TTO group was similar to that in the RALT group (P=0.645) and significantly larger than that in the TCO group (P<0.001). The RALT group had more non-central types of ASD than the TTO and TCO groups (P=0.019 and P<0.001). The operative time in the TTO group was shorter than that in the TCO and RALT groups (P<0.001 and P<0.001). The ventilation time and intensive care unit duration were shorter in the TTO group than in the RALT group (P<0.001 and P<0.001). Hospital duration in the TCO group was shorter than that in the TTO and RALT groups (P<0.001 and P<0.001). There were no residual shunt and mortality in any group in hospital or during follow-up. There was no significant difference in the incidence of total complications among the three groups (P=0.738). CONCLUSION: TCO, TTO, and RALT can be performed with favorable cosmetic and clinical results for closing ASD. Appropriate patient selection is an important factor for successful closure. These techniques are promising alternatives to standard median sternotomy and merit additional study.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Defectos del Tabique Interatrial/cirugía , Dispositivo Oclusor Septal , Resultado del Tratamiento , Cateterismo Cardíaco , Humanos , Tiempo de Internación/estadística & datos numéricos , Tempo Operativo , Estudios Retrospectivos , ToracotomíaRESUMEN
The purpose of this review is to provide a comprehensive update on recent advances in heart transplantation in China. Despite advances in pharmacologic and device treatment of chronic heart failure, long-term morbidity and mortality remain high, and many patients progress to endstage heart failure. Heart transplantation has become standard treatment for selected patients with end-stage heart failure, though challenges still exist. However, multiple advances over the past few years will improve the survival and quality-of-life of heart transplant recipients. This article elaborates on the specific characteristics of heart transplantation in China, the current issues, development trends, and related experiences with heart transplantation in Wuhan Union Hospital.