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Plastic deformation in cells and tissues has been found to play crucial roles in collective cell migration, cancer metastasis, and morphogenesis. However, the fundamental question of how plasticity is initiated in individual cells and then propagates within the tissue remains elusive. Here, we develop a mechanism-based theory of cellular and tissue plasticity that accounts for all key processes involved, including the activation and development of active contraction at different scales as well as the formation of endocytic vesicles on cell junctions and show that this theory achieves quantitative agreement with all existing experiments. Specifically, it reveals that, in response to optical or mechanical stimuli, the myosin contraction and thermal fluctuation-assisted formation and pinching of endocytic vesicles could lead to permanent shortening of cell junctions and that such plastic constriction can stretch neighboring cells and trigger their active contraction through mechanochemical feedbacks and eventually their plastic deformations as well. Our theory predicts that endocytic vesicles with a size around 1 to 2 µm will most likely be formed and a higher irreversible shortening of cell junctions could be achieved if a long stimulation is split into multiple short ones, all in quantitative agreement with experiments. Our analysis also shows that constriction of cells in tissue can undergo elastic/unratcheted to plastic/ratcheted transition as the magnitude and duration of active contraction increases, ultimately resulting in the propagation of plastic deformation waves within the monolayer with a constant speed which again is consistent with experimental observations.
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Junções Intercelulares , Morfogênese/fisiologia , Movimento Celular/fisiologiaRESUMO
INTRODUCTION: The mechanisms of cognitive impairments in Parkinson's disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation. OBJECTIVES: To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model. METHODS: Cognitive performance was measured in wild type and Mac1-/- mice using Morris water maze test. The role and mechanisms of NADPH oxidase (NOX)-NLRP3 inflammasome axis in Mac1-mediated microglial dysfunction, neuronal damage, synaptic degeneration and phosphorylation (Ser129) of α-synuclein were explored by immunohistochemistry, Western blot and RT-PCR. RESULTS: Genetic deletion of Mac1 significantly ameliorated learning and memory impairments, neuronal damage, synaptic loss and α-synuclein phosphorylation (Ser129) caused by paraquat and maneb in mice. Subsequently, blocking Mac1 activation was found to mitigate paraquat and maneb-elicited microglial NLRP3 inflammasome activation in both in vivo and in vitro. Interestingly, stimulating activation of NOX by phorbol myristate acetate abolished the inhibitory effects of Mac1 blocking peptide RGD on paraquat and maneb-provoked NLRP3 inflammasome activation, indicating a key role of NOX in Mac1-mediated NLRP3 inflammasome activation. Furthermore, NOX1 and NOX2, two members of NOX family, and downstream PAK1 and MAPK pathways were recognized to be essential for NOX to regulate NLRP3 inflammasome activation. Finally, a NLRP3 inflammasome inhibitor glybenclamide abrogated microglial M1 activation, neurodegeneration and phosphorylation (Ser129) of α-synuclein elicited by paraquat and maneb, which were accompanied by improved cognitive capacity in mice. CONCLUSIONS: Mac1 was involved in cognitive dysfunction in a mouse PD model through NOX-NLRP3 inflammasome axis-dependent microglial activation, providing a novel mechanistic basis of cognitive decline in PD.
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Maneb , Paraquat , Doença de Parkinson , Animais , Camundongos , alfa-Sinucleína/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Inflamassomos/metabolismo , Integrinas/metabolismo , Macrófagos/metabolismo , Maneb/toxicidade , Transtornos da Memória/metabolismo , Microglia/metabolismo , NADPH Oxidases/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Paraquat/toxicidade , Doença de Parkinson/patologia , Antígeno de Macrófago 1RESUMO
Cadmium tellurium quantum dots (CdTe QDs) as one of the most widely used QDs have been reported the toxicity and biosafety in recent years, little work has been done to reduce their toxicity however. Based on the mechanisms of toxicity of CdTe QDs on liver target organs such as oxidative stress and apoptosis previously reported by other researchers, we investigated the mechanism of action of trace element selenium (Se) to mitigate the hepatotoxicity of CdTe QDs. The experimental results showed that Se-Met at 40-140 µg L-1 could enhance the function of intracellular antioxidant defense system and the molecular structure of related antioxidant enzymes by reduce the production of ROS by 45%, protecting the activity of antioxidants and up-regulating the expression of selenoproteins with antioxidant functions, Gpx1 increase 225% and Gpx4 upregulated 47%. In addition, Se-Met could alleviate CdTe QDs-induced apoptosis by regulating two apoptosis-inducing factors, as intracellular caspase 3/9 expression levels were reduced by 70% and 87%, decreased Ca2+ concentration, and increased mitochondrial membrane potential measurements. Overall, this study indicates that Se-Met has a significant protective effect on the hepatotoxicity of CdTe QDs. Se-Met can be applied to the preparation of CdTe QDs to inhibit its toxicity and break the application limitation.
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Compostos de Cádmio , Doença Hepática Induzida por Substâncias e Drogas , Pontos Quânticos , Selênio , Humanos , Selênio/farmacologia , Pontos Quânticos/toxicidade , Cádmio/toxicidade , Antioxidantes/farmacologia , Compostos de Cádmio/toxicidade , Telúrio/toxicidade , Oxirredução , ApoptoseRESUMO
Background: Implantation of the MitraClip is a safe and effective therapy for mitral valve repair in patients ineligible for surgery or at high risk of adverse surgical outcomes. However, only limited information is available concerning sex differences in transcatheter mitral valve repair. We therefore sought to conduct a comprehensive meta-analysis of studies that investigated differences between men and women in outcomes following MitraClip implantation. Methods: The PubMed and Embase databases were searched until November 2019 for studies reporting outcomes after MitraClip implantation in women versus men. Outcomes included all-cause mortality and major complications at 30 days and one year of follow-up. Results: Six studies (n = 1,109 women; n = 1,743 men) were analyzed. At 30 days, women had a similar risk of postoperative complications, such as stroke, major bleeding, and pericardium effusion, without differences in all-cause mortality, procedure success, or MitraClip usage. At one year, the all-cause mortality, the reduction of mitral regurgitation, and the risk of rehospitalization for heart failure were also comparable between male and female patients. Conclusion: Gender disparity was not found in complications or prognosis of patients undergoing MitraClip implantation. This study suggests that gender should not be considered as a critical factor in the selection of patients as candidates for MitraClip implantation of concern during follow-up.
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Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Mitral , Valva Mitral , Cateterismo Cardíaco/instrumentação , Cateterismo Cardíaco/métodos , Feminino , Próteses Valvulares Cardíacas , Implante de Prótese de Valva Cardíaca/instrumentação , Implante de Prótese de Valva Cardíaca/métodos , Humanos , Masculino , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/cirurgia , Fatores Sexuais , Resultado do TratamentoRESUMO
Acute myocardial infarction is characterized by ischaemia-induced cardiomyocyte apoptosis, in which the endoplasmic reticulum (ER) stress plays an important role. The fatty acid-binding protein-4 (FABP4) has been implicated in regulating ER stress and apoptosis. Yet, whether FABP4 is involved in modulating cardiomyocyte apoptosis remains unclarified. By applying an in vitro model of hypoxia-induced apoptosis of H9c2 cardiomyocytes, we found that FABP4 expression was elevated upon hypoxia stimulation, which was further demonstrated to be transcriptionally activated by the hypoxia-inducible factor 1a (HIF-1α). In addition, the pharmacological inhibition of FABP4 with BMS309403 protected against hypoxia-induced apoptosis in cardiomyocytes, indicating that FABP4 induction is detrimental for cardiomyocyte survival under hypoxic condition. Moreover, BMS309403 attenuated ER stress in cardiomyocytes exposed to hypoxia, which, however, was reversed by tunicamycin, an ER stress activator. More importantly, the protective effect of BMS309403 on cardiomyocytes vanished in the presence of tunicamycin. Thus, these observations establish that FABP4 inhibitor BMS309403 reduces hypoxia-induced cardiomyocyte apoptosis through attenuating excessive ER stress, implying that FABP4 inhibition may be of clinical benefit for MI treatment.
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Apoptose , Compostos de Bifenilo/farmacologia , Citoproteção/efeitos dos fármacos , Estresse do Retículo Endoplasmático , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Miócitos Cardíacos/patologia , Pirazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ativação Transcricional/genética , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: To identify risk factors for minimally invasive surfactant administration (MISA) failure in the treatment of preterm infants with respiratory distress syndrome (RDS) and the influence of MISA failure on neonatal outcome. METHODS: A retrospective analysis was performed for the clinical data of 148 preterm infants with a gestational age of ≤32 weeks and a clinical diagnosis of RDS, who were admitted to the neonatal intensive care unit of eight tertiary hospitals in Beijing, Tianjin and Hebei Province from July 1, 2017 to December 31, 2018 and were treated with MISA (bovine pulmonary surfactant, PS). According to whether MISA failure (defined as the need for mechanical ventilation within 72 hours after MISA) was observed, the infants were divided into two groups: MISA failure group (n=16) and MISA success (n=132). A logistic regression analysis was used to investigate the risk factors for MISA failure and its influence on neonatal outcome. RESULTS: The MISA failure rate was 10.8% (16/148). The logistic regression analysis showed that a high incidence rate of grade >II RDS before PS administration, low mean arterial pressure and high pulse pressure before administration, a low dose of initial PS administration, and long injection time and operation time were the risk factors for MISA failure (OR=5.983, 1.210, 1.183, 1.055, 1.036, and 1.058 respectively, P<0.05). After the control for the above risk factors, the logistic regression analysis showed that the MISA failure group had a significantly higher incidence rate of bronchopulmonary dysplasia (BPD) (OR=8.537, P<0.05). CONCLUSIONS: A high grade of RDS, a low mean arterial pressure, and a high pulse pressure before administration are independent risk factors for MISA failure, and a low dose of initial PS administration, a long injection time, and a long operation time may increase the risk of MISA failure. MISA failure may increase the incidence rate of BPD in preterm infants.
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Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Animais , Displasia Broncopulmonar , Bovinos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , TensoativosRESUMO
This study aimed to analyze the early and mid-term outcomes of aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation.From January 2015 to March 2018, 36 patients (19 men; mean ± standard deviation [SD] age, 46.70 ± 16.60 years) underwent aortic valve replacement with bovine pericardium. The bovine pericardium was intraoperatively measured and shaped using an Ozaki template, according to the shape and size of the individual patient's aortic valve leaflets. Additional procedures were performed, including ventricular septal defect repair in 5 cases, mitral valve reconstruction in 6 cases, tricuspid valve reconstruction in 6 cases, and coronary artery bypass grafting in 3 cases.There were no perioperative deaths. One elderly patient with postoperative respiratory failure recovered after symptomatic treatment. One patient with frequent ventricular tachycardia after intraoperative cardiac re-jump underwent intra-aortic balloon counterpulsation (IABP), and the IABP device was successfully removed on the second postoperative day. Within the first 6 months of follow-up, there were no death events, no reoperation events, and no additional thromboembolic events. Follow-up echocardiography was performed for 6 months, with average left ventricular ejection fraction of 62.01 ± 3.21%, mean transvalvular pressure gradient of 11.17 ± 4.90 mmHg, and mean aortic valve velocity of 1.60 ± 0.58 m/s. Compared with the preoperative transthoracic echocardiography findings, the results at the six-month follow-up were statistically significant (P < 0.05). Mild aortic valve regurgitation occurred in 2 patients (5.56%), whereas other patients had no or only minimal aortic valve regurgitation (n = 34, 94.44%). Moderate aortic valve regurgitation occurred in one patient at 9 months after the initial operation. This was found to be due to infective endocarditis, and a biological valve was finally implanted.Aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation is feasible, and good early and mid-term results are achieved. Long-term results need to be followed up in the future.
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Insuficiência da Valva Aórtica/cirurgia , Bioprótese , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Pericárdio , Adulto , Idoso , Animais , Bovinos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Técnicas de Sutura , Resultado do TratamentoRESUMO
Degradation analysis has been widely used in reliability modeling problems of complex systems. A system with complex structure and various functions may have multiple degradation features, and any of them may be a cause of product failure. Typically, these features are not independent of each other, and the dependence of multiple degradation processes in a system cannot be ignored. Therefore, the premise of multivariate degradation modeling is to capture and measure the dependence among multiple features. To address this problem, this paper adopts copula entropy, which is a combination of the copula function and information entropy theory, to measure the dependence among different degradation processes. The copula function was employed to identify the complex dependence structure of performance features, and information entropy theory was used to quantify the degree of dependence. An engineering case was utilized to illustrate the effectiveness of the proposed method. The results show that this method is valid for the dependence measurement of multiple degradation processes.
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Beyond nigrostriatal dopaminergic system, the noradrenergic locus coeruleus (LC/NE) neurons are also degenerated in patients with Parkinson's disease (PD), the second most common neurodegenerative disorder. We previously reported that microglia-mediated neuroinflammation contributes to LC/NE neurodegeneration. The purpose of this study is aimed to test whether taurine, an endogenous amino acid, could be able to protect LC/NE neurons through inhibition of microglial activation using paraquat and maneb-induced mouse PD model. Taurine (150 mg/kg) was administrated (i.p) to mice 30 min prior to paraquat (10 mg/kg) and maneb (30 mg/kg) intoxication for consecutive 6 weeks (twice per week). The results clearly demonstrated that paraquat and maneb co-exposure resulted in loss of tyrosine hydroxylase-positive neurons in the LC in mice, which was significantly ameliorated by taurine. Mechanistically, inhibition of microglia-mediated neuroinflammation contributed to taurine-afforded neuroprotection. Taurine attenuated paraquat and maneb-induced microglial activation and M1 polarization as well as release of proinflammatory cytokines in brainstem of mice. Taurine also abrogated microglial NADPH oxidase activation and oxidative damage in paraquat and maneb-treated mice. Furthermore, inhibition of nuclear factor-κB (NF-κB) but not signal transducers and activators of transcription 1/3 (STAT1/3) signaling pathway participated in taurine-inhibited microglial activation. Collectively, taurine exerted LC/NE neuroprotection against microglia-mediated neurotoxicity. The robust neuroprotective effects of taurine suggest that taurine may be a promising candidate for potential therapy for patients suffering from PD.
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Locus Cerúleo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/prevenção & controle , Taurina/farmacologia , Animais , Locus Cerúleo/patologia , Masculino , Maneb/toxicidade , Camundongos , Microglia/patologia , NADPH Oxidases/metabolismo , Neurônios/patologia , Paraquat/toxicidade , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
BACKGROUND AND AIM OF THE STUDY: The prosthesis of choice for a tricuspid valve replacement is still unkown. This meta-analysis was undertaken to review the results of mechanical and bioprosthetic valves in the tricuspid position. METHODS: We identified all relevant studies published in the past 20 years (from January 1, 1995 to December 31, 2014) through the Embase, Current Contents, and PubMed databases. The hazard ratio and its 95% confidence limits were utilized to evaluate time-to-event related effects of surgical procedures. The Q-statistic, Index of Inconsistency test, funnel plots, and Egger's test were used to assess the degree of heterogeneity and publication bias. Random effects models were used, and study quality was also assessed. RESULTS: In our meta-analysis, 22 studies published from 1995 to 2014 were reviewed and 2630 patients and 14,694 follow-up years were analyzed. No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, and prosthetic valve failure. The respective pooled hazard ratio estimates were 0.95 (0.79 to 1.16, p = 0.62, I(2) = 29%), 1.20 (0.84 to 1.71, p = 0.33, I(2) = 0%), and 0.35 (0.06 to 2.01, p = 0.24, I(2) = 0%). A higher risk of thrombosis was found in mechanical tricuspid valve prostheses (3.86, 1.38 to 10.82, p = 0.01, I(2) = 0%). CONCLUSIONS: No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, or prosthetic valve failure, but mechanical tricuspid valve prostheses had a higher risk of thrombosis. doi: 10.1111/jocs.12730 (J Card Surg 2016;31:294-302).
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Bioprótese , Doenças das Valvas Cardíacas/cirurgia , Próteses Valvulares Cardíacas , Valva Tricúspide/cirurgia , Humanos , Desenho de PróteseRESUMO
Accelerated degradation testing (ADT) is an efficient technique for evaluating the lifetime of a highly reliable product whose underlying failure process may be traced by the degradation of the product's performance parameters with time. However, most research on ADT mainly focuses on a single performance parameter. In reality, the performance of a modern product is usually characterized by multiple parameters, and the degradation paths are usually nonlinear. To address such problems, this paper develops a new s-dependent nonlinear ADT model for products with multiple performance parameters using a general Wiener process and copulas. The general Wiener process models the nonlinear ADT data, and the dependency among different degradation measures is analyzed using the copula method. An engineering case study on a tuner's ADT data is conducted to demonstrate the effectiveness of the proposed method. The results illustrate that the proposed method is quite effective in estimating the lifetime of a product with s-dependent performance parameters.
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As a transcription factor mainly expressed in cardiovascular system, T-box 20 (TBX20) plays an important role in embryonic cardiovascular system development and adult heart function. Previous studies have identified associations of two SNPs in the T-box DNA-binding domain of TBX20 with congenital heart disease (CHD) in two Caucasian families, but the associations of TBX20 mutations underlying the more common populations with CHD remain to be uncovered. In this study, 25 unrelated Chinese Han neonates with CHD and 25 healthy children as controls were investigated for TBX20 mutations. SNP genotyping was performed by PCR-DNA sequencing. The selected SNPs were well genotyped and SNP rs3999941 was found to be strongly associated with CHD (p = 0.007). The minor allele of rs3999941 showed a high-risk factor for CHD (OR 4.24; 95 % CI 1.41-12.71). Besides, we found a new SNP site located at the 657th nucleotide of the exon 5 of TBX20 gene which may also be associated with CHD, c.657A>C. The frequency was significantly different between two groups (p = 0.011), the minor allele of SNP c.657A>C also showed a risk factor for CHD (OR 2.56; 95 % CI 1.02-6.46). These findings suggested that the TC genotype of SNP rs3999941 and AC genotype of the new SNP c.657A>C in the TBX20 gene may be risk factors for CHD and thus screening of these SNPs may have some implications in the prevention and treatment of CHD in Han Chinese children.
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Éxons , Cardiopatias Congênitas/genética , Polimorfismo de Nucleotídeo Único , Proteínas com Domínio T/genética , Alelos , China , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Mutação , Reação em Cadeia da PolimeraseRESUMO
Determination of protein-ligand binding affinity (PLA) is a key technological tool in hit discovery and lead optimization, which is critical to the drug development process. PLA can be determined directly by experimental methods, but it is time-consuming and costly. In recent years, deep learning has been widely applied to PLA prediction, the key of which lies in the comprehensive and accurate representation of proteins and ligands. In this study, we proposed a multi-modal deep learning model based on the early fusion strategy, called DeepLIP, to improve PLA prediction by integrating multi-level information, and further used it for virtual screening of extracellular signal-regulated protein kinase 2 (ERK2), an ideal target for cancer treatment. Experimental results from model evaluation showed that DeepLIP achieved superior performance compared to state-of-the-art methods on the widely used benchmark dataset. In addition, by combining previously developed machine learning models and molecular dynamics simulation, we screened three novel hits from a drug-like natural product library. These compounds not only had favorable physicochemical properties, but also bound stably to the target protein. We believe they have the potential to serve as starting molecules for the development of ERK2 inhibitors.
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Few studies focused on the roles of high glucose combined with high lipid in placental development or fetal growth. This study was designed to investigate the roles of high glucose combined with high lipid in mitochondrial dysfunction of JEG-3 cells. We determined the cellular proliferation and apoptosis, superoxide dismutase (SOD) activity, concentration of malondialdehyde (MDA), and lactic acid dehydrogenase in control group, high glucose group, high lipid group, and high glucose and high lipid group, together with the mitochondrial dysfunction, Nrf2, HO-1, SMAC, and cytochrome C (Cyt-C) expression. Significant decrease of SOD and significant elevation of MDA was seen in high glucose and high lipid group compared with the other three groups. There was significant decrease in mitochondrial SMAC and Cyt-C in high glucose group, high lipid group, and high glucose and high lipid group compared with those of control group. Nrf2 and HO-1 protein expression in high glucose combined with high lipid group showed significant decrease compared with that of high lipid group or high glucose group. We speculated that combination of high glucose and high lipid induced oxidative stress in JEG-3 cells, and Nrf2/ARE pathway may be related to this process.
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Klotho is a recently discovered protein that has positive effects on all systems of the body, for example, regulating calcium and phosphorus metabolism, protecting nerves, delaying aging and so on. Fibroblast growth factors (FGFs) are a group of polypeptides that function throughout the body by binding with cell surface FGF receptors (FGFRs). Endocrine FGFs require Klotho as a co-receptor for FGFRs. There is increasing evidence that Klotho participates in calcium and phosphorus regulation and metabolic regulation via the FGF-Klotho axis. Moreover, soluble Klotho can function as a separate hormone to regulate homeostasis on various ion channels and carrier channels on the cell surface. This review mainly explains the molecular basis of the membrane signaling mechanism of Klotho.
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Background: Studies on postoperative infection (POI) after surgery for ischemic cardiomyopathy are still lacking. This study aimed to investigate the risk factors of POI and its influence on clinical outcomes in patients undergoing ischemic cardiomyopathy surgery. Methods: The Surgical Treatment for Ischemic Heart Failure (STICH) trial randomized patients with ischemic cardiomyopathy [coronary artery disease (CAD) with left ventricular ejection fraction ≤35%] to surgical and medical therapy. In this study, a post hoc analysis of the STICH trial was performed to assess the risk factors and clinical outcomes of POI in those undergoing coronary artery bypass graft (CABG). Patients were divided according to whether POI developed during hospitalization or within 30 days from operation. Results: Of the 2,136 patients randomized, 1,460 patients undergoing CABG per-protocol was included, with a POI rate of 10.2% (149/1,460). By multivariable analysis, POI was significantly related to patients' age, body mass index, depression, chronic renal insufficiency, Duke CAD Index, and mitral valve procedure. Compared to patients without POI, patients with POI had significantly longer durations of intubation, CCU/ICU and hospital stay, and higher rates of re-operation, in-hospital death and failed discharge within 30 days postoperatively. In addition, these patients had significantly higher risks of all-cause death, cardiovascular death, heart failure death, and all-cause hospitalization during long-term follow-up. However, the influence of POI on all-cause death was mainly found during the first year after operation, and the influence was not significant for patients surviving for more than 1 year. Conclusions: POI was prevalent after surgery for ischemic cardiomyopathy and was closely related to short-term and long-term clinical outcomes, and the effect of POI mainly occurred within the first postoperative year. This study first reported and clarified the relationship between POI and long-term prognosis and the predictors for POI after surgery for ischemic cardiomyopathy worldwide, which may have certain guiding significance for clinical practice. Clinical Trial Registration: https://www.clinicaltrials.gov, identifier (NCT00023595).
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Spontaneous subarachnoid hemorrhage (SAH) is an acute neurologic emergency with poor outcomes, and mitochondrial dysfunction is known as one of the key pathological mechanisms underlying the SAH-induced early brain injury (EBI). 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate (T817MA) is a newly synthesized neurotrophic compound that has been demonstrated to exert protective effects against brain injury. Here, we investigated the effect of T817MA in neuronal injury following experimental SAH both in vitro and in vivo. Primary cultured cortical neurons were treated with oxyhemoglobin (OxyHb) to mimic SAH in vitro, and T817MA at concentrations higher than 0.1 µM reduced OxyHb-induced neuronal injury. T817MA treatment significantly inhibited lipid peroxidation, reduced neuronal apoptosis and attenuated mitochondrial fragmentation. The results of western blot showed that T817MA markedly reduced the expression of mitochondrial fission proteins, fission protein 1 (Fis-1) and dynamin-related GTPase-1 (Drp-1), but prolonged the expression of the postsynaptic protein activity-regulated cytoskeleton-associated protein (Arc). In addition, T817MA significantly increased the expression of sirtuin 1 (Sirt1), which was accompanied by preserved enzymatic of isocitrate dehydrogenase (IDH2) and superoxide dismutase (SOD). Knockdown of Sirt1 and Arc via small interfere RNA (siRNA) transfection partially prevented the T817MA-induced protection in cortical neurons. Furthermore, treatment with T817MA in vivo significantly reduced brain damage and preserved neurological function in rats. The decreased expression of Fis-1 and Drp-1, as well as the increased expression of Arc and Sirt1 were also observed in vivo. Taken together, these data indicate that the neuroprotective agent T817MA protects against SAH-induced brain injury via Sirt1- and Arc-mediated regulation of mitochondrial dynamics.
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Lesões Encefálicas , Fármacos Neuroprotetores , Hemorragia Subaracnóidea , Ratos , Animais , Ratos Sprague-Dawley , Sirtuína 1/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Dinâmica Mitocondrial , Fármacos Neuroprotetores/farmacologia , Lesões Encefálicas/patologia , ApoptoseRESUMO
Osteogenic differentiation of valve interstitial cells (VICs) directly leads to aortic valve calcification, which is a common cardiovascular disease caused by inflammation and metabolic disorder. There is still no ideal drug for its treatment and prevention. The purpose of this study was to explore the effect and molecular mechanism of cepharanthine (CEP), a natural product, on inhibiting the osteogenic differentiation of VICs. First, CCK8 assay was used to evaluate cell viability of CEP on VICs. CEP concentration of 10 µM was the effective dose with slight cytotoxicity, which was used for further study. The alizarin red staining analysis showed that CEP significantly inhibited calcium deposition caused by osteogenic medium related calcification induction. In order to explore the anti-calcification molecular mechanism of CEP, transcriptome and metabolome were synchronously used to discover the possible molecular mechanism and target of CEP. The results showed that CEP inhibited valve calcification by regulating the glycolytic pathway. The molecular docking of CEP and selected key factors in glycolysis showed significant binding energies for GLUT1 (-11.3 kcal/mol), ENO1 (-10.6 kcal/mol), PKM (-9.8 kcal/mol), HK2 (-9.2 kcal/mol), PFKM (-9.0 kcal/mol), and PFKP (-8.9 kcal/mol). The correlation analysis of RUNX2 expression and cellular lactate content showed R2 of 0.7 (p < 0.001). In conclusion, this study demonstrated that CEP inhibited osteoblastic differentiation of VICs by interfering with glycolytic metabolisms via downregulation of the production of lactate and glycolysis-associated metabolites.
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Postoperative pneumonia (POP) is prevalent in patients undergoing cardiovascular surgery, associated with poor clinical outcomes, prolonged hospital stay and increased medical costs. This article aims to clarify the incidence, risk factors, and interventions for POP after cardiovascular surgery. A comprehensive literature search was performed to identify previous reports involving POP after cardiovascular surgery. Current situation, predictors and preventive measures on the development of POP were collected and summarized. Many studies showed that POP was prevalent in various cardiovascular surgical types, and predictors varied in different studies, including advanced age, smoking, chronic lung disease, chronic kidney disease, cardiac surgery history, cardiac function, anemia, body mass index, diabetes mellitus, surgical types, cardiopulmonary bypass time, blood transfusion, duration of mechanical ventilation, repeated endotracheal intubation, and some other risk factors. At the same time, several targeted interventions have been widely reported to be effective to reduce the risk of POP and improve prognosis, including preoperative respiratory physiotherapy, oral care and subglottic secretion drainage. Through the review of the current status, risk factors and intervention measures, this article may play an important role in clinical prevention and treatment of POP after cardiovascular surgery.