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BACKGROUND: Use of sedatives and analgesics is associated with the occurrence of delirium in critically ill patients receiving mechanical ventilation. Dexmedetomidine reduces the occurrence of delirium but may cause hypotension, bradycardia, and insufficient sedation. This substudy aims to determine whether the combination of esketamine with dexmedetomidine can reduce the side effects and risk of delirium than dexmedetomidine alone in mechanically ventilated patients. METHODS: This single-center, randomized, active-controlled, superiority trial will be conducted at The First Affiliated Hospital of Nanjing Medical University. A total of 134 mechanically ventilated patients will be recruited and randomized to receive either dexmedetomidine alone or esketamine combined with dexmedetomidine, until extubation or for a maximum of 14 days. The primary outcome is the occurrence of delirium, while the second outcomes include the number of delirium-free days; subtype, severity, and duration of delirium; time to first onset of delirium; total dose of vasopressors and antipsychotics; duration of mechanical ventilation; ICU and hospital length of stay (LOS); accidental extubation, re-intubation, re-admission; and mortality in the ICU at 14 and 28 days. DISCUSSION: There is an urgent need for a new combination regimen of dexmedetomidine due to its evident side effects. The combination of esketamine and dexmedetomidine has been applied throughout the perioperative period. However, there is still a lack of evidence on the effects of this regimen on delirium in mechanically ventilated ICU patients. This substudy will evaluate the effects of the combination of esketamine and dexmedetomidine in reducing the risk of delirium for mechanically ventilated patients in ICU, thus providing evidence of this combination to improve the short-term prognosis. The study protocol has obtained approval from the Medical Ethics Committee (ID: 2022-SR-450). TRIAL REGISTRATION: ClinicalTrials.gov: NCT05466708, registered on 20 July 2022.
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Delírio , Dexmedetomidina , Quimioterapia Combinada , Hipnóticos e Sedativos , Unidades de Terapia Intensiva , Ketamina , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Humanos , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Dexmedetomidina/uso terapêutico , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/uso terapêutico , Delírio/prevenção & controle , Resultado do Tratamento , Tempo de Internação , Estado Terminal , China , Fatores de Tempo , Feminino , MasculinoRESUMO
Objective: This study evaluated the predictive value of the vasoactive-ventilation-renal (VVR) score in identifying the risk of weaning failure after cardiac surgery and developing a nomogram model to help physicians improve the success rate of weaning from mechanical ventilation in adult patients undergoing postoperative cardiac surgery. Methods: Clinical data were retrospectively collected from adult patients who underwent extracorporeal circulation cardiac surgery at the First Affiliated Hospital of Nanjing Medical University between August 2022 and April 2023 and who were subsequently transferred to the Intensive Care Unit (ICU) and treated with vasoactive drugs. Patients were divided into successful and unsuccessful weaning groups based on first-attempt weaning success. Variable selection was regularized using univariate logistic regression and Least absolute shrinkage and selection operator (LASSO) regularization. Multivariate logistic regression was performed to identify predictors and a nomogram was created to predict the risk of weaning failure. Results: A total of 519 patients were included in the study. After selecting multiple stepwise variables, the VVR score before weaning, the modified Sequential Organ Failure Assessment (mSOFA) score on weaning day, and mechanical ventilation duration before weaning were determined as predictive indicators of weaning failure in adult patients after cardiac surgery. The optimal cut-off values for these indicators were 18.46 points, 4.33 points, and 20.50â h, respectively. The predictive model constructed using these three factors demonstrated good predictive performance. Conclusions: The VVR score before weaning accurately predicts the probability of weaning failure in adult patients after cardiac surgery. The weaning risk-predictive nomogram model, established based on the VVR score, mSOFA score, and mechanical ventilation duration before weaning, demonstrated robust predictive ability.
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The Wolf Creek Conference is a seminal meeting of resuscitation researchers that has significantly influenced scientific advances and patient care in the field of cardiac arrest resuscitation over nearly half a century. Originating in 1975 at the Wolf Creek Lodge in Georgia, the conference was founded by Drs. James Elam, James Jude, and Peter Safar with the aim of improving clinical practices in cardiopulmonary resuscitation (CPR) by stimulating laboratory and clinical research. Over 17 conferences to date, the scope has broadened to encompass the growing field of resuscitation science, participation has expanded to include thought leaders and scientists from both academia and industry, and the proceedings have catalyzed numerous innovations in field. This narrative review highlights the genesis, objectives, proceedings, and impact of the Wolf Creek Conference from 1975 to the present.
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PURPOSE: To investigate the effects of the selective NLRP3 inflammasome inhibitor MCC950 on post-resuscitation myocardial function and survival in a rat model of cardiopulmonary resuscitation (CPR). METHODS: Thirty-six Sprague Dawley rats were randomized into three groups: (1) MCC950, (2) control, and (3) sham. Each group consisted of a 6 h non-survival subgroup (n = 6) and a 48 h survival subgroup (n = 6). Ventricular fibrillation (VF) was induced and untreated for 6 min. CPR was initiated and continued for 8 min. Resuscitation was attempted with a 4 J defibrillation. MCC950 (10 mg/kg) or vehicle was administered via intraperitoneal injection immediately after the return of spontaneous circulation (ROSC). Myocardial function and sublingual microcirculation were measured after ROSC in the non-survival subgroups. Plasma levels of interleukin Iß (IL-1ß) and cardiac troponin I (cTnI) were measured at baseline and 6 h in the non-survival subgroups. Heart tissue was harvested to measure the NLRP3 inflammasome constituents, including NLRP3, apoptosis-associated speck-like protein (ASC), Caspase-1, and IL-1ß. Survival duration and neurologic deficit score (NDS) were recorded and evaluated among survival groups. RESULTS: Post-resuscitation myocardial function and sublingual microcirculation were improved in MCC950 compared with control (p < 0.05). IL-1ß and cTnI were decreased in MCC950 compared to control (p < 0.01). The MCC950 treated groups showed significantly reduced ASC, caspase-1, and IL-1ß compared with the control group (p < 0.05). Survival at 48 h after ROSC was greater in MCC950 (p < 0.05) with improved NDS (p < 0.05). CONCLUSION: Administration of MCC950 following ROSC mitigates post-resuscitation myocardial dysfunction and improves survival.
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Cardiomiopatias , Reanimação Cardiopulmonar , Parada Cardíaca , Ratos , Animais , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Parada Cardíaca/terapia , Sulfonamidas/farmacologia , Caspases , Modelos Animais de DoençasRESUMO
ABSTRACT: Aims: A rapid heart rate (HR) that occurs after cardiopulmonary resuscitation (CPR) is a short-term compensatory mechanism preserving cardiac output. However, if of long duration, it is unfavorable for myocardial function postresuscitation because of disrupted balance between myocardial oxygen supply and demand. This raises the assumption that such a sustained fast HR should be regulated. The present study aimed to investigate the follow-on effect of ivabradine (a specific inhibitor of the I f current of the sinoatrial node)-induced HR reduction (HRR) on postresuscitation myocardial function in a rat model of CPR. Methods and results: Six minutes of ventricular fibrillation and 8 min of CPR were performed on Sprague-Dawley rats. All 32 resuscitated animals were then randomized into saline and ivabradine groups, each group having nonsurvival and survival subgroups (n = 8 each). Saline or ivabradine (0.5 mL/kg) was administered at 1 h postresuscitation. Heart rate, myocardial function as expressed by cardiac output, ejection fraction, and myocardial performance index were assessed at baseline and hourly from 1 to 5 h postresuscitation. Heart rate variability was analyzed at baseline and at 1, 3, and 5 h postresuscitation. Serum epinephrine and cardiac troponin I at baseline and at 1, 3, and 5 h postresuscitation in nonsurvival subgroup were measured. Survival duration in the survival subgroup was observed. The baseline HR was approximately 390 beats/min (bpm). After resuscitation, an average increase of Δ ≈ +15 bpm (relative ratio ≈ +3.8%) with a resultant HR of 405 bpm lasting more than 5 h occurred. Ivabradine group achieved a steady HRR of Δ ≈ -30 bpm (relative ratio ≈ -7.4%) as compared with saline group ( P < 0.01). Postresuscitation myocardial function was significantly worse in the ivabradine group (all P < 0.01). Heart rate variability was significantly impaired in the ivabradine group (all P < 0.05). Serum cardiac troponin I and epinephrine concentration were significantly higher in the ivabradine group (all P < ?0.01). Survival duration was significantly shortened in the ivabradine group as compared with the saline group (388 vs. 526 min, P < ?0.01). Conclusions: Ivabradine-induced HRR increases the severity of postresuscitation myocardial dysfunction and shortens survival duration in a rat model of CPR.
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Cardiomiopatias , Reanimação Cardiopulmonar , Animais , Ratos , Reanimação Cardiopulmonar/métodos , Ivabradina/uso terapêutico , Frequência Cardíaca , Troponina I , Ratos Sprague-Dawley , EpinefrinaRESUMO
Post-resuscitation cerebral ischemia-reperfusion injury (IRI) is a vital contributor to poor neurological prognosis. Exploring novel therapeutics that attenuate cerebral IRI is of great significance. Inflammation plays a role in the development of cerebral IRI after successful cardiopulmonary resuscitation (CPR). Monoacylglycerol lipase (MAGL) is an enzyme that is predominantly responsible for the metabolism of endocannabinoid 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) metabolites, which are associated with inflammation. Therefore, we investigated the efficacy of the MAGL inhibitor, JZL184, on cerebral IRI and further compared the effects to therapeutic hypothermia (TH). Thirty-six rats were randomized into three groups: 1) JZL184; 2) Control; 3) TH (N = 12 for each group). Animals underwent 6 min of ventricular fibrillation (VF) followed with 8 min of CPR. After return of spontaneous circulation (ROSC), rats received an intraperitoneal injection of JZL184 (16 mg/kg) or DMSO (20 mg/ml) or body cooling was initiated. Cerebral microcirculation, brain edema, blood brain barrier (BBB) permeability, serum neuron-specific enolase (NSE), S-100ß, interleukin-6 (IL-6) and interleukin-10 (IL-10) were quantified at 6 h post ROSC. Compared to control, treatment with JZL184 or TH was associated with significantly ameliorated cerebral microcirculation, mitigated brain edema, attenuated BBB permeability, decreased serum levels of NSE, S-100ß and IL-6, and increased serum IL-10 levels (p < 0.05). There was no significant difference in the above measurements between JZL184 and TH. JZL184 has comparable neuroprotective effects to therapeutic hypothermia on global cerebral IRI in a rat model of cardiac arrest (CA).
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Edema Encefálico , Reanimação Cardiopulmonar , Parada Cardíaca , Hipotermia Induzida , Ratos , Animais , Monoacilglicerol Lipases , Interleucina-10/metabolismo , Monoglicerídeos , Edema Encefálico/tratamento farmacológico , Edema Encefálico/complicações , Interleucina-6/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100 , Parada Cardíaca/complicações , Parada Cardíaca/tratamento farmacológico , Inflamação/complicaçõesRESUMO
Background: Previous studies have demonstrated that inflammation and impaired microcirculation are key factors in post-resuscitation syndromes. Here, we investigated whether methylprednisolone (MP) could improve myocardial function and microcirculation by suppressing the systemic inflammatory response following cardiopulmonary resuscitation (CPR) in a rat model of cardiac arrest (CA). Methods: Sprague-Dawley rats were randomly assigned to (1) sham, (2) control, and (3) drug groups. Ventricular fibrillation was induced and then followed by CPR. The rats were infused with either MP or vehicle at the start of CPR. Myocardial function and microcirculation were assessed at baseline and after the restoration of spontaneous circulation. Blood samples were drawn at baseline and 60-min post-resuscitation to assess serum cytokine (TNF-α, IL-1ß, and IL-6) levels. Results: Myocardial function [estimated by the ejection fraction (EF), myocardial performance index (MPI), and cardiac output (CO)] improved post-ROSC in the MP group compared with those in the control group (p < 0.05). MP decreased the levels of the aforementioned pro-inflammatory cytokines and alleviated cerebral, sublingual, and intestinal microcirculation compared with the control (p < 0.05). A negative correlation emerged between the cytokine profile and microcirculatory blood flow. Conclusion: MP treatment reduced post-resuscitation myocardial dysfunction, inhibited pro-inflammatory cytokines, and improved microcirculation in the initial recovery phase in a CA and resuscitation animal model. Therefore, MP could be a potential clinical target for CA patients in the early phase after CPR to alleviate myocardial dysfunction and improve prognosis.
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The systemic inflammatory response following global myocardial ischemia/reperfusion (I/R) injury is a critical driver of poor outcomes. Both pyroptosis and necroptosis are involved in the systemic inflammatory response and contribute to regional myocardial I/R injury. This study aimed to explore the effect of necrosulfonamide (NSA) on post-resuscitation myocardial dysfunction in a rat model of cardiac arrest. Sprague-Dawley rats were randomly categorized to Sham, CPR and CPR-NSA groups. For rats in the latter two groups, ventricular fibrillation was induced without treatment for 6 min, with cardiopulmonary resuscitation (CPR) being sustained for 8 min. Rats were injected with NSA (10 mg/kg in DMSO) or vehicle at 5 min following return of spontaneous circulation. Myocardial function was measured by echocardiography, survival and neurological deficit score (NDS) were recorded at 24, 48, and 72 h after ROSC. Western blotting was used to assess pyroptosis- and necroptosis-related protein expression. ELISAs were used to measure levels of inflammatory cytokine. Rats in the CPR-NSA group were found to exhibit superior post-resuscitation myocardial function, and better NDS values in the group of CPR-NSA. Rats in the group of CPR-NSA exhibited median survival duration of 68 ± 8 h as compared to 34 ± 21 h in the CPR group. After treatment with NSA, NOD-like receptor 3 (NLRP3), GSDMD-N, phosphorylated-MLKL, and phosphorylated-RIP3 levels in cardiac tissue were reduced with corresponding reductions in inflammatory cytokine levels. Administration of NSA significantly improved myocardial dysfunction succeeding global myocardial I/R injury and enhanced survival outcomes through protective mechanisms potentially related to inhibition of pyroptosis and necroptosis pathways.
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Acrilamidas , Cardiomiopatias , Reanimação Cardiopulmonar , Parada Cardíaca , Necroptose , Piroptose , Sulfonamidas , Acrilamidas/farmacologia , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Citocinas , Modelos Animais de Doenças , Parada Cardíaca/complicações , Parada Cardíaca/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Necroptose/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Síndrome de Resposta Inflamatória SistêmicaRESUMO
Background Post-resuscitation syndrome, involves a severe inflammatory response following successful cardiopulmonary resuscitation. The potential mechanism of Vitamin C (VitC) after cardiopulmonary resuscitation on myocardial and cerebral function, duration of survival is undefined. Methods and Results A first set of experiments were done in 18 male Sprague-Dawley rats for the investigation of short-term follow-up, randomized into 3 groups: (1) sham; (2) controls; (3) VitC. Ventricular fibrillation was electrically induced and untreated for 6 minutes. Cardiopulmonary resuscitation including chest compression and mechanical ventilation were then initiated and continued for 8 minutes followed by defibrillation. At 5 minutes after return of spontaneous circulation, either VitC (200 mg/kg) or placebo was administered by intravenous infusion with a syringe pump for half an hour. There were significant improvements in myocardial function and buccal microcirculation in rats treated with VitC after return of spontaneous circulation 4 hours compared with controls. VitC inhibited proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α), SDC-1 (Syndecan-1), and hyaluronic acid in plasma compared with controls (P<0.01). VitC decreased reactive oxygen species production and inhibited p38/MAPK (mitogen-activated protein kinase) pathway phosphorylation. A second set with 20 animals was used for assessing the neurological deficit score after return of spontaneous circulation 72 hours, randomized into 2 groups: 1) controls; 2) VitC. The survival rate and neurological deficit score after return of spontaneous circulation 72 hours were improved in VitC-treated animals compared with those of the control group. Conclusions VitC reduces the severity of post-resuscitation myocardial and cerebral dysfunction and improves the survival. The mechanisms may involve inhibiting transcription of inflammatory cytokines and oxidative stress, thus protecting the integrity of the vascular endothelium. Meanwhile VitC reduces shedding of SDC-1 and alters p38/MAPK phosphorylation and microcirculation.
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Reanimação Cardiopulmonar , Parada Cardíaca , Animais , Ácido Ascórbico/farmacologia , Reanimação Cardiopulmonar/métodos , Modelos Animais de Doenças , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Sindecana-1/uso terapêutico , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The aim of this study was to use dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted magnetic resonance imaging (DWI) to measure changes in blood-brain barrier (BBB) permeability and cerebral edema over time in a rat model of asphyxial cardiac arrest (ACA). ACA was established by endotracheal tube clamping. Male rats were randomized into a sham group (n = 5) and three ACA groups (n = 18). After return of spontaneous circulation (ROSC), the rats were randomized to perform DWI and DCE-MRI exam in the 6 h, 24 h and 72 h timepoint (ROSC + 6 h, ROSC + 24 h, and ROSC + 72 h). Results shows that fifteen of 18 animals achieved successful resuscitation in the ACA groups. The average apparent diffusion coefficient(ADC) value of the whole brain in ROSC + 6 h was markedly lower than those of the sham, ROSC + 24 h, and ROSC + 72 h. The aquaporin-4(AQP4) score in ROSC + 6 h was significantly higher than those in the other groups, which were negatively correlated with the ADC values. The ratio of whole brain to masseter muscle of volume transfer constant (rKtrans), tissue interstitium-to-plasma rate constant(rKep), and fractional extra-cellular space volume(rVe) in ROSC + 6 h were all significantly higher than those in the sham, ROSC + 24 h, and ROSC + 72 h. The transforming growth factor ß1(TGF-ß1) and vascular endothelial growth factor A(VEGF-a) scores in ROSC + 6 h were significantly higher than those in the other groups, which were all positively correlated with rKtrans and rKep. In conclusions, brain injury is a frequent complication after CA and resuscitation. DWI and DCE-MRI can quantitatively evaluate brain injury in term of cerebral edema and BBB permeability after successful CPR.
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Lesões Encefálicas , Reanimação Cardiopulmonar , Parada Cardíaca , Animais , Asfixia , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/etiologia , Modelos Animais de Doenças , Parada Cardíaca/diagnóstico por imagem , Parada Cardíaca/terapia , Imageamento por Ressonância Magnética , Masculino , Ratos , Fator A de Crescimento do Endotélio VascularRESUMO
OBJECTIVES: To investigate the therapeutic potential and underlying mechanisms of exogenous nicotinamide adenine dinucleotide+ on postresuscitation myocardial and neurologic dysfunction in a rat model of cardiac arrest. DESIGN: Thirty-eight rats were randomized into three groups: 1) Sham, 2) Control, and 3) NAD. Except for the sham group, untreated ventricular fibrillation for 6 minutes followed by cardiopulmonary resuscitation was performed in the control and NAD groups. Nicotinamide adenine dinucleotide+ (20 mg/kg) was IV administered at the onset of return of spontaneous circulation. SETTING: University-affiliated research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Nicotinamide adenine dinucleotide+. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and myocardial function were measured at baseline and within 4 hours following return of spontaneous circulation. Survival analysis and Neurologic Deficit Score were performed up to 72 hours after return of spontaneous circulation. Adenosine triphosphate (adenosine triphosphate) level was measured in both brain and heart tissue. Mitochondrial respiratory chain function, acetylation level, and expression of Sirtuin3 and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9 (NDUFA9) in isolated mitochondrial protein from both brain and heart tissue were evaluated at 4 hours following return of spontaneous circulation. The results demonstrated that nicotinamide adenine dinucleotide+ treatment improved mean arterial pressure (at 1 hr following return of spontaneous circulation, 94.69 ± 4.25 mm Hg vs 89.57 ± 7.71 mm Hg; p < 0.05), ejection fraction (at 1 hr following return of spontaneous circulation, 62.67% ± 6.71% vs 52.96% ± 9.37%; p < 0.05), Neurologic Deficit Score (at 24 hr following return of spontaneous circulation, 449.50 ± 82.58 vs 339.50 ± 90.66; p < 0.05), and survival rate compared with that of the control group. The adenosine triphosphate level and complex I respiratory were significantly restored in the NAD group compared with those of the control group. In addition, nicotinamide adenine dinucleotide+ treatment activated the Sirtuin3 pathway, down-regulating acetylated-NDUFA9 in the isolated mitochondria protein. CONCLUSIONS: Exogenous nicotinamide adenine dinucleotide+ treatment attenuated postresuscitation myocardial and neurologic dysfunction. The responsible mechanisms may involve the preservation of mitochondrial complex I respiratory capacity and adenosine triphosphate production, which involves the Sirtuin3-NDUFA9 deacetylation.
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Parada Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , NAD/farmacologia , Doenças do Sistema Nervoso/tratamento farmacológico , Ressuscitação/normas , Animais , Modelos Animais de Doenças , Parada Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , NAD/uso terapêutico , Doenças do Sistema Nervoso/prevenção & controle , Ratos , Ratos Sprague-Dawley/lesões , Ratos Sprague-Dawley/metabolismo , Ressuscitação/métodos , Ressuscitação/estatística & dados numéricosRESUMO
ABSTRACT: Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation myocardial dysfunction (PRMD). Here, we evaluated the therapeutic performance of ferroptosis inhibitors (UAMC-3203âor/and Deferoxamine) on the PRMD in a rat model of cardiac arrest and surveyed the changes of essential ferroptosis markers in the myocardium. Remarkably, all treatments reduce the severity of cardiac dysfunction and microcirculation hypoperfusion after resuscitation compared with control. Consistently, we observe that the ferroptosis marker Glutathione peroxidase 4, 4-hydroxynonenal and non-heme iron altered (1â±â0.060 vs. 0.021â±â0.016, 1â±â0.145 vs. 3.338â±â0.221, 52.010â±â3.587âug/g vs. 70.500â±â3.158âug/g, all Pâ<â0.05) in the myocardium after resuscitation. These changes were significantly suppressed by UAMC-3203 [(0.187â±â0.043, 2.848â±â0.169, all Pâ<â0.05), (72.43â±â4.920âug/g, Pâ >â0.05)], or Deferoxamine (0.203â±â0.025, 2.683â±â0.273, 55.95â±â2.497âug/g, all Pâ<â0.05). Briefly, UAMC-3203âor/and Deferoxamine improve post-resuscitation myocardial dysfunction and provide evidence of ferroptosis involvement, suggesting that ferroptosis inhibitors could potentially provide an innovative therapeutic approach for mitigating the myocardial damage caused by cardiopulmonary resuscitation.
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Reanimação Cardiopulmonar/efeitos adversos , Desferroxamina/uso terapêutico , Ferroptose/efeitos dos fármacos , Parada Cardíaca/terapia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Sideróforos/uso terapêutico , Animais , Cicloexilaminas/agonistas , Modelos Animais de Doenças , Masculino , Fenilenodiaminas/agonistas , Ratos , Ratos Sprague-DawleyRESUMO
According to statistics 2020, female breast cancer (BRCA) became the most commonly diagnosed malignancy worldwide. Prognosis of BRCA patients is still poor, especially in population with advanced or metastatic. Particular functions of each members of the solute carrier 35A (SLC35A) gene family in human BRCA are still unknown regardless of awareness that they play critical roles in tumorigenesis and progression. Using integrated bioinformatics analyses to identify therapeutic targets for specific cancers based on transcriptomics, proteomics, and high-throughput sequencing, we obtained new information and a better understanding of potential underlying molecular mechanisms. Leveraging BRCA dataset that belongs to The Cancer Genome Atlas (TCGA), which were employed to clarify SLC35A gene expression levels. Then we used a bioinformatics approach to investigate biological processes connected to SLC35A family genes in BRCA development. Beside that, the Kaplan-Meier estimator was leveraged to explore predictive values of SLC35A family genes in BCRA patients. Among individuals of this family gene, expression levels of SLC35A2 were substantially related to poor prognostic values, result from a hazard ratio of 1.3 (with 95 percent confidence interval (95% CI: 1.18-1.44), the p for trend (ptrend) is 3.1 × 10-7). Furthermore, a functional enrichment analysis showed that SLC35A2 was correlated with hypoxia-inducible factor 1A (HIF1A), heat shock protein (HSP), E2 transcription factor (E2F), DNA damage, and cell cycle-related signaling. Infiltration levels observed in specific types of immune cell, especially the cluster of differentiation found on macrophages and neutrophils, were positively linked with SLC35A2 expression in multiple BRCA subclasses (luminal A, luminal B, basal, and human epidermal growth factor receptor 2). Collectively, SLC35A2 expression was associated with a lower recurrence-free survival rate, suggesting that it could be used as a biomarker in treating BRCA.
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BACKGROUND: Current guidelines recommend a 50 mm or greater compression depth for manual chest compression in adults. However, whether this uniform compression depth is a suitable requirement for mechanical CPR remains to be determined. We hypothesized that a relatively shallow compression depth (30 mm) would have similar hemodynamic efficacy but fewer complications versus the standard compression depth (50 mm) during mechanical cardiopulmonary resuscitation (CPR) with the miniaturized chest compressor (MCC) in a porcine model. METHODS: In the current study, we used a total of 16 domestic male pigs (38±2 kg). All pigs were exposed to 7 min of ventricular fibrillation (VF) followed by 5 min of CPR. Then the animals were randomly assigned to the shallow (30 mm) group and the standard (50 mm) group. At the second min of CPR, every pig was given epinephrine (20 µg/kg) through the femoral vein and repeated every 3 min. First defibrillation was delivered with a single 120 J shock at 5 min of CPR. Hemodynamics, carotid blood flow (CBF), end-tidal carbon dioxide (ETCO2), coronary perfusion pressure (CPP), intrathoracic pressure (ITP) and arterial blood gas were measured. Rib fractures and lung injuries, as indicated by ground-glass opacification (GGO), as well as intense parenchymal opacification (IPO), were assessed and calculated by quantitative computed tomography (QCT) scan. RESULTS: We found no significant differences in CPP, CBF, or ETCO2 between the both groups throughout the CPR period. After administration of epinephrine, the CPP of all animals increased while ETCO2 and CBF decreased during CPR. A significantly lower intrathoracic positive pressure (ITPP) and systolic artery pressure (SAP) were measured in the shallow group at the first min of CPR. However, we didn't find remarkable differences in these values between the both groups for the next 4 min of CPR. All animals were successfully resuscitated. The shallow group had significantly lower IPO QCT scores compared with the standard group. We found no significant differences in GGO QCT scores after resuscitation between both groups. CONCLUSIONS: Relatively shallow compression depth has similar hemodynamic efficacy but fewer complications versus the standard compression depth.
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Colorectal cancer (CRC) is a heterogeneous disease with changes in the genetic and epigenetic levels of various genes. The molecular assessment of CRC is gaining increasing attention, and furthermore, there is an increase in biomarker use for disease prognostication. Therefore, the identification of different gene biomarkers through messenger RNA (mRNA) abundance levels may be useful for capturing the complex effects of CRC. In this study, we demonstrate that the high mRNA levels of 10 upregulated genes (DPEP1, KRT80, FABP6, NKD2, FOXQ1, CEMIP, ETV4, TESC, FUT1, and GAS2) are observed in CRC cell lines and public CRC datasets. Moreover, we find that a high mRNA expression of DPEP1, NKD2, CEMIP, ETV4, TESC, or FUT1 is significantly correlated with a worse prognosis in CRC patients. Further investigation reveals that CTNNB1 is the key factor in the interaction of the canonical Wnt signaling pathway with 10 upregulated CRC-associated genes. In particular, we identify NKD2, FOXQ1, and CEMIP as three CTNNB1-regulated genes. Moreover, individual inhibition of the expression of three CTNNB1-regulated genes can cause the growth inhibition of CRC cells. This study reveals efficient biomarkers for the prognosis of CRC and provides a new molecular interaction network for CRC.
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The development and progression of colorectal cancer (CRC) involve changes in genetic and epigenetic levels of oncogenes and/or tumor suppressors. In spite of advances in understanding of the molecular mechanisms involved in CRC, the overall survival rate of CRC still remains relatively low. Thus, more research is needed to discover and investigate effective biomarkers and targets for diagnosing and treating CRC. The roles of long non-coding RNAs (lncRNAs) participating in various aspects of cell biology have been investigated and potentially contribute to tumor development. Our recent study also showed that CRNDE was among the top 20 upregulated genes in CRC clinical tissues compared to normal colorectal tissues by analyzing a Gene Expression Omnibus (GEO) dataset (GSE21815). Although CRNDE is widely reported to be associated with different types of cancer, most studies of CRNDE were limited to examining regulation of its transcription levels, and in-depth mechanistic research is lacking. In the present study, CRNDE was found to be significantly upregulated in CRC patients at an advanced TNM stage, and its high expression was correlated with poor outcomes of CRC patients. In addition, we found that knocking down CRNDE could reduce lipid accumulation through the miR-29b-3p/ANGPTL4 axis and consequently induce autophagy of CRC cells.
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Cardiac arrest (CA) remains a major public health issue. Inflammatory responses with overproduction of interleukin-1ß regulated by NLRP3 inflammasome activation play a crucial role in cerebral ischemia/reperfusion injury. We investigated the effects of the selective NLRP3-inflammasome inhibitor MCC950 on post-resuscitation cerebral function and neurologic outcome in a rat model of cardiac arrest. Thirty-six male rats were randomized into the MCC950 group, the control group, or the sham group (N = 12 of each group). Each group was divided into a 6 h non-survival subgroup (N = 6) and a 24 h survival subgroup (N = 6). Ventricular fibrillation (VF) was electrically induced and untreated for 6 min, followed by 8 min of precordial compressions and mechanical ventilation. Resuscitation was attempted with a 4J defibrillation. Either MCC950 (10 mg/kg) or vehicle was injected intraperitoneally immediately after the return of spontaneous circulation (ROSC). Rats in the sham group underwent the same surgical procedures without VF and CPR. Brain edema, cerebral microcirculation, plasma interleukin Iß (IL-1ß), and neuron-specific enolase (NSE) concentration were measured at 6 h post-ROSC of non-survival subgroups, while 24 h survival rate, neurological deficits were measured at 24 h post-ROSC of survival subgroups. Post-resuscitation brain edema was significantly reduced in animals treated with MCC950 (p < 0.05). Cerebral perfused vessel density (PVD) and microcirculatory flow index (MFI) values were significantly higher in the MCC950 group compared with the control group (p < 0.05). The plasma concentrations of IL-1ß and NSE were significantly decreased in animals treated with MCC950 compared with the control group (p < 0.05). 24 h-survival rate and neurological deficits score (NDS) was also significantly improved in the MCC950 group compared with the control group (p < 0.05). NLRP3 inflammasome blockade with MCC950 at ROSC reduces the circulatory level of IL-1ß, preserves cerebral microcirculation, mitigates cerebral edema, improves the 24 h-survival rate, and neurological deficits.
Assuntos
Anti-Inflamatórios/farmacologia , Edema Encefálico/prevenção & controle , Encéfalo/efeitos dos fármacos , Reanimação Cardiopulmonar/efeitos adversos , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Microcirculação/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
The physiology and physiopathology process of mitochondrial function following cardiac arrest remains poorly understood. We aimed to assess mitochondrial respiratory function on the heart and brain homogenates from cardiac arrest rats. The expression level of SIRT1/PGC-1α pathway was measured by immunoblotting. 30 rats were assigned to the CA group and the sham group. Rats of CA were subjected to 6 min of untreated ventricular fibrillation (VF) followed by 8 min of cardiopulmonary resuscitation (CPR). Mitochondrial respiratory function was compromised following CA and I/R injury, as indicated by CIL (451.46 ± 71.48 vs. 909.91 ± 5.51 pmol/min*mg for the heart and 464.14 ± 8.22 vs. 570.53 ± 56.33 pmol/min*mg for the brain), CI (564.04 ± 64.34 vs. 2729.52 ± 347.39 pmol/min*mg for the heart and 726.07 ± 85.78 vs. 1762.82 ± 262.04 pmol/min*mg for the brain), RCR (1.88 ± 0.46 vs. 3.57 ± 0.38 for the heart and 2.05 ± 0.19 vs. 3.49 ± 0.19, for the brain) and OXPHOS coupling efficiency (0.45 ± 0.11 vs. 0.72 ± 0.03 for the heart and 0.52 ± 0.05 vs. 0.71 ± 0.01 for the brain). However, routine respiration was lower in the heart and comparable in the brain after CA. CIV did not change in the heart but was enhanced in the brain. Furthermore, both SIRT1 and PGC-1α were downregulated concurrently in the heart and brain. The mitochondrial respiratory function was compromised following CA and I/R injury, and the major affected respiratory state is complex I-linked respiration. Furthermore, the heart and the brain respond differently to the global I/R injury after CA in mitochondrial respiratory function. Inhibition of the SIRT1/PGC-1α pathway may be a major contributor to the impaired mitochondrial respiratory function.
Assuntos
Encéfalo/metabolismo , Reanimação Cardiopulmonar , Parada Cardíaca/metabolismo , Parada Cardíaca/fisiopatologia , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Animais , Análise da Demanda Biológica de Oxigênio , Modelos Animais de Doenças , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/antagonistas & inibidores , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Respiração , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Espirometria , Fibrilação Ventricular/metabolismoRESUMO
Brain mitochondria are more sensitive to global ischemia compared to heart mitochondria. Complex I in the electron transport chain (ETC) is sensitive to ischemic injury and is a major control point of the rate of ADP stimulated oxygen consumption. The purpose of this study was to explore whether changes in cerebral and myocardial mitochondria differ after cardiac arrest. Animals were randomized into 4 groups (nâ¯=â¯6): 1) Sham 2) VF 3) VF+CPR 4) ROSC 1hr. Ventricular Fibrillation (VF) was induced through a guide wire advanced from the right jugular vein into the ventricle and untreated for 8â¯min. Resuscitation was attempted with a 4J defibrillation after 8â¯min of cardiopulmonary resuscitation (CPR). Brain mitochondria and cardiac mitochondrial subpopulations were isolated. Calcium retention capacity was measured to assess susceptibility to mitochondrial permeability transition pore opening. ADP stimulated oxygen consumption and ETC activity assays were performed. Brain mitochondria are far more sensitive to injury during cardiac arrest and resuscitation compared to cardiac mitochondria. Complex I is highly sensitive to injury in brain mitochondria. With markedly decreased calcium retention capacity, mitochondria contribute to cerebral reperfusion injury. Therapeutic preservation of cerebral mitochondrial activity and mitochondrial function during cardiac arrest may improve post-resuscitation neurologic function.
Assuntos
Encéfalo/metabolismo , Reanimação Cardiopulmonar , Parada Cardíaca/metabolismo , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Difosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Parada Cardíaca/terapia , Masculino , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Consumo de Oxigênio , Ratos Sprague-DawleyRESUMO
Out-of-hospital cardiac arrest (CA) is a leading cause of death in the United States. Severe post-resuscitation cerebral dysfunction is a primary cause of poor outcome. Therefore, we investigate the effects of polyethylene glycol-20k (PEG-20k), a cell impermeant, on post-resuscitation cerebral function. Thirty-two male Sprague-Dawley rats were randomized into four groups: 1) Control; 2) PEG-20k; 3) Sham control; 4) Sham with PEG-20k. To investigate blood brain barrier (BBB) permeability, ten additional rats were randomized into two groups: 1) CPR+Evans Blue (EB); 2) Sham+EB. Ventricular fibrillation was induced and untreated for 8â¯min, followed by 8â¯min of CPR, and resuscitation was attempted by defibrillation. Cerebral microcirculation was visualized at baseline, 2, 4 and 6â¯h after return of spontaneous circulation (ROSC). Brain edema was assessed by comparing wet-to-dry weight ratios after 6â¯h. S-100ß, NSE and EB concentrations were analyzed to determine BBB permeability damage. For results, Post-resuscitation cerebral microcirculation was impaired compared to baseline and sham control (pâ¯<â¯0.05). However, dysfunction was reduced in animals treated with PEG-20k compared to control (pâ¯<â¯0.05). Post-resuscitation cerebral edema as measured by wet-to-dry weight ratio was lower in PEG-20k compared to control (3.23⯱â¯0.5 vs. 3.36⯱â¯0.4, pâ¯<â¯0.05). CA and CPR increased BBB permeability and damaged neuronal cell with associated elevation of S-100ß sand NSE serum levels. PEG-20k administered during CPR improved cerebral microcirculation and reducing brain edema and injury.