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Micro-RNA125b (miR-125b) and tumor protein p53 (p53) are involved in the regulation of mitochondrial dynamics; however, the mechanism of their possible interaction during oxidative stress remains unclear. In this study, we investigated the role and mechanism of miR-125b and p53 in oxidative stress-induced mitochondrial damage in immortalized mouse hippocampal HT22 cells. Following stimulation with H2O2, we observed downregulation of miR-125b expression, upregulation of p53 expression, mitochondria were damaged and increased cell death. Overexpression of miR-125b alleviated mitochondrial damage and inhibited p53 expression. Furthermore, confocal and electron microscopy showed that overexpression of p53 eliminated the protective effect of miR-125b on the mitochondria. Thus, miR-125b alleviates abnormal mitochondrial homeostasis in H2O2-treated HT22 cells by suppressing p53 expression. Our data reveal a new model by which miR-125b influences mitochondrial dynamics.
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Peróxido de Hidrogênio/toxicidade , MicroRNAs/biossíntese , Dinâmica Mitocondrial/fisiologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Camundongos , MicroRNAs/genética , Dinâmica Mitocondrial/efeitos dos fármacosRESUMO
PURPOSE: The primary objective was to demonstrate the relationship between lung ultrasound (LUS) manifestations and the outcomes of intensive care unit (ICU) patients. The secondary objective was to determine the characteristics of LUS manifestations in different subgroups of ICU patients. METHODS: This prospective multi-center cohort study was conducted in 17 ICUs. A total of 1702 patients admitted between August 31, 2017 and February 16, 2019 were included. LUS was performed according to the bedside lung ultrasound in emergency (BLUE)-plus protocol, and LUS scores were calculated. Data on the outcomes and oxygenation indices were analyzed and compared between different primary indication groups. RESULTS: The LUS scores were significantly higher for non-survivors than for survivors and were significantly different between the oxygenation index groups, with higher scores in the lower oxygenation index groups. The LUS score was an independent risk factor for the 28-day mortality. The area under the receiver operating characteristic curve was 0.663 for prediction of the 28-day mortality and 0.748 for prediction of an oxygenation index ≤100. CONCLUSIONS: The LUS score based on the BLUE-plus protocol was an independent risk factor for the 28-day mortality and was important for the prediction of an oxygenation index ≤100. An early LUS score within 24 hours of ICU admission helps predicting the outcome of ICU patients.
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Unidades de Terapia Intensiva , Pulmão , Estudos de Coortes , Humanos , Pulmão/diagnóstico por imagem , Estudos Prospectivos , UltrassonografiaRESUMO
OBJECTIVES: Sepsis associated encephalopathy (SAE) is a common neurological complication of sepsis. Delirium is a common symtom of SAE. The pathophysiology of SAE is still unclear, but several likely mechanisms have been proposed, such as mitochondrial and endothelial dysfunction, neurotransmission disturbances, derangements of calcium homeostasis, cerebral microcirculation dysfunction, and brain hypoperfusion. Near-infrared spectroscopy (NIRS) is a non-invasive measure for regional cerebral oxygen saturation (rSO2), which has attracted more attention these years. Previous studies have reported that abnormal NIRS values were associated with delirium in critically ill patients. Blood pressure management according to NIRS monitoring improved the organ perfusion and prognosis of patients. This study aimed to observe the dynamic changes of rSO2 using NIRS in septic shock patients, and analyze the relationship between them. METHODS: A total of 48 septic patients who admitted to the intensive care unit (ICU) of Xiangya Hospital, Central South University from August 2017 to May 2018, were retrospectively study. Septic shock was diagnosed according to the criteria of sepsis 3.0 defined by the American Association of Critical Care Medicine and the European Society of Critical Care Medicine. NIRS monitoring was performed during the first 6 hours admitted to ICU with sensors placed on the bilateral forehead of patients. The maximum (rSO2max), minimum (rSO2min), mean value, and the variation rate during the first 6 hours of monitor were recorded. The following data were collected upon the first 24 h after admission to the ICU: The baseline data of patients, laboratory examination results (routine blood test, liver and renal function, blood gas analysis, indicators of infection, and coagulation function), scoring system results [Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA)]. Delirium was screened with the Confusion Assessment Method for ICU (CAM-ICU). The length of time on mechanical ventilation (MV), length of ICU-stay, length of hospital-stay, and 28-day mortality were also recorded. The primary outcome was 28-day mortality, and the secondary outcomes were the incidence of delirium, length of ICU-stay, and length of hospital-stay. The differences between survivors and non-survivors, and patients with or without delirium were analyzed, and the risk factors for delirium were assessed. The performance of rSO2-related indexes (rSO2max, rSO2min, the mean value, and the variation rate of rSO2) in predicting 28-day mortality and delirium was analyzed and the cutoff values were determined. RESULTS: The overall 28-day mortality of septic shock patients was 47.92% (23/48), and the incidence of delirium was 18.75% (9/48). The rSO2min was significantly lower in the non-survivors than the survivors (P=0.042). The variation rate of rSO2 was higher in patients with delirium than those without delirium (P=0.006). The independent risk factors for delirium were rSO2max, the level of direct bilirubin (DBIL), and whether achieved the 6-hour bundle. To predict the 28-day mortality of septic shock patients, the area under the receiver operating characteristic curve (AUROC) for rSO2max, rSO2min, the mean value and the variation rate of rSO2 were 0.616, 0.606, 0.623, and 0.504, respectively. To predict the incidence of delirium, AUROC for rSO2max, rSO2min, the mean value and the variation rate of rSO2 were 0.682, 0.617, 0.580, and 0.501, respectively. The best cutoff value for rSO2max in predicting delirium was 77.5% (sensitivity was 0.444, specificity was 0.897). The best cutoff value for rSO2min in predicting delirium was 65.5% (sensitivity was 0.556, specificity was 0.744). CONCLUSIONS: Cerebral anoxia and hyperoxia, as well as the large fluctuation of cerebral oxygen saturation are important factors that affect the outcomes and the incidence of delirium in septic shock patients, which should be paid attention to in clinical practice. Dynamic monitoring of cerebral oxygen saturation and maintain its stability may be of great significance in patients with septic shock.
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Sepse , Choque Séptico , APACHE , Humanos , Unidades de Terapia Intensiva , Saturação de Oxigênio , Prognóstico , Estudos RetrospectivosRESUMO
Sepsis is among the most devastating events in intensive care units. As a complication of sepsis, acute lung injury (ALI) is common and highly associated with poor outcome. The present study demonstrated that abnormal mitochondrial dynamics play a pivotal role in lipopolysaccharide (LPS)-induced ALI. Inhibiting the mitochondrial fission with the specific inhibitor-1 (Mdivi-1) ameliorated ALI as assessed by hematoxylin and eosin (H&E) staining and wet/dry ratio. Furthermore, Mdivi-1 reduced mitogen-activated protein kinases (MAPKs) activation, oxidative stress and apoptosis in the lungs. Plasma pro-inflammation cytokines were also reduced significantly in Mdivi-1-treated mice. In vitro study revealed that Mdivi-1 protected the macrophages from LPS-induced MAPKs activation, oxidative stress and cell apoptosis. Mdivi-1 also inhibited the release of pro-inflammatory cytokines. Morphological analysis showed that Mdivi-1 rescued the macrophages from LPS-induced mitochondrial fragmentation. Moreover, LPS treatment induced significant phosphorylation of Drp1 at Ser616, dephosphorylation at Ser637 and translocation of Drp1 from the cytoplasm to mitochondria, while Mdivi-1 inhibited those effects. Thus, modification of fission to rebuild mitochondrial homeostasis may offer an innovative opportunity for developing therapeutic strategies against ALI.
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Lesão Pulmonar Aguda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quinazolinonas/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Citocinas/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Modelos Animais , Células RAW 264.7RESUMO
SS-31 is a kind of mitochondrion-targeted peptide. Recent studies indicated significant neuroprotective effects of SS-31. In this study, we investigated that SS-31 protected the murine cultured microglial cells (BV-2) against lipopolysaccharide (LPS)-induced inflammation and oxidative stress through stabilizing mitochondrial morphology. The morphological study showed that SS-31 preserved LPS-induced mitochondrial ultrastructure by reducing the fission protein 1 (Fis1) expression. Flow cytometry and Western blot verified that SS-31 defended the BV-2â¯cells against LPS-stimulated inflammation and oxidative stress via suppressing Fis1. To sum up, our study represents that SS-31 preserves BV-2â¯cells from LPS-stimulated inflammation and oxidative stress by down-regulating the Fis1 expression.
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Inflamação , Lipopolissacarídeos/metabolismo , Microglia/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Oligopeptídeos/farmacologia , Estresse Oxidativo , Animais , Lentivirus/metabolismo , Camundongos , Microglia/metabolismo , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The brain is one of the earliest organs to be influenced during sepsis. Sepsis-associated encephalopathy (SAE) is frequent, but seldomly recognized and has no testified pharmacological therapy. In this study, we demonstrated that pentamidine, an antiprotozoal drug, is a good candidate since it blocks S100B/RAGE/NF-κB signaling pathway. Pentamidine ameliorated cecal ligation and puncture (CLP)-induced brain damage assessed by crystal violet staining and hematoxylin and eosin (H&E) staining. Moreover, pentamidine reduced neuroinflammation in mouse hippocampi. Immunofluorescence and Western blot analysis also showed that pentamidine inhibited CLP-induced gliosis and S100B/RAGE/NF-κB pathway activation. Interestingly, it could also attenuate oxidative stress indicated by decreased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and attenuation of malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) consumption. Thus the S100B/RAGE/NF-κB pathway may be crucial in the pathogenesis of SAE and may be a promising pharmacological target to prevent SAE.
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Antiprotozoários/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Pentamidina/uso terapêutico , Subunidade beta da Proteína Ligante de Cálcio S100/antagonistas & inibidores , Animais , Lesões Encefálicas/imunologia , Lesões Encefálicas/patologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Sepsis and sepsis-associated encephalopathy (SAE) are common intensive care unit (ICU) diseases; the morbidity and mortality are high. The present study analyzed the sensitivity of different diagnostic criteria of sepsis 1.0 and 3.0, epidemiological characteristics of sepsis and SAE, and explored its risk factors for death, short-term, and long-term prognosis. METHODS: The retrospective study included patients in ICU from January 2015 to June 2016. After excluding 58 patients, 175 were assigned to either an SAE or a non-SAE group (patients with sepsis but no encephalopathy). The sensitivity of the diagnostic criteria was compared between sepsis 1.0 and 3.0, respectively. Between-group differences in baseline data, Acute Physiology and Chronic Health Evaluation II score (APACHE II score), Sequential Organ Failure Assessment score (SOFA score), etiological data, biochemical indicators, and 28-day and 180-day mortality rates were analyzed. Survival outcomes and long-term prognosis were observed, and risk factors for death were analyzed through 180-day follow-up. RESULTS: The sensitivity did not differ significantly between the diagnostic criteria of sepsis 1.0 and 3.0 (P = .286). The 42.3% incidence of SAE presented a significantly high APACHE II and SOFA scores as well as 28-day mortality and 180-day mortality (all P < .001). The incidence of death was 37.1%. The multivariate stepwise regression analysis demonstrated that the risk of death in SAE group was significantly higher than the non-SAE group (P < .001). Sepsis-associated encephalopathy is a risk factor for sepsis-related death (relative risk [RR] = 2.868; 95% confidence interval: 1.730-4.754; P < .001). Although males showed a significantly high rate of 28-day and 180-day mortality (P = .035 and .045), it was not an independent risk factor for sepsis-related death (P = .072). The long-term prognosis of patients with sepsis was poor with decreased quality of life. No significant difference was observed in prognosis between the SAE and non-SAE groups (P > .05). CONCLUSION: Both diagnostic criteria cause misdiagnosis, and the sensitivity did not differ significantly. The incidence of SAE was high, and 28-day and 180-day mortality rates were significantly higher than those without SAE. Sepsis-associated encephalopathy is a risk factor for poor outcome. The overall long-term prognosis of patients with sepsis was poor, and the quality of life decreased.
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APACHE , Escores de Disfunção Orgânica , Encefalopatia Associada a Sepse/mortalidade , Sepse/mortalidade , Adulto , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Estudos Retrospectivos , Fatores de Risco , Sepse/patologia , Encefalopatia Associada a Sepse/patologiaRESUMO
Sepsis is one of the most common reasons for mortality in Intensive Care Units. As a common but severe neurological complication, sepsis associated encephalopathy (SAE) has always been ignored and there is no generally accepted treatment. In this study, we demonstrated that Mdivi-1 ameliorated brain damage assessed by Nissl staining. Furthermore, Mdivi-1 reduced TUNEL-positive cells in hippocampus, and inhibited S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) release into plasma. Biochemical analysis also showed that Mdivi-1 protected hippocampus from oxidative stresses. Western blot analysis revealed that Mdivi-1, as a Drp1 inhibitor, inhibited LPS induced dynamin-related GTPase (Drp1) increase. Interestingly, it can also attenuate LPS induced optic atrophy 1 (OPA1) and phosphorylated Drp1 (p-Drp1) decrease. Thus Mdivi-1 protected rats from SAE, and this protective effect could be associated with its inhibition of Drp1 and its activation of p-Drp1 and OPA1. Mitochondrial dynamics may be a potential pharmacological therapeutic target for treating SAE.
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Encéfalo/metabolismo , Encéfalo/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Quinazolinonas/administração & dosagem , Encefalopatia Associada a Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/patologia , Animais , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dinaminas/metabolismo , Lipopolissacarídeos , Masculino , Mitocôndrias/patologia , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Encefalopatia Associada a Sepse/metabolismo , Resultado do TratamentoRESUMO
This study aimed to investigate the mechanism underlying the neuroprotective effect of hemin in oxygen-glucose deprivation (OGD)-treated neurons. OGD-treated SH-SY5Y cells (human neuroblastoma cells) were used in the study. The cellular viability of SH-SY5Y cells was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the cell apoptosis rate was determined by flow cytometry analysis with Annexin V-fluorescein isothiocyanate and propidium iodide staining with or without hemin pretreatment. Cell viability and apoptotic activation were detected after hemin administration combined with neuroglobin (Nqb), thioredoxin-1, peroxiredoxin-2, or heme oxygenase-1 siRNA transient transfection. The release of cytochrome c from mitochondria and the interaction between Ngb and cytochrome c were examined with hemin pretreatment. Hemin had a neuroprotective effect in OGD-treated SH-SY5Y cells, which was mainly mediated by the upregulation of Ngb. Moreover, the release of cytochrome c from mitochondria was inhibited by hemin-induced Ngb expression through facilitating the interaction of Ngb with cytochrome c in mitochondria. The present findings provided new insights into the neuroprotective mechanisms of hemin. It was concluded that low-dose hemin pretreatment had a neuroprotective effect in OGD-treated SH-SY5Y cells, through inhibiting cell apoptosis. The neuroprotective effects of hemin following hypoxic-ischemic neuronal damage were mainly mediated by Ngb. One underlying mechanism was hemin-induced overexpression of mitochondrial Ngb, which inhibited endogenous apoptosis via the association with cytochrome c.
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Apoptose/fisiologia , Globinas/biossíntese , Glucose/deficiência , Hemina/farmacologia , Proteínas do Tecido Nervoso/biossíntese , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Humanos , Neuroglobina , Neurônios/efeitos dos fármacosRESUMO
OBJECTIVES: This study was designed to test the effectiveness of common carotid artery sonography in comparison with transthoracic echocardiography (TTE) for cardiac output measurements to provide an easier alternative for cardiac output monitoring in the intensive care unit. METHODS: This study included 148 patients who had common carotid artery Doppler examinations and TTE performed within 8 hours of each other, and the cardiac output measurement results were compared with each other. RESULTS: The mean age of the participants ± SD was 56.8 ± 16.2 years, with male patients composing 54.7% of the cohort. There was no significant difference in carotid and TTE cardiac output between different sexes, age groups, patients with and without mechanical ventilation, and primary indication groups. The overall intraclass correlation coefficient between the carotid and TTE cardiac output was 0.537. In patients with septic shock, multiple trauma, and respiratory failure, the intraclass correlation coefficients between TTE and carotid cardiac output were 0.241, 0.061, and 0.095, respectively. CONCLUSIONS: Carotid cardiac output shows moderate agreement with TTE cardiac output; thus, its use may be considered as an alternative for estimating cardiac output in emergencies and when TTE cardiac output is unobtainable. However, in patients with septic shock, multiple trauma, and respiratory failure, the use of carotid cardiac output is not recommended.
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Débito Cardíaco/fisiologia , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Primitiva/fisiopatologia , Cuidados Críticos/métodos , Ecocardiografia/métodos , Ultrassonografia Doppler/métodos , Idoso , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Although the nicotinamide adenine dinucleotide (NAD(+))/CD38/cyclic ADP ribose (cADPR)/Ca(2+) signaling pathway has been shown to regulate intracellular calcium homeostasis and functions in multiple inflammatory processes, its role in sepsis remains unknown. The aim of this study was to determine whether the NAD(+)/CD38/cADPR/Ca(2+) signaling pathway is activated during sepsis and whether an inhibitor of this pathway, 8-Br-cADPR, protects the organs from sepsis-induced damage. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) or sham laparotomies. NAD(+), cADPR, CD38, and intracellular Ca(2+) levels were measured in the hearts, livers, and kidneys of septic rats at 0, 6, 12, 24, and 48 h after CLP surgery. Rats were also divided into sham, CLP, and CLP+8-Br-cADPR groups, and the hearts, livers, and kidneys were hematoxylin-eosin-stained and assayed for malondialdehyde and superoxide dismutase activities. RESULTS: NAD(+), cADPR, CD38, and intracellular Ca(2+) levels increased in the hearts, livers, and kidneys of septic rats as early as 6-24 h after CLP surgery. Treatment with 8-Br-cADPR inhibited sepsis-induced intracellular Ca(2+) mobilization, attenuated tissue injury, reduced malondialdehyde levels, and increased superoxide dismutase activity in septic rats. CONCLUSIONS: The NAD(+)/CD38/cADPR/Ca(2+) signaling pathway was activated during sepsis in the CLP rat model. Blocking this pathway with 8-Br-cADPR protected hearts, livers, and kidneys from sepsis-induced damage.
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Sinalização do Cálcio/efeitos dos fármacos , ADP-Ribose Cíclica/análogos & derivados , Insuficiência de Múltiplos Órgãos/prevenção & controle , Sepse/complicações , ADP-Ribosil Ciclase/metabolismo , ADP-Ribosil Ciclase 1/metabolismo , Animais , Cálcio/metabolismo , ADP-Ribose Cíclica/metabolismo , ADP-Ribose Cíclica/farmacologia , ADP-Ribose Cíclica/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Masculino , Malondialdeído/metabolismo , Glicoproteínas de Membrana/metabolismo , Insuficiência de Múltiplos Órgãos/etiologia , NAD/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Sepse/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Pre-B cell colony-enhancing factor (PBEF) is a highly conserved pleiotropic protein reported to be an alternate ligand for the insulin receptor (IR). We sought to clarify the relationship between PBEF and insulin signaling by evaluating the effects of PBEF on the localization of the IRß chain to lipid rafts in A549 epithelial cells. We isolated lipid rafts from A549 cells and detected the IR by immunoprecipitation from raft fractions or whole cell lysates. Cells were treated with rPBEF, its enzymatic product nicotinamide adenine dinucleotide (NAD), or the Nampt inhibitor daporinad to study the effect of PBEF on IRß movement. We used coimmunoprecipitation studies in cells transfected with PBEF and IRß constructs to detect interactions between PBEF, the IRß, and caveolin-1 (Cav-1). PBEF was present in both lipid raft and nonraft fractions, whereas the IR was found only in lipid raft fractions of resting A549 cells. The IR-, PBEF-, and Cav-1-coimmunoprecipitated rPBEF treatment resulted in the movement of IRß- and tyrosine-phosphorylated Cav-1 from lipid rafts to nonrafts, an effect that could be blocked by daporinad, suggesting that this effect was facilitated by the Nampt activity of PBEF. The addition of PBEF to insulin-treated cells resulted in reduced Akt phosphorylation of both Ser47³ and Thr³°8. We conclude that PBEF can inhibit insulin signaling through the IR by Nampt-dependent promotion of IR translocation into the nonraft domains of A549 epithelial cells. PBEF-induced alterations in the spatial geometry of the IR provide a mechanistic explanation for insulin resistance in inflammatory states associated with upregulation of PBEF.
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Antígenos CD/metabolismo , Citocinas/metabolismo , Insulina/metabolismo , Pulmão/metabolismo , Microdomínios da Membrana/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Receptor de Insulina/metabolismo , Mucosa Respiratória/metabolismo , Acrilamidas/farmacologia , Antígenos CD/genética , Caveolina 1/genética , Caveolina 1/metabolismo , Linhagem Celular , Citocinas/antagonistas & inibidores , Citocinas/genética , Inibidores Enzimáticos/farmacologia , Humanos , Resistência à Insulina , Pulmão/efeitos dos fármacos , Microdomínios da Membrana/efeitos dos fármacos , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/agonistas , Receptor de Insulina/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
[This corrects the article DOI: 10.1016/j.jointm.2022.08.002.].
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INTRODUCTION: Local anesthetic-induced neurotoxicity contributes to perioperative nerve damage; however, the underlying mechanisms remain unclear. Here, we investigated the role of the paraventricular thalamus (PVT)-nucleus accumbens (NAc) projections in neurotoxicity induced by ropivacaine, a local anesthetic agent. METHODS: Ropivacaine (58 mg/kg, intraperitoneal administration) was used to construct the local anesthetic systemic toxicity (LAST) mice model. We first identified neural projections from the PVT to the NAc through the expression of a retrograde tracer and virus. The inhibitory viruses (rAAV-EF1α-DIO-hm4D(Gi)-mCherry-WPREs: AAV2/retro and rAAV-CaMKII-CRE-WPRE-hGh: AAV2/9) were injected into the mice model to assess the effects of the specific inhibition of the PVT-NAc pathway on neurological behaviors in the presence of clozapine-N-oxide. The inhibition of the PVT-NAc pathway was evaluated by immunofluorescence staining of c-Fos-positive neurons and Ca2+ signals in CaMKIIa neurons. RESULTS: We successfully identified a circuit connecting the PVT and NAc in C57BL/6 mice. Ropivacaine administration induced the activation of the PVT-NAc pathway and seizures. Specific inhibition of NAc-projecting CaMKII neurons in the PVT was sufficient to inhibit the neuronal activity in the NAc, which subsequently decreased ropivacaine-induced neurotoxicity. CONCLUSION: These results reveal the presence of a dedicated PVT-NAc circuit that regulates local anesthetic-induced neurotoxicity and provide a potential mechanistic explanation for the treatment and prevention of LAST.
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Background: When resuscitating patients with septic shock, cerebrovascular reactivity parameters are calculated by monitoring regional cerebral oxygen saturation (rSO2) using near-infrared spectroscopy to determine the optimal blood pressure. Here, we aimed to analyze the impact of cerebral autoregulation-directed optimal blood pressure management on the incidence of delirium and the prognosis of patients with septic shock. Methods: This prospective randomized controlled clinical study was conducted in the Xiangya Hospital of Central South University, China. Fifty-one patients with septic shock (December 2020-May 2022) were enrolled and randomly allocated to the experimental (n=26) or control group (n=25). Using the ICM+ software, we monitored the dynamic changes in rSO2 and mean arterial pressure (MAP) and calculated the cerebrovascular reactivity parameter tissue oxygen reactivity index to determine the optimal blood pressure to maintain normal cerebral autoregulation function during resuscitation in the experimental group. The control group was treated according to the Surviving Sepsis Campaign Guidelines. Differences in the incidence of delirium and 28-day mortality between the two groups were compared, and the risk factors were analyzed. Results: The 51 patients, including 39 male and 12 female, had a mean age of (57.0±14.9) years. The incidence of delirium was 40.1% (23/51), and the 28-day mortality rate was 29.4% (15/51). The mean MAP during the first 24 h of intensive care unit (ICU) admission was higher ([84.5±12.2] mmHg vs. [77.4±11.8] mmHg, P=0.040), and the incidence of delirium was lower (30.8% vs. 60.0%, P=0.036) in the experimental group than in the control group. The use of cerebral autoregulation-directed optimal blood pressure (odds ratio [OR]=0.090, 95% confidence interval [CI]: 0.009 to 0.923, P=0.043) and length of ICU stay (OR=1.473, 95% CI: 1.093 to 1.985, P=0.011) were risk factors for delirium during septic shock. Vasoactive drug dose (OR=8.445, 95% CI: 1.26 to 56.576, P=0.028) and partial pressure of oxygen (PaO2) (OR=0.958, 95% CI: 0.921 to 0.996, P=0.032) were the risk factors for 28-day mortality. Conclusions: The use of cerebral autoregulation-directed optimal blood pressure management during shock resuscitation reduces the incidence of delirium in patients with septic shock. Trial Registration: ClinicalTrials.gov ldentifer: NCT03879317.
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Deep learning (DL) has achieved breakthrough successes in various tasks, owing to its layer-by-layer information processing and sufficient model complexity. However, DL suffers from the issues of both redundant model complexity and low interpretability, which are mainly because of its oversimplified basic McCulloch-Pitts neuron unit. A widely recognized biologically plausible dendritic neuron model (DNM) has demonstrated its effectiveness in alleviating the aforementioned issues, but it can only solve binary classification tasks, which significantly limits its applicability. In this study, a novel extended network based on the dendritic structure is innovatively proposed, thereby enabling it to solve multiple-class classification problems. Also, for the first time, an efficient error-back-propagation learning algorithm is derived. In the extensive experimental results, the effectiveness and superiority of the proposed method in comparison with other nine state-of-the-art classifiers on ten datasets are demonstrated, including a real-world quality of web service application. The experimental results suggest that the proposed learning algorithm is competent and reliable in terms of classification performance and stability and has a notable advantage in small-scale disequilibrium data. Additionally, aspects of network structure constrained by scale are examined.
Assuntos
Algoritmos , Neurônios , Neurônios/fisiologia , SoftwareRESUMO
Background: To investigate the relationship between partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) and the probability of delirium in intensive care units (ICUs). Methods: The investigation was a cross-sectional study that involved the collection of data from patients admitted to the Xiang Ya Hospital Cardiothoracic Surgical Care Unit and Comprehensive Intensive Care Unit from 01 September 2016 to 10 December 2016. Delirium was diagnosed using the simplified version of the Chinese Confusion Assessment Method (CAM) for the ICU. Demographic and medical data were obtained within 24 h of each patient admitted in the ICU. The PaO2/FiO2 of each patient was recorded 24 h after admission in the ICU. The patients were divided into three groups according to PaO2/FiO2 data : normal (PaO2/FiO2 ≥300 mmHg), slightly low (200 ≥PaO2/FiO2 <300 mmHg), and severely low (PaO2/FiO2 <200 mmHg). Baseline characteristics were compared in the three groups. Results of the unadjusted model, minimally adjusted model, and fully adjusted model are presented. Results: A total of 403 participants were included in the study, of which 184 (45.7%) developed delirium. Age (P <0.001), Sequential Organ Failure Assessment (SOFA) score (P <0.001), Acute Physiology and Chronic Health Evaluation (APACHE) II score (P <0.001), mechanical ventilation time (P <0.001), history of hypertension (P=0.040), heart disease (P=0.040), sedation (P=0.001), and PaO2/FiO2 (P=0.006) were significantly associated with delirium in univariate analysis. Multivariate regression analysis models were used to further analyze the associations between PaO2/FiO2 and delirium. In the crude model, for 1 standard deviation (SD) increase in PaO2/FiO2, the odds ratio (OR) of delirium was 0.8 (95% confidence interval [CI]: 0.6-0.9), but there was no significant correlation in the fully adjusted model. There was a non-linear relationship between the PaO2/FiO2 and delirium in a generalized additive model. A two-piecewise linear regression model was used to calculate a PaO2/FiO2 threshold of 243 mmHg. On the left side of the threshold, the OR was 0.9 and the 95% CI was 0.9-1.0 (P=0.013) when PaO2/FiO2 increased by 1 SD. Conclusions: PaO2/FiO2 was negatively associated with delirium when PaO2/FiO2 was below the identified threshold. As a readily available laboratory indicator, PaO2/FiO2 has potential value in the clinical evaluation of risk of delirium in ICU patients.
RESUMO
Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.
Assuntos
Lesões Encefálicas , Disfunção Cognitiva , Sepse , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Hipocampo/metabolismo , Córtex Pré-Frontal , Disfunção Cognitiva/metabolismo , Sepse/metabolismo , Ácido Glutâmico/metabolismo , Lesões Encefálicas/metabolismoRESUMO
AIMS: Sepsis-associated encephalopathy (SAE) often leads to cognitive impairments. However, the pathophysiology of SAE is complex and unclear. Here, we investigated the role of hippocampus (HPC)-prefrontal cortex (PFC) in cognitive dysfunction in sepsis induced by cecal ligation puncture (CLP) in mice. METHODS: The neural projections from the HPC to PFC were first identified via retrograde tracing and viral expression. Chemogenetic activation of the HPC-PFC pathway was shown via immunofluorescent staining of c-Fos-positive neurons in PFC. Morris Water Maze (MWM) and Barnes maze (BM) were used to evaluate cognitive function. Western blotting analysis was used to determine the expression of glutamate receptors and related molecules in PFC and HPC. RESULTS: Chemogenetic activation of the HPC-PFC pathway enhanced cognitive dysfunction in CLP-induced septic mice. Glutamate receptors mediated the effects of HPC-PFC pathway activation in CLP mice. The activation of the HPC-PFC pathway resulted in significantly increased levels of NMDAR, AMPAR, and downstream signaling molecules including CaMKIIa, pCREB, and BDNF in PFC. However, inhibition of glutamate receptors using 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (F)quinoxaline (NBQX), which is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR inhibitor), or D-2-amino-5-phosphonopentanoate (D-AP5), which is an NMDA receptor antagonist abolished this increase. CONCLUSION: Our study reveals the important role of the HPC-PFC pathway in improving cognitive dysfunction in a mouse model of CLP sepsis and provides a novel pathogenetic mechanism for SAE.