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1.
J Clin Ultrasound ; 49(7): 704-714, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34117639

RESUMO

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.


Assuntos
Unidades de Terapia Intensiva , Pulmão , Estudos de Coortes , Humanos , Pulmão/diagnóstico por imagem , Estudos Prospectivos , Ultrassonografia
2.
J Int Med Res ; 49(5): 3000605211013176, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33990145

RESUMO

OBJECTIVE: To investigate the effect of focused ultrasonography on clinical outcomes of septic shock. METHODS: Patients with septic shock were randomized into an integrated cardiopulmonary ultrasonography (ICUS) group and conventional (CON) group. Within 1 hour of admission, the ICUS group underwent ICUS examination for hemodynamic decision-making, while the CON group received standard treatment. The primary endpoint was 28-day mortality after admission. The secondary endpoints were cumulative fluid administration in the first 6, 24, and 72 hours; use of vasoactive drugs; lactate clearance; duration of ventilation; and ICU stay. RESULTS: Ninety-four qualified patients were enrolled (ICUS group, 49; CON group, 45). ICUS showed no significant effect on 28-day mortality. Within the initial 6 hours, the ICUS group tended to have a higher fluid balance and fluid intake than the CON group. The duration of vasopressor support was shorter in the ICUS group. There were no differences in the cumulative fluid infusion within 24 or 72 hours, lactate clearance, ICU stay, or duration of ventilation. CONCLUSIONS: The initially focused ICUS did not affect the clinical outcomes of septic shock, but it tended to be associated with a higher fluid balance within the initial 6 hours and shorter duration of vasopressor support.


Assuntos
Choque Séptico , Hidratação , Hemodinâmica , Humanos , Choque Séptico/diagnóstico por imagem , Choque Séptico/tratamento farmacológico , Ultrassonografia , Vasoconstritores/uso terapêutico
3.
Life Sci ; 277: 119490, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862114

RESUMO

AIMS: Sepsis-associated encephalopathy (SAE) is one of the most common complications of sepsis, and it might lead to long-term cognitive dysfunction and disability. This study aimed to explore the role of S100 calcium binding protein B (S100B)/RAGE/ceramide signaling pathway in SAE. MAIN METHODS: FPS-ZM1 (an inhibitor of RAGE), myriocin and GW4869 (an inhibitor of ceramide) were used to explore the role of S100B/RAGE/ceramide in acute brain injury and long-term cognitive impairment in sepsis. In addition, Mdivi-1 (inhibitor of Drp1) and Drp1 siRNA were utilized to assess the effects of C2-ceramide on neuronal mitochondria, and to explore the specific underlying mechanism in C2 ceramide-induced death of HT22 mouse hippocampal neuronal cells. KEY FINDINGS: Western blot analysis showed that sepsis significantly up-regulated S100B and RAGE. Nissl staining and Morris water maze (MWM) test revealed that inhibition of RAGE with FPS-ZM1 markedly attenuated cecal ligation and puncture (CLP)-induced brain damage and cognitive dysfunction. Furthermore, FPS-ZM1 relieved sepsis-induced C2-ceramide accumulation and abnormal mitochondrial dynamics. Moreover, inhibition of ceramide also showed similar protective effects both in vivo and in vitro. Furthermore, Mdivi-1 and Drp1 siRNA significantly reduced C2-ceramide-induced neuronal mitochondrial fragmentation and cell apoptosis in vitro. SIGNIFICANCE: This study confirmed that S100B regulates mitochondrial dynamics through RAGE/ceramide pathway, in addition to the role of this pathway in acute brain injury and long-term cognitive impairment during sepsis.


Assuntos
Ceramidas/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encefalopatias/complicações , Encefalopatias/metabolismo , Lesões Encefálicas/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Neurônios/metabolismo , Sepse/complicações , Encefalopatia Associada a Sepse/complicações , Encefalopatia Associada a Sepse/fisiopatologia , Transdução de Sinais
4.
Metab Brain Dis ; 36(4): 601-608, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33475982

RESUMO

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.

5.
Medicine (Baltimore) ; 99(51): e23764, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33371141

RESUMO

ABSTRACT: Passive leg raising (PLR) is a convenient and reliable test to predict fluid responsiveness. The ability of thoracic electrical bioimpedance cardiography (TEB) to monitor changes of cardiac output (CO) during PLR is unknown.In the present study, we measured CO in 61 patients with shock or dyspnea by TEB and transthoracic echocardiography (TTE) during PLR procedure. Positive PLR responsiveness was defined as the velocity-time integral (VTI) ≥10% after PLR. TTE measured VTI in the left ventricular output tract. The predictive value of TEB parameters in PLR responders was tested. Furthermore, the agreement of absolute CO values between TEB and TTE measurements was assessed.Among the 61 patients, there were 28 PLR-responders and 33 non-responders. Twenty-seven patients were diagnosed with shock and 34 patients with dyspnea, with 55.6% (15/27) and 54.6% (18/34) non-responders, respectively. A change in TEB measured CO (ΔCO) ≥9.8% predicted PLR responders with 75.0% sensitivity and 78.8% specificity, the area under the receiver operating characteristic curve (AUROC) was 0.79. The Δd2Z/dt2 (a secondary derivative of the impedance wave) showed the best predictive value with AUROC of 0.90, the optimal cut point was -7.1% with 85.7% sensitivity and 87.9% specificity. Bias between TEB and TTE measured CO was 0.12 L/min, and the percentage error was 65.8%.TEB parameters had promising performance in predicting PLR responders, and the Δd2Z/dt2 had the best predictive value. The CO values measured by TEB were not interchangeable with TTE in critically ill settings.


Assuntos
Débito Cardíaco/fisiologia , Cardiografia de Impedância/instrumentação , Hemodinâmica/fisiologia , Adulto , Idoso , Área Sob a Curva , Cardiografia de Impedância/métodos , China , Estado Terminal , Ecocardiografia/métodos , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/tendências , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Estatísticas não Paramétricas
6.
J Mol Neurosci ; 70(12): 2049-2057, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32468218

RESUMO

Sepsis can induce acute and chronic changes in the central nervous system termed sepsis-associated encephalopathy (SAE). Not only cognitive deficits but also anxiety, depression, and post-traumatic stress disorder are common in severe sepsis survivors. In this study, we demonstrated that amitriptyline, a classic tricyclic antidepressant, reduced sepsis-induced brain damage through the tropomyosin receptor kinase A (TrkA) signaling pathway. Amitriptyline ameliorated neuronal loss assessed by Nissl staining in a mouse cecal ligation and puncture (CLP)-induced sepsis model. Furthermore, amitriptyline reduced early gliosis assessed by immunofluorescence and late cognitive deficits assessed by the Morris water maze (MWM) test. Moreover, amitriptyline treatment attenuated oxidative stress indicated by less superoxide dismutase (SOD) and catalase (CAT) activity consumption and malondialdehyde (MDA) accumulation. Interestingly, those protective effects of amitriptyline could be abolished by GW441756, a TrkA signaling pathway inhibitor. Immunoblot directly showed that TrkA signaling pathway-associated proteins, such as Akt and GSK3ß, were involved in the neuroprotective effects of amitriptyline. Thus, amitriptyline appears to be an encouraging candidate to treat cognitive deficits and depression after severe sepsis.

8.
Pulm Pharmacol Ther ; 62: 101918, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251714

RESUMO

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.


Assuntos
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 264.7
10.
Biochem Biophys Res Commun ; 520(1): 171-178, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31582222

RESUMO

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-2 cells against LPS-stimulated inflammation and oxidative stress via suppressing Fis1. To sum up, our study represents that SS-31 preserves BV-2 cells from LPS-stimulated inflammation and oxidative stress by down-regulating the Fis1 expression.


Assuntos
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/metabolismo
11.
Biochem Biophys Res Commun ; 517(2): 221-226, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31331643

RESUMO

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.


Assuntos
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 fármacos
12.
J Intensive Care Med ; 34(11-12): 938-945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28718340

RESUMO

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.


Assuntos
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/patologia
13.
Biochem Biophys Res Commun ; 496(3): 865-871, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29395086

RESUMO

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.


Assuntos
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 Tratamento
14.
Brain Res ; 1678: 56-63, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29030054

RESUMO

BACKGROUND: The CD38/cADPR pathway has been found to play roles in various inflammatory conditions. However, whether CD38 plays a protective or detrimental effect in the central nervous system (CNS) is controversial. The aim of this study was to determine the effect of CD38/cADPR pathway in sepsis associated brain injury. MATERIALS AND METHODS: Male Sprague-Dawley rats were undergone cecal ligation and puncture (CLP) or sham laparotomies. NAD+, cADPR and CD38 were measured in the hippocampus of septic rats at 0, 6, 12, 24, and 48h after CLP surgery. Rats were divided into the sham, CLP group, CLP+ CD38 expression lentivirus (CLP+ CD38 LV), CLP+ CD38 interference lentivirus (CLP+ CD38 Ri), CLP+ negative control lentivirus (CLP+NC) and the CLP+8-Br-cADPR groups. The Western blots of Bcl-2, Bax and iNOS, TUNEL assays, malondialdehyde (MDA) and superoxide dismutase (SOD) assays, transmission electron microscope analysis were performed in the hippocampus of rats. RESULTS: NAD+, cADPR and CD38 levels increased significantly in the hippocampus of septic rats as early as 12-24h after CLP surgery. CD38 knockdown or blocking cADPR with 8-Br-cADPR significantly reduced apoptosis, MDA and SOD activity, iNOS expression and ultrastructural morphology damages in the hippocampus of septic rats. CONCLUSIONS: In this study, we found that the CD38/cADPR pathway was activated in sepsis associated brain injury. Blocking this pathway protected the hippocampus from apoptosis, oxidative stress and ultrastructural morphology damages in septic rats.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribosil Ciclase/metabolismo , ADP-Ribose Cíclica/metabolismo , Glicoproteínas de Membrana/metabolismo , Sepse/metabolismo , Sepse/prevenção & controle , ADP-Ribosil Ciclase/antagonistas & inibidores , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Animais , Apoptose , Lesões Encefálicas/complicações , Lesões Encefálicas/metabolismo , Ceco/cirurgia , ADP-Ribose Cíclica/análogos & derivados , ADP-Ribose Cíclica/antagonistas & inibidores , ADP-Ribose Cíclica/farmacologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
15.
Chin Med J (Engl) ; 130(19): 2354-2360, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28937043

RESUMO

BACKGROUND: The CD38/cyclic ADP-ribose (cADPR) pathway plays a role in various central nervous system diseases and in morphine tolerance, but its role in local anesthetic intoxication is unknown. The aim of this study was to determine the role of the CD38/cADPR pathway in ropivacaine-induced convulsion. METHODS: Forty male Sprague-Dawley rats were randomly divided into five groups (n = 8 per group): sham group, ropivacaine group, ropivacaine+8-Br-cADPR (5 nmol) group, ropivacaine+8-Br-cADPR (10 nmol) group, and ropivacaine+8-Br-cADPR (20 nmol) group (no rats died). Rats were intracerebroventricularly injected with normal saline or 8-Br-cADPR 30 min before receiving an intraperitoneal injection of ropivacaine. Electroencephalography and convulsion behavior scores were recorded. The hippocampus was harvested from each group and subjected to nicotinamide adenine dinucleotide and cADPR assays, Western blotting analysis, and malondialdehyde (MDA) and superoxide dismutase (SOD) assays. RESULTS: Intraperitoneal injection of ropivacaine (33.8 mg/kg) induced convulsions in rats. CD38 and cADPR levels increased significantly following ropivacaine-induced convulsion (P = 0.031 and 0.020, respectively, compared with the sham group). Intraventricular injection of 8-Br-cADPR (5, 10, and 20 nmol) significantly prolonged convulsion latency (P = 0.037, 0.034, and 0.000, respectively), reduced convulsion duration (P = 0.005, 0.005, and 0.005, respectively), and reduced convulsion behavior scores (P = 0.015, 0.015, and 0.000, respectively). Intraventricular injection of 8-Br-cADPR (10 nmol) also increased the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein ratio (P = 0.044) and reduced cleaved Caspase 3/Caspase 3 ratio, inducible nitric oxide synthase, MDA and SOD levels (P = 0.014, 0.044, 0.001, and 0.010, respectively) compared with the ropivacaine group. CONCLUSIONS: The CD38/cADPR pathway is activated in ropivacaine-induced convulsion. Inhibiting this pathway alleviates ropivacaine-induced convulsion and protects the brain from apoptosis and oxidative stress.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Amidas/toxicidade , ADP-Ribose Cíclica/análogos & derivados , ADP-Ribose Cíclica/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Animais , Sinalização do Cálcio/efeitos dos fármacos , ADP-Ribose Cíclica/administração & dosagem , ADP-Ribose Cíclica/uso terapêutico , Masculino , Malondialdeído/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ropivacaina , Convulsões/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
16.
Neuroscience ; 361: 34-42, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-28807785

RESUMO

Whether the CD38/cyclic ADP-ribose (cADPR) pathway plays a protective or detrimental role in neuroinflammation remains controversial. This study aimed to determine the role of CD38 in neuroinflammation using lipopolysaccharide (LPS)-stimulated BV2 microglial cells and co-cultured Neuro-2a (N2a) cells. In monoculture experiments, BV2 cells were divided into control, CD38 interference (CD38Ri), negative control (NC), LPS, CD38Ri+LPS, NC+LPS and 8-Br-cADPR+LPS groups. In co-culture experiments, N2a cells were co-cultured with BV2 cells for 48h. Nicotinamide adenine dinucleotide (NAD+), cADPR and intracellular Ca2+ levels and CD38 expression increased significantly in LPS-stimulated BV2 cells. CD38 knockdown or 8-Br-cADPR treatment significantly reduced NAD+, cADPR and intracellular Ca2+ levels. CD38 knockdown increased iNOS and NO levels in BV2 cells without LPS treatment; however, CD38 knockdown or 8-Br-cADPR treatment reduced iNOS and NO levels in BV2 cells with LPS treatment. CD38 knockdown increased the ratio of TUNEL-positive cells and cleaved Caspase 3/Caspase 3 ratio, and decreased the Bcl-2/Bax ratio in BV2 cells without LPS treatment; however, CD38 knockdown reduced the TUNEL positivity in BV2 cells with LPS treatment. CD38 knockdown or 8-Br-cADPR inhibited TNF-α, IL-6 (interleukin-6) and IL-1ß levels in LPS-stimulated BV2 cells. Co-culture with CD38 knockdown or 8-Br-cADPR-treated BV2 cells did not influence apoptosis or iNOS expression in N2a cells. In conclusion, our results indicate that blocking the CD38/cADPR pathway reduces intracellular Ca2+, NO and the secretion of proinflammatory cytokines. CD38 knockdown exerted a detrimental effect in apoptosis and NO production in normal microglia, but played a protective role in apoptosis and NO production in LPS-stimulated microglia.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , ADP-Ribose Cíclica/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Animais , Técnicas de Cocultura , ADP-Ribose Cíclica/análogos & derivados , Interleucina-6/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Microglia/metabolismo , NAD/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
J Mol Neurosci ; 63(1): 1-8, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28601977

RESUMO

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has no generally accepted treatment due to its complicated pathophysiology. Previously, we demonstrated the protective role of neuroglobin (Ngb) in SAE rats, but the exact mechanism has not been determined. To investigate the potential neuroprotective roles and mechanisms of Ngb, Sprague-Dawley rats were used. Overexpression of Ngb via intracerebroventricular injection with Ngb plasmids attenuated brain damage assessed by hematoxylin and eosin (HE) staining and neurological dysfunction assessed by Morris water maze test. Western blot analysis also showed that the phosphorylation of Akt increased and the protein level of Bax decreased. Furthermore, the protective effect can be abolished by PI3K/Akt pathway inhibitor LY294002. Our results demonstrate that Ngb can protect rats from SAE via a PI3K/Akt/Bax-dependent mechanism.


Assuntos
Terapia Genética , Globinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Animais , Globinas/genética , Masculino , Aprendizagem em Labirinto , Proteínas do Tecido Nervoso/genética , Neuroglobina , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Encefalopatia Associada a Sepse/terapia , Transdução de Sinais , Proteína X Associada a bcl-2/metabolismo
18.
J Ultrasound Med ; 36(9): 1793-1799, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28429475

RESUMO

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.


Assuntos
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 Retrospectivos
19.
Neurochem Res ; 42(8): 2208-2217, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28316021

RESUMO

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.


Assuntos
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 fármacos
20.
Chin Med J (Engl) ; 129(14): 1674-81, 2016 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-27411454

RESUMO

BACKGROUND: Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy (SAE) is still poorly understood. The aim of this prospective and observational study was to investigate the clinical significance of calcium-binding protein A8 (S100A8) in serum and tumor necrosis factor receptor-associated factor 6 (TRAF6) in peripheral blood mononuclear cells (PBMCs) in diagnosing SAE and predicting its prognosis. METHODS: Data of septic patients were collected within 24 h after Intensive Care Unit admission from July 2014 to March 2015. Healthy medical personnel served as the control group. SAE was defined as cerebral dysfunction in the presence of sepsis that fulfilled the exclusion criteria. The biochemical indicators, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation score II, TRAF6 in PBMC, serum S100A8, S100ß, and neuron-specific enolase were evaluated in SAE patients afresh. TRAF6 and S100A8 were also measured in the control group. RESULTS: Of the 57 enrolled patients, 29 were diagnosed with SAE. The S100A8 and TRAF6 concentrations in SAE patients were both significantly higher than that in no-encephalopathy (NE) patients, and higher in NE than that in controls (3.74 ± 3.13 vs. 1.08 ± 0.75 vs. 0.37 ± 0.14 ng/ml, P < 0.01; 3.18 ± 1.55 vs. 1.02 ± 0.63 vs. 0.47 ± 0.10, P < 0.01). S100A8 levels of 1.93 ng/ml were diagnostic of SAE with 92.90% specificity and 69.00% sensitivity in the receiver operating characteristic (ROC) curve, and the area under the curve was 0.86 (95% confidence interval [CI]: 0.76-0.95). TRAF6-relative levels of 1.44 were diagnostic of SAE with 85.70% specificity and 86.20% sensitivity, and the area under the curve was 0.94 (95% CI: 0.88-0.99). In addition, S100A8 levels of 2.41 ng/ml predicted 28-day mortality of SAE with 90.00% specificity and 73.70% sensitivity in the ROC curve, and the area under the curve was 0.88. TRAF6 relative levels of 2.94 predicted 28-day mortality of SAE with 80.00% specificity and 68.40% sensitivity, and the area under the curve was 0.77. Compared with TRAF6, the specificity of serum S100A8 in diagnosing SAE and predicting mortality was higher, although the sensitivity was low. In contrast, the TRAF6 had higher sensitivity for diagnosis. CONCLUSIONS: Peripheral blood levels of S100A8 and TRAF6 in SAE patients were elevated and might be related to the severity of SAE and predict the outcome of SAE. The efficacy and specificity of S100A8 for SAE diagnosis were superior, despite its weak sensitivity. S100A8 might be a better biomarker for diagnosis of SAE and predicting prognosis.


Assuntos
Calmodulina/sangue , Encefalopatia Associada a Sepse/diagnóstico , Fator 6 Associado a Receptor de TNF/sangue , Adulto , Idoso , Biomarcadores/sangue , Calgranulina A/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Encefalopatia Associada a Sepse/sangue
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