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1.
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
2.
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
3.
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.

4.
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
5.
Mol Immunol ; 127: 136-145, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32971400

RESUMO

Sepsis-induced inflammatory damage is a crucial cause of acute kidney injury (AKI), and AKI is an ecumenical fearful complication in approximately half of patients with sepsis. CCAAT/enhancer-binding protein ß (C/EBPß) plays roles in regulating acute phase responses and inflammation. However, the role and mechanism of C/EBPß in AKI are unclear. LPS combined with ATP-treated renal epithelial cells HK2 and cecal ligation-peferation (CLP)-mice were used as models of AKI in vitro and in vivo. Cell damage, the secretion of interleukin-1 beta (IL-1ß), IL-18 and cysteinyl aspartate specific proteinase 1 (caspase-1) activity were tested by LDH, ELISA assay and flow cytometry analysis, respectively. The expression levels of TFAM, C/EBPß, and pyroptosis-related molecules were tested by qRT-PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assessed the interaction between C/EBPß with TFAM. Hematoxylin-Eosin (H&E) staining detected pathological changes of kidney tissues, and immunohistochemistry measured TFAM and C/EBPß in mice kidney tissues. C/EBPß or TFAM were up-regulated in LPS combined with ATP -induced HK2 cells. Knockdown of C/EBPß could suppress cell injury and the secretion of IL-1ß and IL-18 induced by LPS combined with ATP. Furthermore, C/EBPß up-regulated the expression levels of TFAM via directly binding to TFAM promoter. Overexpression of TFAM reversed the effects of C/EBPß deficiency on pyroptosis. Knockdown of C/EBPß could inhibit NLRP3 inflammasome-mediated caspase-1 signaling pathway by inactivating TFAM/RAGE pathway. It was further confirmed in the AKI mice that C/EBPß and TFAM promoted AKI by activating NLRP3-mediated pyroptosis. The interaction of between C/EBPß and TFAM facilitated pyroptosis by activating NLRP3/caspase-1 signal axis, thereby promoting the occurrence of AKI.


Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Inflamassomos/metabolismo , Proteínas Mitocondriais/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Fatores de Transcrição/metabolismo , Trifosfato de Adenosina , Animais , Caspase 1/metabolismo , Linhagem Celular , Humanos , Inflamação/patologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Ligação Proteica , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais
6.
J Nurs Res ; 28(4): e101, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32692119

RESUMO

BACKGROUND: Both high prevalence and incidence rates of delirium occur frequently among patients aged 65 years or older in intensive care units (ICUs) and are accompanied by adverse outcomes. Because of lack of nursing staff resources and imperfect humanistic care, delirium is easily overlooked by both physicians and nurses in the ICU in Mainland China. PURPOSE: This study aimed to explore the incidence rate of delirium and to determine the risk factors among critically ill older patients. METHODS: A prospective observational study was conducted on patients aged 65 years and older who were admitted consecutively to two ICUs of a university-affiliated hospital in China. The Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale were used to assess delirium status twice daily. Patient demographic, laboratory, medical, therapeutic, and prognostic data were collected. RESULTS: One hundred fifteen patients were included as participants, with a median age of 70 years (range 65-93 years). Seventy-six (66.1%) patients presented with delirium. Half of the sample had a hypoactive subtype. Patients who developed delirium had a longer mean length of ICU stay, greater chance of physical restraints use, greater use of fentanyl, and poorer sleep quality. A logistic regression analysis revealed that poor sleep quality (OR = 10.74, 95% CI [1.59, 72.47]) and physical restraints (OR = 13.04, 95% CI [1.57, 107.94]) were significantly associated with delirium. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Delirium is a common aggravation in older patients following ICU admission. The factors found in this study to be independently associated with delirium include poor sleep quality and physical restraints. Both critical care physicians and nurses should pay greater attention to the quality of the ICU stay experienced by their older patients.


Assuntos
Delírio/complicações , Incidência , Idoso , Idoso de 80 Anos ou mais , Delírio/epidemiologia , Delírio/psicologia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Estudos Prospectivos , Fatores de Risco
7.
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.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(3): 313-318, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32385995

RESUMO

OBJECTIVE: To investigate the different outcomes of two types of acute kidney injury (AKI) according to standard of Kidney Disease: Improving Global Outcomes-AKI (KDIGO-AKI), and to analyze the risk factors that affect the prognosis of intensive care unit (ICU) patients in China. METHODS: A secondary analysis was performed on the database of a previous study conducted by China Critical Care Clinical Trial Group (CCCCTG), which was a multicenter prospective study involving 3 063 patients in 22 tertiary ICUs in 19 provinces and autonomous regions of China. The demographic data, scores reflecting severity of illness, laboratory findings, intervention during ICU stay were extracted. All patients were divided into pure AKI (PAKI) and acute on chronic kidney disease (AoCKD). PAKI was defined as meeting the serum creatinine (SCr) standard of KDIGO-AKI (KDIGO-AKISCr) and the estimated glomerular filtration rate (eGFR) at baseline was ≥ 60 mL×min-1×1.73 m-2, and AoCKD was defined as meeting the KDIGO-AKISCr standard and baseline eGFR was 15-59 mL×min-1×1.73 m-2. All-cause mortality in ICU within 28 days was the primary outcome, while the length of ICU stay and renal replacement therapy (RRT) were the secondary outcome. The differences in baseline data and outcomes between the two groups were compared. The cumulative survival rate of ICU within 28 days was analyzed by Kaplan-Meier survival curve, and the risk factors of ICU death within 28 days were screened by Cox multivariate analysis. RESULTS: Of the 3 063 patients, 1 042 were enrolled, 345 with AKI, 697 without AKI. The AKI incidence was 33.11%, while ICU mortality within 28 days of AKI patients was 13.91% (48/345). Compared with PAKI patients (n = 322), AoCKD patients (n = 23) were older [years old: 74 (59, 77) vs. 58 (41, 72)] and more critical when entering ICU [acute physiology and chronic health evaluation II (APACHE II) score: 23 (19, 27) vs. 15 (11, 22)], had worse basic renal function [eGFR (mL×min-1×1.73 m-2): 49 (38, 54) vs. 115 (94, 136)], more basic complications [Charlson comorbidity index (CCI): 3 (2, 4) vs. 0 (0, 1)] and higher SCr during ICU stay [peak SCr for diagnosis of AKI (µmol/L): 412 (280, 515) vs. 176 (124, 340), all P < 0.01]. The mortality and RRT incidence within 28 days in ICU of AoCKD patients were significantly higher than those of PAKI patients [39.13% (9/23) vs. 12.11% (39/322), 26.09% (6/23) vs. 4.04% (13/322), both P < 0.01], while no significant difference was found in the length of ICU stay. Kaplan-Meier survival curve analysis showed that the 28-day cumulative survival rate in ICU in AoCKD patients was significantly lower than PAKI patients (Log-Rank: χ 2 = 5.939, P = 0.015). Multivariate Cox regression analysis showed that admission to ICU due to respiratory failure [hazard ratio (HR) = 4.458, 95% confidence interval (95%CI) was 1.141-17.413, P = 0.032], vasoactive agents treatment in ICU (HR = 5.181, 95%CI was 2.033-13.199, P = 0.001), and AoCKD (HR = 5.377, 95%CI was 1.303-22.186, P = 0.020) were independent risk factors for ICU death within 28 days. CONCLUSIONS: Further detailed classification (PAKI, AoCKD) based on KDIGO-AKISCr standard combined with eGFR is related to ICU mortality in critical patients within 28 days.


Assuntos
Injúria Renal Aguda/sangue , Creatinina/sangue , Adulto , China , Estado Terminal , Humanos , Unidades de Terapia Intensiva , Estudos Prospectivos , Terapia de Substituição Renal , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
9.
Sci Rep ; 10(1): 7718, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382007

RESUMO

We investigated the role of dynamic changes of serum levels S100B protein in brain injury and poor outcome of sepsis. This is a prospective cohort study designed to include 104 adult patients with sepsis who are admitted to ICU from Jan 2015 to Aug 2016. Sepsis was defined as sepsis 3.0. Patients with a GCS score of <15, or at least one positive CAM-ICU score were thought to have brain dysfunction. 59 patients were diagnosed with SAE and the rest 45 patients were diagnosed with non-SAE. Serum S100B was measured on day 1 and 3 after ICU admission. Primary outcomes included brain dysfunction and 28-day/180-day mortality. The SAE group showed a significantly higher APACHE II score, SOFA scores, length of ICU stay, 28-day and 180-day mortality, serum S100B levels on day 1 and day 3. S100B levels on day 1 of 0.226 µg/L were diagnostic for SAE with 80.0% specificity and 66.1% sensitivity, and the area under (AUC) the curve was 0.728, S100B levels on day 3 of 0.144 µg/L were diagnostic for SAE with 84.44% specificity and 69.49% sensitivity, and the AUC was 0.819. In addition, the AUC for S100B on day 3 for predicting 180-day mortality was larger than for S100B on day 1 (0.731 vs. 0.611). Multiple logistic regression analysis showed that S100B3 (p = 0.001) but not S100B1 (p = 0.927) were independently correlated with SAE. Kaplan-Meier survival analysis showed that patients with S100B levels higher than 0.144 µg/L had a lower probability of survival at day 180. There were more patients with encephalopathy and a higher 28-day or 180-day mortality in the ΔS100B + group than in the ΔS100B- group. Multiple logistic regression analysis showed that SAE and IL-6 on day 3 were independently correlated with S100B dynamic increase. These findings suggest that elevated serum S100B levels on day 3 and the dynamic changes of serum S100B levels from day three to one were more associated with brain dysfunction and mortality than that on day 1 in patients with sepsis.


Assuntos
Lesões Encefálicas/sangue , Interleucina-6/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Encefalopatia Associada a Sepse/sangue , Lesões Encefálicas/epidemiologia , Lesões Encefálicas/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Encefalopatia Associada a Sepse/epidemiologia , Encefalopatia Associada a Sepse/patologia
10.
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
11.
Anesthesiology ; 132(6): 1317-1332, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32195705

RESUMO

The COVID-19 outbreak has led to 80,409 diagnosed cases and 3,012 deaths in mainland China based on the data released on March 4, 2020. Approximately 3.2% of patients with COVID-19 required intubation and invasive ventilation at some point in the disease course. Providing best practices regarding intubation and ventilation for an overwhelming number of patients with COVID-19 amid an enhanced risk of cross-infection is a daunting undertaking. The authors presented the experience of caring for the critically ill patients with COVID-19 in Wuhan. It is extremely important to follow strict self-protection precautions. Timely, but not premature, intubation is crucial to counter a progressively enlarging oxygen debt despite high-flow oxygen therapy and bilevel positive airway pressure ventilation. Thorough preparation, satisfactory preoxygenation, modified rapid sequence induction, and rapid intubation using a video laryngoscope are widely used intubation strategies in Wuhan. Lung-protective ventilation, prone position ventilation, and adequate sedation and analgesia are essential components of ventilation management.


Assuntos
Infecções por Coronavirus , Transmissão de Doença Infecciosa/prevenção & controle , Intubação Intratraqueal/normas , Pandemias , Pneumonia Viral , Respiração Artificial/normas , COVID-19 , China , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Hospitais/normas , Humanos , Pandemias/prevenção & controle , Seleção de Pacientes , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão
12.
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
13.
Chin Med J (Engl) ; 132(19): 2340-2347, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31567378

RESUMO

BACKGROUND: Studies have reported mitophagy activation in renal tubular epithelial cells (RTECs) in acute kidney injury (AKI). Phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and E3 ubiquitin-protein ligase Parkin are involved in mitophagy regulation; however, little is known about the role of PINK1-Parkin mitophagy in septic AKI. Here we investigated whether the PINK1-Parkin mitophagy pathway is involved in septic AKI and its effects on cell apoptosis in vitro and on renal functions in vivo. METHODS: Mitophagy-related gene expression was determined using Western blot assay in human RTEC cell line HK-2 stimulated with bacterial lipopolysaccharide (LPS) and in RTECs from septic AKI rats induced by cecal ligation and perforation (CLP). Autophagy-related ultrastructural features in rat RTECs were observed using electron microscopy. Gain- and loss-of-function approaches were performed to investigate the role of the PINK1-Parkin pathway in HK-2 cell mitophagy. Autophagy activators and inhibitors were used to assess the effects of mitophagy modulation on cell apoptosis in vitro and on renal functions in vivo. RESULTS: LPS stimulation could significantly induce LC3-II and BECN-1 protein expression (LC3-II: 1.72 ±â€Š0.05 vs. 1.00 ±â€Š0.05, P < 0.05; BECN-1: 5.33 ±â€Š0.57 vs. 1.00 ±â€Š0.14, P < 0.05) at 4 h in vitro. Similarly, LC3-II, and BECN-1 protein levels were significantly increased and peaked at 2 h after CLP (LC3-II: 3.33 ±â€Š0.12 vs. 1.03 ±â€Š0.15, P < 0.05; BECN-1: 1.57 ±â€Š0.26 vs. 1.02 ±â€Š0.11, P < 0.05) in vivo compared with those after sham operation. Mitochondrial deformation and mitolysosome-mediated mitochondria clearance were observed in RTECs from septic rats. PINK1 knockdown significantly attenuated LC3-II protein expression (1.35 ±â€Š0.21 vs. 2.38 ±â€Š0.22, P < 0.05), whereas PINK1 overexpression markedly enhanced LC3-II protein expression (2.07 ±â€Š0.21 vs. 1.29 ±â€Š0.19, P < 0.05) compared with LPS-stimulated HK-2 cells. LPS-induced proapoptotic protein expression remained unchanged in autophagy activator-treated HK-2 cells and was significantly attenuated in PINK1-overexpressing cells, but was remarkably upregulated in autophagy inhibitor-treated and in PINK1-depleted cells. Consistent results were observed in flow cytometric apoptosis assay and in renal function indicators in rats. CONCLUSION: PINK1-Parkin-mediated mitophagy might play a protective role in septic AKI, serving as a potential therapeutic target for septic AKI.


Assuntos
Injúria Renal Aguda/fisiopatologia , Mitofagia/fisiologia , Proteínas Quinases/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Animais , Proteína Beclina-1/análise , Células Cultivadas , Células Epiteliais/fisiologia , Humanos , Túbulos Renais/citologia , Lipopolissacarídeos , Proteínas Associadas aos Microtúbulos/análise , Ratos , Ratos Sprague-Dawley , Sepse/fisiopatologia
14.
Pathobiology ; 86(5-6): 263-273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430762

RESUMO

BACKGROUND: Mitochondrial transcription factor A (TFAM) plays multiple pathophysiologic roles in mitochondrial DNA (mtDNA) maintenance. However, the role of TFAM in sepsis-induced acute kidney injury (AKI) remains largely unknown. METHODS: Lipopolysaccharide (LPS) treatment of HK-2 cells mimics the in vitro model of AKI inflammation. pcDNA3.1 plasmid was used to construct pcDNA3.1-TFAM. sh-TFAM-543, sh-TFAM-717, sh-TFAM-765, sh-TFAM-904 and pcDNA3.1-TFAM were transfected into HK-2 cells using Lipofectamine 2000. MtDNA transcriptional levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was performed to assess the cell viability. Changes in reactive oxygen species (ROS) and mitochondrial membrane potential in HK-2 cells were detected using the corresponding kits. Immunofluorescence experiment was used to investigate the displacement of TFAM. mRNA and protein expression levels of TFAM and its related genes were measured by qRT-PCR and western blot respectively. Mice in sepsis were administered cecal ligation and puncture surgery. RESULTS: LPS treatment was a non-lethal influencing factor, leading to the upregulation of ROS levels and downregulation of mtDNA copy number and NADH dehydrogenase subunit-1 (ND1) expression, and caused damage to the mitochondria. As the LPS treatment time increased, TFAM was displaced from the periphery of the nucleus to cytoplasm. TFAM reduced ROS and P38MAPK levels by inhibiting toll-like receptor 4 (TLR4) expression, ultimately inhibiting inflammation and repairing mtDNA. CONCLUSIONS: Our results indicate that TFAM repairs mtDNA by blocking the TLR4/ROS/P38MAPK signaling pathway in inflammatory cells, thereby repairing septic tubular epithelial cells, and TFAM may serve as a new target for sepsis therapy.


Assuntos
Proteínas de Ligação a DNA/genética , Células Epiteliais/patologia , Proteínas Mitocondriais/genética , Espécies Reativas de Oxigênio/metabolismo , Sepse/genética , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Fatores de Transcrição/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Linhagem Celular , Humanos , Túbulos Renais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Sepse/patologia
15.
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
16.
J Crit Care ; 52: 172-179, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078998

RESUMO

PURPOSE: We investigated the role of serum Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin C-Terminal Hydrolase-L1 (UCH-L1) in diagnosis of sepsis-associated encephalopathy(SAE), predicting prognosis and long-term quality of life with patients of sepsis. MATERIALS AND METHODS: This is a prospective single center study entailed 105 patients whosuffered from sepsis from Jan 2015 to Aug 2016. Serum concentrations of GFAP and UCH-L1 for diagnosis of SAE and predicting prognosis and long-term quality of life with patients of sepsis were analyzed. RESULTS: The serum concentrations of GFAP and UCH-L1 were higher in SAE group than in no-SAE group (p < .001). GFAP and UCH-L1 produced an AUC of 0.824 and 0.812 respectively for diagnosis of SAE with optimal cut-off values 0.532 ng/ml and 7.72 ng/ml respectively. The optimal cut-off values of GFAP and UCH-L1 to distinguish patients with survivors from non-survivors were 0.536 ng/ml and 8.06 ng/ml with an area under the curve of 0.773 and 0.746. Patients with a higher GFAP levels had worse long-term usual activities and patients with a higher UCH-L1 levels had more long-term pain (P = .026). CONCLUSIONS: Serum concentrations GFAP and UCH-L1 early elevated and associated with sepsis-associated encephalopathy, poor prognosis and quality of life.


Assuntos
Proteína Glial Fibrilar Ácida/metabolismo , Encefalopatia Associada a Sepse/diagnóstico , Ubiquitina Tiolesterase/metabolismo , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Encefalopatia Associada a Sepse/sangue
17.
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
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 43(10): 1112-1117, 2018 Oct 28.
Artigo em Chinês | MEDLINE | ID: mdl-30523232

RESUMO

OBJECTIVE: To investigate the changes of myocardial glucose metabolism in rabbit cardiac arrest models and the effect of hydrogen intervention by 18F-fluroro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) imaging.
 Methods: Fifteen male New Zealand white rabbits were randomly divided into a hydrogen group (n=6), a control group (n=6) and a sham group (n=3). Cardiac arrest (CA) was induced by intravenous injection of potassium chloride. Conventional cardiopulmonary resuscitation (CPR) was initiated after five-minutes CA. The hydrogen group and the control group were mechanically ventilated into mixed gas with 4% hydrogen+96% oxygen and pure oxygen, respectively, for 30 minutes after CPR. Rats in the sham group was performed the same surgical procedure and was injected adrenaline and potassium chloride but did not induce CA. The vital signs at basic state and 30 min after return of spontaneous circulation (ROSC) were recorded in each group. The parameters of CPR were recorded in two CA groups. Myocardial glucose metabolism was assessed by positron emission tomography (PET) at basic state, 2 h and 24 h after ROSC. The maximum standardized uptake value (SUVmax) of 18F-FDG was measured.
 Results: There were no significant differences in the basal body weight and vital signs among the three groups. There was no significant difference in the blood glucose level before PET examination. The 18F-FDG SUVmax in the sham group at three time points was not significantly changed. In the hydrogen group and the control group, the 18F-FDG SUVmax at 2 h after ROSC were significantly higher than the basic level (1.89±0.47 vs 3.47±1.24 and 1.90±0.36 vs 4.26±0.80, respectively). Compared with the control group, the 18F-FDG SUVmax in the hydrogen group was lower at the point at 2 h after ROSC. The 18F-FDG SUVmax in the 2 CA group were down to the basic level at 24 h after ROSC (hydrogen group 2.02±0.64, control group 2.07±0.61).
 Conclusion: Myocardial glucose metabolism in CA rabbits was increased significantly after ROSC, and hydrogen intervention can reduce the degree of glucose metabolism.


Assuntos
Glucose , Parada Cardíaca , Miocárdio/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Reanimação Cardiopulmonar , Glucose/metabolismo , Parada Cardíaca/fisiopatologia , Parada Cardíaca/cirurgia , Masculino , Coelhos , Distribuição Aleatória , Ratos
19.
Crit Care ; 22(1): 229, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30244686

RESUMO

BACKGROUND: There is a lack of large-scale epidemiological data on the clinical practice of enteral nutrition (EN) feeding in China. This study aimed to provide such data on Chinese hospitals and to investigate factors associated with EN delivery. METHODS: This cross-sectional study was launched in 118 intensive care units (ICUs) of 116 mainland hospitals and conducted on April 26, 2017. At 00:00 on April 26, all patients in these ICUs were included. Demographic and clinical variables of patients on April 25 were obtained. The dates of hospitalization, ICU admission and nutrition initiation were reviewed. The outcome status 28 days after the day of investigation was obtained. RESULTS: A total of 1953 patients were included for analysis, including 1483 survivors and 312 nonsurvivors. The median study day was day 7 (IQR 2-19 days) after ICU entry. The proportions of subjects starting EN within 24, 48 and 72 h after ICU entry was 24.8% (84/352), 32.7% (150/459) and 40.0% (200/541), respectively. The proportion of subjects receiving > 80% estimated energy target within 24, 48, 72 h and 7 days after ICU entry was 10.5% (37/352), 10.9% (50/459), 11.8% (64/541) and 17.8% (162/910), respectively. Using acute gastrointestinal injury (AGI) 1 as the reference in a Cox model, patients with AGI 2-3 were associated with reduced likelihood of EN initiation (HR 0.46, 95% CI 0.353-0.599; p < 0.001). AGI 4 was significantly associated with lower hazard of EN administration (HR 0.056; 95% CI 0.008-0.398; p = 0.004). In a linear regression model, greater Sequential Organ Failure Assessment scores (coefficient - 0.002, 95% CI - 0.008 to - 0.001; p = 0.024) and male gender (coefficient - 0.144, 95% CI - 0.203 to - 0.085; p < 0.001) were found to be associated with lower EN proportion. As compared with AGI 1, AGI 2-3 was associated with lower EN proportion (coefficient - 0.206, 95% CI - 0.273 to - 0.139; p < 0.001). CONCLUSIONS: The study showed that EN delivery was suboptimal in Chinese ICUs. More attention should be paid to EN use in the early days after ICU admission.


Assuntos
Nutrição Enteral/normas , Resultado do Tratamento , APACHE , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , China , Estudos Transversais , Nutrição Enteral/métodos , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Modelos de Riscos Proporcionais
20.
Intensive Care Med ; 44(10): 1638-1656, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30105599

RESUMO

PURPOSE: The association between conflicts of interest (COI) and study results or article conclusions in goal-directed hemodynamic therapy (GDHT) research is unknown. METHODS: Randomized controlled trials comparing GDHT with usual care were identified. COI were classified as industry sponsorship, author conflict, device loaner, none, or not reported. The association between COI and study results (complications and mortality) was assessed using both stratified meta-analysis and mixed effects meta-regression. The association between COI and an article's conclusion (graded as GDHT-favorable, neutral, or unfavorable) was investigated using logistic regression. RESULTS: Of the 82 eligible articles, 43 (53%) had self-reported COI, and 50 (61%) favored GDHT. GDHT significantly reduced complications on the basis of the meta-analysis of studies with any type of COI, studies declaring no COI, industry-sponsored studies, and studies with author conflict but not on studies with a device loaner. However, no significant relationship between COI and the relative risk (GDHT vs. usual care) of developing complications was found on the basis of meta-regression (p = 0.25). No significant effect of GDHT was found on mortality. COI had a significant overall effect (p = 0.016) on the odds of having a GDHT-favorable vs. neutral conclusion based on 81 studies. Eighty-four percent of the industry-sponsored studies had a GDHT-favorable conclusion, while only 27% of the studies with a device loaner had the same conclusion grade. CONCLUSIONS: The available evidence does not suggest a close relationship between COI and study results in GDHT research. However, a potential association may exist between COI and an article's conclusion in GDHT research.


Assuntos
Conflito de Interesses , Hidratação , Objetivos , Hemodinâmica , Humanos , Tempo de Internação , Modelos Logísticos , Autorrelato
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