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Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective antiviral treatments including nirmatrelvir/ritonavir can improve their outcomes. However, there might be potential drug-drug interactions when these patients take nirmatrelvir/ritonavir together with immunosuppressants with a narrow therapeutic window, such as tacrolimus and cyclosporine. We present a case of paralytic ileus resulting from tacrolimus toxicity mediated by the use of nirmatrelvir/ritonavir in a patient with systemic lupus erythematosus (SLE). A 37-year-old female SLE patient was prescribed nirmatrelvir/ritonavir without discontinuing tacrolimus. She presented to the emergency room with symptoms of paralytic ileus including persistent abdominal pain, nausea, and vomiting, which were verified to be associated with tacrolimus toxicity. The blood concentration of tacrolimus was measured >30 ng/mL. Urgent medical intervention was initiated, while tacrolimus was withheld. The residual concentration was brought within the appropriate range and tacrolimus was resumed 8 days later. Physicians must be aware of the potential DDIs when prescribing nirmatrelvir/ritonavir, especially to those taking immunosuppresants like tacrolimus.
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Introduction: In the middle of December 2022, the Chinese government adjusted the lockdown policy on coronavirus disease 2019 (COVID-19), a large number of infected patients flooded into the emergency department. The emergency medical staff encountered significant working and mental stress while fighting the COVID-19 pandemic. We aimed to investigate the workload change, and the prevalence and associated factors for depression symptoms among emergency medical staff after the policy adjustment. Methods: We conducted a cross-sectional online survey of emergency medical staff who fought against COVID-19 in Shandong Province during January 16 to 31, 2023. The respondents' sociodemographic and work information were collected, and they were asked to complete the 9-item Patient Health Questionnaire (PHQ-9) then. Univariate and multivariate logistic regression analyses were applied to identify the potential associated factors for major depression. Results: Nine hundred and sixteen emergency medical personnel from 108 hospitals responded to this survey. The respondents' weekly working hours (53.65 ± 17.36 vs 49.68 ± 14.84) and monthly night shifts (7.25 ± 3.85 vs 6.80 ± 3.77) increased after the open policy. About 54.3% of the respondents scored more than 10 points on the PHQ-9 standardized test, which is associated with depressive symptoms. In univariate analysis, being doctors, living with family members aged ≤16 or ≥ 65 years old, COVID-19 infection and increased weekly working hours after the open policy were significantly associated with a PHQ-9 score ≥ 10 points. In the multivariate analysis, only increased weekly working hours showed significant association with scoring ≥10 points. Conclusion: Emergency medical staff' workload had increased after the open policy announcement, which was strongly associated with a higher PHQ-9 scores, indicating a very high risk for major depression. Emergency medical staff working as doctors or with an intermediate title from grade-A tertiary hospitals had higher PHQ-9 scores, while COVID-19 infection and weekly working hours of 60 or more after the open policy were associated with higher PHQ-9 scores for those from grade-B tertiary hospitals. Hospital administrators should reinforce the importance of targeted emergency medical staff support during future outbreaks.
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COVID-19 , Humanos , Idoso , COVID-19/epidemiologia , Estudos Transversais , Carga de Trabalho , Depressão/epidemiologia , SARS-CoV-2 , Pandemias , Controle de Doenças Transmissíveis , Corpo ClínicoRESUMO
OBJECTIVE: This retrospective multicentre observational study was performed to assess the predictors of acute kidney injury (AKI) in patients with acute decompensated heart failure (ADHF) in emergency departments in China. METHODS: In total, 1743 consecutive patients with ADHF were recruited from August 2017 to January 2018. Clinical characteristics and outcomes were compared between patients with and without AKI. Predictors of AKI occurrence and underdiagnosis were assessed in multivariate regression analyses. RESULTS: Of the 1743 patients, 593 (34.0%) had AKI. AKI was partly associated with short-term all-cause mortality and cost. Cardiovascular comorbidities such as coronary heart disease, diabetes mellitus, and hypertension remained significant predictors of AKI in the univariate analysis. AKI was significantly more likely to occur in patients with a lower arterial pH, lower albumin concentration, higher creatinine concentration, and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. Patients treated with inotropic agents were significantly more likely to develop AKI during their hospital stay. CONCLUSION: This study suggests that cardiovascular comorbidities, arterial pH, the albumin concentration, the creatinine concentration, the NT-proBNP concentration, and use of inotropic agents are predictors of AKI in patients with ADHF.
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Injúria Renal Aguda , Insuficiência Cardíaca , Doença Aguda , Injúria Renal Aguda/diagnóstico , Biomarcadores , Serviço Hospitalar de Emergência , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis worldwide. Data on critically ill TBM patients in the intensive care unit (ICU) of China are lacking. We tried to identify prognostic factors of adult TBM patients admitted to ICU in China. METHODS: We conducted a retrospective study on adult TBM in ICU between January 2008 and April 2018. Factors associated with unfavorable outcomes at 28 days were identified by logistic regression. Factors associated with 1-year mortality were studied by Cox proportional hazards modeling. RESULTS: Eighty adult patients diagnosed with TBM (age 38.5 (18-79) years, 45 (56 %) males) were included in the study. An unfavorable outcome was observed in 39 (49 %) patients and were independently associated with Acute Physiology and Chronic Health Evaluation (APACHE) II > 23 (adjusted odds ratio (aOR) 5.57, 95 % confidence interval (CI) 1.55-19.97), Sequential Organ Failure Assessment (SOFA) > 8 (aOR 9.74, 95 % CI 1.46-64.88), and mechanical ventilation (aOR 18.33, 95 % CI 3.15-106.80). Multivariate Cox regression analysis identified two factors associated with 1-year mortality: APACHE II > 23 (adjusted hazard ratio (aHR) 4.83; 95 % CI 2.21-10.55), and mechanical ventilation (aHR 9.71; 95 % CI 2.31-40.87). CONCLUSIONS: For the most severe adult TBM patients of Medical Research Council (MRC) stage III, common clinical factors aren't effective enough to predict outcomes. Our study demonstrates that the widely used APACHE II and SOFA scores on admission can be used to predict short-term outcomes, while APACHE II could also be used to predict long-term outcomes of adult patients with TBM in ICU.
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Tuberculose Meníngea , APACHE , Adulto , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Masculino , Prognóstico , Estudos Retrospectivos , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/epidemiologia , Tuberculose Meníngea/terapiaRESUMO
OBJECTIVE: To find effective methods to improve the distribution and usage efficiency of pre-hospital epidemic emergency care resource (PEECR) by analyzing the PEECR allocation and usage in Jinan City during the coronavirus disease 2019 (COVID-19) epidemic. METHODS: Correlation significance test between the COVID-19 epidemiology sample and the PEECR allocation sample was conducted to estimate whether they came from the same population in Jinan from January 24 to June 30, 2020. The data used in empirical analysis were collected from the Health Commission of Shandong Province's daily epidemic information announcement (definite case increment, suspected case increment, suspected case stock, medical observation stock, close contact increment) and interview with some epidemic branch centers in Jinan City (vehicle using increment). Experiential analysis was used to analyze the waste of PEECR usage. RESULTS: All the 5 COVID-19 epidemiology samples and the PEECR allocation sample came from different population. There was no correlation between the vehicle using increment and definite case increment, suspected case increment, suspected case stock, close contact increment (all P < 0.05), there was a weak correlation between the vehicle using increment and medical observation stock [the correlation coefficient was 0.048, ∈ (0.0, 0.2), P = 0.550]. There was systematic difference between PEECR indicator and COVID-19 epidemiology indicator. The waste in practice was also amplified by improper usage such as unsophisticated allocation, low effectiveness in primary units and unvalid emergency calling. CONCLUSIONS: (1) A primary screening system should be established in control center to decrease the waste of efficiency. (2) Communities and units should improve overall epidemic dealing ability to assist emergency system. (3) The medical treatment ability and protection resource should be increased in normal pre-hospital care.
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Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , China/epidemiologia , Humanos , Alocação de Recursos , SARS-CoV-2RESUMO
AIMS: Atherosclerosis (AS) performs the important pathogenesis which refers to coronaryheart and vascular diseases. Long non-coding RNAs (lncRNAs) was reported to be related to the AS progression. We aimed to probe the role and potential mechanism of Myocardial Infarction Associated Transcript (MIAT) in AS. MATERIALS AND METHODS: Levels of MIAT, microRNA-148b (miR-148b) and pregnancy-associated plasma protein A (PAPPA) were detected by quantitative Real-time polymerase chain reaction (qRT-PCR) in oxidized low-density lipoprotein (ox-LDL)-induced human aorta vascular smooth muscle cells (HA-VSMCs). Proliferation and migration were examined by Cell counting kit-8 (CCK-8) and wound-healing assays, respectively. Protein levels of Ki-67, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2, MMP-9 and PAPPA were examined by western blot assay. Ki-67 and PCNA level was detected by flow cytometry. The interaction among MIAT, miR-148b and PAPPA was confirmed via dual-luciferase reporter and RNA immunoprecipitation (RIP). The biology role of MIAT was detected by an AS model in vivo. KEY FINDINGS: The levels of MIAT and PAPPA were augmented, whereas mature miR-148b level was repressed in ox-LDL-induced AS model. The inhibitory effects of knockdown of MIAT on proliferation and migration were relieved by miR-148b inhibitor. Additionally, miR-148b regulated proliferation and migration by targeting PAPPA. Mechanically, MIAT functioned as sponge of miR-148b to impact PAPPA expression. MIAT knockdown protected AS mice against lipid metabolic disorders in vivo. SIGNIFICANCE: Proliferation and migration were modified by MIAT/miR-148b/PAPPA axis in ox-LDL induced AS cell model, supplying a novel insight into the underlying application of MIAT in the clinical treatment of AS.
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Aterosclerose/patologia , MicroRNAs/genética , Proteína Plasmática A Associada à Gravidez/metabolismo , RNA Longo não Codificante/genética , Animais , Aterosclerose/genética , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Lipoproteínas LDL/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
OBJECTIVE: The aim of the study was to determine whether the inhibition of the G-protein-coupled receptor kinase 2 by adenoviral ßARKct cardiac gene transfer can ameliorate postresuscitation myocardial injury in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. METHODS: Male landrace domestic pigs were randomized into the sham group (anesthetized and instrumented, but ventricular fibrillation was not induced) (nâ=â4), control group (ventricular fibrillation 8âmin, nâ=â8), and ßARKct group (ventricular fibrillation 8âmin, nâ=â8). Hemodynamic parameters were monitored continuously. Blood samples were collected at baseline, 30âmin, 2âh, 4âh, and 6âh after the return of spontaneous circulation (ROSC). Left ventricular ejection fraction was assessed by echocardiography at baseline and 6âh after ROSC. These animals were euthanized, and the cardiac tissue was removed for analysis at 6âh after ROSC. RESULTS: Compared with those in the sham group, left ventricular +dp/dtmax, -dp/dtmax, cardiac output (CO), and ejection fraction (EF) in the control group and the ßARKct group were significantly decreased at 6âh after the restoration of spontaneous circulation. However, the ßARKct treatment produced better left ventricular +dp/dtmax, -dp/dtmax, CO, and EF after ROSC. The ßARKct treatment also produced lower serum cardiac troponin I, CK-MB, and lactate after ROSC. Furthermore, the adenoviral ßARKct gene transfer significantly increased ß1 adrenergic receptors, SERCA2a, RyR2 levels, and decreased GRK2 levels compared to control. CONCLUSIONS: The inhibition of GRK2 by adenoviral ßARKct cardiac gene transfer can ameliorate postresuscitation myocardial injury through beneficial effects on restoring the sarcoplasmic reticulum Ca-handling proteins expression and upregulating the ß1-adrenergic receptor level after cardiac arrest.
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Adenoviridae , Reanimação Cardiopulmonar , Quinase 2 de Receptor Acoplado a Proteína G , Parada Cardíaca , Traumatismos Cardíacos , Transdução Genética , Animais , Modelos Animais de Doenças , Quinase 2 de Receptor Acoplado a Proteína G/biossíntese , Quinase 2 de Receptor Acoplado a Proteína G/genética , Parada Cardíaca/genética , Parada Cardíaca/metabolismo , Parada Cardíaca/patologia , Parada Cardíaca/terapia , Traumatismos Cardíacos/genética , Traumatismos Cardíacos/metabolismo , Traumatismos Cardíacos/patologia , Traumatismos Cardíacos/terapia , Masculino , SuínosRESUMO
Non-coding RNAs (ncRNAs) have been emerging players in cell development, differentiation, proliferation and apoptosis. Based on their differences in length and structure, they are subdivided into several categories including long non-coding RNAs (lncRNAs >200nt), stable non-coding RNAs (60-300nt), microRNAs (miRs or miRNAs, 18-24nt), circular RNAs, piwi-interacting RNAs (26-31nt) and small interfering RNAs (about 21nt). Therein, miRNAs not only directly regulate gene expression through pairing of nucleotide bases between the miRNA sequence and a specific mRNA that leads to the translational repression or degradation of the target mRNA, but also indirectly affect the function of downstream genes through interactions with lncRNAs and circRNAs. The latest studies have highlighted their importance in physiological and pathological processes. MiR-374 family member are located at the X-chromosome inactivation center. In recent years, numerous researches have uncovered that miR-374 family members play an indispensable regulatory role, such as in reproductive disorders, cell growth and differentiation, calcium handling in the kidney, various cancers and epilepsy. In this review, we mainly focus on the role of miR-374 family members in multiple physiological and pathological processes. More specifically, we also summarize their promising potential as novel prognostic biomarkers and therapeutic targets from bench to bedside.
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Biomarcadores Tumorais/genética , Proliferação de Células/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Apoptose/genética , Epilepsia/genética , Epilepsia/patologia , Regulação da Expressão Gênica , Genes Ligados ao Cromossomo X , Humanos , Neoplasias/genética , Neoplasias/patologia , RNA Circular/genética , Inativação do Cromossomo X/genéticaRESUMO
Orexin A is a multifaceted peptide produced in hypothalamus. We examined the effect of orexin A on vascular endothelial cells. Our study showed that orexin A had a profound inhibitory effect against endothelial inflammation by oxidized low-density lipoprotein (ox-LDL) in endothelial cells. Orexin A partially suppressed ox-LDL-induced monocytes THP-1 cells attachment to endothelial cells by limiting expression of vascular molecules including VCAM-1, ICAM-1, and E-selectin. Mechanistically, orexin A ameliorated endothelial dysfunction by reducing MAP kinase p38 and NF-κB activation via its receptor-OX1R. Orexin A suppressed phosphorylation of MAP kinase p38 and the NF-κB cascade kinases IKKα and IκBα, and prevented the shuttle of p65 protein into nuclear. Additionally, we reported that OX1R was expressed in HUVECs. Silence of OX1R completely abolished the inhibitory function of orexin in attachment of THP-1 cells. Collectively, our data suggest that orexin A ameliorated endothelial dysfunction under inflammatory stimuli. © 2018 IUBMB Life, 70(10):961-968, 2018.
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Inflamação/genética , NF-kappa B/genética , Receptores de Orexina/genética , Orexinas/genética , Selectina E/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/patologia , Molécula 1 de Adesão Intercelular/genética , Lipoproteínas LDL/antagonistas & inibidores , Monócitos/metabolismo , Monócitos/patologia , Receptores de Orexina/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/genética , Molécula 1 de Adesão de Célula Vascular/genética , eIF-2 Quinase/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
The present study investigated the effects of nicorandil on cerebral injury following cardiopulmonary resuscitation (CPR) in a swine model of cardiac arrest. CPR was performed on swine following 4 min induced ventricular fibrillation. Surviving animals were randomly divided into 3 groups: A nicorandil group (n=8), a control group (n=8) and a sham group (n=4). The sham group underwent the same surgical procedure to imitate cardiac arrest, but ventricular fibrillation was not induced. When the earliest observable return of spontaneous circulation (ROSC) was detected, the nicorandil and control groups received injections of nicorandil and saline, respectively. Swine serum was collected at baseline and 5 min, 0.5, 3 and 6 h following ROSC. Serum levels of neuron-specific enolase (NSE), S100ß, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured using ELISA. Animals were euthanized and brain tissue samples were collected and assessed using light and electron microscopy 6 h following ROSC. The expression of aquaporin-4 (AQP-4) in the brain tissue was measured using western blotting. Malondialdehyde (MDA) and glutathione (GSH) levels in the brain tissue were determined using thiobarbituric acid and thiobenzoic acid colorimetric methods, respectively. Serum NSE and S100ß were significantly higher in the nicorandil and control groups following CPR, compared with baseline (P<0.05). Additionally, NSE and S100ß levels were significantly lower in the nicorandil group compared with the control (P<0.05). Pathological examinations and electron microscopy indicated that nicorandil reduced brain tissue damage. TNF-α and IL-6 levels were significantly decreased in the nicorandil group compared with the control group (P<0.05). Furthermore, AQP-4 expression in brain tissue 6 h following ROSC was significantly lower in the nicorandil group compared with the control group (P<0.05). MDA and GSH levels in swine brain tissue decreased and increased, respectively, in the nicorandil group compared with the control group (P<0.05). The results of the present study demonstrate that nicorandil exerts a protective effect against brain injury following cardiac arrest by reducing oxidative damage, inflammatory responses and brain edema post-ROSC.
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OBJECTIVE: To observe the effect of mild hypothermia on myocardial ß-adrenergic receptor (ß-AR) signal pathway after cardiopulmonary resuscitation (CPR) in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. METHODS: Healthy male Landraces were collected for reproducing the CA-CPR model (after 8-minute untreated ventricular fibrillation, CPR was implemented). The animals were divided into two groups according to random number table (n = 8). In the mild hypothermia group, the blood temperature of the animals was induced to 33 centigrade and maintained for 6 hours within 20 minutes after return of spontaneous circulation (ROSC) by using a hypothermia therapeutic apparatus. In the control group, the body temperature of the animals was maintained at (38.0±0.5)centigrade with cold and warm blankets. The heart rate (HR), mean arterial pressure (MAP), the maximum rate of increase or decrease in left rentricular pressure (+dp/dt max) were measured during the course of the experiment. The cardiac output (CO) was measured by heat dilution methods before CA (baseline), and 0.5, 1, 3, 6 hours after ROSC respectively, the venous blood was collected to detect the concentration of cTnI. Left ventricular ejection fraction (LVEF) was measured with cardiac ultrasound before CA and 6 hours after ROSC. Animals were sacrificed at 6 hours after ROSC and the myocardial tissue was harvested quickly, the mRNA expression of ß1-AR in myocardium was detected by reverse transcription-polymerase chain reaction (RT-PCR), the contents of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) were detected by enzyme linked immunosorbent assay (ELISA), the protein content of G protein-coupled receptor kinase 2 (GRK2) was detected by Western Blot. RESULTS: After successful resuscitation, the HR of both groups were significantly higher than the baseline values, CO, ±dp/dt max were significantly decreased, MAP were not significantly changed, serum cTnI levels were significantly increased. Compared with the control group, HR at 0.5, 1, 3 hours after ROSC were significantly decreased in mild hypothermia group (bpm: 142.80±12.83 vs. 176.88±15.14, 115.80±11.48 vs. 147.88±18.53, 112.60±7.40 vs. 138.50±12.02, all P < 0.01), CO was significantly increased at 1 hours and 3 hours after ROSC (L/min: 3.97±0.40 vs. 3.02±0.32, 4.00±0.11 vs. 3.11±0.59, both P < 0.01), +dp/dt max at 3 hours and 6 hours was also significantly increased after ROSC [+dp/dt max (mmHg/s): 3 402.5±612.7 vs. 2 130.0±450.6, 3 857.5±510.4 vs. 2 562.5±633.9; -dp/dt max (mmHg/s): 2 935.0±753.2 vs. 1 732.5±513.6, 3 520.0±563.6 vs. 2 510.0±554.3, all P < 0.05], the cTnI was significantly decreased at 3 hours and 6 hours afher ROSC (µg/L: 1.39±0.40 vs. 3.24±0.78, 1.46±0.35 vs. 3.78±0.93, both P < 0.01). The left at 6 hours after ROSC in both groups was decreased as compared with that before CA. The LVEF in the mild hypothermia group was higher than that in the control group (0.52±0.04 vs. 0.40±0.05, P < 0.05). The mRNA expression of ß1-AR, and concentrations of AC and cAMP in hypothermia group were significantly higher than those in control group [ß1-AR mRNA (2-ΔΔCT): 1.18±0.39 vs. 0.55±0.17, AC (ng/L): 197.0±10.5 vs. 162.0±6.3, cAMP (nmol/L): 1 310.58±48.82 vs. 891.25±64.95, all P < 0.05], GRK2 was lower than that in the control group (GRK2/GAPDH: 0.45±0.05 vs. 0.80±0.08, P < 0.05). CONCLUSIONS: Mild hypothermia can reduce the degree of cardiac function injury after CPR, and its mechanism may be related to the reduction of impaired myocardial ß-AR signaling after CPR.
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Parada Cardíaca , Adrenérgicos , Animais , Reanimação Cardiopulmonar , Hipotermia Induzida , Masculino , Suínos , Fibrilação VentricularRESUMO
It has been previously reported that Rhokinase (ROCK) and poly ADP-ribose polymerase (PARP) serve critical roles in myocardial ischemia/reperfusion (I/R) injury. Studies have additionally demonstrated that the activation of ROCK and the expression of PARP are increased in I/R. However, the effect and mechanism of the two proteins remains to be fully elucidated in I/R. In addition, whether they can be influenced by each other is unclear. In the present study, it was demonstrated that ischemia followed by reperfusion resulted in a significant increase in ROCK and PARP. In addition, Y27632 (ROCK inhibitor) and 3aminobenzamide (3AB; PARP inhibitor) pretreatment rescued myocardial infarction size and cardiomyocyte apoptosis. The inhibitory role of Y27632 was observed to be superior to that of the 3AB group. In addition, Y27632 and 3AB diminished extracellular signalrelated kinase (ERK) phosphorylation and the production of tumor necrosis factor α and interleukin 6. Overall, the results of the present study suggested that the inhibition of ROCK leads to reduced myocardial infarction size and cardiomyocyte apoptosis via the PARP/ERK signaling pathway.
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Apoptose , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Feminino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Increasing evidence indicate that the Krüppel-like factor KLF15, a member of Cys2/His2 zinc-finger DNA-binding proteins, attenuates cardiac hypertrophy. However, the role of KLF15 in cardiovascular system is largely unknown and the exact molecular mechanism of its protective function is not fully elucidated. In the present study, we established a mouse model of cardiac hypertrophy and found that KLF15 expression was down-regulated in hypertrophic hearts. To evaluate the roles of KLF15 in cardiac hypertrophy, we generated transgenic mice overexpressing KLF15 of KLF15 knockdown mice and subsequently induced cardiac hypertrophy. The results indicated that KLF15 overexpression protects mice from ISO-induced cardiac hypertrophy, with reduced ratios of heart weight (HW)/body weight (BW) and cross-sectional area. We also observed that KLF15 overexpression attenuated cardiac fibrosis, inhibited apoptosis and induced autophagy in cardiomyocytes compared with KLF15 knockdown mice. More importantly, we found that the KLF15 overexpression inhibited the Akt/mTOR signaling pathway. Taken together, our findings imply that KLF15 possesses potential anti-hypertrophic and anti-fibrotic functions, possibly via regulation of cell death pathways and the inhibition of Akt/mTOR axis. KLF15 may constitute an efficient candidate drug for the treatment of heart failure and other cardiovascular diseases.
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Apoptose , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proteínas de Ligação a DNA/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Regulação da Expressão Gênica , Isoproterenol , Fatores de Transcrição Kruppel-Like , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
INTRODUCTION: Nicorandil, a vasodilatory drug used to treat angina, was reported to protect against myocardial ischemia-reperfusion injury in various animal models. However, its cardioprotective action following cardiac arrest is unknown. We examined the cardioprotective effects of nicorandil in a porcine model of cardiac arrest and resuscitation. METHODS: Ventricular fibrillation was induced electrically for 4min in anesthetized domestic swine, followed by cardiopulmonary resuscitation. Sixteen successfully resuscitated animals were randomized to saline control (n=8) or nicorandil (n=8) groups. Nicorandil (150µg/kg) was administered by central intravenous injection at onset of restoration of spontaneous circulation (ROSC), followed by 3µg/kg/min infusion until reperfusion end. Sham-operated animals received surgery only (n=4). Hemodynamic parameters were monitored continuously. Blood samples were taken at baseline, 5, 30, 180, and 360min after ROSC. Left ventricular ejection fraction was assessed by echocardiography at baseline and 6h after ROSC. The animals were euthanized 6h after ROSC, and the cardiac tissue was removed for analysis. RESULTS: 6 h after ROSC, nicorandil had significantly improved all hemodynamic variables (all P<0.05) except the maximum rate of left ventricular pressure decline and heart rate (P>0.05) compared with the control group. Control animals showed elevated cardiac troponin I and lactate levels compared with sham animals, which were significantly decreased following nicorandil treatment (P<0.05). In the saline control group, the adenosine triphosphate (ATP) content was largely reduced but subsequently rescued by nicorandil (P<0.05). Histopathologic injury was reduced with nicorandil treatment. Nicorandil reduced cardiomyocyte apoptosis as evidenced by reduced terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, decreased Bax and caspase-3 expression, and increased Bcl-2 expression in the myocardium (all P<0.05). CONCLUSION: Nicorandil exhibited cardioprotective effects on myocardial injury following cardiac arrest via improvement in post-resuscitation myocardial dysfunction and energy metabolism, reduction in myocardial histopathologic injury, and antiapoptotic effects.
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Cardiotônicos/farmacologia , Parada Cardíaca/patologia , Nicorandil/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Fibrilação Ventricular/patologia , Animais , Modelos Animais de Doenças , Injeções Intravenosas , Masculino , SuínosRESUMO
Gastric cancer is the second leading cause of cancer-associated mortality and is a frequently occurring cancer worldwide. Multiple drug resistance of gastric cancer cells leads to the poor prognosis. In addition, overexpression of anti-apoptotic protein B-cell lymphoma (Bcl)-2 have been demonstrated in various cancer cells and is closely associated with drug resistance and poor prognosis. Naringenin is a flavonoid that has antimutagenic and anticarcinogenic activities in numerous cancer types. In the present study, naringenin and a Bcl-2 inhibitor, ABT-737, were used to investigate their combinative anticancer effect in the SGC7901 gastric cancer cell line. The results revealed that naringenin and ABT-737 were able to inhibit SGC7901 cell growth and colony formation, alone or in combination. Furthermore, the combination of these drugs was found to further increase the cleavage of caspase-3 and poly ADP-ribose polymerase. Naringenin and ABT-737 also decreased Akt activation and increased p53 expression, suggesting the involvement of these pathways in the inhibition of gastric cell growth.
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OBJECTIVE: To explore the prognostic value of the Acute Kidney Injury Network (AKIN) criteria in patients with acute paraquat (PQ) poisoning. METHODS: A retrospective study on 184 patients with acute PQ poisoning admitted to the Shandong Provincial Hospital from April 2010 to March 2013 was done. The clinical data and AKIN stage were compared between survivors and non-survivors, and multivariate analysis was done by Cox-proportional hazards regression model. Kaplan-Meier method was used to analyze survival rate of the patients in different stages of poisoning. RESULTS: The 60-day mortality was 42.93% (79/184). There were no significant differences between the survival and non-survival groups in respect of gender, simultaneous alcohol drinking, duration between ingestion and gastric lavage, duration between ingestion and first hemoperfusion, and number of hemoperfusion. Significant differences were found between two groups in age, quantity of ingestion, receiving hemoperfusion or not, AKIN stage, and initial laboratory data including white blood cell count, the percentage of neutrophil, blood glucose, blood urea nitrogen, creatinine, ß2-microglobulin (ß2-MG), serum K+, CO2, anion gap, and urinary concentration of PQ. The AKIN stage [odds ratio (OR)=3.242, 95% confidence interval (95%CI) 2.236-4.701, P=0.000], urinary concentrations of PQ (OR=1.773, 95%CI 1.008-3.116, P=0.047), the amount of ingestion (OR=1.003, 95%CI 1.000-1.006, P=0.040), and CO2 (OR=0.094, 95%CI 0.891-0.991, P=0.021) were independent prognostic factors for death among them. Kaplan-Meier survival analysis showed the survival rate of AKIN 3 group was significantly lower than that in AKIN 2 group (5.88% vs. 56.25%, χ2=16.149, P=0.000), AKIN 1 group (5.88% vs. 78.95%, χ2=62.444, P=0.000) and non-AKI group(5.88% vs. 100.0%, χ2=173.549, P=0.000). CONCLUSIONS: The AKIN staging is a reliable marker for mortality prediction in acute PQ poisoning patients. In cases without facilities to determine plasma PQ concentration, the staging of AKIN may be a simple and practical tool for assessing the severity of PQ poisoning.
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Injúria Renal Aguda/diagnóstico , Paraquat/intoxicação , Índice de Gravidade de Doença , Adulto , Feminino , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Only limited data of the long-term effect of levosimendan on renal dysfunction in patients with decompensated heart failure (DHF) have been published previously. To date, there has been no similar study carried out in a Chinese population. DESIGN AND METHODS: A prospective, randomized, placebo-controlled, and double-blind study was performed to investigate the effect of levosimendan on estimated glomerular filtration rate (eGFR) in DHF patients with renal dysfunction during a 30-day period. Sixty-six patients with left ventricular ejection fraction (LVEF) ≤40% and eGFR 15-89 mL/min/1.73 m(2) were randomized in a 1:1 ratio to receive a 24-h infusion with levosimendan or placebo. The B-type natriuretic peptide (BNP) and eGFR were determined at baseline and day 1, 3, 7, 14, 30 after the start of treatment. RESULTS: The eGFR levels were obviously enhanced following levosimendan, peaked at 3 days, sustained for at least 14 days, and returned to baseline by day 30 after starting infusion. In contrast, placebo did not induce any significant changes in eGFR levels during the follow-up. In addition, levosimendan resulted in a distinct decrease in BNP levels in comparison with placebo, and the beneficial effect returned to baseline by day 14 and remained so at day 30 postinfusion. CONCLUSIONS: A 24-h infusion with levosimendan transiently improved the renal dysfunction compared with placebo in patients with DHF, and its beneficial effects persisted for at least 14 days after the initiation of treatment.
Assuntos
Cardiotônicos/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização , Hidrazonas/uso terapêutico , Nefropatias/fisiopatologia , Piridazinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/administração & dosagem , Distribuição de Qui-Quadrado , China , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrazonas/administração & dosagem , Infusões Intravenosas , Nefropatias/sangue , Nefropatias/complicações , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Estudos Prospectivos , Piridazinas/administração & dosagem , Simendana , Volume Sistólico , Fatores de Tempo , Resultado do Tratamento , Micção/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
A nonrandomized controlled study was conducted to evaluate the effect of lipo-prostaglandin E1 (lipo-PGE1) on cystatin C (CysC), ß2-microglobulin (B2MG), and estimated glomerular filtration rate (eGFR) in patients with decompensated heart failure (DHF) and renal dysfunction. A total of 286 enrolled patients with DHF and renal dysfunction were nonrandomly assigned a 7-day standard treatment without (n = 146) or with (n = 140) lipo-PGE1 intervention. According to the baseline eGFR, patients were further classified into mild, moderate, and severe renal dysfunction subgroups. By the end of study period, there was no evidence of an immense improvement in B2MG, CysC, and eGFR in response to standard treatment (all P > 0.05). On the contrary, a noticeable decrease of B2MG and CysC was observed in patients receiving lipo-PGE1 intervention, as well as an increase in eGFR (all P < 0.05). Moreover, lipo-PGE1 intervention led to greater changes in renal function variables from baseline than with standard management (all P < 0.05). Most important, the favorable renal protective effects of lipo-PGE1 were maintained in three subgroups. Lipo-PGE1 intervention brought a substantial renoprotective benefit to hospitalized DHF patients as compared with standard therapy, suggesting it might offer a promising therapeutic option for the management of renal dysfunction associated with DHF.
Assuntos
Alprostadil/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Cistatina C/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Microglobulina beta-2/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , China , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Rim/fisiopatologia , Nefropatias/sangue , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
In the present study, we investigated whether omentin affected the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-α (TNF-α) induced human umbilical vein endothelial cells (HUVECs). Our data showed that omentin decreased TNF-α-induced expression of ICAM-1 and VCAM-1 in HUVECs. In addition, omentin inhibited TNF-α-induced adhesion of THP-1 cells to HUVECs. Further, we found that omentin inhibited TNF-α-activated signal pathway of nuclear factor-κB (NF-κB) by preventing NF-κB inhibitory protein (IκBα) degradation and NF-κB/DNA binding activity. Omentin pretreatment significantly inhibited TNF-α-induced ERK activity and ERK phosphorylation in HUVECs. Pretreatment with PD98059 suppressed TNF-α-induced NF-κB activity. Omentin, NF-kB inhibitor (BAY11-7082) and ERK inhibitor (PD98059) reduced the up-regulation of ICAM-1 and VCAM-1 induced by TNF-α. These results suggest that omentin may inhibit TNF-α-induced expression of adhesion molecules in endothelial cells via blocking ERK/NF-κB pathway.