RESUMO
Hepatocellular carcinoma is one of the most common malignant tumors in the world and shows strong metastatic potential. Current medicine for hepatocellular carcinoma therapy is invalid, while Scutellaria baicalensis Georgi exhibits the pharmaceutical potential to treat liver diseases and liver cancer. Herein, we verified the inhibitory properties and the pivotal molecules regimented by Scutellaria baicalensis on advanced hepatocellular carcinoma. At first, the viability of SK-Hep-1 cells was significantly reduced under treatment of Scutellaria baicalensis extract in a dose-dependent manner without affecting the growth of normal hepatocyte. Scutellaria baicalensis extract application could remarkably cause apoptosis of SK-Hep-1 cells through p53/cytochrome C/poly-ADP ribose polymerase cascades and arrest the cell cycle at the G1/S phase by downregulating cyclin-dependent kinases. Meanwhile, administration of Scutellaria baicalensis extract remarkably attenuated the migration capability as well as suppressed matrix metalloproteinase activity of advanced hepatocellular carcinoma cells. The proteome profiles and network analysis particularly implied that exposure to Scutellaria baicalensis extract downregulated the expression of HSP90ß, and the clinical stage of hepatocellular carcinoma is also positively correlated with the HSP90ß level. Combined treatment of Scutellaria baicalensis extract and HSP90ß siRNAs could markedly enhance the ubiquitination activity and the degradation of vimentin to subsequently inhibit the metastatic property of SK-Hep-1 cells. Moreover, application of Scutellaria baicalensis extract and HSP90ß siRNAs depleted phosphorylation of AKT, which stimulated the expression of p53 and consecutively triggered cell apoptosis. These findings suggest that HSP90ß may be a prospective target for the effective therapy of advanced hepatocellular carcinoma via accelerating apoptosis of hepatocellular carcinoma cells and eliciting mesenchymal-epithelial transition with the administration of Scutellaria baicalensis extract.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Extratos Vegetais , Scutellaria baicalensis , Humanos , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteína Supressora de Tumor p53RESUMO
Background: The latest European System for Cardiac Operative Risk Evaluation (EuroSCORE) II is a well-accepted risk evaluation system for mortality in cardiac surgery in Europe. Objectives: To determine the performance of this new model in Taiwanese patients. Methods: Between January 2012 and December 2014, 657 patients underwent cardiac surgery at our institution. The EuroSCORE II scores of all patients were determined preoperatively. The short-term surgical outcomes of 30-day and in-hospital mortality were evaluated to assess the performance of the EuroSCORE II. Results: Of the 657 patients [192 women (29.22%); age 63.5 ± 12.68 years], the 30-day mortality rate was 5.48%, and the in-hospital mortality rate was 9.28%. The discrimination power of this new model was good in all populations, regardless of 30-day mortality or in-hospital mortality. Good accuracy was also noted in different procedures related to coronary artery bypass grafting, and good calibration was noted for cardiac procedures (p value > 0.05). When predicting surgical death within 30 days, the EuroSCORE II overestimated the risk (observed to expected: 0.79), but in-hospital mortality was underestimated (observed to expected: 1.33). The predictive ability [area under the curve (AUC) of the receiver operating characteristic (ROC) curve] and calibration of the EuroSCORE II for 30-day mortality (0.792) and in-hospital mortality (0.825) suggested that in-hospital mortality is a better endpoint for the EuroSCORE II. Conclusions: The new EuroSCORE II model performed well in predicting short-term outcomes among patients undergoing general cardiac surgeries. For short-term outcomes, in-hospital mortality was better than 30-day mortality as an indicator of surgical results, suggesting that it may be a better endpoint for the EuroSCORE II.
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WHAT IS KNOWN AND OBJECTIVE: The role of continuous/extended beta-lactam infusions (CEIs) in improving clinical outcomes among critically ill patients remains controversial. Therefore, we aimed to compare the clinical efficacy of CEI versus intermittent administration (IA) of beta-lactams by performing a systematic review and meta-analysis. METHODS: PubMed, the Cochrane Library and Embase were searched from inception until December 2018 for studies comparing clinical outcomes of CEI versus IA in critically ill patients. The meta-analysis included 18 randomized controlled trials (RCTs) and 13 non-RCTs. RESULTS AND DISCUSSION: For CEI versus IA, the summary relative risk (RR) for overall mortality and clinical cure was 0.82 (95% confidence interval [CI]: 0.72-0.94) and 1.31 (95% CI: 1.15-1.49), respectively. Subgroup and meta-regression analyses of the loading dose revealed a significantly increased clinical cure rate in the loading-dose group (RR: 1.44, 95% CI: 1.22-1.69), which remained significant after adjustments for beta-lactam type, and association between clinical cure and loading dose for clinical cure (RR: 1.47, 95% CI: 1.20-1.80; p = .001). Subgroup analysis of administration type indicated that both groups had low mortality and high clinical cure rates; however, the heterogeneity analysis did not support an association across continuous infusion and extended infusion groups. Subgroup analysis of the Acute Physiology and Chronic Health Evaluation (APACHE) score was conducted; according to APACHE scores ≥ 16, overall mortality and clinical cure significantly differed between CEI and IA. WHAT IS NEW AND CONCLUSION: CEIs with loading-dose treatment may significantly improve the clinical outcomes in critically ill sepsis or septic shock patients.
Assuntos
Estado Terminal/terapia , beta-Lactamas/administração & dosagem , APACHE , Esquema de Medicação , Mortalidade Hospitalar , Humanos , Infusões Intravenosas , Tempo de Internação , Testes de Sensibilidade Microbiana , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , beta-Lactamas/uso terapêuticoRESUMO
BACKGROUND: Bypass grafting is the standard of care for chronic aorto-iliac occlusive disease (AIOD, aka Leriche Syndrome) but is associated with mortality rates of up to 25% if surgical re-intervention is necessary. Despite a recent shift towards an endovascular-first strategy for TransAtlantic InterSociety Consensus II ("TASC II") C and D lesions, reports from Leriche Syndrome are still limited. PATIENTS AND METHODS: 15 high-risk patients (11 male, 4 female), mean age of 60.6 years, with chronic aorto-iliac occlusive disease were retrospectively reviewed. Retrograde approaches via the bilateral femoral arteries for aortic occlusion less than 4 cm in length and/or antegrade fashion from the brachial artery for juxtarenal type lesions were made. For the latter, thrombolysis prior to angioplasty was also performed. Intraluminal or if necessary, subintimal angioplasty was performed with deployment of either bare metal stents or stentgrafts in a kissing-stent fashion. RESULTS: A total of 28 iliac arteries and 14 occluded abdominal aorta were treated with 100% technical success, of which 25% success were achieved by using subintimal technique. Two minor complications occurred, including vascular rupture and distal emboli in one patient apiece, which were successfully managed via endovascular fashion. There were no complications of renal artery emboli. Primary and secondary patency rates at 1, 3 and 5 years were 92.3% and 100%; 83.9% and 100%; and 83.9% and 100%, respectively. CONCLUSION: Endovascular therapy for chronic aorto-iliac occlusion has a high technical success rate, with good short- and mid-term primary and secondary patency rates and may provide a valid alternative to surgery for high-risk patients.
Assuntos
Arteriopatias Oclusivas , Procedimentos Endovasculares , Síndrome de Leriche , Angioplastia , Arteriopatias Oclusivas/cirurgia , Consenso , Feminino , Humanos , Síndrome de Leriche/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Stents , Resultado do TratamentoRESUMO
BACKGROUND: Severe blunt chest injury sometimes induces acute respiratory failure (ARF), requiring ventilator use. We aimed to evaluate the effect of performing rib fixation with the addition of video-assisted thoracoscopic surgery (VATS) on patients with ARF caused by blunt thoracic injury with ventilator dependence. METHODS: This observational study prospectively enrolled patients with multiple bicortical rib fractures with hemothorax caused by severe blunt chest trauma. All patients received positive pressure mechanical ventilation within 24 h after trauma because of ARF. Some patients who received rib fixation with VATS were enrolled as group 1, and the others who received only VATS were designated as group 2. The length of ventilator use was the primary clinical outcome. Rates of pneumonia and length of hospital stay constituted secondary outcomes. RESULTS: A total of 61 patients were included in this study. The basic demographic characteristics between the two groups exhibited no statistical differences. All patients received operations within 6 days after trauma. The length of ventilator use was shorter in group 1 (3.19 ± 3.37 days vs. 8.05 ± 8.23, P = 0.002). The rate of pneumonia was higher in group 2 (38.1% vs. 75.0%, P = 0.005). The length of hospital stay was much shorter in group 1 (17.76 ± 8.38 days vs. 24.13 ± 9.80, P = 0.011). CONCLUSION: Rib fixation combined with VATS could shorten the length of ventilator use and reduce the pneumonia rate in patients with severe chest blunt injury with ARF. Therefore, this operation could shorten the overall length of hospital stay.
Assuntos
Respiração Artificial , Traumatismos Torácicos , Cirurgia Torácica Vídeoassistida , Desmame do Respirador , Ferimentos não Penetrantes , Adulto , Idoso , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Síndrome do Desconforto Respiratório , Costelas/cirurgia , Traumatismos Torácicos/cirurgia , Ferimentos não Penetrantes/cirurgiaRESUMO
BACKGROUND: Developing a universal strategy to improve the specificity and sensitivity of PEGylated nanoaparticles (PEG-NPs) for assisting in the diagnosis of tumors is important in multimodality imaging. Here, we developed the anti-methoxypolyethylene glycol (mPEG) bispecific antibody (BsAb; mPEG × HER2), which has dual specificity for mPEG and human epidermal growth factor receptor 2 (HER2), with a diverse array of PEG-NPs to confer nanoparticles with HER2 specificity and stronger intensity. RESULT: We used a one-step formulation to rapidly modify the nanoprobes with mPEG × HER2 and optimized the modified ratio of BsAbs on several PEG-NPs (Lipo-DiR, SPIO, Qdot and AuNP). The αHER2/PEG-NPs could specifically target MCF7/HER2 cells (HER2++) but not MCF7/neo1 cells (HER2+/-). The αHER2/Lipo-DiR and αHER2/SPIO could enhance the sensitivity of untargeted PEG-NPs on MCF7/HER2 (HER2++). In in vivo imaging, αHER2/Lipo-DiR and αHER2/SPIO increased the specific targeting and enhanced PEG-NPs accumulation at 175% and 187% on 24 h, respectively, in HER2-overexpressing tumors. CONCLUSION: mPEG × HER2, therefore, provided a simple one-step formulation to confer HER2-specific targeting and enhanced sensitivity and contrast intensity on HER2 positive tumors for multimodality imaging.
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Anticorpos Biespecíficos , Neoplasias da Mama , Sistemas de Liberação de Medicamentos/métodos , Receptor ErbB-2 , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacocinética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Meios de Contraste/química , Meios de Contraste/metabolismo , Feminino , Humanos , Células MCF-7 , Imagem Multimodal , Nanopartículas/química , Nanopartículas/metabolismo , Polietilenoglicóis/química , Receptor ErbB-2/química , Receptor ErbB-2/metabolismoRESUMO
In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe2(µ-SCH2CH2OH)2(NO)4] (DNIC-1) with a sustainable NO-release reactivity (t1/2 = 27.4 ± 0.5 h at 25 °C and 16.8 ± 1.8 h at 37 °C) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable â¢NO-release reactivity on the activation of angiogenesis and wound healing.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Ferro/administração & dosagem , Neovascularização Patológica/prevenção & controle , Óxido Nítrico/metabolismo , Óxidos de Nitrogênio/administração & dosagem , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/prevenção & controle , Animais , Sobrevivência Celular , Células Cultivadas , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Membro Posterior , Humanos , Isquemia/patologia , Isquemia/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Óxido Nítrico/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ferimentos e Lesões/patologia , Peixe-ZebraAssuntos
Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Fístula Artério-Arterial/diagnóstico por imagem , Fístula Artério-Arterial/terapia , Embolização Terapêutica/métodos , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgia , Idoso de 80 Anos ou mais , Fístula Artério-Arterial/complicações , Dor no Peito/etiologia , Angiografia por Tomografia Computadorizada , Ponte de Artéria Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Masculino , Radiografia Torácica , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Three new clerodane diterpenes, (4â2)-abeo-cleroda-2,13E-dien-2,14-dioic acid (1), (4â2)-abeo-2,13-diformyl-cleroda-2,13E-dien-14-oic acid (2), and 16(R&S)- methoxycleroda-4(18),13-dien-15,16-olide (3), were isolated from the unripe fruit of Polyalthia longifolia var. pendula (Annonaceae) together with five known compounds (4-8). The structures of all isolates were determined by spectroscopic analysis. The anti-inflammatory activity of the isolates was evaluated by testing their inhibitory effect on NO production in LPS-stimulated RAW 264.7 macrophages. Among the isolated compounds, 16-hydroxycleroda-3,13-dien-15,16-olide (6) and 16-oxocleroda-3,13-dien-15-oic acid (7) showed promising NO inhibitory activity at 10 µg/mL, with 81.1% and 86.3%, inhibition, respectively.
Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos Clerodânicos/farmacologia , Inflamação/tratamento farmacológico , Polyalthia/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/isolamento & purificação , Humanos , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , CamundongosRESUMO
Hepatic ischemia-reperfusion (IR) injury is a common clinical problem and ROS may be a contributing factor on IR injury. The current study evaluates the potential protective effect of saffron ethanol extract (SEE) in a rat model upon hepatic IR injury. Caspases 3 and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) results showed increased cell death in the IR samples; reversely, minor apoptosis was detected in the SEE/IR group. Pretreatment with SEE significantly restored the content of antioxidant enzymes (SOD1 and catalase) and remarkably inhibited the intracellular ROS concentration in terms of reducing p47phox translocation. Proteome tools revealed that 20 proteins were significantly modulated in protein intensity between IR and SEE/IR groups. Particularly, SEE administration could attenuate the carbonylation level of several chaperone proteins. Network analysis suggested that saffron extract could alleviate IR-induced ER stress and protein ubiquitination, which finally lead to cell apoptosis. Taken together, SEE could reduce hepatic IR injury through modulating protein oxidation and our results might help to develop novel therapeutic strategies against ROS-caused diseases.
Assuntos
Crocus/química , Hepatopatias/metabolismo , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Proteoma/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Catalase/análise , Catalase/metabolismo , Eletroforese em Gel Bidimensional , Etanol , Histocitoquímica , Marcação In Situ das Extremidades Cortadas , Fígado/química , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Carbonilação Proteica , Proteínas/análise , Proteínas/metabolismo , Proteoma/análise , Proteômica , Ratos , Ratos Wistar , Superóxido Dismutase/análise , Superóxido Dismutase/metabolismo , Proteínas UbiquitinadasRESUMO
BACKGROUND: To examine the feasibility of using pulsatility index-adjusted (PI) flow equations to accurately characterize blood volume flow changes using Doppler technique in patients with peripheral artery disease (PAD) before and after percutaneous transluminal angioplasty (PTA). METHODS: PTA was performed on 17 PAD patients (23 target vessels treated, 16 anterior tibial arteries, and 7 posterior tibial arteries). Arterial diameter, peak systolic velocity, PI, time-averaged mean velocity, and measured volume flow (MVF) of dorsalis pedis artery (DPA) and common plantar artery (CPA) were measured with duplex Doppler ultrasound before and after PTA. PI-adjusted volume flows (PIVF) were calculated as part of the MVF/PIVF relative percentage metric. RESULTS: Significant changes (p < 0.001) of the MVF (mean: 33.0 mL/min, range: -20.9-102.2 mL/min) and MVF/PIVF relative percentages (mean: 51.8, range: 5.1-127.2%) in the DPA existed between before and after PTA, whereas no significant changes could be found in the CPA (mean:10.9 mL/min, p = 0.148 and mean: 21.3%, p = 0.146, respectively). Of the 7 treated posterior tibial arteries, the increments of the MVF/PIVF (mean: 60.4%, p = 0.033) was significant but not in the MVF (mean: 26.5 mL/min, p = 0.125). The ankle-brachial index also showed non-significant changes (p = 0.081). All PI-adjusted results matched clinical observations after blood flow restoration. CONCLUSION: No conclusions can be drawn from the comparison of actual measured volume flow between before and after PTA. However, using the MVF/PIVF relative percentage allows for a more objective framework upon which to base clinical observations and provides clarity in situations where direct measurement provides a counter-intuitive or contradictory picture.
Assuntos
Doença Arterial Periférica , Ultrassonografia Doppler , Humanos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/terapia , Ultrassonografia , Artérias da Tíbia/diagnóstico por imagem , Índice Tornozelo-Braço , Velocidade do Fluxo SanguíneoRESUMO
OBJECTIVE: To investigate the impact of metformin on survival of diabetic patients following surgery for colorectal cancer (CRC). METHODS: This was a retrospective cohort study. From Taiwan's population-based National Health Insurance Research Database (NHIRD) we identified 12,512 patients with CRC and type II diabetes who underwent curative surgery between 2000 and 2012. Of these, 6222 patients were included in a matched cohort. Using Cox regression models with time-dependent covariates we examined the impact of metformin on survival. RESULTS: Average duration of follow-up was 49 and 54 months for metformin users and non-users, respectively. Cox proportional hazard model showed that metformin was associated with 5-year overall survival benefit (Hazard ratio, 0.23 [95% CI, 0.20-0.26]) and inverse association with risk of liver metastasis (Hazard ratio, 0.79 [95% CI, 0.68-0.93]). CONCLUSIONS: Metformin was associated with a survival benefit in diabetic patients with CRC following surgery, and an inverse association with risk of liver metastases suggesting a potential anti-tumorigenic effect.
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Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Metformina , Humanos , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Estudos Retrospectivos , Modelos de Riscos Proporcionais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/complicações , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgiaRESUMO
PURPOSE: To evaluate multidetector computed tomographic (CT) images to investigate the prevalence, morphology, natural course, and prognostic effect of intramural blood pools (IBPs) in patients with acute intramural hematoma (IMH). MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Sixty-five patients (41 men; mean age, 65.9 years ± 11.3 [standard deviation]) with acute IMH undergoing three or more multidetector CT examinations during follow-up for 12 months or longer (median = 18 months), except for those undergoing surgery (n = 16), were enrolled. Associated factors of developing and resorption of IBP in IMH were analyzed by using logistic regression. RESULTS: There were 40 IBPs in 10 patients at initial multidetector CT, and 15 new IBPs developed in 11 patients during follow-up. IBPs occurred most in the descending thoracic (55% [31 of 56]) and abdominal (41% [23 of 56]) aorta in 28% (18 of 65) of patients. During 33.8 months (range, 2.8-50 months) of follow-up in these 18 patients, 57% (32 of 56) of IBPs showed complete resorption in 15 patients, 29% (16 of 56) of IBPs showed incomplete resorption in eight patients, and 14% (eight of 56) of IBPs had interrupted follow-up because of surgery or death in three patients. Logistic regression showed that age younger than 70 years (odds ratio [OR], 8.74; 95% confidence interval [CI]: 1.03, 76.9) and IMH wall thickness greater than 10 mm (OR, 4.93; 95% CI: 1.04, 23.0) were associated with developing IBP at initial multidetector CT, while IBP with larger transmural diameter (OR, 1.16; 95% CI: 1.02, 1.31) and multidetector CT-demonstrated connection with intercostal or lumbar artery (63% [35 of 56]) (OR, 5.44; 95% CI: 1.43, 20.9) were associated with incomplete resorption. CONCLUSION: IBPs are frequently observed at multidetector CT in patients with IMH. They may resolve over time or appear during follow-up. These findings are not associated with a poor prognosis, and IBPs should be distinguished from ulcerlike projections.
Assuntos
Doenças da Aorta/diagnóstico por imagem , Hematoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Doenças da Aorta/epidemiologia , Doenças da Aorta/patologia , Feminino , Hematoma/epidemiologia , Hematoma/patologia , Humanos , Modelos Logísticos , Masculino , Prevalência , Prognóstico , Fatores de RiscoRESUMO
Hepatic fibrosis is a wound-healing process caused by prolonged liver damage and often occurs due to hepatic stellate cell activation in response to reactive oxygen species (ROS). Red raspberry has been found to attenuate oxidative stress, mainly because it is rich in bioactive components. In the current study, we investigated the inhibitory effects and associated molecular mechanisms of red raspberry extract (RBE) upon activated hepatic stellate cell (aHSC) in cellular and rat models. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased in the dimethylnitrosamine (DMN)-applied samples, whereas treatment of RBE significantly suppressed the activities of these enzymes. In addition, a histopathological analysis demonstrated that RBE could substantially diminish the hepatic collagen content and alpha-smooth muscle actin (α-SMA) expression induced by DMN. Administration of 250 µg/mL RBE could also arrest the growth and enhance the apoptosis of activated HSC-T6 cells, which was accompanied with elevated levels of activated caspases and poly (ADP-ribose) polymerase (PARP) cleavage. Particularly, RBE application remarkably abolished oxidative damage within the cells and reduced the carbonylation of proteins, which was attributed to the upregulation of catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Moreover, the knockdown of Nrf2 together with the RBE treatment synergistically abrogated the expression of α-SMA and promoted the level of peroxisome proliferator-activated receptor gamma (PPAR-γ), suggesting that RBE could mitigate the transdifferentiation of HSC in a Nrf2-independent manner. These findings implied that the application of RBE could effectively remove oxidative stress and relieve the activation of HSC via modulating the caspase/PARP, Nrf2/HO-1 and PPAR-γ pathways, which may allow the development of novel therapeutic strategies against chemical-caused liver fibrogenesis.
Assuntos
Antifibróticos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rubus , Animais , Antifibróticos/isolamento & purificação , Antioxidantes/isolamento & purificação , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Frutas , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , PPAR gama/metabolismo , Extratos Vegetais/isolamento & purificação , Carbonilação Proteica/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Rubus/química , Transdução de SinaisRESUMO
In this study, a simple and competent metal-organic framework (MOF)-based nickel foam (NF)-supported three-dimensional (3D) immunosensor (Ab-NH2-MIL-88B(Fe2Co)-MOF/NF) was constructed and utilized for the specific recognition of the biomarker cardiac troponin (I) (cTnI). In the present work, biosensor fabrication was progressed through the modification of the NF substrate with the MOF material (NH2-MIL-88B(Fe2Co)-MOF) to enable an amine-functionalized electrode. This amine-functionalized NF electrodes (NH2-MIL-88B(Fe2Co)-MOF/NF) were then biointerfaced with anti-cTnI antibodies, which ended up as Ab-NH2-MIL-88B(Fe2Co)-MOF/NF electrodes. Analytical executions of the constructed bioelectrode were investigated for the quantitative analysis of cTnI in both buffered and serum solutions. Then, the electrochemical studies were carried out using the electrochemical impedance spectroscopy (EIS) method by monitoring changes concerning the charge transfer resistance (Rct) characteristics. The limit of detection (LOD) of the Ab-NH2-MIL-88B(Fe2Co)-MOF/NF immunosensor was achieved to be 13 fg/mL with great specificity. This kind of immunosensor imparts a new platform for the construction and application of MOF-hybrid 3D electrode materials with enhanced electrochemical behavior in cTnI sensing for the first time.
Assuntos
Cobalto/química , Ferro/química , Estruturas Metalorgânicas/química , Níquel/química , Troponina I/análise , Espectroscopia Dielétrica , Eletrodos , Humanos , Estruturas Metalorgânicas/síntese química , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
This study develops an ultrasensitive electrical device, the silicon nanowire-field effect transistor (SiNW-FET) for detection of cardiac troponin I (cTnI) in obesity induced myocardial injury. The biosensor device utilizes metal-oxide-semiconductor (MOS) compatible top-down methodology for the fabrication process. After fabrication, the surface of the SiNW is modified with the cTnI monoclonal antibody (Mab-cTnI) upon covalent immobilization to capture cTnI antigen. The sensitivity of the device is also examined using cTnI at different concentrations with the lowest detection limit of 0.016 ng/mL. The electrocardiogram (ECG), magnetic resonance imaging (MRI), and superior vena cave (SVC) provide more information about cardiac responses in a mouse model of acute myocardial infarction (AMI). Further, magnetic resonance imaging helps to evaluate the cardiac output of an obesity induced myocardial injury mouse model. These methods play an essential role in monitoring the obesity based cardiac injury and hence, these studies were carried out. This is the first report to use the ECG, MRI, and SVC sampling methods to study the obesity based cardiac injury involving Syrian hamsters as animal models. The proposed SiNW-FET in this study shows greater sensitivity than the previously developed devices and demonstrates great potential for future applications in point-of-care (POC) diagnosis.
Assuntos
Biomarcadores/análise , Miocárdio/metabolismo , Nanofios/química , Silício/química , Transistores Eletrônicos , Troponina I/análise , Animais , Eletricidade , Eletrocardiografia , Eletroquímica , Humanos , Medições Luminescentes , Imageamento por Ressonância Magnética , Mesocricetus , Modelos AnimaisRESUMO
The activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are modulated. However, the vimentin-mediated cytoskeletal cross talk, as well as the signaling transduction, which further coordinates the cellular responses during hepatic fibrogenesis, is poorly understood. In the current study, both messenger RNA (mRNA) and the vimentin protein were significantly increased in a time-dependent manner in the dimethylnitrosamine (DMN)-exposed liver. In particular, vimentin was highly expressed in the activated HSCs. Again, the overexpressed vimentin was observed in the plasma samples derived from patients with hepatic fibrosis/cirrhosis, suggesting that vimentin may be a key factor in regulating the progression of liver fibrosis. Meanwhile, vimentin knockdown suppressed the migratory propensity, provoked morphological changes, and disturbed the focal adhesions in the HSCs due to the breakdown of associated cytoskeletal proteins. Western blotting showed that vimentin deletion inhibited proliferating cell nuclear antigen (PCNA) and arrested the Rho GTPase family, thereby impairing the HSCs' growth as well as motility. The phosphorylated extracellular-signal regulated kinase (ERK) and AKT signals were also notably reduced in response to the silence of vimentin. Inhibitors of selected signaling pathways suppressed the migration and differentiation of activated HSCs by regulating specific serine phosphorylated sites on vimentin. Taken together, these findings revealed a novel mechanism of vimentin through which various signaling pathways controlled the proliferation, differentiation, and movement of the HSCs via the ERK/AKT and Rho cascades.
Assuntos
Células Estreladas do Fígado/patologia , Cirrose Hepática/metabolismo , Fígado/patologia , Vimentina/fisiologia , Animais , Apoptose/fisiologia , Linhagem Celular , Movimento Celular , Proliferação de Células/fisiologia , Células Estreladas do Fígado/metabolismo , Humanos , Fígado/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: Serious blunt chest trauma usually induces hemothorax, pneumothorax, and rib fracture. Early video-assisted thoracoscopic surgery (VATS) to evacuate retained hemothorax is one commonly used treatment. In this study, a new strategy was implemented to combine VATS with fractured rib fixation simultaneously. METHODS: This prospective observational study was performed from January 2013 to April 2018. All patients were aged 18 years or older and had blunt chest trauma with displaced fractures in more than three ribs. No patients had acute respiratory failure within 24â¯h after trauma. Patients with retained hemothorax who received VATS constituted the study cohort. Subsequently, patients who received rib fixation during VATS procedures were compared with those who did not. Clinical outcomes such as dose of analgesics, and length of hospital stay were recorded. RESULTS: During the study period, 128 patients were enrolled. Available demographic characteristics of the 2 groups were compared, and no statistical differences were observed. The rates of shorter temporary ventilator dependence after operations were lower in the rib fixation group (0% vs. 24.7%, Pâ¯=â¯0.017). Persistent air leakage more than 5 days after operations were also lower in the rib fixation group (0% vs. 10.4%, Pâ¯=â¯0.001). The length of stay in overall hospital stay were longer for patients who received VATS without rib fixation (9.29⯱â¯2.51 days vs. 12.39⯱â¯4.65, Pâ¯=â¯0.001). Furthermore, the rib fixation group were administered much lower doses of opiates during their hospital stays (52.45⯱â¯15.67â¯mg vs. 77.24⯱â¯50.42â¯mg, Pâ¯=â¯0.001). CONCLUSION: Adding rib fixation during VATS in the management of retained hemothorax can contribute to shorten whole treatment courses. Rib fixation can also reduce pain, thus reducing dependence on analgesics.
Assuntos
Hemotórax/cirurgia , Costelas/cirurgia , Traumatismos Torácicos/cirurgia , Cirurgia Torácica Vídeoassistida/métodos , Ferimentos não Penetrantes/cirurgia , Adulto , Idoso , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Acute rejection (AR) and spontaneous tolerance may occur after allograft orthotopic liver transplants (OLT) performed in certain combinations of donor and recipient rat strains, yet the underlying molecular cascades involved in these conditions remain poorly understood. Comprehensive analysis with proteomic tools revealed that ceruloplasmin was highly expressed during the tolerant period on day 63 post-OLT (POD 63) compared to the rejected samples on POD 14. Meanwhile, cytokine expression profiles implied that the inflammation was significantly stimulated in the AR subjects. Again, protein carbonylation was dramatically upregulated in the rejected subject within the tolerant group. Knockdown of ceruloplasmin would elicit more severe ROS damage, leading to cell death in the presence of H2O2, which induced Nrf2 cascade and the recovery of ceruloplasmin to mediate spontaneous tolerance. In summary, ceruloplasmin may contribute to amending the oxidative stress that eventually causes cell apoptosis and to maintaining the survival of hepatocytes in a drug-free tolerance OLT model.
Assuntos
Ceruloplasmina/metabolismo , Citocinas/metabolismo , Transplante de Fígado/efeitos adversos , Estresse Oxidativo/imunologia , Tolerância ao Transplante/imunologia , Aloenxertos/citologia , Aloenxertos/imunologia , Aloenxertos/patologia , Animais , Apoptose/imunologia , Ceruloplasmina/genética , Ceruloplasmina/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Células Hep G2 , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Peróxido de Hidrogênio/imunologia , Peróxido de Hidrogênio/metabolismo , Fígado/citologia , Fígado/imunologia , Fígado/patologia , Masculino , Proteômica , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Endogâmicos Lew , Transplante HomólogoRESUMO
Hepatic fibrosis may ultimately result in organ failure and death, a reality compounded by the fact that most drugs for liver fibrosis appear to be effective only if given as a prophylactic or early treatment. In a dimethylnitrosamine-induced liver fibrotic model, aspartate aminotransferase/alanine aminotransferase levels could not precisely distinguish the differences between the initial stage of liver fibrosis and normal control, whereas histological examination indicated that dimethylnitrosamine treatment for two weeks has resulted in hepatic fibrogenesis. Comprehensive proteomics identified 12 proteins mainly associated with the interleukin 6-stimulated inflammatory pathway. Coordinately, cytokine profiles showed that dimethylnitrosamine administration would stimulate various signaling pathways leading to liver fibrosis. Of note, apolipoprotein A4 in serum samples obtained from patients in the early stage of liver fibrosis were significantly increased compared to the healthy controls (p<0.001) while the area under curve was 0.966. Moreover, increased apolipoprotein A4 significantly enhanced transforming growth factor beta 1-induced alpha smooth muscle actin expression. In this regard, overexpression of apolipoprotein A4 in early stage of liver fibrosis might magnify and imply the progression of hepatic fibrosis. These findings suggest that apolipoprotein A4 upregulation may correlate with hepatic fibrosis staging and that apolipoprotein A4 together with current biomarker can increase the sensitivity and specificity for the early detection of liver fibrosis in a high-throughput manner.