RESUMO
The health-improving functions of bioactive flavonoids in vitro and in vivo are often limited by their low stability, which could be counteracted by the application of proteins as carriers of flavonoids. Clarification of the mechanism of protein-ligand interaction is crucial for the encapsulation of bioactive components. Herein, common plasma proteins [i.e., bovine serum albumin (BSA), human serum albumin (HSA), human immunoglobulin G (IgG) and fibrinogen (FG)] were compared for their binding characteristics to quercetin, the main component of flavonoids in human diet, in the absence and presence of free Cu2+ (an accelerator for flavonoids' instability) using multi-spectroscopic and computational methods. As a flexible open structure of proteins, both BSA and HSA were found to be the most promising carriers for quercetin and Cu2+ with an affinity on the order of 104 M-1. HSA-diligand complex (i.e., HSA-quercetin-Cu2+) was successfully generated when both quercetin and Cu2+ were added to the HSA solution. The stability and free radical scavenging activity of bioactive quercetin during incubation was promoted in the HSA-diligand complex relative to quercetin-Cu2+ complex. Quercetin/Cu2+ system could induce the formation of reactive oxygen species such as hydrogen peroxide (H2O2) and hydroxide radical (·OH), which were significantly suppressed upon HSA binding. Consistently, the cytotoxicity of the quercetin/Cu2+ system to endothelial cells was reduced in the HSA-diligand complex. These results demonstrate the possibility of developing serum albumin-based carriers for the protection of bioactive flavonoids in their nutritional application.
Assuntos
Flavonoides , Albumina Sérica , Humanos , Flavonoides/química , Albumina Sérica/metabolismo , Quercetina/química , Células Endoteliais/metabolismo , Peróxido de Hidrogênio , Soroalbumina Bovina/química , Albumina Sérica Humana , Espectrometria de Fluorescência/métodos , Ligação ProteicaRESUMO
OBJECTIVE: The optimal neoadjuvant chemoradiotherapy (CRT) regimen in esophageal cancer has not yet been defined. This study was aimed to compare the differences in pathologic response and survival between docetaxel/cisplatin and fluorouracil/cisplatin as neoadjuvant CRT in locally advanced esophageal squamous cell carcinoma (SCC). METHODS: We retrospectively analyzed patients with thoracic esophageal SCC who received neoadjuvant CRT followed by esophagectomy from 2000 to 2014. After adjusting for sex, age, performance status, tumor length, tumor location and clinical TNM stage, 32 docetaxel/cisplatin-treated patients were matched to 62 patients who received fluorouracil/cisplatin at a ratio of 1:2. Treatment toxicity, pathologic complete response (pCR) and survival outcomes were compared between groups. RESULTS: Baseline characteristics were well balanced between groups. The pCR rate in the docetaxel/cisplatin group was higher than that in the fluorouracil/cisplatin group but without significant difference (40.6% vs. 30.6%, P = 0.333). The 3-year overall survival rate in the docetaxel/cisplatin group was 64.9% versus 46.0% in the fluorouracil/cisplatin group (P = 0.039). There were no significant differences in incidence of treatment toxicity during CRT or surgical complications between groups, with the exception of Grade 3-4 hematologic toxicity (37.5% vs. 17.7%, P = 0.035), which was more frequent in the docetaxel/cisplatin group. CONCLUSIONS: Docetaxel/cisplatin might be associated with more favorable survival than fluorouracil/cisplatin in esophageal SCC treated with neoadjuvant CRT. Prospective validation is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Quimiorradioterapia/métodos , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/uso terapêutico , Terapia Neoadjuvante/métodos , Taxoides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Docetaxel , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem , Taxoides/farmacologiaRESUMO
OBJECTIVE: The aim of this study was to investigate the correlation between clinical complete response (cCR) and pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) for esophageal squamous cell cancer (ESCC). METHODS: Between May 2001 and April 2013, a total of 158 patients with thoracic ESCC treated with neoadjuvant CRT followed by surgery were analyzed. Of these patients, 31 had stage IIb disease and 127 had stage III disease. All patients received concurrent platinum-based chemotherapy with conformal radiotherapy (40 Gy in 20 fractions, five fractions per week for 4 weeks). RESULTS: A total of 65 patients (41.1 %) achieved pCR. Of 44 patients (27.8 %) who achieved cCR after neoadjuvant CRT, 32 (72.7 %) also achieved pCR. On the other hand, only 33 (28.9 %) of 114 patients with non-cCR had pCR. The sensitivity, specificity, positive predictive value, and negative predictive value of cCR for predicting pCR was 87.1, 49.2, 71.1, and 72.7 %, respectively. The median follow-up period was 28.9 months, and overall survival (OS) for the entire group was 38.1 months. Patients who achieved cCR had significantly better 3-year OS than those with non-cCR (71.6 % vs. 46.9 %; p = 0.012). CONCLUSIONS: Our results indicate that cCR after neoadjuvant CRT is significantly correlated with pCR and survival of patients with ESCC. Further studies are required to confirm the prognostic value of cCR after neoadjuvant CRT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia , Neoplasias Esofágicas/patologia , Terapia Neoadjuvante , Adulto , Idoso , Carcinoma de Células Escamosas/terapia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Docetaxel , Neoplasias Esofágicas/terapia , Esofagectomia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Radioterapia Conformacional , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
Perfluorooctane sulfonate (PFOS), a representative of perfluorinated compounds in industrial and commercial products, has posed a great threat to animals and humans via environmental exposure and dietary consumption. Herein, we investigated the effects of PFOS binding on the redox state and stability of two hemoproteins (hemoglobin (Hb) and myoglobin (Mb)). Fluorescence spectroscopy, circular dichroism and UV-vis absorption spectroscopy demonstrated that PFOS could induce the conformational changes of proteins along with the exposure of heme cavity and generation of hemichrome, which resulted in the increased release of free hemin. After that, free hemin liberated from hemoproteins led to reactive oxygen species formation, lipid peroxidation, cell membrane damage and loss of cell viability in vascular endothelial cells, while neither Hb nor Mb did show cytotoxicity. Chemical inhibitors of ferroptosis effectively mitigated hemin-caused toxicity, identifying the hemin-dependent ferroptotic cell death mechanisms. These data demonstrated that PFOS posed a potential threat of toxicity through a mechanism which involved its binding to hemoproteins, decreased oxygen transporting capacity, and increased hemin release. Altogether, our findings elucidate the binding mechanisms of PFOS with two hemoproteins, as well as possible risks on vascular endothelial cells, which would have important implications for the human and environmental toxicity of PFOS.
Assuntos
Células Endoteliais , Hemina , Animais , Humanos , Hemina/metabolismo , Células Endoteliais/metabolismo , Oxirredução , Hemoglobinas/química , Dicroísmo Circular , Mioglobina/metabolismoRESUMO
With the ubiquitous applications of perfluorinated compounds such as perfluorooctanoic acid (PFOA) in industrial and commercial products, the toxicity of these engineered materials in environmental and public health is received growing attention. As a typical organic pollutant, PFOA has been extensively found in wildlife and human bodies, and can preferentially bind to serum albumin in vivo. However, the importance of protein-PFOA interactions on the cytotoxicity of PFOA could not be stressed enough. In this study, we used both experimental and theoretical approaches, to investigate the interactions of PFOA with bovine serum albumin (BSA, the most abundant protein in blood). It was found that PFOA could mainly interact with Sudlow site I of BSA to form BSA-PFOA complex, in which van der Waals forces and hydrogen bonds played dominant roles. Moreover, the strong binding of BSA could greatly alter the cellular uptake and distribution of PFOA in human endothelial cells, and result in the decreases of reactive oxygen species formation and cytotoxicity for these BSA-coated PFOA. Consistently, the addition of fetal bovine serum into cell culture medium also significantly mitigated PFOA-induced cytotoxicity, which was attributed to the extracellular complexation between PFOA and serum proteins. Altogether, our study demonstrates that the binding of serum albumin to PFOA could reduce its toxicity by affecting the cellular responses.
Assuntos
Fluorocarbonos , Albumina Sérica , Humanos , Albumina Sérica/química , Células Endoteliais/metabolismo , Soroalbumina Bovina/química , Fluorocarbonos/toxicidade , Fluorocarbonos/química , Espectrometria de Fluorescência , Simulação de Acoplamento MolecularRESUMO
During the wide applications of perfluorinated materials such as perfluorooctane sulfonate (PFOS) in commercial and industrial products, the potential toxicity of these engineered compounds has attracted more and more attention. As a typical environmental pollutant, PFOS could preferentially bind to albumin protein in vivo. However, the role of protein-PFOS interactions in the cytotoxicity of PFOS was not stressed enough. Herein, we investigated the interactions of PFOS with human serum albumin (HSA, the most abundant protein in human plasma) using both experimental and theoretical approaches. It was demonstrated that PFOS could mainly bind to the Sudlow site I of HSA to generate HSA-PFOS complex through hydrogen bonds and van der Waals forces. Toxicity assays with endothelial cells illustrated that the binding of HSA could significantly attenuate the intracellular uptake and subcellular distribution of PFOS, thereby inhibiting the formation of reactive oxygen species and toxicity for those HSA-bound PFOS. Similarly, the presence of fetal bovine serum in the cell culture media greatly reduced PFOS-caused cytotoxicity. Conclusively, our study reveals that the binding of albumin protein to PFOS could mitigate its toxicity by the modulation of cellular responses. The formation of protein-complexed contaminants would significantly reduce the bioavailability of these chemicals and subsequently mitigate their environmental toxicology to the human health.
RESUMO
BACKGROUND: Myocardial calcification is a rare complication in critically ill patients. The prognosis of myocardial calcifications in critically ill patients is very poor if not treated in a timely manner. We describe a rare case of acute extensive myocardial calcifications due to acute myocarditis after receiving extracorporeal membrane oxygenation (ECMO) support. CASE SUMMARY: We report a 17-year-old male patient who developed extensive myocardial calcifications while receiving prolonged ECMO support for severe myocarditis and cardiogenic shock. Extensive myocardial calcifications were confirmed by chest computed tomography (CT). Myocardial calcifications were observed in the left ventricle walls on CT examination 10 days after admission. The patient was then discharged with heart function class II on the NYHA classification. Two years later, the patient was still alive with adequate quality of life. We then included this patient and 7 other cases retrieved from the PubMed, Cochrane Library, EMBASE, and MEDLINE databases in our study, in order to provide a reference for the clinical diagnosis and treatment of this disease. CONCLUSION: Multiple causes including prolonged hemodynamic failure, profound acidosis, high vasopressor doses, and acute renal failure may jointly lead to extensive myocardial calcifications. The precise role of ECMO support in the timing and frequency of acute myocardial calcifications deserves further investigation.
RESUMO
Purpose: To compare the clinical outcomes of induction chemotherapy (IC) followed by chemoradiotherapy (CRT) versus chemoradiotherapy alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Patients and methods: Between 2002 and 2015, 267 ESCC patients who received definitive CRT with docetaxel and cisplatin were enrolled in this study. Through a matched case-control study, 85 patients receiving IC before CRT were matched 1:1 to patients who received CRT alone, according to age, gender, performance status, tumor location, tumor length, and pretreatment TNM stage. Results: The median overall survival (OS) in the IC group was significantly better than that in the CRT group (26.0 vs. 22.0 months), with 3-year OS rates of 30.6% vs. 25.9%, respectively (P = 0.028). However, IC plus CRT was associated with a significantly higher rate of grade 3-4 leukopenia than CRT alone (P = 0.048). The overall clinical response rate was 50.6% after IC in the IC group. The IC responder group showed significantly more favorable OS (P=0.002) and progression-free survival (P=0.001) compared with the IC non-responder group and the CRT group. Multivariate analysis revealed that age ≥ 60 (P = 0.003) and the addition of IC (P=0.016) were independent prognostic factors that affected survival positively. Conclusions: The addition of IC before CRT yielded satisfactory clinical outcomes and manageable toxicities. The combination of IC with CRT might be a promising treatment strategy to further improve systemic control and survival in ESCC. Prospective randomized trials are required to confirm the role of IC.