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1.
Ecotoxicol Environ Saf ; 207: 111280, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937227

RESUMO

As a top-selling neonicotinoid insecticide widely used in the field, thiamethoxam is an environmental pollutant because of the accumulation in ecosystem and has also been reported that it has potential risks to the health of mammals even humans. In order to understand the binding mechanism of thiamethoxam with biological receptors, spectroscopic techniques and theoretical simulations was used to explore the specific interactions between thiamethoxam and proteins. Interestingly, the results indicated that hydrophobic interaction as the main driving force, thiamethoxam formed a single binding site complex with proteins spontaneously, resulting in a decrease in the esterase-like activity of human serum albumin. The results of computer simulation showed that there were hydrophobic, electrostatic and hydrogen bonding interactions between thiamethoxam and receptors. The results of experiment and computer simulation were mutually confirmed, so a model was established for the interaction between the two which uncovered the structural characteristics of the binding site. This research provided new insights for the structure optimization of thiamethoxam, as well as gave an effective reference for evaluating the risk of thiamethoxam systemically in the future.


Assuntos
Inseticidas/química , Modelos Químicos , Soroalbumina Bovina/química , Albumina Sérica Humana/química , Tiametoxam/química , Animais , Sítios de Ligação , Ligação Competitiva , Simulação por Computador , Ecossistema , Esterases/química , Esterases/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Soroalbumina Bovina/metabolismo , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência , Varfarina/química
2.
PLoS One ; 15(11): e0242605, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33232370

RESUMO

Protein-based drugs often require targeted drug delivery for optimal therapy. A successful strategy to increase the circulation time of the protein in the blood is to link the therapeutic protein with an albumin-binding domain. In this work, we characterized such a protein-based drug, GA-Z. Using asymmetrical flow field-flow fractionation coupled with multi-angle light scattering (AF4-MALS) we investigated the GA-Z monomer-dimer equilibrium as well as the molar binding ratio of GA-Z to HSA. Using small angle X-ray scattering, we studied the structure of GA-Z as well as the complex between GA-Z and HSA. The results show that GA-Z is predominantly dimeric in solution at pH 7 and that it binds to monomeric as well as dimeric HSA. Furthermore, GA-Z binds to HSA both as a monomer and a dimer, and thus, it can be expected to stay bound also upon dilution following injection in the blood stream. The results from SAXS and binding studies indicate that the GA-Z dimer is formed between two target domains (Z-domains). The results also indicate that the binding of GA-Z to HSA does not affect the ratio between HSA dimers and monomers, and that no higher order oligomers of the complex are seen other than those containing dimers of GA-Z and dimers of HSA.


Assuntos
Técnicas de Química Analítica/métodos , Proteínas Recombinantes de Fusão/metabolismo , Espalhamento a Baixo Ângulo , Albumina Sérica Humana/metabolismo , Cromatografia em Gel , Dimerização , Humanos , Modelos Moleculares , Peso Molecular , Ligação Proteica , Conformação Proteica
3.
Arch Biochem Biophys ; 694: 108589, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33010229

RESUMO

There is ample evidence in the epidemiological literature that polyphenols, the major non-vitamin antioxidants in plant foods and beverages, have a beneficial effect on heart disease. Until recently other mechanisms which polyphenols exhibit such as cell signaling and regulating nitric oxide bioavailability have been investigated. The oxidation theory of atherosclerosis implicates LDL oxidation as the beginning step in this process. Nine polyphenols from eight different classes and several of their O-methylether, O-glucuronide and O-sulfate metabolites have been shown in this study to bind to the lipoproteins and protect them from oxidation at lysosomal/inflammatory pH (5.2), and physiological pH (7.4). Polyphenols bind to the apoprotein at pH 7.4 with Kb > 106 M-1 and the number of molecules of polyphenols bound per LDL particle under saturation conditions varied from 0.4 for ferulic acid to 13.1 for quercetin. Competition studies between serum albumin and LDL show that substantial lipoprotein binding occurs even in the presence of a great molar excess of albumin, the major blood protein. These in vitro results are borne out by published human supplementation studies showing that polyphenol metabolites from red wine, olive oil and coffee are found in LDL even after an overnight fast. A single human supplementation with various fruit juices, coffee and tea also produced an ex vivo protection against lipoprotein oxidation under postprandial conditions. This in vivo binding is heart-protective based on published olive oil consumption studies. Relevant to heart disease, we hypothesize that the binding of polyphenols and metabolites to LDL functions as a transport mechanism to carry these antioxidants to the arterial intima, and into endothelial cells and macrophages. Extracellular and intracellular polyphenols and their metabolites are heart-protective by many mechanisms and can also function as potent "intraparticle" and intracellular antioxidants due to their localized concentrations that can reach as high as the micromolar level. Low plasma concentrations make polyphenols and their metabolites poor plasma antioxidants but their concentration in particles such as lipoproteins and cells is high enough for polyphenols to provide cardiovascular protection by direct antioxidant effects and by other mechanisms such as cell signaling.


Assuntos
Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Lipoproteínas LDL/metabolismo , Polifenóis/farmacologia , Animais , Antioxidantes/metabolismo , Cardiotônicos/metabolismo , Humanos , Lipoproteínas LDL/química , Oxirredução/efeitos dos fármacos , Polifenóis/metabolismo , Ligação Proteica , Albumina Sérica Humana/metabolismo , Suínos
4.
J Cancer Res Ther ; 16(4): 855-859, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930130

RESUMO

Background: Ghrelin plays a role in mechanisms related to cancer progression - including cell proliferation, invasion and migration, and resistance to apoptosis in the cell lines from several cancers. We investigated the role of ghrelin levels in cancer cachexia-anorexia in patients with locally advanced nonsmall-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT). Materials and Methods: This study involved 84 NSCLC patients who had received concomitant CRT. Blood ghrelin levels were compared before and 3 months after CRT. Meanwhile, changes in body weight of the patients were also investigated with changes in ghrelin levels before and after CRT. Results: Ghrelin levels were significantly decreased in line with changes in patients' weights in patients receiving CRT (P < 0.001). Serum albumin levels and inflammatory-nutritional index were significantly decreased after radiotherapy (RT) (3.01 ± 0.40 g/dL, 0.38 ± 0.20) when compared with its baseline levels (3.40 ± 0.55 g/dL,P < 0.001; 0.86 ± 0.71,P < 0.001, respectively). Serum C-reactive protein levels were significantly increased after CRT (7.49 ± 6.53 mg/L) when compared with its baseline levels (9.54 ± 3.80 mg/L,P = 0.038). After RT, ghrelin levels in patients were positively correlated with body mass index (r = 0.830,P < 0.001) and albumin (r = 0.758,P < 0.001). Conclusion: Ghrelin may play a role in the pathogenesis of weight loss in NSCLC patients. Ghrelin seems to be implicated in cancer-related weight loss. Ghrelin, cancer, and RT all together have a role in tumor-related anorexia-cachexia in patients with NSCLC. Results of this study need further evaluation as regards to its potential role as an adjuvant diagnostic or prognostic marker.


Assuntos
Caquexia/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/terapia , Grelina/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/terapia , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Caquexia/diagnóstico , Caquexia/etiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Albumina Sérica Humana/metabolismo
5.
Scand J Clin Lab Invest ; 80(8): 611-618, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32945705

RESUMO

Coronavirus Disease 2019 is a very fast-spreading infectious disease. Severe forms are marked by a high mortality rate. The objective of this study is to identify routine biomarkers that can serve as early predictors of the disease progression. This is a prospective, single-center, cohort study involving 330 SARS-CoV-2 infected patients who were admitted at the University Hospital of Blida, Algeria in the period between the 27th of March and 22nd of April 2020. The ROC curve was used to evaluate the predictive performance of biomarkers, assessed at admission, in the early warning of progression toward severity. Multivariate logistic regression was used to quantify the independent risk for each marker. After an average follow-up period of 13.9 ± 3.5 days, 143 patients (43.3%) were classified as severe cases. Six biological abnormalities were identified as potential risk markers independently related to the severity: elevated urea nitrogen (>8.0 mmol/L, OR = 9.3 [2.7-31.7], p < .00001), elevated CRP (>42mg/L, OR = 7.5 [2.4-23.3], p = .001), decreased natremia (<133. 6 mmol/L, OR = 6.0 [2.0-17.4], p = .001), decreased albumin (<33.5 g/L, OR = 5.2 [1.7-16.6], p = .003), elevated LDH (>367 IU/L, OR = 4.9 [1.7-14.2], p = .003) and elevated neutrophil to lymphocyte ratio (>7.99, OR = 4.2, [1.4-12.2], p = .009). These easy-to-measure, time-saving and very low-cost parameters have been shown to be effective in the early prediction of the COVID-19 severity. Their use at the early admission stage can improve the risk stratification and management of medical care resources in order to reduce the mortality rate.


Assuntos
Biomarcadores/sangue , /sangue , /diagnóstico , Idoso , Argélia , Nitrogênio da Ureia Sanguínea , Proteína C-Reativa/metabolismo , Estudos de Coortes , Creatinina/sangue , Feminino , Humanos , L-Lactato Desidrogenase/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Fatores de Risco , Albumina Sérica Humana/metabolismo , Índice de Gravidade de Doença , Sódio/sangue
6.
Mol Pharmacol ; 98(6): 648-657, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32978326

RESUMO

Protein tyrosine phosphatase (PTP) 4A3 is frequently overexpressed in human solid tumors and hematologic malignancies and is associated with tumor cell invasion, metastasis, and a poor patient prognosis. Several potent, selective, and allosteric small molecule inhibitors of PTP4A3 were recently identified. A lead compound in the series, JMS-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), has a long plasma half-life (∼ 24 hours) in mice, suggesting possible binding to serum components. We confirmed by isothermal titration calorimetry that JMS-053 binds to human serum albumin. A single JMS-053 binding site was identified by X-ray crystallography in human serum albumin at drug site 3, which is also known as subdomain IB. The binding of JMS-053 to human serum albumin, however, did not markedly alter the overall albumin structure. In the presence of serum albumin, the potency of JMS-053 as an in vitro inhibitor of PTP4A3 and human A2780 ovarian cancer cell growth was reduced. The reversible binding of JMS-053 to serum albumin may serve to increase JMS-053's plasma half-life and thus extend the delivery of the compound to tumors. SIGNIFICANCE STATEMENT: X-ray crystallography revealed that a potent, reversible, first-in-class small molecule inhibitor of the oncogenic phosphatase protein tyrosine phosphatase 4A3 binds to at least one site on human serum albumin, which is likely to extend the compound's plasma half-life and thus assist in drug delivery into tumors.


Assuntos
Iminas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Piridinas/farmacologia , Albumina Sérica Humana/metabolismo , Sítios de Ligação , Calorimetria , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios Enzimáticos , Meia-Vida , Humanos , Iminas/química , Iminas/uso terapêutico , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Tirosina Fosfatases/metabolismo , Piridinas/química , Piridinas/uso terapêutico , Albumina Sérica Humana/ultraestrutura
7.
Geriatr Gerontol Int ; 20(10): 932-937, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32857477

RESUMO

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) is one of the methods of tube feeding in patients who are incapable of oral intake. There are no reports on risk factors for bleeding at PEG construction. Our main objective was to investigate the risks and predictors of bleeding associated with PEG construction. METHODS: This retrospective, observational study included patients who had undergone PEG construction at our institution. To investigate the risks of bleeding associated with PEG construction, we compared the baseline characteristics between bleeding and non-bleeding patients. In terms of early predictors of post-PEG bleeding, we evaluated whether there had been a decrease from baseline of >10% in hemoglobin levels on the day after the procedure. RESULTS: The median preoperative albumin levels were 22.5 g/L (range 20-29 g/L) and 30 g/L (range 18-40 g/L) in the bleeding and non-bleeding groups, respectively (P = 0.014, Mann-Whitney U-test). The median preoperative platelet counts were 177 500 (range 87 000-265 000) and 271 000 (83 000-749 000) in the bleeding and non-bleeding groups, respectively (P = 0.043, Mann-Whitney U-test). The number of patients for whom hemoglobin levels decreased >10% from baseline on the day after the procedure differed significantly between the bleeding and non-bleeding groups (2/4, 50% and 3/58, 5.45%), respectively (P = 0.002, Pearson's χ2 -test). CONCLUSIONS: Low serum albumin and preoperative platelet counts might be risk factors for bleeding. Rigorous follow up is necessary for patients showing a decrease in hemoglobin level ≥10% of their baseline the day after the procedure. Geriatr Gerontol Int 2020; 20: 932-937.


Assuntos
Perda Sanguínea Cirúrgica/estatística & dados numéricos , Nutrição Enteral , Gastrostomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Feminino , Gastroscopia , Hemoglobinas/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica Humana/metabolismo , Adulto Jovem
8.
PLoS One ; 15(8): e0237062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760105

RESUMO

Nutritional status contributes to the regulation of immune responses against pathogens, and malnutrition has been considered as a risk factor for tuberculosis (TB). Mycobacterium tuberculosis (Mtb), the causative agent of TB, can modulate host lipid metabolism and induce lipid accumulation in macrophages, where the bacilli adopt a dormant phenotype. In addition, serum lipid components play dual roles in the regulation of and protection from Mtb infection. We analyzed the relationship between nutritional status and the humoral immune response in TB patients. We found that serum HDL levels are positively correlated with the serum IgA specific for Mtb antigens. Analysis of the relationship between serum nutritional parameters and clinical parameters in TB patients showed that serum albumin and CRP levels were negatively correlated before treatment. We also observed reduced serum LDL levels in TB patients following treatment. These findings may provide insight into the role of serum lipids in host immune responses against Mtb infection. Furthermore, improving the nutritional status may enhance vaccination efficacy.


Assuntos
Imunidade Humoral , Mycobacterium tuberculosis/imunologia , Estado Nutricional/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Proteína C-Reativa/metabolismo , Progressão da Doença , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana/metabolismo , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico
9.
Am J Emerg Med ; 38(9): 1796-1801, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32739850

RESUMO

OBJECTIVE: The objective of this study was to evaluate the association of elevated alveolar-arterial oxygen (A-a O2) gradient with risk of mortality in hospitalized patients with community-acquired pneumonia (CAP). METHODS: This prospective study included 206 patients diagnosed with CAP admitted to the ED. Demographics, comorbidities, arterial blood gas, serum electrolytes, liver-renal functions, complete blood count, NLR, PLR, CRP, CAR, procalcitonin, A-a O2 gradient, expected A-a O2 and A-a O2 difference were evaluated. PSI and CURB-65 scores were classified as follow: a) PSI low risk (I-III) and moderate-high risk (IV-V) groups; b) CURB-65; low risk (0-2) and high risk (3-5) groups. RESULTS: The survival rates of the PSI class (I-III) were significantly higher than the ones of the PSI class (IV-V) (92.1% vs. 62.9%, respectively). The percentage of survivors of the CURB-65 score (0-2) group (81.9%) was higher than the survivors of CURB-65 score (3-5) group (27.8%). Creatinine, BUN, uric acid, phosphorus, RDW, CRP, CAR, procalcitonin, lactate, A-a 02 gradient, expected A-a 02 and A-a 02 difference were significantly higher and basophil was lower in non-survivors. A-a O2 gradient (AUC 0.78), A-a O2 difference (AUC 0.74) and albumin (AUC 0.80) showed highest 30-day mortality prediction. NLR (AUC 0.58) and PLR (AUC 0.55) showed lowest 30-day mortality estimation. Procalcitonin (AUC 0.65), PSI class (AUC 0.81) and PSI score (AUC 0.86) indicated statistically significant higher 30-day mortality prediction. CONCLUSION: A-a O2 gradient, A-a O2 difference and albumin are potent predictors of 30-day mortality in CAP patients in the ED.


Assuntos
Biomarcadores/sangue , Infecções Comunitárias Adquiridas/sangue , Infecções Comunitárias Adquiridas/mortalidade , Inflamação/sangue , Oxigênio/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Gasometria , Estudos Transversais , Eletrólitos/sangue , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Testes de Função Renal , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Pneumonia/mortalidade , Valor Preditivo dos Testes , Estudos Prospectivos , Albumina Sérica Humana/metabolismo , Índice de Gravidade de Doença , Turquia/epidemiologia
10.
Drug Metab Pharmacokinet ; 35(5): 456-465, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32847720

RESUMO

Eight covalent tyrosine kinase inhibitors (TKIs) were investigated to determine the characteristics of their covalent binding to plasma proteins. The data revealed that their covalent binding to plasma proteins is of species difference. In addition to the reports on neratinib and pyrotinib, osimertinib, alflutinib, AST5902, and ibrutinib were confirmed to covalently bind to the Lys-190 of human serum albumin (HSA). Molecular docking was used to simulate the binding mode of TKIs to HSA. The results exhibited the non-covalent interactions between covalent TKIs and HSA, which stabilize the TKIs-HSA complex and explain the selectivity of covalent binding. The t1/2 values of TKIs that are covalently bound to HSA or human plasma proteins were studied in vitro, and the features highly correlated with the t1/2 were determined by quantitative calculations and linear modeling. Reversibility of the covalent binding and the factors affecting the process of reversibility were evaluated. In conclusion, acrylamide moiety of covalent TKIs can covalently bind to lysine residue of HSA, most of which were determined to be Lys-190. The covalent binding is of species difference, especially between animal and human. Except for osimertinib, covalent binding between TKIs and HSA are reversible.


Assuntos
Inibidores de Proteínas Quinases/metabolismo , Albumina Sérica Humana/metabolismo , Acrilamidas/química , Acrilamidas/metabolismo , Adenina/análogos & derivados , Adenina/química , Adenina/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Compostos de Anilina/química , Compostos de Anilina/metabolismo , Animais , Sítios de Ligação , Cães , Haplorrinos , Humanos , Indóis/química , Indóis/metabolismo , Lisina/química , Lisina/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/química , Piperidinas/metabolismo , Inibidores de Proteínas Quinases/química , Piridinas/química , Piridinas/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Coelhos , Ratos , Albumina Sérica Humana/química
11.
J Med Chem ; 63(17): 9965-9976, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787104

RESUMO

Synthetic triterpenoids including CDDO, its methyl ester (CDDO-Me, bardoxolone methyl), and its imidazolide (CDDO-Im) enhance Nrf2-mediated antioxidant and anti-inflammatory activity in many diseases by reacting with thiols on the adaptor protein, Keap1. Unlike monofunctional CDDO-Me, the bifunctional analog, CDDO-Im, has a second reactive site (imidazolide) and can covalently bind to amino acids other than cysteine on target proteins such as glutathione S-transferase pi (GSTP), serum albumin, or Keap1. Here we show for the first time that bifunctional CDDO-Im (in contrast to CDDO-Me), as low as 50 nM, can covalently transacylate arginine and serine residues in GSTP and cross-link them to adjacent cysteine residues. Moreover, we show that CDDO-Im binds covalently to Keap1 by forming permanent Michael adducts with eight different cysteines, and acyl adducts with lysine and several tyrosine residues. Modeling studies suggest that the Tyr 85 adduct stabilizes the Keap1-Cul3 complex, thereby enhancing the potency of CDDO-Im.


Assuntos
Imidazóis/química , Proteína 1 Associada a ECH Semelhante a Kelch/química , Ácido Oleanólico/análogos & derivados , Sequência de Aminoácidos , Proteínas Culina/química , Proteínas Culina/metabolismo , Glutationa S-Transferase pi/química , Glutationa S-Transferase pi/metabolismo , Humanos , Imidazóis/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Simulação de Acoplamento Molecular , Ácido Oleanólico/química , Ácido Oleanólico/metabolismo , Multimerização Proteica/efeitos dos fármacos , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo
12.
Int J Nanomedicine ; 15: 4607-4623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636621

RESUMO

Aim: The interaction of NPs with biological systems may reveal useful details about their pharmacodynamic, anticancer and antibacterial effects. Methods: Herein, the interaction of as-synthesized Co3O4 NPs with HSA was explored by different kinds of fluorescence and CD spectroscopic methods, as well as molecular docking studies. Also, the anticancer effect of Co3O4 NPs against leukemia K562 cells was investigated by MTT, LDH, caspase, real-time PCR, ROS, cell cycle, and apoptosis assays. Afterwards, the antibacterial effects of Co3O4 NPs against three pathogenic bacteria were disclosed by antibacterial assays. Results: Different characterization methods such as TEM, DLS, zeta potential and XRD studies proved that fabricated Co3O4 NPs by sol-gel method have a diameter of around 50 nm, hydrodynamic radius of 177 nm with a charge distribution of -33.04 mV and a well-defined crystalline phase. Intrinsic, extrinsic, and synchronous fluorescence as well as CD studies, respectively, showed that the HSA undergoes some fluorescence quenching, minor conformational changes, microenvironmental changes as well as no structural changes in the secondary structure, after interaction with Co3O4 NPs. Molecular docking results also verified that the spherical clusters with a dimension of 1.5 nm exhibit the most binding energy with HSA molecules. Anticancer assays demonstrated that Co3O4 NPs can selectively lead to the reduction of K562 cell viability through the cell membrane damage, activation of caspase-9, -8 and -3, elevation of Bax/Bcl-2 mRNA ratio, ROS production, cell cycle arrest, and apoptosis. Finally, antibacterial assays disclosed that Co3O4 NPs can stimulate a promising antibacterial effect against pathogenic bacteria. Conclusion: In general, these observations can provide useful information for the early stages of nanomaterial applications in therapeutic platforms.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Cobalto/química , Cobalto/farmacologia , Nanopartículas Metálicas/química , Óxidos/química , Óxidos/farmacologia , Albumina Sérica Humana/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobalto/metabolismo , Escherichia coli/efeitos dos fármacos , Humanos , Células K562 , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Óxidos/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Albumina Sérica Humana/química , Staphylococcus aureus/efeitos dos fármacos , Difração de Raios X
13.
J Stroke Cerebrovasc Dis ; 29(8): 104932, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689619

RESUMO

BACKGROUND: Inflammation and malnutrition play a critical role in the outcomes of patients undergoing carotid artery stenting (CAS). Prognostic nutritional index (PNI) is commonly utilized to evaluate the peri-operative immune-nutritional status of patients undergoing colorectal cancer surgery and is independently associated with survival. We assessed the association between immune-nutritional status, indexed by PNI, and outcomes in CAS patients. METHODS: A total of 615 patients hospitalized for CAS in a tertiary heart center were enrolled in the study. PNI was calculated using the following formula: 10× serum albumin value (g/dL) + 0.005 × total lymphocyte count in the peripheral blood (per mm3). In-hospital and 5-year outcomes (ipsilateral stroke, major stroke, transient ischemic attack, myocardial infarction, and mortality) were compared between the tertiles of PNI. RESULTS: In-hospital outcomes were similar between the groups except the increased mortality in decreasing tertiles of PNI. During a mean follow-up duration of 51.1 months, the lower PNI tertile was related to unfavorable outcomes. After adjusting for multi-model Cox regression analysis, PNI persisted as an independent prognostic factor for mortality and major stroke. CONCLUSION: PNI was independently associated with long-term mortality and major stroke in CAS patients. Malnutrition and inflammation, which can be assessed easily and quickly using PNI, have an important prognostic value in the patients undergoing CAS.


Assuntos
Doenças das Artérias Carótidas/terapia , Procedimentos Endovasculares/instrumentação , Inflamação/diagnóstico , Desnutrição/diagnóstico , Avaliação Nutricional , Estado Nutricional , Stents , Idoso , Biomarcadores/sangue , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Inflamação/complicações , Inflamação/mortalidade , Inflamação/fisiopatologia , Contagem de Linfócitos , Masculino , Desnutrição/complicações , Desnutrição/mortalidade , Desnutrição/fisiopatologia , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica Humana/metabolismo , Fatores de Tempo , Resultado do Tratamento
14.
Nutr Metab Cardiovasc Dis ; 30(10): 1685-1696, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32641219

RESUMO

BACKGROUND AND AIMS: It is recognized that malnutrition increases risk of worse prognosis in patients with various diseases. The present study investigated if poor nutritional status predicts adverse outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: The study enrolled 2299 patients (mean age: 60.01 ± 8.95 years; 71.8% male) with NSTE-ACS who underwent PCI at Beijing Anzhen Hospital from January to December 2015. The entire cohort was divided into training set (n = 1519) and testing set (n = 780) at a ratio of approximate 2 : 1. Nutritional status was assessed by geriatric nutritional risk index (GNRI). The primary endpoint was a composite of adverse events as follows: all-cause death, non-fatal myocardial infarction (MI) and any revascularization. Multivariate Cox analysis showed that GNRI significantly associated with primary endpoint, independent of other risk factors [hazard ratio (HR) 1.159 per 1-point decrease of GNRI, 95% confidence interval (CI) 1.130-1.189, p < 0.001]. The addition of GNRI to a baseline model had an incremental effect on the predictive value for adverse prognosis in training set [AUC: from 0.821 to 0.873, p < 0.001; category-free net reclassification improvement (NRI): 0.313, p < 0.001; integrated discrimination improvement (IDI): 0.108, p < 0.001]. The incremental effect of GNRI was further validated and confirmed in testing set. CONCLUSION: Lower GNRI is a significant predictor of adverse prognosis in patients with NSTE-ACS undergoing PCI. Further studies need to be performed to determine whether nutritional interventions have a positive impact on improving clinical prognosis.


Assuntos
Síndrome Coronariana Aguda/terapia , Avaliação Geriátrica/métodos , Desnutrição/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Avaliação Nutricional , Estado Nutricional , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Fatores Etários , Idoso , Pequim , Biomarcadores/sangue , Índice de Massa Corporal , Feminino , Humanos , Masculino , Desnutrição/mortalidade , Desnutrição/fisiopatologia , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/mortalidade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Albumina Sérica Humana/metabolismo , Resultado do Tratamento
15.
J Cancer Res Ther ; 16(2): 230-237, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474506

RESUMO

Context: Better management strategies are needed to improve the survival of patients with hilar cholangiocarcinoma (HCCA). Aims: This study was designed to examine the effects of different treatment methods on survival and prognostic factors in HCCA. Settings and Design: We retrospectively analyzed the clinical data of 354 patients with HCCA treated at our institution from 2003 to 2013. Materials and Methods: Patients were divided into three groups according to the treatment: the radical resection group, the nonradical resection group, and the biliary drainage-only group. Statistical Analysis Used: The Kaplan-Meier method was used to compare survival rates between the groups, and the independent prognostic factors were assessed using the Cox proportional hazards model. Results: There were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group, and they showed differing survival rates: 1-year survival rates of 70.7%, 49.5%, and 31.3%; 2-year survival rates of 62.9%, 24.7%, and 9.0%; 3-year survival rates of 34.7%, 4.0%, and 0%; and median survival of 21.7 months, 13.6 months, and 8.7 months, respectively. The radical resection group had the longest overall survival (P< 0.001). Treatment method, albumin (ALB), total bilirubin (TBIL), postoperative pathological T-stage, and distant metastasis were identified as independent prognostic indicators of survival. Conclusions: Radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of patients with HCCA.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Procedimentos Cirúrgicos do Sistema Biliar/mortalidade , Bilirrubina/sangue , Biomarcadores Tumorais/sangue , Drenagem/mortalidade , Tumor de Klatskin/patologia , Albumina Sérica Humana/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/terapia , Biomarcadores Tumorais/metabolismo , Feminino , Seguimentos , Humanos , Tumor de Klatskin/sangue , Tumor de Klatskin/mortalidade , Tumor de Klatskin/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
16.
Hum Cell ; 33(3): 590-598, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32474770

RESUMO

Cell lines are powerful tools for research into liver function at the molecular level. However, they are generally unsuitable for rigorously assessing the effects of amino acid composition, because many lines require serum-containing medium for their maintenance. Here, we aimed to investigate the effects of ornithine and arginine, which are included in the characteristic metabolic process in hepatocyte, on a human hepatoma-derived cell line (FLC-4) that can be cultured in serum-free medium. FLC-4 cells were cultured under the following three conditions: + ornithine/ - arginine, - ornithine/ - arginine, and -ornithine/ + arginine. Albumin expression evaluated by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay and showed no obvious differences based on the presence of ornithine or arginine. However, the mRNA levels of two liver-enriched transcription factors (CEBPB and HNF1A), which are involved in regulating albumin expression, were significantly higher in cells grown in medium-containing arginine than that in cells grown in ornithine-containing medium. Western blotting showed that the levels both activating and inhibitory C/EBPß isoforms were significantly increased in cells grown in arginine medium. Furthermore, we have found that depletion of both ornithine and arginine, the polyamine sources, in the medium did not cause polyamine deficiency. When ornithine and arginine were depleted, albumin production was significantly reduced at the mRNA level, CEBPB mRNA levels were increased, and the level of activating form of C/EBPß was increased. The results of this study suggest that in hepatocyte, these two amino acids might have different functions, and because of which they elicit disparate cellular responses.


Assuntos
Aminoácidos/farmacologia , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinoma Hepatocelular/genética , Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/genética , Albumina Sérica Humana/genética , Albumina Sérica Humana/metabolismo , Arginina/farmacologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Meios de Cultura , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Ornitina/farmacologia , RNA Mensageiro/metabolismo
17.
Sci China Life Sci ; 63(11): 1678-1687, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32567003

RESUMO

Coronavirus disease 2019 (COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients (>18 years old) between January 29, 2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups-non-critically ill, critically ill, and death groups-in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol (LDL-C), and high-density lipoproteins cholesterol (HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old (interquartile range (IQR), 52-71). Among the patients enrolled in the study, 2,008 (76.6%) were diagnosed as non-critically ill and 615 (23.4%) were critically ill patients, including 383 (14.6%) critically ill survivors and 232 (8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein (LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time (APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients.


Assuntos
/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Hepatopatias/etiologia , Albumina Sérica Humana/metabolismo , Idoso , China , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Infecções por Coronavirus/mortalidade , Estado Terminal , Citocinas/sangue , Feminino , Humanos , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Tromboplastina/metabolismo , Fatores de Tempo
18.
Ann Hematol ; 99(5): 1111-1119, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32253453

RESUMO

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is the major cause of non-relapse mortality (NRM) in allogeneic hematopoietic stem cell transplantation (alloHSCT). This study aimed to identify variables associated with corticosteroid response and NRM in patients who developed lower GI aGVHD. We retrospectively analyzed the clinical data of patients treated at Yonsei University Severance Hospital between 2008 and 2017. Among 244 recipients of alloHSCT, 48 (19.7%) were diagnosed as lower GI aGVHD at a median of 22 days after alloHSCT. In these cases, 20 (41.6%) patients were resistant to corticosteroid therapy. Corticosteroid resistance was associated with advanced stage of lower GI aGVHD (P = 0.019), low serum albumin (P = 0.006), and elevated CRP (P = 0.030) on day 7 after corticosteroid therapy. NRM rate was significantly higher in the corticosteroid-resistant group compared with the sensitive group (HR 5.339, P = 0.003). Multivariate analysis revealed serum albumin (P = 0.046), and CRP levels (P = 0.032) were independent prognostic factors for NRM. When the patients were classified into 3 groups according to Glasgow prognostic score (GPS), the rate of corticosteroid resistance was significantly higher in the high GPS group compared with the intermediate or low GPS group (83.3 vs. 27.2 and 15.3%, respectively, P < 0.001). We demonstrated that low serum albumin and elevated CRP level on day 7 after corticosteroid therapy are objective biomarkers of corticosteroid resistance and a significant predictor for higher NRM. These simple and practical parameters could be valuable information predicting response and prognosis in lower GI aGVHD.


Assuntos
Proteína C-Reativa/metabolismo , Gastroenteropatias , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Albumina Sérica Humana/metabolismo , Adolescente , Adulto , Aloenxertos , Biomarcadores/sangue , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/etiologia , Gastroenteropatias/mortalidade , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos
19.
Chemistry ; 26(27): 5965-5969, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32237164

RESUMO

Nanoparticles are widely studied as carrier vehicles in biological systems because their size readily allows access through cellular membranes. Moreover, they have the potential to carry cargo molecules and as such, these factors make them especially attractive for intravenous drug delivery purposes. Interest in protein-based nanoparticles has recently gained attraction due to particle biocompatibility and lack of toxicity. However, the production of homogeneous protein nanoparticles with high encapsulation efficiencies, without the need for additional cross-linking or further engineering of the molecule, remains challenging. Herein, we present a microfluidic 3D co-flow device to generate human serum albumin/celastrol nanoparticles by co-flowing an aqueous protein solution with celastrol in ethanol. This microscale co-flow method resulted in the formation of nanoparticles with a homogeneous size distribution and an average size, which could be tuned from ≈100 nm to 1 µm by modulating the flow rates used. We show that the high stability of the particles stems from the covalent cross-linking of the naturally present cysteine residues within the particles formed during the assembly step. By choosing optimal flow rates during synthesis an encapsulation efficiency of 75±24 % was achieved. Finally, we show that this approach achieves significantly enhanced solubility of celastrol in the aqueous phase and, crucially, reduced cellular toxicity.


Assuntos
Microfluídica/métodos , Nanopartículas/química , Albumina Sérica Humana/química , Sistemas de Liberação de Medicamentos , Humanos , Dispositivos Lab-On-A-Chip , Albumina Sérica Humana/metabolismo , Solubilidade
20.
Inorg Chem ; 59(8): 5243-5246, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32255347

RESUMO

The Anderson-type hexamolybdoaluminate functionalized with lauric acid (LA), (TBA)3[Al(OH)3Mo6O18{(OCH2)3CNHCOC11H23}]·9H2O (TBA-AlMo6-LA, where TBA = tetrabutylammonium), was prepared via two synthetic routes and characterized by thermogravimetric and elemental analyses, mass spectrometry, IR and 1H NMR spectroscopy, and powder and single-crystal X-ray diffraction. The interaction of TBA-AlMo6-LA with human serum albumin (HSA) was investigated via fluorescence and circular dichroism spectroscopy. The results revealed that TBA-AlMo6-LA binds strongly to HSA (63% quenching at an HSA/TBA-AlMo6-LA ratio of 1:1), exhibiting static quenching. In contrast to TBA-AlMo6-LA, the nonfunctionalized polyoxometalate, Na3(H2O)6[Al(OH)6Mo6O18]·2H2O (AlMo6), showed weak binding toward HSA (22% quenching at a HSA/AlMo6 ratio of 1:25). HSA binding was confirmed by X-ray structure analysis of the HSA-Myr-AlMo6-LA complex (Myr = myristate). These results provide a promising lead for the design of novel polyoxometalate-based hybrids that are able to exploit HSA as a delivery vehicle to improve their pharmacokinetics and bioactivity.


Assuntos
Compostos de Alumínio/metabolismo , Ácidos Láuricos/metabolismo , Albumina Sérica Humana/metabolismo , Compostos de Alumínio/síntese química , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Dicroísmo Circular , Cristalografia por Raios X , Humanos , Ácidos Láuricos/síntese química , Molibdênio/química , Ligação Proteica , Albumina Sérica Humana/química , Espectrometria de Fluorescência , Triptofano/química
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