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1.
Expert Opin Drug Metab Toxicol ; 15(8): 633-658, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31274340

RESUMO

Introduction: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the 'protein-mediated hepatic uptake' is a violation of 'the free drug hypothesis', but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values. Areas covered: We first review the two 'albumin-facilitated hepatic uptake' models that were recently challenged to improve the in vitro-to-in vivo extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) in vitro compared to the presence of ALB in vivo. Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the 'ALB-mediated hepatic uptake' mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes. Expert opinion: Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the 'ALB-facilitated hepatic uptake' models to cover the remaining uncertainties.


Assuntos
Albuminas/metabolismo , Hepatócitos/metabolismo , Modelos Biológicos , Transporte Biológico , Humanos , Lipídeos/química , Fígado/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Ligação Proteica , Proteínas/metabolismo
2.
Life Sci ; 230: 197-207, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150688

RESUMO

AIMS: Increased amounts of protein, in particular albumin within renal tubular cells (TBCs), induce the expression of inflammatory and fibrogenic mediators, which are adverse prognostic factors in tubulointerstitial fibrosis and diabetic nephropathy (DN). We sought to assess the participation of the thiol-linked tertiary structure of albumin in the mechanism of protein toxicity in a model of TBCs. MATERIALS AND METHODS: Cultured human renal proximal tubular cells, HK-2, were exposed to isolated albumin from patients with and without DN (Stages 0, 1 and 4). The magnitude of change of the albumin tertiary structure, cell viability (LDH leakage), apoptosis (Annexin V), transdifferentiation and reticulum endoplasmic stress (Western blot and flow cytometry) and lysosomal enzyme activity were assessed. KEY FINDINGS: We found that albumin from Stage 4 patients presented >50% higher thiol-dependent changes of tertiary structure compared to Stages 0 and 1. Cells incubated with Stage 4 albumin displayed 5 times less viability, accompanied by an increased number of apoptotic cells; evidence of profibrogenic markers E-cadherin and vimentin and higher expression of epithelial-to-mesenchymal transition markers α-SMA and E-cadherin and of endoplasmic reticulum stress protein GRP78 were likewise observed. Moreover, we found that cathepsin B activity in isolated lysosomes showed a significant inhibitory effect on albumin from patients in advanced stages of DN and on albumin that was intentionally modified. SIGNIFICANCE: Overall, this study showed that thiol-dependent changes in albumin's tertiary structure interfere with the lysosomal proteolysis of renal TBCs, inducing molecular changes associated with interstitial fibrosis and DN progression.


Assuntos
Nefropatias Diabéticas/metabolismo , Lisossomos/fisiologia , Albumina Sérica Humana/fisiologia , Adulto , Idoso , Albuminas/metabolismo , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Linhagem Celular , Sobrevivência Celular , Transdiferenciação Celular , Nefropatias Diabéticas/fisiopatologia , Estresse do Retículo Endoplasmático , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fibrose , Humanos , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Estrutura Terciária de Proteína/fisiologia , Albumina Sérica Humana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vimentina/metabolismo
3.
Biochemistry (Mosc) ; 84(6): 652-662, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31238865

RESUMO

Neutrophil myeloperoxidase (MPO) plays an important role in protecting the body against infections. MPO products - hypohalous acids and phenoxyl radicals - are strong oxidants that can damage not only foreign intruders but also host tissues, including blood plasma proteins. Here, we compared the MPO-induced oxidation of two plasma proteins with antioxidant properties - human serum albumin (HSA) and ceruloplasmin (CP). Incubation of both proteins with hypochlorite (NaOCl) or catalytically active MPO (MPO + H2O2), which synthesizes hypochlorous acid (HOCl) in the presence of chloride ions, resulted in the quenching of protein tryptophan fluorescence. Oxidation-induced changes in the structures of HSA and CP were different. HSA efficiently neutralized MPO-generated oxidants without protein aggregation, while CP oxidation resulted in the formation of large aggregates stabilized by strong covalent bonds between the aromatic amino acid residues. Tyrosine is present in the plasma as free amino acid and also as a component of the polypeptide chains of the proteins. The number of tyrosine residues in a protein does not determine its propensity for aggregate formation. In the case of CP, protein aggregation was primarily due to the high content of tryptophan residues in its polypeptide chain. MPO-dependent oxidation of free tyrosine results in the formation of tyrosyl radicals, that do not oxidize aromatic amino acid residues in proteins because of the high rate of recombination with dityrosine formation. At the same time, free tyrosine can influence MPO-induced protein oxidation due to its ability to modulate HOCl synthesis in the MPO active site.


Assuntos
Albuminas/metabolismo , Ceruloplasmina/metabolismo , Peroxidase/metabolismo , Tirosina/metabolismo , Antioxidantes/metabolismo , Humanos , Oxirredução
4.
Int J Mol Sci ; 20(10)2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091675

RESUMO

Cadmium (Cd2+) in the environment is a significant health hazard. Chronic low Cd2+ exposure mainly results from food and tobacco smoking and causes kidney damage, predominantly in the proximal tubule. Blood Cd2+ binds to thiol-containing high (e.g., albumin, transferrin) and low molecular weight proteins (e.g., the high-affinity metal-binding protein metallothionein, ß2-microglobulin, α1-microglobulin and lipocalin-2). These plasma proteins reach the glomerular filtrate and are endocytosed at the proximal tubule via the multiligand receptor complex megalin:cubilin. The current dogma of chronic Cd2+ nephrotoxicity claims that Cd2+-metallothionein endocytosed via megalin:cubilin causes renal damage. However, a thorough study of the literature strongly argues for revision of this model for various reasons, mainly: (i) It relied on studies with unusually high Cd2+-metallothionein concentrations; (ii) the KD of megalin for metallothionein is ~105-times higher than (Cd2+)-metallothionein plasma concentrations. Here we investigated the uptake and toxicity of ultrafiltrated Cd2+-binding protein ligands that are endocytosed via megalin:cubilin in the proximal tubule. Metallothionein, ß2-microglobulin, α1-microglobulin, lipocalin-2, albumin and transferrin were investigated, both as apo- and Cd2+-protein complexes, in a rat proximal tubule cell line (WKPT-0293 Cl.2) expressing megalin:cubilin at low passage, but is lost at high passage. Uptake was determined by fluorescence microscopy and toxicity by MTT cell viability assay. Apo-proteins in low and high passage cells as well as Cd2+-protein complexes in megalin:cubilin deficient high passage cells did not affect cell viability. The data prove Cd2+-metallothionein is not toxic, even at >100-fold physiological metallothionein concentrations in the primary filtrate. Rather, Cd2+-ß2-microglobulin, Cd2+-albumin and Cd2+-lipocalin-2 at concentrations present in the primary filtrate are taken up by low passage proximal tubule cells and cause toxicity. They are therefore likely candidates of Cd2+-protein complexes damaging the proximal tubule via megalin:cubilin at concentrations found in the ultrafiltrate.


Assuntos
Albuminas/metabolismo , Cádmio/toxicidade , Túbulos Renais Proximais/efeitos dos fármacos , Lipocalina-2/metabolismo , Microglobulina beta-2/metabolismo , Animais , Cádmio/farmacologia , Intoxicação por Cádmio , Linhagem Celular , Túbulos Renais Proximais/citologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Metalotioneína/metabolismo , Ligação Proteica , Ratos , Receptores de Superfície Celular/metabolismo
5.
BMC Gastroenterol ; 19(1): 66, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046687

RESUMO

BACKGROUND: Quality of life (QOL) assessments with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-HCC18, C30 and HCC18 index scores have been shown to be prognostic factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC), independent of disease stage and liver function. Liver function parameters (including bilirubin, albumin, international normalized ratio [INR], Child-Pugh class, ALBI grade, MELD, alkaline phosphatase [ALP]-to-platelet ratio, albumin-to-ALP ratio) have also been found to be independent prognostic factors for OS in HCC patients. There has been scanty data on whether QOL and baseline liver function per se are correlated in HCC patients. This study investigates the correlations between baseline QOL data and liver function variables in HCC patients. METHODS: From 2007 to 2011, 517 patients were enrolled. Baseline QOL was assessed at diagnosis using the EORTC QLQ-C30 and QLQ-HCC18; thereafter C30 and HCC18 index scores were derived. Clinical and laboratory data were collected. For liver function assessment, Child-Pugh class, ALBI grade, MELD, ALP-to-platelet ratio and albumin-to-ALP ratio were derived. Correlation analyses were performed between QOL and liver function data. RESULTS: Complete QOL data were available in 472 HCC patients. After adjusting for clinical variables, significant correlations were found between QOL (QLQ-C30 and QLQ-HCC18) and dichotomized liver function variables (including Child-Pugh class, ALBI grade and the presence of ascites). It was demonstrated that QOL had significant and potentially clinically important correlations with continuous liver function variables (albumin, bilirubin, ALP and albumin-to-ALP ratio), with the highest Spearman's rank correlation coefficient (rho) exceeding 0.4. HCC18 and C30 index scores were also significantly correlated with these liver function variables. HCC18 index score, which had rho up to 0.37, generally performed better than C30 index score, which had rho up to 0.33. CONCLUSIONS: In HCC patients, baseline QOL assessment (using EORTC QLQ-C30, QLQ-HCC18, C30 index-score or HCC18 index-score) is significantly correlated with liver function. Based on the findings of this study, future trials are warranted to assess whether treatment to enhance liver function could improve HCC patients' QOL.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Neoplasias Hepáticas/fisiopatologia , Fígado/fisiopatologia , Qualidade de Vida , Idoso , Albuminas/metabolismo , Fosfatase Alcalina/metabolismo , Ascite/etiologia , Bilirrubina/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Coeficiente Internacional Normatizado , Fígado/metabolismo , Testes de Função Hepática , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Contagem de Plaquetas , Inquéritos e Questionários , Análise de Sobrevida
6.
Ter Arkh ; 91(1): 71-77, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-31090375

RESUMO

AIM: To evaluate the association of a complex of cardiovascular risk factors and genetic markers with the development of high albuminuria among patients with arterial hypertension in the population of Mountain Shoriya, taking into account ethnicity. MATERIALS AND METHODS: A clinical epidemiological study of a compactly residing population in remote areas of Mountain Shoria was carried out. 1409 people were examined [901 people - representatives of the indigenous nationality (Shorians), 508 people - representatives of non-indigenous nationality (90% of them are Caucasians)]. Hypertension was diagnosed according to the National Guidelines of the Russian Society of Cardiology/the Russian Medical Society on Arterial Hypertension (2010). All patients underwent clinical, laboratory and instrumental investigation. To study the state of the kidneys, the concentration (the presence of elevated levels) of albumin (albuminuria) in the morning portion of urine by an immunoturbidimetric method was analyzed. Polymorphisms of genes ACE (I/D, rs4340), АGT (c.803T>C, rs699), AGTR1 (А1166С, rs5186), ADRB1 (с.145A>G, Ser49Gly, rs1801252), ADRA2B (I/D, rs28365031), MTHFR (c.677С>Т, Ala222Val, rs1801133) and NOS3 (VNTR, 4b/4a) were tested using PCR. RESULTS: In the group of shors with arterial hypertension, high albuminuria was associated with polymorphisms of the ACE genes (OR=2.05), ADRA2B (OR=6.00), elevated triglyceride level (OR=2.86), decreased index of cholesterol of high density lipoproteins (OR=5.57) and increased index of low density lipoproteins (OR=2.49); in the new population - with polymorphisms of the AGTR1 genes (OR=8.66), ADRA2B (OR=6.53), MTHFR (OR=7.16), obesity (OR=2.72), and abdominal obesity (OR=3.14). CONCLUSION: The primary predictors determining the development of high albuminuria among patients with arterial hypertension in both ethnic groups were genetic ones. In addition to them, non-genetic risk factors also contributed to the development of this organ damage to the kidneys: age and lipid metabolism disorders in representatives of indigenous nationality; age and abdominal obesity in the examined patients non-indigenous nationality.


Assuntos
Albuminas/metabolismo , Albuminúria/etnologia , Doenças Cardiovasculares/genética , Grupos Étnicos/genética , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Receptores Adrenérgicos alfa 2/genética , Albuminúria/genética , Doenças Cardiovasculares/etnologia , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hipertensão/etnologia , Lipoproteínas HDL/metabolismo , Obesidade Abdominal/etnologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Fatores de Risco , Federação Russa/epidemiologia , Triglicerídeos/metabolismo
7.
Phytomedicine ; 59: 152902, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981184

RESUMO

BACKGROUND: Curcuminoids, mainly present in the plant rhizomes of turmeric (Curcuma longa), consist of mainly three forms (curcumin (CUR), bisdemethoxycurcumin (BDMC) and demethoxycurcumin (DMC)). It has been reported that different forms of curcuminoids possess different biological activities. However, the mechanisms associated with these differences are not well-understood. Recently, our laboratory found differences in the cellular uptake of these curcuminoids. Therefore, it has been inferred that these differences contribute to the different biological activities. PURPOSE: In this study, we investigated the mechanisms of differential cellular uptake of these curcuminoids. METHOD: Based on our previous study, we hypothesized the differential cellular uptake is caused by (I) polarity, (II) transporters, (III) metabolism rate of curcuminoids and (IV) medium components. These four hypotheses were each investigated by (I) neutralizing the polarities of curcuminoids by encapsulation into poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs), (II) inhibition of polyphenol-related absorption transporters, (III) analysis of the cellular curcuminoids and their metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and (IV) use of different mediums in cell study. RESULTS: The differential cellular uptake was not affected by (I-III). However, when investigating (IV), not only CUR but also BDMC and DMC were incorporated into cells when serum free media was used. Furthermore, when we used the serum free medium containing bovine serum albumin (BSA), only CUR was taken up but BDMC and DMC were not. Therefore, we identified that the differential cellular uptake of curcuminoids is caused by the medium components, especially BSA. Also, the fluorescence quenching study suggested that differential cellular uptake is due to the different interaction between BSA and each curcuminoid. CONCLUSION: The differential cellular uptake of curcuminoids was caused by the different interaction between curcuminoids and BSA. The results from this study might give clues on the mechanisms by which curcuminoids exhibit different physiological activities.


Assuntos
Albuminas/metabolismo , Curcumina/análogos & derivados , Curcumina/farmacocinética , Albuminas/química , Linhagem Celular , Cromatografia Líquida , Curcuma/química , Curcumina/química , Humanos , Monócitos/efeitos dos fármacos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Espectrometria de Massas em Tandem/métodos
8.
Mediators Inflamm ; 2019: 7537649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930689

RESUMO

Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world's most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports-and is supported by-uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as "leaky gut." Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation.


Assuntos
Albuminas/metabolismo , Cirrose Hepática/metabolismo , Animais , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Cirrose Hepática/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Nutrients ; 11(4)2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31010101

RESUMO

Limited studies have assessed the associations of pretreatment serum glutamine level with clinicopathological characteristics and prognosis of colorectal cancer (CRC) patients. This study focuses on clarifying the clinical significance of baseline serum glutamine level in CRC patients. We retrospectively examine 123 patients with newly diagnosed CRC between 2009 and 2011. The associations of pretreatment serum glutamine level with clinicopathological characteristics, proinflammatory cytokines, overall survival (OS), and progression-free survival (PFS) were analyzed. We executed univariate and multivariate analyses to assess the associations between serum glutamine level and clinicopathological variables able to predict survival. Low glutamine levels were associated with older age, advanced stage, decreased albumin levels, elevated carcinoembryonic antigen levels, higher C-reactive protein levels, higher modified Glasgow prognostic scores, and higher proinflammatory cytokine levels. Furthermore, patients with low glutamine levels had poorer OS and PFS than those with high glutamine levels (p < 0.001 for both). In multivariate analysis, pretreatment glutamine level independently predicted OS (p = 0.016) and PFS (p = 0.037) in CRC patients. Pretreatment serum glutamine level constitutes an independent prognostic marker to predict survival and progression in CRC patients.


Assuntos
Neoplasias Colorretais/sangue , Glutamina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , Biomarcadores Tumorais , Proteína C-Reativa/metabolismo , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
10.
Proc Natl Acad Sci U S A ; 116(12): 5399-5404, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30833403

RESUMO

Three-dimensional renal tissues that emulate the cellular composition, geometry, and function of native kidney tissue would enable fundamental studies of filtration and reabsorption. Here, we have created 3D vascularized proximal tubule models composed of adjacent conduits that are lined with confluent epithelium and endothelium, embedded in a permeable ECM, and independently addressed using a closed-loop perfusion system to investigate renal reabsorption. Our 3D kidney tissue allows for coculture of proximal tubule epithelium and vascular endothelium that exhibits active reabsorption via tubular-vascular exchange of solutes akin to native kidney tissue. Using this model, both albumin uptake and glucose reabsorption are quantified as a function of time. Epithelium-endothelium cross-talk is further studied by exposing proximal tubule cells to hyperglycemic conditions and monitoring endothelial cell dysfunction. This diseased state can be rescued by administering a glucose transport inhibitor. Our 3D kidney tissue provides a platform for in vitro studies of kidney function, disease modeling, and pharmacology.


Assuntos
Túbulos Renais Proximais/metabolismo , Reabsorção Renal , Albuminas/metabolismo , Glucose/metabolismo , Humanos , Imagem Tridimensional , Túbulos Renais Proximais/irrigação sanguínea , Túbulos Renais Proximais/ultraestrutura , Microscopia Eletrônica , Modelos Biológicos , Reabsorção Renal/fisiologia
11.
Mater Sci Eng C Mater Biol Appl ; 99: 264-274, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889700

RESUMO

Heterometal oxide nanoparticles of bioessential metals are shedding new light to nanoparticle-inspired bioapplications. Pairing bioreactive elements like copper and iron can affect the redox dynamic and biological profile of the nanomaterial. Given the complexity of physicochemical properties, biological activity and toxicity concerns, extensive exploration is demanded, especially when active and less active oxidation states participate as in case of cuprous-ferric delafossite CuFeO2 (copper(I)-iron(III)), a less widespread nanomaterial. In that vein, CuFeO2 nanoparticles were synthesized and biological profile was evaluated in comparison with cuprous oxide (Cu2O NPs) counterpart, an already established antimicrobial agent. Interactions with bacteria, proteins and DNA were examined. Cu2O NPs exhibited stronger antibacterial activity (IC50 < 25 µg/ml) than CuFeO2 NPs (IC50 > 100 µg/ml). In vitro exposure of nanoparticles on plasmid DNA unveiled toxicity in the form of DNA damage for Cu2O and enhanced biocompatibility for CuFeO2 NPs. Genotoxicity estimated by the frequency of sister chromatid exchanges, cytostaticity based on the proliferating rate indices and cytotoxicity based on the mitotic indices at human peripheral lymphocyte cultures were all significantly lower in the case of CuFeO2 NPs. Furthermore, through in vitro albumin denaturation assay, CuFeO2 NPs showed better performance in protein denaturation protection, correlating in superior anti-inflammatory activity than Cu2O and similar to acetylsalicylic acid. Synergy of copper(I)-iron(III) in nanoscale is apparent and gives rise to fruitful bioapplications and perspectives.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Cobre/química , DNA/metabolismo , Compostos Férricos/farmacologia , Mutagênicos/toxicidade , Nanopartículas/toxicidade , Proteínas/metabolismo , Albuminas/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Clivagem do DNA/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nanopartículas/química , Nanopartículas/ultraestrutura , Desnaturação Proteica/efeitos dos fármacos , Análise Espectral Raman , Difração de Raios X
12.
Clin Appl Thromb Hemost ; 25: 1076029619835383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30857397

RESUMO

Inflammation has been implicated in the pathogenesis of endothelial dysfunction, atherosclerosis, and microvascular coronary dysfunction. In this context, it is thought that fibrinogen, high-sensitive C-reactive protein (hsCRP), and albumin may be associated with the pathogenesis of coronary slow flow (CSF). We aimed to evaluate the ratios of fibrinogen-to-albumin and hsCRP-to-albumin in patients with CSF compared to patients with angiographically normal coronary arteries and stable coronary artery disease (CAD). In all, 65 patients with CSF, 65 patients with newly diagnosed stable CAD, and 65 control participants with angiographically normal coronary arteries were included. The coronary flow rates of all patients were determined by the Thrombolysis in Myocardial Infarction frame count method. Fibrinogen, hsCRP, and albumin levels were analyzed in all patients, and the fibrinogen-to-albumin and hsCRP-to-albumin ratios were calculated. The baseline characteristics of the 3 groups were similar. The plasma albumin level was significantly lower, whereas the fibrinogen and the hsCRP levels were significantly higher, in the CSF and CAD groups compared to the controls. The fibrinogen-to-albumin and hsCRP-to-albumin ratios were significantly higher in both the CSF and the CAD groups compared to the control group. The hsCRP-to-albumin ratio was positively correlated with the mean Thrombolysis in Myocardial Infarction frame count in the whole study population. According to the receiver-operating characteristic analysis, the efficacies of the fibrinogen-to-albumin and hsCRP-to-albumin ratios in predicting CSF were significant. The fibrinogen-to-albumin and hsCRP-to-albumin ratios, which were increased by a reciprocal change, suggest that inflammation may play a role in the pathogenesis of CSF.


Assuntos
Albuminas/metabolismo , Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico , Fibrinogênio/metabolismo , Inflamação/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
J Colloid Interface Sci ; 546: 312-323, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30927595

RESUMO

An electrostatic nanocomplex between naturally occurring ε-poly-l-lysine (εPL) and ß-cyclodextrin sulphate (sCD) was designed, and its capacity to entrap four model proteins with high or low molecular weight and isoelectric point, i.e., lactoferrin, albumin, actinidin, and lysozyme, was investigated. The optimal formulations gave nanocomplexes with an average diameter around 276 ±â€¯16 nm, a ζ-potential of -39 ±â€¯1.5 mV, and a spherical shape with a core-shell structure. Different strategies were pursued to increase the entrapment efficiency for selected proteins, which led to 40-100% entrapment depending on the protein type. Under simulated gastric conditions with pepsin, the complexes protected lactoferrin and albumin against proteolysis, whereas actinidin and lysozyme were intrinsically stable. In Caco-2 cells, these complexes transiently decreased the trans-epithelial electrical resistance, indicating the potential to enhance the paracellular permeability of bioactive macromolecules. Thus, these εPL-sCD complexes would be a promising system for loading diverse proteins for gastric protection and enhancing intestinal absorption.


Assuntos
Albuminas/metabolismo , Cisteína Endopeptidases/metabolismo , Sistemas de Liberação de Medicamentos , Trato Gastrointestinal/efeitos dos fármacos , Lactoferrina/metabolismo , Muramidase/metabolismo , Polilisina/farmacologia , Substâncias Protetoras/farmacologia , beta-Ciclodextrinas/farmacologia , Albuminas/análise , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cisteína Endopeptidases/análise , Relação Dose-Resposta a Droga , Humanos , Lactoferrina/análise , Estrutura Molecular , Muramidase/análise , Tamanho da Partícula , Polilisina/química , Substâncias Protetoras/química , Relação Estrutura-Atividade , Propriedades de Superfície , beta-Ciclodextrinas/química
14.
Toxicol Lett ; 308: 34-49, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30872129

RESUMO

Cardiorenal syndrome (CRS) remains a global health burden with a lack of definitive and effective treatment. Protein-bound uremic toxin (PBUT) overload has been identified as a non-traditional risk factor for cardiac, renal and vascular dysfunction due to significant albumin-binding properties, rendering these solutes non-dialyzable upon the state of irreversible kidney dysfunction. Although limited, experimental studies have investigated possible mechanisms in PBUT-mediated cardiac, renal and vascular effects. The ultimate aim is to identify relevant and efficacious targets that may translate beneficial outcomes in disease models and eventually in the clinic. This review will expand on detailed knowledge on mechanisms involved in detrimental effects of PBUT, specifically affecting the heart, kidney and vasculature, and explore potential effective intracellular targets to abolish their effects in CRS initiation and/or progression.


Assuntos
Albuminas/metabolismo , Vasos Sanguíneos/patologia , Síndrome Cardiorrenal/metabolismo , Rim/patologia , Miocárdio/patologia , Toxinas Biológicas/metabolismo , Uremia/metabolismo , Vasos Sanguíneos/metabolismo , Síndrome Cardiorrenal/patologia , Síndrome Cardiorrenal/urina , Fibrose , Humanos , Rim/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Toxinas Biológicas/urina , Uremia/patologia , Uremia/urina
15.
Clin Appl Thromb Hemost ; 25: 1076029618824418, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808220

RESUMO

Increased coronary thrombus burden is known to be a strong predictor of adverse cardiovascular (CV) outcomes. C-reactive protein to albumin ratio (CAR) can be used as a surrogate marker of pro-inflammation which is closely related to prothrombotic state. We aimed to evaluate the association between CAR and coronary thrombus burden in patients who presented with acute coronary syndrome (ACS). Patients who presented with ACS and treated with primary percutaneous coronary intervention were included in the study. Patients were divided into 2 groups as high thrombus burden and low thrombus burden. The study population included 347 patients with non-ST-segment elevation myocardial infarction (169 [48.7%]) and ST-segment elevation myocardial infarction (178 [51.3%]). The CAR was significantly higher in patients with higher thrombus burden (24.4 [1.2-30.2] vs 31.9 [2.2-31.3], P < .001). Independent predictors for increased thrombus burden were higher CRP level (odds ratio [OR]: 0.047; 95% confidence interval [CI]: 0.004-0.486; P = .010), lower serum albumin level (OR: 0.057; 95% CI: 0.033-0.990; P = .049), higher CAR (OR: 1.13; 95% CI: 1.03-1.23; P = .008), higher neutrophil-lymphocyte ratio (OR: 1.18; 95% CI: 1.05-1.31; P = .004), and baseline troponin I level (OR: 1.06; 95% CI: 1.01-1.13; P = .017). Novel CAR can be used as a reliable marker for increased coronary thrombus burden that is associated with adverse CV outcomes.


Assuntos
Síndrome Coronariana Aguda/sangue , Albuminas/metabolismo , Proteína C-Reativa/metabolismo , Trombose Coronária/sangue , Síndrome Coronariana Aguda/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
Arch Virol ; 164(4): 1069-1083, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30783772

RESUMO

The blood-brain barrier (BBB) is a physical barrier that restricts the passage of cells and molecules as well as pathogens into the central nervous system (CNS). Some viruses enter the CNS by disrupting the BBB, while others can reach the CNS without altering the integrity of the BBB. Even though dengue virus (DENV) is not a distinctive neurotropic virus, the virus is considered to be one of the leading causes of neurological manifestations. In this study, we found that DENV is able to compromise the integrity of a murine in vitro blood-brain barrier (BBB) model, resulting in hyperpermeability, as shown by a significant increase in sucrose and albumin permeability. Infection of brain endothelial cells (ECs) was facilitated by the presence of glycans, in particular, mannose and N-acetyl glucosamine residues, on cell surfaces and viral envelope proteins, and the requirement for glycan moieties for cell infection was serotype-specific. Direct viral disruption of brain ECs was observed, leading to a significant decrease in tight-junction protein expression and peripheral localization, which contributed to the changes in BBB permeability. In conclusion, the hyperpermeability and breaching mechanism of BBB by DENV are primarily due to direct consequences of viral infection of ECs, as shown in this in vitro study.


Assuntos
Barreira Hematoencefálica/virologia , Vírus da Dengue/fisiologia , Dengue/virologia , Albuminas/metabolismo , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/virologia , Técnicas de Cocultura , Dengue/metabolismo , Vírus da Dengue/classificação , Vírus da Dengue/genética , Células Endoteliais/metabolismo , Células Endoteliais/virologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Sorogrupo , Sacarose/metabolismo , Junções Íntimas/metabolismo
17.
Niger J Clin Pract ; 22(2): 186-193, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729941

RESUMO

Background: Alteration in the homeostasis of trace elements such as magnesium may play a role in the development of epileptic seizures. This study aims to investigate the levels of serum magnesium in people with idiopathic generalized epileptic (IGE) seizures and symptomatic seizures in Northeast Nigeria. Materials and Methods: Serum magnesium level was measured using atomic absorption spectrometry among 40 adults with IGE, 20 adults with symptomatic epileptic seizures, and 30 healthy controls. Serum calcium, potassium, phosphate, and albumin were also measured. Results: The mean serum magnesium level was significantly lower among people with epilepsy compared with the controls [0.79 ± 0.18 mmol/L vs 0.90 mmol/L ± 0.17, P = 0.007, 95% confidence interval (CI): (-0.189 to -0.031)]. People with IGE had significantly lower levels of magnesium compared with those with symptomatic seizures [0.74 ± 0.17 mmol/L vs 0.9 ± 0.16 mmol/L, P < 0.001 95% CI: (-0.251 to -0.069)]. The mean magnesium level for all groups was in the reference range, but the lowest levels were observed in those with IGE. There is no significant correlation between the level of serum magnesium and the severity of seizure attacks. There was significantly lower level of calcium in people with IGE compared with those with symptomatic seizures [2.3 ± 0.13 mmol/L vs 2.4 ± 0.16 mmol/L, P = 0.012, 95% CI: (-0.177 to 0.023)] or controls [2.3 ± 0.13 mmol/L vs 2.4 ± 0.12 mmol/L, P < 0.01, 95% CI: (-0.156 to -0.044)]. No significant differences were observed in the levels of potassium, phosphate, and albumin. Conclusion: This study suggests that low serum magnesium and calcium may play a role in IGE, and supplementation may be useful in reducing seizures in Black patients with epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Magnésio/sangue , Convulsões/tratamento farmacológico , Adolescente , Adulto , Albuminas/metabolismo , Cálcio/sangue , Estudos Transversais , Epilepsia/sangue , Epilepsia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Fosfatos/sangue , Potássio/sangue , Convulsões/sangue , Convulsões/epidemiologia , Espectrofotometria Atômica , Adulto Jovem
18.
Fish Physiol Biochem ; 45(3): 965-976, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30656452

RESUMO

Lipopolysaccharides (LPS) and salinity are important variables in aquatic environments. High concentration of LPS and large changes in salinity seriously threat the survival of a variety of organisms, including fish. To reveal the effects of salinity and LPS on a fish immune response, we measured the immune-related parameters (total leukocyte count, total serum protein, albumin and globulin concentrations, complement C3 concentration, and lysozyme activity) and genes (the expressions of TNF-α, IL-1ß, and SOCS1-3 at the mRNA and protein levels) of juvenile Takifugu fasciatus exposed to phosphate buffered saline (PBS) or LPS (25 µg mL-1) under different salinities (0, 15, and 30 ppt) for 24 h. Changes in key immunological indicators suggested that the LPS challenge induced considerable damage to T. fasciatus, whereas an increase in salinity mitigated the harmful effects. Moreover, although the immune responses in blood and other selected tissues (gill and kidney) were suppressed with an increase in salinity, the increased response in liver in saltwater enabled T. fasciatus to conquer large salinity variation during migration. The appropriate addition of salts appeared to be a sensible strategy to mitigate LPS-induced toxicity in the aquaculture of T. fasciatus.


Assuntos
Salinidade , Tolerância ao Sal , Takifugu/imunologia , Envelhecimento , Albuminas/metabolismo , Animais , Proteínas Sanguíneas/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Citocinas/genética , Citocinas/metabolismo , Exposição Ambiental/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Brânquias/fisiologia , Globulinas/metabolismo , Muramidase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Água/química
19.
Int J Mol Sci ; 20(3)2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30691015

RESUMO

The novel histone deacetylase inhibitor CG200745 was initially developed to treat various hematological and solid cancers. We investigated the molecular mechanisms associated with the renoprotective effects of CG200745 using deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. DOCA strips (200 mg/kg) were implanted into rats one week after unilateral nephrectomy. Two weeks after DOCA implantation, DSH rats were randomly divided into two groups that received either physiological saline or CG200745 (5 mg/kg/day) for another two weeks. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson's trichrome staining. The renal expression of fibrosis and inflammatory markers was detected by semiquantitative immunoblotting, a polymerase chain reaction, and immunohistochemistry. Pathological signs such as glomerulosclerosis, tubulointerstitial fibrosis, increased systolic blood pressure, decreased creatinine clearance, and increased albumin-to-creatinine ratios in DSH rats were alleviated by CG200745 treatment compared to those manifestations in positive control animals. Furthermore, this treatment counteracted the increased expression of αSMA, TGF-ß1, and Bax, and the decreased expression of Bcl-2 in the kidneys of DSH rats. It also attenuated the increase in the number of apoptotic cells in DSH rats. Thus, CG200745 can effectively prevent the progression of renal injury in DSH rats by exerting anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.


Assuntos
Acetato de Desoxicorticosterona/efeitos adversos , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Hipertensão/tratamento farmacológico , Nefropatias/prevenção & controle , Naftalenos/administração & dosagem , Actinas/metabolismo , Albuminas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Creatinina/metabolismo , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/complicações , Nefropatias/metabolismo , Masculino , Naftalenos/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo
20.
Int J Mol Med ; 43(1): 103-116, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30365068

RESUMO

Liver fibrosis is a serious threat to human health, and there is currently no effective clinical drug for treatment of the disease. Although Galectin­1 is effective, its role in liver function, inflammation, matrix metalloproteinases and the activation of hepatic stellate cells (HSCs) remains to be elucidated. The aim of the present study was to elucidate the effect of Galectin­1 on the activation, proliferation and apoptosis of HSCs in a mouse model of liver fibrosis. Following successful model establishment and tissue collection, mouse HSCs (mHSCs) were identified and an mHSC line was constructed. Subsequently, to determine the role of Galectin­1 in liver fibrosis, the expression levels of transforming growth factor (TGF)­ß1, connective tissue growth factor (CTGF) and α­smooth muscle actin (α­SMA) pre­ and post­transfection were evaluated by reverse transcription­quantitative polymerase chain reaction and western blot analyses. In addition, the effects of Galectin­1 on the biological behavior and mitochondrial function of mHSCs were determined using a 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay, flow cytometry and a scratch test. It was first observed that the expression levels of Galectin­1, TGF­ß1, CTGF and α­SMA were downregulated by silencing the gene expression of Galectin­1. Additionally, silencing the gene expression of Galectin­1 inhibited cell cycle progression, proliferation and migration but induced the apoptosis of mHSCs from mice with liver fibrosis. Furthermore, the in vivo experimental results suggested that silencing the gene expression of Galectin­1 improved liver fibrosis. Collectively, it was concluded that silencing the gene expression of Galectin­1 ameliorates liver fibrosis and that functionally suppressing Galectin­1 may be a future therapeutic strategy for liver fibrosis.


Assuntos
Apoptose , Galectina 1/genética , Inativação Gênica , Células Estreladas do Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Actinas/metabolismo , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Bilirrubina/metabolismo , Ciclo Celular/genética , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Modelos Animais de Doenças , Galectina 1/metabolismo , Células Estreladas do Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
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