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1.
Anticancer Res ; 41(10): 5097-5106, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593460

RESUMO

AIM: D3 lymph node dissection (LND) for stage II and III colon cancer has been shown to improve prognosis, however, it generally increases surgical stress. Studies have reported that the C-reactive protein/albumin ratio (CAR) may be a useful inflammatory-nutritional biomarker to predict postoperative complications and poor prognosis for with various types of cancer. Our purposes were to assess the short- and long-term outcomes of D3 LND in patients with a high preoperative CAR (≥ 0.04). PATIENTS AND METHODS: This was a retrospective cohort analysis reviewing a prospectively collected database of Yokohama City University and three affiliated hospitals. A total of 449 patients with stage II or III colon cancer with high CAR who underwent primary resection with D2 or D3 LND were identified between 2008 and 2020. The primary and secondary outcomes of interests were the 3-year recurrence-free survival and postoperative complication rates. RESULTS: After propensity matching, 230 patients were evaluated. There was no significant difference between the D3 and D2 groups in the rate of postoperative complications overall (14.8% versus 11.3%, p=0.558), however, the incidence of anastomotic leakage tended to be greater in the D3 group (9.6% versus 2.6%, p=0.050). The long-term findings showed that there was no significant difference between the two groups (3-year recurrence-free survival rate: 77.2% versus 77.2%, p=0.880). CONCLUSION: D3 LND did not improve survival outcomes for patients with colon cancer with a poor CAR in this study. D2 LND may be a treatment option for patients with stage II-III colon cancer with a high preoperative CAR.


Assuntos
Albuminas/metabolismo , Biomarcadores Tumorais/metabolismo , Proteína C-Reativa/metabolismo , Neoplasias do Colo/mortalidade , Excisão de Linfonodo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
2.
Anticancer Res ; 41(10): 5195-5202, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593472

RESUMO

BACKGROUND/AIM: Population aging results in increasing numbers of elderly persons undergoing surgery for colorectal cancer. We sought to identify objective preoperative indicators of outcomes, with a view toward development of safe, effective treatments for such patients. PATIENTS AND METHODS: The study included 99 patients aged 80 years or more, who were treated surgically for stage I- III colorectal cancer. Preoperative nutritional status was compared retrospectively between those who suffered postoperative complications (n=40) and those who did not (n=59). RESULTS: Univariate analysis revealed low prealbumin (PreAlb) concentration (p=0.032) and low platelet-to-lymphocyte ratio (p=0.116) as risk factors for postoperative complications. Multivariate analysis showed preoperative PreAlb concentration to be an independent risk factor (OR=0.884; 95% confidence interval=0.791-0.989; p=0.024) associated with postoperative length of hospital stay (coef.=-0.336, p=0.002). CONCLUSION: PreAlb, a rapid turnover protein, shows promise as a simple predictor of postoperative complications in elderly patients treated for colorectal surgery.


Assuntos
Albuminas/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/mortalidade , Tempo de Internação/estatística & dados numéricos , Cuidados Pré-Operatórios , Idoso de 80 Anos ou mais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Cirurgia Colorretal , Feminino , Seguimentos , Humanos , Masculino , Estado Nutricional , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
3.
PLoS One ; 16(10): e0258616, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34679113

RESUMO

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have markedly improved the prognosis of many patients with advanced non-small cell lung cancer (NSCLC). However, the relationship between the patient's nutritional/immunologic status and the outcomes of ICI treatment remains unclear. In previous retrospective studies, we reported that the controlling nutritional status (CONUT) score, skeletal muscle area, and neutrophil-to-lymphocyte ratio were independent predictors of the response of NSCLC patients to anti-PD-1 drugs. The aim of this prospective multi-center study is to investigate the clinical impact of pre-treatment nutritional/immunologic indices and early post-treatment changes in the indices on treatment outcomes in advanced NSCLC. The main inclusion criteria are: (1) stage IV NSCLC, or stage III NSCLC not applicable for definitive chemoradiotherapy; (2) treatment with ICIs (monotherapy or combined with chemotherapy) as first-line therapy; and (3) available data on PD-L1 expression on tumor cells. A total of 300 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2025.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Albuminas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Colesterol/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Contagem de Linfócitos , Masculino , Estadiamento de Neoplasias , Estado Nutricional , Prognóstico , Estudos Prospectivos , Resultado do Tratamento
4.
PLoS Pathog ; 17(10): e1010037, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34710198

RESUMO

The opportunistic pathogen Candida glabrata is the second most frequent causative agent of vulvovaginal candidiasis (VVC), a disease that affects 70-75% of women at least once during their life. However, C. glabrata is almost avirulent in mice and normally incapable of inflicting damage to vaginal epithelial cells in vitro. We thus proposed that host factors present in vivo may influence C. glabrata pathogenicity. We, therefore, analyzed the impact of albumin, one of the most abundant proteins of the vaginal fluid. The presence of human, but not murine, albumin dramatically increased the potential of C. glabrata to damage vaginal epithelial cells. This effect depended on macropinocytosis-mediated epithelial uptake of albumin and subsequent proteolytic processing. The enhanced pathogenicity of C. glabrata can be explained by a combination of beneficial effects for the fungus, which includes an increased access to iron, accelerated growth, and increased adhesion. Screening of C. glabrata deletion mutants revealed that Hap5, a key regulator of iron homeostasis, is essential for the albumin-augmented damage potential. The albumin-augmented pathogenicity was reversed by the addition of iron chelators and a similar increase in pathogenicity was shown by increasing the iron availability, confirming a key role of iron. Accelerated growth not only led to higher cell numbers, but also to increased fungal metabolic activity and oxidative stress resistance. Finally, the albumin-driven enhanced damage potential was associated with the expression of distinct C. glabrata virulence genes. Transcriptional responses of the epithelial cells suggested an unfolded protein response (UPR) and ER-stress responses combined with glucose starvation induced by fast growing C. glabrata cells as potential mechanisms by which cytotoxicity is mediated.Collectively, we demonstrate that albumin augments the pathogenic potential of C. glabrata during interaction with vaginal epithelial cells. This suggests a role for albumin as a key player in the pathogenesis of VVC.


Assuntos
Albuminas/metabolismo , Candida glabrata/patogenicidade , Candidíase Vulvovaginal/microbiologia , Células Epiteliais/microbiologia , Animais , Feminino , Humanos , Camundongos
5.
Chem Commun (Camb) ; 57(72): 9144-9147, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498647

RESUMO

Haemoglobin (Hb)-albumin (HSA) trimers were synthesized using five distinct Hb variants in which the structures were genetically and chemically tuned as an artificial O2 carrier and used as a red blood cell (RBC) substitute. The trimers were found to have moderately low O2 affinity (p50 = 23-34 Torr, 37 °C) and high co-operativity, yielding a maximum O2 transport efficiency 1.8-fold higher than that of human RBCs.


Assuntos
Albuminas/metabolismo , Hemoglobinas/metabolismo , Oxigênio/metabolismo , Albuminas/química , Albuminas/genética , Eritrócitos/química , Eritrócitos/metabolismo , Hemoglobinas/química , Hemoglobinas/genética , Humanos , Oxigênio/química
6.
Cells ; 10(9)2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34571946

RESUMO

Chronic liver diseases (CLDs) are complex diseases that cause long-term inflammation and infection, which in turn accelerate their development. The usage of albumin in patients with CLDs has been debated for years. Human serum albumin (HSA) plays a key role in immunomodulation during the process of CLDs. The correlation between albumin and C-reactive protein (CRP) in CLD patients was analyzed by linear regression with the Pearson statistic. The damage of THP-1 and primary cells was evaluated by measuring the lactate dehydrogenase (LDH) in the supernatant. Immunofluorescence staining was performed to determine underlying pathways in Kupffer cells (KCs). Albumin negatively correlated with infection in patients with CLDs. In vitro experiments with THP-1 cells and KCs showed that albumin reduced LDH release after stimulation with bacterial products, while no differences in hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were detected. Moreover, immunofluorescence staining revealed an increase of p-ERK and p-NF-kB p65 density after albumin treatment of KCs stimulated by bacterial products. In conclusion, albumin could assist CLD patients in alleviating inflammation caused by bacterial products and might be beneficial to patients with CLDs by securing KCs from bacteria-induced damage, providing a compelling rationale for albumin therapy in patients with CLDs.


Assuntos
Albuminas/metabolismo , Macrófagos do Fígado/metabolismo , Hepatopatias/metabolismo , Bactérias/patogenicidade , Linhagem Celular , Células Endoteliais/imunologia , Feminino , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/microbiologia , Humanos , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Células THP-1
7.
Biomark Med ; 15(13): 1167-1175, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34406031

RESUMO

Aim: To investigate whether C-reactive protein/albumin ratio (CAR) has an association with new onset atrial fibrillation (NOAF) in SARS-CoV-2. Materials & methods: This study included 782 patients with SARS-CoV-2 infection, who were hospitalized in Turkey. The end point of the study was an occurrence of NOAF. Results: NOAF was identified in 41 patients (5.2%). Subjects who developed NOAF had a higher CAR compared with those who did not develop NOAF (p < 0.001). In the multivariate logistic regression analysis the CAR (odds ratio = 2.879; 95% CI: 1.063-7.793; p = 0.037) was an independent predictor of NOAF. Conclusion: A high level of CAR in blood samples is associated with an increased risk of developing NOAF in SARS-CoV-2.


Assuntos
Albuminas/metabolismo , Fibrilação Atrial/metabolismo , Proteína C-Reativa/metabolismo , COVID-19/complicações , Idoso , Fibrilação Atrial/complicações , COVID-19/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Turquia
8.
Sci Rep ; 11(1): 17013, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426643

RESUMO

Diabetes mellitus (DM) is considered an independent risk factor for atrial fibrillation (AF). The excess risk in relation to the presence of proteinuria has not been well elucidated. Our aim was to determine the association between the incidence of AF and proteinuria in diabetic population. A total of 240,499 individuals aged ≥ 60 years from the Korea National Health Insurance Service-Senior cohort from 2004 to 2014 were included. 4.2% of individuals with DM and 3.7% of controls were diagnosed with AF during a median follow-up period of 7.2 years. Amongst controls (participants without proteinuria and DM), DM only, proteinuria only, and DM with proteinuria groups, the crude incidences of AF were 0.58, 0.70, 0.96, 1.24 per 100 person-years respectively. Compared with controls, the weighted risk of AF was increased by 11% (hazard ratio = 1.11, 95% confidence interval = 1.02-1.20, P = .001), 48% (hazard ratio = 1.48, 95% confidence interval = 1.30-1.69, P < .001), and 66% (hazard ratio = 1.66, 95% confidence interval = 1.26-2.18, P < .001) in the DM only, proteinuria only, and DM with proteinuria groups, respectively (P for trend < .001). Degree of proteinuria in diabetic patients was associated with a significantly higher rate of incident AF in dose dependent manner. Thus, assessing proteinuria by a simple urine dipstick test could provide a useful adjunct to risk assessment for AF in elderly population with DM.


Assuntos
Fibrilação Atrial/complicações , Diabetes Mellitus Tipo 2/complicações , Proteinúria/complicações , Idoso , Albuminas/metabolismo , Fibrilação Atrial/epidemiologia , Estudos de Coortes , Creatinina/metabolismo , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Incidência , Masculino , República da Coreia/epidemiologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia
9.
Sci Rep ; 11(1): 16648, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404824

RESUMO

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) supports patients suffering from refractory cardiogenic shock. Thromboembolic complications (TeC) are common in VA-ECMO patients and are associated with increased morbidity and mortality. Valid markers to predict TeC in VA-ECMO patients are lacking. The present study investigated the predictive value of baseline Fibrinogen-Albumin-Ratio (FAR) for in-hospital TeC in patients undergoing VA-ECMO. This retrospective cohort study included patients who underwent VA-ECMO therapy due to cardiogenic shock at the University Hospital Duesseldorf, Germany between 2011 and 2018. Main exposure was baseline FAR measured at initiation of VA-ECMO therapy. The primary endpoint was the in-hospital incidence of TeC. In total, 344 patients were included into analysis (74.7% male, mean age 59 ± 14 years). The in-hospital incidence of TeC was 34%. Receiver operating characteristics (ROC) curve of FAR for in-hospital TeC revealed an area under the curve of 0.67 [95% confidence interval (CI) 0.61-0.74]. Youden index determined a cutoff of 130 for baseline FAR. Multivariate logistic regression revealed an adjusted odds-ratio of 3.72 [95% CI 2.26-6.14] for the association between FAR and TeC. Baseline FAR is independently associated with in-hospital TeC in patients undergoing VA-ECMO. Thus, FAR might contribute to the prediction of TeC in this cohort.


Assuntos
Albuminas/metabolismo , Oxigenação por Membrana Extracorpórea , Fibrinogênio/metabolismo , Tromboembolia/sangue , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Biomark Med ; 15(11): 807-820, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34284639

RESUMO

Aim: We aimed to determine the prognostic values of the National Early Warning Score 2 (NEWS2) and laboratory parameters during the first week of COVID-19. Materials & methods: All adult patients who were hospitalized for confirmed COVID-19 between 11 March and 11 May 2020 were retrospectively included. Results: Overall, 611 patients were included. Our results showed that NEWS2, procalcitonin, neutrophil/lymphocyte ratio and albumin at D0, D3, D5 and D7 were the best predictors for clinical deterioration defined as a composite of ICU admission during hospitalization or in-hospital death. Procalcitonin had the highest odds ratio for clinical deterioration on all days. Conclusion: This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for clinical deterioration in patients with COVID-19.


Assuntos
COVID-19/metabolismo , Pró-Calcitonina/metabolismo , Albuminas/metabolismo , Mortalidade Hospitalar , Humanos , Linfócitos/metabolismo , Neutrófilos/metabolismo , Razão de Chances
11.
Toxicol Lett ; 350: 194-201, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34303790

RESUMO

The phosphotriesterase of the bacterium Brevundimonas diminuta (BdPTE) is a naturally occurring enzyme that catalyzes the hydrolysis of organophosphate (OP) nerve agents as well as pesticides and offers a potential treatment of corresponding intoxications. While BdPTE mutants with improved catalytic efficiencies against several OPs have been described, unexpectedly, less efficient breakdown of an OP was observed upon application in an animal model compared with in vitro measurements. Here, we describe detailed inhibition studies with the high-activity BdPTE mutant 10-2C3(C59M/C227A) by human plasma components, indicating that this enzyme is inhibited by serum albumin. The inhibitory activity is mediated by depletion of crucial zinc ions from the BdPTE active site, either via the known high-affinity zinc binding site of albumin or via chemical complex formation with its free thiol side chain at position Cys34. Albumin pre-charged with zinc ions or carrying a chemically blocked Cys34 side chain showed significantly reduced inhibitory activity; in fact, the combination of both measures completely abolished BdPTE inhibition. Consequently, the available zinc ion concentration in blood plays an important role for BdPTE activity in vivo and should be taken into account for therapeutic development and application of a catalytic OP scavenger.


Assuntos
Albuminas/farmacologia , Proteínas de Bactérias/farmacologia , Inibidores Enzimáticos/farmacologia , Intoxicação por Organofosfatos/tratamento farmacológico , Hidrolases de Triester Fosfórico/metabolismo , Hidrolases de Triester Fosfórico/uso terapêutico , Compostos de Sulfidrila/metabolismo , Albuminas/metabolismo , Proteínas de Bactérias/metabolismo , Caulobacteraceae/química , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Inibidores Enzimáticos/metabolismo , Modelos Animais , Compostos Organofosforados/metabolismo , Compostos de Sulfidrila/sangue
12.
Aging (Albany NY) ; 13(12): 16816-16833, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34182541

RESUMO

BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening disease worldwide, and effective pharmaceutical treatment is still lacking. Celastrol is a plant-derived triterpene which showed neuroprotective potential in several types of brain insults. This study aimed to investigate the effects of celastrol on early brain injury (EBI) after SAH. METHODS: A total of sixty-one male Sprague-Dawley rats were used in this study. Rat SAH endovascular perforation model was established to mimic the pathological changes of EBI after SAH. Multiple methods such as 3.0T MRI scanning, immunohistochemistry, western blotting and propidium iodide (PI) labeling were used to explore the therapeutic effects of celastrol on SAH. RESULTS: Celastrol treatment attenuated SAH-caused brain swelling, reduced T2 lesion volume and ventricular volume in MRI scanning, and improved overall neurological score. Albumin leakage and the degradation of tight junction proteins were also ameliorated after celastrol administration. Celastrol protected blood-brain bairrer integrity through inhibiting MMP-9 expression and anti-neuroinflammatory effects. Additionally, necroptosis-related proteins RIP3 and MLKL were down-regulated and PI-positive cells in the basal cortex were less in the celastrol-treated SAH group than that in untreated SAH group. CONCLUSIONS: Celastrol exhibits neuroprotective effects on EBI after SAH and deserves to be further investigated as an add-on pharmaceutical therapy.


Assuntos
Barreira Hematoencefálica/patologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Necroptose/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Triterpenos Pentacíclicos/uso terapêutico , Hemorragia Subaracnóidea/complicações , Albuminas/metabolismo , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/complicações , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas/diagnóstico por imagem , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/patologia , Regulação para Baixo/efeitos dos fármacos , Inflamação/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Fármacos Neuroprotetores/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hemorragia Subaracnóidea/diagnóstico por imagem , Análise de Sobrevida , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacos
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071680

RESUMO

Albumin is the main protein of blood plasma, lymph, cerebrospinal and interstitial fluid. The protein participates in a variety of important biological functions, such as maintenance of proper colloidal osmotic pressure, transport of important metabolites and antioxidant action. Synthesis of albumin takes place mainly in the liver, and its catabolism occurs mostly in vascular endothelium of muscle, skin and liver, as well as in the kidney tubular epithelium. Long-lasting investigation in this area has delineated the principal route of its catabolism involving glomerular filtration, tubular endocytic uptake via the multiligand scavenger receptor tandem-megalin and cubilin-amnionless complex, as well as lysosomal degradation to amino acids. However, the research of the last few decades indicates that also additional mechanisms may operate in this process to some extent. Direct uptake of albumin in glomerular podocytes via receptor for crystallizable region of immunoglobulins (neonatal FC receptor) was demonstrated. Additionally, luminal recycling of short peptides into the bloodstream and/or back into tubular lumen or transcytosis of whole molecules was suggested. The article discusses the molecular aspects of these processes and presents the major findings and controversies arising in the light of the research concerning the last decade. Their better characterization is essential for further research into pathophysiology of proteinuric renal failure and development of effective therapeutic strategies.


Assuntos
Albuminas/metabolismo , Endotélio Vascular/metabolismo , Túbulos Renais Proximais/metabolismo , Rim/metabolismo , Fígado/metabolismo , Animais , Endocitose , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Podócitos/metabolismo , Receptores Fc/metabolismo
14.
mBio ; 12(3): e0053121, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34154403

RESUMO

Albumin is abundant in serum but is also excreted at mucosal surfaces and enters tissues when inflammation increases vascular permeability. Host-associated opportunistic pathogens encounter albumin during commensalism and when causing infections. Considering the ubiquitous presence of albumin, we investigated its role in the pathogenesis of infections with the model human fungal pathogen, Candida albicans. Albumin was introduced in various in vitro models that mimic different stages of systemic or mucosal candidiasis, where it reduced the ability of C. albicans to damage host cells. The amphipathic toxin candidalysin mediates necrotic host cell damage induced by C. albicans. Using cellular and biophysical assays, we determined that albumin functions by neutralizing candidalysin through hydrophobic interactions. We discovered that albumin, similarly, can neutralize a variety of fungal (α-amanitin), bacterial (streptolysin O and staurosporin), and insect (melittin) hydrophobic toxins. These data suggest albumin as a defense mechanism against toxins, which can play a role in the pathogenesis of microbial infections. IMPORTANCE Albumin is the most abundant serum protein in humans. During inflammation, serum albumin levels decrease drastically, and low albumin levels are associated with poor patient outcome. Thus, albumin may have specific functions during infection. Here, we describe the ability of albumin to neutralize hydrophobic microbial toxins. We show that albumin can protect against damage induced by the pathogenic yeast C. albicans by neutralizing its cytolytic toxin candidalysin. These findings suggest that albumin is a toxin-neutralizing protein that may play a role during infections with toxin-producing microorganisms.


Assuntos
Albuminas/metabolismo , Candida albicans/patogenicidade , Proteínas Fúngicas/metabolismo , Interações Hospedeiro-Patógeno , Membrana Mucosa/microbiologia , Candidíase/microbiologia , Linhagem Celular , Células Cultivadas , Feminino , Proteínas Fúngicas/biossíntese , Células HT29 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Vagina/citologia , Fatores de Virulência
15.
Nat Commun ; 12(1): 3855, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158477

RESUMO

Human voltage-gated proton channels (hHv1) extrude protons from cells to compensate for charge and osmotic imbalances due metabolism, normalizing intracellular pH and regulating protein function. Human albumin (Alb), present at various levels throughout the body, regulates oncotic pressure and transports ligands. Here, we report Alb is required to activate hHv1 in sperm and neutrophils. Dose-response studies reveal the concentration of Alb in semen is too low to activate hHv1 in sperm whereas the higher level in uterine fluid yields proton efflux, allowing capacitation, the acrosomal reaction, and oocyte fertilization. Likewise, Alb activation of hHv1 in neutrophils is required to sustain production and release of reactive oxygen species during the immune respiratory burst. One Alb binds to both voltage sensor domains (VSDs) in hHv1, enhancing open probability and increasing proton current. A computational model of the Alb-hHv1 complex, validated by experiments, identifies two sites in Alb domain II that interact with the VSDs, suggesting an electrostatic gating modification mechanism favoring the active "up" sensor conformation. This report shows how sperm are triggered to fertilize, resolving how hHv1 opens at negative membrane potentials in sperm, and describes a role for Alb in physiology that will operate in the many tissues expressing hHv1.


Assuntos
Albuminas/metabolismo , Mediadores da Inflamação/metabolismo , Canais Iônicos/metabolismo , Neutrófilos/metabolismo , Capacitação Espermática/fisiologia , Reação Acrossômica/fisiologia , Albuminas/química , Sequência de Aminoácidos , Fertilização/fisiologia , Humanos , Ativação do Canal Iônico/fisiologia , Canais Iônicos/química , Canais Iônicos/genética , Masculino , Potenciais da Membrana/fisiologia , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios Proteicos , Prótons , Sêmen/citologia , Sêmen/metabolismo , Homologia de Sequência de Aminoácidos , Espermatozoides/fisiologia , Eletricidade Estática
16.
Biochim Biophys Acta Gen Subj ; 1865(9): 129950, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34144121

RESUMO

BACKGROUND: Tubule-interstitial injury (TII) is one of the mechanisms involved in the progression of renal diseases with progressive proteinuria. Angiotensin II (Ang II) type 1 receptor blockers (ARBs) have been successfully used to treat renal diseases. However, the mechanism correlating treatment with ARBs and proteinuria is not completely understood. The hypothesis that the anti-proteinuric effect of losartan is associated with the modulation of albumin endocytosis in PT epithelial cells (PTECs) was assessed. METHODS: We used a subclinical acute kidney injury animal model (subAKI) and LLC-PK1 cells, a model of PTECs. RESULTS: In subAKI, PT albumin overload induced TII development, measured by: (1) increase in urinary lactate dehydrogenase and γ-glutamyltranspeptidase activity; (2) proteinuria associated with impairment in megalin-mediated albumin reabsorption; (3) increase in luminal and interstitial space in tubular cortical segments. These effects were avoided by treating the animals with losartan, an ARB. Using LLC-PK1 cells, we observed that: (1) 20 mg/mL albumin increased the secretion of Ang II and decreased megalin-mediated albumin endocytosis; (2) the effects of Ang II and albumin were abolished by 10-8 M losartan; (3) MEK/ERK pathway is the molecular mechanism underlying the Ang II-mediated inhibitory effect of albumin on PT albumin endocytosis. CONCLUSION: Our results show that PT megalin-mediated albumin endocytosis is a possible target during the treatment of renal diseases patients with ARB. GENERAL SIGNIFICANCE: The findings obtained in the present work represents a step forward to the current knowledge on about the role of ARBs in the treatment of renal disease.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Albuminas/antagonistas & inibidores , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Losartan/farmacologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores , Injúria Renal Aguda/metabolismo , Albuminas/metabolismo , Angiotensina II/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
FASEB J ; 35(6): e21673, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34042213

RESUMO

Lysophosphatidylinositol (LPI) is a glycero-lysophospholipid and a natural agonist against GPR55. The roles of the LPI/GPR55 axis in the pathogenesis of inflammation have been controversial. In the present study, we attempted to elucidate the roles of the LPI/GPR55 axis in inflammation, especially the secretion of inflammatory cytokines, IL-6 and TNF-α from macrophages. We treated RAW264.7 cells and mouse peritoneal macrophages (MPMs) with LPI and observed that LPI induced the secretion of IL-6 and TNF-α from these cells, as well as the phosphorylation of p38. These responses were inhibited by treatment with CID16020046 (CID), an antagonist against GPR55, or SB202190, an inhibitor of p38 cascade or knockdown of GPR55 with siRNA. Treatment with CID or ML-193, another antagonist against GPR55, attenuated the elevation of inflammatory cytokines in the plasma or tissue of db/db mice and in a septic mouse model induced using lipopolysaccharide, suggesting contributions to the improvement of insulin resistance and protection against organ injuries by treatment with CID or ML-193, respectively. In human subjects, although the serum LPI levels were not different, the levels of LPI in the lipoprotein fractions were lower and the levels in the lipoprotein-depleted fractions were higher in subjects with diabetes. LPI bound to albumin induced the secretion of IL-6 and TNF-α from RAW264.7 cells to a greater degree than LPI bound to LDL or HDL. These results suggest that LPI, especially the albumin-bound form, induced inflammatory cytokines depending on the GPR55/p38 pathway, which might contribute to the pathogenesis of obesity-induced inflammation and acute inflammation.


Assuntos
Albuminas/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Mediadores da Inflamação/metabolismo , Lisofosfolipídeos/farmacologia , Macrófagos/imunologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL
18.
J Physiol ; 599(14): 3437-3446, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34036593

RESUMO

The kidney proximal tubule (PT) efficiently recovers the low level of albumin and other proteins that normally escape the glomerular filtration barrier. Two large receptors, megalin and cubilin/amnionless (CUBAM), bind to and efficiently retrieve these predominantly low molecular-weight proteins via clathrin-mediated endocytosis. Studies in cell culture models suggest that PT cells may sense changes in shear stress to modulate recovery of filtered proteins in response to normal variations in filtration rate. Impairments in PT endocytic function lead to the excretion of filtered proteins into the urine (tubular proteinuria). Remarkably, when the glomerular filtration barrier is breached, the PT is able to recover excess albumin with a capacity that is orders of magnitude higher than normal. What mediates this excess capacity for albumin uptake under nephrotic conditions, and why doesn't it compensate to prevent tubular proteinuria? Here we propose an integrated new working model to describe the PT recovery of filtered proteins under normal and nephrotic states. We hypothesize that uptake via the fluid phase provides excess capacity to recover high concentrations of filtered proteins under nephrotic conditions. Further, concentration of tubular fluid along the tubule axis will enhance the efficiency of uptake in more distal regions of the PT. By contrast to cells where fluid phase and receptor-mediated uptake are independent pathways, expression of megalin is required to maintain apical endocytic pathway integrity and is essential for both uptake mechanisms. This model accounts for both the high-affinity and the high-capacity responses to filtration load in physiological and pathological states.


Assuntos
Túbulos Renais Proximais , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Albuminas/metabolismo , Transporte Biológico , Endocitose , Humanos , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteinúria/metabolismo
19.
Clin Nutr ESPEN ; 43: 223-229, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34024518

RESUMO

BACKGROUND AND AIMS: Several factors that worsen the prognosis of the new coronavirus SARS-CoV-2 have been identified, such as obesity or diabetes. However, despite that nutrition may change in a lockdown situation, little is known about the influence of malnutrition among subjects hospitalized due to COVID-19. Our study aimed to assess whether the presence of malnutrition among patients admitted due to COVID-19 had any impact on clinical outcomes compared with patients with the same condition but well nourished. METHODS: 75 patients admitted to hospital due to COVID-19 were analyzed cross-sectionally. Subjective Global Assessment (SGA) was completed by phone interview. Clinical parameters included were extracted from the electronic medical record. RESULTS: According to the SGA, 27 admitted due to a COVID-19 infection had malnutrition. Patients not well nourished were older than patients with a SGA grade A (65 ± 14.1 vs 49 ± 15.1 years; p < 0.0001). Length of hospital stay among poorly nourished patients was significantly higher (18.4 ± 15.6 vs 8.5 ± 7.7 days; p = 0.001). Mortality rates and admission to ICU were greater among subjects with any degree of malnutrition compared with well-nourished patients (7.4% vs 0%; p = 0.05 and 44.4% vs 6.3%; p < 0.0001). CRP (120.9 ± 106.2 vs 60.8 ± 62.9 mg/l; p = 0.03), D-dimer (1516.9 ± 1466.9 vs 461.1 ± 353.7 ng/mL; p < 0.0001) and ferritin (847.8 ± 741.1 vs 617.8 ± 598.7mcg/l; p = 0.03) were higher in the group with malnutrition. Haemoglobin (11.6 ± 2.1 vs 13.6 ± 1.5 g/dl; p < 0.0001) and albumin 3.2 ± 0.7 vs 4.1 ± 0.5 g/dl; p < 0.0001) were lower in patients with any degree of malnutrition. CONCLUSIONS: The presence of a poor nutritional status is related to a longer stay in hospital, a greater admission in the ICU and a higher mortality.


Assuntos
COVID-19 , Mortalidade Hospitalar , Hospitalização , Unidades de Terapia Intensiva , Tempo de Internação , Desnutrição/complicações , Estado Nutricional , Adulto , Albuminas/metabolismo , Proteína C-Reativa/metabolismo , COVID-19/mortalidade , Controle de Doenças Transmissíveis/métodos , Estudos Transversais , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Masculino , Desnutrição/mortalidade , Desnutrição/terapia , Pessoa de Meia-Idade , Avaliação Nutricional , Pandemias , Prognóstico , SARS-CoV-2 , Índice de Gravidade de Doença
20.
PLoS One ; 16(5): e0229550, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983976

RESUMO

BACKGROUND: HIV management remains concerning and even more challenging in the frame of comorbidities like malnutrition that favors disease progression and mortality in resource-limited settings (RLS). OBJECTIVE: To describe the nutritional parameters of antiretroviral therapy (ART) recipients (without nutritional support) with respect to CD4 count and virological failure. METHODS: A cross-sectional study was conducted from October to December 2018 among 146 consenting participants enrolled in two health facilities of the East-Region of Cameroon. Socio-demographic data, basic clinical information and treatment history were collected; blood samples were collected by venipuncture for laboratory analysis (HIV-1 viral load, CD4 Tcells measurement and biochemical analysis) performed at the "Chantal Biya" International Reference Center", Yaounde, Cameroon. The nutritional profile was assessed by using anthropometric and biochemical parameters. Data were analyzed using Excel 2016, Graph pad prism version 6; Spearman correlation and Kruskal-Wallis test were used; with p<0.05 considered statistically significant. RESULTS: Median [IQR] age was 42 [33-51] years, 76.0% (111/146) were female and median [IQR] duration on ART was 54 [28-86] months. Of these participants, 11.6% (17/146) were underweight based on the body mass index and 4.7% (7/146) were at the stage of advanced weight loss. According to immunovirological responses, 44.5% (65/146) were immunocompromised (CD4<500 cell/µl) and 75.3% (110/146) had an undetectable viremia (<40 copies/mL). CD4 count inversely correlated with total protein concentration (r = -0.18, p = 0.005**). Viremia was inversely correlated with albumin (r = -0.21; p = 0.047*), nutritional risk index (r = -0.28; p = 0.013*), total cholesterol (r = -0.27; p = 0.007**), and positively correlated with total protein (r = 0.27; p<0.001**) concentrations. CONCLUSION: In this RLS, with patients having about five years of ART-experience, malnutrition appears to be driven mainly by a poor BMI, indicating that about one of ten patients falls within this severe condition. However, the largely normal nutritional profiles should be interpreted with caution, considering local realities and food support programs in place. The present outcomes highlight the need for monitoring nutritional status of people receiving ART in RLS, toward the design of optimal food interventions.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/virologia , Estado Nutricional , Adulto , Albuminas/metabolismo , Camarões , Colesterol/sangue , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral
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