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The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.
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BACKGROUND AND AIMS: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.
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Vesículas Extracelulares , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Molécula de Adesão da Célula Epitelial/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Vesículas Extracelulares/metabolismo , Biomarcadores , Modelos Animais de Doenças , Dieta HiperlipídicaRESUMO
The pancreas fat content has been poorly investigated in essential hypertension. The authors aim to relate pancreas and liver fat content with parameters measuring insulin resistance, beta-cell function and also with markers of endothelial dysfunction and platelet or endothelial cell destruction. The authors studied a group of 40 male hypertensive patients with well-controlled blood pressure, maintaining a stable weight, and having not changed their medication during the last year. Pancreas fat content was correlated with HOMA-IR (r = .616, p < .001), HOMA-S (r = -.439, p < .005), beta cell function parameter (r = .457, p < .005), and QUICKI (r = .412, p < .01), whereas liver fat was not patients in the highest quartile of pancreas fat content had more circulating endothelial microparticles than patients in the other quartiles (median 129 [94.3-200] vs. 60.9 [49.4-88.8], p = .002). However, patients in the highest quartile of the pancreas fat content distribution did not differ from the lowest in hyperemic response after ischemia nor circulating platelet microparticles count. Liver fat content was not related to any of the parameters studied. In a multivariate stepwise binary logistic regression analysis (Wald Method) circulating endothelial microparticles remain significantly associated with pancreas fat content after adjusting for confounding factors, such as tobacco, diabetes mellitus, hypercholesterolemia, or metabolic syndrome. Our results reflect that in essential hypertension, pancreas fat content is superior to liver fat to study beta-cell functionality and insulin resistance. Moreover, the authors described for the first time that pancreas fat content is related to endothelial cell destruction. Further studies are needed to confirm this point.
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Hipertensão , Resistência à Insulina , Humanos , Masculino , Insulina , Pâncreas , Hipertensão Essencial , HomeostaseRESUMO
Metabolic dysfunction-associated fatty liver disease (MAFLD) prevalence and incidence is rising globally. It is associated with metabolic comorbidities, obesity, overweight, type 2 diabetes mellitus, and at least two metabolic risk factors, such as hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, and cardiovascular risk, increasing the risk of mortality. The excessive accumulation of fat comprises apoptosis, necrosis, inflammation and ballooning degeneration progressing to fibrosis, cirrhosis, and liver decompensations including hepatocellular carcinoma development. The limitation of approved drugs to prevent MAFLD progression is a paradigm. This review focuses on recent pathways and targets with evidence results in phase II/III clinical trials.
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Extracellular vesicles (EVs) are membrane-derived vesicles released by a variety of cell types, including hepatocytes, hepatic stellate cells, and immune cells in normal and pathological conditions. Depending on their biogenesis, there is a complex repertoire of EVs that differ in size and origin. EVs can carry lipids, proteins, coding and non-coding RNAs, and mitochondrial DNA causing alterations to the recipient cells, functioning as intercellular mediators of cell-cell communication (auto-, para-, juxta-, or even endocrine). Nevertheless, many questions remain unanswered in relation to the function of EVs under physiological and pathological conditions. The development and optimization of methods for EV isolation are crucial for characterizing their biological functions, as well as their potential as a treatment option in the clinic. In this manuscript, we will comprehensively review the results from different studies that investigated the role of hepatic EVs during liver diseases, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, fibrosis, and hepatocellular carcinoma. In general, the identification of patients with early-stage liver disease leads to better therapeutic interventions and optimal management. Although more light needs to be shed on the mechanisms of EVs, their use for early diagnosis, follow-up, and prognosis has come into the focus of research as a high-potential source of 'liquid biopsies', since they can be found in almost all biological fluids. The use of EVs as new targets or nanovectors in drug delivery systems for liver disease therapy is also summarized.
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Vesículas Extracelulares , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Vesículas Extracelulares/metabolismo , Biomarcadores/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Neoplasias Hepáticas/metabolismoRESUMO
The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m2), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.
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Hepatopatia Gordurosa não Alcoólica , Animais , Carbamoil-Fosfato Sintase (Amônia)/genética , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Fígado/metabolismo , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ureia/metabolismoRESUMO
BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer. METHODS: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+ CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort. RESULTS: EpCAM+ CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025). CONCLUSION: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Wilson's disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. The onset of the disease frequently includes manifestations related to the liver (as chronic liver disease or acute liver failure) and neurological symptoms, although it can sometimes be asymptomatic. Despite it being more frequent in young people, WD has been described in all life stages. Due to its fatal prognosis, WD should be suspected in all patients with unexplained biochemical liver abnormalities or neurological or psychiatric symptoms. The diagnosis is established with a combination of clinical signs and tests, including the measurement of ceruloplasmin, urinary copper excretion, copper quantification in liver biopsy, or genetic assessment. The pharmacological therapies include chelating drugs, such as D-penicillamine or trientine, and zinc salts, which are able to change the natural history of the disease, increasing the survival of these patients. In some cases of end-stage liver disease or acute liver failure, liver transplantation must be an option to increase survival. In this narrative review, we offer an overview of WD, focusing on the importance of clinical suspicion, the correct diagnosis, and treatment.
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BACKGROUND: The combination of alpha-fetoprotein (AFP) and squamous cell carcinoma antigen immunocomplex (SCCA-IgM) have been proposed for its use in the screening of hepatocellular carcinoma (HCC). Current screening programs for all cirrhotic patients are controversial and a personalized screening is an unmet need in the precision medicine era. AIM: To determine the role of the combination of SCCA-IgM and AFP in predicting mid- and long-term appearance of HCC. METHODS: Two-hundred and three cirrhotic patients (Child A 74.9%, B 21.2%, C 3.9%) were followed-up prospectively every six months to screen HCC by ultrasound and AFP according to European Association for the Study of the Liver guidelines. The estimation cohort was recruited in Italy (30.5%; 62/203) and validation cohort from Spain (69.5%; 141/203). Patients underwent to evaluate SCCA-IgM by enzyme-linked immunosorbent assay (Hepa-IC, Xeptagen, Italy) and AFP levels at baseline. Patients were followed-up for 60 mo, being censored at the time of the appearance of HCC. RESULTS: There were 10.8% and 23.1% of HCC development at two- and five-years follow-up. Patients with HCC showed higher levels of SCCA-IgM than those without it (425.72 ± 568.33 AU/mL vs 195.93 ± 188.40 AU/mL, P = 0.009) during the five-year follow-up. In multivariate analysis, after adjusting by age, sex, aspartate transaminase and Child-Pugh, the following factors were independently associated with HCC: SCCA-IgM [Hazard ratio (HR) = 1.001, 95%CI: 1.000-1.002; P = 0.003], AFP (HR = 1.028, 95%CI: 1.009-1.046; P = 0.003) and creatinine (HR = 1.564 95%CI: 1.151-2.124; P = 0.004). The log-rank test of the combination resulted in 7.488 (P = 0.024) in estimation cohort and 11.061 (P = 0.004) in the validation cohort, and a 100% of correctly classified rate identifying a low-risk group in both cohorts in the two-year follow-up. CONCLUSION: We have constructed a predictive model based on the combination of SCCA-IgM and AFP that provides a new HCC screening method, which could be followed by tailored HCC surveillance for individual patients, especially for those cirrhotic patients belonging to the subgroup identified as low-risk of HCC development.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Antígenos de Neoplasias , Biomarcadores Tumorais , Humanos , Imunoglobulina M , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Serpinas , alfa-FetoproteínasAssuntos
Hipertensão/fisiopatologia , Hipotensão/fisiopatologia , Sistema Nervoso Periférico/fisiopatologia , Degeneração Estriatonigral/fisiopatologia , Síncope Vasovagal/fisiopatologia , Pressão Sanguínea , Eletrocardiografia , Eletrocardiografia Ambulatorial , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipotensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/fisiopatologia , Degeneração Estriatonigral/diagnóstico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação VentricularRESUMO
Background & aims. G-allele of PNPLA3 (rs738409) favours triglycerides accumulation and steatosis. In this study, we examined the effect of quercetin and natural extracts from mushroom and artichoke on reducing lipid accumulation in hepatic cells. MATERIAL AND METHODS: Huh7.5 cells were exposed to oleic acid (OA) and treated with quercetin and extracts to observe the lipid accumulation, the intracellular-TG concentration and the LD size. Sterol regulatory element binding proteins-1 (SREBP-1), peroxisome proliferator-activated receptor (PPARα-γ) and cholesterol acyltransferase (ACAT) gene expression levels were analysed. RESULTS: Quercetin decreased the intracellular lipids, LD size and the levels of intracellular-TG through the down-regulation of SREBP-1c, PPARγ and ACAT1 increasing PPARα. The natural-extracts suppressed OA-induced lipid accumulation and the intracellular-TG. They down-regulate the hepatic lipogenesis through SREBP-1c, besides the activation of lipolysis through the increasing of PPARα expression. CONCLUSIONS: Quercetin and the aqueous extracts decrease intracellular lipid accumulation by down-regulation of lipogenesis and up-regulation of lipolysis.
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Hepatócitos/efeitos dos fármacos , Lipase/genética , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Extratos Vegetais/farmacologia , Quercetina/farmacologia , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Acetiltransferase/metabolismo , Agaricales , Linhagem Celular Tumoral , Cynara scolymus , Flores , Genótipo , Hepatócitos/metabolismo , Humanos , Lipase/metabolismo , Lipogênese/genética , Lipólise/genética , Proteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Oleico/toxicidade , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Fenótipo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
BACKGROUND: Alcoholic fermentation of fruits has generated novel products with high concentrations of bioactive compounds and moderate alcohol content. The aim of this study was to evaluate the potential effect on cardiovascular risk factors of the regular consumption by healthy humans of a beverage obtained by alcoholic fermentation and pasteurization of orange juice. RESULTS: Thirty healthy volunteers were enrolled in a randomized controlled study. The experimental group (n = 15) drank 500 mL orange beverage (OB) per day for 2 weeks (intervention phase), followed by a 3-week washout phase. Blood samples were collected at baseline (E-T0) and at the end of the intervention (E-T1) and washout (E-T2) phases. Controls (n = 15) did not consume OB during a 2-week period. OB intake significantly increased oxygen radical absorbance capacity (43.9%) and reduced uric acid (-8.9%), catalase (CAT) (-23.2%), thiobarbituric acid reactive substances (TBARS) (-30.2%) and C-reactive protein (-2.1%) (E-T1 vs. E-T0). These effects may represent longer-term benefits, given the decreased uric acid (-8.9%), CAT (-34.6%), TBARS (-48.4%) and oxidized low-density lipoprotein (-23.9%) values recorded after the washout phase (E-T2 vs. E-T0). CONCLUSION: The regular consumption of OB improved antioxidant status and decreased inflammation state, lipid peroxidation and uric acid levels. Thus OB may protect the cardiovascular system in healthy humans and be considered a novel functional beverage. © 2017 Society of Chemical Industry.
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Antioxidantes/metabolismo , Bebidas/análise , Citrus sinensis/metabolismo , Sucos de Frutas e Vegetais/microbiologia , Inflamação/dietoterapia , Peroxidação de Lipídeos , Pichia/metabolismo , Adulto , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Catalase/metabolismo , Citrus sinensis/química , Citrus sinensis/microbiologia , Feminino , Fermentação , Frutas/química , Frutas/metabolismo , Frutas/microbiologia , Sucos de Frutas e Vegetais/análise , Voluntários Saudáveis , Humanos , Inflamação/genética , Inflamação/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
BACKGROUND: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by hypertension and proteinuria. The HELLP syndrome is the most severe form of PE. The aim of the present study was to determine different potential biomarkers that may help us perform an early diagnosis of the disease, assess on the severity of the disease, and/or predict maternal or fetal adverse outcomes. METHODS: We measured serum levels of total and fetal circulating cell-free DNA (cfDNA), soluble endoglin, soluble form of vascular endothelial growth factor receptor, and placental growth factor in a healthy control group of pregnant women (n = 26), patients with mild (n = 37) and severe PE (n = 25), and patients with HELLP syndrome (n = 16). RESULTS: We observed a gradual and strong relationship between all the biomarkers mentioned and the range of severity of PE, with the highest levels in patients with HELLP syndrome. Nevertheless, only the values of total cfDNA were able to significantly differentiate severe PE and HELLP syndrome (20957 ± 2784 vs. 43184 ± 8647 GE/ml, P = 0.01). Receiver operating characteristic (ROC) curves were constructed (i) for the healthy group with respect to the groups with PE and (ii) for patients with PE with respect to the group with HELLP syndrome; sensitivity and specificity values at different cutoff levels were calculated in each case. The maximum ROC area under the curve value for PE and HELLP syndrome (with respect to controls) was 0.91 (P < 0.001). CONCLUSIONS: The measured biomarkers of cell damage, angiogenesis, and antiangiogenesis may reflect the severity of PE, with higher levels in patients who develop HELLP syndrome. In addition, these biomarkers may also help predict adverse fetal and maternal outcomes.
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Proteínas Angiogênicas/sangue , Ácidos Nucleicos Livres/sangue , Síndrome HELLP/sangue , Pré-Eclâmpsia/sangue , Adulto , Área Sob a Curva , Estudos de Casos e Controles , Ácidos Nucleicos Livres/genética , Diagnóstico Diferencial , Endoglina/sangue , Feminino , Síndrome HELLP/diagnóstico , Síndrome HELLP/genética , Humanos , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Valor Preditivo dos Testes , Gravidez , Terceiro Trimestre da Gravidez/sangue , Curva ROC , Índice de Gravidade de Doença , Regulação para Cima , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
STUDY OBJECTIVES: This study tries to assess the endothelial function in vivo using flow-mediated dilatation (FMD) and several biomarkers of endothelium formation/restoration and damage in patients with obstructive sleep apnoea (OSA) syndrome at baseline and after three months with CPAP therapy. DESIGN: Observational study, before and after CPAP therapy. SETTING AND PATIENTS: We studied 30 patients with apnoea/hypopnoea index (AHI) >15/h that were compared with themselves after three months of CPAP therapy. FMD was assessed non-invasively in vivo using the Laser-Doppler flowmetry. Circulating cell-free DNA (cf-DNA) and microparticles (MPs) were measured as markers of endothelial damage and the vascular endothelial growth factor (VEGF) was determined as a marker of endothelial restoration process. MEASUREMENTS AND RESULTS: After three month with CPAP, FMD significantly increased (1072.26 ± 483.21 vs. 1604.38 ± 915.69 PU, p< 0.005) cf-DNA and MPs significantly decreased (187.93 ± 115.81 vs. 121.28 ± 78.98 pg/ml, p<0.01, and 69.60 ± 62.60 vs. 39.82 ± 22.14 U/µL, p<0.05, respectively) and VEGF levels increased (585.02 ± 246.06 vs. 641.11 ± 212.69 pg/ml, p<0.05). These changes were higher in patients with more severe disease. There was a relationship between markers of damage (r = -0.53, p<0.005) but not between markers of damage and restoration, thus suggesting that both types of markers should be measured together. CONCLUSIONS: CPAP therapy improves FMD. This improvement may be related to an increase of endothelial restoration process and a decrease of endothelial damage.
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Pressão Positiva Contínua nas Vias Aéreas , Endotélio Vascular/patologia , Apneia Obstrutiva do Sono/terapia , Adulto , Biomarcadores/sangue , Micropartículas Derivadas de Células/patologia , DNA/sangue , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apneia Obstrutiva do Sono/diagnóstico , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Preeclampsia is a pregnancy-related disorder associated with increased cardiovascular risk for the offspring. Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that participate in the formation of vasculature during development. However, the effect of preeclampsia on fetal levels of ECFCs is largely unknown. In this study, we sought to determine whether cord blood ECFC abundance and function are altered in preeclampsia. We conducted a prospective cohort study that included women with normal (n=35) and preeclamptic (n=15) pregnancies. We measured ECFC levels in the umbilical cord blood of neonates and characterized ECFC phenotype, cloning-forming ability, proliferation, and migration toward vascular endothelial growth factor-A and fibroblast growth factor-2, in vitro formation of capillary-like structures, and in vivo vasculogenic ability in immunodeficient mice. We found that the level of cord blood ECFCs was statistically lower in preeclampsia than in control pregnancies (P=0.04), a reduction that was independent of other obstetric factors. In addition, cord blood ECFCs from preeclamptic pregnancies required more time to emerge in culture than control ECFCs. However, once derived in culture, ECFC function was deemed normal and highly similar between preeclampsia and control, including the ability to form vascular networks in vivo. This study demonstrates that preeclampsia affects ECFC abundance in neonates. A reduced level of ECFCs during preeclamptic pregnancies may contribute to an increased risk of developing future cardiovascular events.
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Células Endoteliais/patologia , Sangue Fetal/citologia , Pré-Eclâmpsia/patologia , Células-Tronco/patologia , Adulto , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Gravidez , Estudos Prospectivos , Fatores de Risco , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
BACKGROUND: Patients infected with the human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease due to increased inflammation and persistent immune activation. CD163 is a macrophage scavenger receptor that is involved in monocyte-macrophage activation in HIV-infected patients. CD163 interacts with TWEAK, a member of the TNF superfamily. Circulating levels of sTWEAK and sCD163 have been previously associated with cardiovascular disease, but no previous studies have fully analyzed their association with HIV. OBJECTIVE: The aim of this study was to analyze circulating levels of sTWEAK and sCD163 as well as other known markers of inflammation (hsCRP, IL-6 and sTNFRII) and endothelial dysfunction (sVCAM-1 and ADMA) in 26 patients with HIV before and after 48 weeks of antiretroviral treatment (ART) and 23 healthy subjects. RESULTS: Patients with HIV had reduced sTWEAK levels and increased sCD163, sVCAM-1, ADMA, hsCRP, IL-6 and sTNFRII plasma concentrations, as well as increased sCD163/sTWEAK ratio, compared with healthy subjects. Antiretroviral treatment significantly reduced the concentrations of sCD163, sVCAM-1, hsCRP and sTNFRII, although they remained elevated when compared with healthy subjects. Antiretroviral treatment had no effect on the concentrations of ADMA and sTWEAK, biomarkers associated with endothelial function. The use of protease inhibitors as part of antiretroviral therapy and the presence of HCV-HIV co-infection and/or active HIV replication attenuated the ART-mediated decrease in sCD163 plasma concentrations. CONCLUSION: HIV-infected patients showed a proatherogenic profile characterized by increased inflammatory, immune-activation and endothelial-dysfunction biomarkers that partially improved after ART. HCV-HIV co-infection and/or active HIV replication enhanced immune activation despite ART.
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Antirretrovirais/uso terapêutico , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Coinfecção/sangue , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Hepatite C/sangue , Receptores de Superfície Celular/sangue , Fatores de Necrose Tumoral/sangue , Adulto , Arginina/análogos & derivados , Arginina/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Coinfecção/tratamento farmacológico , Citocina TWEAK , Feminino , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Hepacivirus/isolamento & purificação , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto JovemRESUMO
Blood-derived endothelial colony-forming cells (ECFCs) have robust vasculogenic potential that can be exploited to bioengineer long-lasting human vascular networks in vivo. However, circulating ECFCs are exceedingly rare in adult peripheral blood. Because the mechanism by which ECFCs are mobilized into circulation is currently unknown, the reliability of peripheral blood as a clinical source of ECFCs remains a concern. Thus, there is a need to find alternative sources of autologous ECFCs. Here we aimed to determine whether ECFCs reside in the vasculature of human white adipose tissue (WAT) and to evaluate if WAT-derived ECFCs have equal clinical potential to blood-derived ECFCs. We isolated the complete endothelial cell (EC) population from intact biopsies of normal human subcutaneous WAT by enzymatic digestion and selection of CD31(+) cells. Subsequently, we extensively compared WAT-derived EC phenotype and functionality to bonafide ECFCs derived from both umbilical cord blood and adult peripheral blood. We demonstrated that human WAT is indeed a dependable source of ECFCs with indistinguishable properties to adult peripheral blood ECFCs, including hierarchical clonogenic ability, large expansion potential, stable endothelial phenotype, and robust in vivo blood vessel-forming capacity. Considering the unreliability and low rate of occurrence of ECFCs in adult blood and that biopsies of WAT can be obtained with minimal intervention in an ambulatory setting, our results indicate WAT as a more practical alternative to obtain large amounts of readily available autologous ECFCs for future vascular cell therapies.
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Tecido Adiposo Branco/irrigação sanguínea , Células-Tronco Adultas/citologia , Células Endoteliais/citologia , Células-Tronco Hematopoéticas/citologia , Neovascularização Fisiológica , Adulto , Animais , Divisão Celular , Separação Celular , Ensaio de Unidades Formadoras de Colônias , Sangue Fetal/citologia , Xenoenxertos , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Nus , Microvasos/crescimento & desenvolvimento , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Especificidade de ÓrgãosRESUMO
BACKGROUND: Olive oil polyphenols have been associated with several cardiovascular health benefits. This study aims to examine the influence of a polyphenol-rich olive oil on blood pressure (BP) and endothelial function in 24 young women with high-normal BP or stage 1 essential hypertension. METHODS: We conducted a double-blind, randomized, crossover dietary-intervention study. After a run-in period of 4 months (baseline values), two diets were used, one with polyphenol-rich olive oil (â¼30 mg/day), the other with polyphenol-free olive oil. Each dietary period lasted 2 months with a 4-week washout between diets. Systolic and diastolic BP, serum or plasma biomarkers of endothelial function, oxidative stress, and inflammation, and ischemia-induced hyperemia in the forearm were measured. RESULTS: When compared to baseline values, only the polyphenol-rich olive oil diet led to a significant (P < 0.01) decrease of 7.91 mm Hg in systolic and 6.65 mm Hg of diastolic BP. A similar finding was found for serum asymmetric dimethylarginine (ADMA) (-0.09 ± 0.01 µmol/l, P < 0.01), oxidized low-density lipoprotein (ox-LDL) (-28.2 ± 28.5 µg/l, P < 0.01), and plasma C-reactive protein (CRP) (-1.9 ± 1.3 mg/l, P < 0.001). The polyphenol-rich olive oil diet also elicited an increase in plasma nitrites/nitrates (+4.7 ± 6.6 µmol/l, P < 0.001) and hyperemic area after ischemia (+345 ± 386 perfusion units (PU)/sec, P < 0.001). CONCLUSIONS: We concluded that the consumption of a diet containing polyphenol-rich olive oil can decrease BP and improve endothelial function in young women with high-normal BP or stage 1 essential hypertension.
Assuntos
Pressão Sanguínea , Gorduras Insaturadas na Dieta/administração & dosagem , Endotélio Vascular/fisiopatologia , Antebraço/irrigação sanguínea , Hipertensão/dietoterapia , Óleos de Plantas/administração & dosagem , Polifenóis/administração & dosagem , Adulto , Fatores Etários , Biomarcadores/sangue , Estudos Cross-Over , Método Duplo-Cego , Endotélio Vascular/metabolismo , Feminino , Humanos , Hiperemia/fisiopatologia , Hipertensão/sangue , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Mediadores da Inflamação/sangue , Azeite de Oliva , Estresse Oxidativo , Índice de Gravidade de Doença , Fatores Sexuais , Espanha , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJETIVO: Determinar la frecuencia de Candida en cavidad bucal de niños con riesgo de desarrollar infecciones oportunistas y establecer si existe asociación entre la frecuencia de esta colonización bucal y tres tipos de población en riesgo. MÉTODOS: Se estudiaron cuatro grupos de población infantil de México: grupo VIH/sida bajo terapia antirretroviral altamente activa (TAAA) (35 niñas y 25 niños); grupo desnutrición (26 niñas y 29 niños); grupo tarahumara (37 niñas y 20 niños), una de las poblaciones étnicas más pobres del país, y grupo control (8 niñas y 21 niños aparentemente sanos). Los niños con VIH/sida fueron inmunológica y virológicamente clasificados según los criterios de EC-Clearinghouse, mientras que la desnutrición fue determinada a través del índice peso/talla de la Organización Mundial de la Salud. Se tomó una muestra de la mucosa bucal con hisopo estéril, que fue incubada en agar dextrosa Sabouraud y en CHROMagar-Candida®. Las especies de Candida se confirmaron con la prueba API ID32C. RESULTADOS: Los grupos VIH/sida y desnutrición mostraron la frecuencia más alta de Candida spp. (51,7 por ciento y 38,2 por ciento, respectivamente) mientras que el grupo tarahumara presenta una frecuencia semejante a la del grupo control (17,5 por ciento vs 10,3 por ciento). Respecto a las especies de Candida, el grupo desnutrición mostró la mayor diversidad: C. albicans, C. tropicalis, C. krusei y C. glabrata. CONCLUSIONES: Los infantes con inmunodeficiencia y con desnutrición requieren de estrategias diseñadas para disminuir la colonización bucal candidal y disminuir el riesgo de infecciones oportunistas.
OBJECTIVE: Determine the frequency of candida in the oral cavity of children with a risk of developing opportunistic infections, and establish if there is an association between the frequency of this oral colonization and three categories of at-risk populations. METHODS: Four infant population groups in Mexico were studied: an HIV/AIDS group undergoing highly active antiretroviral therapy (35 girls and 25 boys); a malnourished group (26 girls and 29 boys); a group from the Tarahumara indigenous people, one of the poorest ethnic populations in the country (37 girls and 20 boys); and a control group (8 girls and 21 boys in apparently good health). The children with HIV/AIDS were immunologically and virologically classified according to the EC Clearinghouse criteria, while malnutrition was determined through the World Health Organization's weight/height index. A sample of oral mucosa was taken with a sterile swab, which was incubated in Sabouraud dextrose agar and in Candida CHROMagar®. The species of candida were confirmed through the API ID32C test. RESULTS: The HIV/AIDS and malnutrition groups showed the higher frequency of Candida spps (51.7 percent and 38.2 percent, respectively), while the frequency level in the Tarahumara group was similar to that of the control group (17.5 percent versus 10.3 percent). With regard to the species of candida, the malnutrition group had the greatest diversity: C. albicans, C. tropical, C. krusei, and C. glabrata. CONCLUSIONS: The children with HIV/AIDS and malnutrition require strategies designed to reduce oral candidal colonization and reduce the risk of opportunistic infections.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Candidíase Bucal/epidemiologia , Infecções por HIV/epidemiologia , Indígenas Norte-Americanos/estatística & dados numéricos , Desnutrição/epidemiologia , Candida/isolamento & purificação , Portador Sadio/epidemiologia , Comorbidade , Estudos Transversais , Hospedeiro Imunocomprometido , México , Mucosa Bucal/microbiologia , Infecções Oportunistas/epidemiologia , Populações Vulneráveis/estatística & dados numéricosRESUMO
Neurotrophins acting through high-affinity tyrosine kinase receptors (trkA, trkB, and trkC) play a crucial role in regulating survival and maintenance of specific neuronal functions after injury. Adult motoneurons supplying extraocular muscles survive after disconnection from the target, but suffer dramatic changes in morphological and physiological properties, due in part to the loss of their trophic support from the muscle. To investigate the dependence of the adult rat extraocular motoneurons on neurotrophins, we examined trkA, trkB, and trkC mRNA expression after axotomy by in situ hybridization. trkA mRNA expression was detectable at low levels in unlesioned motoneurons, and its expression was downregulated 1 and 3 days after injury. Expression of trkB and trkC mRNAs was stronger, and after axotomy a simultaneous, but inverse regulation of both receptors was observed. Thus, whereas a considerable increase in trkB expression was seen about 2 weeks after axotomy, the expression of trkC mRNA had decreased at the same post-lesion period. Injured extraocular motoneurons also experienced an initial induction in expression of calcitonin gene-related peptide and a transient downregulation of cholinergic characteristics, indicating a switch in the phenotype from a transmitter-specific to a regenerative state. These results suggest that specific neurotrophins may contribute differentially to the survival and regenerative responses of extraocular motoneurons after lesion.