RESUMO
The development of de novo albuminuria during chronic renin-angiotensin system (RAS) suppression is a clinical entity that remains poorly recognized in the biomedical literature. It represents a clear increment in global cardiovascular (CV) and renal risk that cannot be counteracted by RAS suppression. Although not specifically considered, it is clear that this entity is present in most published and ongoing trials dealing with the different forms of CV and renal disease. In this review, we focus on the mechanisms promoting albuminuria, and the predictors and new markers of de novo albuminuria, as well as the potential treatment options to counteract the excretion of albumin. The increase in risk that accompanies de novo albuminuria supports the search for early markers and predictors that will allow practising physicians to assess and prevent the development of de novo albuminuria in their patients.
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Albuminúria/etiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Inibidores da Enzima Conversora de Angiotensina , Animais , Humanos , Sistema Renina-Angiotensina , Pesquisa Translacional BiomédicaRESUMO
INTRODUCTION: The application of new proteomics methods may help to identify new diagnostic/predictive molecular markers in an attempt to improve the clinical management of atherosclerosis. Areas covered: Technological advances in proteomics have enhanced its sensitivity and multiplexing capacity, as well as the possibility of studying protein interactions and tissue structure. These advances will help us better understand the molecular mechanisms at play in atherosclerosis as a biological system. Moreover, this should help identify new predictive/diagnostic biomarkers and therapeutic targets that may facilitate effective risk stratification and early diagnosis, with the ensuing rapid implementation of treatment. This review provides a comprehensive overview of the novel methods in proteomics, including state-of-the-art techniques, novel biological samples and applications for the study of atherosclerosis. Expert commentary: Collaboration between clinicians and researchers is crucial to further validate and introduce new molecular markers to manage atherosclerosis that are identified using the most up to date proteomic approaches.
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Aterosclerose/diagnóstico , Proteômica/métodos , Aterosclerose/etiologia , Humanos , Modelos Biológicos , Mapeamento de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Fatores de RiscoRESUMO
BACKGROUND: Hypertension is a multi-factorial disease of increasing prevalence and a major risk factor for cardiovascular mortality even in the presence of adequate treatment. Progression of cardiovascular disease (CVD) occurs frequently during chronic renin-angiotensin-system (RAS) suppression, and albuminuria is a marker of CV risk. High prevalence of albuminuria in treated hypertensive patients has been demonstrated, but there are no available markers able to predict evolution. The aim of this study was the identification of novel indicators of albuminuria progression measurable in urine of diabetic and non-diabetic patients. METHODS: 1143 hypertensive patients under chronic treatment were followed for a minimum period of 3 years. Among them, 105 diabetic and non-diabetic patients were selected and classified in three groups according to albuminuria development during follow-up: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Differential urine analysis was performed by 2D gel electrophoresis (2D-DIGE) and further confirmed by liquid chromatography-mass spectrometry. Non-parametric statistical tests were applied. RESULTS: CD59 glycoprotein and alpha-1 antitrypsin (AAT) resulted already altered in patients developing albuminuria de novo, with a similar response in those with maintained albuminuria. A prospective study in a sub-group of normoalbuminuric patients who were clinically followed up for at least 1 year from urine sampling, revealed CD59 and AAT proteins significantly varied in the urine collected from normoalbuminurics who will negatively progress, serving as predictors of future albuminuria development. CONCLUSIONS: CD59 and AAT proteins are significantly altered in hypertensive patients developing albuminuria. Interestingly, CD59 and AAT are able to predict, in normoalbuminuric individuals, who will develop albuminuria in the future, being potential predictors of vascular damage and CV risk. These findings contribute to early identify patients at risk of developing albuminuria even when this classical predictor is still in the normal range, constituting a novel strategy towards a prompt and more efficient therapeutic intervention with better outcome.
Assuntos
Albuminúria/etiologia , Anti-Hipertensivos/uso terapêutico , Antígenos CD59/urina , Nefropatias Diabéticas/etiologia , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , alfa 1-Antitripsina/urina , Idoso , Albuminúria/diagnóstico , Albuminúria/fisiopatologia , Albuminúria/urina , Biomarcadores/urina , Estudos de Casos e Controles , Cromatografia Líquida , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Eletroforese em Gel Bidimensional , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Hipertensão/urina , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Proteômica/métodos , Medição de Risco , Fatores de Risco , Espectrometria de Massas em Tandem , Fatores de Tempo , UrináliseRESUMO
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Metabolômica , IntestinosRESUMO
AIMS: The aim of this study was to determine whether arterial stiffness assessed with the biochemical parameter active matrix metalloproteinase (MMP)-9 and the clinical parameters pulse pressure (PP) and pulse wave velocity predicts the response to spironolactone in resistant hypertension (RH). METHODS AND RESULTS: Ambulatory blood pressure (BP) and active MMP-9 (measured by zymography and ELISA) were measured at baseline, and patients were classified as having pseudo-RH or RH. Patients with RH received spironolactone and the response was determined after 8 weeks by ambulatory BP monitoring: those who achieved BP goals were considered controlled (CRH) and those who did not were considered uncontrolled (UCRH). Plasma active MMP-9 was significantly higher in patients with RH than with pseudo-RH, and correlated with 24 h systolic BP and PP. Receiver operating characteristic analysis indicated that active MMP-9 could predict the response to spironolactone, and its combination with 24 h PP and pulse wave velocity significantly improved this prediction. Moreover, plasma of patients with UCRH induced the MMP-9 expression pathway. CONCLUSION: We propose active MMP-9 as a useful biomarker to identify patients with RH who will not respond to spironolactone. Combining MMP-9 activity with classical arterial stiffness parameters improves the prediction of the clinical response to spironolactone and might contribute to guide the most appropriate therapeutic decisions for patients with RH.
Assuntos
Hipertensão , Rigidez Vascular , Monitorização Ambulatorial da Pressão Arterial , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Metaloproteinase 9 da Matriz/uso terapêutico , Análise de Onda de Pulso , Espironolactona/efeitos adversosRESUMO
Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn's disease (CD). Both diseases show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells that play a key role in tolerance maintenance in the gastrointestinal mucosa. Although it has been reported that DC recruitment by the intestinal mucosa is more prominent in IBD patients, the specific mechanisms governing this migration are currently unknown. In this study, the expression of several homing markers and the migratory profile of circulating DC subsets towards intestinal chemo-attractants were evaluated and the effect of biological drugs with different mechanisms of action, such as anti-TNFα or anti-integrin α4ß7 (vedolizumab), on this mechanism in healthy controls (HCs) and IBD patients was also assessed. Our results revealed that type 2 conventional DCs (cDC2) express differential homing marker profiles in UC and CD patients compared to HCs. Indeed, integrin ß7 was differentially modulated by vedolizumab in CD and UC. Additionally, although CCL2 displayed a chemo-attractant effect over cDC2, while biological therapies did not modulate the expression of the homing markers, we paradoxically found that anti-TNF-treated cDC2 increased their migratory capacity towards CCL2 in HCs and IBD. Our results therefore suggest a key role for cDC2 migration towards the intestinal mucosa in IBD, something that could be explored in order to develop novel diagnostic biomarkers or to unravel new immunomodulatory targets in IBD.
RESUMO
Inflammatory bowel disease (IBD) has become a global disease encompassing a group of progressive disorders characterized by recurrent chronic inflammation of the gut with variable disease courses and complications. Despite recent advances in the knowledge of IBD pathophysiology, the elucidation of its etiopathology and progression is far from fully understood, requiring complex and multiple approaches. Therefore, limited clinical progress in diagnosis, assessment of disease activity, and optimal therapeutic regimens have been made over the past few decades. This review explores recent advances and challenges in tissue proteomics with an emphasis on biomarker discovery and better understanding of the molecular mechanisms underlying IBD pathogenesis. Future multi-omic studies are required for the comprehensive molecular characterization of disease biology in real time with a future impact on early detection, disease monitoring, and prediction of the clinical outcome.
Assuntos
Doenças Inflamatórias Intestinais , Proteômica , Doença Crônica , Humanos , Inflamação , Doenças Inflamatórias Intestinais/diagnósticoRESUMO
BACKGROUND: Intestinal dendritic cells (DC) and macrophages drive disease progression in patients with inflammatory bowel disease (IBD). We aimed to characterize the activation and homing profile of human circulating DC and monocyte subsets in healthy control patients (CP) and IBD patients. METHODS: Eighteen CP and 64 patients with IBD were categorized by diagnoses of Crohn disease (CD) and ulcerative colitis (UC), either endoscopically active (inflamed) or quiescent. Circulating type 1 conventional DC, type 2 conventional DC, plasmacytoid DC, classical monocytes, nonclassical monocytes, and intermediate monocytes were identified by flow cytometry in each individual and characterized for the expression of 18 markers. Association between DC/monocytes and IBD risk was tested by logistic regression. Discriminant canonical analyses were performed to classify the patients in their own endoscopy category considering all markers on each subset. RESULTS: CCRL1, CCR3, and CCR5 expression on circulating type 1 DC; CCRL1 expression on nonclassical monocytes; and CCR9 and ß7 expression on classical monocytes allowed us to discriminate among the different study groups. Indeed, the same markers (excluding ß7) were also associated with IBD when all DC and monocyte subsets were considered at the same time. CONCLUSIONS: Monitoring the phenotype of human circulating DC and monocyte subsets may provide novel tools as biomarkers for disease diagnosis (CD/UC) or mucosal status (inflamed/noninflamed) in the absence of an invasive colonoscopy.
Assuntos
Colite Ulcerativa , Doença de Crohn , Células Dendríticas/imunologia , Monócitos/imunologia , Biomarcadores , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Humanos , FenótipoRESUMO
Aging and chronic kidney disease (CKD) are important interrelated cardiovascular risk (CVR) factors linked to oxidative stress, but this relationship has not been well studied in older adults. We assessed the global oxidative status in an older population with normal to severely impaired renal function. We determined the oxidative status of 93 older adults (mean age 85 years) using multimarker scores. OxyScore was computed as index of systemic oxidative damage by analyzing carbonyl groups, oxidized low-density lipoprotein, 8-hydroxy-2'-deoxyguanosine, and xanthine oxidase activity. AntioxyScore was computed as index of antioxidant defense by analyzing catalase and superoxide dismutase (SOD) activity and total antioxidant capacity. OxyScore and AntioxyScore were higher in subjects with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 than in peers with eGFR >60 mL/min/1.73 m2, with protein carbonyls, catalase, and SOD activity as major drivers. Older adults with a recent cardiovascular event had similar OxyScore and AntioxyScore as peers with eGFR >60 mL/min/1.73 m2. Multivariate linear regression analysis revealed that both indices were associated with decreased eGFR independently of traditional CVR factors. Interestingly, AntioxyScore was also associated with diuretic treatment, and a more pronounced increase was seen in subjects receiving combination therapy. The associations of AntioxyScore with diuretic treatment and eGFR were mutually independent. In conclusion, eGFR is the major contributor to the imbalance in oxidative stress in this older population. Given the association between oxidative stress, CKD, and CVR, the inclusion of renal function parameters in CVR estimators for older populations, such as the SCORE-OP, might improve their modest performance.
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Antioxidantes/metabolismo , Biomarcadores/metabolismo , Diuréticos/efeitos adversos , Estresse Oxidativo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , EspanhaRESUMO
Aims: Current cardiovascular (CV) risk prediction algorithms are able to quantify the individual risk of CV disease. However, CV risk in young adults is underestimated due to the high dependency of age in biomarker-based algorithms. Because oxidative stress is associated with CV disease, we sought to examine CV risk stratification in young adults based on oxidative stress to approach the discovery of new markers for early detection of pathology. Results: Young adults were stratified into (i) healthy controls, (ii) subjects with CV risk factors, and (iii) patients with a reported CV event. Plasma samples were analyzed using FASILOX, a novel approach to interrogate the dynamic thiol redox proteome. We also analyzed irreversible oxidation by targeted searches using the Uniprot database. Irreversible oxidation of cysteine (Cys) residues was greater in patients with reported CV events than in healthy subjects. These results also indicate that oxidation is progressive. Moreover, we found that glutathione reductase and glutaredoxin 1 proteins are differentially expressed between groups and are proteins involved in antioxidant response, which is in line with the impaired redox homeostasis in CV disease. Innovation: This study, for the first time, describes the oxidative stress (reversible and irreversible Cys oxidation) implication in human plasma according to CV risk stratification. Conclusion: The identification of redox targets and the quantification of protein and oxidative changes might help to better understand the role of oxidative stress in CV disease, and aid stratification for CV events beyond traditional prognostic and diagnostic markers. Antioxid. Redox Signal. 35, 602-617.
Assuntos
Doenças Cardiovasculares , Doenças Cardiovasculares/diagnóstico , Cisteína/metabolismo , Humanos , Oxirredução , Estresse Oxidativo/fisiologia , Proteoma/metabolismo , Fatores de RiscoRESUMO
INTRODUCTION: Lunasin is a soybean bioactive peptide with a variety of beneficial properties against chronic disorders. However, its effect in human primary intestinal cells remains unknown. Hence, this study aims to characterize its ex vivo biological activity in the human intestinal mucosa. METHODS AND RESULTS: Human intestinal biopsies, obtained from healthy controls, are ex vivo conditioned with lunasin both in the presence/absence of lipopolysaccharide (LPS). Peptide maintains its stability during biopsy culture by HPLC-MS/MS analysis. Lunasin is bioactive in the human mucosa, as it induces IL-1ß, TNF-α, IL-17A, CCL2, and PGE2/COX-2 gene expression together with an increased expression of tolerogenic IL-10 and TGFß, while it also downregulates the expression of iNOS and subunit p65 from NF-κB. Indeed, lunasin also abrogates the LPS-induced pro-inflammatory response, downregulating IL-17A, IFNγ, and IL-8 expression, and inducing IL-10 and TGFß expression. These results are also mirrored in the cell-free culture supernatants at the protein level by Multiplex. Moreover, lunasin further induces a regulatory phenotype and function on human intestinal conventional dendritic cell and macrophage subsets as assessed by flow cytometry. CONCLUSIONS: We hereby have characterized lunasin as an immunomodulatory peptide with potential capacity to prevent immune and inflammatory-mediated disorders in the human gastrointestinal tract.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Proteínas de Soja/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Células Apresentadoras de Antígenos/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Proteínas de Soja/imunologiaRESUMO
Objective: Severe pressure ulcers (PUs) do not respond to conservative wound therapy and need surgical repair. To better understand the pathogenesis and to advance on new therapeutic options, we focused on the proteomic analysis of PU, which offers substantial opportunities to identify significant changes in protein abundance during the course of PU formation in an unbiased manner. Approach: To better define the protein pattern of this pathology, we performed a proteomic approach in which we compare severe PU tissue from spinal cord injury (SCI) patients with control tissue from the same patients. Results: We found 76 proteins with difference in abundance. Of these, 10 proteins were verified as proteins that define the pathology: antithrombin-III, alpha-1-antitrypsin, kininogen-1, alpha-2-macroglobulin, fibronectin, apolipoprotein A-I, collagen alpha-1 (XII) chain, haptoglobin, apolipoprotein B-100, and complement factor B. Innovation: This is the first study to analyze differential abundance protein of PU tissue from SCI patients using high-throughput protein identification and quantification by tandem mass tags followed by liquid chromatography tandem mass spectrometry. Conclusion: Differential abundance proteins are mainly involved in tissue regeneration. These proteins might be considered as future therapeutic options to enhance the physiological response and permit cellular repair of damaged tissue.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Úlcera por Pressão/metabolismo , Traumatismos da Medula Espinal/complicações , Cicatrização , Adulto , Idoso , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera por Pressão/etiologia , Úlcera por Pressão/patologia , Proteômica , Fatores de Risco , Traumatismos da Medula Espinal/patologia , Adulto JovemRESUMO
Adipose tissue secretes molecules that can promote activity in Crohn's disease. We aimed to evaluate the role of serum adipokines as possible biomarkers in Crohn's disease. Serum samples were obtained from 40 patients with endoscopically active or quiescent Crohn's disease and 36 healthy controls. Serum leptin, ghrelin, resistin and adiponectin levels were analysed by Multiplex in a Luminex 200 system technology. Receiver Operating Characteristic curves were performed to evaluate the adipokines discriminatory capacity. A logistic regression adjusted by possible confounders (i.e. gender, age, BMI) was performed for those adipokines that showed an area under the curve > 0.7. No differences were found in age, gender or BMI among groups. Distribution for serum resistin was different among the three groups of study, and only this adipokine showed an area under the curve of 0.75 comparing actives patients and healthy control groups. Resistin median concentration was selected as a cut-off for a logistic regression analysis; odds ratio along its 95% confidence interval adjusted by gender, age, and BMI yielded a value of 5.46 (1.34-22.14) comparing actives patients and healthy controls. High concentration of serum resistin is probably associated to activity, being this association independent of gender, age or BMI.
Assuntos
Adipocinas/sangue , Biomarcadores/sangue , Doença de Crohn/diagnóstico , Adiponectina/sangue , Adulto , Estudos de Casos e Controles , Doença de Crohn/sangue , Feminino , Seguimentos , Grelina/sangue , Humanos , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Resistina/sangueRESUMO
The predictive value of traditional cardiovascular risk estimators is limited, and young and elderly populations are particularly underrepresented. We aimed to investigate the urine metabolome and its association with cardiovascular risk to identify novel markers that might complement current estimators based on age. Urine samples were collected from 234 subjects categorized into three age-grouped cohorts: 30-50 years (cohort I, young), 50-70 years (cohort II, middle-aged), and > 70 years (cohort III, elderly). Each cohort was further classified into three groups: (a) control, (b) individuals with cardiovascular risk factors, and (c) those who had a previous cardiovascular event. Novel urinary metabolites linked to cardiovascular risk were identified by nuclear magnetic resonance in cohort I and then evaluated by target mass spectrometry quantification in all cohorts. A previously identified metabolic fingerprint associated with atherosclerosis was also analyzed and its potential risk estimation investigated in the three aged cohorts. Three different metabolic signatures were identified according to age: 2-hydroxybutyrate, gamma-aminobutyric acid, hypoxanthine, guanidoacetate, oxaloacetate, and serine in young adults; citrate, cyclohexanol, glutamine, lysine, pantothenate, pipecolate, threonine, and tyramine shared by middle-aged and elderly adults; and trimethylamine N-oxide and glucuronate associated with cardiovascular risk in all three cohorts. The urinary metabolome contains a metabolic signature of cardiovascular risk that differs across age groups. These signatures might serve to complement existing algorithms and improve the accuracy of cardiovascular risk prediction for personalized prevention. KEY MESSAGES: ⢠Cardiovascular risk in the young and elderly is underestimated. ⢠The urinary metabolome reflects cardiovascular risk across all age groups. ⢠Six metabolites constitute a metabolic signature of cardiovascular risk in young adults. ⢠Middle-aged and elderly adults share a cardiovascular risk metabolic signature. ⢠TMAO and glucuronate levels reflect cardiovascular risk across all age groups.
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Biomarcadores/urina , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/urina , Metaboloma , Metabolômica , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/etiologia , Estudos Transversais , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Espectrometria de Massas , Metabolômica/métodos , Pessoa de Meia-Idade , Ressonância Magnética Nuclear Biomolecular , Vigilância em Saúde Pública , Curva ROC , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
Several models are available to calculate the risk of developing cardiovascular complications in mid-life. The estimation of lifetime risk in the long-term remains an unmet clinical need. We previously identified new molecular plasma signatures for cardiovascular risk stratification in a young population (30-50-years old). The aim of the present study was to determine if the specific signature found in young population changes with age. Proteomic analysis was performed in plasma samples obtained from different age groups, middle-age (50-70-years old, n = 63) and elderly (>70-years old, n = 61), which, in turn were classified into 3 subgroups according to cardiovascular risk. Our previous results in a young population clearly showed two different proteomic signatures. Building on these findings, targeted-mass spectrometry and turbidimetry analyses were used to test these signatures in middle-age and elderly populations. This strategy identified three common proteomic signatures between young and adult patients related to cardiovascular stratification, organ damage and risk prediction. Furthermore, receiver operating characteristic analysis revealed the potential value of these novel markers for lifetime risk stratification. Our results provide new insight into altered molecular mechanisms in the pathogenesis of cardiovascular disease and, more importantly, identify novel protein panels that can stratify patients throughout life. SIGNIFICANCE: Our results revealed three common proteomic signatures between young and adult patients related to cardiovascular stratification, organ damage and risk prediction. The results obtained provide a deeper insight into the pathogenesis of CV diseases and allow the identification of novel protein panels to stratify patients according to CV risk throughout life. While current estimators calculate the risk of having a CV event considering age as the most important factor to CV disease, our results represent an alternative to traditional CV risk factors, allowing the stratification of CV risk regardless of the age. Using a combination of traditional markers and established algorithms with these findings as a future preventive strategy, could facilitate an adequate assessment of CV risk.
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Doenças Cardiovasculares , Adulto , Idoso , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Humanos , Pessoa de Meia-Idade , Plasma , Proteômica , Fatores de RiscoRESUMO
Resistant hypertension prevalence is progressively increasing, and prolonged exposure to suboptimal blood pressure control results in higher cardiovascular risk and end-organ damage. Among various antihypertensive agents, spironolactone seems the most effective choice to treat resistant hypertension once triple therapy including a diuretic fails. However success in blood pressure control is not guaranteed, adverse effects are not negligible, and no clinical tools are available to predict patient's response. Complementary to our previous study of resistant hypertension metabolism, here we investigated urinary proteome changes with potential capacity to predict response to spironolactone. Twenty-nine resistant hypertensives were included. A prospective study was conducted and basal urine was collected before spironolactone administration. Patients were classified in responders or nonresponders in terms of blood pressure control. Protein quantitation was performed by liquid chromatography-mass spectrometry; ELISA and target mass spectrometry analysis were performed for confirmation. Among 3310 identified proteins, HP (haptoglobin) and HPR (haptoglobin-related protein) showed the most significant variations, with increased levels in nonresponders compared with responders before drug administration (variation rate, 5.98 and 7.83, respectively). Protein-coordinated responses were also evaluated by functional enrichment analysis, finding oxidative stress, chronic inflammatory response, blood coagulation, complement activation, and regulation of focal adhesions as physiopathological mechanisms in resistant hypertension. In conclusion, protein changes able to predict patients' response to spironolactone in basal urine were here identified for the first time. These data, once further confirmed, will support clinical decisions on patients' management while contributing to optimize the rate of control of resistant hypertensives with spironolactone.
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Antígenos de Neoplasias/urina , Pressão Sanguínea/efeitos dos fármacos , Resistência a Medicamentos , Haptoglobinas/urina , Hipertensão/tratamento farmacológico , Espironolactona/uso terapêutico , Idoso , Biomarcadores/urina , Feminino , Humanos , Hipertensão/fisiopatologia , Hipertensão/urina , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND AND AIMS: The predictive value of traditional CV risk calculators is limited. Novel indicators of CVD progression are needed particularly in the young population. The main aim of this study was the identification of a molecular profile with added value to classical CV risk estimation. METHODS: Eighty-one subjects (30-50 years) were classified in 3 groups according to their CV risk: healthy subjects; individuals with CV risk factors; and those who had suffered a previous CV event. The urine proteome was quantitatively analyzed and significantly altered proteins were identified between patients' groups, either related to CV risk or established organ damage. Target-MS and ELISA were used for confirmation in independent patients' cohorts. Systems Biology Analysis (SBA) was carried out to identify functional categories behind CVD. RESULTS: 4309 proteins were identified, 75 of them differentially expressed. ADX, ECP, FETUB, GDF15, GUAD and NOTCH1 compose a fingerprint positively correlating with lifetime risk estimate (LTR QRISK). Best performance ROC curve was obtained when ECP, GDF15 and GUAD were combined (AUCâ¯=â¯0.96). SBA revealed oxidative stress response, dilated cardiomyopathy, signaling by Wnt and proteasome, as main functional processes related to CV risk. CONCLUSIONS: A novel urinary protein signature is shown, which correlates with CV risk estimation in young individuals. Pending further confirmation, this six-protein-panel could help in CV risk assessment.
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Biomarcadores/urina , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Medicina Preventiva/métodos , Adrenodoxina/urina , Adulto , Cardiologia , Sistema Cardiovascular , Proteína Catiônica de Eosinófilo/urina , Feminino , Fetuína-B/urina , Fator 15 de Diferenciação de Crescimento/urina , Guanina Desaminase/urina , Humanos , Masculino , Pessoa de Meia-Idade , Proteoma , Receptor Notch1/análise , Medição de Risco , Fatores de Risco , Biologia de SistemasRESUMO
Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells (APCs) in active inflammatory bowel disease (IBD). The IBD mucosa produced higher levels of pro-inflammatory cytokines referred to healthy controls (HCs). Peptides B7 and B12, however, did not ameliorate the mucosal cytokine milieu in IBD. Human circulating APCs (B-cells, monocytes, plasmacytoid dendritic cells (pDCs), and conventional dendritic cells (cDCs)) were characterized by flow cytometry in presence/absence of the peptides. Circulating B-cells, monocytes, and cDCs from IBD patients were more activated than those from HCs. Peptide B7, but not B12, decreased CCR2 expression on all APC subsets from HC, but not IBD patients. Moreover, both peptides tend to further increase their pro-inflammatory profile in IBD. In summary, IBD patients display mucosal and circulating APC pro-inflammatory properties. Peptide B7 immunomodulatory capacity elicited over circulating APCs from HC, but not IBD patients, suggests the presence of disrupted modulatory mechanisms for this peptide in IBD. Future studies should address the effect of bacteria-derived immunomodulatory peptides in non-inflamed (quiescent) IBD patients.
Assuntos
Células Apresentadoras de Antígenos , Proteínas de Bactérias/farmacologia , Citocinas , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Produtos Biológicos/farmacologia , Células Cultivadas , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Peptídeos/farmacologiaRESUMO
STUDY DESIGN: Retrospective comparative analysis. OBJECTIVE: Study early-onset scoliosis (EOS) graduated patients to establish founded criteria for graduation decision making and determine the risks and benefits of definitive fusion. SUMMARY OF BACKGROUND DATA: EOS is treated by growth-friendly techniques until skeletal maturity. Afterwards, patients can be "graduated," either by definitive fusion (posterior spinal fusion [PSF]) or by retaining the previous implants (Observation) with no additional surgery. Criteria for this decision making and the outcomes of definitive fusion are still underexplored. METHODS: We analyzed a consecutive cohort of "graduated" patients after a distraction-based lengthening program. We gathered demographic, radiographic, and surgical data. The results of the two final treatment options were compared after 2 years' follow-up. RESULTS: A total of 32 patients were included. Four patients had incomplete records. Thirteen underwent PSF, and 15 were observed. The mean age at initial treatment was 8 ± 3 years, with a mean follow-up of 8.3 ± 2.9 years. Both groups had similar preoperative and final radiographic parameters (p > .05). The criteria for undergoing PSF were as follows: implant-related complications, main curve magnitude (PSF = 63.2° ± 9° vs. OBS = 47.9° ± 15°; p = .008), curve progression >10°, and sagittal misalignment (SVA). During PSF 12/13 patients underwent multiple osteotomies, one vertebrectomy, and 3 costoplasties. Surgical time was 291.5 ± 58 minutes; blood loss was 946 ± 375 mL; and the number of levels fused was 13.7. Coronal deformity was corrected 31%, T1-S1 length gained was 31 ± 19.6 mm and T1-T12 length gained was 9.3 ± 39 mm; kyphosis was reduced by 22%. However, coronal balance worsened by 2.3 ± 30.8 mm. No major complications were encountered in these patients. CONCLUSIONS: Graduation by PSF depended on unacceptable or progressive major curve deformity, sagittal misalignment, or complications with previous implants. Observation depended on curve stabilization, Cobb <50°, and coronal misalignment <20 mm. Definitive fusion effectively corrected coronal and sagittal deformity and increased trunk height. However, it exposed patients to a very demanding surgery without improvement in coronal balance. LEVEL OF EVIDENCE: Level III, therapeutic.
Assuntos
Escoliose/cirurgia , Fusão Vertebral/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Tomada de Decisão Clínica , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Medição de RiscoRESUMO
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