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Background and Objectives: Aspirin (ASA) is a commonly used antithrombotic drug that has been demonstrated to reduce venous thromboembolism. The aim was to analyze if geriatric COVID-19 patients undergoing a 100 mg/day Aspirin (ASA) treatment prior to hospitalization differ in hospital outcome compared to patients without previous ASA therapy. Materials and Methods: An observational retrospective study was carried out using an anonymized database including geriatric COVID-19 patients (March to April 2020) admitted to Madrid Hospitals Group. A group of COVID-19 patients were treated with low ASA (100 mg/day) prior to COVID-19 infection. Results: Geriatric ASA-treated patients were older (mean age over 70 years; n = 41), had higher frequency of hypertension and hyperlipidemia, and upon admission had higher D-dimer levels than non-ASA-treated patients (mean age over 73 years; n = 160). However, patients under ASA treatment did not show more frequent pulmonary thromboembolism (PE) than non-ASA-treated patients. ASA-treated geriatric COVID-19-infected patients in-hospital < 30 days all-cause mortality was more frequent than in non-ASA-treated COVID-19 patients. In ASA-treated COVID-19-infected geriatric patients, anticoagulant therapy with low molecular weight heparin (LMWH) significantly reduced need of ICU care, but tended to increase in-hospital < 30 days all-cause mortality. Conclusions: Prior treatment with a low dose of ASA in COVID-19-infected geriatric patients increased frequency of in-hospital < 30 days all-cause mortality, although it seemed to not increase PE frequency despite D-dimer levels upon admission being higher than in non-ASA users. In ASA-treated geriatric COVID-19-infected patients, addition of LMWH therapy reduced frequency of ICU care, but tended to increase in-hospital < 30 days all-cause mortality.
Assuntos
Aspirina , Tratamento Farmacológico da COVID-19 , Humanos , Idoso , Aspirina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Estudos Retrospectivos , HospitaisRESUMO
Long-term therapy with low Aspirin (ASA) dose is basis to prevent thrombotic acute events. However, the anti-platelet mechanisms of ASA remain not completely known. The aim was to analyze if in vitro exposure of human megakaryocytes to low ASA concentration may alter the apoptotic features of the newly formed platelets. Cultured Meg-01 cells, a human megakaryoblastic cell line, were stimulated to form platelets with 10 nmol/L phorbol 12-myristate-13-acetate (PMA) in the presence and absence of ASA (0.33 mmol/L). Results revealed that platelet-like particles (PLPs) derived from ASA-exposed Meg-01 cells, showed higher content of pro-apoptotic proteins Bax and Bak than PLPs from non-ASA incubated Meg-01 cells. It was accompanied of reduced cytochrome C oxidase activity and higher mitochondrial content of PTEN-induced putative kinase-1 in PLPs from ASA-incubated Meg-01 cells. However, only after calcium ionophore A23187 stimulation, caspase-3 activity, the cytosolic cytochrome C content, and reduction of mitochondrial membrane potential were higher in PLPs from ASA-incubated megakaryocytes than in those from Meg-01 without ASA. Nitric oxide synthase 3 content was higher in PLPs from ASA-exposed Meg-01 cells than in PLPs from non-ASA incubated Meg-01 cells. The L-arginine antagonist, NG-Nitro-L-arginine Methyl Ester, reduced caspase-3 activity in A23187-stimulated PLPs generated from ASA-incubated Meg-01 cells. As conclusions exposure of megakaryocyte to ASA promotes that the newly generated PLPs have, under stimulating condition, higher sensitivity to go into apoptosis than those PLPs generated from Meg-01 cells without ASA. It could be associated with differences in mitochondrial functionality and NO formation.
Assuntos
Apoptose/efeitos dos fármacos , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Potencial da Membrana Mitocondrial/imunologia , Aspirina/farmacologia , HumanosRESUMO
An inadequate platelet response to aspirin (ASA) has been identified in some patients under chronic ASA treatment. The aim of this study was to analyze if ASA-sensitive and ASA-resistant platelets have differences in their apoptotic capability. Clinically stable ischemic coronary patients who had been taking ASA (100 mg/d) for at least 9 months before inclusion were divided into ASA-resistant (n = 11) and ASA-sensitive (n = 13) groups as defined by the PFA-100 test. Platelets from ASA-sensitive patients showed higher expression of the proapoptotic proteins Bak and Bax than those from ASA-resistant patients, although only Bak protein remained different when the results were adjusted by age. In resting platelets, neither caspase-3 activity nor cytosolic cytochrome C levels were different between both experimental groups. Stimulation of platelets with calcium ionophore (10 nmol/L, A23187) increased caspase-3 activity (1.91-fold higher; P < 0.05) and cytosolic cytochrome C levels (1.84-fold higher; P < 0.05) to a higher degree in ASA-sensitive than in ASA-resistant platelets. In conclusion, ASA-sensitive platelets seem to be better prepared to undergo apoptosis during robust platelet activation.
Assuntos
Proteínas Reguladoras de Apoptose/sangue , Apoptose/efeitos dos fármacos , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Plaquetas/metabolismo , Plaquetas/patologia , Calcimicina/farmacologia , Ionóforos de Cálcio/farmacologia , Caspase 3/sangue , Resistência a Medicamentos , Complexo IV da Cadeia de Transporte de Elétrons/sangue , Feminino , Humanos , Masculino , Isquemia Miocárdica/sangue , Isquemia Miocárdica/patologia , Ativação Plaquetária/efeitos dos fármacos , Resultado do Tratamento , Proteína Killer-Antagonista Homóloga a bcl-2/sangue , Proteína X Associada a bcl-2/sangueRESUMO
BACKGROUND: The presence of intraluminal thrombus and mitochondrial dysfunction in human abdominal aortic aneurysms (AAAs) have been associated with aneurysmal growth and rupture. The objective of the study was to study if endogenous factor Xa (FXa) may modulate mitochondrial functionality and expression of proteins associated with mitophagy in human AAAs. METHODS: AAA sites with intraluminal thrombus were obtained from 6 patients undergoing elective AAA surgery repair. Control samples were collected from 6 organ donors. The effect of FXa was analyzed by in vitro incubation of AAA with 50 nmol/L rivaroxaban, an oral FXa inhibitor. RESULTS: The enzymatic activities of citrate synthase, a biomarker of mitochondrial density, and cytochrome C oxidase, a biomarker of mitochondrial respiratory chain functionality, were significantly reduced in the AAA sites with respect to the healthy aorta (citrate synthase activity in µU/min/µg protein: control: 3.51 ± 0.22 vs. AAA: 0.37 ± 0.15.; P < 0.01; cytochrome C oxidase activity in µOD/min/µg protein: control: 8.05 ± 1.57 vs. AAA: 3.29 ± 1.05; P < 0.05). The addition of rivaroxaban to AAA reverted the activity of both citrate synthase and cytochrome C oxidase to similar values to control. Mitochondrial Drp-1 expression was higher in AAA sites than in either control aortas or rivaroxaban-incubated AAA sites. Cytosolic content of Drp-1 phosphorylated at Ser637, mitochondrial Parkin, and mitochondrial PINK1-Parkin interaction were significantly reduced in the AAA sites with respect to control aortas. For all these parameters, rivaroxaban-incubated AAA showed similar values compared with control aortas. CONCLUSIONS: In human AAA, rivaroxaban improved mitochondrial functionality that was associated with changes in proteins related to mitophagy. Its opens possible new effects of endogenous FXa on the mitochondria in the human AAA site.
Assuntos
Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Rivaroxabana/farmacologia , Trombose/tratamento farmacológico , Adulto , Idoso , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitofagia/efeitos dos fármacos , Trombose/metabolismo , Trombose/patologiaRESUMO
Retrorectal cystic hamartomas, or tailgut cysts, are complex congenital cystic lesions which arise from embryologic tissues. Fewer than 200 cases have been reported worldwide, with women outnumbering men by 3:1. They are asymptomatic in 50% of the cases; the remainder present with back pain or mass effect as the most common symptoms. Malignant transformation rarely occurs. Guided biopsy is controversial, while surgery is the therapy of choice. We report the case of a 31-year-old woman complaining about perineal and vague lower abdominal pain, who was submitted to magnetic resonance imaging, which revealed a multilocular cystic, well-circumscribed retrorectal mass. Subsequently, laparoscopic excision was successfully accomplished. Operative time was 175 min. Intra- and post-operative course was uneventful. Hospital stay was 75 h. While any malignancy suspicion should lead to open surgery, given the risk of rupture, we support the benefits of laparoscopy may also be applied.
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AIMS: To evaluate if rivaroxaban, an oral factor Xa (FXa) inhibitor, could modify the expression in vitro of inflammatory and oxidative stress biomarkers in abdominal aortic aneurysmal (AAA) sites showing intraluminal thrombus. METHODS: AAA sites with intraluminal mural thrombus were obtained from six patients undergoing elective AAA repair. In addition, control abdominal aortic samples were obtained from six organ donors. AAA sites were incubated in the presence and absence of 50 nmol l-1 rivaroxaban. RESULTS: AAA sites showing thrombus demonstrated higher content of FXa than control. Interleukin-6 levels released from AAA [Control: median: 23.45 (interquartile range: 16.17-37.15) vs. AAA: median: 153.07 (interquartile range: 100.80-210.69) pg ml-1 mg tissue-1 , P < 0.05] and the expression levels of nitric oxide synthase 2 were significantly higher in AAA than in control. The protein expression level of NADPH oxidase subunits gp67-and gp91-phox, but did not gp47-phox, were also significantly higher in the AAA sites than in control. Addition of rivaroxaban to AAA sites explants significantly reduced the release of interleukin-6 [median: 51.61 (interquartile range: 30.87-74.03) pg ml-1 mg tissue-1 , P < 0.05 with respect to AAA alone] and the content of nitric oxide synthase 2, gp67 and gp91-phox NADPH subunits. The content of matrix metallopeptidase 9 was significantly higher in the AAA sites as compared to control. Rivaroxaban also reduced matrix metallopeptidase 9 content in AAA sites to similar levels to control. CONCLUSIONS: FXa inhibition by rivaroxaban exerted anti-inflammatory and antioxidative stress properties in human AAA sites, suggesting a role of FXa in these mechanisms associated with the pathogenesis of AAA.
Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Rivaroxabana/farmacologia , Adulto , Idoso , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/etiologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , NADPH Oxidase 2/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfoproteínas/metabolismoRESUMO
Mitochondria are essential for the maintenance of normal physiological function of tissue cells. Mitochondria are subject to dynamic processes in order to establish a control system related to survival or cell death and adaptation to changes in the metabolic environment of cells. Mitochondrial dynamics includes fusion and fission processes, biogenesis, and mitophagy. Modifications of mitochondrial dynamics in organs involved in energy metabolism such as the pancreas, liver, skeletal muscle, and white adipose tissue could be of relevance for the development of insulin resistance, obesity, and type 2 diabetes. Mitochondrial dynamics and the factors involved in its regulation are also critical for neuronal development, survival, and function. Modifications in mitochondrial dynamics in either agouti-related peptide (AgRP) or pro-opiomelanocortin (POMC), circuits which regulates feeding behavior, are related to changes of food intake, energy balance, and obesity development. Activation of the sympathetic nervous system has been considered as a crucial point in the pathogenesis of hypertension among obese individuals and it also plays a key role in cardiac remodeling. Hypertension-related cardiac hypertrophy is associated with changes in metabolic substrate utilization, dysfunction of the electron transport chain, and ATP synthesis. Alterations in both mitochondrial dynamics and ROS production have been associated with endothelial dysfunction, development of hypertension, and cardiac hypertrophy. Finally, it might be postulated that alterations of mitochondrial dynamics in white adipose tissue could contribute to the development and maintenance of hypertension in obesity situations through leptin overproduction. Leptin, together with insulin, will induce activation of sympathetic nervous system with consequences at renal, vascular, and cardiac levels, driving to sodium retention, hypertension, and left ventricular hypertrophy. Moreover, both leptin and insulin will induce mitochondrial alterations into arcuate nucleus leading to signals driving to increased food intake and reduced energy expenditure. This, in turn would perpetuate white adipose tissue excess and its well-known metabolic and cardiovascular consequences.
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Hipertensão/fisiopatologia , Mitocôndrias/metabolismo , Doenças Mitocondriais/complicações , Obesidade/fisiopatologia , Animais , Metabolismo Energético , Humanos , Hipertensão/complicações , Resistência à Insulina , Obesidade/complicações , Sistema Nervoso Simpático/metabolismoRESUMO
There is interest to analyse newer biomarkers to identify healthy individuals at risk to develop cardiovascular disease (CVD) incidents and death. To determine in healthy individuals new circulating protein biomarkers, whose systemic levels may be associated with the risk of future development of CVD incidents and death. The study was performed in 82 individuals from the Malmö Diet and Cancer study cohort, free from CVD of whom 41 developed CVD and 41 did not. Plasma proteins related to inflammation and thrombo-coagulating processes were analysed. α1-antitrypsin isotype 3 plasma levels were significantly higher while apolipoprotein J plasma levels were lower in participants that developed CVD incidents than those that did not develop acute cardiovascular episode. Of 82 participants, 17 died by CVD causes. There were proteins whose expression in plasma was significantly higher in participants suffering CVD death as compared with those that did not die by CVD. These proteins included: fibrinogen ß-chain isotypes 1 and 3, fibrinogen-γ-chain isotype 2, vitamin D-binding protein isotypes 1, 2 and 3, α1-antitrypsin isotypes 3 and 6, haptoglobin isotypes 3,4,5 and 5, haemopexin isotypes 1 and 2, and Rho/Rac guanine nucleotide exchange factor 2. Moreover, apolipoprotein J plasma levels were found lower in participants that died by cardiovascular cause. Association between plasma levels of proteins and CVD death was independent of age, gender, conventional risk factors and plasma C-reactive protein levels. Several protein plasma levels and protein isotypes related to inflammation and thrombo-coagulating phenomena were independently associated with the risk of future CVD death.
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Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Saúde , Idoso , Proteínas Sanguíneas/metabolismo , Estudos de Casos e Controles , Feminino , Fibrinogênio/metabolismo , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína de Ligação a Vitamina D/sangueRESUMO
BACKGROUND: Several mechanisms have been proposed to explain why some platelets have a reduced response to aspirin (ASA). Among them, it was reported an increased circulating level of vitamin-D-binding protein (DBP). In addition, nitric oxide (NO) released from mononuclear cells was involved in the antiplatelet effects of ASA. The aim was to analyse the relationship between platelet response to ASA and both NO generation and vitamin-D-binding protein content in mononuclear cells. MATERIALS AND METHODS: Mononuclear cells were obtained from patients with stable coronary artery disease that were divided by a platelet functionality test (PFA-100) as ASA-sensitive (n=23) and ASA resistant (n=27). RESULTS: Both the release of NO (determined by nitrite+nitrate concentration) and the expression of endothelial-type NO synthase (eNOS) were higher in mononuclear cells from ASA sensitive as compared with those from ASA-resistant patients. There was a positive correlation between either the release of NO and the expression of eNOS protein in mononuclear cells with the ability of ASA to inhibit platelet activity. DBP content in mononuclear cells was higher in ASA resistant than in ASA sensitive. The level of DBP content in mononuclear cells was negatively associated with the ability of ASA to inhibit platelets. However, in vitro experiments suggested that there was no association between DBP and NO production by mononuclear cells. CONCLUSIONS: Mononuclear cells from patients with platelets with lower responsiveness to ASA showed a reduced ability to produce NO.
Assuntos
Aspirina/farmacologia , Óxido Nítrico/biossíntese , Inibidores da Agregação Plaquetária/farmacologia , Idoso , Plaquetas , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/metabolismo , Resistência a Medicamentos , Feminino , Humanos , Interleucina-6/biossíntese , Leucócitos Mononucleares/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteína de Ligação a Vitamina D/metabolismoRESUMO
AIM: Further to its pivotal role in haemostasis, factor Xa (FXa) promotes effects on the vascular wall. The purpose of the study was to evaluate if FXa modifies the expression level of energy metabolism and oxidative stress-related proteins in femoral arteries obtained from type 2 diabetic patients with end-stage vasculopathy. METHODS: Femoral arteries were obtained from 12 type 2 diabetic patients who underwent leg amputation. Segments from the femoral arteries were incubated in vitro alone and in the presence of 25 nmol l(-1) FXa and 25 nmol l(-1) FXa + 50 nmol l(-1) rivaroxaban. RESULTS: In the femoral arteries, FXa increased triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase isotype 1 expression but decreased pyruvate dehydrogenase expression. These facts were accompanied by an increased content of acetyl-CoA. Aconitase activity was reduced in FXa-incubated femoral arteries as compared with control. Moreover, FXa increased the protein expression level of oxidative stress-related proteins which was accompanied by an increased malonyldialdehyde arterial content. The FXa inhibitor, rivaroxaban, failed to prevent the reduced expression of pyruvate dehydrogenase induced by FXa but reduced acetyl-CoA content and reverted the decreased aconitase activity observed with FXa alone. Rivaroxaban + FXa but not FXa alone increased the expression level of carnitine palmitoyltransferase I and II, two mitochondrial long chain fatty acid transporters. Rivaroxaban also prevented the increased expression of oxidative stress-related proteins induced by FXa alone. CONCLUSIONS: In femoral isolated arteries from type 2 diabetic patients with end-stage vasculopathy, FXa promoted disruption of the aerobic mitochondrial metabolism. Rivaroxaban prevented such effects and even seemed to favour long chain fatty acid transport into mitochondria.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Fator Xa/farmacologia , Artéria Femoral/metabolismo , Acetilcoenzima A/análise , Idoso , Carnitina O-Palmitoiltransferase/genética , Angiopatias Diabéticas/metabolismo , Metabolismo Energético , Feminino , Glicólise , Humanos , Masculino , Mitocôndrias/metabolismo , Morfolinas/farmacologia , Estresse Oxidativo , Rivaroxabana , Tiofenos/farmacologiaRESUMO
INTRODUCTION: Evidences have been suggested that phosphodiesterase type 5 (PDE5) inhibition promotes vasculoprotective benefits in patients with cardiovascular diseases. AIM: The aim of this study is to analyze the systemic effect of PDE5 inhibition in type 2 diabetes mellitus patients with erectile dysfunction (ED) determining changes in the expression levels of plasma proteins. METHODS: Seventeen patients with controlled type 2 diabetes mellitus and ED were included in the study. Patients received vardenafil hydrochloride 20 mg on demand during 12 weeks. At the beginning and 12 weeks after vardenafil administration, plasma samples were collected and analyzed using proteomics. MAIN OUTCOME MEASURES: International Index of Erectile Function-Erectile Function Domain (IIEF-EFD) and plasma protein expression before and after vardenafil administration. Nitrate/nitrite release, PDE5, and soluble guanylate cyclase (sGC) expression and cyclic guanosine monophosphate (cGMP) content in cultured bovine aortic endothelial cells (BAECs). RESULTS: The IIEF-EFD score was markedly improved after 12 weeks of vardenafil administration. Plasma levels of alpha 1-antitrypsin isotypes 4 and 6 and ß-tropomyosin were decreased, whereas apolipoprotein AI isoype 5 was increased 12 weeks after vardenafil administration. Only ß-tropomyosin plasma levels were inversely correlated with IIEF-EFD score. Tropomyosin has been added to cultured BAECs and after 24 hours reduced the protein expression level of sGC-ß1 subunit and decreased the cGMP content. Tropomyosin did not modify PDE5 expression and nitric oxide release in BAECs as compared with control BAECs. Vardenafil (10 µg/mL) did not modify sGC-ß1 subunit expression in tropomyosin + vardenafil-incubated BAECs; however, vardenafil significantly reversed the reduction of cGMP content induced by tropomyosin. CONCLUSION: Vardenafil administration improved erectile functionality in controlled type 2 diabetes mellitus patients with ED, which was associated with reduction of circulating plasma ß-tropomyosin levels. Tropomyosin affected by itself the cGMP generating system suggesting a possible new mechanism involved in ED. Vardenafil reversed the reduction effect of cGMP content elicited by tropomyosin in BAECs.
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Diabetes Mellitus Tipo 2/complicações , Disfunção Erétil/tratamento farmacológico , Imidazóis/uso terapêutico , Ereção Peniana/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Tropomiosina/fisiologia , Animais , Bovinos , GMP Cíclico/metabolismo , Disfunção Erétil/sangue , Disfunção Erétil/etiologia , Guanilato Ciclase/metabolismo , Humanos , Imidazóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Diester Fosfórico Hidrolases/metabolismo , Piperazinas/administração & dosagem , Receptores Citoplasmáticos e Nucleares/metabolismo , Guanilil Ciclase Solúvel , Sulfonas/administração & dosagem , Sulfonas/uso terapêutico , Triazinas/administração & dosagem , Triazinas/uso terapêutico , Tropomiosina/sangue , Dicloridrato de VardenafilaRESUMO
BACKGROUND: Heart produces ATP through long-chain fatty acids beta oxidation. PURPOSE: To analyze whether in ventricular myocardium, high-fat diet may modify the expression of proteins associated with energy metabolism before myocardial function was affected. METHODS: Wistar Kyoto rats were divided into two groups: (a) rats fed standard diet (control; n = 6) and (b) rats fed high-fat diet (HFD; n = 6). Proteins from left ventricles were analyzed by two-dimensional electrophoresis, mass spectrometry and Western blotting. RESULTS: Rats fed with HFD showed higher body weight, insulin, glucose, leptin and total cholesterol plasma levels as compared with those fed with standard diet. However, myocardial functional parameters were not different between them. The protein expression of 3-ketoacyl-CoA thiolase, acyl-CoA hydrolase mitochondrial precursor and enoyl-CoA hydratase, three long-chain fatty acid ß-oxidation-related enzymes, and carnitine-O-palmitoyltransferase I was significantly higher in left ventricles from HFD rats. Protein expression of triosephosphate isomerase was higher in left ventricles from HFD rats than in those from control. Two α/ß-enolase isotypes and glyceraldehyde-3-phosphate isomerase were significantly increased in HFD rats as compared with control. Pyruvate and lactate contents were similar in HFD and control groups. Expression of proteins associated with Krebs cycle and mitochondrial oxidative phosphorylation was higher in HFD rats. CONCLUSIONS: Expression of proteins involved in left ventricle metabolic energy was enhanced before myocardial functionality was affected in rats fed with HFD. These findings may probably indicate higher cardiac energy requirement due to weight increase by HFD.
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Dieta Hiperlipídica , Metabolismo Energético , Redes e Vias Metabólicas/fisiologia , Miocárdio/metabolismo , Sobrepeso/metabolismo , Acetil-CoA C-Aciltransferase/genética , Acetil-CoA C-Aciltransferase/metabolismo , Animais , Western Blotting , Peso Corporal , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/sangue , Enoil-CoA Hidratase/genética , Enoil-CoA Hidratase/metabolismo , Ácidos Graxos/metabolismo , Gliceraldeído 3-Fosfato/genética , Gliceraldeído 3-Fosfato/metabolismo , Processamento de Imagem Assistida por Computador , Insulina/sangue , Ácido Láctico/análise , Leptina/sangue , Masculino , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação Oxidativa , Palmitoil-CoA Hidrolase/genética , Palmitoil-CoA Hidrolase/metabolismo , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Ácido Pirúvico/análise , Ratos , Ratos Endogâmicos WKY , Triglicerídeos/sangue , Triose-Fosfato Isomerase/genética , Triose-Fosfato Isomerase/metabolismoRESUMO
Chronic pancreatitis (CP) is a relatively uncommon, complex and highly heterogeneous disease. There is no clear pattern applicable to the initial stages of CP, which hampers its early diagnosis. Some of the complications of CP, especially chronic pain, can be difficult to manage. There is wide variation in the diagnosis and treatment of CP and its complications among centers and health professionals. The Spanish Pancreatic Club has developed a consensus document on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. A list of questions was drawn up. Each question was reviewed by two experts. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. The first part of the consensus document focusses on the diagnosis of CP and its complications.
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Pancreatite Crônica/diagnóstico , HumanosRESUMO
Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.
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Pancreatite Crônica/terapia , Árvores de Decisões , Humanos , Apoio NutricionalRESUMO
Stroke patients have a high risk of vascular recurrence. Biomarkers related to vascular recurrence, however, remain to be identified. The aim of the study was to identify, through proteomic analysis, plasma biomarkers associated with vascular recurrence within one year after the first ischemic stroke. This is a substudy (n = 134) of a large prospective multicenter study of post-stroke patients with an ischemic stroke. Plasma samples were obtained at inclusion. Among the identified proteins, only plasma levels of desmoplakin I were associated with protection against a new vascular event (Odds ratio: 0.64; 95% CI: 0.46-0.89; p = 0.009) after adjustment for hypercholesterolemia, statins and previous atherothrombotic stroke subtype. A greater number of patients without vascular recurrence had been treated with statins within three months of the recent ischemic stroke. Only patients who had been taking statins for 3 months after the ischemic stroke and did not suffer vascular recurrence over a follow-up year, have higher levels of desmoplakin I at the time of inclusion (Odds ratio 0.49; 95% CI: 0.28-0.86; p = 0.013). Increased desmoplakin I levels, determined within 1-3 months of the first ischemic stroke, could be a biomarker for statin responsiveness against a new vascular event in post-ischemic stroke patients taking statins early (1-3 months) after the ischemic stroke.
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Biomarcadores/sangue , Isquemia Encefálica/sangue , Desmoplaquinas/sangue , Acidente Vascular Cerebral/sangue , 1-Alquil-2-acetilglicerofosfocolina Esterase/análise , Idoso , Sequência de Aminoácidos , Western Blotting , Isquemia Encefálica/complicações , Proteína C-Reativa/análise , Doenças Cardiovasculares/complicações , Eletroforese em Gel Bidimensional , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doenças do Sistema Nervoso/etiologia , Estudos Prospectivos , Proteômica , Recidiva , Acidente Vascular Cerebral/etiologia , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: The purpose of this study was to evaluate the expression of proteins related to cytoskeleton and energetic metabolism at abdominal aortic aneurysm (AAA) sites using proteomics. Several remodeling-related mechanisms have been associated with AAA formation but less is known about the expression of proteins associated with cytoskeleton and energetic metabolism in AAAs. METHODS: AAA samples (6.73 ± 0.40 cm size) were obtained from 13 patients during elective aneurysm repair. Control abdominal aortic samples were obtained from 12 organ donors. Proteins were analyzed using two-dimensional electrophoresis and mass spectrometry. RESULTS: The expression of filamin was increased in the AAA site compared to control abdominal aortic samples while microfibril-associated glycoprotein-4 isotype 1, annexin A5 isotype 1, and annexin A2 were reduced compared with control abdominal aortic samples. Reduction in expression level of energetic metabolism-associated proteins such as triosephosphate isomerase, glyceraldehyde 3-phosphate dehydrogenase, and cytosolic aldehyde dehydrogenase was also observed in AAAs compared to controls. Reduction of triosephosphate isomerase expression was also observed by Western blot, which was accompanied by diminished triosephosphate isomerase activity. At the AAA site, pyruvate dehydrogenase expression was reduced and the content of both lactate and pyruvate was increased with respect to controls without changes in lactate dehydrogenase activity. CONCLUSIONS: The present results suggest that an anaerobic metabolic state may be favored further to reduce the expression of cytoskeleton-related proteins. The better knowledge of molecular mechanism involved in AAAs may favor development of new clinical strategies.
Assuntos
Anexina A2/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Proteínas Contráteis/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica , Idoso , Anexina A2/genética , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/cirurgia , Western Blotting , Estudos de Casos e Controles , Proteínas Contráteis/genética , Proteínas do Citoesqueleto/genética , Eletroforese em Gel Bidimensional , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Proteínas da Matriz Extracelular/genética , Frutose-Bifosfato Aldolase/genética , Frutose-Bifosfato Aldolase/metabolismo , Humanos , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Espectrometria de Massas , Pessoa de Meia-Idade , Fatores de Processamento de RNA , Valores de Referência , Sensibilidade e Especificidade , Técnicas de Cultura de Tecidos , Triose-Fosfato Isomerase/genética , Triose-Fosfato Isomerase/metabolismoRESUMO
Long QT syndrome (LQTS) is closely associated with syncope, seizure, and sudden death but LQTS is frequently misdiagnosed as epilepsy. LQTS and epilepsy both belong to the group of ion channelopathies that manifest in the heart and brain. Therefore, genetic analysis of genes associated with potassium and sodium homeostasis and electrical disorders may reveal a link between epilepsy and lethal cardiac arrhythmia. Here, the authors report a young woman who suffered recurrent seizure episodes and syncopes that occurred while walking and also during rest. She showed electroencephalogram abnormalities and a pathological prolonged QTc interval in electrocardiogram. The patient and the patient's asymptomatic family members underwent genetic screening of the three genes most frequently associated with LQTS: KCNQ1, KCNH2, and SCN5A. The patient and the family members did not show DNA alterations in the genes KCNQ1 and SCN5A associated with LQT-1 and LQT-3, respectively. However, the patient showed a de novo mutation 2587TâC in exon 10 of KCNH2 gene associated with LQT-2. The mutation caused a stop codon substitution (R863X) in the HERG channel, leading to a 296-amino acid deletion. The patient's asymptomatic relatives did not show the KCNH2 gene mutation. R863X alteration in HERG channel may be involved in both prolonged QTc interval and epilepsy. This fact raises the possibility that R863X alteration in KCNH2-encoded potassium channel may confer susceptibility for epilepsy and cardiac LQT-2 arrhythmia.
Assuntos
Epilepsia/genética , Síndrome do QT Longo/genética , Mutação/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Arginina/genética , Análise Mutacional de DNA , Eletrocardiografia , Eletroencefalografia , Epilepsia/complicações , Saúde da Família , Feminino , Humanos , Síndrome do QT Longo/complicações , Adulto JovemRESUMO
Statins, in addition to healthy lifestyle interventions, are the cornerstone of lipid-lowering therapy. Other low-density lipoprotein (LDL)-lowering drugs include ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. As new evidence emerges from new clinical trials, therapeutic goals change, leading to renewed clinical guidelines. Nowadays, LDL goals are getting lower, leading to the "lower is better" paradigm in LDL-cholesterol (LDL-C) management. Several observational studies have shown that LDL-C control in real life is suboptimal in both primary and secondary preventions. It is critical to enhance the adherence to guideline recommendations through shared decision-making between clinicians and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities. This narrative review summarizes the evidence regarding the benefits of lipid-lowering drugs in reducing cardiovascular events, the pleiotropic effect of statins, real-world data on overtreatment and undertreatment of lipid-lowering therapies, and the changing LDL-C in targets in the clinical guidelines of dyslipidemias over the years.
RESUMO
PURPOSE: Combination of Rivaroxaban plus Aspirin improved cardiovascular outcome in patients with stable cardiovascular disease. The aim was to determine if Rivaroxaban and acetylsalicylic acid alone or in combination may protect mitochondrial mitophagy in human coronary artery endothelial cells (HCAEC) exposed to D-glucose. METHODS: HCAEC were incubated under different conditions: 5 mmol/L glucose D-glucose (control), 30 mmol/L D-Glucose with and without 50 nmol/L Rivaroxaban (Rivaroxaban), 0.33 mmol/L ASA (ASA) or Rivaroxaban (12.5 nmol/L)+ASA (0.33 mmol/L; (Riva+ASA). RESULTS: HCAEC incubated with D-glucose showed an increased Factor Xa expression. The mitochondrial content of Pink-1 and Parkin were significantly reduced in high glucose-incubated HCAEC compared to control. Rivaroxaban+ASA significantly increased the mitochondrial content of Pink-1 and Parkin, and the mitochondrial membrane potential compared to D-Glucose group. Both ASA alone and Riva+ASA reduced reactive oxygen species (ROS) and tissue factor production induced by high glucose exposure. CONCLUSION: Under high glucose condition combining Rivaroxaban+ASA increased the mitochondrial content of Pink-1 and Parkin, restored mitochondria membrane potential and reduced ROS and tissue factor expression in HCAEC. It suggests potential effects induced by dual use of Rivaroxaban and ASA on the coronary endothelium subjected to high glucose condition.
Assuntos
Aspirina , Rivaroxabana , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Endotélio , Fator Xa/metabolismo , Fator Xa/farmacologia , Glucose/metabolismo , Humanos , Mitocôndrias , Mitofagia , Espécies Reativas de Oxigênio/metabolismo , Rivaroxabana/metabolismo , Rivaroxabana/farmacologia , Tromboplastina/metabolismo , Tromboplastina/farmacologia , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Background: Mitochondria have been involved in host defense upon viral infections. Factor Xa (FXa), a coagulating factor, may also have influence on mitochondrial functionalities. The aim was to analyze if in human pulmonary microvascular endothelial cells (HPMEC), the SARS-CoV-2 (COVID-19) spike protein subunits, S1 and S2 (S1+S2), could alter mitochondrial metabolism and what is the role of FXA. Methods: HPMEC were incubated with and without recombinants S1+S2 (10 nmol/L each). Results: In control conditions, S1+S2 failed to modify FXa expression. However, in LPS (1 µg/mL)-incubated HPMEC, S1+S2 significantly increased FXa production. LPS tended to reduce mitochondrial membrane potential with respect to control, but in higher and significant degree, it was reduced when S1+S2 were present. LPS did not significantly modify cytochrome c oxidase activity as compared with control. Addition of S1+S2 spike subunits to LPS-incubated HPMEC significantly increased cytochrome c oxidase activity with respect to control. Lactate dehydrogenase activity was also increased by S1+S2 with respect to control and LPS alone. Protein expression level of uncoupled protein-2 (UCP-2) was markedly expressed when S1+S2 were added together to LPS. Rivaroxaban (50 nmol/L), a specific FXa inhibitor, significantly reduced all the above-mentioned alterations induced by S1+S2 including UCP-2 expression. Conclusions: In HPMEC undergoing to preinflammatory condition, COVID-19 S1+S2 spike subunits promoted alterations in mitochondria metabolism suggesting a shift from aerobic towards anaerobic metabolism that was accompanied of high FXa production. Rivaroxaban prevented all the mitochondrial metabolic changes mediated by the present COVID-19 S1 and S2 spike subunits suggesting the involvement of endogenous FXa.