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1.
Circ Res ; 132(3): 290-305, 2023 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-36636919

RESUMO

BACKGROUND: SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear. METHODS: We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B2, and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation. RESULTS: Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B2 biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox (phagocyte oxidase) upregulation. CONCLUSIONS: The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.


Assuntos
COVID-19 , Trombose , Humanos , Anticorpos Monoclonais/farmacologia , Plaquetas/metabolismo , COVID-19/metabolismo , Estudos Transversais , SARS-CoV-2 , Trombose/etiologia , Trombose/metabolismo , Tromboxanos/metabolismo , Tromboxanos/farmacologia , Receptor 4 Toll-Like/metabolismo
2.
Eur J Clin Invest ; 54(4): e14140, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38050790

RESUMO

BACKGROUND: Traditional combustion cigarette (TCC) smoking is an established risk factor for several types of cancer and cardiovascular diseases. Circulating microRNAs (miRNAs) represent key molecules mediating pathogenetic mechanisms, and potential biomarkers for personalized risk assessment. TCC smoking globally changes the profile of circulating miRNAs. The use of heat-not-burn cigarettes (HNBCs) as alternative smoking devices is rising exponentially worldwide, and the circulating miRNA profile of chronic HNBC smokers is unknown. We aimed at defining the circulating miRNA profile of chronic exclusive HNBC smokers, and identifying potentially pathogenetic signatures. METHODS: Serum samples were obtained from 60 healthy young subjects, stratified in chronic HNBC smokers, TCC smokers and nonsmokers (20 subjects each). Three pooled samples per group were used for small RNA sequencing, and the fourth subgroup constituted the validation set. RESULTS: Differential expression analysis revealed 108 differentially expressed miRNAs; 72 exclusively in TCC, 10 exclusively in HNBC and 26 in both smoker groups. KEGG pathway analysis on target genes of the commonly modulated miRNAs returned cancer and cardiovascular disease associated pathways. Stringent abundance and fold-change criteria nailed down our functional bioinformatic analyses to a network where miR-25-3p and miR-221-3p are main hubs. CONCLUSION: Our results define for the first time the miRNA profile in the serum of exclusive chronic HNBC smokers and suggest a significant impact of HNBCs on circulating miRNAs.


Assuntos
Fumar Cigarros , MicroRNA Circulante , MicroRNAs , Neoplasias , Humanos , Temperatura Alta , Voluntários Saudáveis , MicroRNAs/genética
3.
Arterioscler Thromb Vasc Biol ; 43(10): e396-e403, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37586040

RESUMO

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome characterized by platelet anti-PF4 (platelet-activating antiplatelet factor 4)-related thrombosis. Platelet-neutrophil interaction has been suggested to play a role, but the underlying mechanism has not been fully elucidated. METHODS: The study included 10 patients with VITT after ChAdOx1 (chimpanzee adenovirus Oxford 1) nCoV-19 (Oxford-AstraZeneca) vaccine administration, 10 patients with ischemic stroke (IS), 10 patients with acute deep vein thrombosis, and 10 control subjects in whom blood levels of neutrophil extracellular traps (NETs), soluble TF (tissue factor), and thrombin generation were examined. Furthermore, we performed in vitro studies comparing the effect of serum from patients and controls on NETs formation. Finally, immunohistochemistry was performed in cerebral thrombi retrieved from a patients with VITT and 3 patients with IS. RESULTS: Compared with patients with IS, patients with deep vein thrombosis, controls, and patients with VITT had significantly higher blood values of CitH3 (citrullinated histone H3), soluble TF, D-dimer, and prothrombin fragment 1+2 (P<0.0001). Blood CitH3 significantly correlated with blood soluble TF (Spearman rank correlation coefficient=0.7295; P=0.0206) and prothrombin fragment 1+2 (Spearman rank correlation coefficient=0.6809; P<0.0350) in patients with VITT. Platelet-neutrophil mixture added with VITT plasma resulted in higher NETs formation, soluble TF and thrombin generation, and platelet-dependent thrombus growth under laminar flow compared with IS and deep vein thrombosis plasma; these effects were blunted by PAD4 (protein arginine deiminase 4) and cathepsin G inhibitors, anti-FcγRIIa (Fc receptor for IgG class IIa), and high doses of heparin. Immunohistochemistry analysis showed a more marked expression of PAD4 along with more diffuse neutrophil infiltration and NETs formation as well as TF and cathepsin expression in VITT thrombus compared with thrombi from patients with IS. CONCLUSIONS: Patients with VITT display enhanced thrombogenesis by PAD4-mediated NETs formation via cathepsin G-mediated platelet/neutrophil interaction.


Assuntos
Trombocitopenia , Trombose , Vacinas , Humanos , Neutrófilos , Catepsina G , Trombina , Trombose/prevenção & controle
4.
Int J Mol Sci ; 25(11)2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38891768

RESUMO

Gut-dysbiosis-induced lipopolysaccharides (LPS) translocation into systemic circulation has been suggested to be implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to assess if oleuropein (OLE), a component of extra virgin olive oil, lowers high-fat-diet (HFD)-induced endotoxemia and, eventually, liver steatosis. An immunohistochemistry analysis of the intestine and liver was performed in (i) control mice (CTR; n = 15), (ii) high-fat-diet fed (HFD) mice (HFD; n = 16), and (iii) HFD mice treated with 6 µg/day of OLE for 30 days (HFD + OLE, n = 13). The HFD mice developed significant liver steatosis compared to the controls, an effect that was significantly reduced in the HFD + OLE-treated mice. The amount of hepatocyte LPS localization and the number of TLR4+ macrophages were higher in the HFD mice in the than controls and were lowered in the HFD + OLE-treated mice. The number of CD42b+ platelets was increased in the liver sinusoids of the HFD mice compared to the controls and decreased in the HFD + OLE-treated mice. Compared to the controls, the HFD-treated mice showed a high percentage of intestine PAS+ goblet cells, an increased length of intestinal crypts, LPS localization and TLR4+ expression, and occludin downregulation, an effect counteracted in the HFD + OLE-treated mice. The HFD-fed animals displayed increased systemic levels of LPS and zonulin, but they were reduced in the HFD + OLE-treated animals. It can be seen that OLE administration improves liver steatosis and inflammation in association with decreased LPS translocation into the systemic circulation, hepatocyte localization of LPS and TLR4 downregulation in HFD-induced mouse model of NAFLD.


Assuntos
Glucosídeos Iridoides , Iridoides , Lipopolissacarídeos , Hepatopatia Gordurosa não Alcoólica , Azeite de Oliva , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Glucosídeos Iridoides/farmacologia , Camundongos , Azeite de Oliva/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Masculino , Iridoides/farmacologia , Regulação para Baixo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia
5.
Microvasc Res ; 149: 104557, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37268038

RESUMO

BACKGROUND: Endothelial dysfunction, assessed by flow-mediated dilation (FMD), is related to poor prognosis in patients with COVID-19 pneumonia (CP). In this study, we explored the interplay among FMD, NADPH oxidase type 2 (NOX-2) and lipopolysaccharides (LPS) in hospitalised patients with CP, community acquired pneumonia (CAP) and controls (CT). METHODS: We enrolled 20 consecutive patients with CP, 20 hospitalised patients with CAP and 20 CT matched for sex, age, and main cardiovascular risk factors. In all subjects we performed FMD and collected blood samples to analyse markers of oxidative stress (soluble Nox2-derived peptide (sNOX2-dp), hydrogen peroxide breakdown activity (HBA), nitric oxide (NO), hydrogen peroxide (H2O2)), inflammation (TNF-α and IL-6), LPS and zonulin levels. RESULTS: Compared with controls, CP had significant higher values of LPS, sNOX-2-dp, H2O2,TNF-α, IL-6 and zonulin; conversely FMD, HBA and NO bioavailability were significantly lower in CP. Compared to CAP patients, CP had significantly higher levels of sNOX2-dp, H2O2, TNF-α, IL-6, LPS, zonulin and lower HBA. Simple linear regression analysis showed that FMD inversely correlated with sNOX2-dp, H2O2, TNF-α, IL-6, LPS and zonulin; conversely FMD was directly correlated with NO bioavailability and HBA. Multiple linear regression analysis highlighted LPS as the only predictor of FMD. CONCLUSION: This study shows that patients with COVID-19 have low-grade endotoxemia that could activate NOX-2, generating increased oxidative stress and endothelial dysfunction.


Assuntos
COVID-19 , Endotoxemia , Pneumonia , Doenças Vasculares , Humanos , Endotoxemia/diagnóstico , Lipopolissacarídeos , Peróxido de Hidrogênio , Interleucina-6 , Fator de Necrose Tumoral alfa , COVID-19/diagnóstico , Estresse Oxidativo
6.
J Pathol ; 258(2): 136-148, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35751644

RESUMO

Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome-MetS, and type 2 diabetes mellitus-DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and real-time quantitative polymerase chain reaction (RT-qPCR) analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by screening of 30 secreted cytokines, with a significant reduction in vascular endothelial growth factor (VEGF) and endoglin confirmed by enzyme-linked immunoassay (ELISA). DM2-CSCs showed significantly reduced support for endothelial cells in angiogenic assays, and significantly increased H2 O2 release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Diabetes Mellitus Tipo 2 , Fator A de Crescimento do Endotélio Vascular , Autofagia , Diabetes Mellitus Tipo 2/genética , Endoglina/metabolismo , Células Endoteliais/metabolismo , Fibrose , Humanos , Estresse Oxidativo , Células Estromais/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
J Autoimmun ; 129: 102832, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35512480

RESUMO

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) is emerging as a novel cardiovascular risk factor. Levels of PCSK9 in thrombotic primary antiphospholipid syndrome (PAPS) have never been investigated. METHODS: Cross sectional comparison of baseline characteristics of 91 PAPS patients enrolled in the multicenter prospective ATHERO-APS cohort study. PCSK9 levels were categorized into tertiles and the association with arterial and recurrent thrombosis were assessed by univariable and multivariable logistic regression analysis. RESULTS: Median age was 51 years and 71.4% (n = 65) were women. Overall, 33% (n = 30) experienced an arterial event while 31% (n = 28) had recurrent thrombotic events. Median PCSK9 levels were 1243 (1100-1650) pg/ml. Patients in the third PCSK9 tertile (>1458 pg/ml) showed a higher prevalence of dyslipidemia, lupus anticoagulant positivity and a history of previous arterial and recurrent thrombosis than patients in the first and second tertile. PCSK9 levels were higher in arterial than venous thrombosis (1502 vs. 1180 pg/ml, p = 0.002), and in patients with recurrent vs isolated thrombosis (1680 vs. 1150 pg/m, p < 0.001). High plasma PCSK9 levels were associated with a 4-fold increase risk for arterial events and with a 10-fold increase risk for recurrent thrombosis after adjustment for confounding factors. CONCLUSION: These preliminary data suggest that PCSK9 levels are increased in PAPS patients with arterial and recurrent thrombosis. Its role as a possible therapeutic target in PAPS needs further studies.


Assuntos
Síndrome Antifosfolipídica , Trombose , Síndrome Antifosfolipídica/epidemiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Estudos Prospectivos , Trombose/epidemiologia
8.
Heart Fail Rev ; 27(1): 119-134, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-32500365

RESUMO

Therapeutic intervention for prostate cancer mostly relies on eliminating circulating androgen or antagonizing its effect at the cellular level. As the use of endocrine therapies grows, an under-reported incidence of cardiovascular toxicities occurs in prostate cancer patients. In this review, we summarize data of clinical studies, investigating the cardiovascular and metabolic alterations associated with the use of old and new endocrine drugs (gonadotropin-releasing hormone [GnRH] agonists and antagonists, androgen receptor inhibitors, 17α-hydroxylase/c-17,20-lyase [CYP17] inhibitor) in prostate cancer. To date, studies looking for links between cardiovascular complications and hormone-mediated therapies in prostate cancer have reached conflicting results. Several confounding factors, such as age of patients and related cardiovascular liability, other comorbidities, and use of concomitant drugs, have to be carefully evaluated in future clinical trials. Further research is needed given the continuous advancements being made in prostate cancer treatment.


Assuntos
Doenças Cardiovasculares , Neoplasias da Próstata , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico
9.
Circ Res ; 126(10): 1415-1442, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32379574

RESUMO

Previous studies reported an inverse association between healthy dietary patterns (such as Mediterranean diet) and the incidence of cardiovascular events. As the mechanism accounting for cardiovascular disease is prevalently due to the atherothrombosis, where a pivotal role is played by platelet activation, it would be arguable that diets with protective effects against cardiovascular disease exert an anti-atherothrombotic effect via inhibition of platelet activation. There are several and sparse typologies of studies, which investigated if single nutrients by diets recognized as having cardiovascular protection may exert an antithrombotic effect. The most investigated nutrients are key components of the Mediterranean diets such as fruits and vegetables, fish, olive oil, and wine; other diets with protective effects include nuts and cocoa. Here we summarize experimental and human interventional studies which investigated the antithrombotic effects of such nutrients in experimental models of thrombosis or analyzed biomarkers of clotting, platelet, and fibrinolysis activation in human; furthermore in vitro studies explored the underlying mechanism at level of several cell lines such as platelets or endothelial cells. In this context, we analyzed if nutrients affect simultaneously or separately clotting, platelet, and fibrinolysis pathways giving special attention to the relationship between oxidative stress and thrombosis as most nutrients are believed to possess antioxidant properties.


Assuntos
Aterosclerose/prevenção & controle , Coagulação Sanguínea , Plaquetas/metabolismo , Dieta Saudável , Estado Nutricional , Valor Nutritivo , Comportamento de Redução do Risco , Trombose/prevenção & controle , Animais , Aterosclerose/sangue , Aterosclerose/epidemiologia , Aterosclerose/fisiopatologia , Modelos Animais de Doenças , Humanos , Ativação Plaquetária , Fatores de Proteção , Espécies Reativas de Oxigênio/sangue , Medição de Risco , Fatores de Risco , Trombose/sangue , Trombose/epidemiologia , Trombose/fisiopatologia , Resultado do Tratamento
10.
Pediatr Allergy Immunol ; 33 Suppl 27: 22-26, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35080308

RESUMO

BACKGROUND: Allergic rhinitis (AR) is one of the most common allergic diseases affecting children. Objective assessment of nasal obstruction is possible through active anterior rhinomanometry (AAR). Several factors, such as passive smoke exposure (PSE), are triggers for worsening nasal obstruction and chronic inflammation. PSE affects bacterial eubiosis in the upper respiratory tract. This study evaluates the influence of PSE and cotinine levels on both nasal obstruction and local microbiome composition in children with AR. METHODS: Fifty patients (aged between 6 and 16 years) with AR monosensitized grass pollen were enrolled. They underwent skin prick tests, a nasal swab to evaluate the microbial composition of the anterior nostrils, a basal AAR, a post-decongestion AAR, and spirometry. Serum cotinine levels were assessed to evaluate PSE. RESULTS: A significantly lower percentage of mean nasal flow (mNF%) was observed before and after hydrazine administration in subjects exposed to passive smoke (Exp group) compared with the non-exposed group. In contrast, higher cotinine levels were observed in the Exp group than in the controls. PSE has been associated with a decrease in biodiversity and a change in the nasal microbiome composition; instead, although to a different extent, the abundance of specific taxa resulted in being correlated to cotinine levels and nasal flow. CONCLUSION: Children with AR exposed to passive smoke with positive serum cotinine could represent a risk factor for developing nasal obstruction and microbial dysbiosis, suggesting their possible role in pathophysiological processes.


Assuntos
Microbiota , Rinite Alérgica , Adolescente , Criança , Disbiose , Humanos , Projetos Piloto , Fumar
11.
Br J Clin Pharmacol ; 88(1): 155-165, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34087003

RESUMO

BACKGROUND AND PURPOSE: Corticosteroids are often prescribed to community-acquired pneumonia (CAP) patients, but the relationship with major cardiovascular events (MACEs) is unclear. EXPERIMENTAL APPROACH: 541 CAP patients were recruited (334 males, mean age 71.9 ± 16.2 years). High-sensitivity troponin T (hs-cTnT) was measured at admission, during the hospital stay and at discharge. MACE occurrence was registered during a long-term follow-up. KEY RESULTS: Overall, 318 patients (59%) showed hs-cTnT elevation >99th percentile (>0.014 µg/L). Age, heart failure and the increasing quintiles of hs-cTnT (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.82-2.58, P < .001) predicted MACEs. Among patients with hs-cTnT >0.014 µg/L at admission, 102 patients (31%) were on corticosteroids and showed lower hs-cTnT increase (P = .021), (NADPH) oxidase-2 (Nox2) activation (P = .005) and incidence of MACEs than untreated ones (HR 0.64, 95% CI 0.41-0.97, P = .038); no effect of corticosteroids on MACEs was observed in CAP patients with normal troponin. In vitro study showed that glucocorticoids have an antioxidant effect via downregulation of Nox2 activity. CONCLUSION AND IMPLICATIONS: The study provides evidence that corticosteroid use is associated with lower increase of hs-cTnT and incidence of MACEs in CAP patients.


Assuntos
Infecções Comunitárias Adquiridas , Insuficiência Cardíaca , Pneumonia , Corticosteroides/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/epidemiologia , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/tratamento farmacológico , Pneumonia/epidemiologia , Prognóstico , Troponina T
12.
Int J Mol Sci ; 23(16)2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-36012617

RESUMO

Although the first discovery of a non-coding RNA (ncRNA) dates back to 1958, only in recent years has the complexity of the transcriptome started to be elucidated. However, its components are still under investigation and their identification is one of the challenges that scientists are presently facing. In addition, their function is still far from being fully understood. The non-coding portion of the genome is indeed the largest, both quantitatively and qualitatively. A large fraction of these ncRNAs have a regulatory role either in coding mRNAs or in other ncRNAs, creating an intracellular network of crossed interactions (competing endogenous RNA networks, or ceRNET) that fine-tune the gene expression in both health and disease. The alteration of the equilibrium among such interactions can be enough to cause a transition from health to disease, but the opposite is equally true, leading to the possibility of intervening based on these mechanisms to cure human conditions. In this review, we summarize the present knowledge on these mechanisms, illustrating how they can be used for disease treatment, the current challenges and pitfalls, and the roles of environmental and lifestyle-related contributing factors, in addition to the ethical, legal, and social issues arising from their (improper) use.


Assuntos
Neoplasias , Medicina de Precisão , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , RNA Mensageiro/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Transcriptoma
13.
Thorax ; 76(6): 618-620, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34157671

RESUMO

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.


Assuntos
Endotélio Vascular/fisiopatologia , Temperatura Alta , Estresse Oxidativo , Ativação Plaquetária/fisiologia , Fumar/metabolismo , Produtos do Tabaco/estatística & dados numéricos , Vaping , Idoso , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/fisiopatologia
14.
HIV Med ; 22(6): 434-444, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33426758

RESUMO

OBJECTIVES: This study aimed to assess whether gut-derived lipopolysaccharide (LPS) could affect platelet function in HIV-1 patients with residual viral load. METHODS: In 23 HIV-1 patients on effective antiretroviral treatment, 10 treatment-naïve HIV-1 subjects and 20 healthy subjects (HS), LPS, zonulin, markers of platelet activation and oxidative stress were evaluated. In vitro, platelets from HS were exposed to plasma from HIV-1-infected treated and untreated patients. RESULTS: Compared with HS, LPS was higher in treated and treatment-naïve subjects with HIV-1 (7.7 ± 2.9, 80.9 ± 13.7 and 75.3 ± 22.6 pg/mL, P < 0.001 vs. HS) as well as serum zonulin (1.3 ± 0.5, 6.1 ± 1.5 and 5.3 ± 1.7 ng/mL, P < 0.001 vs. HS). LPS and zonulin were correlated in HIV patients (Spearman correlation coefficient (rS) = 0.73, P < 0.0001). Levels of soluble CD40 ligand (sCD40L), soluble P-selectin (sP-selectin) and thromboxane B2 (TxB2 ) were higher in HIV-1-treated and treatment-naïve subjects compared with HS as well as NADPH oxidase 2 (NOX2) activation and hydrogen peroxide (H2 O2 ) production. In vitro, sCD40L, sP-selectin and TxB2 production, NOX2 activation and p47phox phosphorylation were higher in platelets exposed to plasma from HIV-1 patients with different viral load compared with the exposure to plasma from HS. This effect was blunted in platelets pre-treated with TLR4 or TLR7 inhibitors. CONCLUSIONS: Low-grade endotoxaemia and persistent viraemia increase platelet function with a mechanism mediated by NOX2 in patients with HIV-1 infection.


Assuntos
Infecções por HIV , Lipopolissacarídeos , Plaquetas , Ligante de CD40 , Infecções por HIV/tratamento farmacológico , Humanos , Lipopolissacarídeos/farmacologia , Ativação Plaquetária , Carga Viral
15.
Hepatology ; 72(2): 470-485, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31808577

RESUMO

BACKGROUND AND AIMS: Lipopolysaccharides (LPS) is increased in nonalcoholic fatty liver disease (NAFLD), but its relationship with liver inflammation is not defined. APPROACH AND RESULTS: We studied Escherichia coli LPS in patients with biopsy-proven NAFLD, 25 simple steatosis (nonalcoholic fatty liver) and 25 nonalcoholic steatohepatitis (NASH), and in mice with diet-induced NASH. NASH patients had higher serum LPS and hepatocytes LPS localization than controls, which was correlated with serum zonulin and phosphorylated nuclear factor-κB expression. Toll-like receptor 4 positive (TLR4+ ) macrophages were higher in NASH than simple steatosis or controls and correlated with serum LPS. NASH biopsies showed a higher CD61+ platelets, and most of them were TLR4+ . TLR4+ platelets correlated with serum LPS values. In mice with NASH, LPS serum levels and LPS hepatocyte localization were increased compared with control mice and associated with nuclear factor-κB activation. Mice on aspirin developed lower fibrosis and extent compared with untreated ones. Treatment with TLR4 inhibitor resulted in lower liver inflammation in mice with NASH. CONCLUSIONS: In NAFLD, Escherichia coli LPS may increase liver damage by inducing macrophage and platelet activation through the TLR4 pathway.


Assuntos
Lipopolissacarídeos/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Modelos Animais de Doenças , Escherichia coli , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Eur Heart J ; 41(33): 3156-3165, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31898723

RESUMO

AIMS: Low-grade endotoxaemia is detectable in human circulation but its role in thrombosis is still unclear. METHODS AND RESULTS: We measured serum lipopolysaccharide (LPS) concentration, soluble P-selectin (sP-selectin), a marker of platelet activation, and zonulin, a marker of gut permeability, in peripheral circulation, coronary thrombi, and intracoronary blood of patients with ST-elevation myocardial infarction (STEMI, n = 50) and stable angina (SA) (n = 50), respectively, and in controls (n = 50). Experimental study was carried out in mice to assess if Escherichia coli-LPS (E. coli-LPS) possess thrombotic property. Coronary thrombi from STEMI showed higher concentrations of LPS, sP-selectin vs. intracoronary blood of SA and peripheral blood of controls (P < 0.001). Zonulin was higher in STEMI compared to the other two groups [4.57 (3.34-5.22); 2.56 (0.41-4.36); 1.95 (1.22-2.65) ng/mL; P < 0.001] and correlated with LPS (Rs = 0.585; P < 0.001). Escherichia coli DNA was positive in 34% of STEMI vs. 12% of SA and 4% of controls (P < 0.001). In a subgroup of 12 STEMI, immunohistochemical analysis of coronary thrombi showed positivity for leucocyte Toll-like receptor 4 (TLR4), cathepsin G, and LPS from E. coli in 100%, 80%, and 25% of samples, respectively. E. coli-LPS injected in mice to reach LPS concentrations like those detected in coronary thrombi was associated with enhanced artery thrombosis and platelet activation, an effect blunted by TLR4 inhibitor co-administration. In vitro study demonstrated that LPS from E. coli enhanced platelet aggregation via TLR4-mediated leucocyte cathepsin G activation. CONCLUSION: ST-elevation myocardial infarction patients disclose an enhanced gut permeability that results in LPS translocation in human circulation and eventually thrombus growth at site of artery lesion via leucocyte-platelet interaction.


Assuntos
Endotoxemia , Infarto do Miocárdio , Trombose , Receptor 4 Toll-Like , Animais , Artérias , Escherichia coli , Humanos , Camundongos
18.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281247

RESUMO

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.


Assuntos
Hiperlipoproteinemia Tipo II/tratamento farmacológico , Inibidores de PCSK9 , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/análise , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Itália , Lipoproteínas LDL/análise , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , NADPH Oxidase 2/análise , NADPH Oxidase 2/sangue , Pró-Proteína Convertase 9/genética
19.
Eur J Clin Invest ; 50(10): e13378, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32860457

RESUMO

BACKGROUND: To systematically review clinical and biochemical characteristics associated with the severity of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19). MATERIALS AND METHODS: Systematic review of observational studies from PubMed, ISI Web of Science, SCOPUS and Cochrane databases including people affected by COVID-19 and reporting data according to the severity of the disease. Data were combined with odds ratio (OR) and metanalysed. Severe COVID-19 was defined by acute respiratory distress syndrome, intensive care unit admission and death. RESULTS: We included 12 studies with 2794 patients, of whom 596 (21.33%) had severe disease. A slightly higher age was found in severe vs non-severe disease. We found that prevalent cerebrovascular disease (odds ratio [OR] 3.66, 95% confidence interval [CI] 1.73-7.72), chronic obstructive pulmonary disease (OR: 2.39, 95% CI 1.10-5.19), prevalent cardiovascular disease (OR: 2.84, 95% CI 1.59-5.10), diabetes (OR: 2.78, 95% CI 2.09-3.72), hypertension (OR: 2.24, 95% CI 1.63-3.08), smoking (OR: 1.54, 95% CI 1.07-2.22) and male sex (OR: 1.22, 95% CI 1.01-1.49) were associated with severe disease. Furthermore, increased procalcitonin (OR: 8.21, 95% CI 4.48-15.07), increased D-Dimer (OR: 5.67, 95% CI 1.45-22.16) and thrombocytopenia (OR: 3.61, 95% CI 2.62-4.97) predicted severe infection. CONCLUSION: Characteristics associated with the severity of SARS-CoV-2 infection may allow an early identification and management of patients with poor outcomes.


Assuntos
Doenças Cardiovasculares/epidemiologia , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/epidemiologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Pneumonia Viral/metabolismo , Pró-Calcitonina/metabolismo , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/epidemiologia , Trombocitopenia/epidemiologia , Betacoronavirus , COVID-19 , Transtornos Cerebrovasculares/epidemiologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Humanos , Hipertensão/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Prevalência , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores Sexuais
20.
Curr Atheroscler Rep ; 22(2): 8, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034541

RESUMO

PURPOSE OF REVIEW: Modified risk products (MRP) are promoted as a safer alternative to traditional combustion cigarettes (TCC) in chronic smokers. Evidence for their lower hazardous profile is building, despite several controversies. Yet, it is unclear whether individual responses to MRP differ among consumers. We hypothesized that different clusters of subjects exist in terms of acute effects of MRP. RECENT FINDINGS: Pooling data from a total of 60 individuals, cluster analysis identified at least three clusters (labelled 1 to 3) of subjects with different electronic vaping cigarettes (EVC) effects and at least two clusters (labelled 4 to 5) of subjects with different heat-not-burn cigarettes (HNBC) effects. Specifically, oxidative stress, platelet aggregation, and endothelial dysfunction after EVC were significantly different cluster-wise (all p < 0.05), and oxidative stress and platelet aggregation after HNBC were significantly different (all p < 0.05). In particular, subjects belonging to Cluster 1 appeared to have less detrimental responses to EVC usage than subjects in Cluster 2 and 3, as shown by non-significant changes in flow-mediated dilation (FMD) and less marked increase in Nox2-derived peptide (NOX). Conversely, those assigned to Cluster 3 had the worst reaction in terms of changes in FMD, NOX, and P-selectin. Furthermore, individuals belonging to Cluster 4 responded unfavorably to both HNBC and EVC, whereas those in Cluster 5 interestingly showed less adverse results after using HNBC than EVC. Results for main analyses were consistent employing different clusters, tests, and bootstrap. Individual responses to MRP differ and smokers aiming at using EVC or HNBC as a risk reduction strategy should consider trying different MRP aiming at finding the one which is less detrimental, with subjects resembling those in Cluster 1 preferably using EVC and those resembling Cluster 5 preferably using HNBC.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Comportamento de Redução do Risco , Produtos do Tabaco/efeitos adversos , Vaping/efeitos adversos , Vaping/sangue , Adulto , Análise por Conglomerados , Feminino , Humanos , Masculino , NADPH Oxidase 2/sangue , Estresse Oxidativo , Selectina-P/sangue , Agregação Plaquetária , Estudos Prospectivos , Vasodilatação , Adulto Jovem
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