Publications by authors named "Cristina Nocella"

86 Publications

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

Int J Mol Sci 2021 Jul 3;22(13). Epub 2021 Jul 3.

I Clinica Medica, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy.

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. 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. Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 ( < 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. PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.
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http://dx.doi.org/10.3390/ijms22137193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267646PMC
July 2021

Impact of chronic use of heat-not-burn cigarettes on oxidative stress, endothelial dysfunction and platelet activation: the SUR-VAPES Chronic Study.

Thorax 2021 06 19;76(6):618-620. Epub 2021 Apr 19.

IRCCS NeuroMed, Pozzilli, Italy.

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.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215900DOI Listing
June 2021

Corticosteroid use, myocardial injury and in-hospital cardiovascular events in patients with community-acquired pneumonia.

Br J Clin Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Mediterranea Cardiocentro, Naples, Italy.

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.
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http://dx.doi.org/10.1111/bcp.14936DOI Listing
June 2021

Beneficial effects of a combination of natural product activators of autophagy on endothelial cells and platelets.

Br J Pharmacol 2021 05 24;178(10):2146-2159. Epub 2021 Apr 24.

Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy.

Background And Purpose: Oxidative stress and insufficient autophagy activity are associated with inflammatory processes and are common features of many cardiovascular diseases (CVDs). We investigated if a combination of natural activators of autophagy could modulate oxidative stress, platelet aggregation and endothelial cell survival and function in response to stress.

Experimental Approach: Ex vivo platelet aggregation and activation, H O production and autophagy were measured in platelets of subjects at high cardiovascular risk, including smokers, patients with metabolic syndrome (MetS) and patients with atrial fibrillation (AF). In vitro, the effects of a mixture of natural pro-autophagy molecules and antioxidants on platelets and human umbilical vein endothelial cells (HUVECs) were evaluated.

Key Result: Autophagy appeared to be inhibited, whereas aggregation was increased in platelets from AF and MetS patients and in smokers, as compared with healthy subjects. Treatment of platelets isolated from these patients with a mixture composed of trehalose, spermidine, catechin and epicatechin (Mix1) or with a mixture composed of trehalose, spermidine and nicotinamide (Mix2), significantly reduced platelet activation and oxidative stress, and increased autophagy, compared with the effect of each compound alone. Similarly, treatment of HUVECs with a combination of these compounds exhibited beneficial effects and increased endothelial cell survival, nitric oxide bioavailability and angiogenesis in response to stress in a potentiated manner.

Conclusion And Implications: A combination of natural activators of autophagy could inhibit platelet activity and oxidative stress and improve endothelial cell survival and function in a potentiated manner representing a useful strategy to reduce the effect of risk factors on CVD occurrence.

Linked Articles: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
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http://dx.doi.org/10.1111/bph.15399DOI Listing
May 2021

The Role of Antioxidants Supplementation in Clinical Practice: Focus on Cardiovascular Risk Factors.

Antioxidants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

Faculty of Medicine and Surgery, Sapienza University of Rome, 04100 Latina, Italy.

Oxidative stress may be defined as an imbalance between reactive oxygen species (ROS) and the antioxidant system to counteract or detoxify these potentially damaging molecules. This phenomenon is a common feature of many human disorders, such as cardiovascular disease. Many of the risk factors, including smoking, hypertension, hypercholesterolemia, diabetes, and obesity, are associated with an increased risk of developing cardiovascular disease, involving an elevated oxidative stress burden (either due to enhanced ROS production or decreased antioxidant protection). There are many therapeutic options to treat oxidative stress-associated cardiovascular diseases. Numerous studies have focused on the utility of antioxidant supplementation. However, whether antioxidant supplementation has any preventive and/or therapeutic value in cardiovascular pathology is still a matter of debate. In this review, we provide a detailed description of oxidative stress biomarkers in several cardiovascular risk factors. We also discuss the clinical implications of the supplementation with several classes of antioxidants, and their potential role for protecting against cardiovascular risk factors.
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http://dx.doi.org/10.3390/antiox10020146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909411PMC
January 2021

Lipopolysaccharide induces platelet activation in HIV patients: the role of different viral load patterns.

HIV Med 2021 Jul 10;22(6):434-444. Epub 2021 Jan 10.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

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 B (TxB ) were higher in HIV-1-treated and treatment-naïve subjects compared with HS as well as NADPH oxidase 2 (NOX2) activation and hydrogen peroxide (H O ) production. In vitro, sCD40L, sP-selectin and TxB production, NOX2 activation and p47 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.
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http://dx.doi.org/10.1111/hiv.13059DOI Listing
July 2021

Inhibition of miR-155 Attenuates Detrimental Vascular Effects of Tobacco Cigarette Smoking.

J Am Heart Assoc 2020 12 2;9(24):e017000. Epub 2020 Dec 2.

Department of Medical-Surgical Sciences and Biotechnologies Sapienza University of Rome Latina Italy.

Background The role of microRNAs dysregulation in tobacco cigarette smoking-induced vascular damage still needs to be clarified. We assessed the acute effects of tobacco cigarette smoking on endothelial cell-related circulating microRNAs in healthy subjects. In addition, we investigated the potential role of microRNAs in smoking-dependent endothelial cell damage. Methods and Results A panel of endothelial-related microRNAs was quantified in healthy subjects before and after smoking 1 tobacco cigarette. Serum levels of miR-155 were found to be significantly increased shortly after smoking. We also observed a progressive and significant miR-155 accumulation in culture media of human endothelial cells after 30 minutes and up to 4 hours of cigarette smoke condensate treatment in vitro without evidence of cell death, indicating that miR-155 can be released by endothelial cells in response to smoking stress. Cigarette smoke condensate appeared to enhance oxidative stress and impair cell survival, angiogenesis, and NO metabolism in human endothelial cells. Notably, these effects were abrogated by miR-155 inhibition. We also observed that miR-155 inhibition rescued the deleterious effects of cigarette smoke condensate on endothelial-mediated vascular relaxation and oxidative stress in isolated mouse mesenteric arteries. Finally, we found that exogenous miR-155 overexpression mimics the effects of smoking stress by inducing the upregulation of inflammatory markers, impairing angiogenesis and reducing cell survival. These deleterious effects were associated with downregulation of vascular endothelial growth factor and endothelial NO synthetase. Conclusions Our results suggest that miR-155 dysregulation may contribute to the deleterious vascular effects of tobacco smoking.
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http://dx.doi.org/10.1161/JAHA.120.017000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955400PMC
December 2020

Interplay between Nox2 Activity and Platelet Activation in Patients with Sepsis and Septic Shock: A Prospective Study.

Oxid Med Cell Longev 2020 27;2020:4165358. Epub 2020 Oct 27.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Although preclinical studies highlighted the potential role of NADPH oxidase (NOX) in sepsis, only few studies evaluated the oxidative stress in patients with sepsis and septic shock. The objective of the study is to appraise the oxidative stress status and platelet function in patients with sepsis and septic shock compared to healthy controls.

Methods And Results: Patients with sepsis or septic shock admitted to the hospital Policlinico Umberto I (Sapienza University, Rome) underwent a blood sample collection within 1 hour from admission. Platelet aggregation, serum thromboxane B2 (TxB2), soluble NOX2-derived peptides (sNox2-dp), and hydrogen peroxide breakdown activity (HBA) were measured and compared to those of healthy volunteers. Overall, 33 patients were enrolled; of these, 20 (60.6%) had sepsis and 13 (39.4%) septic shock. Compared to healthy controls ( = 10, age 67.8 ± 3.2, male 50%), patients with sepsis and septic shock had higher platelet aggregation (49% (IQR 45-55), 60% (55.75-67.25), and 73% (IQR 69-80), respectively, < 0.001), higher serum TxB2 (77.5 (56.5-86.25), 122.5 (114-131.5), and 210 (195-230) pmol/L, respectively, < 0.001), higher sNox2-dp (10 (7.75-12), 19.5 (17.25-21), and 33 (29.5-39) pg/mL, respectively, < 0.001), and lower HBA (75% (67.25-81.5), 50% (45-54.75), and 27% (21.5-32.5), respectively, < 0.001). Although not statistically significant, a trend in higher levels of serum TxB2 and sNox2-dp in patients who died was observed.

Conclusions: Patients with septic shock exhibit higher Nox2 activity and platelet activation than patients with sepsis. These insights joined to better knowledge of these mechanisms could guide the identification of future prognostic biomarkers and new therapeutic strategies in the scenario of septic shock.
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http://dx.doi.org/10.1155/2020/4165358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641261PMC
May 2021

The Microenvironment of Decellularized Extracellular Matrix from Heart Failure Myocardium Alters the Balance between Angiogenic and Fibrotic Signals from Stromal Primitive Cells.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Department of Medical Surgical Sciences and Biotechnologies, Sapienza University, Corso della Repubblica 79, 04100 Latina, Italy.

Cardiac adverse remodeling is characterized by biological changes that affect the composition and architecture of the extracellular matrix (ECM). The consequently disrupted signaling can interfere with the balance between cardiogenic and pro-fibrotic phenotype of resident cardiac stromal primitive cells (CPCs). The latter are important players in cardiac homeostasis and can be exploited as therapeutic cells in regenerative medicine. Our aim was to compare the effects of human decellularized native ECM from normal (dECM-NH) or failing hearts (dECM-PH) on human CPCs. CPCs were cultured on dECM sections and characterized for gene expression, immunofluorescence, and paracrine profiles. When cultured on dECM-NH, CPCs significantly upregulated cardiac commitment markers (CX43, NKX2.5), cardioprotective cytokines (bFGF, HGF), and the angiogenesis mediator, NO. When seeded on dECM-PH, instead, CPCs upregulated pro-remodeling cytokines (IGF-2, PDGF-AA, TGF-β) and the oxidative stress molecule HO. Interestingly, culture on dECM-PH was associated with impaired paracrine support to angiogenesis, and increased expression of the vascular endothelial growth factor (VEGF)-sequestering decoy isoform of the KDR/VEGFR2 receptor. Our results suggest that resident CPCs exposed to the pathological microenvironment of remodeling ECM partially lose their paracrine angiogenic properties and release more pro-fibrotic cytokines. These observations shed novel insights on the crosstalk between ECM and stromal CPCs, suggesting also a cautious use of non-healthy decellularized myocardium for cardiac tissue engineering approaches.
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http://dx.doi.org/10.3390/ijms21217903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662394PMC
October 2020

T2238C atrial natriuretic peptide gene variant and cardiovascular events in patients with atrial fibrillation: A substudy from the ATHERO-AF cohort.

Int J Cardiol 2021 01 28;322:245-249. Epub 2020 Aug 28.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, Latina 40100, Italy; IRCCS Neuromed, Località Camerelle, Pozzilli, (IS), 86077, Italy; This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Background: The T2238C variant of the atrial natriuretic peptide (ANP) gene has emerged as a novel risk factor for the incidence of cardiovascular events. However, the impact of this variant on cardiovascular outcome in patients with atrial fibrillation (AF) is unknown.

Methods: We included 557 anticoagulated patients with non-valvular AF randomly selected from the prospective ATHERO-AF cohort. Patients underwent genetic analysis for the T2238C/ANP variant and were grouped as wild type or heterozygous or homozygous for C2238 variant allele. Primary endpoint was a composite of cardiovascular events (CVEs) including cardiovascular death, fatal/non-fatal ischemic stroke and myocardial infarction. Overall, 429 patients carried the TT wild type genotype, 110 patients (19.7%) were heterozygous (T/C) and 18 patients (3.2%) were homozygous (CC).

Results: Incidence of CVEs was higher in homozygous patients for C2238 allele at unadjusted analysis (log-rank test, p = 0.042 for additive model, p = 0.043 for recessive model). The multivariable Cox proportional hazards regression analysis confirmed that C2238 ANP allele was associated with CVEs in the additive (p = 0.008) and recessive models (p = 0.005).

Conclusions: Carrier status for the C2238/ANP variant allele is associated with an increased risk of CVEs in anticoagulated AF patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.077DOI Listing
January 2021

Poor Adherence to Mediterranean Diet and Serum Lipopolysaccharide are Associated with Oxidative Stress in Patients with Non-Alcoholic Fatty Liver Disease.

Nutrients 2020 Jun 10;12(6). Epub 2020 Jun 10.

I Clinica Medica, Department of Clinical Internal, Anestesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome 00185, Italy.

Oxidative stress plays a pivotal role in non-alcoholic fatty liver disease (NAFLD). Factors inducing oxidative stress in NAFLD may be several; however, a relationship with the adherence to Mediterranean Diet (Med-diet) and with serum lipopolysaccharide (LPS) has been poorly investigated in this setting. The aim was to investigate factors associated with impaired oxidative stress in NAFLD, focusing on the potential role of LPS and Med-diet. We enrolled 238 consecutive outpatients from the PLINIO study, in whom we measured the soluble Nox2-derived peptide (sNox2-dp), a marker of systemic oxidative stress, and serum LPS. Adherence to Med-diet was investigated by a nine-item validated dietary questionnaire. Serum sNox2-dp and LPS were higher in patients with NAFLD compared to those without (25.0 vs. 9.0 pg/mL, < 0.001 and 62.0 vs. 44.9 pg/mL, < 0.001, respectively). In patients with NAFLD, the highest sNox2-dp tertile was associated with the top serum LPS tertile (Odds Ratio (OR): 4.71; p < 0.001), APRI > 0.7 (OR: 6.96; p = 0.005) and Med-diet-score > 6 (OR: 0.14; p = 0.026). Analyzing individual foods, the daily consumption of wine (OR: 0.29, = 0.046) and the adequate weekly consumption of fish (OR: 0.32, = 0.030) inversely correlated with the top sNox2-dp tertile. In conclusion, patients with NAFLD showed impaired oxidative stress. Levels of sNox2 correlated with serum LPS and with low adherence to Med-Diet.
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http://dx.doi.org/10.3390/nu12061732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352324PMC
June 2020

Diet Supplementation, Probiotics, and Nutraceuticals in SARS-CoV-2 Infection: A Scoping Review.

Nutrients 2020 Jun 8;12(6). Epub 2020 Jun 8.

Department of Public Health and Infectious Diseases, Sapienza, University of Rome, 00185 Rome, Italy.

The severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) global pandemic is a devastating event that is causing thousands of victims every day around the world. One of the main reasons of the great impact of coronavirus disease 2019 (COVID-19) on society is its unexpected spread, which has not allowed an adequate preparation. The scientific community is fighting against time for the production of a vaccine, but it is difficult to place a safe and effective product on the market as fast as the virus is spreading. Similarly, for drugs that can directly interfere with viral pathways, their production times are long, despite the great efforts made. For these reasons, we analyzed the possible role of non-pharmacological substances such as supplements, probiotics, and nutraceuticals in reducing the risk of Sars-CoV-2 infection or mitigating the symptoms of COVID-19. These substances could have numerous advantages in the current circumstances, are generally easily available, and have negligible side effects if administered at the already used and tested dosages. Large scientific evidence supports the benefits that some bacterial and molecular products may exert on the immune response to respiratory viruses. These could also have a regulatory role in systemic inflammation or endothelial damage, which are two crucial aspects of COVID-19. However, there are no specific data available, and rigorous clinical trials should be conducted to confirm the putative benefits of diet supplementation, probiotics, and nutraceuticals in the current pandemic.
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http://dx.doi.org/10.3390/nu12061718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352781PMC
June 2020

Is There an Association Between Atherosclerotic Burden, Oxidative Stress, and Gut-Derived Lipopolysaccharides?

Antioxid Redox Signal 2020 May 18. Epub 2020 May 18.

Division I Medical Clinic, Department of Clinical, Internistic, Anaesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Recent studies hypothesized a role of gut microbiota favoring atherosclerosis an increased oxidative stress, but data in peripheral artery disease (PAD) have not been provided yet. The aim of this study was to assess serum lipopolysaccharide (LPS) as well as oxidative stress in PAD patients and controls (CT). Furthermore, we wanted to analyze the relationship between LPS and the severity of atherosclerosis in the lower limb arteries. Eighty consecutive subjects, including 40 PAD patients and 40 CT were recruited. A cross-sectional study was performed to compare serum LPS, soluble Nox2-derived peptide (sNox2-dp), hydrogen peroxide (HO), HO breakdown activity (HBA) and ankle brachial index (ABI) in these two groups. Serum zonulin was used to assess gut permeability. Compared with CT, PAD patients had significant higher values of LPS, zonulin, sNox2-dp, and HO; conversely ABI and HBA were significantly lower in PAD patients. LPS serum levels were associated with atherosclerotic burden as depicted by the inverse correlation with ABI. LPS was also associated with oxidative stress as shown by its direct correlation with markers of oxidative stress such as sNox2-dp, serum HO, and HBA. Finally, we found a significant correlation between LPS and zonulin. A multiple linear regression analysis showed that LPS was significantly associated only with ABI. These findings suggest that LPS is elevated in PAD patients with a close association with the atherosclerotic burden and oxidative stress. The correlation between LPS and zonulin suggests that changes in gut permeability could be a potential trigger of LPS translocation in the peripheral circulation.
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http://dx.doi.org/10.1089/ars.2020.8109DOI Listing
May 2020

Erectile and diastolic dysfunction: two sides of the same coin or same sides of two different coins?

Minerva Cardioangiol 2020 Aug 23;68(4):291-294. Epub 2020 Apr 23.

Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy.

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http://dx.doi.org/10.23736/S0026-4725.20.05283-4DOI Listing
August 2020

Gut microbiota and myocardial infarction.

Eur Heart J 2020 06;41(23):2221-2222

Mediterranea, Cardiocentro, Via Orazio 2, 80122 Napoli, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehaa222DOI Listing
June 2020

A novel role of MMP2 in regulating platelet NOX2 activation.

Free Radic Biol Med 2020 05 5;152:355-362. Epub 2020 Apr 5.

Mediterranea, Cardiocentro, 80122, Napoli, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100, Latina, Italy. Electronic address:

NOX2 has a key role for cellular production of reactive oxidant species (ROS) and although the mechanism of its activation is well known, little is known about its regulation. Metallo-proteinases (MMPs) regulate numerous protein activities both in physiological and pathological conditions but their interplay with NOX2 and ROS formation is still unclear. We performed experimental studies in human platelets and polymorphonuclear leukocytes (PMNs) to investigate the interplay of MMP2 with NOX2 activity. In collagen-stimulated platelets and in PMA-stimulated PMNs from healthy subjects, an immediate burst of ROS was detected at 10 min to then decline at 20 min. Coincidentally, sNOX2-dp, a split-off product of NOX2, increased and peaked at 10 min. ROS production was persistent whereas sNOX2dp is not released in cells treated with MMP2 inhibitor compared to other MMPs inhibitors. Western blot analysis showed the highest MMP2 expression on the cell membrane 10 min after stimulation. Moreover, the co-immunoprecipitation assay confirms the interaction between MMP2 and NOX2 that formed an active immuno-complex. Treating cells with NOX2ds-tat, an inhibitor of NADPH oxidase, significantly reduced ROS formation, sNOX2-dp, MMP2 expression and MMP2-NOX2-complex, which were all restored if cells were added with HO. The study provides the first evidence that MMP2 has a key role in blunting platelet NOX2 activity and eventually ROS formation.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.03.033DOI Listing
May 2020

PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation.

Antioxidants (Basel) 2020 Apr 2;9(4). Epub 2020 Apr 2.

Mediterranea Cardiocentro, 80122 Naples, Italy.

Background: High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) is predictive of cardiovascular events (CVEs) in atrial fibrillation (AF). We hypothesized that PCSK9 may directly induce platelet activation (PA).

Methods: We measured platelet aggregation, recruitment, Thromboxane B2 (TxB2) formation and soluble P-selectin levels as markers of PA and soluble Nox2-derived peptide (sNox2-dp), HO, isoprostanes and oxidized Low-Density-Lipoprotein (oxLDL) to analyze oxidative stress (OS) in 88 patients having PCSK9 values < ( = 44) or > ( = 44) 1.2 ng/mL, balanced for age, sex and cardiovascular risk factors. Furthermore, we investigated if normal ( = 5) platelets incubated with PCSK9 (1.0-2.0 ng/mL) alone or with LDL (50 µg/mL) displayed changes of PA, OS and down-stream signaling.

Results: PA and OS markers were significantly higher in patients with PCSK9 levels > 1.2 ng/mL compared to those with values < 1.2 ng/mL ( < 0.001). Levels of PCSK9 significantly correlated with markers of PA and OS. Platelets incubation with PCSK9 increased PA, OS and p38, p47 and Phospholipase A2 (PLA2) phosphorylation. These changes were amplified by adding LDL and blunted by CD36 or Nox2 inhibitors. Co-immunoprecipitation analysis revealed an immune complex of PCSK9 with CD36.

Conclusions: We provide the first evidence that PCSK9, at concentration found in the circulation of AF patients, directly interacts with platelets via CD36 receptor and activating Nox2: this effect is amplified in presence of LDL.
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http://dx.doi.org/10.3390/antiox9040296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222182PMC
April 2020

Oxidative stress and gut-derived lipopolysaccharides in children affected by paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

BMC Pediatr 2020 03 18;20(1):127. Epub 2020 Mar 18.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Background: Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections syndrome (PANDAS) identifies patients with acute onset of obsessive-compulsive and tic disorders. The objective of this study was to evaluate serum NOX2 levels, as well as 8-iso-prostaglandin F2α (8-iso-PGF2α) and lipopolysaccharide (LPS) of PANDAS patients.

Methods: In this study we wanted to compare serum levels of soluble NOX2-dp (sNOX-2-dp), iso-PGF2α and LPS in 60 consecutive subjects, including 30 children affected by PANDAS and 30 controls (CT) matched for age and gender. Serum zonulin was used as intestinal permeability assay.

Results: Compared with CT, PANDAS children had increased serum levels of sNOX-2-dp, 8-iso-PGF2α and LPS. Bivariate analysis showed that serum sNOX2-dp was significantly correlated with LPS (Rs = 0.359; p = 0.005), zonulin (Rs = 0.444; p < 0.001) and 8-iso-PGF2α (Rs = 0.704; p < 0.001). Serum LPS significantly correlated with zonulin (Rs = 0.610; p < 0.001), and 8-iso-PGF2α (Rs = 0.591; p = 0.001). Finally, a multiple linear regression analysis showed that serum 8-iso-PGF2α and zonulin were the only independent variables associated with sNOX2-dp (R = 68%).

Conclusion: This study shows that children affected by PANDAS have high circulating levels of sNOX2-dp, isoprostanes and of LPS that could be involved in the process of neuroinflammation.
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http://dx.doi.org/10.1186/s12887-020-02026-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079429PMC
March 2020

Oxidative Stress and Gut-Derived Lipopolysaccharides in Neurodegenerative Disease: Role of NOX2.

Oxid Med Cell Longev 2020 31;2020:8630275. Epub 2020 Jan 31.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Background: Neurodegenerative diseases (ND) as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis represent a growing cause of disability in the developed countries. The underlying physiopathology is still unclear. Several lines of evidence suggest a role for oxidative stress and NADPH oxidase 2 (NOX2) in the neuropathological pathways that lead to ND. Furthermore, recent studies hypothesized a role for gut microbiota in the neuroinflammation; in particular, lipopolysaccharide (LPS) derived from Gram-negative bacteria in the gut is believed to play a role in causing ND by increase of oxidative stress and inflammation. The aim of this study was to assess NOX2 activity as well as serum 8-iso-prostaglandin F2 (8-iso-PGF2 (8-iso-PGF2.

Methods: One hundred and twenty-eight consecutive subjects, including 64 ND patients and 64 controls (CT) matched for age and gender, were recruited. A cross-sectional study was performed to compare serum activity of soluble NOX2-dp (sNOX2-dp), blood levels of isoprostanes, serum HO, and LPS in these two groups. Serum zonulin was used to assess gut permeability.

Results: Compared with CT, ND patients had higher values of sNOX2-dp, 8-iso-PGF2 (8-iso-PGF2 < 0.001), zonulin (Rs = 0.411; < 0.001), zonulin (Rs = 0.411; < 0.001), zonulin (Rs = 0.411; (8-iso-PGF2 < 0.001), zonulin (Rs = 0.411; < 0.001), zonulin (Rs = 0.411; (8-iso-PGF2 < 0.001), zonulin (Rs = 0.411; , 0.459; < 0.001), zonulin (Rs = 0.411; (8-iso-PGF2, 0.459; < 0.001), zonulin (Rs = 0.411; = 57%).

Conclusion: This study provides the first report attesting that patients with ND have high NOX2 activation that could be potentially implicated in the process of neuroinflammation.
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http://dx.doi.org/10.1155/2020/8630275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016401PMC
September 2020

Profiling the Acute Effects of Modified Risk Products: Evidence from the SUR-VAPES (Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking) Cluster Study.

Curr Atheroscler Rep 2020 02 7;22(2). Epub 2020 Feb 7.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100, Latina, Italy.

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.
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http://dx.doi.org/10.1007/s11883-020-0824-4DOI Listing
February 2020

Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction.

Eur Heart J 2020 09;41(33):3156-3165

Mediterranea Cardiocentro, via Orazio 2, Napoli 80122, Italy.

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.
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http://dx.doi.org/10.1093/eurheartj/ehz893DOI Listing
September 2020

Oleuropein-enriched chocolate by extra virgin olive oil blunts hyperglycaemia in diabetic patients: Results from a one-time 2-hour post-prandial cross over study.

Clin Nutr 2020 07 21;39(7):2187-2191. Epub 2019 Sep 21.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Mediterranea, Cardiocentro-Napoli, Italy. Electronic address:

Background & Aims: Oleuropein, a component of extra virgin olive oil (EVOO), reduces post-prandial glycemia with a mechanism counteracting oxidative stress-mediated incretin down-regulation. In this study we evaluated if the intake of an oleuropein-enriched chocolate could have positive effects on glycaemia and insulin levels in patients with type 2 diabetes mellitus (T2DM) and healthy subjects (HS).

Methods: Twenty-five consecutive T2DM patients and 20 HS were recruited. Participants were randomized to receive 40 g oleuropein-enriched chocolate by EVOO or 40 g control chocolate spread in a cross-over design. Serum glucose, insulin, glucagon-like peptide-1 (GLP1), and dipeptidyl-peptidase-4 (DPP4) were measured before and 2 h after chocolate intake.

Results: In T2DM, the pairwise comparisons showed that intake of oleuropein-enriched chocolate was associated with a significantly less increase of blood glucose compared to control; GLM analysis showed a significant difference for treatments with respect to glucose (p = 0.04), GLP1 (p < 0.001) and DPP-4 activity (p = 0.01). In HS, the pairwise comparisons showed that, after oleuropein-enriched chocolate intake, blood glucose concentration and DPP4 activity did not change; conversely a significant increase was observed for insulin and GLP1. After control chocolate intake, a significant increase for blood glucose, insulin levels and DPP4 activity were observed while GLP1 did not change.

Conclusion: The study shows that using EVOO as source of oleuropein administration of 40 g oleuropein-enriched chocolate is associated with a modest increase or no change of glycemia in T2DM and HS respectively, via an incretin-mediated mechanism.
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http://dx.doi.org/10.1016/j.clnu.2019.09.006DOI Listing
July 2020

Glutathione infusion before primary percutaneous coronary intervention: a randomised controlled pilot study.

BMJ Open 2019 08 8;9(8):e025884. Epub 2019 Aug 8.

Department of Heart and Great Vessels, Sapienza University of Rome, Rome, Italy.

Objective: In the setting of reperfused ST-elevation myocardial infarction (STEMI), increased production of reactive oxygen species (ROS) contributes to reperfusion injury. Among ROS, hydrogen peroxide (HO) showed toxic effects on human cardiomyocytes and may induce microcirculatory impairment. Glutathione (GSH) is a water-soluble tripeptide with a potent oxidant scavenging activity. We hypothesised that the infusion of GSH before acute reoxygenation might counteract the deleterious effects of increased HO generation on myocardium.

Methods: Fifty consecutive patients with STEMI, scheduled to undergo primary angioplasty, were randomly assigned, before intervention, to receive an infusion of GSH (2500 mg/25 mL over 10 min), followed by drug administration at the same doses at 24, 48 and 72 hours elapsing time or placebo. Peripheral blood samples were obtained before and at the end of the procedure, as well as after 5 days. HO production, 8-iso-prostaglandin F2α (PGF2α) formation, HO breakdown activity (HBA) and nitric oxide (NO) bioavailability were determined. Serum cardiactroponin T (cTpT) was measured at admission and up to 5 days.

Results: Following acute reperfusion, a significant reduction of HO production (p=0.0015) and 8-iso-PGF2α levels (p=0.0003), as well as a significant increase in HBA (p<0.0001)and NO bioavailability (p=0.035), was found in the GSH group as compared with placebo. In treated patients, attenuated production of HO persisted up to 5 days from the index procedure (p=0.009) and these changes was linked to those of the cTpT levels (r=0.41, p=0.023).

Conclusion: The prophylactic and prolonged infusion of GSH seems to determine a rapid onset and persistent blunting of HO generation improving myocardial cell survival. Nevertheless, a larger trial, adequately powered for evaluation of clinical endpoints, is ongoing to confirm the current finding.

Trial Registration Number: EUDRACT 2014-00448625; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701599PMC
August 2019

Interaction between serum endotoxemia and proprotein convertase subtilisin/kexin 9 (PCSK9) in patients with atrial fibrillation: A post-hoc analysis from the ATHERO-AF cohort.

Atherosclerosis 2019 10 4;289:195-200. Epub 2019 Jul 4.

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy; Mediterranea Cardiocentro, Napoli, 80122, Italy. Electronic address:

Background And Aims: Lipopolysaccharides (LPS) is emerging as a novel risk factor for cardiovascular events (CVEs). Furthermore, in vitro evidence suggested that LPS may elicit proprotein convertase subtilisin/kexin 9 (PCSK9) expression, but their relationship in vivo has not been investigated.

Methods: We conducted a post-hoc analysis of a prospective, single centre cohort study of 907 patients with non-valvular atrial fibrillation (AF). At baseline, PCSK9, LPS and NADPH oxidase (sNox2-dp) were measured. PCSK9 and LPS were correlated with the incidence of CVEs.

Results: Median PCSK9 and LPS were 1200 [900-1970] and 49.9 [15.0-108.2] pg/ml, respectively. LPS and PCSK9 were significantly correlated (rS 0.378, p < 0.001). Logistic regression analysis showed that LPS was associated with PCSK9 above the median (odds ratio [OR] 1.727 95% confidence interval [CI] 1.147-2.600 p = 0.009). Other factors associated with PCSK9 above the median were sNox2-dp (OR 1.759 C.I. 95% 1.167-2.650, p = 0.007), use of antiplatelet drugs (OR 0.437 95%CI 0.219-0.871 p = 0.017) and high adherence to Mediterranean diet (OR 0.737 95%CI 0.643-0.845 p = 0.001). Olive oil (OR 0.376 95%CI 0.185-0.763, p = 0.001) and wine (OR 0.460 95%CI 0.289-0.733 p = 0.007) were negatively associated with PCSK9. Patients with concomitant high PCSK9 and LPS (LPS ≥88 pg/ml and PCSK9 ≥1570 pg/ml) had an increased risk of CVEs compared to those with low levels (LPS <24.3 pg/ml and PCSK9 <1000 pg/ml, Log-Rank test, p = 0.022).

Conclusions: This study demonstrated, for the first time in vivo, that circulating levels of PCSK9 and LPS are associated with a mechanism possibly involving NADPH oxidase activation. Patients with concomitant increase of PCSK9 and LPS showed a higher risk of CVEs.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.07.002DOI Listing
October 2019

Impairment between Oxidant and Antioxidant Systems: Short- and Long-term Implications for Athletes' Health.

Nutrients 2019 06 15;11(6). Epub 2019 Jun 15.

Faculty of Medicine and Surgery, Course E, Sapienza University of Rome, 04100 Latina (LT), Italy.

The role of oxidative stress, an imbalance between reactive oxygen species production (ROS) and antioxidants, has been described in several patho-physiological conditions, including cardiovascular, neurological diseases and cancer, thus impacting on individuals' lifelong health. Diet, environmental pollution, and physical activity can play a significant role in the oxidative balance of an organism. Even if physical training has proved to be able to counteract the negative effects caused by free radicals and to provide many health benefits, it is also known that intensive physical activity induces oxidative stress, inflammation, and free radical-mediated muscle damage. Indeed, variations in type, intensity, and duration of exercise training can activate different patterns of oxidant-antioxidant balance leading to different responses in terms of molecular and cellular damage. The aim of the present review is to discuss (1) the role of oxidative status in athletes in relation to exercise training practice, (2) the implications for muscle damage, (3) the long-term effect for neurodegenerative disease manifestations, (4) the role of antioxidant supplementations in preventing oxidative damages.
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http://dx.doi.org/10.3390/nu11061353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627820PMC
June 2019

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis.

Hepatol Commun 2019 Apr 2;3(4):504-512. Epub 2019 Mar 2.

Department of Internal Medicine and Medical Specialties Sapienza University of Rome Rome Italy.

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the study and 4 healthy subjects (HSs) were entered in the study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; = 0.012) and serum albumin (OR, -0.422; = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand ( = 0.0238), soluble Nox2-derived peptide (sNox2-dp; < 0.0001), and urinary excretion of isoprostanes ( = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD40L (Spearman's rank correlation coefficient [ ], -0.33; < 0.001), sNox2-dp ( , -0.57; < 0.0001), and urinary excretion of isoprostanes ( -0.48; < 0.0001) levels. The study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2α-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation.
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http://dx.doi.org/10.1002/hep4.1317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442692PMC
April 2019

Acute Effects of Heat-Not-Burn, Electronic Vaping, and Traditional Tobacco Combustion Cigarettes: The Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking ( SUR - VAPES ) 2 Randomized Trial.

J Am Heart Assoc 2019 03;8(6):e010455

2 IRCCS NEUROMED Pozzilli Italy.

Background Little clinical research on new-generation heat-not-burn cigarettes ( HNBC ) in comparison with electronic vaping cigarettes ( EVC ) and traditional tobacco combustion cigarettes ( TC ) has been reported. We aimed to appraise the acute effects of single use of HNBC , EVC, and TC in healthy smokers. Methods and Results This was an independent, cross-over, randomized trial in 20 TC smokers, with allocation to different cycles of HNBC , EVC , and TC . All participants used all types of products, with an intercycle washout of 1 week. End points were oxidative stress, antioxidant reserve, platelet activation, flow-mediated dilation, blood pressure, and satisfaction scores. Single use of any product led to an adverse impact on oxidative stress, antioxidant reserve, platelet function, flow-mediated dilation, and blood pressure. HNBC had less impact than EVC and TC on soluble Nox2-derived peptide (respectively, P=0.004 and 0.001), 8-iso-prostaglandin F2α- III ( P=0.004 and <0.001), and vitamin E ( P=0.018 and 0.044). HNBC and EVC were equally less impactful than TCs on flow-mediated dilation ( P=0.872 for HNBC versus EVC ), HO ( P=0.522), HO breakdown activity ( P=0.091), soluble CD 40 ligand ( P=0.849), and soluble P-selectin ( P=0.821). The effect of HNBC and, to a lesser extent EVC , on blood pressure was less evident than that of TC , whereas HNBC appeared more satisfying than EVC (all P<0.05). Conclusions Acute effects of HNBC , EVC, and TC are different on several oxidative stress, antioxidant reserve, platelet function, cardiovascular, and satisfaction dimensions, with TCs showing the most detrimental changes in clinically relevant features. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 03301129.
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http://dx.doi.org/10.1161/JAHA.118.010455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475061PMC
March 2019

Nox2-mediated platelet activation by glycoprotein (GP) VI: Effect of rivaroxaban alone and in combination with aspirin.

Biochem Pharmacol 2019 05 13;163:111-118. Epub 2019 Feb 13.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Mediterranea, Cardiocentro-Napoli, Italy. Electronic address:

Factor Xa (FXa) has been reported to activate platelet via interaction with glycoprotein (GP) VI but the underlying mechanism has not been fully elucidated. We investigated if Nox2-derived oxidative stress is implicated in FXa-induced platelet aggregation (PA), and the effect of a FXa inhibitor, namely rivaroxaban, with or without aspirin (ASA), on PA. We performed an in vitro study measuring convulxin-induced PA, thromboxane (Tx) B and isoprostanes biosynthesis, soluble Nox2-dp (sNox2-dp), a marker of Nox2 activation, soluble GPVI (sGPVI) and PLA activation in platelets from healthy subjects (n = 5) added with and without a Nox2 inhibitor. The same variables were also examined in platelets treated with rivaroxaban (15-60 ng/ml), combined or less with ASA (25 µM). Convulxin-stimulated platelets increased sGPVI, sNox2-dp, HO, eicosanoid biosynthesis and PLA phosphorylation, which were all inhibited by a Nox2 inhibitor. Rivaroxaban alone significantly reduced PA, sGPVI, TxB and isoprostanes biosynthesis, concomitantly with Syk, sNox2-dp and PLA activation in a dose-dependent fashion; a significant effect was achieved with 30 ng/ml rivaroxaban. Docking simulation analysis showed that rivaroxaban interacts with GPVI. In platelets co-incubated with ASA, rivaroxaban amplified the ASA antiplatelet effect, which was achieved with 30 ng/ml and prevalently attributable to Nox2 inhibition and impaired isoprostane biosynthesis. Here we show that rivaroxaban, at concentrations achievable in human circulation, inhibits PA via GPVI interaction and eventually Nox2-mediated isoprostanes biosynthesis and amplifies the ASA antiplatelet effect.
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http://dx.doi.org/10.1016/j.bcp.2019.02.016DOI Listing
May 2019

Dark Chocolate Intake Positively Modulates Redox Status and Markers of Muscular Damage in Elite Football Athletes: A Randomized Controlled Study.

Oxid Med Cell Longev 2018 21;2018:4061901. Epub 2018 Nov 21.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Intensive physical exercise may cause increase oxidative stress and muscular injury in elite football athletes. The aim of this study was to exploit the effect of cocoa polyphenols on oxidative stress and muscular injuries induced by intensive physical exercise in elite football players. Oxidant/antioxidant status and markers of muscle damage were evaluated in 24 elite football players and 15 controls. Furthermore, the 24 elite football players were randomly assigned to either a dark chocolate (>85% cocoa) intake ( = 12) or a control group ( = 12) for 30 days in a randomized controlled trial. Oxidative stress, antioxidant status, and muscle damage were assessed at baseline and after 30 days of chocolate intake. Compared to controls, elite football players showed lower antioxidant power and higher oxidative stress paralleled by an increase in muscle damage markers. After 30 days of dark chocolate intake, an increased antioxidant power was found in elite athletes assuming dark chocolate. Moreover, a significant reduction in muscle damage markers (CK and LDH, < 0.001) was observed. In the control group, no changes were observed with the exception of an increase of sNox2-dp, HO, and myoglobin. A simple linear regression analysis showed that sNox2-dp was associated with a significant increase in muscle damage biomarker release ( = 0.001). An study also confirmed that polyphenol extracts significantly decreased oxidative stress in murine myoblast cell line C2C12-derived. These results indicate that polyphenol-rich nutrient supplementation by means of dark chocolate positively modulates redox status and reduced exercise-induced muscular injury biomarkers in elite football athletes. This trial is registered with NCT03288623.
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http://dx.doi.org/10.1155/2018/4061901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280237PMC
January 2019

Digoxin and Platelet Activation in Patients With Atrial Fibrillation: In Vivo and In Vitro Study.

J Am Heart Assoc 2018 11;7(22):e009509

1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy.

Background Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation ( AF ). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation. Methods and Results Post hoc analysis of a prospective study of anticoagulated patients with AF . Patients were divided into 2 groups balanced for age, sex, and cardiovascular risk factors: digoxin users (n=132) and nonusers (n=388). Urinary excretion of 11-dehydro-thromboxane B (TxB), a marker of platelet activation, and serum digoxin concentration ( SDC ) were measured. In vitro experiments were performed on platelets from healthy subjects and AF patients, which were incubated with scalar doses of digoxin (0.6-2.4 ng/mL) with or without prestimulation with a sub-threshold of collagen. Median 11-dehydro-TxB was 105.0 ( interquartile range, 60.0-190.0) ng/mg creatinine, and median SDC was 0.65 ( interquartile range, 0.40-1.00) ng/mL. Urinary 11-dehydro-TxB and SDC were correlated ( r=0.350, P<0.001). Patients in the upper tertile of SDC showed higher 11-dehydro-TxB compared with non-digoxin users ( P=0.019). In vitro study showed an increased basal platelet activation in patients with AF compared with healthy subjects . Digoxin (2.4 ng/mL) induced calcium mobilization, PAC -1 (procaspase-activating compound 1) and platelet aggregation in AF patients but not in healthy subjects . After pretreatment with a sub-threshold of collagen, digoxin dose-dependent induced calcium mobilization, arachidonic acid release, TxB biosynthesis, PAC -1 and soluble platelet selectin expression, and platelet aggregation, which were inhibited by antibody against digoxin. Conclusions We found a significant in vivo correlation between SDC and platelet activation. Supratherapeutic SDC increased in vitro platelet aggregation via calcium-related phospholipase A phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin.
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http://dx.doi.org/10.1161/JAHA.118.009509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404445PMC
November 2018
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