Publications by authors named "Federico Carbone"

153 Publications

Adiponectin involved in portal flow hepatic extraction of 13C-metacethin in obesity and non-alcoholic fatty liver.

Eur J Intern Med 2021 Apr 15. Epub 2021 Apr 15.

Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari 70124, Italy. Electronic address:

Obesity and non-alcoholic fatty liver disease (NAFLD) are high prevalence, inter-related conditions at increased risk for advanced liver diseases and related mortality. Adiponectin and leptin have divergent roles in the pathogenesis of fat accumulation and NAFLD. However, the relationships between body and liver fat accumulation, early modification of liver function and unbalanced adipokine levels are still scarcely explored. We studied by (13C)-methacetin breath test ((13C)-MBT) 67 adults stratified according to body mass index, and to presence/absence of ultrasonographic nonalcoholic fatty liver disease (uNAFLD). uNAFLD was detected in 20%, 73% and 96% of normal weight, overweight and obese subjects, respectively. The delta over baseline after 15 min (DOB), a marker of hepatic extraction efficiency from portal blood flow, was lower in obese than in normal weight subjects, and in subjects with-, as compared to those without uNAFLD. The cumulative percent dose recovery after 30 min (cPDR), a marker of liver microsomal function, was lower in uNAFLD patients. DOB was positively correlated with adiponectin levels in obese and in uNAFLD patients. uNAFLD patients also showed a positive correlation between cPDR values and adiponectin. Our data indicate the existence of early alterations of liver function in obese and in patients with uNAFLD. These dysfunctions are linked to altered leptin/adiponectin balance and can be identified noninvasively by (13C)-MBT.
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http://dx.doi.org/10.1016/j.ejim.2021.03.036DOI Listing
April 2021

Pharmacological Properties of the Plant-Derived Natural products Cannabinoids and Implications for Cardiovascular Health.

Adv Exp Med Biol 2021 ;1308:249-255

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.

The global march towards legalization of marijuana consumption is pursued in reason of the supposed harmless properties of this plant. Actually, a wide range of cannabinoids is endogenously produced and interacts with different classes of receptors ubiquitously distributed in the human body. Such endocannabinoid system (ECS) modulates several functions in health and disease. However, studies on synthetic ligands with selective agonist/antagonist activity on specific cannabinoid receptors, have clarified how complex the cannabinoid system is. The whole biological activity of cannabis sativa remains difficult to establish, due to the fact that it is a complex mixture of phytocannabinoids with different or even opposing effects. Δ9-tetrahydrocannabinol is the most represented phytocannabinoid in the marijuana plant and then the most studied compound. It has been widely associated with adverse CV effects in marijuana smokers. Conversely, less is known about the role of other phytocannabinoids. Here, we summarized the current knowledge about the effects of phytocannabinoids in CV disease, mainly focusing on atherosclerosis and myocardial infarction. We critically discussed clinical and experimental evidence linking phytocannabinoids to CV disease, attempting at explaining some controversies and suggesting the direction for future studies.
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http://dx.doi.org/10.1007/978-3-030-64872-5_17DOI Listing
April 2021

Cytokines as therapeutic targets for cardio- and cerebrovascular diseases.

Basic Res Cardiol 2021 Mar 26;116(1):23. Epub 2021 Mar 26.

IRCCS Ospedale Policlinico San Martino Genoa, Italian Cardiovascular Network, Genoa, Italy.

Despite major advances in prevention and treatment, cardiac and cerebral atherothrombotic complications still account for substantial morbidity and mortality worldwide. In this context, inflammation is involved in the chronic process leading atherosclerotic plaque formation and its complications, as well as in the maladaptive response to acute ischemic events. For this reason, modulation of inflammation is nowadays seen as a promising therapeutic strategy to counteract the burden of cardio- and cerebrovascular disease. Being produced and recognized by both inflammatory and vascular cells, the complex network of cytokines holds key functions in the crosstalk of these two systems and orchestrates the progression of atherothrombosis. By binding to membrane receptors, these soluble mediators trigger specific intracellular signaling pathways eventually leading to the activation of transcription factors and a deep modulation of cell function. Both stimulatory and inhibitory cytokines have been described and progressively reported as markers of disease or interesting therapeutic targets in the cardiovascular field. Nevertheless, cytokine inhibition is burdened by harmful side effects that will most likely prevent its chronic use in favor of acute administrations in well-selected subjects at high risk. Here, we summarize the current state of knowledge regarding the modulatory role of cytokines on atherosclerosis, myocardial infarction, and stroke. Then, we discuss evidence from clinical trials specifically targeting cytokines and the potential implication of these advances into daily clinical practice.
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http://dx.doi.org/10.1007/s00395-021-00863-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823PMC
March 2021

Circulating Levels of Sclerostin Predict Glycemic Improvement after Sleeve Gastrectomy.

Nutrients 2021 Feb 15;13(2). Epub 2021 Feb 15.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, 6 Viale Benedetto XV, 13132 Genoa, Italy.

Among the different effects of bariatric surgery, here we focus on bone-derived inflammatory molecules, and in particular, sclerostin; an osteocyte product potentially associated with cardio-metabolic diseases. In 94 morbidly obese patients undergoing laparoscopic sleeve gastrectomy (SG), over-time changes in anthropometric and biochemical measures-including insulin resistance (IR) indexes-were correlated with serum sclerostin levels. Sclerostin was positively associated with anthropometric indexes of obesity, and inversely with IR, namely homeostatic model assessment for peripheral insulin sensitivity (HOMA2%S) (r = -0.218; = 0.045). Sclerostin emerged as the only significant predictor of HOMA2-%S normalization, independently of demographic and anthropometric variables (OR 1.01 (95% CI 1.00-1.02); = 0.024). We also identified two distinct patterns of serum sclerostin change: the higher/lower sclerostin levels at baseline, the greater their post-surgical reduction/increase ( < 0.001 for all subgroups). Among those two patterns, especially the post-surgery increase in serum sclerostin was associated with lean mass reduction, without any association with IR indexes. Although counterintuitive, this change was likely dependent on the post-surgical increase in bone turnover. In conclusion, baseline serum levels of sclerostin correlate with anthropometric measures of obesity and IR, and the ability to predict glycemic improvements after SG. Specifically, serum sclerostin was closely associated with peripheral insulin sensitivity (HOMA2-%S), thus supporting the role of skeletal muscle/bone interactions in metabolic diseases.
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http://dx.doi.org/10.3390/nu13020623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918938PMC
February 2021

Relationship between serum myostatin levels and carotid-femoral pulse wave velocity in healthy young male adolescents: the MACISTE study.

J Appl Physiol (1985) 2021 Apr 25;130(4):987-992. Epub 2021 Feb 25.

Department of Medicine, University of Perugia, Perugia, Italy.

Serum myostatin (sMSTN) is a proteic compound that regulates skeletal muscle growth, adipogenesis, and production of extracellular matrix. Its relationship with functional and structural properties of the arterial wall is still understudied. We aimed at evaluating the association between sMSTN and carotid-femoral pulse wave velocity (cf-PWV), a measure of aortic stiffness, in a cohort of healthy male adolescents. Fifteen healthy male adolescents were recruited among the participants of the Metabolic And Cardiovascular Investigation at School, TErni (MACISTE) study, a cross-sectional survey conducted at the "Renato Donatelli" High School in Terni, Italy. sMSTN was measured through enzyme-linked immunosorbent assay. cf-PWV was measured through high-fidelity applanation tonometry. Muscle strength and body composition were measured through handgrip and bioimpedentiometry, respectively. sMSTN levels showed a skewed distribution (median: 6.0 ng/mL, interquartile range: 2.2-69.2 ng/mL). Subjects with sMSTN above median value showed higher values of brachial diastolic blood pressure and increased cf-PWV (6.1 ± 1.1 m/s vs. 4.6 ± 0.7 m/s, < 0.01) values, compared with their counterparts. Such difference remained significant after controlling for age, mean BP, heart rate, body mass index -score, waist-to-height ratio, body mass/lean mass ratio, and amount of physical activity ( = 0.02). The association between log-transformed sMSTN and cf-PWV was direct and linear, and independent from the effect of confounders at the multivariate analysis ( = 0.02). In this preliminary report, sMSTN was independently associated with cf-PWV, a measure of aortic stiffness, in healthy male adolescents. Our results shed lights on the potential role of myokines in the pathogenesis of systemic hypertension and atherosclerosis. Serum myostatin, a proteic compound known to regulate skeletal muscle growth and production of extracellular matrix, is independently associated with increased aortic stiffness in healthy male adolescents. This result sheds lights on the potential novel role of myokines in the early development of systemic hypertension and early vascular aging, as well as on their inhibition as a hypothetical therapeutic strategy to counteract vascular aging at an early stage of physical development.
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http://dx.doi.org/10.1152/japplphysiol.00782.2020DOI Listing
April 2021

Ficolin-2 serum levels predict the occurrence of acute coronary syndrome in patients with severe carotid artery stenosis.

Pharmacol Res 2021 Apr 26;166:105462. Epub 2021 Jan 26.

Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. Electronic address:

Background And Purpose: erosion of vulnerable atherosclerotic plaques may cause life-threatening thromboembolic complications. There is indeed an urgent need to recognize a clear-cut biomarker able to identify vulnerable plaques. Here, we focused on circulating proteins belonging to the lectin pathway (LP) of complement activation.

Methods: we analyzed mannose-binding lectin (MBL), ficolin-1, -2 and -3 (LP initiators) levels by ELISA in sera from n = 240 of an already published cohort of patients undergoing endarterectomy for severe carotid stenosis and followed-up until 18 months after surgery. Immunofluorescence followed by confocal and polarized light microscopy was used to detect LP initiator intraplaque localization. Spearman's rank test was drawn to investigate correlation between serum LP levels and circulating inflammatory proteins or intraplaque components. Survival analyses were then performed to test the predictive role of LP on long-term adverse outcome.

Results: ficolins, but not MBL, correlated positively with 1) high circulating levels of inflammatory markers, including MPO, MMP-8, MMP-9, ICAM-1, osteopontin, neutrophil elastase, and; 2) immune cell intraplaque recruitment. Immunofluorescence showed ficolins in calcified plaques and ficolin-2 in cholesterol-enriched plaque regions in association with macrophages. In the multivariate survival analysis, ficolin-2 serum levels predicted a major adverse cardiovascular event during the follow-up, independently of symptomatic status and inflammatory markers (hazard ratio 38.6 [95 % CI 3.9-385.2]).

Conclusions: ficolins support intraplaque immune cell recruitment and inflammatory processes ultimately leading to plaque vulnerability. Especially for ficolin-2 a strong predictive value toward adverse cardiovascular events was demonstrated. This evidence offers potentially new pharmacological target to dampen the inflammatory mechanisms leading to plaque vulnerability.
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http://dx.doi.org/10.1016/j.phrs.2021.105462DOI Listing
April 2021

Diabetic cardiomyopathy and inflammation: development of hostile microenvironment resulting in cardiac damage.

Minerva Cardioangiol 2021 Jan 11. Epub 2021 Jan 11.

IRCCS Ospedale Policlinico San Martino Genoa, Italian Cardiovascular Network, Genoa, Italy -

Diabetes mellitus is emerging as a major risk factor for heart failure. Diabetic cardiomyopathy is defined as a myocardial dysfunction that is not caused by underlying hypertension or coronary artery disease. Studies about clinical features, natural history and outcomes of the disease are few and often conflicting, because a universally accepted operative definition of diabetic cardiomyopathy is still lacking. Hyperglycemia and related metabolic and endocrine disorders are the triggering factors of myocardial damage in diabetic cardiomyopathy through multiple mechanisms. Among these mechanisms, inflammation has a relevant role, similar to other chronic myocardial disease, such as hypertensive or ischemic heart disease. A balance between inflammatory damage and healing processes is fundamental for homeostasis of myocardial tissue, whereas diabetes mellitus produces an imbalance, promoting inflammation and delaying healing. Therefore, diabetes-related chronic inflammatory state can produce a progressive qualitative deterioration of myocardial tissue, which reflects on progressive left ventricular functional impairment, which can be either diastolic, with prevalent myocardial hypertrophy, or systolic, with prevalent myocardial fibrosis. The aim of this narrative review is to summarize the existing evidence about the role of inflammation in diabetic cardiomyopathy onset and development. Ultimately, potential pharmacological strategies targeting inflammatory response will be reviewed and discussed.
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http://dx.doi.org/10.23736/S0026-4725.20.05454-7DOI Listing
January 2021

Impaired Inhibitory Control of Saccadic Eye Movements in Cervical Dystonia: An Eye-Tracking Study.

Mov Disord 2021 Jan 8. Epub 2021 Jan 8.

Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

Background: The pathophysiology of cervical dystonia is still unclear. Recent evidence points toward a network disorder affecting several brain areas. The objective of this study was to assess the saccadic inhibition as a marker of corticostriatal function in cervical dystonia.

Methods: We recruited 31 cervical dystonia patients and 17 matched healthy controls. Subjects performed an overlap prosaccade, an antisaccade, and a countermanding task on an eye tracker to assess automatic visual response and response inhibition.

Results: Cervical dystonia patients made more premature saccades (P = 0.041) in the overlap prosaccade task and more directional errors in the antisaccade task (P = 0.011) and had a higher rate of failed inhibition in the countermanding task (P = 0.001).

Conclusions: The results suggest altered saccadic inhibition in cervical dystonia, possibly as a consequence of dysfunctional corticostriatal networks. Further studies are warranted to confirm whether these abnormalities are affected by the available therapies and whether this type of impairment is found in other focal dystonias. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28486DOI Listing
January 2021

Updating concepts on atherosclerotic inflammation: From pathophysiology to treatment.

Eur J Clin Invest 2021 May 24;51(5):e13467. Epub 2021 Feb 24.

Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa, Genoa, Italy.

Background: Atherosclerosis is recognized as a systemic low-grade inflammatory disease. Furthermore, the dysregulation of the inflammatory response and its timely resolution is a pivotal process in determining the clinical manifestations of cardiac and cerebral acute ischaemia following atherothrombosis.

Methods: This narrative review is based on the material searched on PubMed up to October 2020. The search terms we used were as follows: "atherosclerosis, inflammation, acute myocardial infarction and ischemic stroke" in combination with "biomarker, inflammatory cells and molecules, treatment."

Results: The expected goal of addressing inflammation for the treatment of atherosclerosis and its acute ischaemic complications is reducing mortality and morbidity related to atherosclerotic cardiovascular disease, which are currently the first cause of death and disability worldwide. In this narrative review, we summarize the evidence about the main cellular and molecular mechanisms of inflammation in atherogenesis, atherothrombosis and acute ischaemic complications, with particular focus on the potential molecular targets for novel pharmacological treatments.

Conclusion: Although a large amount of evidence from animal models of atherothrombotic disease, and promising results of clinical trials, anti-inflammatory treatments against atherosclerosis are not yet recommended. A deepest understanding of pathophysiological mechanisms underlying the mechanisms driving resolution of the acute inflammation will probably allow to identify the optimal molecular target.
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http://dx.doi.org/10.1111/eci.13467DOI Listing
May 2021

The role of potassium in atherosclerosis.

Eur J Clin Invest 2021 Mar 27;51(3):e13454. Epub 2020 Nov 27.

Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Atherosclerosis (AS) is a chronic progressive inflammatory condition with a leading prevalence worldwide. Endothelial dysfunction leads to low-density lipoprotein trafficking into subendothelial space and the subsequent form of oxidized LDL (ox-LDL) within intimal layer, perpetuating the vicious cycle of endothelial dysfunction. K+ exerts beneficial effects in vascular wall by reducing LDL oxidization, vascular smooth muscle cells (VSMCs) proliferation, and free radical generation. K+ also modulates vascular tone through a regulatory effect on cell membrane potential.

Materials And Methods: The most relevant papers on the association between 'potassium channels' and 'atherosclerosis' were selected among those deposited on PubMed from 1990 to 2020.

Results: Here, we provide a short narrative review that elaborates on the role of K+ in atherosclerosis. This review also update the current knowledge about potential pharmacological agents targeting K+ channels with a special focus on pleiotropic activities of agents such as statins, sulfonylureas and dihydropyridines.

Conclusion: In this review, the mechanism of different K+ channels on vascular endothelium will be summarized, mainly focusing on their pathophysiological role in atherosclerosis and potential therapeutic application.
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http://dx.doi.org/10.1111/eci.13454DOI Listing
March 2021

Atherosclerotic plaque vulnerability is increased in mouse model of lupus.

Sci Rep 2020 10 27;10(1):18324. Epub 2020 Oct 27.

Division of Cardiology, Foundation for Medical Researches, Department of Medicine Specialties, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1211, Geneva 4, Switzerland.

Anti-apolipoprotein A-1 (anti-apoA-1 IgG) and anti-double stranded DNA (anti-dsDNA IgG) autoantibodies have been described as mediators of atherogenesis in mice and humans. In the present study, we aim to investigate the association between atherosclerotic parameters, autoantibodies and plaque vulnerability in the context of systemic lupus erythematosus (SLE). We therefore bred a lupus prone-mouse model (Nba2.Yaa mice) with Apoe mice resulting in ApoeNba2.Yaa mice spontaneously producing anti-apoA-1 IgG antibodies. Although ApoeNba2.Yaa and Apoe mice subject to a high cholesterol diet displayed similar atherosclerosis lesions size in aortic roots and abdominal aorta, the levels of macrophage and neutrophil infiltration, collagen, MMP-8 and MMP-9 and pro-MMP-9 expression in ApoeNba2.Yaa mice indicated features of atherosclerotic plaque vulnerability. Even though ApoeNba2.Yaa mice and Apoe mice had similar lipid levels, ApoeNba2.Yaa mice showed higher anti-apoA-1 and anti-dsDNA IgG levels. ApoeNba2.Yaa mice displayed a reduction of the size of the kidney, splenomegaly and lymph nodes (LN) hypertrophy. In addition, anti-apoA-1 and anti-dsDNA IgG increased also in relation with mRNA levels of GATA3, IL-4, Bcl-6 and CD20 in the spleen and aortic arch of ApoeNba2.Yaa mice. Our data show that although atherosclerosis-lupus-prone ApoeNba2.Yaa mice did not exhibit exacerbated atherosclerotic lesion size, they did show features of atherosclerotic plaque destabilization in correlation with the increase of pro-atherogenic autoantibodies.
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http://dx.doi.org/10.1038/s41598-020-74579-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591560PMC
October 2020

Anti-Apolipoprotein A-1 IgG Influences Neutrophil Extracellular Trap Content at Distinct Regions of Human Carotid Plaques.

Int J Mol Sci 2020 10 19;21(20). Epub 2020 Oct 19.

Division of Cardiology, Foundation for Medical Researches, Department of Medicine Specialties, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1211 Geneva, Switzerland.

Background: Neutrophils accumulate in atherosclerotic plaques. Neutrophil extracellular traps (NET) were recently identified in experimental atherosclerosis and in complex human lesions. However, not much is known about the NET marker citrullinated histone-3 (H3Cit) expression and functionality in human carotid plaques. Moreover, the association between the proatherosclerotic autoantibody anti-apolipoprotein A-1 (anti-ApoA-1 IgG) and NET has never been investigated.

Methods: Atherosclerotic plaques have been obtained from 36 patients with severe carotid stenosis that underwent carotid endarterectomy for severe carotid stenosis. Samples were sectioned into upstream and downstream regions from the same artery segment. Plaque composition and expression of NET markers neutrophil elastase (NE) and H3Cit were quantified by immunohistochemistry. H3Cit expression and function was evaluated by immunofluorescence and confocal analysis in a subset of patients.

Results: Pathological features of vulnerable phenotypes were exacerbated in plaques developed at downstream regions, including higher accumulation of neutrophils and enhanced expression of NE and H3Cit, as compared to plaques from upstream regions. The H3Cit signal was also more intense in downstream regions, with significant extracellular distribution in spaces outside of neutrophils. The percentage of H3Cit colocalization with CD66b (neutrophils) was markedly lower in downstream portions of carotid plaques, confirming the extrusion of NET in this region. In agreement, the maximum distance of the H3Cit signal from neutrophils, extrapolated from vortex distance calculation in all possible directions, was also higher in downstream plaques. The serum anti-ApoA-1index positively correlated with the expression of H3Cit in downstream segments of plaques. Expression of the H3Cit signal outside of neutrophils and H3Cit maximal distance from CD66b-positive cells increased in plaques from serum positive anti-ApoA-1 patients compared with serum negative patients.

Conclusion: NET elements are differentially expressed in upstream versus downstream regions of human carotid plaques and may be influenced by circulating levels of anti-ApoA-1 IgG. These findings could warrant the investigation of NET elements as potential markers of vulnerability.
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http://dx.doi.org/10.3390/ijms21207721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588926PMC
October 2020

Emerging role for the inflammatory biomarker osteopontin in adverse cardiac remodeling.

Biomark Med 2020 10 15;14(14):1303-1306. Epub 2020 Oct 15.

First Clinic of internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.

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http://dx.doi.org/10.2217/bmm-2020-0455DOI Listing
October 2020

Recombinant Tissue Plasminogen Activator (r-tPA) Induces In-Vitro Human Neutrophil Migration via Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1).

Int J Mol Sci 2020 Sep 23;21(19). Epub 2020 Sep 23.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.

Thrombolysis is the gold standard treatment for acute ischemic stroke. Besides its fibrinolytic role, recombinant tissue plasminogen activator (r-tPA) holds several non-fibrinolytic functions. Here, we investigated the potential role of r-tPA on human primary neutrophil migration in vitro. By means of modified Boyden chamber migration assay and checkerboard analysis we showed a dose-dependent chemotactic effect of r-TPA with a maximum effect reached by 0.03 mg/mL (0.003-1 mg/mL). Pre-incubation with MAP kinases inhibitors allowed the identification of PI3K/Akt, but not ERK1/2 as the intracellular pathway mediating the observed effects. Furthermore, by means of real-time PCR, immunocytochemistry and cytofluorimetry we demonstrated that the r-tPA receptor low density lipoprotein receptor-related protein 1 (LRP-1) is synthetized and expressed by neutrophils in response to r-tPA and TNF-α. Inhibition of LRP-1 by receptor-associated protein (RAP), prevented r-tPA-mediated F-actin polymerization, migration and signal through Akt but not ERK1/2. Lastly, also neutrophil degranulation in response to r-tPA seems to be mediated by LRP-1 under adhesion conditions. In conclusion, we show that r-tPA induces neutrophil chemotaxis through LRP-1/Akt pathway. Blunting r-tPA-mediated neutrophil activation might be beneficial as an adjuvant therapy to thrombolysis in this setting.
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http://dx.doi.org/10.3390/ijms21197014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582901PMC
September 2020

Anti-ApoA-1 IgGs predict resistance to waist circumference reduction after Mediterranean diet.

Eur J Clin Invest 2021 Mar 27;51(3):e13410. Epub 2020 Sep 27.

Clinica Medica "A. Murri", Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy.

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http://dx.doi.org/10.1111/eci.13410DOI Listing
March 2021

Serum osteopontin predicts glycaemic profile improvement in metabolic syndrome: A pilot study.

Eur J Clin Invest 2021 Mar 25;51(3):e13403. Epub 2020 Sep 25.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.

Prediabetes is often observed in patients with Metabolic Syndrome (MetS) and might be associated with metabolic and inflammatory alterations. Here, we investigated whether the inflammatory molecule osteopontin (OPN) might have a prognostic impact in a cohort of MetS patients (n = 85) with baseline normal glycaemia or impaired fasting glucose (IFG) over one year of recommended pharmacological treatments and Mediterranean diet. Patients were then followed up for 12 months with intermediate evaluation after 6 months. At all time points, anthropometric and clinical data were recorded, alongside with haematological and biochemical profiles, including serum concentrations of OPN. As expected, Mediterranean diet improves glycaemic profile in patients with IFG. Baseline serum OPN failed to be associated with baseline anthropometric or biochemical variables. At baseline, higher levels of OPN were shown in patients with IFG as compared to normal glycaemia. Two distinct subgroups of patients in whom OPN decreased or remained stable/increased at follow-up were identified. When higher serum OPN levels were observed at baseline, greater reduction was observed at 1-year follow-up. Reduction in circulating OPN levels was associated with metabolic improvement in terms of blood pressure, LDL-c, HDL-c, and glycaemia. At both univariate and adjusted logistic regression analyses, serum OPN emerged as an independent predictor of glycaemic profile improvement at 1-year follow-up (adjOR 1.05 [1.00-1.10]; P = .041). In conclusion, pharmacological and dietetic interventions improved glycaemic profile in patients with MetS. In particular, glycaemic improvement was demonstrated in patients who also reduce circulating OPN levels. Higher OPN levels at baseline predict normalization of glycaemic profile.
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http://dx.doi.org/10.1111/eci.13403DOI Listing
March 2021

Statins: Epidrugs with effects on endothelial health?

Eur J Clin Invest 2020 Dec 13;50(12):e13388. Epub 2020 Sep 13.

Halal Research Center of IRI, FDA, Tehran, Iran.

Background: Epigenetic events involving the methylation of CpG cites in DNA, histone modifications and noncoding RNAs correlated with many essential processes in human cells and diseases, such as cancer and cardiovascular diseases. HMG-CoA reductase inhibitors (statins)-the LDL cholesterol-lowering drugs-are broadly used in cardio- and cerebro-vascular diseases. It is well established that statins exert pleiotropic functions, but how they exert effects on epigenetic modifications independently of HMG-CoA reductase inhibition is not yet clear. Thereby, understanding these mechanisms may pave the way for further clinical application of statin therapy.

Design: Following and electronic database search, studies reporting substantial effects of statins on epigenetic reprogramming in both cultured cells and in vivo models were retrieved and reviewed.

Results: Epigenetic mechanisms play an essential role in cellular development and function, and data collected in the past few years have revealed that many of the pleiotropic properties of statins are mediated by epigenetic mechanisms. Furthermore, those 'nonclassical' effects are not limited to CV field but they would extend to other conditions such as malignancies.

Conclusion: This review suggests that the epigenetic effects of statins mediate, at least in part, the pleiotropic actions of these drugs but further validation of such effects in clinical studies is yet to be provided.
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http://dx.doi.org/10.1111/eci.13388DOI Listing
December 2020

Non-Motor Symptoms in Parkinson's Disease are Reduced by Nabilone.

Ann Neurol 2020 10 31;88(4):712-722. Epub 2020 Aug 31.

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

Objective: The objective of this study was to assess the efficacy and safety of nabilone, a synthetic tetrahydrocannabinol analogue, as a treatment for non-motor symptoms (NMS) in Parkinson's disease (PD).

Methods: This was a phase II placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal trial conducted at the Medical University Innsbruck. A random sample of 47 patients with PD with stable motor disease and disturbing NMS defined by a score of ≥4 points on the Movement Disorder Society - Unified PD Rating Scale-I (MDS-UPDRS-I) underwent open-label nabilone titration (0.25 mg once daily to 1 mg twice daily, phase I). Responders were randomized 1:1 to continue with nabilone or switch to placebo for 4 weeks (phase II). The primary efficacy criterion was the change of the MDS-UPDRS-I between randomization and week 4. Safety was analyzed in all patients who received at least one nabilone dose.

Results: Between October 2017 and July 2019, 19 patients received either nabilone (median dose = 0.75 mg) or placebo. At week 4, mean change of the MDS-UPDRS-I was 2.63 (95% confidence interval [CI] 1.53 to 3.74, p = 0.002, effect size = 1.15) in the placebo versus 1.00 (95% CI -0.16 to 2.16, p = 0.280, effect size = 0.42) in the nabilone-group (difference: 1.63, 95% CI 0.09 to 3.18, p = 0.030, effect size = 0.66). Seventy-seven percent of patients had adverse events (AEs) during open-label titration, most of them were transient. In the double-blind phase, similar proportions of patients in each group had AEs (42% in the placebo group and 32% in the nabilone group). There were no serious AEs.

Interpretation: Our results highlight the potential efficacy of nabilone for patients with PD with disturbing NMS, which appears to be driven by positive effects on anxious mood and night-time sleep problems.

Trial Registry: ClinicalTrials.gov (NCT03769896) and EudraCT (2017-000192-86). ANN NEUROL 2020;88:712-722.
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http://dx.doi.org/10.1002/ana.25864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540547PMC
October 2020

Supremacy of echocardiography in the diagnostic workup of systemic AL amyloidosis.

Eur Heart J 2020 09;41(36):3487

Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - IRCCS Italian Cardiovascular Network, Genoa, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehaa535DOI Listing
September 2020

Inflammatory Biomarkers for Cardiovascular Risk Stratification in Familial Hypercholesterolemia.

Rev Physiol Biochem Pharmacol 2020 ;177:25-52

Halal Research Center of IRI, FDA, Tehran, Iran.

Familial hypercholesterolemia (FH) is a frequent autosomal genetic disease characterized by elevated concentrations of low-density lipoprotein cholesterol (LDL) from birth with increased risk of premature atherosclerotic complications. Accumulating evidence has shown enhanced inflammation in patients with FH. In vessels, the deposition of modified cholesterol lipoproteins triggers local inflammation. Then, inflammation facilitates fatty streak formation by activating the endothelium to produce chemokines and adhesion molecules. This process eventually results in the uptake of vascular oxidized LDL (OxLDL) by scavenger receptors in monocyte-derived macrophages and formation of foam cells. Further leukocyte recruitment into the sub-endothelial space leads to plaque progression and activation of smooth muscle cells proliferation. Several inflammatory biomarkers have been reported in this setting which can be directly synthetized by activated inflammatory/vascular cells or can be indirectly produced by organs other than vessels, e.g., liver. Of note, inflammation is boosted in FH patients. Inflammatory biomarkers might improve the risk stratification for coronary heart disease and predict atherosclerotic events in FH patients. This review aims at summarizing the current knowledge about the role of inflammation in FH and the potential application of inflammatory biomarkers for cardiovascular risk estimation in these patients.
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http://dx.doi.org/10.1007/112_2020_26DOI Listing
January 2021

Dysfunctional high-density lipoprotein: the role of myeloperoxidase and paraoxonase-1.

Curr Med Chem 2020 Jul 15. Epub 2020 Jul 15.

Halal Research Center of IRI, FDA, Tehran. Iran.

Low circulating high-density lipoproteins (HDL) are not only a defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte-derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation, and then acts as a protective factor against ASCVD. Noteworthy, recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview on in vitro and experimental animal models, finally focusing on clinical evidence from cohort of patients with ASCVD and metabolic syndrome.
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http://dx.doi.org/10.2174/0929867327999200716112353DOI Listing
July 2020

The role of resistin and myeloperoxidase in severe sepsis and septic shock: Results from the ALBIOS trial.

Eur J Clin Invest 2020 Oct 13;50(10):e13333. Epub 2020 Jul 13.

IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Genoa, Italy.

Background: Inflammatory biomarkers are useful in detecting patients with sepsis. The prognostic role of resistin and myeloperoxidase (MPO) has been investigated in sepsis.

Materials And Methods: Plasma resistin and MPO were measured on days 1, 2 and 7 in 957 patients enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. The association between resistin and MPO levels on day 1, 2 and 7 and 90-day mortality was assessed.

Results: Plasma resistin and MPO concentrations were higher at day 1 and decreased until day 7. Both biomarkers were positively correlated with each other and with physiological parameters. Higher levels of resistin and MPO on day 1 were associated with the development of new organ failures. Patients experiencing death at 90 days showed higher levels of resistin and MPO compared with survivors. At day 1, only MPO in the 4th quartile (Q4), but not resistin, was found to predict 90-day death (adjusted hazard ratio [aHR] 1.55 vs Q1). At day 2, resistin in the Q3 and Q4 predicted a > 40% increase in mortality as also did MPO in the Q4. On day 7, Q4 resistin was able to predict 90-day mortality, while all quartiles of MPO were not.

Conclusions: High levels of MPO, but not of resistin, on day 1 were able to predict 90-day mortality. These findings may either suggest that early hyper-activation of neutrophils is detrimental in patients with sepsis or reflect the burden of the inflammatory process caused by sepsis. Further studies are warranted to deepen these aspects (ALBIOS ClinicalTrials.gov Identifier: NCT00707122).
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http://dx.doi.org/10.1111/eci.13333DOI Listing
October 2020

SARS-CoV-2: What is known and what there is to know-Focus on coagulation and lipids.

Eur J Clin Invest 2020 Jul 25;50(7):e13311. Epub 2020 Jun 25.

Department of Endocrinology, Diabetology and Metabolic Diseases, Faculty of Medicine and Health Sciences, Deurne/Antwerp University of Antwerp, Antwerp, Belgium.

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http://dx.doi.org/10.1111/eci.13311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300477PMC
July 2020

SARS-CoV-2 outbreak and lockdown in a Northern Italy hospital. Comparison with Scandinavian no-lockdown country.

Eur J Clin Invest 2020 Jun 7:e13302. Epub 2020 Jun 7.

IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy.

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http://dx.doi.org/10.1111/eci.13302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300436PMC
June 2020

Serum adiponectin levels are associated with presence of carotid plaque in women with systemic lupus erythematosus.

Nutr Metab Cardiovasc Dis 2020 06 27;30(7):1147-1151. Epub 2020 Mar 27.

IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy.

Background And Aim: Systemic lupus erythematosus (SLE) is associated with accelerated atherogenesis. Traditional risk factors do not seem to fully explain this process in patients with SLE and no other imaging/serum biomarkers have so far improved risk stratification. Here, we focused on the role of adiponectin in women with SLE.

Methods And Results: This is a sub-analysis of a validated cohort enrolling eighty females (age 18-65 years) affected by SLE. Patient underwent a single blood sampling and carotid echography. Serum adipocytokines (i.e. leptin, resistin and adiponectin) were assessed by enzyme-linked immunosorbent assay (ELISA). Patients with a carotid plaque (n = 23) were older, with longer duration of the disease, chronic use of corticosteroids, and immunosuppressive therapies. As expected, patients with a carotid plaque had increased vascular risk and high serum levels of inflammatory biomarkers, total and LDL cholesterol and adiponectin. Significant positive correlation between serum adiponectin and presence of a carotid plaque was found independently of patient age, SCORE Risk Charts, duration of disease, and SLE treatments.

Conclusions: These results indicate that high serum adiponectin is associated with accelerated carotid atherosclerosis in SLE young women and it might be useful to improve vascular risk stratification in this patient setting.
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http://dx.doi.org/10.1016/j.numecd.2020.03.020DOI Listing
June 2020

Early osteopontin levels predict mortality in patients with septic shock.

Eur J Intern Med 2020 08 11;78:113-120. Epub 2020 May 11.

IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy; First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.

Background: Inflammatory biomarkers could be useful to stratify the risk of sepsis adverse outcome and potentially improving the clinical management. Here, we investigated the prognostic role of the inflammatory molecule osteopontin (OPN) in patients with severe sepsis with and without septic shock.

Material And Methods: This is a sub-analysis of 957 patients with sepsis/septic shock from the Albumin Italian Outcome Sepsis (ALBIOS) study. Alongside demographic, clinical, and laboratory data, we assessed plasmatic values of OPN at day 1, 2 and 7 after enrolment. The primary outcome was the predictive role of OPN values at day 1on death for any cause at 28 days after enrolment.

Results: Plasma OPN values at day 1 were higher in patients with septic shock and correlated with the severity of multi-organ dysfunction. Once categorized for 28-day mortality, survivors were characterized by lower OPN levels at each time point and statistically significant drop overtime (p<0.001 for all). Similarly, OPN reduction during the first 7 days was associated with reduced hospitalization and mortality overtime. Multivariate logistic and Cox regression models confirmed plasma OPN at day 1 as predictor of both 28- and 90-day mortality and infection resolution as well, independently of demographic, clinical and therapeutic variables. However, this prognostic value was limited to septic shock patients.

Conclusions: In patients with septic shock, OPN plasma levels at day 1 predict a poor clinical outcome. These results provide the rationale for future pathophysiological studies aimed at clarifying the mechanisms triggered by OPN in septic shock (ALBIOS ClinicalTrials.gov Identifier: NCT00707122).
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http://dx.doi.org/10.1016/j.ejim.2020.04.035DOI Listing
August 2020

Epigenetics in atherosclerosis: key features and therapeutic implications.

Expert Opin Ther Targets 2020 08 1;24(8):719-721. Epub 2020 Jun 1.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences , Mashhad, Iran.

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http://dx.doi.org/10.1080/14728222.2020.1764535DOI Listing
August 2020

Plaque vulnerability and adverse outcomes: The long road to fight atherosclerosis.

Eur J Clin Invest 2020 06 15;50(6):e13253. Epub 2020 May 15.

IRCCS Ospedale Policlinico San Martino Genova - Italian Cardiovascular Network, Genoa, Italy.

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http://dx.doi.org/10.1111/eci.13253DOI Listing
June 2020

Macrophages in the pathophysiology of NAFLD: The role of sex differences.

Eur J Clin Invest 2020 Jun 15;50(6):e13236. Epub 2020 May 15.

IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy.

Nonalcoholic fatty liver disease (NAFLD) is a multifactorial pathological condition, which recognizes a certain sexual dimorphism. Experimental and clinical studies provided evidence for a critical role of macrophages in NAFLD development and progression. Especially, liver-resident macrophages (also known as Kupffer cells) are likely the common final pathway of several pro-steatosic signals. A huge amount of danger-associated molecular patterns recognized by Kupffer cells is provided within the liver by lipid and glucose toxicity. Other pro-inflammatory signals come from surrounding tissues into the portal vein, directly to the liver: they come from dysfunctional adipocytes, adipose tissue macrophages and gut dysbiosis. These complex crosstalks are differently represented across sexes, as sexual hormones control many of these processes. Sexual dimorphism then modulates metabolic and inflammatory cascades driving the liver from a simple steatosis to NAFLD and beyond. Here, metabolic and inflammatory mechanisms underlying NALFD pathophysiology will be updated. A special attention will be paid to describe sex-related differences that could provide insights for patient stratification and more tailored therapeutic approaches.
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http://dx.doi.org/10.1111/eci.13236DOI Listing
June 2020