Ilaria Zanotti

• University of Parma

In the present study, we investigated the potential biological effects of proteins and peptides extracted from four different commercial quinoa grain varieties: Black (B), Red (R), White (W), and Royal White (RO), using Caco‐2 cells as a proliferation model. Concentration–response curves were constructed to evaluate cytotoxicity and antiproliferati...

Background: Alzheimer’s disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other...

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the...

Despite significant therapeutic advancements, morbidity and mortality following myocardial infarction (MI) remain unacceptably high. This clinical challenge is primarily attributed to two significant factors: delayed reperfusion and the myocardial injury resulting from coronary reperfusion. Following reperfusion, there is a rapid intracellular pH s...

Aim: Impairment of cholesterol homeostasis is one of the multiple etiopathological mechanisms at the origin of both cardiovascular and neurodegenerative diseases. The PCSK9 protein, known for its role in the degradation of hepatic LDLR and plasma cholesterol regulation, is expressed also in the CNS, where it exacerbates -amyloid neurotoxicity and...

In tumors, the multi drug resistance phenomenon may occur through the efflux of chemotherapeutic drugs out of cancer cells, impeding their accumulation, and eventually reducing their toxicity. This process is mediated by transporters overexpressed in the plasma membranes of tumor cells, among which is the P-glycoprotein/multidrug resistance 1/ATP-b...

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder associated with pulmonary emphysema and bronchiectasis. Its management currently consists of weekly infusions of plasma-purified human AAT, which poses several issues regarding plasma supplies, possible pathogen transmission, purification costs, and parenteral administration. Here, we inves...

High-density lipoproteins (HDLs) represent physiological carriers of lipids and proteins, the activity of which has been related to cardiovascular health for decades [...]

The ability to accept cholesterol from cells and to promote reverse cholesterol transport (RCT) represents the best characterized antiatherogenic function of HDL. Studies carrying out in animal models have unraveled the multiple mechanisms by which these lipoproteins drive cholesterol efflux from macrophages and cholesterol uptake to the liver. Mor...

Background and aims Cholesterol efflux capacity is a functional property of high-density lipoproteins (HDL) reflecting the efficiency of the atheroprotective reverse cholesterol transport process in humans. Its relationship with calcific aortic valve stenosis (CAVS) has not been fully assessed yet. Methods We evaluated HDL-CEC in a patient populat...

Reverse cholesterol transport (RCT) is a physiological mechanism protecting cells from an excessive accumulation of cholesterol. When this process begins in vascular macrophages, it acquires antiatherogenic properties, as has been widely demonstrated in animal models. Dietary lipids, despite representing a fundamental source of energy and exerting...

High density lipoproteins (HDLs) are commonly known for their anti-atherogenic properties that include functions such as the promotion of cholesterol efflux and reverse cholesterol transport, as well as antioxidant and anti-inflammatory activities. However, because of some chronic inflammatory diseases, such as type 2 diabetes mellitus (T2DM), sign...

Patients with type 2 diabetes mellitus (T2DM) remain at increased cardiovascular residual risk and endothelial dysfunction, even after optimizing metabolic control and treatment by sodium-glucose-2 transporter inhibitors (SGLT2-is). The present study was based on the hypothesis that proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9i) therap...

Background: The investigation of the interactions between cells and active materials is pivotal in the emerging 3D printing-biomaterial application fields. Here, lipidomics has been used to explore the early impact of alginate (ALG) hydrogel architecture (2D films or 3D printed scaffolds) and the type of gelling agent (CaCl2 or FeCl3) on the lipid...

Here, a formulation of silver nanoparticles (AgNPs) and two natural polymers such as alginate (ALG) and nanocrystalline cellulose (CNC) was developed for the 3D printing of scaffolds with large surface area, improved mechanical resistance and sustained capabilities to promote antimicrobial and cytotoxic effects. Mechanical resistance, water content...

The Eph-ephrin is a cell-cell communication system generating a forward signal in cell expressing Eph receptors and a reverse signal in ephrin-ligand expressing cells. While clearly involved in the insurgence and progression of cancer, the understanding of the molecular mechanisms regulated by this system needs development; this is a hurdle to the...

Background and aim: Obesity-related decline in high-density lipoprotein (HDL) functions such as cholesterol efflux capacity (CEC) has supported the notion that this lipoprotein dysfunction may contribute for atherogenesis among obese patients. We investigated if potentially other HDL protective actions may be affected with weight gain and these ch...

Objective: Obesity-related decline in high-density lipoprotein (HDL) functions such as cholesterol efflux capacity (CEC) has supported the notion that this lipoprotein dysfunction may contribute for atherogenesis among obese patients. Besides, potentially other HDL protective actions may be affected with weight gain and these changes may occur even...

Despite decades of therapeutic advances, myocardial infarction remains a leading cause of death worldwide. Recent studies have identified HDLs (high-density lipoproteins) as a potential candidate for mitigating coronary ischemia/reperfusion injury via a broad spectrum of signaling pathways. HDL ligands, such as S1P (sphingosine-1-phosphate), Apo (a...

It is now apparent that a variety of deleterious mechanisms intrinsic to myocardial infarction (MI) exists and underlies its high residual lethality. Indeed, despite effective coronary patency therapies, ischemia and reperfusion (I/R) injury accounts for about 50% of the infarcted mass. In this context, recent studies in animal models have demonstr...

Several studies have demonstrated that polyphenol-enriched diets may have beneficial effects against the development of degenerative diseases, including atherosclerosis and disorders affecting the central nervous system. This activity has been associated not only with antioxidant and anti-inflammatory properties, but also with additional mechanisms...

The reduction of plasma apolipoprotein B (apoB) containing lipoproteins has long been pursued as the main modifiable risk factor for the development of cardiovascular disease (CVD). This has led to an intense search for strategies aiming at reducing plasma apoB-lipoproteins, culminating in reduction of overall CV risk. Despite 3 decades of progress...

It has been well established that moderate alcohol consumption inversely correlates with cardiovascular morbidity and mortality, whereas binge alcohol drinking increases cardiovascular disease risk. The aim of this study was to assess in vivo the impact of different drinking patterns on reverse cholesterol transport (RCT); the atheroprotective proc...

The development of nutraceutical ingredients has risen as a nutritional solution for health prevention. This study evaluated the effects of Oleactiv®, an ingredient developed for the prevention of atherogenesis, in hypercholesterolemic hamsters. Oleactiv® is a polyphenol-rich ingredient obtained from artichoke, olive and grape extracts as part of f...

Aim: Traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Serum cholesterol efflux capacity (CEC) is an atheroprotective function of HDL recently identified as a novel marker of CVD risk. We evaluated the association between serum CEC and atherosclerotic burden or telomer...

Aim: Traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Serum cholesterol efflux capacity (CEC) is an atheroprotective function of HDL recently identified as a novel marker of CVD risk. We evaluated the association between serum CEC and atherosclerotic burden or telomer...

Background: Aortic valve calcification (AVC) is one of the most common form of heart valve disease and affects 3% of the population. No pharmacological treatments have been identified yet; however, proprotein convertase subtisilin kexin type 9 (PCSK9) inhibitors have been proposed to reduce AVC progression. We aimed to evaluate the role of PCSK9 in...

Several studies revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic...

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elic...

Trimethylamine-N-oxide (TMAO) is a small organic molecule, derived from the intestinal and hepatic metabolism of dietary choline and carnitine. Although the involvement of TMAO in the framework of many chronic diseases has been recently described, no evidence on its putative role in the central nervous system has been provided. The aim of this stud...

It is well established that the Eph/ephrin system plays a central role in the embryonic development, with minor implications in the physiology of the adult. However, it is overexpressed and deregulated in a variety of tumors, with a primary involvement in tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration....

Scope: Consumption of products rich in flavan-3-ols, such as tea and cocoa, has been associated with decreased obesity, partially dependent on their capacity to enhance energy expenditure. Despite these phenolics having been reported to increase the thermogenic program in brown and white adipose tissue, flavan-3-ols are vastly metabolised in vivo...

Metadynamics (META-D) is currently emerging as a powerful method for the efficient computation of multidimensional free-energy surfaces describing the protein-ligand binding process. The knowledge of this surface is potentially critical in lead optimization campaign, as it can elucidate the mechanism of action of a small molecule at its receptor pr...

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) may have extra-hepatic effects on cholesterol homeostasis of vascular macrophages. In this study, we aimed to investigate PCSK9 role on the anti-atherogenic process of ATP binding cassette transporter A1 (Abca1)-mediated cholesterol efflux. Methods: Abca1-mediated cholest...

Gut microbiota is a very interesting, yet largely unexplored ecosystem inside the human body. Its importance for the pathophysiology of atherosclerosis is being unraveled by recent studies, demonstrating dual effects on the development of atherosclerotic plaque. On one hand, commensal bacteria may exert deleterious activity by increasing risk facto...

Both alterations of lipid/lipoprotein metabolism and inflammatory events contribute to the formation of the atherosclerotic plaque, characterized by the accumulation of abnormal amounts of cholesterol and macrophages in the artery wall. Reverse cholesterol transport (RCT) may counteract the pathogenic events leading to the formation and development...

Bifidobacteria are members of the human gut microbiota, which are known to influence the metabolic abilities of their host. Here, we investigated the capabilities of bifidobacteria to reduce cholesterol levels in synthetic growth media, clearly demonstrating assimilation of this molecule by particular bifidobacterial strains, including Bifidobacter...

Collated observations from several epidemiological studies have demonstrated that dietary intake of (poly)phenols from nuts, coffee, cocoa, grapes, and berries may protect against the development of atherosclerosis. Whereas this beneficial activity has previously been linked mainly to antioxidant or anti-inflammatory properties, recently emerging d...

The EPH receptor A2 (EPHA2) represents an attractive anticancer target. With the aim to identify novel EPHA2 receptor antagonists, a virtual screening campaign, combining shape-similarity and docking calculations, was conducted on a set of commercially available compounds. A combined score, taking into account both ligand- and structure-based resul...

LCAT (lecithin:cholesterol acyltransferase) catalyzes the transacylation of a fatty acid of lecithin to cholesterol, generating a cholesteryl ester and lysolecithin. The knowledge of LCAT atomic structure and the identification of the amino acids relevant in controlling its structure and function are expected to be very helpful to understand the en...

Background and purpose: The Eph receptor tyrosine kinases and their ephrin ligands are key players in tumorigenesis and many reports have correlated changes in their expression with a poor clinical prognosis in many solid tumours. Agents targeting the Eph-ephrin system might emerge as new tools useful for the inhibition of different components of...

Despite the efficacy in reducing acute rejection events in organ transplanted subjects, long term therapy with cyclosporine A is associated with increased atherosclerotic cardiovascular morbidity. We studied whether this drug affects the antiatherogenic process of the reverse cholesterol transport from macrophages in vivo. Cyclosporine A 50 mg/kg/d...

CsA effect on cholesterol efflux from Caco-2 cells. Caco-2 cells were cultured on membranes transwell plates for 2 weeks. After the differentiation period, cells were labeled with [3H]-cholesterol 2 µCi/ml for 24 h and successively equilibrated in presence or absence of T0901317 10 µM for 24 h. A: Cholesterol efflux was promoted to cell medium for...

Effect of 14 day treatment with CsA on body weight in mice injected with MPM. C57BL/6 mice were treated with CsA as described in Figure 1. Body weight was measured at baseline, on day 7 and on day 14 of the pharmacological treatment. Data are presented as mean ± SD (n = 7). (DOCX)

Effect of 14 day treatment with CsA on body weight in mice injected with J774. C57BL/6 mice were treated with CsA as described in Figure 1. Body weight was measured at baseline, on day 7 and on day 14 of the pharmacological treatment. Data are presented as mean ± SD (n = 5). (DOCX)

CsA treatment effect on plasma lipid levels in mice receiving J774. C57BL/6 mice were treated with CsA 50 mg/kg/d (black bar) or vehicle (white bar) for 14 days. The day before the sacrifice, mice were intraperitoneally injected with [3H]-cholesterol-loaded J774, in order to quantify macrophage RCT in vivo. Total cholesterol (TC), HDL-cholesterol (...

Effect of 14 day treatment with CsA on liver weight in mice injected with MPM. C57BL/6 mice were treated with CsA as described in Figure 1. On day 14 of the pharmacological treatment, mice were sacrificed and liver was collected after perfusion with a saline solution. Data are presented as mean ± SD of the wet weight. (n = 7). (DOCX)

Effect of 14 day treatment with CsA on liver weight in mice injected with J774. C57BL/6 mice were treated with CsA as described in Figure 1. Body weight was measured at baseline, on day 7 and on day 14 of the pharmacological treatment. Data are presented as mean ± SD (n = 5). (DOCX)

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Intracellular lipid homeostasis is regulated by multiple mechanisms devoted to the tight control of cholesterol levels. Cholesterol efflux to extracellular acceptors represents a cellular response to excess accumulation of lipids that occurs by both passive and active processes and was shown to exert a beneficial, antiatherosclerotic activity. Up t...

Intracellular lipid homeostasis is regulated by multiple mechanisms devoted to the tight control of cholesterol levels. Cholesterol efflux to extracellular acceptors represents a cellular response to excess accumulation of lipids that occurs by both passive and active processes and was shown to exert a beneficial, antiatherosclerotic activity. Up t...

Ro 11-1464 is a thienotriazolodiazepine previously described to selectively stimulate apolipoprotein A-I (apoA-I) production and mRNA level in human liver cells. Here, we studied its effects upon oral administration to human apoA-I transgenic (hapoA-I) mice. HapoA-I mice were treated for 5 days with increasing doses of Ro 11-1464. Macrophage revers...

To assess the role of apolipoprotein (apo) E in macrophage reverse cholesterol transport (RCT) in vivo. ApoE exerts an antiatherosclerotic activity by regulating lipoprotein metabolism and promoting cell cholesterol efflux. We discriminated between macrophage and systemic apoE contribution using an assay of macrophage RCT in mice. The complete abse...

The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. Patients were referred to the clinic because of almost complete HDL deficiency. The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux wa...

The liver X receptors (LXRs) have been shown to affect lipoprotein plasma profile, lipid metabolism, and reverse cholesterol transport (RCT). In the present study, we investigated whether a short-term administration of the synthetic LXR agonist T0901317 (T0) to mice may affect RCT by modulating the capacity of plasma to promote cellular lipid efflu...

Carriers of the apolipoprotein A-IMilano (A-IM) variant present with severe reductions of plasma HDL levels, not associated with premature coronary heart disease (CHD). Sera from 14 A-IM carriers and matched controls were compared for their ability to promote ABCA1-driven cholesterol efflux from J774 macrophages and human fibroblasts. When both cel...

The promotion of lipid efflux from macrophages is an important ATP binding cassette A1 (ABCA1)-mediated antiatherosclerotic mechanism that prevents peripheral tissues from foam cell accumulation. Statins exert beneficial antiatherosclerotic effects on cardiovascular disease correlated to the cholesterol-lowering properties and the pleiotropic activ...

Cholesterol efflux is achieved by several mechanisms. This study examines contributions of these pathways to efflux to human serum. Human fibroblasts were stably transfected with SR-BI while ABCA1 was upregulated. Quantitation of cholesterol efflux to human serum demonstrated that there was efflux from cells without either protein. Expression of AB...

We investigated the interaction of oxidized low density lipoprotein (OxLDL) with the ATP-binding cassette A1 (ABCA1) pathway in J774 macrophages. Cellular efflux to apolipoprotein AI (apo-AI) of OxLDL-derived cholesterol was lower than efflux of cholesterol derived from acetylated low density lipoprotein (AcLDL). ABCA1 upregulation by 8-(4-chloroph...

ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of lipids from cells to lipid-poor apolipoproteins. In this article, we characterize the effect of probucol on cellular ABCA1-mediated lipid efflux. Probucol inhibited cholesterol efflux up to 80% in J774 macrophages expressing ABCA1. In Fu5AH hepatoma cells that contain scavenger rece...

ATP binding cassette A1 (ABCA1) is responsible in vivo for the formation of HDL by promoting the lipidation of apoprotein A-I (apoA-I) via cholesterol and phospholipid efflux from the liver. Treatment of patients with statins produces an increase in HDL plasma level, but the underlying mechanism is not completely understood. In this work we investi...