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Beyond the well-known effects on cognitive impairment of the Mediterranean diet, a number of studies have investigated the possible action on cognitive decline of different botanicals and phytochemicals, most of which are well-known anti-inflammatory or antioxidant agents with a good tolerability and safety profile. In particular, the current literature supports the use of Ginkgo biloba, resveratrol, epigallocatechin-3-gallate and l-theanine, Theobroma cacao, Bacopa monnieri, Crocus sativus and curcumin, which might have a positive impact on cognitive impairment used alone or in combination with other nutraceuticals or traditional drugs. Then, the aim of the present study was to review and comment the available evidence on botanicals and phytochemicals with a clinically demonstrable effect on cognitive decline. For this reason, we carefully reviewed studies published in English language from 1970 to April 2017 on botanicals and phytochemical claiming to show an effect on cognitive impairment in humans. Thus, the terms 'botanicals', 'dietary supplements', 'herbal drug', 'nutraceuticals', 'phytochemical', 'cognitive impairment', 'Alzheimer's disease', 'clinical trial', and 'humans', alone and in combinations, were incorporated into an electronic search strategy in both MEDLINE (National Library of Medicine, Bethesda, MD) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). As it emerges from this systematic review, the use of some phytochemicals and botanicals seems to be very promising in order to delay the onset and progression of neurodegenerative and other age-related diseases. However, further well-designed clinical research is certainly needed to finally confirm the efficacy and safety profile of these compounds., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aflatoxicosis is a deleterious medical condition that results from aflatoxins (AFs) or ochratoxins (OTs). Contamination with these toxins exerts detrimental effects on the liver, kidneys, reproductive organs, and also on immunological and cardiovascular systems. Aflatoxicosis is closely associated with overproduction of reactive oxygen species (ROS) as key contributors to oxidative and nitrosative stress responses, and subsequent damages to lipids, proteins, RNA, and DNA. The main target organ for AF toxicity is the liver, where DNA adducts, degranulation of endoplasmic reticulum, increased hepatic lipid peroxide, GSH depletion, mitochondrial dysfunction, and reduction of enzymatic and non-enzymatic antioxidants are manifestations of aflatoxicosis. Curcuma longa L. (turmeric) is a medicinal plant widely utilized all over the world for culinary and phytomedical purposes. Considering the antioxidant characteristic of curcumin, the main active component of turmeric, this review is intended to critically summarize the available evidence supporting possible effectiveness of curcumin against aflatoxicosis. Curcumin can serve as a promising candidate for attenuation of the adverse consequences of aflatoxicosis, acting mainly through intrinsic antioxidant effects aroused from its structure, modulation of the immune system as reflected by interleukin-1β and transforming growth factor-β, and interfering with AF's biotransformation by cytochrome P450 isoenzymes CYP1A, CYP3A, CYP2A, CYP2B, and CYP2C., (© 2017 Wiley Periodicals, Inc.)

Introduction: Cardiovascular diseases (CVDs) are the leading cause of mortality and disability in developed countries, whereas a large portion of patients in primary prevention have uncontrolled level of CVD risk factors. Dietary supplementation with bioactive natural compounds with demonstrated lipid-lowering effects is currently supported by the international guidelines for CVD prevention and some international expert panels., Areas Covered: This review provides insights on issues concerning the tolerability and safety of the most commonly used nutraceuticals with demonstrated lipid-lowering effect in humans. They will be then divided into three main categories according to their mechanism of action (cholesterol synthesis inhibitors, intestinal cholesterol absorption inhibitors, and LDL-C excretion stimulants) and their pharmacological profile will be discussed., Expert Opinion: A growing body of preclinical, epidemiological and clinical evidence has defined the tolerability and safety profile of the most commonly used lipid-lowering nutraceuticals. In the most part of cases, the side effects are mild and reversible. However, detailed knowledge of specific health risks and pharmacological interactions for each individual compound is needed for the management of frail patients, such as children, elderly, patients with liver or renal failure, and patients consuming numerous drugs.

Metabolic syndrome (MetS) is characterized as a group of cardiometabolic risk factors that raise the risk for heart disease and other health problems, such as diabetes mellitus and stroke. Treatment strategies include pharmacologic interventions and supplementary (or "alternative") treatments. Nutraceuticals are derived from food sources (isolated nutrients, dietary supplements and herbal products) that are purported to provide health benefits, in addition to providing basic nutritional value. Nutraceuticals are claimed to prevent chronic diseases, improve health, delay the aging process, increase life expectancy, and support the structure and function of the body. The study of the beneficial effects of nutraceuticals in patients with MetS, including product standardization, duration of supplementation and definition of optimal dosing, could help better define appropriate treatment. This review focuses on widely marketed nutraceuticals (namely polyphenols, omega-3 fatty acids, macroelements and vitamins) with clinically demonstrated effects on more than one component of MetS.

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 elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1β, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1β (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR -/- bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR -/- and LDLR +/+ , respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.

The extracts of red yeast rice represent a nutraceutical with proven cholesterol lowering effect. Its efficacy is proportional to the concentration on monacolin K in the extract that could reach the amount of 10 mg per daily dose. The daily assumption of monacolin K could then reduce LDL-cholesterol plasma levels by 15-25% in 6-8 weeks. The LDL-cholesterol reduction is associated with a proportional reduction in total cholesterolemia, non-HDL cholesterolemia, plasma apolipoprotein B, high-sensitivity C-reactive protein, and matrix metalloproteinases 2 and 9. Then, the red yeast rice lipid-lowering efficacy is associated with a significant improvement of endothelial function and pulse wave velocity, which are well-known and validated instrumental biomarkers of vascular aging. Beyond the cholesterol lowering efficacy and the statin-like mechanism of action, the risk of the use of monacolin K 10 mg per day are minimal, and mild myalgias could be foreseen only in frail patients previously intolerant to minimal statin dosages. In conclusion, red yeast rice titrated in monacolin K represents a good therapeutic tool for the management of moderate hypercholesterolemias in patients with low added cardiovascular disease risk.

Obesity and high blood pressure (BP) are strongly related and weight loss is mightily associated with a significant BP decrease. The aim of the present meta-analysis was to evaluate and quantify the BP decrease associated with orlistat use in randomized controlled trials. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to June 05, 2017, to identify randomized controlled trials investigating the impact of orlistat on blood pressure. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Our meta-analysis included 27 randomized controlled clinical trials which comprehended overall 8150 subjects (4419 in the orlistat group and 3731 in the control one). We observed a statistically significant decreasing effect of orlistat on both systolic BP (-1.15 mmHg [-2.11, -0.19]) and diastolic BP (-1.07 mmHg [-1.69, -0.45]), regardless of its dosage. Significant associations were found between changes in systolic BP and diastolic BP with treatment duration but not with corresponding baseline BP values. In conclusion, Orlistat use contributes weight loss associated decrease in BP in overweight and obese subjects., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Polyphenols are a family of natural antioxidants that in recent years have been studied and tested for their potential benefits towards cardiovascular diseases., Objective: The aim of this review is to focus the attention on the presumed lipid-lowering and atheroprotective effects of polyphenols, administered either as individual molecules (nutritional supplements) and as functional foods, on the basis of the evidence coming from randomized controlled trials (RCTs) and their meta-analyses., Method: A search strategy was conducted to identify studies in PubMed (January 1980 to September 2016); in particular, we have included human clinical trials, reviews and meta-analyses when they offered suitable insights and elucidations regarding the action of polyphenols on lipid profile and cardiovascular disease risk., Results: Literature data on polyphenols suggest that they potentially could exert an effect on lipid profile, especially by reducing the oxidation of LDL-C. Polyphenols from cocoa, grape, green tea, berries and soy are the ones that have shown more clinically relevant effect. However, quantitative data on cholesterol reduction are still unclear and often conflicting., Conclusion: Polyphenols, if taken in adequate dosages, can exert in some cases a positive effect on the prevention of cardiovascular risk and lipid oxidation, despite an unclear effect on lipid levels., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Host lipid metabolism influences viral replication and lifecycle of hepatitis C virus. Our aim was to evaluate changes in glucose and lipid metabolism of patients with chronic hepatitis C after therapy with direct acting antivirals (DAA)., Material and Methods: We considered patients consecutively treated between January and November 2015 recording clinical data at baseline and week 24 of follow-up. Frozen serum samples were used for apolipoprotein A1 (apoA1), apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)]. Wilcoxon test was utilized to estimate trends and Logistic Regression for predictors of lipid changes., Results: We enrolled 100 patients, mostly cirrhotic (81%) and with genotype 1b (59%). Ninety-three patients achieved sustained virological response (SVR), while 7 relapsed. Homeostasis model assessment of insulin resistance declined (from 3 to 2.7, p &lt; 0.001); non-high density lipoprotein (HDL) cholesterol increased from 102 ± 29 to 116 ± 35 (p &lt; 0.001), and Lp(a) from 5.6 ± 6.5 to 9.8 ± 11.5 mg/dL (p &lt; 0.001). Rise of low-density lipoprotein/HDL and apoB/apoA1 ratio were registered (from 1.79 ± 1.10 to 2.08 ± 1.05 and from 0.48 ± 0.18 to 0.53 ± 0.18 mg/dL, p &lt; 0.001). We conducted a subanalysis on patients with relapse. In this subgroup, no change of lipid profile was recorded. At multivariate analysis emerged that the addition of ribavirin to DAA, represented an independent predictor of increased Lp(a) (OR 3.982, 95% CI 1.206-13.144, p = 0.023)., Conclusion: DAA therapy led to reduction of insulin resistance. In contrast, pro-atherogenic lipid changes were observed in patients with SVR. Further studies will be necessary to evaluate the cardiovascular balance between amelioration of glucose metabolism and negative changes of lipid profile.

Artichoke is a component of the Mediterranean diet. Therefore, the aim of this meta-analysis was to determine if artichoke extract supplementation affected human lipid parameters. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases up to March 28, 2017, to identify RCTs investigating the impact of artichoke extracts on plasma lipid levels. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Meta-analysis of data from 9 trials including 702 subjects suggested a significant decrease in plasma concentrations of total cholesterol (WMD: -17.6 mg/dL, 95%CI: -22.0, -13.3, p < 0.001), Low Density Lipoprotein-Cholesterol (LDL-C; WMD: -14.9 mg/dL, 95%CI: -20.4, -9.5, p = 0.011) and triglycerides (WMD: -9.2 mg/dL, 95%CI: -16.2, -2.1, p = 0.011). No significant alteration in plasma High Density Lipoprotein-Cholesterol (HDL-C) concentrations was observed (WMD: 1.0 mg/dL, 95%CI: -1.1, 3.1, p = 0.333). A significant association between the LDL-lowering effect of artichoke and baseline LDL-C concentrations (slope: -0.170; 95%CI: -0.288, 0.051; p = 0.005) was observed. Thus, supplementation with artichoke extract was associated with a significant reduction in both total and LDL-C, and triglycerides, suggesting that supplementation may be synergistic with lipid-lowering therapy in patients with hyperlipidemia.

Introduction: Hypercholesterolemia is the main modifiable risk factor for atherosclerosis progression and cardiovascular disease (CVD) development. Its pharmacological management is usually based on the prescription of statins, that in some cases are not however fully effective to reach the desired Low-Density-Lipoproteins cholesterol (LDL-C) target, or are not tolerated by patients due to side effects. Areas covered: This manuscript summarizes the basic properties of the emerging new classes of lipid-lowering drugs such as ezetimibe, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, and Microsomal Triglyceride Transfer Protein (MTP) inhibitors, also citing new drugs in development. Our aim is to describe the main pharmacodynamic and pharmacokinetic characteristics, the available efficacy, tolerability and safety data obtained in randomized clinical trials where these drugs were tested. Expert opinion: Non-statin lipid-lowering drugs can be considered an excellent strategy to reduce the residual CV risk, also represented by non-target LDL-C values and high lipoprotein(a) serum levels. In particular, the approved PCSK9 inhibitors (Evolocumab and Alirocumab) have been very effective in optimizing plasma LDL-C values and reducing CV event risk.

Background: Polyphenols are bioactive compounds that can be found mostly in foods like fruits, cereals, vegetables, dry legumes, chocolate and beverages such as coffee, tea and wine. They are extensively used in the prevention and treatment of cardiovascular disease (CVD) providing protection against many chronic illnesses. Their effects on human health depend on the amount consumed and on their bioavailability. Many studies have demonstrated that polyphenols have also good effects on the vascular system by lowering blood pressure, improving endothelial function, increasing antioxidant defences, inhibiting platelet aggregation and low-density lipoprotein oxidation, and reducing inflammatory responses., Methods: This review is focused on some groups of polyphenols and their effects on several cardiovascular risk factors such as hypertension, oxidative stress, atherogenesis, endothelial dysfunction, carotid artery intima-media thickness, diabetes and lipid disorders., Results: It is proved that these compounds have many cardio protective functions: they alter hepatic cholesterol absorption, triglyceride biosynthesis and lipoprotein secretion, the processing of lipoproteins in plasma, and inflammation. In some cases, human long-term studies did not show conclusive results because they lacked in appropriate controls and in an undefined polyphenol dosing regimen., Conclusion: Rigorous evidence is necessary to demonstrate whether or not polyphenols beneficially impact CVD prevention and treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Uric acid (UA), the final product of purine catabolism, may be associated with an increased risk of cardiovascular disease., Aim: The aim of this meta-analysis of randomized placebo-controlled trials was to evaluate whether lowering serum UA (SUA) levels with allopurinol is associated with improved flow-mediated dilation (FMD), a validated marker of early vascular damage., Methods: A literature search was carried out from inception until 20 June 2017. Meta-analysis was performed using an inverse variance-weighted, random-effects model with standardized mean difference (SMD) as the effect size estimate., Results: Meta-analysis of data from the ten eligible randomized controlled trials (RCTs), with 670 subjects, suggested a significant increase in FMD following allopurinol treatment (weighted mean difference [WMD] 1.79%, 95% confidence interval [CI] 1.01-2.56, p < 0.001; I 2 : 86.77%). The effect size was robust and remained significant after omission of each single study. Subgroup analyses of RCTs based on the administered dose or duration of treatment did not reveal any significant impact of these variables on FMD change. Nor was a significant association found between allopurinol-induced changes in SUA levels and FMD (slope 0.46, p = 0.253), whereas baseline FMD significantly influenced the degree of FMD improvement following allopurinol treatment (slope 0.52, p = 0.022). Nitroglycerin-mediated dilation was not altered by allopurinol treatment (WMD 0.88%, 95% CI - 1.15-2.91, p = 0.395; I 2 : 80.88%)., Conclusion: This meta-analysis of available RCTs suggests a significant benefit from allopurinol intake in increasing FMD in humans, independent of its effect on SUA levels.

Scope: We aimed examining apple polyphenols' effect on uricemia and endothelial function in a sample of overweight subjects., Methods and Results: This was a two-phased study. In vitro experiment aimed to evaluate apple polyphenols' ability to lower uric acid in comparison with allopurinol. In vivo study consisted in a randomized, double-blind, parallel placebo-controlled clinical trial involving 62 overweight volunteers with suboptimal values of fasting plasma glucose (100 mg/dL≤FPG≤125 mg/dL), randomized to 300 mg apple polyphenols or placebo for 8 weeks. Apple polyphenols extract inhibited xanthine oxidase activity, with an IC50 = 130 ± 30 ng/mL; reducing uric acid production with an IC50 = 154 ± 28 ng/mL. During the trial, after the first 4 weeks of treatment, FPG decreased in the active treated group (-6.1%, p < 0.05), while no significant changes were observed regarding the other hematochemistry parameters. After 4 more weeks of treatment, active-treated patients had an improvement in FPG compared to baseline (-10.3%, p < 0,001) and the placebo group (p < 0,001). Uric acid (-14.0%, p < 0.05 versus baseline; p < 0.05 versus placebo) and endothelial reactivity (0.24±0.09, p = 0.009 versus baseline; p < 0.05 versus placebo) significantly improved too., Conclusion: In vivo, apple polyphenols extract has a positive effect on vascular oxidative stress and endothelium function and reduce FPG and uric acid by inhibiting xanthine oxidase, as our In vitro experiment attests., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Several epidemiological studies have demonstrated the existence of a correlation between high serum uric acid (SUA) levels, hypertension, and chronic kidney disease (CKD). Xantine oxidase inhibitors (XOI) are the most powerful uric acid lowering drugs, with presumed beneficial effects on cardiovascular and renal system. The multifactorial mechanism linking hyperuricemia with cardiovascular and renal diseases involves both the SUA level and the xanthine oxidase (XO) activity. In this context, the clinical research has been recently focused at assessing the efficacy of urate-lowering drugs active on XO in patients with abnormal blood pressure values and renal dysfunction. The mechanism of action responsible for the beneficial effect of XOI has not completely elucidated, and long-term studies involving large population samples are needed. In particular, XOI could play an important role in the management of hypertension and CKD, especially in patients not entirely controlled by conventional therapies. In the present review, we summarize the results of recent clinical trials that largely support a positive effect of allopurinol and febuxostat on blood pressure, glomerular filtration rate (GFR), and serum creatinine in different populations of patients. Will these drugs be considered a reliable choice or alternative to currently used drugs for the hypertension and kidney failure treatment? The debate is open, but much evidence is accumulating and supporting this role.

Introduction: Cholesterol lowering treatment is mainly based on statins eventually associated to adjunctive drugs of different class such as ezetimibe. In the present review, we analysed the pharmacokinetics, efficacy and safety of ezetimibe + simvastatin drug association. Areas covered: The bio-equivalence of ezetimibe and simvastatin when co-administrated in separate tablets or combined in a single pill is well documented. Ezetimibe is absorbed in small intestine, reaching peak plasma concentrations in 4-12 h, with a plasma half-life of 22 h. Simvastatin, ingested as a prodrug, is hydrolyzed in liver to its active beta-hydroxyacid metabolite, reaching peak plasma concentrations in 2-4 h, with a plasma half-life of approximately 5 h. The available evidence support the clinical efficacy of this drug combination, both in term of LDL-cholesterol reduction and cardiovascular risk decrease. Expert opinion: The synergistic action of these two drugs and the efficacy and safety extensively demonstrated of their association (in particular in the large IMProved Reduction of Outcomes: Vytorin Efficacy International Trial -IMPROVE-IT-) promote its clinical use, especially in subjects with high cardiovascular risk who need to optimize their LDL-Cholesterolemia, but also in patients who cannot tolerate high-dose of more powerful statins.

Background: Phytosterols and red yeast rice are largely studied cholesterol-lowering nutraceuticals, respectively inhibiting the bowel absorption and liver synthesis of cholesterol. Our aim was to test the effect on lipid profile of phytosterols, red yeast rice and their association., Methods: We performed a three parallel arms, double blind, clinical trial randomizing 90 moderately hypercholesterolemic subjects to treatment with phytosterols 800 mg (group 1), red yeast rice standardized to contain 5 mg monacolins from Monascus purpureus (group 2), or both combined nutraceuticals (group 3)., Results: After 8 weeks of treatment, in group 1 no significant variation of lipid parameters has been detected. In group 2 a significant reduction ( p  < 0.001) of LDL-Cholesterol (-20.5% vs. baseline) and Apolipoprotein B (-14.4% vs. baseline) as it occurred in group 3 (LDL-Cholesterol vs. baseline: -27.0%, Apolipoprotein B vs. baseline: -19.0%) ( P  < 0.001). LDL-Cholesterol and Apolipoprotein B changes were significantly different comparing group 2 with group 1 ( P  < 0.05), and group 3 with group 1 ( P  < 0.05). LDL-Cholesterol change was also significantly higher in group 3 than in group 2 ( P  < 0.05)., Conclusion: The association of phytosterol and red yeast rice seems to have additive cholesterol lowering effect, reaching a clinically significant LDL-Cholesterol reduction in mildly hypercholesterolemic patients., Trial Registration: ClinicalTrial.gov ID: NCT02603276, Registered 27/08/2015.

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting., (© The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: A number of natural compounds have individually demonstrated to improve glucose and lipid levels in humans., Aim: To  evaluate the short-term glucose and lipid-lowering activity in subjects with impaired fasting glucose., Methods: To assess the effects of a combination of nutraceuticals based on Lagerstroemia speciosa, Berberis aristata, Curcuma longa, Alpha-lipoic acid, Chrome picolinate and Folic acid, we performed a double-blind, parallel group, placebo-controlled, randomized clinical trial in 40 adults affected by impaired fasting glucose (FPG = 100-125 mg/dL) in primary prevention of cardiovascular disease. After a period of 2 weeks of dietary habits correction only, patients continued the diet and began a period of 8 weeks of treatment with nutraceutical or placebo. Data related to lipid pattern, insulin resistance, liver function and hsCRP were obtained at the baseline and at the end of the study., Results: No side effects were detected in both groups of subjects. After the nutraceutical treatment, and compared to the placebo-treated group, the enrolled patients experienced a significant improvement in TG (-34.7%), HDL-C (+13.7), FPI (-13.4%), and HOMA-Index (-25%) versus the baseline values. No significant changes were observed in the other investigated parameters in both groups (Body Mass Index, LDL-C, hsCRP)., Conclusions: The tested combination of nutraceuticals showed clinical efficacy in the improvement of TG, HDL-C, FPI and HOMA-Index, with an optimal tolerability profile. Further confirmation is needed to verify these observations on the middle and long term with a larger number of subjects.

Berberine (BBR) is an isoquinoline alkaloid found in different plant families such as Berberidaceae, Ranunculaceae, and Papaveraceae. BBR is well-known for its anti-inflammatory, lipid-modifying, anticancer, anti-diabetic, antibacterial, antiparasitic and fungicide activities. Multiple pharmacological actions of BBR stem from different molecular targets of this phytochemical. MicroRNAs (miRs) are single-stranded, evolutionary conserved, small non-coding RNA molecules with a length of 19-23 nucleotides that are involved in RNA silencing and post-transcriptional regulation of gene expression through binding to the 3'-untranslated region (3'UTR) of target mRNA. MiRs emerged as important regulatory elements in almost all biological processes like cell proliferation, apoptosis, differentiation and organogenesis, and numerous human diseases such as cancer and diabetes. BBR was shown to regulate the expression of miRs in several diseases. Here, we reviewed the target miRs of BBR and the relevance of their modulation for the potential treatment of serious human diseases like multiple myeloma, hepatocellular carcinoma, colorectal cancer, gastric cancer, ovarian cancer and glioblastoma. The role of miR regulation in the putative anti-diabetic effects of BBR is discussed, as well., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Competing Interests: Maciej Banach: speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Sanofi-Aventis and Valeant; consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Lilly, MSD, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant; Arrigo F.G. Cicero: consultant for the R&D of Meda SpA and received research grants from IBSA SpA; Olivier Descamps: speakers bureau: Amgen, MSD, Sanofi-Aventi; consultant to Amgen, Astrazeneca, MSD, Sanofi-Aventis and Phacobel; Grants from Sanofi, MSD and Amgen; Niki Katsiki has given talks, attended conferences and participated in trials sponsored by Amgen, Angelini, Astra Zeneca, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk, Sanofi and WinMedica; Gustavs Latkovskis: speakers bureau: Amgen, Astra-Zeneca, Bayer, Berlin-Chemie/Menarini, Boehringer Ingelheim, GlaxoSmithCline, Mylan, Novo Nordisk, Pfizer, Sanofi-Aventis, Servier, Siemens Laboratories; research grant on the topic of polyprenols and coenzyme Q10 from Pharma and Chemistry Competence Center of Latvia; Dimitri P. Mikhailidis: has given talks and attended conferences sponsored by MSD, AstraZeneca and Libytec; Peter P. Toth: speakers bureau: Amarin, Amgen, Kowa, Merck, Novartis, Regeneron, Sanofi-Aventis; consultant to Amgen, AstraZeneca, Kowa, Merck, and Regeneron; Dragos Vinereanu has given talks and attended conferences sponsored by BMS/Pfizer, Novartis, Servier, Amgen, Bayer, AstraZeneca. Speaker fees from Pfizer, Novartis, Servier, Bayer, AstraZeneca, Terapia; Michal Vrablik reports personal fees from Abbott, Actavis, AstraZeneca, Amgen, BMS, Genzyme, KRKA, MSD, Novartis, Pfizer and Sanofi-Regeneron; Gani Bajraktari, Alessandro Colletti, Dragan M. Djuric, Marat Ezhov, Zlatko Fras, Kausik K. Ray, Michel Langlois, Olena Mitchenko, Demosthenes B. Panagiotakos, Gyorgy Paragh, Bernhard Paulweber, Daniel Pella, Christos Pitsavos, Željko Reiner, Manfredi Rizzo, Amirhossein Sahebkar, Maria-Corina Serban, Laurence S. Sperling, and Nathan D. Wong have no conflict of interest.

Introduction: There is a growing interest in nutraceuticals improving cardiovascular risk factor levels and related organ damage., Methods: This double-blind, placebo-controlled randomized clinical trial aims to compare the effect of a combined nutraceutical containing red yeast rice (10 mg), phytosterols (800 mg), and L-tyrosol (5 mg) on lipid profile, blood pressure, endothelial function, and arterial stiffness in a group of 60 patients with polygenic hypercholesterolemia resistant to Mediterranean diet., Results: After 8 weeks of treatment, when compared to the placebo group, the active treated patients experienced a more favorable percentage change in total cholesterol (-16.3% vs 9.9%, P < 0.001 always), LDL-C (-23.4% vs -13.2%, P < 0.001 always), and hepatic steatosis index (-2.8%, P < 0.01 vs -1.8%, P < 0.05). Moreover, ALT (-27.7%, P < 0.001), AST (-13.8%, P = 0.004), and serum uric acid (-12.3%, P = 0.005) were reduced by the tested nutraceutical compound both compared to randomization and to placebo, which did not affect these parameters (P < 0.01 for all). Regarding the hemodynamic parameters, there was a decrease of systolic blood pressure (-5.6%) with the active treatment not observed with placebo (P < 0.05 vs baseline and placebo) and endothelial reactivity improved, too (-13.2%, P < 0.001 vs baseline). Consequently, the estimated 10-year cardiovascular risk score improved by 1.19% (SE 0.4%) (P = 0.01) in the nutraceutical-treated patients., Conclusion: The tested nutraceutical association is able to improve the positive effects of a Mediterranean diet on a large number of CV risk factors and consequently of the estimated CV risk., Trial Registration: ClinicalTrials.gov identifier NCT02492464., Funding: IBSA Farmaceutici.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The article is a substantial duplication of an earlier published paper by the same group of authors (below), to which no reference was made during the manuscript submission or review process: Acarbose actions on insulin resistance and inflammatory parameters during an oral fat load. Giuseppe Derosa, Pamela Maffioli, Ilaria Ferrari, Elena Fogari, Angela D'Angelo, Ilaria Palumbo, Sabrina Randazzo, Lucio Bianchi, Arrigo FG Cicero. European Journal of Pharmacology 651 (2011) 240-250. http://doi:10.1016/j.ejphar.2010.11.015. The authors had declared during the editorial process that the article had not been published or was under consideration elsewhere. The article is being retracted per journal policy and academic standards., (Copyright © 2016.)

Cardiovascular diseases (CVDs) are one of the major causes of mortality and disability in Western countries. Prevention is known to be the cornerstone to lessen the incidence of CVDs and also to reduce the economic burden of both the citizen and the healthcare system. "Interventional medicine" certainly puts lifestyle modification as the first therapeutic step, including a healthy diet and physical activity. Secondly, a large body of research individuated a number of food and plant bioactives, which are potentially efficacious in preventing and reducing some highly prevalent CV risk factors, such as hypercholesterolemia, hypertension, vascular inflammation and vascular compliance. Some lipid- and blood pressure-lowering bioactives were studied for their impact on human vascular health, particularly as regards endothelial function and arterial stiffness. Several nutraceuticals showed additive or synergistic properties in combination, sometimes (but not always) allowing a reduction of the administered dose of extracts and determining a "multi-factorial" final effect on many cardiovascular risk factors. Thus, this review focuses on available evidence regarding the effects of berberine, plant sterols, green tea extract, soy, curcumin, cocoa, pycnogenol, lycopene, olive oil, soluble fibers, garlic, resveratrol, beetroot, mineral salts and vitamins on the lipid profile, blood pressure, inflammatory and endothelial markers, and vascular compliance. Future clinical research studies will have to focus more on middle term modification of the instrumental markers of vascular aging than on short-term effects on indirect laboratory risk markers.

In the past few years, increasing interest has been directed to bioactive peptides of animal and plant origin: in particular, researchers have focused their attention on their mechanisms of action and potential role in the prevention and treatment of cancer, cardiovascular and infective diseases. We have developed a search strategy to identify these studies in PubMed (January 1980 to May 2016); particularly those papers presenting comprehensive reviews or meta-analyses, plus in vitro and in vivo studies and clinical trials on those bioactive peptides that affect cardiovascular diseases, immunity or cancer, or have antioxidant, anti-inflammatory and antimicrobial effects. In this review we have mostly focused on evidence-based healthy properties of bioactive peptides from different sources. Bioactive peptides derived from fish, milk, meat and plants have demonstrated significant antihypertensive and lipid-lowering activity in clinical trials. Many bioactive peptides show selective cytotoxic activity against a wide range of cancer cell lines in vitro and in vivo, whereas others have immunomodulatory and antimicrobial effects. Furthermore, some peptides exert anti-inflammatory and antioxidant activity, which could aid in the prevention of chronic diseases. However, clinical evidence is at an early stage, and there is a need for solid pharmacokinetic data and for standardized extraction procedures. Further studies on animals and randomized clinical trials are required to confirm these effects, and enable these peptides to be used as preventive or therapeutic treatments., Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc., (© 2016 The British Pharmacological Society.)

Background and Aims: Oxidized LDL (oxLDL) or pro-inflammatory stimuli lead to increased oxidative stress linked to endothelial dysfunction and atherosclerosis. The oxLDL receptor-1 (LOX1) is elevated within atheromas and cholesterol-lowering statins inhibit LOX1 expression. Berberine (BBR), an alkaloid extracted from plants of gender Berberis, has lipid-lowering and anti-inflammatory activity. However, its role in regulating LOX1-mediated signaling is still unknown. The aim of this study was to investigate the effect of BBR on oxLDL- and TNFα-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs) and to compare it with that of lovastatin (LOVA)., Methods and Results: Cytotoxicity was determined by lactate dehydrogenase assay. Antioxidant capacity was measured with chemiluminescent and fluorescent method and intracellular ROS levels through a fluorescent dye. Gene and protein expression levels were assayed by qRT-PCR and western blot, respectively. HUVECs exposure to oxLDL (30 μg/ml) or TNFα (10 ng/ml) for 24 h led to a significant increase in LOX1 expression, effect abrogated by BBR (5 μM) and LOVA (5 μM). BBR but not LOVA treatment abolished the TNFα-induced cytotoxicity and restored the activation of Akt signaling. In spite of a low direct antioxidant capacity, both compounds reduced intracellular ROS levels generated by treatment of TNFα but only BBR inhibited NOX2 expression, MAPK/Erk1/2 signaling and subsequent NF-κB target genes VCAM and ICAM expression, induced by TNFα., Conclusions: These findings demonstrated for the first time that BBR could prevent the oxLDL and TNFα - induced LOX1 expression and oxidative stress, key events that lead to NOX, MAPK/Erk1/2 and NF-κB activation linked to endothelial dysfunction., Chemical Compounds Studied in This Article: Berberine (PubChem CID: 2353); Lovastatin (PubChem CID: 53232)., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulating levels are significantly associated with an increased risk of cardiovascular events. This study aimed to evaluate the relationship between circulating levels of PCSK9 and arterial stiffness, an early instrumental biomarker of cardiovascular disease risk, in a large sample of overall healthy participants., Methods and Results: From the historical cohort of the Brisighella Heart Study, after exclusion of active smokers, participants in secondary prevention for cardiovascular disease, and patients in treatment with statins or vasodilating agents, we selected 227 premenopausal women and 193 age-matched men and 460 postmenopausal women and 416 age-matched men. In these participants, we evaluated the correlation between PCSK9 plasma circulating levels and pulse wave velocity. Postmenopausal women showed higher PCSK9 levels (309.9±84.1 ng/mL) compared with the other groups ( P <0.001). Older men had significant higher levels than younger men (283.2±75.6 versus 260.9±80.4 ng/mL; P =0.008). In the whole sample, pulse wave velocity was predicted mainly by age (B=0.116, 95% CI 0.96-0.127, P <0.001), PCSK9 (B=0.014, 95% CI 0.011-0.016, P <0.001), and serum uric acid (B=0.313, 95% CI 0.024-0.391, P =0.026). Physical activity, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and estimated glomerular filtration rate were not associated with pulse wave velocity ( P >0.05).By considering the subgroups described, age and PCSK9 levels were mainly associated with pulse wave velocity, which also correlated with serum uric acid in postmenopausal women., Conclusions: In the Brisighella Heart Study cohort, circulating PCSK9 is significantly related to arterial stiffness, independent of sex and menopausal status in women., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

There is a direct relationship between fructose intake and serum levels of uric acid (UA), which is the final product of purine metabolism. Recent preclinical and clinical evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, and cardiovascular disease. It is probably also an independent risk factor for chronic kidney disease, Type 2 diabetes, and cognitive decline. These relationships have been observed for high serum UA levels (>5.5 mg/dL in women and >6 mg/dL in men), but also for normal to high serum UA levels (5-6 mg/dL). In this regard, blood UA levels are much higher in industrialized countries than in the rest of the world. Xanthine-oxidase inhibitors can reduce UA and seem to minimize its negative effects on vascular health. Other dietary and pathophysiological factors are also related to UA production. However, the role of fructose-derived UA in the pathogenesis of cardiometabolic disorders has not yet been fully clarified. Here, we critically review recent research on the biochemistry of UA production, the relationship between fructose intake and UA production, and how this relationship is linked to cardiometabolic disorders.

Atrial septal aneurysm (ASA), common finding in normal echocardiographies, has been described in association with transient ischemic attacks (TIAs)/strokes, as well as hypertensive end-organ damage such as left ventricular (LV) hypertrophy. Aim of this study was to assess if a cluster of echocardiographic aspects could characterize TIA hypertensive patients. A cross-sectional study on patients with history of TIA, referring to a Hypertension Center echolab, has been performed. A total of 5223 patients received transthoracic echocardiography. TIA patients were 292 (5.6%). A total of 102 age/sex-matched patients without TIA have been collected as controls. The main characteristic of TIA patients resulted ASA/bulging (B) (TIA 61%, controls 6%, P = .0001). Other aspect was LV concentric remodeling (TIA 32.3%, controls 20.8%, P = .029) and mitral flow aspects of diastolic dysfunction. After adjustment for age and hypertension, ASA/B (odds ratio [OR] = 62.4, 95% confidence interval [CI]: 13.6-73.9, P < .001), followed by LV concentric hypertrophy (OR = 2.1, 95% CI: 1.1-4.3, P = .043), was associated with a positive TIA history. A binary logistic regression performed in ASA/B patients, identified relative wall thickness as the strongest TIA-associated aspect (OR = 53.4, 95% CI: 11.9-74.18, P = .001). ASA/B, common finds in general population, could carry a significant incremental possibility of association with TIA when concentric geometry, frequent hypertensive aspect, is present as well., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood. It represents a major public health issue, with a prevalence of over 23 million worldwide. The lifetime risk of developing HF is one in five and the most important risk factors identified are ischemic heart disease, hypertension, smoking, obesity and diabetes. Preventive approaches are based on improvements of lifestyle, associated with pharmacological therapy. Several nutraceuticals have shown interesting clinical results in prevention of HF as well as in the treatment of the early stages of the disease, alone or in association with pharmacological therapy., Aim: The aim of this review is to resume the available clinical evidence on phytochemicals effect on HF prevention and/or treatment., Methods: A systematic search strategy was developed to identify trials in PubMed (January 1980 to April 2016). The terms 'nutraceuticals', 'dietary supplements', 'herbal drug' and 'heart failure' were incorporated into an electronic search strategy., Results: Clinical trials reported that the intake of some nutraceuticals (hawthorn, coenzyme Q10, L-carnitine, Dribose, Carnosine, Vitamin D, Some probiotics, Omega-3 PUFAs, Beet nitrates) is associated with improvements in functional parameters such as ejection fraction, stroke volume and cardiac output in HF patients, with minimal side effects. These findings were sometimes reinforced by subsequent meta-analyses, which further concluded that benefits tended to be greater in earlier stage HF. The main mechanisms involved are antioxidant, antinflammatory, anti-ischemic and antiaggregant effects., Conclusions: Evidence suggests that the supplementation with nutraceuticals may be a useful option for effective management of HF, with the advantage of excellent clinical tolerance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Oxidative stress is implicated in the pathogenesis of a lot of age-related pathologies and some types of cancers. Carotenoids have shown antioxidant properties, due to the ability to quench singlet oxygen and to scavenge free radicals that may prevent and treat a wide range of chronic diseases. The aim of this review is to discuss the clinical evidence present in literature about the effects of carotenoids on human health and to evaluate their effectiveness in the prevention and treatment of many chronic diseases., Method: We reviewed studies on carotenoids claiming to show an effect in the prevention and treatment of many chronic diseases. In particular, we focused our attention on clinical trials published on Natural Medicine Comprehensive Database and PubMed., Results: A great number of clinical trials reported the beneficial effects of carotenoids on human health, in particular against skin, eye, hepatic, cardiovascular diseases and some types of cancer. Nevertheless, a few study evaluated the intake of carotenoids alone and sometimes the results are discording. Furthermore, irrational or excessive use of antioxidants may produce risk of potential toxicity., Conclusion: The antioxidant activity of carotenoids, taken with the diet or through nutritional supplements, seems to benefit human health. Therefore, it is necessary to test them alone and to evaluate their safety in longterm clinical trials on a large and heterogeneous sample of people., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: The aim of our study was to evaluate the tolerability and efficacy of alternative approaches to improve cholesterolemia control in patients with statin-related myalgia treated with ezetimibe., Research Design and Methods: We retrospectively evaluated 3534 Clinical Report Forms (CRFs) filled in the period June 2012-June 2015 for first visits to the lipid clinic of the University of Bologna. For this study, we selected 252 CRFs based on the following criteria: statin-related myalgia, previous failed treatment with at least two low-dosed statins, well tolerated treatment with ezetimibe. Then, the following lipid-lowering treatments were added in order to improve the ezetimibe low density lipoprotein cholesterol (LDL-C) lowering efficacy, based on clinical judgment: fenofibrate 145 mg, rosuvastatin 5 mg 1 tablet/week, rosuvastatin 5 mg 2 tablets/week, red yeast rice (standardized in monacolin K 3 mg) + berberine 500 mg, berberine 500 mg b.i.d., phytosterols 900 mg + psyllium fiber 3.5 g b.i.d. Patients continuing to claim a tolerable myalgia were then treated with coenzyme Q10 nanoemulsions 200 mg/day., Results: The treatment with standard lipid-lowering diet plus ezetimibe alone was associated with a mean LDL-C reduction of 17 ± 2%. The additive LDL-lowering effect with the various tested treatment was: -16 ± 2% with fenofibrate 145 mg/day, -13 ± 1% with rosuvastatin 5 mg 1 tablet/week, -17 ± 3% with rosuvastatin 5 mg 2 tablets/week, -19 ± 4% with red yeast rice + berberine, -17 ± 4% with berberine b.i.d. and -10 ± 3% with phytosterols + psyllium b.i.d.; 11% of the patients treated with fenofibrate required treatment modification because of myalgia recurrence, while the percentage was negligible for the other tested treatments. In patients with residual tolerable myalgia, treatment with coenzyme Q10 for 8 weeks was associated with a mean improvement of the graduated myalgia score from 4.8 ± 1.9 to 2.9 ± 1.3 (p = 0.013)., Conclusions: Some alternative treatments seems to be effective and well tolerated, thus improving the ezetimibe effect on cholesterolemia.

Background: Tumor necrosis factor-α (TNF-α) is a key inflammatory mediator and its reduction is a therapeutic target in several inflammatory diseases. Curcumin, a bioactive polyphenol from turmeric, has been shown in several preclinical studies to block TNF-α effectively. However, clinical evidence has not been fully conclusive., Objective: The aim of the present meta-analysis was to evaluate the efficacy of curcumin supplementation on circulating levels of TNF-α in randomized controlled trials (RCTs)., Methods: The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to September 21, 2015, to identify RCTs investigating the impact of curcumin on circulating TNF-α concentration. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response., Results: Eight RCTs comprising nine treatment arms were finally selected for the meta-analysis. There was a significant reduction of circulating TNF-α concentrations following curcumin supplementation (WMD: -4.69pg/mL, 95% CI: -7.10, -2.28, p<0.001). This effect size was robust in sensitivity analysis. Meta-regression did not suggest any significant association between the circulating TNF-α-lowering effects of curcumin with either dose or duration (slope: 0.197; 95% CI: -1.73, 2.12; p=0.841) of treatment., Conclusion: This meta-analysis of RCTs suggested a significant effect of curcumin in lowering circulating TNF-α concentration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We selected 247 subjects from 29 large familial hypercholesterolemia (FH) kindreds from 550 probable FH subjects in Emilia Romagna (Italy) on the basis of LDL-cholesterol plasmatic levels and family trees, in order to define the best diagnostic criteria for heterozygous patients. Familial hypercholesterolemia is a monogenic disease of cholesterol metabolism inherited as an autosomal dominant trait and characterised by early cardiovascular disease. A low xanthomas and xanthelasmas prevalence was found (8.6%); coronary heart disease (CHD) death occurs very frequently in heterozygous males (72% of all deaths; mean age at death 52 years), while in females the primary cause of death was thrombotic stroke (55%; mean age 69 years). Total cholesterol (TC) mean values were 389.8 (m) and 373.3 mg/dl (f) for FH trait carriers, and 223.3 (m) and 228.8 (f) for healthy relatives. No age-related change in TC was found in heterozygotes, while unaffected relatives of FH families showed mean TC and LDL-C values, and a TC frequency distribution and a TC age-related increasing trend similar to the expected values for the Italian population. The TC frequency distribution curve appeared bimodal, with a mid-point between heterozygous and homozygous FH modal values of 280 mg/dl. To identify the FH patients, the final FH heterozygosity risk was evaluated in an unselected free-living population (from 0.07 to 0.8%, respectively, for TC between 265-274 and 295-304 mg/dl) and in hypercholesterolemic families (31 to 83%, and the same TC classes). Our conclusion is that the clinical picture is rarely pathognomonic, while the FH heterozygosity final risk evaluation and the 280 mg/dl cut-off point can be used to guide the practical clinical diagnosis and to select the patients destined for B-E receptor activity evaluation.