Clinical Approach in the Management of Paediatric Patients with Familial Hypercholesterolemia: A National Survey Conducted by the LIPIGEN Paediatric Group.

Detection and treatment of patients with familial hypercholesterolemia (FH) starting from childhood is fundamental to reduce morbidity and mortality. The activity of National realities such as the LIPIGEN (LIpid transPort disorders Italian GEnetic Network) Paediatric Group, founded in 2018, is a milestone in this context. The aim of this exploratory survey, conducted in October 2021 among Italian lipid clinics included in the LIPIGEN Paediatric Group, was to investigate the current clinical approach in the management and treatment of paediatric patients with suspected FH. A digital questionnaire composed of 20 questions investigating nutritional treatment and nutraceutical and pharmacological therapy for children and adolescents with FH was proposed to the principal investigators of 30 LIPIGEN centres. Twenty-four centres responded to the section referring to children aged < 10 years and 30 to that referring to adolescents. Overall, 66.7% of children and 73.3% of adolescents were given lipid-lowering nutritional treatment as the first intervention level for at least 3-4 months (29.2% and 23.3%) or 6-12 months (58.3% and 53.3%). Nutraceuticals were considered in 41.7% (regarding children) and 50.0% (regarding adolescents) of the centres as a supplementary approach to diet. Lipid-lowering drug therapy initiation was mainly recommended (91.7% and 80.0%). In 83.3% of children and 96.7% of adolescents, statins were the most frequently prescribed drug. We highlighted several differences in the treatment of paediatric patients with suspected FH among Italian centres; however, the overall approach is in line with the European Atherosclerosis Society (EAS) recommendations for FH children and adolescents. We consider this survey as a starting point to reinforce collaboration between LIPIGEN centres and to elaborate in the near future a consensus document on the management of paediatric patients with suspected FH so as to improve and uniform detection, management, and treatment of these patients in our country.

The effects of phytochemicals on serum triglycerides in subjects with hypertriglyceridemia: A systematic review of randomized controlled trials.

This systematic review aimed to evaluate the efficacy of phytochemicals on lipid parameters in patients with hypertriglyceridemia (HTG). A comprehensive search was performed in PubMed/Medline, Scopus, ISI Web of Science, and Google Scholar from inception up to October 2021 to recognize randomized controlled trials (RCTs) assessing the effects of phytochemicals on lipid profiles in patients with HTG. Forty-eight RCTs including 53 arms and comprising 3,478 HTG patients met the eligibility criteria. Phytochemicals significantly reduced the serum levels of triglycerides in 32 out 53 arms, total cholesterol in 22 out of 51, low-density lipoprotein cholesterol in 21 out of 48, very low-density lipoprotein cholesterol in 1 out of 5, apolipoprotein B in 2 out of 4, and lipoprotein(a) levels in 2 out of 4 arms. Furthermore, phytochemicals supplementation increased the levels of high-density lipoprotein cholesterol in 15 out of 48 arms. In brief, phytochemicals supplementation might have beneficial effects on HTG. In most of the studies, phytochemicals had a favorable effect on at least one of the lipid parameters.

Prevalence of vitamin D deficiency and its prognostic impact on patients hospitalized with COVID-19.

OBJECTIVES: Although hypovitaminosis D appears to be highly prevalent in patients with coronavirus disease 2019 (COVID-19), its impact on their prognosis remains unclear. METHODS: In this study, serum 25-hydroxyvitamin D (Vit-D) level was measured in 200 patients hospitalized with COVID-19. The association between Vit-D and the composite endpoint of intensive care unit (ICU) admission/in-hospital death was explored using univariable and multivariable analyses. Also, serum Vit-D level in patients with COVID-19 was compared with that in age- and sex-balanced COVID-19-negative controls (i.e., 50 inpatients with sepsis). RESULTS: Serum Vit-D level was comparable between patients with COVID-19 and COVID-19-negative inpatients with sepsis (P = 0.397). No significant differences were found in serum Vit-D level according to COVID-19 severity at the time of hospital admission (P = 0.299). Incidence rates of the composite endpoint of ICU admission/in-hospital death did not differ significantly between patients with either Vit-D deficiency (i.e., Vit-D <20 ng/mL) or severe Vit-D deficiency (i.e., Vit-D <12 ng/mL) and those without (31% vs 35% with P = 0.649, and 34% vs 30% with P = 0.593, respectively). Vit-D level and status (i.e., Vit-D deficiency and severe Vit-D deficiency) were not prospectively associated with the risk of the composite endpoint of ICU admission/in-hospital death (P > 0.05 for all Cox regression models). CONCLUSIONS: Regardless of the potential usefulness of Vit-D measurement to guide appropriate supplementation, Vit-D does not appear to provide helpful information for the stratification of in-hospital prognosis in patients with COVID-19.

Impact of nutraceuticals on markers of systemic inflammation: Potential relevance to cardiovascular diseases - A position paper from the International Lipid Expert Panel (ILEP).

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.

Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system.

Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential antitumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

Hypercholesterolemia and cardiovascular disease: What to do before initiating pharmacological therapy.

The availability of efficient lipid-lowering drugs has substantially reduced the incidence and mortality for cardiovascular disease (CVD). Despite that, CVD still represents a major cause of death and disability; efforts are thus required to prevent this disease, since reducing the established CV risk factors may slow or prevent the onset of cardiovascular events. Current guidelines recommend a healthier lifestyle for all CV risk categories, as it may have a beneficial impact on several risk factors; in individuals with a low-to-moderate hypercholesterolemia, which are not eligible for a pharmacological approach and are not far from the cholesterol target recommended for their risk category, functional foods or nutraceuticals may be considered as supplement to reduce their CV risk status. Of note, counseling and lifestyle intervention in people at moderate CV risk represents a major issue for both preventing a further risk increase and reducing the need for drugs. Studies on general populations have clearly indicated that lifestyle interventions translate into a clinical benefit, with reduction of the incidence of myocardial infarction and the risk of developing type 2 diabetes.

Toll-like receptors as novel therapeutic targets for herpes simplex virus infection.

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.

Dietary natural products as emerging lipoprotein(a)-lowering agents.

Elevated plasma lipoprotein(a) (Lp(a)) levels are associated with an increased risk of cardiovascular disease (CVD). Hitherto, niacin has been the drug of choice to reduce elevated Lp(a) levels in hyperlipidemic patients but its efficacy in reducing CVD outcomes has been seriously questioned by recent clinical trials. Additional drugs may reduce to some extent plasma Lp(a) levels but the lack of a specific therapeutic indication for Lp(a)-lowering limits profoundly reduce their use. An attractive therapeutic option is natural products. In several preclinical and clinical studies as well as meta-analyses, natural products, including l-carnitine, coenzyme Q 10 , and xuezhikang were shown to significantly decrease Lp(a) levels in patients with Lp(a) hyperlipoproteinemia. Other natural products, such as pectin, Ginkgo biloba, flaxseed, red wine, resveratrol and curcuminoids can also reduce elevated Lp(a) concentrations but to a lesser degree. In conclusion, aforementioned natural products may represent promising therapeutic agents for Lp(a) lowering.

NUtraceutical TReatment for hYpercholesterolemia in HIV-infected patients: The NU-TRY(HIV) randomized cross-over trial.

BACKGROUND AND AIMS: Despite hypercholesterolemia has been recognized to increase cardiovascular risk in human immunodeficiency virus (HIV)-infected patients, cholesterol-lowering therapy is underused in this population, due to fear of drug-drug interactions with antiretroviral therapy (ART). We investigated the effects of a nutraceutical combination (NC) on lipid profile, proprotein convertase subtilisin/kexin type 9 (PCSK9), subclinical inflammation and arterial stiffness in ART-treated HIV-infected patients. METHODS: This was a prospective randomized open-label trial with a cross-over design including 30 stable HIV-infected patients on ART with low-density lipoprotein cholesterol (LDL-C) >115 mg/dL, not taking lipid-lowering treatment. After a 3-week lipid stabilization period, the effects associated with 3 months of an oral NC containing red yeast rice and berberine vs. no active treatment (noNC) were assessed for plasma total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), lipoprotein(a), PCSK9, high-sensitivity C-reactive protein (hs-CRP) levels and aortic pulse wave velocity (aPWV). RESULTS: At baseline, significant correlations between PCSK9 levels, age (rho = -0.51, p=0.004), waist circumference (rho = 0.36, p=0.005) and CD4+ cell count (rho = -0.40, p=0.027) were observed. NC treatment effects corrected for noNC were significant for TC (-14%, p<0.001), LDL-C (-19%, p<0.001), PCSK9 (-12%, p=0.02), hs-CRP (-14%, p=0.03) and aPWV (-6%, p=0.005). No significant effects were observed for HDL-C, TG and lipoprotein(a). NC treatment was safe and no significant alterations in muscle, liver and immunovirological parameters were observed. No carry over effect was recorded. CONCLUSIONS: The tested NC significantly reduced plasma cholesterol and PCSK9 levels, attenuated subclinical inflammation and improved arterial stiffness in stable HIV-infected patients on ART.

Effect of omega-3 supplements on plasma apolipoprotein C-III concentrations: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Apolipoprotein C-III (apo C-III) is a key regulator of triglycerides metabolism. The aim of this meta-analysis was to assess the effect of fish omega-3 polyunsaturated fatty acids (PUFAs) on apo C-III levels. METHODS: Randomized placebo-controlled trials investigating the impact of omega-3 on apo C-III levels were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters. RESULTS: This meta-analysis comprising 2062 subjects showed a significant reduction of apo C-III concentrations following treatment with omega-3 (WMD: -22.18 mg/L, 95% confidence interval: -31.61, -12.75, p < .001; I2: 88.24%). Subgroup analysis showed a significant reduction of plasma apo C-III concentrations by eicosapentaenoic acid (EPA) ethyl esters but not omega-3 carboxylic acids or omega-3 ethyl esters. There was a greater apo C-III reduction with only EPA as compared with supplements containing EPA and docosahexaenoic acid (DHA) or only DHA. A positive association between the apo C-III-lowering effect of omega-3 with baseline apo C-III concentrations and treatment duration was found. CONCLUSIONS: This meta-analysis has shown that omega-3 PUFAs might significantly decrease apo C-III. Key messages Omega-3 PUFA supplements significantly reduce apo C-III plasma levels, particularly in hypertriglyceridemic patients when applied in appropriate dose (more than 2 g/day) Triglyceride (TG)-lowering effect is achieved via peroxisome proliferator-activated receptors α Further studies should address the effect of omega-3 PUFAs alone or with other lipid-lowering drugs in order to provide a final answer whether apo C-III could be an important target for prevention of cardiovascular disease New apo C-III antisense oligonucleotide drug (Volanesorsen) showed to be promising in decreasing elevated TGs by reducing levels of apo C-III mRNA.

Cholesterol-Lowering Nutraceuticals Affecting Vascular Function and Cardiovascular Disease Risk.

PURPOSE OF REVIEW: The aim of this review is to provide an update on the effects of the dietary supplementation with cholesterol-lowering nutraceuticals and nutraceutical combinations affecting vascular function and CV risk in clinical interventional studies. RECENT FINDINGS: Current evidence supports the mild-to-moderate cholesterol-lowering efficacy of red yeast rice, berberine, plant sterols, fibers, and some nutraceutical combinations whereas data on the individual cholesterol-lowering action of other nutraceuticals are either less striking or even inconclusive. There is also promising evidence on the vascular protective effects of some of the aforementioned nutraceuticals. However, except for red yeast rice, clinical interventional studies have not investigated their impact on CV outcomes. Evidence of both cholesterol-lowering and vascular protection is a prerogative of few single nutraceuticals and nutraceutical combinations, which may support their clinical use; however, caution on their uncontrolled adoption is necessary as they are freely available on the market and, therefore, subject to potential misuse.

Biological and pharmacological evaluation of dimethoxycurcumin: A metabolically stable curcumin analogue with a promising therapeutic potential.

Dimethoxycurcumin (DiMC) is a synthetic analog of curcumin with superior inter-related pro-oxidant and anti-cancer activity, and metabolic stability. Numerous studies have shown that DiMC reserves the biologically beneficial features, including anti-inflammatory, anti-carcinogenic, and cytoprotective properties, almost to the same extent as curcumin exhibits. DiMC lacks the phenolic-OH groups as opposed to curcumin, dimethoxycurcumin, and bis-demethoxycurcumin that all vary in the number of methoxy groups per molecule, and has drawn the attentions of researchers who attempted to discover the structure-activity relationship (SAR) of curcumin. In this regard, tetrahydrocurcumin (THC), the reduced and biologically inert metabolite of curcumin, denotes the significance of the conjugated α,ß diketone moiety for the curcumin activity. DiMC exerts unique molecular activities compared to curcumin, including induction of androgen receptor (AR) degradation and suppression of the transcription factor activator protein-1 (AP-1). The enhanced AR degradation on DiMC treatment suggests it as a novel anticancer agent against resistant tumors with androgenic etiology. Further, DiMC might be a potential treatment for acne vulgaris. DiMC induces epigenetic alteration more effectively than curcumin, although both showed no direct DNA hypomethylating activity. Given the metabolic stability, nanoparticulation of DiMC is more promising for in vivo effectiveness. However, studies in this regard are still in its infancy. In the current review, we portray the various molecular and biological functions of DiMC reported so far. Whenever possible, the efficiency is compared with curcumin and the reasons for DiMC being more metabolically stable are elaborated. We also provide future perspective investigations with respect to varying DiMC-nanoparticles.

Curcumin as an Adjunct Therapy and microRNA Modulator in Breast Cancer.

BACKGROUND: Pathogenesis of breast cancer is paralleled by distinct alterations in the expression profile of several microRNAs (miRNAs). Recent studies have shown that miRNAs can serve as diagnostic and prognostic markers, and also as therapeutic targets in breast cancer. Curcumin is a biologically active dietary polyphenol that has emerged with strong anti-tumor properties that are also documented in breast cancer. METHODS: A multi-database electronic search was performed to provide an overview of curcumin as an adjunct therapy and miRNA modulator in breast cancer and highlight the significance of observations for the treatment of cancer therapies. RESULTS: The putative anti-tumor properties of curcumin are mediated by diverse mechanisms including inhibition of cell proliferation, metastasis, migration, invasion and angiogenesis, and induction of G2/M cell cycle arrest, apoptosis and paraptosis. Recent evidence implies that curcumin can interact with several oncogenic and tumorsuppressive miRNAs involved in different stages of breast cancer. In this context, up-regulation of miR181b, miR-34a, miR-16, miR-15a and miR-146b-5p, and down-regulation of miR-19a and miR-19b have been shown following the treatment of several breast cancer cell lines with curcumin. These effects lead to the suppression of tumorigenesis and metastasis, and induction of apoptosis. CONCLUSION: Curcumin appears as an important miRNA modulator in breast cancer. However, further investigations are warranted to elucidate the impact of curcumin on miRNA transcriptome profile of breast cancer and the resulting impact of experimental models.

Effect of soy isoflavone supplementation on plasma lipoprotein(a) concentrations: A meta-analysis.

BACKGROUND: Soy supplementation has been shown to reduce total and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol. However, contradictory effects of soy isoflavone supplementation on lipoprotein(a) [Lp(a)] have been reported suggesting the need for a meta-analysis to be undertaken. OBJECTIVE: The aim of the study was to investigate the impact of supplementation with soy isoflavones on plasma Lp(a) levels through a systematic review and meta-analysis of eligible randomized placebo-controlled trials. METHODS: The search included PubMed-Medline, Scopus, ISI Web of Knowledge, and Google Scholar databases (by March 26, 2017), and quality of studies was evaluated according to Cochrane criteria. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. RESULTS: Ten eligible studies comprising 11 treatment arms with 973 subjects were selected for the meta-analysis. Meta-analysis did not suggest any significant alteration of plasma Lp(a) levels after supplementation with soy isoflavones (standardized mean difference: 0.08, 95% confidence interval: -0.05, 0.20, P = .228). The effect size was robust in the leave-one-out sensitivity analysis. In meta-regression analysis, neither dose nor duration of supplementation with soy isoflavones was significantly associated with the effect size. CONCLUSION: This meta-analysis of the 10 available randomized placebo-controlled trials revealed no significant effect of soy isoflavones treatment on plasma Lp(a) concentrations.

Lipid-lowering activity of artichoke extracts: A systematic review and meta-analysis.

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.

Regulation of PCSK9 by nutraceuticals.

PCSK9 (proprotein convertase subtilisin kexin type 9) is a liver secretory enzyme that regulates plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels through modulation of LDL receptor (LDLR) density on the surface of hepatocytes. Inhibition of PCSK9 using monoclonal antibodies can efficiently lower plasma LDL-C, non-high-density lipoprotein cholesterol and lipoprotein (a). PCSK9 inhibition is also an effective adjunct to statin therapy; however, the cost-effectiveness of currently available PCSK9 inhibitors is under question. Nutraceuticals offer a safe and cost-effective option for PCSK9 inhibition. Several nutraceuticals have been reported to modulate PCSK9 levels and exert LDL-lowering activity. Mechanistically, those nutraceuticals that inhibit PCSK9 through a SREBP (sterol-responsive element binding protein)-independent pathway can be more effective in lowering plasma LDL-C levels compared with those inhibiting PCSK9 through the SREBP pathway. The present review aims to collect available data on the nutraceuticals with PCSK9-inhibitory effect and the underlying mechanisms.

Curcumin as a natural regulator of monocyte chemoattractant protein-1.

Monocyte chemoattractant/chemotactic protein-1 (MCP-1), a member of the CC chemokine family, is one of the key chemokines that regulate migration and tissue infiltration of monocytes/macrophages. Its role in the pathophysiology of several inflammatory diseases has been widely recognized, thus making MCP-1 a possible target for anti-inflammatory treatments. Curcumin (diferuloylmethane) is a natural polyphenol derived from the rhizomes of Curcuma Longa L. (turmeric). Anti-inflammatory action underlies numerous pharmacological effects of curcumin in the control and prevention of several diseases. The purpose of this review is to evaluate the effects of curcumin on the regulation of MCP-1 as a key mediator of chemotaxis and inflammation, and the biological consequences thereof. In vitro studies have shown that curcumin can decrease MCP-1 production in various cell lines. Animal studies have also revealed that curcumin can attenuate MCP-1 expression and improve a range of inflammatory diseases through multiple molecular targets and mechanisms of action. There is limited data from human clinical trials showing the decreasing effect of curcumin on MCP-1 concentrations and improvement of the course of inflammatory diseases. Most of the in vitro and animal studies confirm that curcumin exert its MCP-1-lowering and anti-inflammatory effects by down-regulating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathway. As yet, there is limited data from human clinical trials showing the effect of curcumin on MCP-1 levels and improvement of the course of inflammatory diseases. More evidence, especially from human studies, is needed to better assess the effects of curcumin on circulating MCP-1 in different human diseases and the role of this modulatory effect in the putative anti-inflammatory properties of curcumin.

Is There a Role for Curcumin Supplementation in the Treatment of Non-Alcoholic Fatty Liver Disease? The Data Suggest Yes.

Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease. NAFLD is considered a multifactorial disease and a clinically relevant hepatic manifestation of metabolic syndrome. NAFLD is often accompanied by a constellation of metabolic and non-metabolic alterations, like dyslipidemia, insulin resistance in the liver and peripheral tissues, inflammation and oxidative stress; therefore, treatment of NAFLD should be directed at correcting all of these disturbances. The natural polyphenol curcumin has been the subject of increasing research for the treatment of NAFLD due to its lipid-modifying, antioxidant, anti-inflammatory, insulinsensitizing, anti-steatotic, and anti-fibrotic properties. The therapeutic efficacy of curcumin has been demonstrated in several experimental models of NAFLD, however, clinical evidence is still scarce. The present review summarizes the current knowledge on the impact of curcumin supplementation on different biochemical and histopathological features of NAFLD.