A Nutraceutical Containing Chlorogenic Acid and Luteolin Improves Cardiometabolic Parameters in Subjects with Pre-Obesity: A 6-Month Randomized, Double-Blind, Placebo-Controlled Study.

Pre-obesity is a condition that predisposes to the risk of developing obesity, cardiovascular diseases (CVD), and diabetes. Our previous study demonstrated that a Cynara cardunculus (L.) based nutraceutical named Altilix® (Bionap, Italy), containing chlorogenic acid and luteolin extracts, was able to improve several hepatic and cardio-metabolic parameters. Given this background, we conducted a post-hoc analysis of the Altilix® study in order to analyze the supplement's effects in the subgroup of pre-obesity subjects on anthropometry (weight and waist circumference), glucose metabolism (HbA1C, HOMA-IR, and HOMA-ß), lipid profile (total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol), hepatic functionality (FLI, AST, ALT and AST/ALT), carotid-media thickness (CIMT) and endothelial function (FMD). Fifty subjects from the original study cohort (which consisted of 100 subjects) were chosen with BMI ≥ 25 and < 30 kg/m2. All subjects received the Altilix® supplement (150 mg/day) or placebo using a computer-based random allocation system. After six months of treatment Altilix® significantly reduced body weight, glycemic, and lipid parameters (total cholesterol, triglycerides, LDL-cholesterol) and improved hepatic functionality, CIMT, and FMD. In conclusion, these results confirm that Altilix® supplementation has a significant effect on cardiometabolic parameters not only in obese subjects but also in pre-obesity subjects.

An overview of statin-induced myopathy and perspectives for the future.

Introduction: Statins remain the most commonly prescribed lipid-lowering drug class for the treatment of atherosclerotic cardiovascular disease. Their well-recognized side effects are known as statin-associated muscle symptom (SAMS). Some advances in this field have been made in recent years, but the understanding of the mechanisms has lagged. Investigating the specific role of the anti-HMGCR autoantibody, pharmacokinetic genetic variants, characterization of the known phenotypes of statin toxicity, in relation to clinical markers of disease, is of high importance.Areas covered: We summarized currently available findings (on PubMed) related to SAMS and discussed the therapeutic approaches, risk factors, drug interactions, potential novel systems, algorithms and biomarkers for SAMS detection. CoQ10 supplementation has been suggested as a complementary approach to manage SAMS, while vitamin D levels may be useful for both the diagnosis and management.Expert Opinion/Commentary: Further studies might help to understand the easiest way to diagnose SAMS, suitable prevention and an effective non-statin therapy. This review sheds new light on the future directions in both research and clinical practice, which will help with rapid risk assessment, identification of the SAMS risk factors in order to decrease the incidence of statins' adverse effects, and the most effective therapy.

Altilix® Supplement Containing Chlorogenic Acid and Luteolin Improved Hepatic and Cardiometabolic Parameters in Subjects with Metabolic Syndrome: A 6 Month Randomized, Double-Blind, Placebo-Controlled Study.

The objective was to evaluate the effects of 6 months of supplementation with Altilix®, containing chlorogenic acid and its derivatives, and luteolin and its derivatives, on cardiovascular risk and hepatic markers in subjects with metabolic syndrome (MetS). A randomized, double-blind, placebo-controlled study was performed in 100 subjects with MetS with a follow-up period of 6 months; 50 subjects were randomized to Altilix® (26 men and 24 women, mean age 63 ± 8 years) and the other 50 to placebo (28 men and 22 women, mean age 63 ± 11 years). Anthropometric, cardiometabolic, and hepatic parameters were assessed at baseline and at the end of follow-up. Carotid intima-media thickness and endothelial function were assessed by doppler ultrasound and by flow-mediated dilation of the brachial artery, respectively. The presence and degree of non-alcoholic fatty liver disease (NAFLD) was assessed by the fatty liver index (FLI), and subjects were divided into three subgroups: (1) without NAFLD; (2) with borderline NAFLD; and (3) with NAFLD. After 6 months of Altilix® supplementation, we found a significant improvement vs. placebo in most of the evaluated parameters, including body weight (-2.40% (95% CI -3.79, -1.01); p < 0.001), waist circumference (-2.76% (95% CI -4.55, -0.96); p = 0.003), HbA1c (-0.95% (95% CI -1.22, -0.67); p < 0.001), plasma lipids, FLI (-21.83% (95% CI -27.39, -16.27); p < 0.001), hepatic transaminases, flow-mediated dilation (10.56% (95% CI 5.00, 16.12); p < 0.001), and carotid intima-media thickness (-39.48% (95% CI -47.98, -30.97); p < 0.001). Further, the improvement in cardiometabolic variables was independent of the degree of hepatic steatosis. Altilix® supplementation improved hepatic and cardio-metabolic parameters in MetS subjects. Altilix® supplementation was a beneficial approach in the management of hepatic and cardiometabolic alterations in MetS subjects.

The Role of Nutraceuticals in Statin Intolerant Patients.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

Natural approaches in metabolic syndrome management.

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.

Management of Statin Intolerance in 2018: Still More Questions Than Answers.

Statin therapy is generally well tolerated and very effective in the prevention and treatment of cardiovascular disease, regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, myopathy, rhabdomyolysis, and diabetes mellitus, among others). Patients frequently discontinue statin therapy without medical advice because of perceived side effects and consequently increase their risk for cardiovascular events. In patients with statin intolerance, it may be advisable to change the dose, switch to a different statin, or try an alternate-day regimen. If intolerance is associated with all statins-even at the lowest dose-non-statin drugs and certain nutraceuticals can be considered. This review focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its management, including emerging alternative therapies.

Nutraceuticals as an Important Part of Combination Therapy in Dyslipidaemia.

Several risk factors such as abnormality of lipid metabolism (e.g. high levels of low-density lipoprotein cholesterol (LDL-C), elevated triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C)) play a central role in the aetiology of cardiovascular disease (CVD). Nutraceutical combination together with a cholesterol- lowering action, when associated with suitable lifestyle, should furnish an alternative to pharmacotherapy in patients reporting statin-intolerance and in subjects at low cardiovascular risk. The present review is focused on nutraceuticals and their synergetic combinations demonstrating a beneficial effect in the management of dyslipidaemia. Several nutraceuticals have been shown to positively modulate lipid metabolism having different functions. Plant sterols and soluble fibres can, for example, decrease the intestinal assimilation of lipids and increase their elimination. Furthermore, berberine and soybean proteins improve the cholesterol uptake in the liver. Policosanols, monacolins and bergamot inhibit hydroxy-methyl-glutaryl coenzyme A reductase (HMGCoA reductase) enzyme action determining the cholesterol hepatic synthesis. Moreover, pomegranate can decrease LDL oxidation and positively affect subclinical atherosclerosis; red yeast rice and berberine play, instead, an important role on endothelial dysfunction and psyllium, plant sterols and bergamot have positive effects on LDL subclasses. To the best of our knowledge, there are no long-term large-scale studies on the anti-atherogenic effect of the nutraceuticals that are available on the market. Thus, further clinical studies should investigate in order to achieve long term tolerability and safety and to provide a better nutraceutical combination tailored to the patient needs.

The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex (CubipyOXA) leads to cell death in NCI-H292 cancer cells.

Cell survival and proliferation are central to carcinogenesis, involving various mechanisms among which those that impede apoptosis are important. In this, the role of the molecular chaperone Hsp60 is unclear since it has been reported that it can be both, pro- or anti-apoptotic. A solution to this riddle is crucial to the development of anti-cancer therapies targeting Hsp60. We addressed this question using a tumor cell line, NCI-H292, and [Cu(3,5-bis(2'-pyridyl)-1,2,4-oxadiazole)2(H2O)2](ClO4)2, CubipyOXA, a copper-containing compound with cytotoxic properties. We treated cells with various doses of the compound and measured cell viability; apoptosis indicators; and levels of Hsp60, pro-Caspase-3 (pC3), Caspase-3 (C3), and complex Hsp60/pC3, with complementary methods. The quantitative dose-response curves of the levels of Hsp60, activated C3, inactivated pC3, Hsp60/pC3 complex and indicators of cell apoptosis, and cell death, all coincided to show that CubipyOXA has pro-apoptotic activity and promotes cell death. The curves also indicate that the pro-apoptotic effects of CubipyOXA could likely be due to a lowering of Hsp60 levels and to its blocking the formation of the Hsp60/pC3 complex and/or its dissociating the complex when already formed, thus, interfering with the anti-apoptotic action of Hsp60. These findings shed some light on how a tumor cell may avert apoptosis using Hsp60 and point to the anti-cancer potential of drugs, such as CubipyOXA, which interfere with Hsp60/pC3 complex formation, and thus allow the apoptotic cascade to proceed. In view of these findings it becomes clear that the novel compound CubipyOXA should be considered a potential, high-efficiency antitumor agent deserving further testing.

Nutraceuticals as Lipid-Lowering Treatment in Pregnancy and Their Effects on the Metabolic Syndrome.

Maternal nutrition and lifestyle before and during pregnancy influence both mother and offspring's health and can be correlated with the metabolic syndrome in later life. Findings from animal and human studies indicate that nutrition during pregnancy has an important role in microbiological, metabolic, physiologic and immunologic development and homeostasis. A low nutritional intake in early pregnancy may represent a risk for adverse effects during pregnancy as well as on birth outcome. It seems that dietary supplementation with probiotics in perinatal period may represent safe and practical approach in dealing with the most common adverse pregnancy outcomes such as obesity and gestational diabetes. The SPRING (Study of Probiotics in the prevention of Gestational diabetes) will give important answers about potential benefits of probiotics in pregnant women who are obese and overweight and otherwise at the high risk for complications during pregnancy. Fish oil supplementation during the last trimester of pregnancy showed no effects on plasma lipids and lipoproteins in offspring, as well as on their adiposity. The effect of hypercholesterolemia during pregnancy on both mothers and child needs to be further investigated as it could have a biological role. The guidelines for the eventual clinical approach currently do not exist. Potential benefits of nutraceuticals on several metabolic parameters have been suggested. Limited evidence does not allow to draw final conclusions on preventive health strategies and dietary patterns that should be promoted during pregnancy. Further prospective and intervention studies are needed to establish it. Healthy lifestyle and dietary advice with appropriate supplements usage should be considered.

The effect of bergamot on dyslipidemia.

BACKGROUND: Statins are the most common used lipid lowering drugs but they may cause adverse effects and despite their well-established therapeutic benefits residual cardiovascular (CV) risk remains. The use of other lipid lowering drugs and nutraceuticals alone or as add-on lipid-modifying therapy can be an option in such cases. Several studies have reported health-related properties of the Citrus fruits, among which bergamot (Citrus bergamia Risso) differs from others by particularly high content of certain compounds. PURPOSE: This narrative review summarizes the current evidence on the effects of bergamot on lipid parameters based on studies involving animals and humans. MAIN EVIDENCE: This natural supplement may lead to effective lipid-lowering treatment. Its lipid-lowering activity is attributed to different flavonoids. However, the exact mechanisms involved remain unclear. CONCLUSION: It is expected that ongoing and future studies will confirm the benefit of bergamot in dyslipidemic and other cardiometabolic disorders, potentially leading to reduced overall CV risk.

Anti-cytokine therapy for prevention of atherosclerosis.

BACKGROUND: Currently a chronic inflammation is considered to be the one of the most important reasons of the atherosclerosis progression. A huge amount of researches over the past few decades are devoted to study the various mechanisms of inflammation in the development of atherosclerotic lesions. PURPOSE: To review current capabilities of anti-inflammatory therapy for the prevention and treatment of atherosclerosis and its clinical manifestations. METHODS: Appropriate articles on inflammatory cytokines in atherosclerosis and anti-inflammatory prevention of atherosclerosis were searched in PubMed Database from their respective inceptions until October 2015. SECTIONS: "The role of inflammatory cytokines in the development of atherosclerotic lesions" describes available data on the possible inflammatory mechanisms of the atherogenesis with a special attention to the role of cytokines. "Modern experience of anti-inflammatory therapy for the treatment of atherosclerosis" describes modern anti-inflammatory preparations with anti-atherosclerotic effect including natural preparations. In "the development of anti-inflammatory herbal preparation for atherosclerosis prevention" an algorithm is demonstrated that includes screening of anti-cytokine activity of different natural products, the development of the most effective combination and estimation of its effect in cell culture model, in animal model of the acute aseptic inflammation and in a pilot clinical trial. A natural preparation "Inflaminat" based on black elder berries (Sambucus nigra L.), violet tricolor herb (Viola tricolor L.) and calendula flowers (Calendula officinalis L.) possessing anti-cytokine activity was developed using the designed algorithm. The results of the following 2-year double blind placebo-controlled clinical study show that "Inflaminat" reduces carotid IMT progression, i.e. has anti-atherosclerotic effect. CONCLUSION: Anti-cytokine therapy may be a promising direction in moderation of atherogenesis, especially when it begins on the early stages of subclinical atherosclerosis. The use of herbal preparations with anti-cytokine mechanism of action is the most perspective for timely prevention of atherosclerosis, as they have no significant side effects and can be prescribed for long-term administration.

Effect of a Natural Supplement Containing Curcuma Longa, Guggul, and Chlorogenic Acid in Patients With Metabolic Syndrome.

The impact of a natural supplement (Kepar; Rikrea, Italy), containing several plant extracts such as curcuma longa, silymarin, guggul, chlorogenic acid, and inulin, was evaluated in 78 patients with metabolic syndrome (MetS; 45 men; age: 62 ± 9 years). Kepar at a dose of 2 pills/d was given for 4 months as add-on therapy to the ongoing treatment, maintained at fixed doses for the entire study. Anthropometric variables, plasma lipids, glucose parameters, and oxidative stress were measured at baseline and after 4 months. We found significant reductions in body weight (from 81.1 ± 13.5 to 79.4 ± 12.5 kg, P < .0001), body mass index (from 29.6 [23.7] to 29.3 [21.9] kg/m(2), P = .001), and waist circumference (from 105 ± 11 to 102 ± 10 cm, P = .0004) as well as in fasting glucose (from 6.5 [11.7] to 6.4 [7.6] mmol/L, P = .014) and total cholesterol (from 4.8 ± 1.4 to 4.5 ± 1.0 mmol/L, P = .03). No significant changes were found in the other appraised parameters, including oxidative stress. In conclusion, after few months of treatment Kepar seems to exert beneficial effects in patients with MetS. Larger studies with a longer follow-up period are needed to confirm these preliminary findings.

Nutraceuticals in lipid-lowering treatment: a narrative review on the role of chitosan.

Lipid-lowering drugs may cause adverse effects and, although lipid targets may be achieved, a substantial residual cardiovascular (CV) risk remains. Treatment with agents mimicking proteins present in the body, such as incretin-based therapies, provided promising results. However, in order to improve lipids and CV risk, lifestyle measures remain important. Some researchers focused on nutraceuticals that may beneficially affect metabolic parameters and minimize CV risk. Chitosan, a dietary fiber, can regulate lipids with benefit on anthropometric parameters. The beneficial properties of dietary supplements (such as green tea extract, prebiotics, plant sterols, and stanols) on plasma lipids, lipoproteins, blood pressure, glucose, and insulin levels and their anti-inflammatory and anti-oxidant effects are documented. However, larger, prospective clinical trials are required to confirm such benefits. Such treatments may be recommended when lipid-lowering drugs are neither indicated nor tolerated as well as in order to achieve therapeutic targets and/or overcome residual CV risk.

Emerging approaches for the treatment of hypertriglyceridemia.

Hypertriglyceridemia is frequent in diabetic and obese subjects, who are at increased risk for cardiovascular diseases (CVD). Increased triglycerides (TG) are a hallmark of atherogenic dyslipidemia, representing a marker of atherogenic small dense low-density lipoproteins (sdlDL). Importantly, non-fasting/postprandial TG measurements tend to be emphasized in clinical practice for the prediction of CVD, and TG-lowering agents (primarily fibrates) have a beneficial effect on atherogenic dyslipidemia, reducing TG-rich particles and ultimately lowering the production of sdlDL. The combination of omega-3 fatty acids and statins is also recommended, and widely used in clinical practice for subjects with hypertriglyceridemia. However, a consensus on the optimal clinical use of these pharmacological agents is not fully established yet, and additional large clinical studies are needed. It seems that there is a favorable association between fish consumption and mortality from CVD, but it remains to be confirmed by future trials. Finally, there are a number of novel therapies, such as those targeting microsomal transport protein and its inhibitors, which represent new promising option for treating subjects with hypertriglyceridemia.

Synergistic effect of Gentiana lutea L. on methyl methanesulfonate genotoxicity in the Drosophila wing spot test.

ETHNOPHARMACOLOGICAL RELEVANCE: Gentiana lutea L., the yellow gentian, is herb known for its pharmacological properties, with a long tradition of use for the treatment of a variety of diseases including the use as a remedy for digestion, also in food products and in bitter beverages. The aim of the present study is to evaluate, for the first time, genotoxicity of gentian alone, and its antigenotoxicity against methyl methanesulfonate (MMS). MATERIALS AND METHODS: The water infusion of the underground part of gentian were evaluated in vivo using the Drosophila wing spot test, at the dose commonly used in traditional medicine. For antigenotoxic study two types of treatment with gentian and MMS were performed: chronic co-treatment, as well as post-treatment with gentian after acute exposure with MMS. RESULTS: Water infusion of gentian alone did not exhibit genotoxicity. The results of co- and post-treatment experiments with gentian show that gentian enhanced the frequency of mutant clones over the values obtained with MMS alone, instead of reducing the genotoxicity of MMS, for 22.64% and 27.13% respectively. CONCLUSIONS: This result suggests a synergism of gentian with MMS, and indicates that water infusion of gentian used in traditional medicine may have particular effects with regard to genotoxicity indicating careful use.

Tissue expression analysis of FeMT3, a drought and oxidative stress related metallothionein gene from buckwheat (Fagopyrum esculentum).

Metallothionein type 3 (MT3) expression has previously been detected in leaves, fruits, and developing somatic embryos in different plant species. However, specific tissular and cellular localization of MT3 transcripts have remained unidentified. In this study, in situ RNA-RNA analysis revealed buckwheat metallothionein type 3 (FeMT3) transcript localization in vascular elements, mesophyll and guard cells of leaves, vascular tissue of roots and throughout the whole embryo. Changes in FeMT3 mRNA levels in response to drought and oxidative stress, as well as ROS scavenging abilities of the FeMT3 protein in yeast were also detected, indicating possible involvement of FeMT3 in stress defense and ROS related cellular processes.

Buckwheat (Fagopyrum esculentum Moench) FeMT3 gene in heavy metal stress: protective role of the protein and inducibility of the promoter region under Cu(2+) and Cd(2+) treatments.

The protective role in vivo of buckwheat metallothionein type 3 (FeMT3) during metal stress and the responsiveness of its promoter to metal ions were examined. Increased tolerance to heavy metals of FeMT3 producing Escherichia coli and cup1(Delta) yeast cells was detected. The defensive ability of buckwheat MT3 during Cd and Cu stresses was also demonstrated in Nicotiana debneyii leaves transiently expressing FeMT3. In contrast to phytochelatins, the cytoplasmatic localization of FeMT3 was not altered under heavy metal stress. Functional analysis of the corresponding promoter region revealed extremely high inducibility upon Cu(2+) and Cd(2+) treatments. The confirmed defense ability of FeMT3 protein in vivo and the great responsiveness of its promoter during heavy metal exposure make this gene a suitable candidate for biotechnological applications.