Introduction

Cardiovascular disease, and in particular coronary heart disease (CHD), is the main cause of mortality in developed countries [1]. In atherosclerosis development, cholesterol, and in particular low-density lipoprotein (LDL) cholesterol, plays the main role: usually atherosclerosis begins with endothelial damage caused by high blood pressure, smoking, or high cholesterol. The cornerstone of hypolipidemic treatment should be appropriated lifestyle modifications and statin treatment, or 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors [2]. Statins are demonstrably effective in reducing cholesterol [3], but they also have some potential adverse effects, including muscle pain with creatine phosphokinase (CPK) elevation, fatigue and weakness, and liver transaminases increase [4].

The incidence of adverse events is dose related; the higher the dose of statin is, the more frequent can be the adverse events. Because of those adverse events, patients may seek alternative therapies to manage their hypercholesterolemia, including newer hypolipidemic therapies such as PCSK9 inhibitors, even if their use is limited by the high cost.

For all these reasons, in recent years, the nutraceutical market has rapidly increased. Nutraceuticals are dietary supplements. They contain a concentrated form of a presumed bioactive substance originally derived from a food, but now present in a nonfood matrix, and used to enhance health in dosages exceeding those obtainable from normal foods [5]. Several substances have shown positive benefits for lipid profile, such as Berberis aristata, omega-3, krill oil, and cinnamon [6–11].

In particular, in this study we focused our attention on two nutraceutical combinations aimed to improve lipid profile, one called Rossopuro Forte (S1), a blend of natural components derived from rice and fermented rice (monacolin K 3%, γ-oryzanol, and γ-aminobutyric acid) developed by Giellepi S.p.A. (Lissone, Monza MB, Italy) and one called Rossopuro (S2) containing monacolin K 3% alone.

In this context, we planned a study to evaluate the efficacy and safety of the two nutraceutical agents in a sample of C57BL/6J mice fed with a standard diet (SD), or high-fat diet (HFD), or HFD with the addition of S1 or S2. The primary outcomes were the effects of these nutraceutical combinations on the lipid profile; the secondary outcomes were considered the changes in C-reactive protein (CRP).

Material and methods

Results

Discussion

In our study we observed a better effect of the combination of monacolin K, γ-oryzanol, and γ-aminobutyric acid compared to monacolin K alone, probably due to the synergic effect of the various components. Monacolin K has been extensively studied. Several intervention studies have demonstrated that red yeast rice containing 5 to 10 mg of monacolin K lowers elevated LDL-C levels by about 22% to 27% [12–14]. The European Food Safety Authority considers that a daily intake of 10 mg of monacolin K from red yeast rice contributes to the maintenance of a normal LDL-C plasma level. Less known is γ-oryzanol. Rice (Oryza sativa L.) bran is a by-product produced in processing rice. Traditionally, rice bran, produced as a by-product during milling, is considered as waste. However, it is a fact that rice bran comprises up to 10% of rough rice and is a rich natural source of important antioxidant polyphenolics, flavonoids, phytic acid, vitamin E and γ-oryzanol. Gamma-oryzanol is an anti-oxidant compound associated with decreases in plasma cholesterol, cholesterol absorption, and platelet aggregation [15]. Oryzanol has also been used to treat hyperlipidemia and disorders of menopause and to increase the muscle mass [16]. On the other side, γ-aminobutyric acid is one of the many nutritional components in brown rice and pre-germinated brown rice with slight germination. It has been reported that pre-germinated brown rice rich in γ-aminobutyric acid effectively reduced glucose levels in diabetic rats [17]. γ-Aminobutyric acid also showed anti-anxiety effects [18] and positive effects against chronic renal failure [19]. γ-Oryzanol was also suggested to show blood cholesterol lowering [20] and anti-oxidant effects [21].

In conclusion, the study showed that a nutraceutical combination containing monacolin K 3%, γ-oryzanol, and γ-aminobutyric acid is more effective than monacolin K 3% alone in reducing the negative effects of a HFD in a sample of specific pathogen-free 4-week-old male C57BL/6J mice. These data are really interesting, and are a good starting point for future studies in humans. Of course, nutraceuticals cannot replace an appropriate lifestyle, but should be complementary, and used before starting traditional therapy in low cardio-metabolic risk patients. We also need to consider that an improvement of lipid profile does not always translate into a net cardiovascular benefit for the patient. Studies examining “hard” clinical endpoints are necessary to prove the efficacy of a hypolipidemic treatment, because at present nutraceuticals lack such major studies.