The Impact of Red Yeast Rice Extract Use on the Occurrence of Muscle Symptoms and Liver Dysfunction: An Update from the Adverse Event Reporting Systems and Available Meta-Analyses.

Red yeast rice (RYR) has a cholesterol-lowering effect due to the presence of bioactive components (monacolins, mainly monacolin K) that act by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The European Food Safety Authority (EFSA) assessed the use of RYR and, while pointing out several uncertainties regarding the available data, raised a warning related to the safety of RYR when used as a food supplement at a dose of monacolin as low as 3 mg/day. In their decision in June 2023, EFSA approved the use of monacolins from RYR at doses less than 3 mg/day. We therefore decided to interrogate the different adverse event reporting systems (FAERS and CAERS) and analyse the characteristics of the cases reported to be associated with RYR supplements, and we reviewed the most recent meta-analyses with a focus on the occurrence of muscle symptoms and liver dysfunction. In terms of all musculoskeletal disorders from September 2013 (when the first case related to RYR consumption was recorded) to 30 September 2023, 363,879 cases were reported in the FAERS, with the number of cases related to RYR consumption being very small and accounting for 0.008% of cases. In the same time frame, 27,032 cases of hepatobiliary disorders were reported, and the cases attributable to RYR ingestion accounted for 0.01% of all cases. A low rate of muscle symptoms and liver dysfunction attributed to RYR ingestion was also observed in the CAERS database, where only 34 cases of adverse muscle events and 10 cases of adverse liver events reported RYR as the suspect product, while 19 cases of both muscle events and 10 cases of adverse liver events reported it as a concomitant product. This profile mirrors that of meta-analyses of randomised clinical trials of RYR, in which RYR use was not associated with either liver dysfunction or muscular adverse symptoms.

Rhabdomyolysis or Severe Acute Hepatitis Associated with the Use of Red Yeast Rice Extracts: an Update from the Adverse Event Reporting Systems.

PURPOSE OF REVIEW: Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for atherosclerotic cardiovascular disease (ASCVD), and lowering LDL-C reduces the risk of cardiovascular adverse events. Among natural approaches known for their lipid-lowering properties, red yeast rice (RYR) has a cholesterol-lowering effect due to the presence of bioactive components (monacolins) that act by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In August 2018, the European Food Safety Authority (EFSA) concluded in its assessment of the use of RYR (further amended in June 2022) that monacolins from RYR raise significant safety concerns when used as a food supplement at a dose of 10 mg/day. In particular, individual cases of serious adverse effects of monacolins from RYR have been reported at intakes as low as 3 mg/day. The EFSA Panel pointed out several uncertainties regarding the available data. RECENT FINDINGS: We conducted an in-depth and updated analysis of the serious adverse events, with a focus on rhabdomyolysis and acute hepatitis, associated with the consumption of RYR. An analysis of the Food and Drug Administration reporting systems revealed a very small number of cases of rhabdomyolysis or severe acute hepatitis associated with RYR use. In addition, only a few case reports of these serious adverse events associated with RYR use have been published. Based on data from adverse event reporting systems and available case reports, the occurrence of rhabdomyolysis or severe acute hepatitis that could be associated with the use of RYR appears to be extremely rare compared to the occurrence with statins, which is rare to common.

MOMAST® Reduces the Plasmatic Lipid Profile and Oxidative Stress and Regulates Cholesterol Metabolism in a Hypercholesterolemic Mouse Model: The Proof of Concept of a Sustainable and Innovative Antioxidant and Hypocholesterolemic Ingredient.

MOMAST® is a patented natural phenolic complex, rich in tyrosol (9.0 g/kg, Tyr), hydroxityrosol (43,5 g/kg, OH-Tyr), and verbascoside (5.0 g/Kg), which is obtained from the OVW by-product of the Coratina cultivar with potent direct antioxidant activity (measured by DPPH and FRAP assays, respectively). Indeed, MOMAST® represents an innovative sustainable bioactive ingredient which has been obtained with ethical and empowering behavior by applying the principles of a circular economy. In the framework of research aimed at fostering its health-promoting activity, in this study it was clearly demonstrated that MOMAST® treatment reduced the oxidative stress and levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, and increased the HDL levels, without changes in the triglyceride (TG) levels in Western diet (WD)-fed mice. The modulation of the plasmatic lipid profile is similar to red yeast rice (RYR) containing Monacolin K (3%). In addition, at the molecular level in liver homogenates, similarly to RYR, MOMAST® exerts cholesterol-lowering activity through the activation of LDL receptor, whereas, unlike RYR, MOMAST® reduces proprotein convertase subtilisin/kexin type 9 (PCSK9) protein levels via hepatic nuclear factor 1 (HNF1)-α activation. Hence, this study provides the proof of concept regarding the hypocholesterolemic activity of MOMAST, which could be successfully exploited as an active ingredient for the development of innovative and sustainable dietary supplements and functional foods.

Low Dose Monacolin K Combined with Coenzyme Q10, Grape Seed, and Olive Leaf Extracts Lowers LDL Cholesterol in Patients with Mild Dyslipidemia: A Multicenter, Randomized Controlled Trial.

Certain nutraceuticals, mainly containing red yeast rice, might be considered as an alternative therapy to statins in patients with dyslipidemia, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. The aim of this study was to assess the lipid-lowering activity and safety of a dietary supplement containing a low dose of monacolin K combined with coenzyme Q10, grape seed and olive tree leaf extracts in patients with mild hypercholesterolemia. In total, 105 subjects with mild hypercholesterolemia (low-density lipoprotein cholesterol LDL-C levels 140-180 mg/dL) and low CV risk were randomly assigned into three treatment groups: lifestyle modification (LM), LM plus a low dosage of monacolin K (3 mg), and LM plus a high dosage of monacolin K (10 mg) and treated for 8 weeks. The primary endpoint was the reduction of LDL-C and total cholesterol (TC). LDL-C decreased by 26.46% on average (p < 0.001) during treatment with 10 mg of monacolin and by 16.77% on average during treatment with 3 mg of monacolin (p < 0.001). We observed a slight but significant reduction of the triglyceride levels only in the high-dose-treated group (mean -4.25%; 95% CI of mean -11.11 to 2.61). No severe adverse events occurred during the study. Our results confirm the LDL-C-lowering properties of monacolin are clinically meaningful even in lower doses of 3 mg/day.

A Nutraceutical Compound Containing a Low Dose of Monacolin K, Polymethoxyflavones, Phenolic Acids, Flavonoids, and Hydroxytyrosol Improves HDL Functionality.

BACKGROUND: In earlier studies, it has been observed that 8-week treatment with a novel nutraceutical compound (NC) containing low monacolin K dose, polymethoxyflavones, phenolic acids, flavonoids, and hydroxytyrosol improves lipid profile and endothelial function and reduces the level of oxidized low-density lipoprotein (oxLDL). We hypothesize that this effect might be, at least in part, explained by positive modulation exerted by the NC on the atheroprotective function of high-density lipoprotein (HDL). AIM: This study aimed to evaluate whether the NC could influence determinants of HDL function. METHODS: Forty-five subjects with low-moderate dyslipidaemia were enrolled and treated for 8 weeks with the NC, followed by 4 weeks of washout. Blood samples were collected at every time point to evaluate changes in lipid profile, endothelial function, oxLDL, and markers of HDL function, such as the anti-oxidant activities of paraoxonase-1, glutathione peroxidase-3 (Gpx3), lipoprotein-phospholipase A2 (Lp-PLA2), and pro-oxidant activity of myeloperoxidase (MPO). RESULTS: Although the concentration of HDL-C did not change, the activity of Lp-PLA2 significantly decreased upon treatment (-11.6%, p<0.001) and returned to baseline level 4 weeks after the end of treatment. In contrast, Gpx3 increased after treatment (+5%, p<0.01) and remained unvaried after 4 weeks. Both MPO activity and concentration significantly decreased after the washout period (-33 and 32%, p<0.001). CONCLUSION: For the first time, it was found that the administration of an NC with beneficial effects on lipid homeostasis also positively impacts HDL function by improving the balance between protective and damaging determinants. Further investigation is required to corroborate our findings.

The Role of Nutraceutical Supplements, Monacolin K and Astaxanthin, and Diet in Blood Cholesterol Homeostasis in Patients with Myopathy.

Several studies suggest that different combinations of nutraceutical supplements may improve the lipid profile, representing a viable alternative to statins. However, their effects on individuals with myopathy need to be investigated. The aim of our study was to explore the mid- and long-term physiological effects of monacolin k (5 mg) and astaxanthin (0.1 mg) supplements in association with a low-energy/fat diet in a group of subjects with mild myopathy. Eighty subjects (44 women) took part in this observational study. Participants were assigned to the experimental group (EG, n = 40, 24 women) treated with a low-energy/fat diet (1200-1500 Kcal/day and 15-20% lipids) in combination with monacolin k (5 mg) and astaxanthin (0.1 mg) supplementation, and to the control group (CG, n = 40, 20 women) treated only with a low-energy/fat diet (1200-1500 Kcal/day and 15-20% lipids). BMI and biochemical parameters (blood glucose, total cholesterol, HDL, LDL, triglycerides, C-reactive protein (CRP) and creatine phosphokinase-CPK) were collected at baseline (T0), after 12 (T1) and 24 (T2) weeks. A mixed factorial ANOVA was performed to determine if there were significant main effects and/or interactions between time and treatment. Treatment (EG vs. CG) was entered as the between-subjects factor and time (T0 vs. T1 vs. T2) as the within-subject factor. We found a significant improvement in total cholesterol, HDL, LDL, PCR and CPK parameters in EG compared with CG. Our results highlight the efficacy and safety of combined use of monacolin k (5 mg) and astaxanthin (0.1 mg) in combination with a low-energy/fat diet in the treatment of dyslipidemia.

Identification of the high-yield monacolin K strain from Monascus spp. and its submerged fermentation using different medicinal plants.

BACKGROUND: Medical plants confer various benefits to human health and their bioconversion through microbial fermentation can increase efficacy, reduce toxicity, conserve resources and produce new chemical components. In this study, the cholesterol-lowering monacolin K genes and content produced by Monascus species were identified. The high-yield monacolin K strain further fermented with various medicinal plants. The antioxidant and anti-inflammatory activities, red pigment and monacolin K content, total phenolic content, and metabolites in the fermented products were analyzed. RESULTS: Monacolin K was detected in Monascus pilosus (BCRC 38072), and Monascus ruber (BCRC 31533, 31523, 31534, 31535, and 33323). It responded to the highly homologous mokA and mokE genes encoding polyketide synthase and dehydrogenase. The high-yield monacolin K strain, M. ruber BCRC 31535, was used for fermentation with various medicinal plants. A positive relationship between the antioxidant capacity and total phenol content of the fermented products was observed after 60 days of fermentation, and both declined after 120 days of fermentation. By contrast, red pigment and monacolin K accumulated over time during fermentation, and the highest monacolin K content was observed in the fermentation of Glycyrrhiza uralensis, as confirmed by RT-qPCR. Moreover, Monascus-fermented medicinal plants including Paeonia lactiflora, Alpinia oxyphylla, G. uralensis, and rice were not cytotoxic. Only the product of Monascus-fermented G. uralensis significantly exhibited the anti-inflammatory capacity in a dose-dependent manner in lipopolysaccharide-induced Raw264.7 cells. The metabolites of G. uralensis with and without fermentation (60 days) were compared by LC/MS. 2,3-Dihydroxybenzoic acid, 3,4-dihydroxyphenylglycol, and 3-amino-4-hydroxybenzoate were considered to enhance the antioxidant and anti-inflammatory ability. CONCLUSIONS: Given that highly homologous monacolin K and citrinin genes can be observed in Monascus spp., monacolin K produced by Monascus species without citrinin genes can be detected through the complementary methods of PCR and HPLC. In addition, the optimal fermentation time was important to the acquisition of antioxidants, red pigment and monacolin K. These bioactive substances were significantly affected by medicinal plants over fermentation time. Consequently, Monascus-fermented G. uralensis had a broad spectrum of biological activities.

Randomized, Double-Blind, Placebo-Controlled Trial to Test the Effects of a Nutraceutical Combination Monacolin K-Free on the Lipid and Inflammatory Profile of Subjects with Hypercholesterolemia.

BACKGROUND: Nutraceutical combinations (NCs) against hypercholesterolemia are increasing in the marketplace. However, the availability of NCs without monacolin K is scarce even though the statin-intolerant population needs it. METHODS: This study is a parallel-group, randomized, placebo-controlled, double-blind trial. We evaluated the effects of the NC containing phytosterols, bergamot, olive fruits, and vitamin K2 on lipid profile and inflammatory biomarkers in 118 subjects (mean age ± SD, 57.9 ± 8.8 years; 49 men and 69 women) with hypercholesterolemia (mean total cholesterol ± SD, 227.4 ± 20.8 mg/dL) without clinical history of cardiovascular diseases. At baseline and 6 and 12 weeks of treatment, we evaluated lipid profile (total, LDL and HDL cholesterol, and triglycerides), safety (liver, kidney, and muscle parameters), and inflammatory biomarkers such as hs-CRP, leukocytes, interleukin-32, and interleukin-38 and inflammatory-microRNAs (miRs) miR-21, miR-126, and miR-146a. RESULTS: Compared to the placebo, at 6 and 12 weeks, NC did not significantly reduce total cholesterol (p = 0.083), LDL cholesterol (p = 0.150), and triglycerides (p = 0.822). No changes were found in hs-CRP (p = 0.179), interleukin-32 (p = 0.587), interleukin-38 (p = 0.930), miR-21 (p = 0.275), miR-126 (p = 0.718), miR-146a (p = 0.206), myoglobin (p = 0.164), and creatine kinase (p = 0.376). Among the two reported, only one adverse event was probably related to the nutraceutical treatment. CONCLUSIONS: The evaluated nutraceutical combination did not change serum lipid profile and inflammatory parameters, at least not with the daily dose applied in the present study.

Preparation of Monascus-fermented ginkgo seeds: optimization of fermentation parameters and evaluation of bioactivity.

In this study, a high monacolin K yield was achieved through solid-state fermentation of Ginkgo biloba seeds. Monascus purpureus suspension made from red yeast rice was used as spore inoculum. Fermentation conditions in solid-state fermentation were optimized using response surface methodology, and the optimal conditions for the maximum monacolin K yield (17.71 ± 1.57 mg/g) were 0.22% ammonium sulfate, 0.34% ammonium chloride, 0.05% magnesium sulfate, fermentation time of 12 days, inoculation volume of 11%, and temperature of 27 °C. The total phenolic content of Monascus-fermented ginkgo seeds attained 9.67 mg GAE/g, 4.88-fold higher than that of unfermented ginkgo seeds. The scavenging abilities of DPPH and ABTS free radicals increased to 9.79 mg TE/g and 13.92 mg TE/g, respectively. These findings highlight the importance of investigating the optimal fermentation conditions for maximum monacolin K yield and the utilization value of ginkgo seed as fermentation substrate for higher bioactivities. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01078-z.

A descriptive study of commercial herbal dietary supplements used for dyslipidemia-Sales data and suspected adverse reactions.

Herbal dietary supplements (HDS) used for dyslipidemia represent a category of concern in Italy for suspected adverse reactions (ARs). However, we cannot estimate their safety, as we do not know their commercial profile. Sales data of HDS, and particularly, those used for dyslipidemia, were monitored for 2 years in two pharmacies of Rome. Meanwhile, spontaneous reports of suspected ARs potentially related to dyslipidemia supplements were collected by the Italian Phytovigilance System. The 50% of the total dietary supplements are herbal-derived; the 9% of HDS are recommended for dyslipidemia. From our data, 113 different brands have claims for improving lipids profile and 91% of them are multiingredient preparations. Fifteen spontaneous reports of suspected ARs concerned HDS used, for dyslipidemia. The most frequent ARs were joint, abdominal, and muscles pain; vomiting; erythema and hematological disorders; nausea; and rhabdomyolysis. Our findings point out the limited compliance of commercial dyslipidemia-HDS and scientific research about their intrinsic safety. A wide range of ingredients could not support the risk/benefit profile of the supplement. The variable compositions of HDS do not assure the safety, as they do not support the reproducibility of their pharmacological activities. This study could contribute to optimize consumer guidance about what they purchase and consume.

The Activity of Ten Natural Extracts Combined in a Unique Blend to Maintain Cholesterol Homeostasis-In Vitro Model.

BACKGROUND: Hypercholesterolemia is a major cause of cardiovascular disease and statins, the HMGCoA inhibitors, are the most prescribed drugs. Statins reduce the production of hepatic cholesterol, leading to greater expression of the LDL receptor and greater absorption of circulating LDL, reducing peripheral LDL levels. Unfortunately, statins are believed to induce myopathy and other severe diseases. To overcome this problem, safe nutraceuticals with the same activity as statins could hold great promise in the prevention and treatment of hypercholesterolemia. In this study, the anti-cholesterol efficacy of a new nutraceutical, called Esterol10®, was evaluated. METHODS: HepG2 cells were used to study the biological mechanisms exerted by Esterol10® analyzing different processes involved in cholesterol metabolism, also comparing data with Atorvastatin. RESULTS: Our results indicate that Esterol10® leads to a reduction in total hepatocyte cholesterol and an improvement in the biosynthesis of free cholesterol and bile acids. Furthermore, the anti-cholesterol activity of Esterol10® was also confirmed by the modulation of the LDL receptor and by the accumulation of lipids, as well as by the main intracellular pathways involved in the metabolism of cholesterol. CONCLUSIONS: Esterol10® is safe and effective with anti-cholesterol activity, potentially providing an alternative therapy to those based on statins for hypercholesterolemia disease.

A Combination of Lactoplantibacillus plantarum Strains CECT7527, CECT7528, and CECT7529 Plus Monacolin K Reduces Blood Cholesterol: Results from a Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Dietary supplements have been proposed to help manage blood cholesterol, including red yeast rice (RYR) extracts, plant sterols and stanols, beta-glucans, and some probiotics. This study was conducted to evaluate the efficacy of RYR (containing 10 mg of monacolin K) combined with 109 CFU of three Lactoplantibacillus plantarum strains (CECT7527, CECT7528, and CECT7529). METHODS: A 12-week randomized, double-blinded, placebo-controlled clinical trial was conducted. In total, 39 adult patients were enrolled, having total cholesterol (TC) ≥200 mg/dL, and being statin-naïve or having recently stopped statin treatment because of intolerance. Active product or placebo were taken once daily, and subjects were evaluated at baseline, 6, and 12 weeks. RESULTS: Study groups were comparable at baseline, except for history of recent hypercholesterolemia treatment (81% in active vs. 22% in placebo). Changes in LDL cholesterol and TC became significant compared to placebo (mean difference between groups and standard error of the mean = 23.6 ± 1.5 mg/dL, p = 0.023 and 31.4 ± 1.9 mg/dL, p = 0.011, respectively) upon adjusting for the baseline imbalance in hypercholesterolemia treatment. No adverse effects were noted during the study. CONCLUSION: This combination of 10 mg of monacolin K and L. plantarum strains was well tolerated and achieved a statistically significant greater reduction in LDL-C and TC in the intervention group compared to the placebo, once adjusting for recent history of hypercholesterolemia treatment.

Red Yeast Rice for Hypercholesterolemia: JACC Focus Seminar.

The extracts of red yeast rice (RYR) are currently the most effective cholesterol-lowering nutraceuticals. This activity is mainly due to monacolin K, a weak reversible inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, whose daily consumption causes a reduction in low-density lipoprotein (LDL)-cholesterol plasma levels up to 15% to 25% within 6 to 8 weeks. The decrease in LDL-cholesterol is accompanied by a proportional decrease in total and non-high-density lipoprotein cholesterol, plasma apolipoprotein B, and high-sensitivity C-reactive protein. Some trials suggest that RYR use is associated with improvement in endothelial function and arterial stiffness, whereas a long-term study supports its role in the prevention of cardiovascular events. Despite the statin-like mechanism of action, the risk related to 3 to 10 mg monacolin K taken per day is minimal (mild myalgia in previously severely statin-intolerant subjects). RYR could represent a therapeutic tool to support lifestyle improvement in managing mild to moderate hypercholesterolemia in low-risk patients, including those who cannot be treated with statins or other LDL-cholesterol-lowering therapies.

Interactions of Oxysterols with Atherosclerosis Biomarkers in Subjects with Moderate Hypercholesterolemia and Effects of a Nutraceutical Combination (Bifidobacterium longum BB536, Red Yeast Rice Extract) (Randomized, Double-Blind, Placebo-Controlled Study).

BACKGROUND: Oxysterol relationship with cardiovascular (CV) risk factors is poorly explored, especially in moderately hypercholesterolaemic subjects. Moreover, the impact of nutraceuticals controlling hypercholesterolaemia on plasma levels of 24-, 25- and 27-hydroxycholesterol (24-OHC, 25-OHC, 27-OHC) is unknown. METHODS: Subjects (n = 33; 18-70 years) with moderate hypercholesterolaemia (low-density lipoprotein cholesterol (LDL-C:): 130-200 mg/dL), in primary CV prevention as well as low CV risk were studied cross-sectionally. Moreover, they were evaluated after treatment with a nutraceutical combination (Bifidobacterium longum BB536, red yeast rice extract (10 mg/dose monacolin K)), following a double-blind, randomized, placebo-controlled design. We evaluated 24-OHC, 25-OHC and 27-OHC levels by gas chromatography/mass spectrometry analysis. RESULTS: 24-OHC and 25-OHC were significantly correlated, 24-OHC was correlated with apoB. 27-OHC and 27-OHC/total cholesterol (TC) were higher in men (median 209 ng/mL and 77 ng/mg, respectively) vs. women (median 168 ng/mL and 56 ng/mg, respectively); 27-OHC/TC was significantly correlated with abdominal circumference, visceral fat and, negatively, with high-density lipoprotein cholesterol (HDL-C). Triglycerides were significantly correlated with 24-OHC, 25-OHC and 27-OHC and with 24-OHC/TC and 25-OHC/TC. After intervention, 27-OHC levels were significantly reduced by 10.4% in the nutraceutical group Levels of 24-OHC, 24-OHC/TC, 25-OHC, 25-OHC/TC and 27-OHC/TC were unchanged. CONCLUSIONS: In this study, conducted in moderate hypercholesterolemic subjects, we observed novel relationships between 24-OHC, 25-OHC and 27-OHC and CV risk biomarkers. In addition, no adverse changes of OHC levels upon nutraceutical treatment were found.

Effectiveness and Safety of Novel Nutraceutical Formulation Added to Ezetimibe in Statin-Intolerant Hypercholesterolemic Subjects with Moderate-to-High Cardiovascular Risk.

The effectiveness of statins in the primary and secondary prevention of cardiovascular (CV) diseases has been widely proven. However, the onset of adverse events associated with their use prevents to achieve the therapeutic targets recommended by the guidelines (GL) for the management of dyslipidemia. In the event of statin intolerance, the GL recommend to use bile acid sequestrants, fibrates, and ezetimibe in monotherapy, but their benefits in improving lipid pattern are quite modest. This study aims at evaluating the effectiveness and safety of a nutraceutical compound (NC) associated with ezetimibe (EZE) on the lipid profile in statin-intolerant patients with moderate-to-high CV risk. Ninety-six statin-intolerant hypertensive and hypercholesterolemic subjects treated pharmacologically with EZE 10 mg daily were randomized in open label (n = 48) to take for 3 months a NC containing Monacolin-K (MK), Berberine Hydrochloride (BC), t-Resveratrol (RES), Quercetin (QUER), and Chromium (CH) in the form of a gastro-resistant tablet that improves enteric bioaccessibility and bioavailability of these substances. The control group (n = 48) took only EZE in monotherapy at the same dosage; both groups followed a standardized lipid-lowering diet. The total serum cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine phosphokinase (CPK) levels were compared at the follow-up in both groups using Student's t-test. TC and LDL levels reduced in both groups, but were lower in the group treated with EZE + NC (-25.9% vs. -15%, P < .05 and -38.7% vs. -21.0%, P < .05, respectively). No changes were observed in either group regarding a decrease in TG (-9.4% vs. -11.7%, NS) and an increase in HDLC (+4.2% vs. +1.1%, NS). The AST, ALT, and CPK levels increased in the group treated with the EZE + NC compared to the control group, but were still within the acceptable range. There was no difference concerning the lipid-lowering treatment between gender, and no patient withdrew from the study. In the short term, the EZE + NC combination therapy is well tolerated and effective in improving TC and LDLC levels in statin-intolerant patients with moderate-to-high CV risk.

Efficacy of Nutraceutical Combination of Monacolin K, Berberine, and Silymarin on Lipid Profile and PCSK9 Plasma Level in a Cohort of Hypercholesterolemic Patients.

The guidelines for the treatment of dyslipidemias include the use of nutraceuticals (NUTs) in association with lifestyle modifications to achieve therapeutic goals. In NUT pill, different substances may be associated; in this study we investigated a combined NUT containing monacolin K (MonK)+KA (1:1), berberine (BBR), and silymarin. The aim of the study was to evaluate low-density lipoprotein cholesterol (LDL-C) reduction in 53 patients suffering from polygenic hypercholesterolemia, characterized by a low/intermediate cardiovascular risk calculated with SCORE algorithm. The effects on lipid profile of 2-month treatment with NUT containing MonK+KA (1:1), BBR, and sylimarin, were compared with Atorvastatin (ATO) 10 mg administrated in a matched control group. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the cholesterol loading capacity (CLC) were determined at baseline and at the end of the study in NUT-treated group; variations were assessed. NUT was effective as lipid-lowering agent with a wide interindividual response variability (mean LDL-C from 170.8 ± 19.9 to 123.8 ± 20.0 with a change of -47.0 ± 21.5 mg/dL; P < .001) and the effect was similar to that induced by ATO. The use of NUT significantly modified PCSK9 levels (P < .01) and CLC (P < .001), ultimately suppressing the serum-mediated foam cell generation directly measured on human macrophages. NUT reduces LDL-C levels with an effect similar to what is induced by 10 mg of ATO and ex vivo improves the functional profile of lipoproteins with antiatherogenic action.

Development of an Improved Menopausal Symptom-Alleviating Licorice (Glycyrrhiza uralensis) by Biotransformation Using Monascus albidulus.

Licorice (Glycyrrhiza uralensis) contains several compounds that have been reported to alleviate menopausal symptoms via interacting with estrogen receptors (ERs). The compounds exist mainly in the form of glycosides, which exhibit low bioavailability and function. To bioconvert liquiritin and isoliquiritin, the major estrogenic compounds, to the corresponding deglycosylated liquiritigenin and isoliquiritigenin, respectively, licorice was fermented with Monascus, which has been demonstrated to deglycosylate other substances. The contents of liquiritigenin and isoliquiritigenin in Monascus-fermented licorice increased by 10.46-fold (from 38.03 µM to 379.75 µM) and 12.50-fold (from 5.53 µM to 69.14 µM), respectively, compared with their contents in non-fermented licorice. Monascus-fermented licorice exhibited 82.5% of the ERß binding activity of that observed in the positive control (17 ß-estradiol), whereas the non-fermented licorice exhibited 54.1% of the binding activity in an in vivo ER binding assay. The increase in the ERß binding activity was associated with increases in liquiritigenin and isoliquiritigenin contents. Liquiritigenin acts as a selective ligand for ERß, which alleviates menopausal symptoms with fewer side effects, such as heart disease and hypertension, compared with a ligand for ERα. In addition, Monascus-fermented licorice contained 731 mg/kg of monacolin K, one of the metabolites produced by Monascus that reduces serum cholesterol. Therefore, Monascus-fermented licorice is a promising material for the prevention and treatment of menopausal syndrome with fewer side effects.

Metabolomics Analysis of the Effect of Glutamic Acid on Monacolin K Synthesis in Monascus purpureus.

Monacolin K is a secondary metabolite produced by Monascus with beneficial effects on health, including the ability to lower cholesterol. We previously showed that the yield of monacolin K was significantly improved when glutamic acid was added to the fermentation broth of Monascus purpureus M1. In this study, we analyzed M. purpureus in media with and without glutamic acid supplementation using a metabolomic profiling approach to identify key metabolites and metabolic pathway differences. A total of 817 differentially expressed metabolites were identified between the two fermentation broths on day 8 of fermentation. Pathway analysis of these metabolites using the KEGG database indicated overrepresentation of the citric acid cycle; biotin metabolism; and alanine, aspartate, and glutamate metabolic pathways. Six differentially expressed metabolites were found to be related to the citric acid cycle. The effect of citric acid as an exogenous additive on the synthesis of monacolin K was examined. These results provide technical support and a theoretical basis for further studies of the metabolic regulatory mechanisms underlying the beneficial effects of monacolin K and medium optimization, as well as genetic engineering of Monascus M1 for efficient monacolin K production.

Red Yeast Rice for Hypercholesterolemia.

The extract of red yeast rice (RYR) is the most effective cholesterol-lowering nutraceutical on the market. In particular, its effectiveness is directly related to the amount of monacolin K within the extract (up to 10 mg/day). Consuming monacolin K on a daily basis reduces low-density lipoprotein (LDL) cholesterol plasma levels between 15% and 25% within 6 to 8 weeks. Certainly, the decrease in LDL-cholesterol is accompanied by a similar reduction in total cholesterol, non-high-density lipoprotein cholesterol, plasma apolipoprotein B, matrix metalloproteinases 2 and 9, and high-sensitivity C-reactive protein. Furthermore, the RYR lipid-lowering effect is associated with significant improvements in pulse wave velocity and endothelial function, which are validated and reliable biomarker tools able to detect vascular aging. Although it has a mechanism of action similar to statins, a daily consumption of between 3 and 10 mg monacolin K has only minimal associated risks, and mild myalgias are seen only in the frailest patients (those who also cannot tolerate minimal dosages of statin). The monacolin K found in RYR is a safe and effective supplement for managing mild to moderate hypercholesterolemia in people with no additional cardiovascular risk factors.

Lovastatin in lactone and hydroxy acid forms and citrinin in red yeast rice powders analyzed by HPTLC-UV/FLD.

For the analysis of pigment-rich red yeast rice products, a fast quantitative high-performance thin-layer chromatography (HPTLC) method was newly developed and validated. The active ingredient lovastatin, present in lactone (LL) and hydroxy acid forms (LH), as well as the mycotoxin citrinin were analyzed in 19 red yeast rice products, including powders, dietary supplements, and Chinese proprietary medicines (Xuezhikang and Zhibituo). The HPTLC method including sample preparation allows a high throughput of matrix-rich samples (10 min per analysis) and is highly cost-efficient (running costs of 0.5 Euro per analysis). For a fast protocol, application volumes up to 10 µL were selected although higher application volumes will lower still the LODs, which were 30 mg/kg for LL and LH as well as 4 mg/kg for citrinin. Thanks to the minimalistic sample preparation, the overall mean recovery rate was good (109.9% ± 5.9%; repeated measurements of the three analytes per fresh sample preparation at three spike levels). Repeated calibrations (five per analyte) in the red yeast rice matrix showed highly satisfying determination coefficients (≥ 0.9991; mean 0.9996). For three analytes at three concentration levels, the obtained mean intermediate precisions in red yeast rice matrix analyzed over the whole procedure including sample preparation were highly satisfying (≤ 2.6%). Citrinin was not detectable in the samples down to the given LOD of 4.0 mg/kg for the 10-µL sample volume applied. The mean content of lovastatin in 15 RYR powders was 8.7 g/kg, with a rang of 1.5-26.2 g/kg. The content of lovastatin in Zhibituo tablets and Xuezhikang capsules was determined to be 2.7 and 11.1 g/kg, respectively. The two commercially available RYR dietary supplement samples showed the highest lovastatin contents of 40.7 and 41.4 g/kg. By these figures of merit, the HPTLC method was proven to be suited for the control of such matrix-rich, fermented food. Graphical abstract.