Printer Friendly

The effect of bergamot on dyslipidemia.

ABSTRACT

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.

Keywords:

Bergamot

Cardiovascular risk

Dyslipidemia

LDL cholesterol

Introduction

Therapeutic approaches of dyslipidemia currently rely on the use of statins, pharmacological inhibitors of cholesterol biosynthesis that act on the key enzyme 3-hydroxy-3-methylglutaryl-Co-enzyme A (HMG-CoA) reductase (Athyros et al. 2014). Despite the fact that statin therapy reduces the incidence of major coronary events, coronary revascularization and stroke (Baigent et al. 2005), many patients, especially those with type 2 diabetes and metabolic syndrome (MetS), do not reach their lipid targets and remain at high cardiovascular (CV) risk (Jones 2008). Patients on statins may also have various side effects such as myalgia, myopathy or liver disease and rhabdomyolysis which interfere with adherence to treatment, especially if high doses of statins are required (Banach et al. 2015a, 2015b). New-onset diabetes (NOD) is another important issue to consider in patients treated with statins (Athyros and Mikhailidis 2012; Banach et al. 2013; Katsiki et al. 2015). If statins cannot be used or do not achieve guideline targets an alternative therapeutic approach is recommended. This includes other lipid lowering drugs, with the possibilities of combination therapy (Katsiki et al. 2013; Rizzo et al. 2013a) and/or natural compounds present in the human diet (Patti et al. 2015; Serban et al. 2015; Ursoniu et al. 2015).

In vitro and in vivo studies indicate that Citrus juices positively influence lipid metabolism (Gorinstein et al. 2004) and high contents of bioactive compounds of Citrus fruits may lead to reduced risk of CV disease (CVD) (Benavente-Garcia and Castillo 2008). Bergamot, the common name of the fruit Citrus bergamia Risso (family Rutaceae), differs from other Citrus fruits because of its composition and the high content of flavonoids (such as neoeriocitrin, neohesperidin, naringin, rutin, neodesmin, rhoifolin and poncirin) (Dugo et al. 2005; Nogata et al. 2006). The beneficial properties of the juice of C. bergamia have been investigated in several studies indicating antimicrobial (Sanchez-Gonzalez et al. 2010), analgesic (Sakurada et al. 2011), anti-inflammatory (Impellizzeri et al. 2014; Trombetta et al. 2010) and glucose and lipid-lowering properties (Mollace et al. 2011).

The purpose of this review was to summarize the current state of knowledge about the effects of bergamot on lipids based on preclinical and clinical studies. Both experimental and epidemiological studies suggest that the polyphenols, particularly flavonoids, present in bergamot also exert antioxidant effects that may be related to a hypolipemic effect (Devaraj et al. 2004).

Search strategy: We searched PubMed and Scopus listings for relevant publications up to September 2015 using combinations of the following keywords; "bergamot", "cardiovascular risk", "dyslipidemia", "lipids", "lipoproteins", "low density lipoprotein", "high density lipoprotein", "lipid-lowering drugs", "nutraceuticals", "natural compounds" and "statin".

Effects of bergamot on lipid metabolism: evidence from pre-dinical studies

As mentioned above, bergamot (C. bergamia) possesses a high content flavonoid glycosides in its juice and albedo, such as neoeriocitrin, neohesperidin, naringin, rutin, neodesmin, rhoifolin and poncirin (Dugo et al. 2005; Nogata et al. 2006) and some statinlike compounds (Di Donna et al. 2009). Three flavanones extracted from the bergamot peel, the 3-hydroxy-3-methyl-glutary! flavanones enriched fraction (HMGF: brutieridin, melitidin and HMG-neoeriocitrin), act like statins, having a behavior similar to simvastatin in a model of hypercholesterolemic rats (Di Donna et al. 2014). Both simvastatin and HMGF exerted beneficial effects on high-density lipoproteins cholesterol (HDL-C)/low-density lipoproteins cholesterol (LDL-C) ratio and decreased levels of total cholesterol (TC; 30% and 20%, respectively; that also was observed in liver TC: 11% and 35%, respectively), TG (32 and 20%, respectively, and for hepatic TG about 18% and 35%, respectively), very low density lipoproteins cholesterol (VLDL-C; 33% and 28%, respectively) and LDL-C levels (24% and 40%, respectively), while HDL-C increased exclusively in the HMGF-treated rats (20%) compared with the untreated group (Di Donna et al. 2014). Such HMGF effects have been confirmed by positive gene regulation in the liver together establishing a promising nutraceutical strategy for the control of hypercholesterolemia, a main factor responsible for increased CVD risk (Di Donna et al. 2014). In addition, naringin, also present in grapefruit, as well as neoeriocitrin and rutin have been reported to be active in animal models of atherosclerosis (Choe et al. 2001) and have been shown to inhibit the oxidation of LDL (Yu et al. 2005), supporting that bergamot may prevent atherosclerosis (Miceli et al. 2007). Briefly, C. bergamia has been administered to hyperlipidemic rats (1 ml/rat/day) in order to investigate its protective effect on the liver (Miceli et al. 2007). A significant reduction in serum TC (29.27%), triglycerides (TG; 46.12%), and LDL-C levels (51.72%) and an increase in HDL-C levels (27.61%) were reported. Additionally, it was suggested that such hypocholesterolemic effect of C. bergamia may be mediated by the increase in fecal neutral sterols and total bile acids excretion (Miceli et al. 2007).

In addition to the hypolipidemic effect, bergamot showed radical scavenging activity in the rat model, while histopathological observations showed a protective role on hepatic parenchyma (Miceli et al. 2007). Similarly, the protective effect of treatment with bergamot juice (1 ml/day, for 30 days) against hypercholesterolemic diet-induced renal injury in rats has been investigated (Trovato et al. 2010). Plasma levels of TC, TG and LDL-C fell significantly, while HDL-C levels increased. Plasma creatinine levels did not change compared with hyperlipidemic controls. However, bergamot juice administration significantly decreased malondialdehyde levels, a good biomarker of oxidative stress, one of the major aldehydes formed during lipid peroxidation. In addition, the histological observations of the kidney supported the biochemical findings and suggested a protective effect of bergamot juice in the development of renal damage in hypercholesterolemic rats (Trovato et al. 2010). Furthermore, the antioxidant potential of bergamot juice was examined in two in vitro systems: in the free radical 1,1-diphenyl-2- picrylhydrazyl (DPPH) assay the juice showed a noticeable effect on scavenging free radicals, and in the reducing power assay it showed a strong activity as well. These findings suggest that a protective role of bergamot in hypercholesterolemic dietinduced renal damage may be attributed to its antioxidant properties (Trovato et al., 2010). These 2 studies (Miceli et al. 2007; Trovato et al. 2010) support the hypolipemic and vasoprotective effects of bergamot and its constituents (flavonoids and pectins) on vascular damage induced by stress that may also lead to reduced CVD risk.

Polyphenols, particularly, flavonoids, such as melitidin and brutieridin in combination with other flavonoid glycosides present in bergamot, are suggested to be responsible for reducing cholesterol levels (Dugo et al. 2005; Nogata et al. 2006). However, the exact mechanism of hypolipidemic activity remains unclear. Leopoldini et al. (Leopoldini et al. 2010) applied the density functional theory to study the mode of binding of the flavonoid conjugates, brutieridin and melitidin, quantified in bergamot fruit extracts, to the active site of HMG-CoA reductase. This was compared with that of simvastatin, in order to obtain better insight into the inhibition process of this key enzyme in sterol biosynthesis. Brutieridin and melitidin were identified to be structural analogues of statins and to partially occupy the site that accepts the part of the CoA substrate, similar to the binding mode of simvastatin (Leopoldini et al. 2010). Consistent with the presence of the HMG-like moiety, brutieridin and melitidin compounds seem to be competitive inhibitors of HMG-CoA reductase with respect to the binding of HMG-CoA. Similarly, our previous study showed that flavonolignans modulate lipid homeostasis by regulating the expression and activity of acyl-CoA oxidase, stearoyl-CoA desaturase 1 and liver-fatty acid binding protein (Salamone et al. 2012).

It has been suggested that both tangerine peel extract and a mixture of two citrus flavonoids, naringin and hesperidin, reduce cholesterol levels by modulating the activities of HMG-CoA reductase and acyl CoA:cholesterol O-acyltransferase (ACAT) (Bok et al. 1999). Binding to bile acids and increasing the turnover rate of blood and liver cholesterol were reported as a possible mechanism (Bok et al. 1999). As mentioned above, bergamot improves fecal excretion of sterols in rats (Miceli et al. 2007), suggesting that the hypocholesterolemic effect of bergamot may be mediated by the increase in fecal neutral sterols and total bile acids excretion as well as that the intake of bergamot may reduce the risk of CVD through its radical scavenging function and hypocholesterolemic action.

In vitro studies in human hepatoma cell line (HepG2) have shown that naringenin and hesperetin reduce the availability of lipids for the assembly of apolipoprotein (apo) B-containing lipoproteins, an effect mediated by the reduction of ACAT activity (Wilcox et al. 2001). Lectin-like oxyLDL receptor-1 (LOX-1) is involved in the proliferation of smooth muscle cells (SMCs) and neointima formation in injured blood vessels. The effects of the nonvolatile fraction, the antioxidant component of bergamot essential oil on LOX-1 expression and free radical generation were investigated in an experimental model of rat angioplasty (Mollace et al. 2008). The treatment reduced neointima proliferation together with free radical formation and LOX-1 expression in a dose-dependent manner suggesting that natural antioxidants may be relevant in the treatment of vascular disorders in which proliferation of SMCs and oxyLDL-related endothelial cell dysfunction are involved.

Table 1 summarizes the main findings of the pre-clinical studies which are discussed above.

Effects of bergamot on lipid metabolism; evidence from clinical studies

Numerous nutraceutical products were considered to have beneficial effects in the treatment of dyslipidemia (Rizzo et al. 2014) and MetS (Patti et al. 2015). Up to date few clinical trial were conducted to investigate the effects of bergamot in patients with dyslipidemia and related diseases and these will be discussed below.

Some studies compared the effects of bergamot and statins evaluating their vasoprotective and lipid-lowering efficacy. A prospective, open-label, parallel group, placebo-controlled study enrolled 77 patients with mixed dyslipidemia (Gliozzi et al. 2013).

The patients were randomly assigned to a control group treated with placebo (n = 15), two groups received orally administered rosuvastatin (10 and 20 mg/daily for 30 days; n = 16 for each group), a group receiving bergamot (bergamot-derived polyphenolic fraction, BPF) alone orally (1000 mg/daily for 30 days; n = 15) and a group receiving BPF (1000 mg/daily given orally) plus rosuvastatin (10 mg/daily for 30 days; n = 15) (Gliozzi et al. 2013). Both doses of rosuvastatin (10 or 20 mg) and BPF reduced TC (195 [+ or -] 3, 174 [+ or -] 4 and 191 [+ or -] 5 mg/dl, respectively, versus 275 [+ or -] 4 mg/dl [placebo]; p < 0.05), LDL-C (115 [+ or -] 4, 87 [+ or -] 3 and 113 [+ or -] 4 mg/dl, respectively, versus 190 [+ or -] 2 mg/dl [placebo]; p < 0.05), the ratio of LDL-C/HDL-C as well as urinary mevalonate compared with the control group (p < 0.05). Of interest, the addition of bergamot to rosuvastatin greatly enhanced the effect of rosuvastatin on the lipemic profile (a significant reduction in TG levels (152 [+ or -] 5 mg/dl [rosuvastatin 10 mg + BPF 1000 mg] and 200 [+ or -] 4 mg/dl [rosuvastatin 10 mg], respectively, versus 235 [+ or -] 5 mg/dl [placebo]; p < 0.05), the further reduction in urinary mevalonate and an additive vasoprotective effect was found only in the combination treatment). This lipid-lowering effect was associated with significant reductions in biomarkers used to detect vascular oxidative damage (such as malondialdehyde, oxyLDL receptor LOX-1 and protein kinase B (PKB), suggesting a multi-action improved potential for bergamot in patients taking statins (Gliozzi et al. 2013).

The same authors in another study (Gliozzi et al. 2014) assessed the effect of BPF in 107 patients with MetS and non-alcoholic fatty liver disease (NAFLD). The patients were divided into two groups: one treated with placebo and the second received bergamot at dose 650 mg twice a day for 120 consecutive days. In the group treated with bergamot, a significant reduction in fasting plasma glucose, serum LDL-C, including small dense LDL (sdLDL), known to be more atherogenic particles, and TG with an increase in HDL-C was found. This effect was accompanied by a significant reduction in NAFLD metabolic and ultrasonic biomarkers (Gliozzi et al. 2014). Both elevated sdLDL levels and NAFLD have been related to increased CVD risk and thus their improvement will further reduce vascular risk (Athyros et al. 2015; Katsiki et al. 2014b; Mikhailidis et al. 2011a, 2011b; Nikolic et al. 2013). Furthermore, it should be taken into account that natural polyphenols may express their antioxidant and protective effect through the ability to induce the expression of various vitagenes playing a major role in the maintenance of cellular redox system (Barbagallo et al. 2013; Lee et al. 2015). In particular, such compounds serve as good inducer of heme oxygenase which is an enzymatic system involved in the endothelial antioxidant and survival system both in vitro and in vivo studies (Kushida et al. 2002; Novo et al. 2011; Sacerdoti et al. 2005).

All these findings suggest the clinical significance of bergamot use because of its potential influence on quality and not only on quantity of LDL that is related to overall cardiometabolic risk (Mikhailidis et al. 2011a; Nikolic et al. 2013). As discussed above, bergamot raises HDL-C levels, however, there is a need to establish if this supplement also influences HDL quality. This is an important issue given that several disorders can cause structural and functional changes resulting in the formation of dysfunctional HDL (Garcia-Rios et al. 2014; Otocka-Kmiecik et al. 2012).

In another double-blind, randomized, placebo-controlled trial the reduction of lipid parameters in patients who had to discontinue statin due to alterations in serum creatine kinase (CK) levels and muscle aches was evaluated (Mollace et al. 2011). The patients were divided into 4 groups: (A) 104 subjects with just hypercholesterolemia, HC (LDL-cholesterol levels [greater than or equal to] 130 mg/dl) treated with oral bergamot (500 mg/day); (B) 42 patients with hyperlipidemia (hypercholesterolemia and hypertryglyceridemia, HC/HT) treated with bergamot (1000 mg/day); (C) 59 patients with mixed hyperlipidemia and blood glucose > 110 mg/dl (MetS group), HC/HT/HG treated with placebo; and (D) 32 patients who discontinued treatment with simvastatin because of muscle cramps and significant increase in serum CK levels treated with bergamot 1500 mg/day after a washout period of 60 days (Mollace et al. 2011). Treatment with bergamot (500 and 1000 mg/day) for 30 consecutive days in patients with isolated HC (group A), mixed hyperlipidemia (HC/HT, B group) and MetS (group C) led to a strong reduction in TC (A+B+C 21.8% [500 mg/day] and 29.4% [1000 mg/day] versus 0.1%[placebo]; p < 0.001 for all), LDL-C levels (A+B+C 24.1% [500 mg/day] and 30.6% [1000 mg/day] versus 1.1% [placebo]; p < 0.001 for all) and a significant dose-dependent increase of HDL-C levels in most subjects (A+B+C 22.3% [500 mg/day] and 40.1% [1000 mg/day] versus 1.2% [placebo]; p < 0.001 for all). A significant reduction was also observed for TG levels in patients with HT (28.2% [500 mg/day] and 37.9% [1000 mg/day] versus 0.1% [placebo]; p < 0.001 for all). In patients with MetS an improvement in the glycemic profile (reduction in blood glucose levels) also occurred (18.9% [500 mg/day] and 22.4% [1000 mg/day] versus 0.5% [placebo]) (p < 0.0001). No significant changes were found between the parameters of average TC in the placebo group. Similarly, among patients who stopped taking statins, treatment with bergamot (1500 mg/day) was very efficient: TC and LDLC levels were reduced (by mean of 25 and 27.6%, respectively; p < 0.001) without re-appearance of side effects. These data suggest that bergamot induces complex effects on metabolic regulation and could be considered as an alternative treatment in patients who are intolerant to statins (Mollace et al. 2011). Furthermore, its lipid and glycemic effects may result in a reduction of CV risk.

Table 2 summarizes the main findings of the clinical studies discussed above.

Ongoing clinical studies and future perspectives

An ongoing prospective study (NCT02205567) (Clinicaltrials, 2015) will show, for the first time, if the natural, dietary supplement based on Bergavif (Fisiolip, Bioactive Natural Products [Bionap] srl, Italy) available in Italy, affects atherogenic lipoproteins and a marker of subdinical atherosclerosis, carotid intimamedia thickness (cIMT). This bergamot (C. bergamia)-derived product is obtained by extracting the main flavonoids contained in bergamot juice (28% flavonoids; the principal ones are: naringin, neoeriocitrin, neohesperidin) and suggested dosage is 0.5-1 g/day in subjects with mild dyslipidemia. In the ongoing study 160 dyslipidemic subjects (moderate hypercholesterolemia; LDL-C > 109 mg/dl) are included and divided in 2 treatment groups: (1) 500 mg/day, and, (2) 1000 mg/day. Bergamot is given as add-on therapy to ongoing medications (such as antihypertensive and hypoglycemic therapies) for 6 months. The study has just been completed and the results are expected in the following months. However, large prospective studies are still required to evaluate the clinical implications of bergamot.

On the basis of the current evidence, this natural supplement may lead to effective lipid-lowering treatment in subjects who are statin intolerant or as add-on therapy in those who do not reach LDL-C goals despite being on statins. In addition, it might exert other favorable cardiometabolic effects in dyslipidemic patients that remain to be confirmed by ongoing and future large, prospective studies. The positive results of such studies may expand the use of this natural supplement in other populations such as subjects with pre-diabetes and MetS.

In addition, it should be noted that currently there is not enough scientific information to determine an appropriate range of doses for bergamot. As discussed above, few clinical studies using bergamot have been performed up to date and the doses ranged from 500 to 1000 mg/daily (in one study 650 mg twice daily). Some authors reported that in the absence of guidelines for the dosage of bergamot two to four 500 mg of extract in capsules is recommended to be taken once or twice a day for a month, while after that one capsule daily is enough to maintain this supplement in the blood (Herbwisdom, 2015). In order to determine the appropriate dose of bergamot several factors related to each patient (such as the age, health status and other conditions like allergy or sensitivity to bergamot or its components, pregnancy and breastfeeding) should be considered (Webmd, 2015). Additionally, the recommendations on the label should be followed together with physicians' advice given that various bergamot derived extracts (with different composition) are available as dietary supplements. Caution is recommended when medications which increase sensitivity to sunlight (photosensitizing drugs) are used as they may interact with bergamot (Webmd, 2015).

Finally, it should be highlighted that the most frequently used extract of bergamot in cosmetic, pharmaceutical and food industries is its essential oil and juice while the peel and the external part of the fruit which is rich in sugars, fibers, and other residual substances is underutilized (Mandalari et al. 2006). In the present review we discussed the potential hypolipidemic effects of bergamot attributed to polyphenols, in particular to flavonoids. However, bergamot also contains a polysaccharide and a fibrous-woody fraction that can be used in food integrators and in dietary products in order to reduce the sensation of hunger (Giannetti et al. 2010; Mandalari et al. 2006).

Potential advantages of bergamot compared with statins

The available literature data suggests that bergamot may exert lipid-lowering effects as statins, even with some advantages: (1) it also raises HDL-C, that can be of particular clinical significance given that a low HDL-C level is an independent risk factor (Toth et al. 2014); (2) it can reduce TG accumulation in the liver, a common problem in obese people, and it binds cholesterol to bile acids. Although, there is no available data about bergamot's effect on postprandial lipemia (PPL), future studies may show the benefits on this CV risk predictor given that nutritional supplementation in this condition is recommended by different authors including an expert panel group (Kolovou et al. 2011; Rizzo et al. 2013b) and actually all 3 risk factors (fasting TG, PPL and non-HDL-C) might be affected (Katsiki et al. 2014a; Stefanutti et al. 2014); (3) as a potent antioxidant, bergamot protects against free radical damage in the body, including the vascular endothelium, an important determinant of CV health; yet, bergamot initiates adenosine monophosphate (AMP)-activated PK (AMPK), a central regulator of energy, and thus is involved in glucose and fatty acid metabolism.

As discussed above, although few studies assessed the effects of bergamot on glycemic parameters (Gliozzi et al. 2014; Gliozzi et al. 2013; Mollace et al. 2011), the current positive results are not to be underestimated. Together with the finding that naringin improved overall insulin sensitivity and glucose tolerance (Li et al. 2006), it is reasonable to conduct future, large trials which will deal with this issue as statin-related NOD is documented (Katsiki et al. 2015). If bergamot might improve insulin sensitivity and other glycemic parameters, it could reduce the risk of NOD as well.

It remains to be established if there are any interactions with statins given that bergamot is a source of bergamottin which is believed to be responsible for the grapefruit juice effects on the metabolism of some drugs, including statins (Li et al. 2007; Nogata et al. 2006). However, bergamot does not appear to have the same effect (Bergamethealth, 2015). Any decision about co-administration should be made by a physician taking the available evidence into consideration. Bergamot may be an option with lower doses of statins in individuals at low risk or when there is statin intolerance and there should be no interactions (Bergamethealth, 2015). Bergamot appears safe to take with all other medications. However, caution is advised when using other supplements that also may decrease blood glucose, and medications which increase sensitivity to sunlight (photosensitizing drugs).

Conclusions

Results from animal and human studies suggest that bergamot has beneficial effects on plasma lipids. Although several studies performed up to date suggest a statin-like effect, further investigation is needed to establish the use of this natural supplement in daily clinical practice, alone or in combination with lipid-lowering drugs, to help achieve therapeutic targets. Hopefully, ongoing and future studies will lead to the development of a new phytotherapeutic strategy in hyperlipemia, but also in other metabolic disorders. This could also decrease overall cardiometabolic risk, including the risk for atherosclerosis and CVD.

ARTICLE INFO

Article history:

Received 29 September 2015

Revised 30 November 2015

Accepted 1 December 2015

Conflict of interest

This review was written independently. The authors did not receive financial or professional help with the preparation of the manuscript. The authors have given talks, attended conferences and participated in advisory boards and trials sponsored by various pharmaceutical companies.

References

Athyros, V.G., Mikhailidis, D.P., 2012, Pharmacotherapy: statins and new-onset diabetes mellitus-a matter for debate. Nat. Rev. Endocrinol. 8, 133-134.

Athyros, V.G., Tziomalos, K., Karagiannis, A., Mikhailidis, D.P., 2014. Hypolipidaemic drug treatment: yesterday is not gone yet, today is challenging and tomorrow is coming soon; let us combine them all. Curr. Pharm. Des. 20, 6350-6357.

Athyros, V.G., Tziomalos, K., Katsiki, N., Doumas, M., Karagiannis, A., Mikhailidis, D.P., 2015. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update. World J. Gastroenterol. 21, 6820-6834.

Baigent, C., Keech, A., Kearney, P.M., Blackwell, L, Buck, G., Pollicino, C., Kirby, A., Sourjina, T., Peto, R., Collins, R., Simes, R., Cholesterol Treatment Trialists, C., 2005. Efficacy and safety of cholesterol-lowering treatment: prospective metaanalysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366, 1267-1278.

Banach, M., Malodobra-Mazur, M., Gluba, A., Katsiki, N., Rysz, J., Dobrzyn, A., 2013. Statin therapy and new-onset diabetes: molecular mechanisms and clinical relevance. Curr. Pharm. Des. 19. 4904-4912.

Banach, M., Rizzo, M., Toth, P.P., Famier, M., Davidson, M.H., Al-Rasadi, K., Aronow, W.S., Athyros, V., Djuric, D.M., Ezhov, M.V., Greenfield, R.S., Hovingh, G.K., Kostner, K., Serban, C., Lighezan, D., Fras, Z., Moriarty, P.M., Muntner, P., Goudev, A., Ceska, R., Nicholls, S.J., Broncel, M., Nikolic, D., Pella, D., Puri, R., Rysz, j., Wong, N.D., Bajnok, L., Jones, S.R., Ray, K.K., Mikhailidis, D.P., 2015. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Expert Opin. Drug Safety 14, 935-955.

Banach, M., Rizzo, M., Toth, P.P., Famier, M., Davidson, M.H., Al-Rasadi, K., Aronow, W.S., Athyros, V., Djuric, D.M., Ezhov, M.V., Greenfield, R.S., Hovingh, G.K., Kostner, K., Serban, C., Lighezan, D., Fras, Z., Moriarty, P.M., Muntner, P., Goudev, A., Ceska, R., Nicholls, S.J., Broncel, M., Nikolic, D., Pella, D., Puri, R., Rysz, J., Wong, N.D., Bajnok, L., Jones, S.R., Ray, K.K., Mikhailidis, D.P., 2015. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch. Med. Sci. 11, 1-23.

Barbagallo, I., Galvano, F., Frigiola, A., Cappello, F., Riccioni, G., Murabito, P., D'Orazio, N., Torella, M., Gazzolo, D., Li Volti, G., 2013. Potential therapeutic effects of natural heme oxygenase-1 inducers in cardiovascular diseases. Antioxid. Redox. Signal 18, 507-521.

Benavente-Garcia, O., Castillo, J., 2008. Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. J. Agric. Food Chem. 56, 6185-6205.

Bok, S.H., Lee, S.H., Park, Y.B., Bae, K.H., Son, K.H.. Jeong, T.S., Choi, M.S., 1999. Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methylglutaryl-CoA reductase and acyl CoA: cholesterol transferase are lower in rats fed citrus peel extract or a mixture of citrus bioflavonoids. J. Nutr. 129, 1182-1185.

Choe, S.C., Kim, H.S., Jeong, T.S., Bok, S.H., Park, Y.B., 2001, Naringin has an antiatherogenic effect with the inhibition of intercellular adhesion molecule-1 in hypercholesterolemic rabbits. J. Cardiovasc. Pharmacol. 38, 947-955.

Devaraj, S., Jialal, I., Vega-Lopez, S., 2004. Plant sterol-fortified orange juice effectively lowers cholesterol levels in mildly hypercholesterolemic healthy individuals. Arterioscler. Thromb. Vase. Biol. 24, e25-e28.

Di Donna, L., De Luca, G., Mazzotti, F., Napoli, A., Salerno, R., Taverna, D., Sindona, G., 2009. Statin-like principles of bergamot fruit (Citrus bergamia): isolation of 3- hydroxymethylglutaryl flavonoid glycosides. J. Nat. Prod 72, 1352-1354.

Di Donna, L, iacopetta, D., Cappello, A.R., Gallucci, G., Martello, E., Fiorillo, M., Dolce, V., Sindona, G., 2014. Hypocholesterolaemic activity of 3-hydroxy3-methyl-glutaryl flavanones enriched fraction from bergamot fruit (Citrus bergamia): "In vivo" studies. J. Funct. Foods 7, 558-568.

Dugo, P., Presti, M.L., Ohman, M., Fazio, A., Dugo, G., Mondello, L., 2005. Determination of flavonoids in citrus juices by micro-HPLC-ESI/MS. J. Sep. Sci. 28. 11491156.

Garcia-Rios, A., Nikolic, D., Perez-Martinez, P., Lopez-Miranda, J., Rizzo, M., Hoogeveen, R.C., 2014. LDL and HDL subfractions, dysfunctional HDL: treatment options. Curr. Pharm. Des. 20, 6249-6255.

Giannetti, V., Boccacci Mariani, M., Testani, E., D'Aiuto, V., 2010. Evaluation of flavonoids and furocoumarins in bergamot derivatives by HPLC-DAD. J. Commodity Sci. Technol. Quality 49, 63-72.

Gliozzi, M., Carresi, C., Musolino, V., Palma, E., Muscoli, C., Vitale, C., Gratteri, S., Muscianisi, G., Janda, E., Muscoli, S., Romeo, F., Ragusa, S., Mollace, R., Walker, R., Ehrlich, J., Mollace, V., 2014. The effect of bergamot-derived polyphenolic fraction on LDL small dense particles and nonalcoholic fatty liver disease in patients with metabolic syndrome. Adv. Biol. Chem. 4, 129-137.

Gliozzi, M., Walker, R., Muscoli, S., Vitale, C., Gratteri, S., Carresi, C., Musolino, V., Russo, V., Janda, E., Ragusa, S., Aloe, A., Palma, E., Muscoli, C., Romeo. F., Mollace, V., 2013. Bergamot polyphenolic fraction enhances rosuvastatininduced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia. Int. J. Cardiol. 170, MOMS.

Gorinstein, S., Leontowicz, H., Leontowicz, M., Krzeminski, R., Gralak, M., Martin- Belloso, O., Delgado-Licon, E., Haruenkit, R., Katrich, E., Park, Y.S., Jung, S.T., Trakhtenberg, S., 2004. Fresh Israeli Jaffa blond (Shamouti) orange and Israeli Jaffa red Star Ruby (Sunrise) grapefruit juices affect plasma lipid metabolism and antioxidant capacity in rats fed added cholesterol. J. Agric. Food Chem. 52, 4853-4859.

Impellizzeri, D., Bruschetta, G., Di Paola, R., Ahmad, A., Campolo, M., Cuzzocrea, S., Esposito, E., Navarra, M., 2015. The anti-inflammatory and antioxidant effects of bergamot juice extract (BJe) in an experimental model of inflammatory bowel disease. Clin. Nutr. 34, 1146-1154.

Jones. P.H., 2008. Expert perspective: reducing cardiovascular risk in metabolic syndrome and type 2 diabetes mellitus beyond low-density lipoprotein cholesterol lowering. Am. J. Cardiol. 102, 41L-47L.

Katsiki, N., Athyros, V.G., Karagiannis, A., 2014a. Achieving lipid targets in primary care settings. Curr. Med. Res. Opin. 30. 1971-1974.

Katsiki, N., Athyros. V.G., Karagiannis, A., Wierzbicki, A.S., Mikhailidis, D.P., 2014b. Should we expand the concept of coronary heart disease equivalents? Curr. Opin. Cardiol. 29, 389-395.

Katsiki, N., Nikolic, D., Montalto, G., Banach, M., Mikhailidis. D.P., Rizzo, M., 2013. The role of fibrate treatment in dyslipidemia: an overview. Curr. Pharm. Des. 19, 3124-3131.

Katsiki, N., Rizzo, M., Mikhailidis, D.P., Mantzoros, C.S., 2015. New-onset diabetes and statins: throw the bath water out, but, please, keep the baby!. Metabolism 64. 471-475.

Kolovou, G.D., Mikhailidis, D.P., Kovar, J., Lairon, D., Nordestgaard, B.G., Ooi, T.C., Perez-Martinez, P., Bilianou, H., Anagnostopoulou, K.. Panotopoulos, G., 2011. Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement. Curr. Vase. Pharmacol. 9, 258-270.

Kushida, T., LiVolti, G., Goodman, A.I., Abraham, N.G., 2002. TNF-alpha-mediated cell death is attenuated by retrovirus delivery of human heme oxygenase1 gene into human microvessel endothelial cells. Transplant Proc. 34, 29732978.

Lee, S.E., Yang, H., Son, G.W., Park, H.R., Park, C.S., Jin, Y.H., Park, Y.S., 2015. Eriodictyol protects endothelial cells against oxidative stress-induced cell death through modulating ERK/Nrf2/ARE-Dependent heme oxygenase-1 expression. Int. J. Mol. Sci. 16, 14526-14539.

Leopoldini, M., Malaj, N., Toscano, M., Sindona, G., Russo, N., 2010, On the inhibitor effects of bergamot juice flavonoids binding to the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme. J. Agric. Food Chem. 58,10768-10773.

Li, J.M., Che, C.T., Lau, C.B., Leung, P.S., Cheng, C.H., 2006. Inhibition of intestinal and renal Na+glucose cotransporter by naringenin. Int. J. Biochem. Cell Biol. 38, 985-995.

Li, P., Callery, P.S., Gan, L.S., Balani, S.K., 2007. Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction. Drug Metab. Dispos. 35, 1203-1208.

Mandalari, G., Bennett, R.N., Bisignano, G., Saija, A., Dugo, G., Lo Curto, R.B., Faulds, C.B., Waldron, K.W., 2006. Characterization of flavonoids and pectins from bergamot (Citrus bergamia Risso) peel, a major byproduct of essential oil extraction, J. Agric. Food Chem. 54, 197-203.

Miceli, N., Mondello, M.R., Monforte, M.T., Sdrafkakis. V., Dugo, P., Crupi, M.L., Taviano, M.F., De Pasquale, R., Trovato, A., 2007. Hypolipidemic effects of citrus bergamia Risso et Poiteau juice in rats fed a hypercholesterolemic diet. J. Agric. Food Chem. 55, 10671-10677.

Mikhailidis, D.P., Elisaf, M., Rizzo, M., Berneis, K., Griffin, B., Zambon, A., Athyros, V., de Graaf, J., Marz, W., Parhofer, K.G., Rini, G.B., Spinas, G.A., Tomkin, G.H., Tselepis, A.D., Wierzbicki, A.S., Winkler, K., Florentin, M., Liberopoulos, E., 2011a. European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr. Vase. Pharmacol. 9, 533-571.

Mikhailidis, D.P., Elisaf, M., Rizzo, M., Berneis, K., Griffin, B., Zambon, A., Athyros, V., de Graaf, J., Marz, W., Parhofer, K.G., Rini, G.B., Spinas, G.A., Tomkin, G.H., Tselepis, A.D., Wierzbicki, A.S., Winkler, K., Florentin, M., Liberopoulos, E., 2011b. European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses: executive summary. Curr. Vase. Pharmacol. 9, 531-532.

Mollace, V., Ragusa, S., Sacco, L, Muscoli, C., Sculco, F., Visalli, V., Palma, E., Muscoli, S., Mondello, L., Dugo, P., Rotiroti, D., Romeo, F., 2008. The protective effect of bergamot oil extract on lecitine-like oxyLDL receptor-1 expression in balloon injury-related neointima formation. J. Cardiovasc. Pharmacol. Ther. 13, 120-129.

Mollace, V., Sacco, L, Janda, E., Malara, C., Ventrice, D., Colica, C., Visalli, V., Muscoli, S., Ragusa, S., Muscoli, C., Rotiroti, D., Romeo, F., 2011. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies. Fitoterapia 82, 309-316.

Nikolic, D., Katsiki, N., Montalto, G., Isenovic, E.R., Mikhailidis, D.P., Rizzo, M., 2013. Lipoprotein subfractions in metabolic syndrome and obesity: clinical significance and therapeutic approaches. Nutrients 5, 928-948.

Nogata, Y., Sakamoto, K., Shiratsuchi, H., Ishii, T., Yano, M., Ohta, H., 2006. Flavonoid composition of fruit tissues of citrus species. Biosci. Biotechnol. Biochem. 70, 178-192.

Novo, G., Cappello, F., Rizzo, M., Fazio, G., Zambuto, S., Tortorici, E., Marino Gammazza, A., Corrao, S., Zummo, G., De Macario, E.C., Macario, A.J., Assennato, P., Novo, S., Li Volti, G.. 2011. Hsp60 and heme oxygenase-1 (Hsp32) in acute myocardial infarction. Transl. Res. 157, 285-292.

Otocka-Kmiecik, A., Mikhailidis, D.P., Nicholls, S.J., Davidson, M., Rysz, J., Banach, M., 2012. Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease? Prog. Lipid Res. 51, 314-324.

Patti, A.M., Katsiki, N., Nikolic, D., Al-Rasadi, K., Rizzo. M., 2015. Nutraceuticals in lipid-lowering treatment: a narrative review on the role of chitosan. Angiology 66, 416-421.

Rizzo, M., Barylski, M., Rizvi, A.A., Montalto, G., Mikhailidis, D.P., Banach, M., 2013. Combined dyslipidemia: should the focus be LDL cholesterol or atherogenic dyslipidemia? Curr. Pharm. Des. 19, 3858-3868.

Rizzo. M., Giglio, R.V., Nikolic, D., Patti, A.M., Campanella, C., Cocchi, M., Katsiki, N., Montalto, G., 2014. Effects of chitosan on plasma lipids and lipoproteins: a 4-month prospective pilot study. Angiology 65, 538-542.

Rizzo, M., Perez-Martinez, P., Nikolic, D., Montalto, G., Lopez-Miranda, J., 2013. Emerging approaches for the treatment of hypertriglyceridemia. Expert Opin. Pharmacother. 14, 1869-1873.

Sacerdoti, D., Colombrita, C., Ghattas, M.H., Ismaeil, E.F., Scapagnini, G., Bolognesi, M., Li Volti, G., Abraham, N.G., 2005. Heme oxygenase-1 transduction in endothelial cells causes downregulation of monocyte chemoattractant protein-1 and of genes involved in inflammation and growth. Cell. Mol. Biol. (Noisy-le-grand) 51, 363-370.

Sakurada, T., Mizoguchi, H., Kuwahata, H., Katsuyama, S., Komatsu, T., Morrone, LA, Corasaniti, M.T., Bagetta, G., Sakurada, S., 2011. Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism. Pharmacol. Biochem. Behav. 97, 436-443.

Salamone, F., Galvano, F., Cappello, F., Mangiameli, A., Barbagallo, L, Li Volti, G., 2012. Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis. Transl. Res. 159, 477-486.

Sanchez-Gonzalez, L, Chifer, M., Chiralt, A., C., G.-M., 2010. Physical properties of edible chitosan films containing bergamot essential oil and their inhibitory action on Penicillium italicum. Carbohydr. Polym. 82, 277-283.

Serban, M.C., Sahebkar, A.. Dragan, S., Stoichescu-Hogea, G., Ursoniu, S., Andrica, F., Banach, M.. 2015. A systematic review and meta-analysis of the impact of Spirulina supplementation on plasma lipid concentrations. Clin. Nutr. pii: S02615614(15)00240-X.

Stefanutti, C., Labbadia, G., Athyros, V.G., 2014. Hypertriglyceridaemia, postprandial lipaemia and non-HDL cholesterol. Curr. Pharm. Des. 20, 6238-6248.

Toth, P.P., Barylski, M., Nikolic, D., Rizzo, M., Montalto. G., Banach, M., 2014. Should low high-density lipoprotein cholesterol (HDL-C) be treated? Best Pract. Res. Clin. Endocrinol. Metab. 28, 353-368.

Trombetta, D., Cimino, F., Cristani, M., Mandalari, G., Saija, A., Ginestra, G., Speciale, A., Chirafisi, J., Bisignano, G., Waldron, K., Narbad, A., Faulds, C.B., 2010. In vitro protective effects of two extracts from bergamot peels on human endothelial cells exposed to tumor necrosis factor-alpha (TNF-alpha). J. Agric. Food Chem. 58, 8430-8436.

Trovato, A., Taviano, M.F., Pergolizzi, S., Campolo, L., De Pasquale. R., Miceli, N., 2010. Citrus bergamia Risso 8> Poiteau juice protects against renal injury of diet- induced hypercholesterolemia in rats. Phytother. Res. 24, 514-519.

Ursoniu, S., Sahebkar, A., Serban, M.C., Banach, M., 2015. Lipid profile and glucose changes after supplementation with astaxanthin: a systematic review and meta-analysis of randomized controlled trials. Arch. Med. Sci. 11, 253-266.

Wilcox, L.J., Borradaile, N.M., de Dreu, L.E., Huff, M.W., 2001. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. J. Lipid Res. 42, 725-734.

www.bergamethealth.com. Frequently Asked Questions Regarding Bergamot (Citrus Bergamot). Available from: http://bergamethealth.com/frequently-askedquestions/(accessed on 01 September 2015).

www.clinicaltrials.gov. Bergamot and Cardio-Metabolic Risk Factors (NCT02205567). Available from: https://dinicaltrials.gov/ct2/show/NCr022055677ternH4CT 022055678nank=l (accessed on 01 September 2015).

www.herbwisdom.com. Bergamot Orange (Citrus Bergamia). Available from: http:// www.herbwisdom.com/herb-bergamot-orange.html (accessed on 16 November 2015).

www.webmd.com. Bergamot. Available from: http://www.webmd.com/vitaminssupplements/ingredientmono-142- bergamot%20oil.aspx?activeingredientid= 142&activeingredientname=bergamot%20oil (accessed on 16 November 2015).

Yu. J., Wang, L., Walzem, R.L., Miller, E.G., Pike, L.M., Patil, B.S., 2005. Antioxidant activity of citrus limonoids, flavonoids, and coumarins. J. Agric. Food Chem. 53, 2009-2014.

Rosaria Vincenza Giglio (a,b), Angelo Maria Patti (a,b), Dragana Nikolic (a), Giovanni Li Volti (b,c), Khalid Al-Rasadi (d), Niki Katsiki (e), Dimitri P. Mikhailidis (f), Giuseppe Montalto (a), Ekaterina Ivanova (g), Alexander N. Orekhov (h), Manfredi Rizzo (a,b), *

(a) Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy

(b) Euro-Mediterranean Institute of Science and Technology, Palermo, Italy

(c) Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy

(d) Department of Clinical Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman

(e) Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece

(f) Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free campus. University College London Medical School, University College London (UCL), Pond Street, London, UK

(g) Department of Development and Regeneration, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium

(h) Laboratory of Angiopathology, Institute for Atherosclerosis Research (Skolkovo), Moscow, Russia

Abbreviations: ACAT, acyl CoA:cholesterol O-acyltransferase; AMP, adenosine monophosphate; Apo, apolipoprotein; BPF, bergamot-derived polyphenolic fraction; cIMT, carotid intima-media thickness; CK, creatine kinase; CV, cardiovascular; CVD, cardiovascular disease; DPPH, l,l-diphenyl-2-picrylhydrazyl; HC, hypercholesterolemia; HDL-C, high-density lipoproteins cholesterol; HepG2, human hepatoma cell line; HG, high blood glucose (>110); HMG-CoA, 3-hydroxy-3-methylglutarylCo-enzyme A; HMGF, 3-hydroxy-3-methyl-glutaryl flavanones; HT, hypertryglyceridemia; LDL-C, low-density lipoproteins cholesterol; LOX-1, lectin-like oxyLDL receptor-1; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; NOD, new-onset diabetes; PK, protein kinase; PPL, postprandial lipemia; sdLDL, small dense LDL; SMCs, smooth muscle cells; TC, total cholesterol; TG, triglycerides; VLDL-C, very low density lipoproteins cholesterol.

* Corresponding author at: Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy. Tel.: +39 091 6552945; fax: +39 091 6552945.

E-mail address: manfredi.rizzo@unipa.it (M. Rizzo).

http://dx.doi.org/10.1016/j.phymed.2015.12.005
Table 1
The main findings of the pre-clinical studies discussed in the review.

Study             Model             Bergamot phenols

Choe et al.       Rabbits           Naringin
(2001)

Yu et al.         A variety of in   Limonin, limonin 17-beta-D-
(2005)            vitro models      glucopyranoside, apigenin,
                                    scutellarein, kaempferol, rutin
                                    trihydrate, neohesperidin,
                                    neoeriocitrin, naringenin,
                                    naringin, coumarin (bergapten)

Miceli et al.     Wistar rats       Neoeriocitrin, naringin,
(2007)                              neohesperidin

Trovato et al.    Wistar rats       DPPH radical of bergamot juice
(2010)

Leopoldini et     Enzyme            Brutieridin, melitidin
al. (2010)

Mollace et al.    Wistar rats       Neoeriocitrin, naringin,
(2011)                              neohesperidin, melitidin,
                                    brutieridin

Di Donna et al.   Bergamot          Brutieridin, melitidin
(2009)            (Citrus
                  bergamia)

Bok et al.        Rats              Mixture of naringin and hesperidin
(1999)

Di Donna et al.   Rats              Brutieridin, melitidin and HMG-
(2014)                              neoeriocitrin

Wilcox et al.     Human hepatoma    Naringenin and hesperetin
(2001)            cell line.
                  HepG2

Mollace et al.    Smooth muscle     Nonvolatile fraction of bergamot
(2008)            cells

Study             Aim                                  Duration

Choe et al.       Effects on blood lipids and aortic   8 weeks
(2001)            fatty streaks

Yu et al.         Antioxidant activity on LDL          47 h
(2005)

Miceli et al.     Hypolipidemic effects of Citrus      1 month
(2007)            bergamia juice 
Trovato et al.    Protective effect of citrus          1 month
(2010)            bergamia juice against
                  hypercholesterolemic diet-induced
                  renal injury

Leopoldini et     Interaction with the active site     --
al. (2010)        of the human HMGR enzyme to have
                  insights on possible inhibitory
                  effect

Mollace et al.    Effect of bergamot extract in        1 month
(2011)            diet-induced hyperlipemia

Di Donna et al.   \ The structures and possible        4 h
(2009)            reduction of cholesterol levels

Bok et al.        Effects on plasma and hepatic        42 days
(1999)            lipids, hepatic enzyme activities,
                  and the excretion of fecal neutral
                  sterols

Di Donna et al.   Effects on lipids and lipoproteins   3 weeks
(2014)

Wilcox et al.     Reduction activity and expression    24 h
(2001)            of ACAT2 and MTP

Mollace et al.    LOX-1 expression and free radical    14 days
(2008)            generation

Study             Main outcomes

Choe et al.       [down arrow] Cholesterol levels
(2001)            [down arrow] Fatty streak formation

Yu et al.         Strong antioxidant activity of
(2005)            flavonoids on LDL

Miceli et al.     [down arrow] Cholesterol
(2007)            [down arrow] triglycerides
                  [down arrow] LDL-C
                  [up arrow] HDL-C

Trovato et al.    Protective role in
(2010)            hypercholesterolemic diet-induced
                  renal damage that may be
                  attributed to its antioxidant
                  properties

Leopoldini et     Positive interaction with the
al. (2010)        active site of the human HMGR
                  enzyme with inhibitory effect

Mollace et al.    Inhibition of HMG-CoA reductase
(2011)            activity and enhanced reactive
                  vasodilation

Di Donna et al.   [down arrow] Cholesterol levels
(2009)

Bok et al.        Inhibition of HMG-CoA reductase
(1999)            and ACAT activities and
                  cholesterol biosynthesis in the
                  liver

Di Donna et al.   Beneficial effects on HDL-LDL
(2014)            ratio
                  [down arrow] VLDL-C level

Wilcox et al.     [down arrow] In activity and
(2001)            expression of ACAT2 and MTP

Mollace et al.    [down arrow] Neointima proliferation
(2008)            [down arrow] free radical formation
                  [down arrow] LOX-1 expression

DPPH, l,l-diphenyl-2-picrylhydrazyl; LOX-1, lectin-like oxyLDL
receptor-1; ACAT2, acyl CoA: cholesterol O-acyltransferase; MTP,
microsomal triglyceride transfer pro-tein; VLDL-C, very low density
lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol;
HDL-C, high density lipoprotein cholesterol; HMG-CoA, 3-hydroxy-3-
methylglutaryl-Co-enzyme A; HMGR, 3-hydroxy-3-methyl-glutaryl
flavanones enriched fraction.

Table 2
The main findings of the clinical studies discussed in the manuscript.

Study                    Patients (n)   Bergamot phenols

Mollace et al. (2011)    237            Neoeriocitrin, naringin,
                                        neohesperidin, melitidin.
                                        brutieridin

Gliozzi et al. (2013)    77             Neoeriocitrin, naringin and
                                        neohesperidin plus
                                        Rosuvastatin

Gliozzi M et al. (2014)  107            Neoeriocitrin, naringin and
                                        neohesperidin

Study                    Aim                           Duration

Mollace et al. (2011)    Effect of bergamot in diet-   1 month
                         induced hyperlipemia

Gliozzi et al. (2013)    Enhanced effect of bergamot   1 month
                         add on rosuvastatin-induced
                         hypolipidemic and
                         vasoprotective response

Gliozzi M et al. (2014)  Effect of bergamot on         2 months
                         lipoprotein subfraction
                         profile and NAFLD

Study                    Main outcomes

Mollace et al. (2011)    [down arrow] Cholesterol level
                         [down arrow] LDL-C
                         [down arrow] Triglycerides levels
                         [down arrow] Glucose levels
                         [up arrow] HDL-C

Gliozzi et al. (2013)    Addition of bergamot to rosuvastatin
                         [up arrow] Rosuvastatin-
                         induced effect on serum
                         lipemic profile compared to
                         rosuvastatin alone;
                         [down arrow] Biomarkers of
                         oxidative vascular damage

Gliozzi M et al. (2014)  Amelioration of the lipemic
                         and glycemic serum profile
                         [down arrow] Small dense LDL
                         [up arrow] HDL-C
                         [down arrow] Liver steatosis

LDL-C, low density lipoprotein cholesterol; HDL-C. high density
lipoprotein cholesterol; NAFLD. non-alcoholic fatty liver disease.
COPYRIGHT 2016 Urban & Fischer Verlag
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2016 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Giglio, Rosaria Vincenza; Patti, Angelo Maria; Nikolic, Dragana; Li Volti, Giovanni; Rasadi, Khalid
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Sep 28, 2016
Words:7261
Previous Article:Role of phytochemicals in the management of metabolic syndrome.
Next Article:Cardiovascular aspects of geriatric medicines in traditional Persian medicine; a review of phytochemistry and pharmacology.
Topics:

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters