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Bergamot (Citrus bergamia Risso) Flavonoids and Their Potential Benefits in Human Hyperlipidemia and Atherosclerosis: an Overview

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Elevated serum cholesterol, triglycerides and LDL levels are often associated with an increased incidence of atherosclerosis and coronary artery disease. The most effective therapeutic strategy against these diseases is based on statins administration, nevertheless some patients, especially those with metabolic syndrome fail to achieve their recommended LDL targets with statin therapy, moreover, it may induce many serious side effects. Several scientific studies have highlighted a strong correlation between diets rich in flavonoids and cardiovascular risk reduction. In particular, Citrus bergamia Risso, also known as bergamot, has shown a significant degree of hypocholesterolemic and antioxidant/radical scavenging activities. In addition, this fruit has attracted considerable attention due to its peculiar flavonoid composition, since it contains some flavanones that can act as natural statins. Hence, the study of bergamot flavonoids as metabolic regulators offers a great opportunity for screening and discovery of new therapeutic agents. Cholesterol metabolism, flavonoid composition and potential therapeutic use of C. bergamia Risso will be discussed in the following review.
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Bergamot (Citrus bergamia Risso) Flavonoids and Their Potential Benefits
in Human Hyperlipidemia and Atherosclerosis: an Overview
A.R. Cappello*,#, V. Dolce*,#, D. Iacopetta, M. Martello, M. Fiorillo, R. Curcio, L. Muto and
D. Dhanyalayam
Department of Pharmacy, Health and Nutritional Sciences, University of
Calabria, 87036 Arcavacata di Rende (Cosenza) Italy
Abstract: Elevated serum cholesterol, triglycerides and LDL levels are often
associated with an increased incidence of atherosclerosis and coronary artery disease.
The most effective therapeutic strategy against these diseases is based on statins
administration, nevertheless some patien ts, especially those with metabolic syndrome
fail to achieve their recommended LDL targets with statin therapy, moreover, it may
induce many serious side effects. Several scientific studies have highlighted a strong
correlation between diets rich in flavonoids and cardiovascular risk reduction. In
particular, Citrus bergamia Risso, also known as bergamot, has shown a significant degree of hypocholesterolemic and
antioxidant/radical scavenging activities. In addition, this fruit has attracted considerable attention due to its peculiar
flavonoid composition, since it contains some flavanones that can act as natural statins. Hence, the study of bergamot
flavonoids as metabolic regulators offers a great opportunity for screening and discovery of new therapeutic agents.
Cholesterol metabolism, flavonoid composition and potential therapeutic use of C. bergamia Risso will be discussed in
the following review.
Keywords: Bergamot fruit, flavonoids, hyperlipidemia, atherosclerosis, 3-hydroxy-3-methylglutaryl-CoA reductase enzyme.
INTRODUCTION
The risk for atherosclerosis and coronary heart disease is
increased in patients with elevated serum concentrations of
low-density lipoproteins cholesterol (LDL), total cholesterol
(TC) and triglicerides (TG) [1-5]. Several meta-analysis
studies showed that statin therapy can reduce the 5-year
incidence of cardiovascular diseases, by about one fifth per
mmol/L reduction in LDL cholesterol [6-8].
It is well-known that statins are able to inhibit 3-hydroxy-
3-methylglutaryl-CoA reductase (HMGR) activity, the rate-
limiting enzyme of cholesterol biosynthesis [9]. Statin
administration is one of the most widely used approaches to
lower serum LDL level and to reduce cardiovascular event
rates [10-12]. However, many patients, especially those with
the dyslipidemia associated with metabolic syndrome, are
unable to reach their lipid treatment goals on statins alone
[2]. Furthermore, patients might be statin-intolerant and
experience significant side-effects [3], hence the importance
of finding new drugs acting as statins.
Some foods were shown to possess these therapeutic
properties; in particular, daily consumption of Citrus fruit
*Address correspondence to these authors at the Department of Pharmacy,
Health and Nutritional Sciences, University of Calabria 87036 Arcavacata di
Rende (Cosenza) Italy; Tel: +39 0 984493177; Fax: +39 0 984493107;
E-mail: annarita.cappello@unical.it; and Tel: +39 0 984493119; Fax: +39 0
984493107; E-mail: vincenza.dolce@unical.it;
$These authors contributed equally to this work.
juice was shown to positively influence serum lipid levels
and to decrease coronary heart disease risk [13]. Their
hypolipidemic effects can be due to the presence of
flavonoids, pectins and ascorbic acid, which have a high
antioxidant potential and may interfere with cholesterol
metabolism [14-19].
Flavonoids are aromatic secondary plant metabolites,
having strong antioxidant and radical scavenging activities
[15, 20]. Their intake was associated with a reduced risk for
certain chronic diseases such as cardiovascular disorders and
cancerous processes [21-23]. Flavonoids exhibited antiviral,
antimicrobial and anti-inflammatory activities [23-25],
moreover, they were able to inhibit human platelet aggregation
[26] and to support a correct immune response [27].
Bergamot, the common name of Citrus bergamia Risso,
belongs to the family Rutaceae, subfamily Esperidea and it
has been widespread in the Mediterranean area for centuries.
Over the past few years, thanks to the growing interest in
bioactive compounds, bergamot fruit has attracted attention
for its remarkable flavonoid composition. The first part of
this review will report an overview on cholesterol
metabolism, in the second part, literature data regarding
flavonoid composition and distribution in bergamot fruit will
be analysed. The last part will focus on the scientific
evidence concerning the bioactivities of bergamot flavonoids
and their potential utility for human health as well as their
uses in atherosclerosis and coronary heart disease
treatments.
A.R. Cappello
D. Dhanyalayam
2 Mini-Reviews in Medicinal Chemistry , 2015, Vol. 15, No. 0 Cappello et al.
1. CHOLESTEROL HOMEOSTASIS AND REGULA-
TION
Cholesterol body homeostasis is mainly due to the
regulation of its endogenous synthesis, intestinal absorption,
excretion and hepatic conversion (Fig. 1).
Cholesterol de novo synthesis occurs mainly in the liver
and, in human, it accounts for more than 70% of body
cholesterol. Cholesterol intestinal absorption depends on diet
composition. Excess liver cholesterol can be directly
excreted as biliary sterols or converted into bile acids, both
are eliminated via feces.
Cholesterol absorption is controlled by at least two types
of transporters, Niemann-Pick C1-Like 1 (NPC1L1) as
influx transporter and ATP-Binding Cassette (ABC) proteins
as efflux transporters [28]. NPC1L1 transports cholesterol
from intestinal lumen into enterocytes and it reabsorbs free
cholesterol back into hepatocyte from bile [29]. ABCG5 and
ABCG8 reduce cholesterol absorption in the intestinal lumen
and exclude cholesterol from liver to the bile duct (Fig. 1).
ABCG1 and ABCA1 are involved in reverse cholesterol
transport, the pathway by which peripheral cell cholesterol
can be returned to the liver for excretion [30].
Regulation of cholesterol homeostasis is achieved by
proteins such as sterol regulatory element-binding proteins
(SREBPs) and AMP-Activated Protein Kinase (AMPK); by
nuclear receptors such as peroxisome proliferator activated
receptors (PPARs) and liver X receptors (LXRs); by
microRNAs (miRNAs).
SREBPs are key transcription regulators encoded by two
genes, SREBP-1 and SREBP-2. SREBP-1 upregulates the
transcription of some hepatic lipogenic genes [31-35].
SREBP-2 modulates the transcription of some sterol
Fig. (1). Overview of cholesterol homeostasis and regulation in liver, small intestine, extraepatic tissues, and plasma. The regulation is
indicated with black arrows. indicates activation while indicates inhibition. ABCA1, ABCG1, and ABCG5/G8: ATP-binding cassette
transporters; ACAT: acyl CoA:cholesterol acyltransferase; AMPK: AMP-activated protein kinase; BA: bile acid; C: cholesterol; CE:
cholesteryl ester; CEH: cholesteryl ester hydrolase; CM: chylomicrons; HDL: high-density lipoprotein; HMGR: 3-hydroxy-3-methylglutaryl-
CoA reductase; LDL: low-density lipoprotein; LDLR: low-density lipoprotein receptor; LXR: liver X receptor; M: mevalonate; miR-33a:
microRNA-33a; MTP: microsomal triglyceride transfer protein; NPC1L1: Niemann-Pick C1-Like 1; PPAR: peroxisome proliferator
activated receptor delta; SREBP2: sterol regulatory element binding protein-2; VLDL: very low density lipoprotein.
Potential Benefits of Bergamot Flavonoids Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 0 3
biosynthetic genes [36], for instance, when hepatocyte
cholesterol content is low, expressions of HMGR and LDLR
are upregulated [36] (Fig. 1).
AMPK is a critical player in energy homeostasis at both
cellular and whole body levels. An increased AMP to ATP
ratio leads to AMPK activation through phosphorylation by
at least three different upstream kinases [37]; in particular,
when cellular cholesterol content is high, AMPK inactivates
HMGR by phosphorylation (Fig. 1) [38].
PPARs are members of nuclear hormone receptors
superfamily that act as ligand-dependent transcription factors
[39, 40]. PPARα directly upregulates the transcription of
genes involved in cholesterol catabolism [41]. PPARγ
integrates the control of energy, lipid and glucose
homeostasis [42-44] and its activation also redirects effluxed
cholesterol from liver toward adipose tissue uptake via
scavenger receptor type-BI [45]. PPARδ activation elevates
serum HDL levels by increasing the expression of ABCA1
[30], it can reduce cholesterol absorption by decreasing
NPC1L1 intestinal expression [29] and it also potentiates
fecal neutral sterol secretion by increasing transintestinal
cholesterol efflux [46].
LXRs play a primary role in reverse cholesterol transport,
modulating the expression of several target genes as
ABCA1, ABCG1, ABCG4 ABCG5, ABCG8 and apoE [47-
50]. In the liver, when cellular cholesterol content is high,
LXRs activation induces cholesterol excretion and/or efflux
[50, 51].
MicroRNAs promote the down-regulation of their target
genes by binding to specific regions located in the 3’ UTR of
their target mRNA [52]. MIR-33a is believed to minimize
cholesterol export by the post-transcriptional repression of
ABCA1 transporter (Fig. 1) [53, 54].
2. FLAVONOIDS IN BERGAMOT TISSUES
Plant flavonoids are a large group of very different
compounds sharing the common feature of phenolic moieties
[55]. The presence of a relatively large number of flavonoids
is the result of many different possible combinations among
polyhydroxylated aglycones and a limited number of mono-
and disaccharides. The most commonly found sugars are
hexoses, such as glucose, galactose and rhamnose or
pentoses such as arabinose and xylose. They are, with a few
notable exceptions, plant metabolites deriving from the
shikimate pathway and the phenylpropanoid metabolism
[56]. In recent years, flavonoids have attracted tremendous
attention due to the protection that they provide against some
types of cardiovascular diseases [57]. As a consequence,
many studies have been directed to the characterization of
the flavonoid fractions and to the isolation of the most
representative flavonoids present in the most common Citrus
species, as well as of flavonoids present in many local
species such as C. bergamia Risso [58, 59]. Bergamot fruit
presents an external part, epicarp or flavedo yellow coloured;
a middle part, mesocarp or albedo, that is a spongy white
inner layer and an inner part, endocarp or pulp. A lbedo and
flavedo peeled off together are called peel. Bergamot
essential oil is obtained from this fraction by cold press; it is
composed of a volatile (9396%) and a non-volatile fraction
(47%).
The classes of flavonoids present in C. bergamia Risso
fractions are flavanones and flavones. Flavanones are present
as flavanone-O-glycosides, recently, flavanones diglycosides
carrying the 3-hydroxy-3-methylglutaric acid (HMG) moiety
have also been detected [60-62]. Flavones are present as
flavone-O-glycosides, flavone-C-glycosides or polymethoxy-
flavones (Table 1).
A comparative study on flavonoid composition in fruit
tissues of different Citrus species has been reported by
Nogata et al. [59], showing that bergamot fruit has a peculiar
flavonoid composition. In particular, it contains neoeriocitrin
in ex ceptionally large amount (288 mg/100 g fresh weight)
and it is relatively rich in neohesperidin, naringin, poncirin,
rhoifolin, and neodiosmin (590, 438, 1240, 43 and 33
mg/100 g fresh weight, respectively) with respect to the
other Citrus fruits analyzed. Furthermore, it contains very
little amount of hesper idin (2 mg/100 g fresh weight).
Table 1 lists structure and tissue distribution of
flavonoids, in C. bergamia Risso as described in literature.
Flavanone-O-glycosides are present in all the analysed
parts, in particular the most abundant are naringin,
neoeriocitrin, neohesperidin and poncirin, whereas hesperidin
and neoponcirin have been detected in a very low amount
[59]. They are also present in the peel, but it could be noted
that wh en it is splitted into albedo and flavedo, these
compounds are mainly present in albedo [59]. Moreover,
poncirin, which is present in huge amount in hand-squeezed
juice, is absent in industrial juice, this may be due to the
pressing process used to extract industrial juices [58]. In
addition, three acylated flavanones, which seem to
correspond to di-oxalate derivatives of neoeriocitrin,
naringin and neohesperidin, have been identified in bergamot
juice [63]. The HMG-conjugated flavanones, brutieridin,
melitidin and HMG-neoeriocitrin have also been detected at
different concentrations depending on the ripening stage;
they may be found in bergamo t fruit either in juice or in
albedo and flavedo [60-62].
Flavone-O-glycosides present a different tissue
distribution. All these compounds are present in the peel,
with the exception of chrysoeriol 7-O-neohesperidoside,
chrysoeriol 7-O-neohesperidoside-4’-glucoside and rhoifolin
4’- glucoside [59, 64]. Diosmetin mono-glucoside, diosmetin
mono-rhamnoside and apigenin mono-glucoside/mono-
rhamnoside has been detected in bergamot peel [64] but not
in albedo and flavedo. It could be explained because,
according to this author, bergamot peel is a mix of seeds,
pulp and deoiled flavedo after essential oil and juice
extraction. Furthermore, rutin, that is absent in albedo, has
been found in large amount in flavedo [64]. All these
compounds have been revealed in the juice [58, 59, 63, 65-
67], with the exception of diosmetin mono-rhamnoside and
diosmetin mono-glucoside; this latter has been detected in
industrial juice, probably because fruit industrial processing
leads to juices contaminated with peel constituents [58].
4 Mini-Reviews in Medicinal Chemistry , 2015, Vol. 15, No. 0 Cappello et al.
Table 1. Flavonoids identified in bergamot fruit.
Peel
Albedo
Flavedo
Juice
Industrial
juice
O
R2
R3
OOH
R1
[59, 84,
92]
[59, 60,
79]
[59, 60,
79]
[58-60,
64-67,
79]
[58]
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Potential Benefits of Bergamot Flavonoids Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 0 5
(Table 1) Contd….
Peel
Albedo
Flavedo
Juice
Industrial
juice
O
R5
R6
R1
OOH
R4
R3
R2
[59, 84,
92]
[59, 60,
79]
[59, 60,
79]
[58-60,
64-67,
79]
[58]
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6 Mini-Reviews in Medicinal Chemistry , 2015, Vol. 15, No. 0 Cappello et al.
(Table 1) Contd….
Peel
Albedo
Flavedo
Juice
Industrial
juice
O
R3
OMe
R1
OOMe
R2
MeO
MeO
[59, 84,
92]
[59, 60,
79]
[59, 60,
79]
[58-60,
64-67,
79]
[58]
X
X
X
X
X
X
X
Flavone-C-glycosides are mainly present in the juice,
similarly to flavanone-O-glycosides some of these compounds
lack in industrial juice [58, 63, 65-68]. In bergamot essential
oil (data not showed) only two flavonoids have been
detected: sinensetin and tetra-O-methylscutellarein. This
latter has been detected in essential oil [69].
3. HYPOLIPIDEMIC AND ANTIATHEROSCLERO-
TIC PROPERTIES OF BERGAMOT DERIVATIVES
Hypolipidemic effects of Citrus species are due to
several components, such as flavonoids, pectins and ascorbic
acid. Flavonoids are believed to inhibit LDL oxidation and to
increase LDL reuptake, furthermore, they can interfere with
fecal excretion of bile acids and with HMGR, LDLR and
FASN functions [14, 70-72]. In particular, naringin seems to
be active on atherosclerosis, as demonstrated by animal
studies [73], neoeriocitrin is believed to strongly inhibit LDL
oxidation [74] whereas, HMG-flavonoids could be able to
inhibit HMGR [60]. These observations have provided the
rationale to investigate the protective hypolipidemic effect of
bergamot extracts in animal models and in human patients.
Miceli et al. [75] demonstrated that daily administration
of bergamot juice to hypercholesterolemic rats caused a
significant reduction in TC, TG and LDL levels, an increase
in serum HDL levels and a protective effect on hepatic
parenchyma. In addition, fecal output of total bile acids and
neutral sterols was enhanced in the bergamot juice treated
group in comparison with the hyperlipidemic group. These
results are in agree with previous studies, which
hypothesized that pectins and flavonoids were able to lower
serum cholesterol levels by modulating hepatic HMG-CoA
concentration. It could be noted that in this study, the
potential side-effect due to bergamottin presence in bergamot
juice was not investigated. Bergamot juice is rich in
bergamottin (ranging from 18 to 61 mg/L) [63, 66], a
furanocoumarin compound that inhibits cytochrome P450
34A enzyme activity, significantly increasing the oral
bioavailability of several drugs metabolized primarily by this
cytochrome [74, 76].
This problem was overcome by Mollace et al. [77], that
analyzed the hypolipidemic effect of a defurocoumarinizated
bergamot-derived polyphenolic fraction supplemented with
ascorbic acid on animal models of diet-induced
hyperlipidemia and in patients suffering from metabolic
syndrome [77]. They found that oral administration of this
fraction both in animal and in patients, caused a significant
reduction of TC, TG and glycemia with a concomitant
increase of HDL levels. In particular, in 59 patients with
metabolic syndrome a 30-days treatment period with
bergamot-derived polyphenolic fraction, administred at the
dose of 1 g/die, reduced the serum levels of TC, LDL and
TG by 30%, 33% and 41%, respectively [26]. This effect
was associated with a significant improvement in vascular
reactivity in patients with both hyperlipidemia and
hyperglycemia, suggesting a potential protective role for the
use of bergamot-derived polyphenolic fraction in these
patients.
Recent prospective studies, led on patients with
hyperlipidemia demonstrated that administration of a
defurocoumarinizated bergamot-derived polyphenolic fraction
was able to reduce TC level by 31%. In the same conditions,
rosuvastatin administration (10 mg/die) caused a similar
reduction of TC content (30%). Their association produced a
considerable enhancement of rosuvastatin hypolipidemic
effect, causing a reduction of TC level by 38%, normalizing
the serum lipid profile [78].
The authors suggested that the observed hypolipidemic
effect could be mainly due to the presence in bergamot-
derived polyphenolic fraction of melitidin, brutieridin and
HMG-neoeriocitrin. This hypothesis was investigated by Di
Donna et al. [79] in a hypercholesterolemic rat model, by
measuring the effects on lipid profile of administration of
HMG-flavanones enriched fraction (62% of brutieridin, 14%
of melitidin and 15% of HMG-neoeriocitrin), extracted from
bergamot fruit, in comparison with simvastatin. HMGR,
LDLR and FASN transcription levels and their correlated
protein amounts were evaluated.
Potential Benefits of Bergamot Flavonoids Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 0 7
In this study, simvastatin and HMG-flavanones enriched
fraction singularly administrated reduced levels of TC (30%,
20% respectively), TG (32%, 20% respectively), VLDL
(33%, 28% respectively) and LDL (24%, 40% respectively),
whereas an increase of 20% in HDL content was observed
exclusively in rats treated by HMG-flavanones enriched
fraction [61]. Furthermore, according to the previously
published data, HMGR, LDLR and FAS transcription levels
were found up-regulated. An increased amount of their
corresponding proteins was detected [80]. Genotoxicity and
toxicity were not observed by testing HMG-flavanones
enriched fraction in vitro. The authors hypothesized that
HMGR inhibition leads to a reduction of endogenous
cholesterol level which, in turn, is responsible of HMGR and
LDLR transcriptional up-regulation, as well of the higher
LDLR exposure within the hepatocytes membrane, through a
compensatory mechanism based on SREBPs pathway.
Furthermore, it was highlighted that cholesterol depletion
below a certain threshold is known to be responsible for
FASN genic transcription increase, via SREBPs activation,
which is one of the observed effects. It was suggested that
transcriptional up-regulation of these genes and the
corresponding increased protein amounts could be occurred
via SREBPs pathway (Fig. 2).
Beside the already described hypolipidemic effect,
flavonoids, in particular naringin, have received considerable
attention because of their antioxidant/radical scavenging
properties [15, 20]. Increasing clinical evidences support the
hypothesis that phospholipid oxidation products may play a
role in atherosclerosis. This was firstly suggested by
demonstrating that mildly oxidized LDL proatherogenic
activities were present in the fraction containing oxidized
phospholipids. Subsequently, phospholipid oxidation products
were reported to accumulate in hyperlipidemic plasma,
atherosclerotic lesions and in several diseases that predispose
to stroke [81-83].
Trombetta et al. [84] reported that two flavonoid-rich
extracts from bergamot peel, endowed with radical-
scavenging properties and lacking genotoxic activity, were
able to prevent alterations induced by the pleiotropic
inflammatory cytokine tumor necrosis factor-α (TNF-α) on
human umbilical vein endothelial cells (HUVECs). This
study was led by monitoring intracellular levels of
malondialdehyde, reduced and oxidized glutathione levels,
superoxide dismutase activity and the activation status of
nuclear factor-κB. To clarify the mechanisms involved in
flavonoid protective activity, flavonoid-rich extracts were
tested in vitro for their ability to inhibit cyclooxygenase-1
(COX-1) and cyclooxygenase-2 (COX-2) activity, in a
human whole blood model. Conversely to literature data
[85], authors excluded that the protective effect of bergamot
peel extracts against TNF-α-induced changes in HUVECs
might be due to their capability to inhibit COX-1 or COX-2
pathways, because these phytocomplexes were unable to
modify prostaglandin E2 and tromboxan B2 release when
they were tested on human whole blood.
Several investigations suggested that phospholipid oxidation
products may play a pathogenic role in progressive renal
damage [86, 87]. A prominent mechanism probably involved
in the deleterious effects of hypercholesterolemia on the
kidney was an increased formation of reactive oxygen species.
In addition, oxidized LDL particles were injurious to
renal tubular epithelial cells and they might contribute to
tubulointerstitial damage and glomerulosclerosis [88].
In an experimental model of short-term diet-induced
Fig. (2). Model depicting HMG flavanones enriched fraction effects on lipids metabolism elicited in rat hepatocytes (from Di Donna et al
2014 [61]). Black arrows indicate H MG flavanones enriched fraction effects on genes, enzymes and metabolites levels. indicates
enzymatic inhibition. ACAT: Acyl-CoA:cholesterol acyltransferase; CE: cholesteryl ester; CEH: cholesteryl ester hydrolase; FASN: fatty
acid synthase; HDL: high-density lipoprotein; HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA; HMGR: 3-hydroxy-3-methylglutaryl-CoA
reductase; LDL: low density lipoprotein; LDLR: low density lipo protein receptor; SREBPs: sterol response elem ent binding proteins; TG:
triglycerides; VLDL: very low density lipoprotein.
8 Mini-Reviews in Medicinal Chemistry , 2015, Vol. 15, No. 0 Cappello et al.
hypercholesterolemia [89], a significant decrease in renal
lipid peroxidation was observed after bergamot juice
administration, as shown by the low malondialdehyde levels
found. Furthermore, analysis of kidney histopathological
sections supported the biochemical data, indicating a
protective effect of bergamot juice on the development of
kidney injury induced by the hypercholesterolemic diet. The
authors hypothesized that the beneficial effect on renal
parenchyma was due to the great abundance of flavonoids in
bergamot juice, believed to reduce oxidative damage in vivo.
CONCLUSION
HMGR inhibitors (statins) are the most effective,
practical and largely prescribed class of drugs for reducing
LDL concentrations [10, 11]. Nevertheless some patients,
especially those with metabolic syndrome do not achieve
their recommended LDL targets with statin therapy [77, 90].
Moreover, statins may induce many side effects, including
myalgia, myopathy, liver diseases and rhabdomyolysis [91].
Many studies demonstrated a relationship between the intake
of flavonoid-rich foods and a reduced risk for cardiovascular
disease [13]. Bergamot fruit is very rich in many peculiar
bioactive flavonoids compared to other Citrus fruits [15-18],
hence their evaluation as metabolic regulators might
represent an attractive strategy in drug discovery. The aim of
this review is to provide an overview on all flavonoids
detected in C. bergamia Risso and on the current knowledge
of their hypolipidemic effects [58-69], summarizing the
results obtained from different in vivo studies [61, 75, 77, 89].
All data reported suggest that C. bergamia Risso
flavonoids might be used in nutraceutical products or in
functional foods, even if additional studies are needed to
fully reveal their interaction with upstream mediators of lipid
metabolism pathways. Furthermore, since only few studies
on flavonoids administration in humans are available, further
clinical studies are required to focus on dose, bioavailability,
efficacy and safety of this class of flavonoids in humans.
LIST OF ABBREVIATIONS
ABC = ATP-Binding Cassette
AMPK = AMP- activated protein kinase
COX-1 = cyclooxygenase-1
COX-2 = cyclooxygenase-2
FASN = fatty acid synthase
HDL = high-density lipoprotein
HMG-CoA = 3-hydroxy-3-methylglutaryl-CoA
HMGR = 3-hydroxy-3-methylglutaryl-CoA reductase
HUVECs = human umbilical vein endothelial cells
LDL = low-density lipoprotein
LDLR = low-density lipoprotein receptor
LXRs = liver X receptors
microRNAs = miRNAs
NPC1L1 = Niemann-Pick C1-Like 1
PPARs = peroxisome proliferator activated receptors
SREBPs = sterol regulatory element-binding proteins
TC = total cholesterol
TG = triglicerides
TNF-α = tumor necrosis factor-α
VLDL = very low-density lipoprotein
CONFLICT OF INTEREST
The author(s) confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
We thank Dr. Bela Oszvari for critical reading of the
manuscript.
SUPPLEMENTARY MATERIALS
Supplementary material is available on the publisher’s
web site along with the published article.
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Ann. Intern. Med., 2009, 150(12), 858-868.
Received: ????????, 2015 Revised: ????????, 2015 Accepted: ???????????, 2015
... In general, polysaccharides can be divided into two categories: homo-polysaccharides and hetero-polysaccharides. A typical homo-polysaccharide is defined as having only one monosaccharide repeating on the chain, while a hetero-polysaccharide is composed of two or more categories Studies have shown that eating foods rich in flavonoids is associated with lower cardiovascular risk because of a significant reduction in cholesterol levels and free radical scavenging activity [43,44]. Flavonoids can regulate the imbalance of lipid metabolism by inhibiting lipid peroxidation and endogenous lipid biosynthesis and promoting lipid redistribution and exogenous lipid metabolism, significantly reducing TG, TC and LDL-C levels [45]. ...
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... For meat products, the value of 2 for h/H ratio was referenced. Values higher than 2 correspond to meats of superior nutritional quality with an abundance of fatty acids that promote the reduction of plasma cholesterol (hypocholesterolaemic), and thus a decreased risk of cardiovascular diseases [57][58][59][60][61]. ...
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The aim of this study was to analyze the influence of distinct production systems and seasonal variation in the Brazilian Eastern Amazon on the meat lipid composition of water buffaloes. Water buffaloes were reared in commercial farms in the Eastern Amazon either in extensive systems (Marajó Island, Nova Timboteua and Santarém locations), during rainy or dry seasons, or intensive (feedlot) systems. Animals reared in extensive systems were fed natural pastures, and those reared in feedlots were fed sorghum silage and commercial pellets. Buffaloes were slaughtered and ribeye muscle (longissimus lumborum) samples collected. Lipid-soluble antioxidant vitamins and fatty acids were analyzed. The nutritional value of meat from buffaloes reared in Marajó Island extensive system during the rainy season was higher than that of other systems, as it had lower levels of cholesterol and higher amounts of α-tocopherol associated with higher hypocholesterolaemic/hypercholesterolaemic ratio and lower index of atherogenic. Also, this meat had lower percentages of saturated fatty acids and higher proportions of mono- and polyunsaturated fatty acids (PUFA), particularly n − 3PUFA, with increased PUFA/saturated fatty acids ratio and decreased n − 6/ n − 3PUFA ratio. However, all extensive systems produced meat with a relatively low index of thrombogenicity values, which is advantageous for human health.
... It is well known that elevated serum cholesterol levels and proinflammatory factors drive atherogenesis [4]. Flavonoids, a common component of many Chinese traditional herbs, have been shown to interfere with the progression of AS [15], as evidenced by the findings that flavonoids can reduce vascular fragility and abnormal permeability [5,6,8,16], but the effects of total flavonoids from the Apocynum venetum leaf on the pathogenesis of AS and the underlying mechanisms have not been well studied. In our study, we found that AVF treatment significantly ameliorated hyperlipidemia, inflammation, and adhesion factors in a rat AS model induced by an HCD and VD 3 , suggesting that AVF can attenuate the initiation and progression of AS. ...
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To investigate the antiatherosclerotic effects of flavonoids extracted from Apocynum venetum (AVF) leaves in atherosclerotic rats and the underlying mechanisms, a total of 72 male Wistar rats were randomly divided into six groups: control group, model group, simvastatin group, low-dose AVF group, medium-dose AVF group, and high-dose AVF group. Atherosclerosis in rats was induced with a high-fat diet and an intraperitoneal injection of VD3 once daily for three contiguous days at a total injection dose of 70 U/kg. At the end of the 13th week, total serum cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) contents were measured. The hematoxylin-eosin (HE) staining was applied to evaluate the morphological changes. The ELISA method was used to detect related inflammatory factors and oxidative stress indicators. The corresponding protein expression and the mRNA level were detected by western blot analysis and reverse transcriptase PCR. HE staining showed that the thoracic aorta wall was thickened, and the aortic subendothelial foam cells and lipid vacuoles were reduced in the medium/high-AVF groups. Similarly, the TC, TG, LDL-C, and malondialdehyde (MDA) levels in the model group were significantly higher, but the HDL-C level and superoxide dismutase (SOD) activity were lower than those of the control group, and these effects were ameliorated by treatment with simvastatin or AVF. ELISA results showed that compared with the control group, the model group C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor- (TNF-) results were significantly increased, and the medium AVF and high AVF could significantly reduce the expression of related inflammatory factors. The AVF inhibited intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin mRNA and related protein expression in the aorta in atherosclerotic rats. Western blot analysis also showed that AVF can significantly reduce the protein expression of fractalkine (FKN), spleen tyrosine kinase (SYK), and p38 mitogen-activated protein kinase (p38) in the rat aorta. We believe that the AVF can effectively reduce blood lipid levels in rats with atherosclerosis and delay atherosclerotic progression by inhibiting excessive inflammatory factors and inhibiting related adhesion factors. The underlying mechanism may be related to the FKN/SYK/p38 signaling pathway activity. Our results contribute to validating the traditional use of the Apocynum leaf extract in the treatment of atherosclerosis. 1. Introduction Atherosclerosis (AS) is a systemic and diffuse arterial wall lesion caused by the accumulation of cholesterol in the intima of the artery and its branch vessels. It is usually accompanied by the proliferation of smooth muscle cells in the intima, subsequent thickening of the arterial vessels, and yellow AS plaques. The pathogenesis of AS is a complicated process, which is believed to be multifactorial. However, it is agreed that lipid metabolism disorders and inflammatory reactions are the pathological basis of AS [1]. In particular, the formation of foam cells, including macrophages and other cell types such as endothelial and vascular smooth muscle cells that contain deposited free and esterified cholesterol [2], plays an essential role in the development of AS [3]. Thus, efforts have been made to search for solutions to prevent lipid metabolism disorders and inflammatory reactions. Flavonoids are polyphenolic phytochemicals extensively distributed in plants, including vegetables and fruits such as flowers, seeds, and nuts. They have been shown to exhibit a broad spectrum of biological properties. In cardiovascular research, recent studies have shown that flavonoids exhibit several physical activities, including reducing vascular fragility and abnormal permeability, dilating the coronary artery, and diminishing platelet aggregation and free radical oxidation [4–7]. For example, Wang et al. [8] found that total flavonoids of Astragalus ameliorate AS by reducing the area of AS plaques and decreasing the circulating levels of TG and TC. Apocynum venetum L. (Luobuma and dogbane), a plant species of the Apocynaceae family, is widely distributed in China. Apocynum venetum (AVF) leaf extracts are used as additives in tea and for medicinal purposes. In modern medicine, AVF is used to treat hypertension, palpitations, insomnia, and neurasthenia [9–11]. Kwan et al. [12] demonstrated that the endothelium-dependent relaxation induced by AVF was potent with a maximal rate of relaxation occurring at 10 μg/mL, which could be inhibited by the NO synthase inhibitor NG-nitro-L-arginine (L-NAME) and the K⁺ channel blocker tetramethylammonia. It has been proposed that this effect could be due to its nitric oxide-releasing and superoxide-scavenging properties. Therefore, in this study, we aimed to explore the impacts of AVF on AS in a rat AS model induced by vitamin D3 (VD3) and HCD feeding and the related mechanisms. 2. Materials and Methods 2.1. Establishment of an Atherosclerosis Model and Experimental Groups Seventy-two SPF-grade healthy male Wistar rats weighing 180–200 g were purchased from the Experimental Animal Center of Jilin University. All animals were individually caged, had free access to drinking water, and were weighed weekly. After one week of adaptive feeding, the rats were randomly divided into the following six groups: control group (CON), model group (MOD), simvastatin group (SIM), and low-, medium-, and high-dose AVF-treated groups (low AVF, medium AVF, and high AVF) (12 rats per group). Except for the CON group, the animals received an intraperitoneal injection of VD3 once daily for three contiguous days at a total injection dose of 70 U/kg and were fed a high-fat diet until the end of the experiment. The 12 rats of the CON group were intraperitoneally injected with an equal volume of normal saline and fed normal feed. During the experiment, animals in the low-, medium-, and high-dose AVF groups received daily gavage of AVF at doses of 25, 50, and 100 mg/kg/d, respectively, and animals in the SIM group received simvastatin at 4 mg/kg (gavage). The dosage of AVF is mainly based on the therapeutic effect of AVF on cardiovascular diseases in previous articles. Zhang et al. studied the protection of AVF against pirarubicin-induced cardiotoxicity. The doses of AVF were 25 mg/kg, 50 mg/kg, and 100 mg/kg [7]. Kim et al. used 70 mg/kg AVF to explore its antihypertensive pharmacological effects [13]. The high-fat diet comprised 80.8% basic diet, 3.5% cholesterol, 10% lard, 0.2% propylthiouracil, 0.5% sodium cholate, and 5% white granulated sugar. The modeling method used in this experiment was redesigned by our laboratory based on the previous modeling methods and had been recognized by peers. Hu et al. used this method to replicate the rat model of atherosclerosis and verified the antiatherosclerotic effect of icariin [14]. The study was approved by the Animal Care and Ethics Committee of Jilin University (Changchun, China; Grant no. 20170503) and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. All experimental animals were euthanized by inhalation of CO2 (30% volume displacement per minute). 2.2. Reagents Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD), and malonaldehyde (MDA) test kits were purchased from Nanjing Jiancheng Bioengineering Institute, China. VD3 injection was purchased from Shanghai General Pharmaceutical, China. Simvastatin tablets were purchased from Merck, Hangzhou, China. Sodium cholate and cholesterol were purchased from Sigma, USA. The antibody of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, fractalkine (FKN), spleen tyrosine kinase (SYK), and p38 mitogen-activated protein kinase (p38) were purchased from Abcam, USA. C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor- (TNF-) determination kits were purchased from Shanghai Meixin Biological Engineering, China. Apocynum venetum flavonoids (AVF, flavonoid content ≥72%) were purchased from Nanjing Jingzhu Biotechnology Co., Ltd., China. 2.3. Blood Lipid Examination When the experiment was terminated at the end of the 13th week, serum was collected from each group (2000 rpm, 15 min, 4°C). Serum TC and TG, LDL-C, and HDL-C contents were measured according to the kit instructions. 2.4. Morphological Examination The full length of the rat thoracic aorta is approximately 2 cm. The proximal end (0.5 cm) was fixed with 10% formalin, embedded in paraffin, and prepared as 5 μm-thick sections. The sections were subjected to serial alcohol deparaffinization and stained with hematoxylin-eosin (HE). Differences in histology between the rat aortic tissues of various groups were observed under a light microscope. 2.5. ELISA Detection of Inflammatory Factors and Oxidative Stress Levels When the experiment was terminated at the end of the 13th week, serum was collected from each group (2000 rpm, 15 min, 4°C). Levels of CRP, IL-6, TNF-, MDA, and SOD in serum were analyzed with appropriate ELISA kits based on provided directions. 2.6. Quantitative PCR Rat aorta (80 mg) of the CON, MOD, and AVF groups was used for RNA extraction using 1 ml TRIzol (Invitrogen, USA). mRNA expression was quantified using the TransScript Green Two-Step qRT-PCR Supermix (TransGen Biotech, Beijing, China). All primers were obtained from GeneCopoeia (USA). The sequences of primers are listed as follows: the ICAM-1 primer sequences were as follows: forward primer 5′-CGTGACCTGGACACACCTAC-3′ and reverse primer 5′-TGTCCCAGCTTTCCCATCTC-3′. The VCAM-1 primer sequences were as follows: forward primer 5′-CTACATGAGGGTGCTGCTGT-3′ and reverse primer 5′-GAACAACGGAATCCCCAACC-3′. The E-selectin primer sequences were as follows: forward primer 5′-CCACATGTGCAGGGGTACAG-3′ and reverse primer 5′-ATCCGTTGAGTGTCCAACCC-3′. GAPDH was used as an internal reference; the primer sequences were as follows: forward primer 5′-GTTACCAGGGCTGCCTTCTC-3′ and reverse primer 5′-GATGGTGATGGGTTTCCCGT-3′. The PCR conditions were as follows: denaturation at 94°C for 30 s, followed by 45 cycles at 94°C for 5 s, 60°C for 15 s, and 72°C for 10 s; the CT value of each sample was recorded. Based on the CT values for the target gene and reference genes, we used to represent the relative expression levels of the target gene, according to CT = (CT target − CT reference) experiment − (CT target − CT reference) control. 2.7. Western Blot Analysis A rat aortic sample (100 mg) was diced, placed in 1 ml of RIPA lysis buffer (containing one μmol/L PMSF), and fully homogenized, followed by centrifugation at 12,000 g for 20 min. A total of 100 μg of total protein per sample was separated on 10% sodium dodecyl sulfate-polyacrylamide gels by electrophoresis at 120 V for one hour, followed by a transfer onto polyvinylidene difluoride membranes at 100 V for one hour. The membranes were then blocked with 5% nonfat dry milk in Tris-buffered saline containing Tween 20 (0.15 M NaCl, 20 mM Tris-HCl, pH 7.4, and 0.05% Tween 20) for one hour at room temperature, followed by incubation with specific primary antibodies (anti-p38, anti-FKN, and anti-SYK; 1 : 1000 dilution; Abcam, USA) at 4°C overnight. Then, the membranes were incubated with a horseradish peroxidase-conjugated secondary antibody (1 : 5000 dilution; Santa Cruz Biotechnology, USA). The specific protein bands were detected with enhanced chemiluminescence reagent (Amersham, USA). GAPDH antibody (Sigma, USA) was used as an internal control. 2.8. Statistical Analysis All statistical analyses were carried out using the statistical package SPSS 19.0 (IBM Corp., USA). Data were presented as the mean ± standard deviation (SD) (n = 12). Multiple groups were compared using the one-way analysis of variance followed by the least significant difference test. Statistical significance was defined as . 3. Results 3.1. Comparison of the General Condition and Blood Lipid Levels of the Rats As shown in Figure 1(a), the rats showed slow weight gain after feeding with high-fat diets. Starting from the 3rd week, the weight of rats on the high-fat diet was significantly lower than that of the CON group () fed with the usual diet, and there was no significant difference in the body weight of the other groups. (a)
... In fact, cholesterol-lowering drugs are able to reduce cancer incidence and cancer-related mortality [122]. To date, it is known that BPF possesses several hypolipidizing properties against many metabolic dysfunctions [123][124][125][126]. ...
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Background Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented. Objectives The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk. Methods This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Results Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB. Conclusions The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.
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The citrate carrier (CiC), characteristic of animals, and the dicarboxylate–tricarboxylate carrier (DTC), characteristic of plants and protozoa, belong to the mitochondrial carrier protein family whose members are responsible for the exchange of metabolites, cofactors, and nucleotides between the cytoplasm and the mitochondrial matrix. Most of the functional data on these transporters are obtained from the studies performed with the protein purified from rat, eel yeast, and maize mitochondria or recombinant proteins from different sources incorporated into phospholipid vesicles (liposomes). The functional data indicate that CiC is responsible for the efflux of acetyl-CoA from the mitochondria to the cytosol in the form of citrate, the primer for fatty acid, cholesterol synthesis, and histone acetylation. Like the CiC, the citrate exported by DTC from the mitochondria to the cytosol in exchange for oxaloacetate can be cleaved by citrate lyase to acetyl-CoA and oxaloacetate and used for fatty acid elongation and isoprenoid synthesis. In addition to its role in fatty acid synthesis, CiC is involved in other processes such as gluconeogenesis, insulin secretion, inflammation, and cancer progression, whereas DTC is involved in the production of glycerate, nitrogen assimilation, ripening of fruits, ATP synthesis, and sustaining of respiratory flux in fruit cells. This review provides an assessment of the current understanding of CiC and DTC structural and biochemical characteristics, underlying the structure–function relationship of these carriers. Furthermore, a phylogenetic relationship between CiC and DTC is proposed. © 2014 IUBMB Life, 2014
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Statins are the most commonly prescribed drugs to reduce cardiometabolic risk. Besides the well-known efficacy of such compounds in both preventing and treating cardiometabolic disorders, some patients experience statin-induced side effects. We hypothesize that the use of natural bergamot-derived polyphenols may allow patients undergoing statin treatment to reduce effective doses while achieving target lipid values. The aim of the present study is to investigate the occurrence of an enhanced effect of bergamot-derived polyphenolic fraction (BPF) on rosuvastatin-induced hypolipidemic and vasoprotective response in patients with mixed hyperlipidemia. A prospective, open-label, parallel group, placebo-controlled study on 77 patients with elevated serum LDL-C and triglycerides was designed. Patients were randomly assigned to a control group receiving placebo (n=15), two groups receiving orally administered rosuvastatin (10 and 20mg/daily for 30days; n=16 for each group), a group receiving BPF alone orally (1000mg/daily for 30days; n=15) and a group receiving BPF (1000mg/daily given orally) plus rosuvastatin (10mg/daily for 30days; n=15). Both doses of rosuvastatin and BPF reduced total cholesterol, LDL-C, the LDL-C/HDL-C ratio and urinary mevalonate in hyperlipidemic patients, compared to control group. The cholesterol lowering effect was accompanied by reductions of malondialdehyde, oxyLDL receptor LOX-1 and phosphoPKB, which are all biomarkers of oxidative vascular damage, in peripheral polymorphonuclear cells. Addition of BPF to rosuvastatin significantly enhanced rosuvastatin-induced effect on serum lipemic profile compared to rosuvastatin alone. This lipid-lowering effect was associated with significant reductions of biomarkers used for detecting oxidative vascular damage, suggesting a multi-action enhanced potential for BPF in patients on statin therapy.