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Abstract and Figures

Dihydrochalcones are a class of secondary metabolites, whose demand in biological and pharmacological applications is rapidly growing. Phloretin is one of the best known and abundant dihydrochalcone characterized by the presence of 2,6-dihydroxyacetophenone pharmacophore. It is a versatile molecule with anticancer, antiosteoclastogenic, antifungal, antiviral, anti-inflammatory, antibacterial and estrogenic activities and able to increase the fluidity of biological membranes and penetration of administered drugs. In this review we have performed a critical evaluation of available literature as far as phloretin beneficial effects and activation/block of intracellular signal cascade are of concern. In addition, we supply useful information on its chemical properties, sources and bioavailability.
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Health effects of phloretin: from chemistry to medicine
Sahar Behzad .Antoni Sureda .Davide Barreca .Seyed Fazel Nabavi .
Luca Rastrelli .Seyed Mohammad Nabavi
Received: 9 October 2016 / Accepted: 2 March 2017 / Published online: 7 March 2017
ÓSpringer Science+Business Media Dordrecht 2017
Abstract Dihydrochalcones are a class of secondary
metabolites, whose demand in biological and phar-
macological applications is rapidly growing. Phloretin
is one of the best known and abundant dihydrochal-
cone characterized by the presence of 2,6-dihydrox-
yacetophenone pharmacophore. It is a versatile
molecule with anticancer, antiosteoclastogenic, anti-
fungal, antiviral, anti-inflammatory, antibacterial and
estrogenic activities and able to increase the fluidity of
biological membranes and penetration of administered
drugs. In this review we have performed a critical
evaluation of available literature as far as phloretin
beneficial effects and activation/block of intracellular
signal cascade are of concern. In addition, we supply
useful information on its chemical properties, sources
and bioavailability.
Keywords Anticancer Dihydrochalcones
Phenolic compound Phloretin
Natural products supply inexhaustible sources of
molecules with remarkable biological properties and
functionalities. The properties of these molecules are
tightly related to the basic skeleton and to the presence
of specific substituents, which confer them, just to
mention a few, the ability to interact with macro-
molecules, modulated signal cascade, change perme-
ability and fluidity of membranes. Phloretin and its
derivatives (mainly glycosyl forms) are naturally
occurring dihydrochalcones identified in apple, kum-
quat, pear, strawberry and vegetables (Barreca et al.
2011,2013; Gosch et al. 2009; Hilt et al. 2003a; Tsao
et al. 2003). It is a phenylpropanoid lacking the
heterocyclic C ring and the double bond between aand
bpositions on the three carbon atoms bridge between
homocycles rings A and B. This former makes
phloretin a very flexible molecule, able to bind
S. Behzad
Department of Pharmacognosy, School of Pharmacy,
Shahid Beheshti University of Medical Sciences, Tehran,
A. Sureda
Grup de Nutricio
`ria i Estre
`s Oxidatiu,
CIBEROBN (Physiopathology of Obesity and Nutrition),
University of Balearic Islands, Palma, Illes Balears, Spain
D. Barreca
Dipartimento di Scienze Chimiche, biologiche,
farmaceutiche ed ambientali, University of Messina, Viale
F. Stagno d’Alcontres 31, 98166 Messina, Italy
S. F. Nabavi S. M. Nabavi (&)
Applied Biotechnology Research Center, Baqiyatallah
University of Medical Sciences,
P.O. Box 19395-5487, Tehran, Iran
L. Rastrelli
Dipartimento di Farmacia, University of Salerno, Via
Giovanni Paolo II, 84084 Fisciano, Italy
Phytochem Rev (2017) 16:527–533
DOI 10.1007/s11101-017-9500-x
efficiently with biological macromolecules. These
interactions and block/activation of intracellular sig-
naling pathways result in striking biological properties
(such us antifungal, anticancer, antioxidant, antibac-
terial, antiosteoclastogenic, estrogenic, antiviral, and
anti-inflammatory activities) (Calliste et al. 2000; Kim
et al. 2012;Rajaetal.2003; Stangl et al. 2005; Yang
et al. 2001). Phloretin can be utilized also as a
penetration enhancer of administered drugs. In fact,
after its binding to biological membranes, it increases
their fluidity (Nakamura et al. 2003; Rezk et al. 2002).
Moreover, it modulates Ca
level and down-regu-
lates the secretion of IL-2 of human normal lympho-
cytes and counteracts advanced glycation end
products formation (Calliste et al. 2000; Fordham
et al. 2014; Kim et al. 2012; Nakamura et al. 2003;
Raja et al. 2003; Rezk et al. 2002; Stangl et al. 2005;
Yang et al. 2001). Recently, U
¨llen et al. (2012)
reported its cytoprotective activity in prevention and/
or treatment of acrolein-associated human diseases
and Barreca et al. (2014,2017a,b) described its
antiaggregation potentiality on the protein fibrillation,
neuroprotective properties and antimicrobial activity
against Staphylococcus aureus ATCC 6538, Listeria
monocytogenes ATCC 13932, methicillin-resistant S.
aureus clinical strains and Salmonella typhimurium
ATCC 13311. In particular in Staphylococcus aureus,
it modulates the activities of key enzymes, influencing
the energetic metabolism of the microorganism.
Overall the specific functions and potentialities of this
molecule are being revealed rapidly, especially taking
into account its low toxicity, high antioxidant activity
and potential health-promotion applications.
Dihydrochalcones (1,3-diaryl-2-propen-1-ones) are
phenolic compounds characterized by a flavonoid
skeleton, diphenylpropan (C6-C3-C6), with the
absence of heterocyclic C ring. Indeed, these sec-
ondary metabolites are mainly precursors of flavo-
noids in plants. Phloretin [20,40,60-trihydroxy-3-(4-
hydroxy phenyl)-propiophenone] (Fig. 1), a crys-
talline phenolic ketone and its most abundant glyco-
sylated products, phloridzin (phloretin-20-O-
glucoside) and phloretin-20-O-(20-O-xylosyl) gly-
coside are simple dihydrochalcones. Several other
derivatives such as 3-hydroxyphloretin, sieboldin (3-
hydroxyphloretin-40-O-glucoside), trilobatin (phlore-
tin-40-O-glucoside), phloretin-40-O-galloyl glucoside,
nothofagin (phloretin-30-C-glucoside) and glycy-
phyllin (phloretin-20-O-rhamnoside) have been iso-
lated from natural sources (Gaucher et al. 2013;
Harborne 2013; Iwashina et al. 2012). In phloretin,
two aromatic phenol rings (ring A and B), hydroxyl
groups and a carbonyl group are responsible for a wide
spectrum of pharmacological effects. The antioxidant
pharmacophore of phloretin is 20,60-dihydroxyace-
tophenone, in which the contribution of carbonyl and
OH groups of ring A enhances its activity, whereas, the
substitution of one hydroxyl moiety by a sugar (as in
the case of phloridzin) reduces the activity compared to
phloretin (Bentes et al. 2011; Rezk et al. 2002).
Sources and bioavailability
To date, about 200 dihydrochalcones have been
isolated from more than 300 plant families. Apple tree
(Malus spp.), belonging to the Rosaceae family, is the
predominant source of glycosylated phloretin deriva-
tives and aglycone. However, they are present in
several other genera like Symplocos spp. (Symplo-
caceae) (Polya, 2003), Kalmia spp. (Ma et al. 2016;
Polya 2003), Pieris japonica,Rhododendron spp.
(Ericaceae) (Polya 2003), Linderalucida (Lauraceae),
Fragaria x ananassa (Rosaceae) (Hilt et al. 2003b),
Balanophora spp. (Balanophoraceae) (de Bernonville
et al. 2010), Piper elongatum (Piperaceae), Lithocar-
puspolystachyus (Fagaceae) (Li et al. 2014), Lactuca
sativa (Asteraceae), Corylopsis spp. (Hamameli-
daceae) (Iwashina et al. 2012), Hovenia Lignum (An
et al. 2007), Ziziphus spp. (Rhamnaceae) (Pawlowska
et al. 2009), Smilax glyciphylla (Smilaceae) (Huang
et al. 2013), Fagopyrum esculentum (Polygonaceae)
(Nagatomo et al. 2014) and Aspalathuslinearis
Fig. 1 Chemical structure of phloretin
528 Phytochem Rev (2017) 16:527–533
(Fabaceae), as reported in Table 1. In Rosaceae family,
Malus domestica L. (apple) and Fragaria x ananassa
Duch. (strawberry) have widespread use in the food
market and are good sources of flavonoids and phenolic
compounds in human diet. Apple is a widely planted
fruit crop in the world and it has an important role in the
daily diet. Profiles of phloretin derivatives can vary
greatly in different parts of apple fruits in faction of the
cultivars. Approximately 838.0, 429.0, 59.0 and
4.1 mg/kg dry weight of phloridzin were reported in
unripe fruit, peel, pulp and apple juice, respectively
(Rana and Bhushan 2015). This content was signifi-
cantly decreased and ranged from *19.0
to *49.0 mg/kg of dry matter in strawberry (Hilt
et al. 2003a). Phloretin has been also isolated from
leaves, barks and roots of the apple trees. In contrast to
dessert fruits (which supply 1.0 mg phloretin starting
from 100 g of product), apple juice and cider would be
the main source of dihydrochalcones intake (which
supply *1.0–5.0 mg phloretin from 250.0 ml). Other
apple products, like jam and jelly, also provide less
than 1.0 mg/100 g. However, variable phloretin con-
tent could be clearly seen in industrial or domestic
apple juice products. In industrial process, whole parts
of fruits are used and oxidative enzymes are inactive
due to high temperature. Active forms of these
enzymes might degrade dihydrochalcones (Toma
´n and Clifford 2000).
The bioavailability of the flavonoid is influenced by
the presence of sugar moieties, molecular weight,
metabolic conversion and gut microflora degradation.
Glycosylated flavonoid with complex skeleton may
have lower absorption (Thilakarathna and Rupasinghe
2013). Glycosides of phloretin are hydrolyzed by
small intestine microbial enzymes (LPH:lactase phlo-
ridzin hydrolase) and cytosolic b-glucosidases in the
enterocytes, producing phloretin aglycone and free
sugars. The reaction of deglycosylation of Phloretin-
20-O-glycoside is much more rapid than that of the
corresponding disaccharide substituents. Metabolic
conversion may occur in intestine or liver. A range of
simple phenols, such as 3-(40-hydroxyphenyl) propi-
onic acid (phloretic acid) and 1,3,5-trihydroxy ben-
zene (phloroglucinol), are generated after degradation
of phloretin by colon microflora. These results are in
agreement with the metabolism of other flavonoids
(Borges et al. 2013; Spencer and Crozier 2012;
´n and Clifford 2000).
Several studies have showed that after oral inges-
tion of phloretin, in the form of aglycone or as the
glycoside substutuents, it has been quickly absorbed in
the intestine and appeared in the plasma. Some
unconjugated forms, glucoronide and sulphurated
metabolites of phloretin could be also identified in
the plasma. At the first 10 h of oral consumption of
phloretin compounds, there is no significant difference
in plasma level of total phloretin, but it changes,
tending to go back to baseline, after 24 h due to urine
excretion (Crespy et al. 2001; Spencer and Crozier
Health effects of phloretin
In the past years, attentions have been focused on
flavonoids, indicating that they are a functionalized
chemical group of compounds with many biological
activities. The use of these compounds can be a
pharmacological strategy for different pathologies. As
other flavonoids, phloretin has been described to
display, among others, antioxidant, anti-inflammatory
and anticarcinogenic activities.
It is known that the action of endogenous antiox-
idant defense systems is completed together with
Table 1 Plants in which has been identified phloretin or its
glycosylated derivatives
Species Family
Malus spp. Rosaceae
Fragaria x ananassa Rosaceae
Symplocos spp. Symplocaceae
Kalmia spp. Ericaceae
Pieris japonica Ericaceae
Rhododendron spp. Ericaceae
Lindera lucida Lauraceae
Balanophora spp. Balanophoraceae
Piper elongatum Piperaceae
Lithocarpus polystachyus Fagaceae
Lactuca sativa Asteraceae
Corylopsis spp. Hamamelidaceae
Hovenia Lignum Rhamnaceae
Ziziphus spp. Rhamnaceae
Smilax glyciphylla Smilaceae
Fagopyrum esculentum Polygonaceae
Aspalathus linearis Fabaceae
Phytochem Rev (2017) 16:527–533 529
exogenous antioxidants, such as polyphenols, to
suppress oxidative stress. The antioxidant effects
induced by phloretin not only correlate with the
presence of hydroxyl moieties in its chemical struc-
ture, but it is also influenced by the presence of a
carbonyl group (Bors et al. 1990; Rezk et al. 2002).
Discrepancies in the obtained results are due to the use
of different concentrations of this flavonoid or to the
conditions applied. Many works have reported the
capacity of phloretin to scavenge different reactive
oxygen species (ROS), including peroxynitrite (Bors
et al. 1990), hydroxyl radical (Rezk et al. 2002)or
superoxide anion (Leu et al. 2006). Other works have
also described the capacity of phloretin to reduce the
lipid peroxidation caused by different agents (Liu et al.
2015; Nakamura et al. 2003; Ratty and Das 1988; Ren
et al. 2016; Zhu et al. 2009). Phloretin is also able to
activate transcription factors, inducing the expression
of antioxidant genes and improving enzymatic antiox-
idant defense system, through complex mechanisms
almost completely unknown (Fig. 2). Phloretin has
been described to increase the superoxide dismutase
(SOD) and glutathione peroxidase (GPx) activities in a
concentration-dependent manner (Liu et al. 2015; Ren
et al. 2016). Contrary to the above results, Galati and
collaborators (Galati et al. 2002) described a proox-
idative capacity of phloretin in hepatocytes of rats,
although this result could be related to the activation of
some transcription factors related with the anti-
tumoral activity of the flavonoid. Phloretin also
promotes the synthesis of non-enzymatic antioxidant
defenses, such as the reduced glutathione (GSH),
which is usually used as a marker of oxidative stress.
Moreover, some other works have also described the
ability of the above mention flavonoid to avoid GSH
depletion, such as in cortical brain of rats (Liu et al.
2015) or in keratinocytes (Shin et al. 2014).
Phloretin has anti-inflammatory effects, modulat-
ing the immune cell activity. The compound inhibits
the expression and secretion of diverse pro-inflamma-
tory agents including cytokines, such as IL-6, IL-8 and
TNF-a, chemokines and adhesion molecules (Huang
et al. 2015; Jung et al. 2009; Van Raemdonck et al.
2015). In addition, phloretin treatment decreases the
expression of other pro-inflammatory proteins such as
cyclooxigenase-2 (COX-2) and the inducible isoforms
of the nitric oxide synthase (iNOS) (Chang et al.
2012). In this way, phloretin treatment decreases the
synthesis of nitric oxide and prostaglandin E
The mechanism of action seems to be related to the
Scavenger of ROS
Decrease level of:
Superoxide anion
Hydroxyl radical
Increase level of :
Activation of
involved in
Activator of
SOD and
Reducer of lipid
level of :
Decrease expression
of COX-2 and iNOS
Suppression of NF-κβ
Reduction of
prostaglandin E2and
Nitric oxide level
Effect on cancer
Cytotoxic and
Apoptotic activity
of perforin or
granzyme B
Release of
Cytocrome C
Activation of :
Caspase 9,
Caspase 3,
of p53
Decrease of
Activation of
immune cells
against tumor
Fig. 2 Schematic representation of phloretin’s cellular effects and of its block/activation of protein activities and transcription factors
530 Phytochem Rev (2017) 16:527–533
suppression of the NF-jb transcription factor activa-
tion, a master regulator of the inflammatory process in
mammalian cells, through a mechanism involving
extracellular signal-regulated kinase 1/2 (ERK1/2),
p38 mitogen-activated protein kinase (p38 MAPK),
and c-Jun N-terminal kinase (JNK) (Gambhir et al.
2015; Hoesel and Schmid 2013). Several studies
evidenced a significant attenuation in the inflamma-
tory response induced by LPS, IL-1aor TNF-aby
phloretin treatment (Fordham et al. 2014). Related to
the phloretin anti-inflammatory effects, an inhibitory
activity against immunoglobulin E (IgE)-mediated
allergic responses has been evidenced (Chung et al.
Another important effect of phloretin is the asso-
ciation to the protective effects against tumor growing,
triggering cell death in malignant cells by either direct
or indirect mechanisms (de Oliveira 2016). Different
authors have investigated the capacity of phloretin to
potentiate the activity of immune cells against tumor
cells favoring cellular proliferation and differentiation
and enhancing the cytotoxic activity up-regulating
proteins such as perforin or granzyme B (Nusse and
Varmus 1992; Zhu et al. 2013). In other studies the
treatment of cancer cells with phloretin significantly
has suppressed the growth of these cancer cells. The
mechanisms of action of phloretin is related to the
increase of apoptotic rates (evidenced by cytochrome
c release in the cytosol), the activation of caspase-9
and caspase-3, the increase of poly (ADP-ribose)
polymerase (PARP) cleavage and Bax levels, the up-
regulation of P53, and the decrease of Bcl-2 amount
(Fig. 2), leading to DNA fragmentation and cell death
(Kim et al. 2009; Park et al. 2007; Yang et al. 2009). It
has been proposed that phloretin pro-apoptotic activity
could be mediated through the production of ROS and
the inhibition of glucose transporter 2 (GLUT2)
interfering with glucose uptake (Liu et al. 2016). This
is a well known role of phloretin; in fact, its naturally
occurring glucoside (phlorizin) and, to a lesser extent,
phloretin, for instance, have been an essential model to
reveal the role of sodium glucose co-transporter type 2
(SGLT2) inhibition in the treatment of hyperglycemia
(Bays 2013). This property has been confirmed also by
animal studies, affected by hyperglycemia and insulin
resistance. In fact, phlorizin is a competitive inhibitor
of both SGLT1 and SGLT2. The low selectivity for
SGLT2 versus SGLT1 is one of the reasons for its
unsuitable use for treatment of hyperglycemia.
Actually, researchers try to develop phlorizin deriva-
tives with more stability, higher bioavailability and
selectivity towards SGLT2 to overcome these prob-
lems (Bays 2013).
Finally, it is also important to note that phloretin has
been suggested to exert other activities including the
suppression of biofilm formation (Lee et al. 2011), the
modulation of lipid metabolism and adipocytes
metabolism, all element that open a potential use in
the treatment of obesity or insulin resistance (Hassan
et al. 2007; Shu et al. 2014), or in the regulation of
bone dynamics, increasing bone mineral density and
content (Feng 2005; Lee et al. 2014).
Conclusion and recommendations
In the last two decades, a great deal of attentions has
been focused on diet as source of nutraceuticals. The
useful and interesting biological activities of phloretin
make it a reference point as far asthe potentiality to exert
health promoting properties on human organism are of
concern. In particular, just to mention a few, the abilities
to modulate signal cascade and the energy metabolism,
to avoid the depletion of intracellular antioxidant system
and the growth of some cancer cell typologies have
attracted the attention of researchers to produce new
compounds with specific therapeutic targets, due to
phloretin remarkable involvement in organism wellness
and the almost completely absence of toxicity. Never-
theless, the in vivo studies focusing on its effects are
scarce and further studies are needed to better under-
stand its activities on human organisms and to promote
its development, as well as its use as nutraceutical in
food supplements and pharceutical products, which can
increase the potentiality of the administered drug and
decrease their potential side effects.
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... Dihydrochalcones (1,3-diaryl-2-propen-1-ones) are chemically characterized as open-chain flavonoids, in which the two aromatic rings are linked by a three-carbon α, β-saturated carbonyl system (Stompor et al. 2019). These features make phloretin a very flexible molecule, able to bind with macromolecules, modulate signal cascade, and change permeability and fluidity of membranes (Behzad et al. 2017). Over the past decades, numerous studies have revealed that a diet rich in polyphenolic compounds plays an important role in reducing the risk of cancer, cardiovascular diseases, inflammation, diabetes, and degenerative disorders. ...
... Among dietary sources, apple is an important source of such phytochemicalsthere is an old saying stating that "An apple a day keeps the doctor away." Thus, one of the polyphenols found in apples is phloretin which has received much attention, and extensive research studies have reported a plethora of biological effects, including anticancer, anti-inflammatory, antimicrobial, antioxidant, neuroprotective, antidiabetic, and hepato-and cardioprotective activities (Behzad et al. 2017;Choi 2019;de Oliveira 2016;Mariadoss et al. 2019a;Nakhate et al. 2022). ...
... Apple-derived products, such as juice and cider, are the main source of phloretin intake (1.0-5.0 mg/250 mL). Other apple products, like jam and jelly, supply less than 1.0 mg phloretin/100 g (Behzad et al. 2017). Additional sources of phloretin include strawberries (Fragaria  ananassa, Rosaceae), kumquat (Citrus japonica, Rutaceae), pears (Pyrus ssp., Rosaceae), honeybush (Cyclopia subternata, Fabaceae), sweet tea (Lithocarpus polystachyus, Fagaceae), hottentot-fig (Carpobrotus edulis, Aizoaceae), Japanese andromeda (Pieris japonica, Ericaceae), mountain laurel (Kalmia latifolia, Ericaceae), Japanese raisin tree (Hovenia dulcis, Rhamnaceae), and alpine azalea (Kalmia procumbens, Ericaceae) (de Oliveira 2016). ...
... The growth of cancer cells could be significantly inhibited by using phloretin (MH2) to treat cancer cells. The mechanism of action was related to the increase cell apoptosis rate, the activation of caspase-9 and caspase-3 proteins, the increased levels of PARP cleavage and Bax, the upregulation levels of p53 and the reduction in Bcl-2, which led to DNA fragmentation and cell death [44]. Phloretin (MH2) (0.15 mM) could accelerate the apoptosis of melanoma 4A5 cells in B16 mice. ...
... The growth of cancer cells could be significantly inhibited by using phloretin (MH2) to treat cancer cells. The mechanism of action was related to the increase cell apoptosis rate, the activation of caspase-9 and caspase-3 proteins, the increased levels of PARP cleavage and Bax, the up-regulation levels of p53 and the reduction in Bcl-2, which led to DNA fragmentation and cell death [44]. Phloretin (MH2) (0.15 mM) could accelerate the apoptosis of melanoma 4A5 cells in B16 mice. ...
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Malus hupehensis (MH), as a natural resource, contains various active ingredients such as polyphenols, polysaccharides, proteins, amino acids, volatile substances, and other components. Increasingly, studies have indicated that MH showed a variety of biological activities, including antioxidant, hypoglycemic, hypolipidemic, anti-cancer, anti-inflammatory activities, and other activities. Hence, MH has attracted wide interest because of its high medical and nutritional value. It is necessary to review the active components and biological activities of MH. This paper systematically reviewed the chemical substances, biological activities, and potential problems of MH to further promote the related research of MH and provide an important reference for its application and development in medicine and food.
... Dihydrochalcones (also known as 1,3-diaryl-2-propen-1-ones) are phenolic compounds having a diphenylpropan (C6-C3-C6) flavonoid skeleton and no heterocyclic C ring. In fact, the majority of these secondary metabolites in plants are precursors of flavonoids ( Figure 2) [22]. A wide range of pharmacological actions are produced by two aromatic phenol rings (rings A and B), hydroxyl groups, and a carbonyl group in phloretin. ...
... Extensive studies on the anticancer activities of phloretin on different cell lines such as prostrate, lung, oral, breast, and liver have been explored and documented [35]. The anticancer activity of phloretin via inducing apoptosis, inhibiting cell growth, and regulating the cell cycle has been reported by many researchers; further studies have also reported the role of phloretin in inducing mitochondrial-mediated apoptosis in cancer cell lines [22,35] (Figure 5). It has been demonstrated that phloretin and phloretin nanoparticles (PhNPs) induce apoptosis in cancer cell lines via the upregulation of BAX, cytochrome c, PARP, caspases 3 and 9, apoptotic activating factor (APAF) and by downregulating the expression of Bcl-2 [15,33]. ...
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Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.
... Phloretin is one of the best known and abundant dihydrochalcone characterized by the presence of 2,6-dihydroxyacetophenone pharmacophore. It is a versatile molecule with anticancer, anti-osteoclastogenic, antifungal, antiviral, anti-inflammatory, antibacterial and estrogenic activities and able to increase the fluidity of biological membranes and penetration of administered drugs (Behzad et al., 2017). Ingesting chestnut rose fruit may offer health benefits due to the presence of these phytochemicals. ...
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Chestnut rose (Rosa roxburghii Tratt.) is an underutilized plant in the Rosaceae family that originates from southwest of China. This study used UHPLC-IM-QTOF and UPLC-QQQ to analyze the free and bound phenolic fractions in three cultivars of chestnut rose fruit from different producing areas. The optimization of IM feature acquisition was conducted firstly. Then, 23 phenolics were reported in chestnut rose fruit for the first time. Differential phenolics profiles were observed between cultivars and fractions, with 24 phenolics further quantified. Catechin, procyanidin B1, gallic acid, ellagic acid and isoquercitrin were the five most abundant phenolics. Most of the phenolics were more abundant in the free fraction than in the bound fraction. As many phenolics were reported with functions such as antioxidant, antidiabetic and anti-cancer, the chestnut rose fruit could serve as a healthy functional supplement foods in the form of juice, oral solution and powder, as well as an ingredient for functional foods.
... Moreover, supplement of phloretin suppressed the expression of pro-inflammatory genes (Alsanea et al., 2017). Like other flavonoids, phloretin possesses strong antioxidant and antiinflammatory activity (Behzad et al., 2017), which likely explains the anti-obesity effect of phloretin. ...
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Obesity has become one of the major threats to human health across the globe. The rhizomes of Polygonatum sibiricum have shown promising anti-obesity effect. However, the metabolic and genetic basis mediating this beneficial effect are not fully resolved. It is well known that older rhizomes of P. sibiricum exert stronger pharmacological effects. Here, we performed high-resolution metabolome profiling of P. sibiricum rhizomes at different growth stages, and identified that three candidate anti-obesity metabolites, namely phloretin, linoleic acid and α-linolenic acid, accumulated more in adult rhizomes. To elucidate the genetic basis controlling the accumulation of these metabolites, we performed transcriptome profiling of rhizomes from juvenile and adult P. sibiricum. Through third-generation long-read sequencing, we built a high-quality transcript pool of P. sibiricum, and resolved the genetic pathways involved in the biosynthesis and metabolism of phloretin, linoleic acid and α-linolenic acid. Comparative transcriptome analysis revealed altered expression of the genetic pathways in adult rhizomes, which likely lead to higher accumulation of these candidate metabolites. Overall, we identified several metabolic and genetic signatures related to the anti-obesity effect of P. sibiricum. The metabolic and transcriptional datasets generated in this work could also facilitate future research on other beneficial effects of this medicinal plant.
... It possesses a wide variety of pharmacological properties for instance anticancer, antioxidative, antiinflammatory, antifungal, antiviral, anti-microbial, anti-allergic, anti-thrombotic, hepatoprotective, and estrogenic activities [13][14][15]. Besides being involved in the activation of apoptotic-associated gene expression and signal transduction in molecular pathways, it can increase the fluidity of biological membranes and penetration of administered drugs [16,17] The present study investigated the potential molecular pathways underlying the neuroprotective benefits of PLT against ROT-induced neurotoxicity in SH-SY5Y cells and C57BL/6 mice in terms of antioxidative, anti-apoptotic, and autophagic molecular signaling pathways. ...
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Background: Parkinson's disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities. Objective: To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axisMethods:The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α-Synuclein (α-SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), and heme oxygenase-1 (HO-1), autophagic (mTOR, Atg5,7, p62, Beclin, and LC3B-I/II), were evaluated both in in vitro and in vivo. Results: PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, and α-SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein. Conclusion: Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management.
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The formulation of eco-friendly biodegradable packaging has received great attention during the last decades as an alternative to traditional widespread petroleum-based food packaging. With this aim, we designed and tested the properties of polyhydroxyalkanoates (PHA)-based bioplastics functionalized with phloretin as far as antioxidant, antimicrobial, and morpho-mechanic features are concerned. Mechanical and hydrophilicity features investigations revealed a mild influence of phloretin on the novel materials as a function of the concentration utilized (5, 7.5, 10, and 20 mg) with variation in FTIR e RAMAN spectra as well as in mechanical properties. Functionalization of PHA-based polymers resulted in the acquisition of the antioxidant activity (in a dose-dependent manner) tested by DPPH, TEAC, FRAR, and chelating assays, and in a decrease in the growth of food-borne pathogens (Listeria monocytogenes ATCC 13932). Finally, apple samples were packed in the functionalized PHA films for 24, 48, and 72 h, observing remarkable effects on the stabilization of apple samples. The results open the possibility to utilize phloretin as a functionalizing agent for bioplastic formulation, especially in relation to food packaging.
Polyphenolic aglycones featuring two sugars individually attached via C‐glycosidic linkage (di‐C‐glycosides) represent a rare class of plant natural products with unique physicochemical properties and biological activities. Natural scarcity of such di‐C‐glycosides limits their use‐inspired exploration as pharmaceutical ingredients. Here, we show a biocatalytic process technology for reaction‐intensified production of the di‐C‐β‐glucosides of two representative phenol substrates, phloretin (a natural flavonoid) and phenyl‐trihydroxy‐acetophenone (a phenolic synthon for synthesis), from sucrose. The synthesis proceeds via an iterative two‐fold C‐glycosylation of the respective aglycone, supplied as inclusion complex with 2‐hydroxypropyl β‐cyclodextrin for enhanced water solubility of up to 50 mmol/L, catalyzed by a kumquat di‐C‐glycosyltransferase (di‐CGT); and it uses UDP‐Glc provided in situ from sucrose by a soybean sucrose synthase, with catalytic amounts (≤ 3 mol%) of UDP added. Time course analysis reveals the second C‐glycosylation as rate‐limiting (0.4–0.5 mmol/L/min) for the di‐C‐glucoside production. With internal supply from sucrose keeping the UDP‐Glc at a constant steady‐state concentration (≥ 50% of the UDP added) during the reaction, the di‐C‐glycosylation is driven to completion (≥ 95% yield). Contrary to the mono‐C‐glucoside intermediate which is stable, the di‐C‐glucoside requires the addition of reducing agent (10 mmol/L 2‐mercaptoethanol) to prevent its decomposition during the synthesis. Both di‐C‐glucosides are isolated from the reaction mixtures in excellent purity (≥ 95%), and their expected structures are confirmed by NMR. Collectively, this study demonstrates efficient glycosyltransferase cascade reaction for flexible use in natural product di‐C‐β‐glucoside synthesis from expedient substrates. This article is protected by copyright. All rights reserved.
The human Na ⁺ /H ⁺ antiporter NHA2 ( SLC9B2 ) transports Na ⁺ or Li ⁺ across the plasma membrane in exchange for protons, and is implicated in various pathologies. It is a 537 amino acids protein with an 82 residues long hydrophilic cytoplasmic N-terminus followed by a transmembrane part comprising 14 transmembrane helices. We optimized the functional expression of Hs NHA2 in the plasma membrane of a salt-sensitive Saccharomyces cerevisiae strain and characterized a set of mutated or truncated versions of Hs NHA2 in terms of their substrate specificity, transport activity, localization and protein stability. We identified a highly conserved proline 246, located in the core of the protein, as being crucial for ion selectivity. The replacement of P246 with serine or threonine resulted in antiporters with altered substrate specificity and increased resistance to the Hs NHA2-specific inhibitor phloretin that were not only highly active at an acidic pH of 4.0 (like the native antiporter), but also at neutral pH. We also experimentally confirmed the importance of a putative salt bridge between E215 and R432 for antiporter function and structural integrity. Truncations of the first 50 - 70 residues of the N-terminus doubled the transport activity of Hs NHA2, whilst changes in the charge at positions E47, E56, K57, or K58 decreased the antiporter’s transport activity. Thus, the hydrophilic N-terminal part of the protein appears to allosterically autoinhibit its cation transport. Our data also show this in vivo approach to be useful for a rapid screening of SNP’s effect on Hs NHA2 activity.
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Phloretin, a flavonoid present in various plants, has been reported to exert anticarcinogenic effects. However, the mechanism of its chemo-preventive effect on human glioblastoma cells is not fully understood. This study aimed to investigate the molecular mechanism of phloretin and its associated chemo-preventive effect in human glioblastoma cells. The results indicate that phloretin inhibited cell proliferation by inducing cell cycle arrest at the G0-G1 phase and induced apoptosis of human glioblastoma cells. Phloretin-induced cell cycle arrest was associated with increased expression of p27 and decreased expression of cdk2, cdk4, cdk6, cyclinD and cyclinE. Moreover, the PI3K/AKT/mTOR signaling cascades were suppressed by phloretin in a dose-dependent manner. In addition, phloretin triggered the mitochondrial apoptosis pathway and generated reactive oxygen species (ROS). This was accompanied by the up-regulation of Bax, Bak and c-PARP and the down-regulation of Bcl-2. The antioxidant agents N-acetyl-L-cysteine and glutathione weakened the effect of phloretin on glioblastoma cells. In conclusion, these results demonstrate that phloretin exerts potent chemo-preventive activity in human glioblastoma cells through the generation of ROS.
Flavonoids exert a multiplicity of biological effects on humans and can have beneficial implications for numerous disease states. Flavonoids and Related Compounds: Bioavailability and Function examines current knowledge regarding the absorption, metabolism, and bioavailability of individual flavonoids and related phenolic compounds. Profiling the latest evidence of their impact on various human pathological conditions, the book summarizes current thinking with regard to the biotransformation and conjugation of individual compounds in the gastrointestinal tract, liver, large intestine, and cells. It highlights a topic that has been largely ignored-namely the extent to which dietary phenolics components undergo metabolism in the large intestine. It also explores the generation of bacterially derived metabolites. Individual chapters discuss which metabolites enter the circulatory system and are likely to offer protective actions against human diseases. Edited by internationally recognized leaders in the field, the book presents contributions by a panel of experts who demonstrate the potential of flavonoids in ameliorating a range of disease states, including cardiovascular disease, Alzheimer’s and Parkinson’s disease and other neurodegenerative disorders, and cancer. The research presented in this volume provides a reliable starting point for further inquiry and experimentation.
Phloretin and phlorizin are the two strong natural antioxidants whose biological and pharmacological applications are rapidly growing in different human pathological conditions. The neuroprotective activity of the two flavonoids has been analyzed on cell culture of neuroblastoma cells. The neuroprotective activity of the two flavonoids has been analyzed on cell culture of neuroblastoma cells and evaluated by testing cell vitality, mitochondrial transmembrane potential and ROS production, antioxidant enzymes detection, activation of caspase 3, DNA damage, protein carbonylation, lipid peroxidation, and superoxide anion scavenging activity. Incubation of cells with rotenone caused cell death and significant increase in intracellular reactive oxygen species, activation of caspase 3, and variation in mitochondrial transmembrane potential. Although, rotenone exposure caused a significant increase of antioxidant enzymes, high levels of lipid peroxidation were also observed. Phloretin or phlorizin, at micromolar concentration, reduced rotenone-induced cell death by scavenging ability against superoxide anion radical, one of the main effectors of rotenone toxicity at level of mitochondrial respiratory chain complex I. Under our experimental conditions, a reduction of the intracellular ROS levels with consequent normalization of the aforementioned antioxidant enzymes occurred. Concomitantly, we observed the inhibition of caspase 3 activity and DNA damage. This study shows the promising neuroprotective ability of the two dihydrochalcones able to protect human differentiated neuroblastoma cells (commonly used as model of Parkinson's disease) from injury induced by rotenone, actively scavenging ROS, normalizing mitochondrial transmembrane potential and consequently avoiding energy depletion. © 2017 BioFactors, 2017.
The involvement of choline and its metabolite trimethylamine-_N_-oxide (TMAO) in endothelial dysfunction and atherosclerosis has been repeatedly confirmed. Phloretin, a dihydrochalcone flavonoid usually present in apples, possesses a variety of biological activities including vascular nutrition. This study was designed to investigate whether phloretin could alleviate or prevent high choline-induced vascular endothelial dysfunction and liver injury in mice. Mice were provided with 3% high choline water and given phloretin orally daily for 10 weeks. The high choline-treated mice showed the significant dyslipidemia and hyperglycemia with the impaired liver and vascular endothelium (_p_ < 0.01). Administration of phloretin at 200 and 400 mg/kg bw significantly reduced the choline-induced elevation of serum TC, TG, LDL-C, AST, ALT, ET-1 and TXA2 (_p_ < 0.01), and markedly antagonized the choline-induced decrease of serum PGI2, HDL-C and NO levels. Furthermore, phloretin elevated hepatic SOD and GSH-P_x_ activities and decreased hepatic MDA levels of the mice exposed to high choline water. Moreover, histopathological test with the H&E and Oil Red O staining of liver sections confirmed the high choline diet-caused liver steatosis and the hepatoprotective effect of phloretin. These findings suggest that high choline causes oxidative damage, and phloretin alleviate vascular endothelial dysfunction and liver injury.
Phloretin (C15 H14 O5 ), a dihydrochalcone flavonoid, is mainly found in fruit, leaves, and roots of apple tree. Phloretin exerts antioxidant, anti-inflammatory, and anti-tumor activities in mammalian cells through mechanisms that have been partially elucidated throughout the years. Phloretin bioavailability is well known in humans, but still remains to be better studied in experimental animals, such as mouse and rat. The focus of the present review is to gather information regarding the mechanisms involved in the phloretin-elicited effects in different in vitro and in vivo experimental models. Several manuscripts were analyzed and data raised by authors were described and discussed here in a mechanistic manner. Comparisons between the effects elicited by phloretin and phloridzin were made whenever possible, as well as with other polyphenols, clarifying questions about the use of phloretin as a potential therapeutic agent. Toxicological aspects associated to phloretin exposure were also discussed here. Furthermore, a special section containing future directions was created as a suggestive guide towards the elucidation of phloretin-related actions in mammalian cells and tissues. © 2016 BioFactors, 2016.
Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancer cases and the prognosis of NSCLC patients is unsatisfactory since 5-year survival rate of NSCLC is still as low as 11%. Natural compounds derived from plants with few or no side effects have been recognized as alternative or auxiliary cure for cancer patients. Phloretin is such an agent possessing various pharmacological activities; however, there is scarce information on its anticancer effects on NSCLC. It was evaluated and confirmed, in the present study, that phloretin inhibited proliferation and induced apoptosis in A549, Calu-1, H838 and H520 cells in a dose-dependent manner, phloretin also suppressed the invasion and migration of NSCLC cells. We further confirmed that phloretin dose-dependently suppressed the expression of Bcl-2, increased the protein expression of cleaved-caspase-3 and -9, and deregulated the expression of matrix metalloproteinases (MMP)-2 and -9 on gene and protein levels. Besides, evaluations revealed that phloretin enhanced the anticancer effects of cisplatin on inhibition of proliferation and induction of apoptosis in NSCLC cells. Moreover, phloretin facilitated the effects of cisplatin on deregulation of Bcl-2, MMP-2 and -9, and upregulation of cleaved-caspase-3 and -9. In conclusion, the present study demonstrated that phloretin possessed anticancer effects and enhanced the anticancer effects of cisplatin on NSCLC cell lines by suppressing proliferation, inducing apoptosis and inhibiting invasion and migration of the cells through regulating apoptotic pathways and MMPs.