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Flavonoids are polyphenolic compounds with powerful Ebtesam A Al-Suhaimi et al.
and strong antioxidant, anti-inflammatory and anti-cancer
activity. Citrus flavonoids mainly influence blood and 3. BIOLOGICAL ACTIVITY OF FLAVONOIDS
microvascular endothelial cells by blocking regulatory
enzymes, which mediate cell division and activation (7). 3.1. Anti-inflammatory effects
The polyphenolic content of citrus fruit was reported to
consist 81-97 % flavanones, while the remaining Inflammation is a physiological response that is
accounted for flavones, flavonols, hydroxycinnamic acids brought on by different circumstances such as infection or
and coumarins (8). Despite being under investigation for tissue injury. Studies have revealed that an array of
long time, the mechanisms underlying the biological action responses triggered by the immune system leads to
of these compounds are not yet completely understood (9). inflammation (16). There is increased level of
inflammatory markers, free radicals lipid peroxides
Flavonoids having various pharmacological activities whenever there is incidence of inflammation. This is due
are attributed by inhibiting action of enzymes in cellular to the fact that inflammation disturbs signaling pathways.
stimulation. The in vitro elucidation shows that flavonoids There is also evidence suggesting that inflammation plays
alter enzymes status such as lipooxygenases, kinases, a key role in healing wounds and fighting infections.
phospholipases, ATPase, cyclooxygenases, and However, if inflammation persists for longer periods of
phosphodiesterases (10, 11, 12). Furthermore, flavonoids time it stimulates progression of many chronic diseases
tend to react and bind with nucleotide regulatory enzymes including cancer (16, 17).
(7). Citrus flavonoids also actively scavenge the free
radicals and, therefore, show antagonist effect on aging The events that occur during inflammation include the
and degenerative events mediated by oxidative stress (13). recruitment of leukocytes and mast cells. This leads to
The prime focus of this review narrates the mechanistic what is known as a ‘respiratory burst’. There is an
action of flavonoids and discusses their biological activity increased level of oxygen uptake at the site of damage and
in regards to modulating key regulatory enzymes, hence an increase in the reactive oxygen species (18).
signaling cascades etc. to facilitate the treatment of cancer.
Inflammatory calls also produce some mediators like
2. CHEMICAL COMPOSITION OF FLAVONOIDS cytokines and chemokines. These molecules act by
recruiting more inflammatory cells to the site of damage
A number of phytochemical compounds have been thereby increasing the number of ROS. These are the key
identified as flavanoids amongst which polyphenolic mediators involved in inflammation and include other
terpenoids have been studied most extensively. They have molecules such as metabolites of arachidonic acid.
a characteristic structure C6-C3-C6 structure. Majority of Together they are capable of activating signal cascades and
flavonoids are formed by a combination of hydroxyl, inducing changes in transcription factors. The transcription
methoxy, and O-glycoside groups that are attached to this factors include NF-?B, HIF1-a, AP-1, NFAT and Nrf2.
C3-C6-C3 structure (14). Flavonoids are further divided Other factors apart from chemokines and cytokines
into flavones, flavonols, flavanones, flavanols, mediate the inflammatory response, these include COX-2,
anthocyanins and isoflavones. The different classes occur iNOS, differential expression of certain micro RNAs. All
due to a difference in the C3 element of the flavonoid these contribute to an increase in the oxidative stress (19).
structure (14). When this state of increased ROS and oxidative stress
persists it leads to the disruption of healthy surrounding
Flavonoids are considered as hydroxylated phenolic cells and tissue and therefore leads to the incidence of
compounds that are produced as a result of a microbial cancer (20).
infection in plants. Their characteristic 15 carbon structure
(C6-C3-C6) includes two benzene rings commonly 3.1.1. In vitro studies
referred to as A and B rings. The A and B rings are joined
together by a heterocyclic pyrane ring referred to as the C Daphne genkwa also known as D.genkwa is a
ring. The different classes of flavonoids occur because of medicinal plant that has a large number of flavonoids
different levels of oxidation and because of substitutions at associated with anti-inflammatory response. In a study
the C ring. Different compounds within each class exist conducted on HT-29 and SW-480 human colorectal cancer
because of substitutions at the two benzene rings. cells, it was concluded that flavonoids found in D.genkwa
have an ability to regulate the immune system by
Flavonoids occur in three forms, either as aglycones inhibiting the production of inflammatory cytokines (21).
(aglycosides) and glycosides or sometimes as methylated
derivatives. The basic structure mentioned above (i.e C6- in vitro studies have determined that flavonoids are
C3-C6) is the aglycone structure (15). Aglycosides capable of inhibiting the synthesis and activity of a variety
(without sugar) or glycosides (containing sugar) are two of pro-inflammatory mediators such as cytokines, adhesion
main forms of citrus flavonoids. Glycosides contain single molecules, eicosanoids etc. Molecular mechanism includes
or multiple sugars attached to the basic flavonoid skeleton the inhibition of various transcription factors such as the
(9). NF-kappaB, AP-1 and stimulation of Nrf2 (nuclear factor-
erythroid 2-related factor 2 (22). In a study conducted by
298 Zhang et al (2014), it was determined that apigenin, which
is a non-toxic natural flavonoid has the potential to inhibit
lipopolysaccharide induced inflammation through multiple
mechanisms. Macrophages were utilized and it was seen
that apigenin inhibited LPS induced production of
@Real Academia Nacional de Farmacia. Spain
