2582

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Current Pharmaceutical Design, 2021, 27, 2582-2604
REVIEW ARTICLE
ISSN: 1381-6128
eISSN: 1873-4286

Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory and

Antioxidant Substances
Impact
Factor:
3.116

Marcin Ożarowski1, and Tomasz M. Karpiński2,*

1
Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants, Poznań, Poland; 2Chair and Department of Medical
Microbiology, Faculty of Medical Sciences, Poznań University of Medical Sciences, Poznań, Poland

ARTICLE HISTORY
Received: February 28, 2020
Accepted: April 19, 2020
DOI:
10.2174/1381612826666200526150113

Current Pharmaceutical Design
Abstract: There is increasing interest in evaluating anti-inflammatory activities of plant substances such as ex-
tracts and flavonoid rich fractions. A promising source of new medicinal drugs may be species from the Passi-
floraceae family. The most interesting group of principal chemical substances in Passiflora species are polyphe-
nolic compounds, including flavonoids (quercetin, rutin, apigenin, luteolin, chrysin, and C-glycosylflavones i.e.,
vitexin, isovitexin, orientin, isoorientin), due to their antioxidant activity demonstrated in various studies. How-
ever, each extract from Passiflora spp. as multi-component mixtures should be estimated for chemical composi-
tion (in the standardization process) and its activity using in vitro and in vivo tests. The current standard for drug
discovery and development from plants indicates that only collective assessment allows estimating plant sub-
stances by definition of the origin of raw materials and their quality, methods of extractions, and metabolite pro-
files. Increasingly, due to complex phytochemical procedures to obtain extracts, individual flavonoid compounds
are also tested for anti-inflammatory action. However, it should be emphasized that various sources of potential
new drugs from plant origin are not mutually exclusive, but are complementary. A review of bibliographic data
includes the following information about Passiflora species, such as distribution, classification, phytochemical
compounds, the anti-inflammatory activity of the extracts, the anti-inflammatory activity of flavonoids, and anti-

oxidant potential. The review concluded that extracts and flavonoids (mainly quercetin, apigenin, and vitexin)
from Passiflora spp. can be a valuable source of anti-inflammatory and anti-oxidative medications for the preven-
tion and treatment of many diseases, which occur with complex inflammatory processes.
Keywords: Passifloraceae, Passiflora, flavonoids, anti-inflammatory, antioxidant, chrysin.

The effectiveness of available anti-inflammatory therapy using

1. INTRODUCTION
Inflammatory processes have a multifactorial course, including
chain reactions in various pathways at the subcellular, cellular, and
tissue level with various signaling molecules and immune cells.
However, it should be noted that inflammation is a physiological,
biological defense process against infection and tissue damage [1].
It is well known that these processes are adapted by inflammatory
mediators such as cytokines: interleukins, tumor necrosis factor-α,
prostaglandins, leukotrienes released by macrophages and leukocytes,
reactive oxygens species; moreover, during pathophysiological proc-
esses of inflammatory diseases, they may occur with antioxidative
stress [2].
In the 21st century, there is a need for novel, innovative medici-
nal products, not only against diseases associated with inflamma-
tory processes for which there are generally no effective medica-
tions, e.g., inflammatory bowel disease (IBD, including ulcerative
colitis and Crohn’s disease), cancers, rheumatoid arthritis, asthma,
diabetes, psoriasis, hypertension, neuropathic pain, neurodegenera-
tive disorders (including Alzheimer’s and Parkinson’s diseases),
neuroinflammatory diseases like sclerosis multiplex [1, 3-7], but
also for diseases that may occur in the future. It should be noted
that inflammatory diseases are increasingly prevalent in various
populations [1].
nonsteroidal anti-inflammatory drugs (NSAIDs) is still not satisfac-
tory. Moreover, this group of medicinal drugs belongs to the most
widely prescribed medicines. However, there are many adverse
effects observed in patients after treatment of frequent inflamma-
tory diseases i.e., serious cardiovascular events, gastrointestinal
complications (mucosal injury, ulcers, bleeding), hypertension, and
renal disturbances [8, 9]. This situation may be more complicated
because mild-to-moderate inflammatory diseases have a long time
of duration, and very often their symptoms return after remission
like in ulcerative colitis [10], rheumatoid arthritis [11], multiple
sclerosis [12]. For this reason, patients have to use NSAIDs for a
long time. Additionally, many therapies have not shown therapeutic
benefits for a variety of reasons [13, 14]. Thus, there is an increas-
ing demand for new drugs with no side effects, showing better effi-
cacy.
In recent years, interdisciplinary research has focused on many
levels to develop more effective and safer therapeutics. It is also
happening in the development of more favorable therapies for in-
flammatory diseases, including the search for new medicinal drugs
from natural sources, plants, and their extracts containing promising
chemical compounds, i.e. flavonoids which possess anti-
inflammatory activity [2, 15-17]. Passiflora spp. can have a great
value in this aspect.

2. PASSIFLORA SPECIES: DISTRIBUTION, CLASSIFICA-

*Address correspondence to this author at the Chair and Department of
Medical Microbiology, Faculty of Medical Sciences, Poznań University of
Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland;
Tel: +48-61-854-61-38; E-mail: tkarpin@ump.edu.pl
TION, FRUITS AND EXTRACTS MARKET
Ornamental and medicinal plants from the family Passi-
floraceae Juss. ex DC. grow in tropical, subtropical, and temperate

1873-4286/21 $65.00+.00 © 2021 Bentham Science Publishers

Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory
regions, mainly in South America (Brazil, Colombia, Peru, Bolivia,
etc.) [18, 19]. Approximately 96% of the species are distributed in
the Americas (mainly in Brazil and Colombia). However, there are
records of species in India, China, Southeastern Asia, Australia, the
Pacific islands, and neighboring regions [19]. Few species are dis-
tributed in Europe i.e. P. caerulea (the blue passionflower) now
grows wildly in Spain [20] and is cultivated in gardens of Poland
[21].
Currently, species of the family Passifloraceae Juss. ex Roussel
sensu stricto, belong to 36 plant genera, and the Plant List includes
932 accepted species names [22]. Passiflora L. is the most repre-
sentative genus in the Passifloraceae family, containing more than
500 species [23]. It should be noted that new species from the Pas-
sifloraceae family are still being discovered. Additionally, more
than 330 hybrids have been described [24]. In North America and
Europe, the most well-known species with a long tradition of me-
dicinal use worldwide is Passiflora incarnata L. (the purple pas-
sionflower), described in the European Medicines Agency, the
European Pharmacopoeia, and the British Herbal Pharmacopoeia
[25]. In contrast, in Brazil and Colombia - P. alata Curtis (the fra-
grant grenadilla) and P. edulis Sims (the purple and yellow passion-
fruit or maracujá) are official species in the Brazilian Pharmaco-
poeia [26].
Numerous Passiflora species, in addition to phytotherapeutic
use, are characterized by the growing agronomic significance not
only in Brazil and Colombia but also in India, as they are cultivated
plants, being the source of nutritious fruits, hence they are of great
importance in the global fruit industry (m.in. P. alata Curtis, P.
cincinnata Mast., P. edulis Sims, P. quadrangularisL., P. ligularis
A. Juss., P. maliformis L., P. nitida Kunth, P. setacea D.C.) [27,
28]. Previously, the world’s production of passion fruits showed an
annual production that exceeds 900,000 tons in Brazil [29]. Addi-
tionally, according to the market research report, the global passion-
flower extracts market value was estimated to be USD 2.55 billion
in 2018. The global passionflower extracts market includes phar-
maceutical, nutraceutical, personal care, food, and beverage sectors
[30].
3. PASSIFLORA EXTRACTS AND THEIR PHYTOCHEMI-
CAL COMPOUNDS
Currently, there is an intense scientific interest in drug discov-
ery and development based on herbal medicines. At the same time,
one should not forget that therapies of complementary and alterna-
tive medicine are becoming increasingly popular around the world
[31, 32]. These two tendencies are not mutually exclusive, and they
indicate that a detailed study of plant sources is comprehensive and
complementary in the searching for a new therapeutic solution,
including diseases with inflammatory processes. According to
Atanasov et al. [32], developing trends indicate that natural prod-
ucts will be among the most important sources of new therapeutic
drugs in the future.
One of the most popular forms of plant substances is the ex-
tracts that can be an interesting source of pharmacologically active
compounds for future applications. It has been known for a long
time that crude and fractionated plant extracts are a promising com-
plex composition of primary and secondary metabolites, showing
activity through synergy in their action [32, 33]. The herbal drug
preparations, mainly extracts, differ in chemical compositions, be-
cause they are obtained from various parts of plants growing in
different climate and ecological conditions. It was observed that the
populations of the same Passiflora spp. growing in different geo-
graphical areas would have different profiles in their chemical
compounds [34]. Furthermore, plant extracts are obtained using
various processes such as extraction, fractionation, distillation,
fermentation, hydrolysis using different reagents, and many variants
of technological equipment and parameters (i.e. temperature and
time of extraction) in standard conditions [35-38]. For this reason,
Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2583
for their therapeutic application, extracts should always be stan-
dardized to a defined content of a constituent or a group of sub-
stances with known therapeutic activity during the manufacturing
processes and quality control [35]. Such standardized (phytochemi-
cally characterized) herbal extracts and their therapeutical applica-
tions are the basis of rational phytotherapy.
Species from the Passifloraceae family deliver two kinds of
valuable raw materials: nutritious fruits and aerial parts containing
leaves and flowers, which have active chemical compounds. It
needs to be highlighted that today, not only fruits but also leaves of
Passiflora are accepted as a component of a healthy diet used in the
prevention or reduction of symptoms of many diseases. Studies
showed that fruits of P. edulis contain flavonoids (quercetin and
derivatives, rutin, kaempferol, chrysin, apigenin, luteolin), C-
glycosylflavones (orientin, isoorientin, vitexin, schaftoside,
isoschaftoside) [39, 40], carotenoids and vitamin C [37]. Moreover,
the fresh pulp of the fruits of P. subpeltata contains epicatechins,
carbohydrates, and proteins [41]. Whereas, the leaves of cultivated
species of Passiflora are renewable, and this green biomass can be
further used as a bioactive food additive and as a source of promis-
ing anti-inflammatory pharmaceuticals.Many studies showed vari-
ous flavonoids (flavon-C-, and C,O-, and O-glycosides) present in
the extracts from the leaves of Passiflora [42-51].
Recently, phytochemical comparison of alcoholic extracts from
leaves of three species of Passiflora (P. alata, P. caerulea, P. in-
carnata) revealed that flavonoids such as O,C-glycosides of api-
genin, luteolin and chrysin dominated in these species (>60% for P.
incarnata, 50% for P. caerulea, 40% for P. alata). C-glycosides
have been observed in a high level in P. caerulea (>30%) and P.
incarnata (>20%) [52]. Moreover, other studies phytochemically
examined extracts from fruit pulps, from fruit peels (flavedo and
albedo), leaves, bark, and seeds [53, 54].
It has been concluded that quercetin (3,3’,4’,5,7-pentahy-
droxyflavone) (Fig. 1) is present in some extracts of Passiflora i.e.,
from the leaves of Passiflora subpeltata [48]. Moreover, glycosides
of quercetin were found in the extracts of P. caerulea and P. alata
[49], P. leschenaultii [51], P. edulis var. flavicarpa [55], and P.
subpeltata [41]. Rutin (3,3′,4′,5,7-pentahydroxyflavone-3-
rhamnoglucoside;rutoside) was detected in the extract of Passiflora
leschenaultii [96], P. subpeltata [48], P. incarnata [56]. Chrysin
(5,7-dihydroxyflavone) and its glycosides are found in extracts i.e.,
Passiflora caerulea and P. incarnata [39,49, 57, 58]. Luteolin (3',
4', 5,7-tetrahydroxyflavone) and its C-glycosides belong to the
group of flavonoids present in the extracts of P. incarnata [49, 59,
60], P. edulis [47,61], P. alata and P. caerulea [49]. Few studies
revealed their anti-inflammatory activity in various tests [62-67].
Apigenin had been isolated from the aerial parts of P. incar-
nata [68] and from the pericarp of P. quadrangularis [69]. How-
ever, different glycosides of apigenin like vitexin and isovitexin
derivatives are more often detected in various Passiflora species
[38, 39,49]. Vitexin, a well-known flavonoid, is present in P.
foetida [70], P. caerulea [71, 72], P. edulis var. flavicarpa, P.
manicata, and P. tripartita var. mollissima [46, 54]. However, gly-
cosides of vitexin were detected in P. alata [73], P. quadrangularis,
P. manicata [46], P. caerulea, and P. incarnata [49]. Other C-
glycosylflavonoids, such as isovitexin, orientin, and isoorientin
are characteristic chemical compounds detected in extracts from
many species of Passiflora (i.e. P. edulis) [49, 54, 72, 74-77]. Be-
sides this, Ożarowski et al., [49] revealed that extracts from leaves
of Passiflora species contain compounds with terpenoid structures:
blumenols B and C (megastigmanes), and cyclopassifloic acid glu-
coside, the activity of which is poorly studied. On the other side, it
is well known, that flavonoids and phenolic acids occurring in vari-
ous extracts from Passiflora are taken into account as novel thera-
peutic agents in the prevention and treatment of Alzheimer’s dis-
ease, disorders associated with inflammation [16], liver injury with
2584 Current Pharmaceutical Design, 2021, Vol. 27, No. 22
Quercetin
Chrysin
Vitexin
Orientin
Fig. (1). Chemical structure of the main flavonoids of Passiflora spp.
inflammatory processes [67], colitis [78], or bacterial infections
[79].
4. RECENT PROFILE OF ACTIVITIES - IN VITRO, IN VIVO
AND CLINICAL TRIALS OF PASSIFLORA EXTRACT
Biological and pharmacological activities of preparations from
Passiflora species depend on the presence of phenolic compounds,
mainly flavonoids. In the past years, several preclinical experiments
demonstrated that alcoholic extracts of aerial parts of various spe-
cies of Passiflora, including flowers and leaves, have many activi-
ties such as sedative, anxiolytic, antidepressant [80], memory-
enhancing activity [81], anti-diarrhoeal, spasmolytic [72], antidia-
betic [82, 83], and anti-allodynic effects in neuropathic pain [84],
with antinociceptive [85], anti-leukemic [49], hepato-, nephro-,
gastroprotective [86, 87], neuroprotective effects [88, 89], = antimi-
crobial [90] and antioxidative activity shown in various in vitro and
in vivo tests [20, 40, 41, 50, 73, 75, 82, 91-96]. Nowadays, there is
growing scientific evidence that the extracts of Passiflora have anti-
inflammatory properties [45,48, 54, 55, 72, 85, 95, 97-99]. Recent
Ożarowski and Karpiński
Rutin
Luteolin Apigenin
Isovitexin
Isoorientin
results also demonstrated that not only leaf extracts possess activi-
ties but also peels of Passiflora edulis, which improve insulin sensi-
tivity [100] and have shown intestinal anti-inflammatory effects in
animal models of colitis [53, 54, 97], with antioxidant activity [89].
Moreover, the bark of the same species reduced dyslipidemia [61].
Few randomized-controlled clinical trials confirmed some pharma-
cological activities of these plant substances [18], i.e. P. incarnata
showed anxiolytic effect [101-103], improved sleep efficiency and
quality [104, 105], relieved nervous restlessness [106], exerted anti-
hypertensive properties [107] and alleviated osteoarthritis symp-
toms (pain) [108]. Furthermore, peel of Passiflora edulis f. flavi-
carpa decreased insulin resistance in patients with diabetes type 2
[109].
Today, extracts of Passifloraspecies (mainly P. incarnata, and
P. edulis) are popularly used for the prevention and treatment of
various central nervous system diseases such as anxiety, insomnia,
and depression [18, 98]. However, a large number of patients from
America use products containing extracts of Passifloraspecies for
the treatment of wounds, boils, earaches, and liver diseases. In con-
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory
trast, in Europe, these products are preferred in order to provide
relieve from agitation and restlessness. According to prognosis for
the development of the market for herbal medicinal products, such
applications are anticipated to create growth opportunities for the
extracts of Passiflora species in the near future [110].
It needs to be highlighted, that mechanisms of action of natural
chemical compounds, including antioxidant and anti-inflammatory
pathways might create a new therapeutic window for many dis-
eases, i.e. colitis [53, 54, 111], hypertension [107], osteoarthritis
[108], neuropathic pain [84, 85] or Alzheimer’s disease [16, 112-
115], occurring with pathogenetic processes such as inflammation
and oxidative stress.
5. ANTI-INFLAMMATORY ACTIVITY OF PASSIFLORA
SPECIES
Several studies have shown that various species of Passiflora
containing phenolic compounds revealed anti-inflammatory proper-
ties during in vitro and in vivo tests, such as in non-obese diabetic
mice, models of mouse colitis, pleurisy, air pouch inflammation,
and paw edema. Many species of Passiflora are a source of juice
and pulp containing fiber and polyphenols, including flavonoids,
however, a significant amount of waste is generated [54]. Recent
extensive studies have reported several novel aspects of extracts
from fruit pulps, and also from fruit peels (flavedo and albedo),
leaves, bark, and seeds, which are studied for their healthy proper-
ties. It was observed that single flavonoids also demonstrated this
effect very often together with antioxidant activity. State of the art
in this field shows the potential beneficial effects of these by-
products of the fruit industry in many diseases occurring with in-
flammatory processes.
5.1. Studies of Anti-Inflammatory Activity of Complex Extracts
5.1.1. The Action of Extracts During the Inflammatory Process in
Colitis
Many clinical studies described pathological processes during
inflammatory bowel diseases (IBD), including ulcerative colitis and
Crohn’s disease, which are chronic and multifactorial disorders of
the gastrointestinal tract and may lead to progression of colon can-
cer [116]. Furthermore, these diseases with uncontrolled inflamma-
tion can be progressive and challenging to treat using conventional
therapy [117]. Today, several studies have been carried out to
search the new anti-inflammatory drugs, including flavonoid-rich
extracts from leaves and peels of fruits of many species of Passi-
flora, which were tested in various animal models of colitis.
Anti-inflammatory properties of extracts from leaves and fruit
peels of Passiflora edulis were observed in a series of studies by
Cazarin et al. [53, 54, 97]. The activity of aqueous extract of Passi-
flora edulis leaves was investigated in colitis in rats induced by
intracolonic administration of 2,4,6-trinitrobenzene sulphonic acid.
The leaf extract containing significant amounts of isoorientin, ori-
entin, isovitexin, and vitexin, was administered to rats at a dose of
1100 µg mL−1 for 2 weeks. Biochemical analyses showed that the
extract reduced the level of pro-inflammatory mediators in intesti-
nal tissues such as fivefold reduction of IL-1βand two-fold for
TNF-α [97]. More detailed information taken from these studies is
shown in Table 1.
In the subsequent study [53], in animals with colitis, which was
developed through the application of 2,4,6-trinitrobenzenesulphonic
acid, powdered peels of fruits of Passiflora edulis were tested.
However, the macroscopic and microscopic evaluations of the in-
flamed mucosa did not show attenuation of the damage of tissues in
the model of colitis after the consumption of a diet with peels. On
the other site, peels of fruits of Passiflora edulis as a source of fla-
vonoids and fibers, increased the count of Bifidobacterium and
Lactobacillus, hence intake of peels exhibited an effect, modulating
the microbiota in the intestinal area. Currently, it is well known
Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2585
that abnormal composition in the gut microbiota can be associated
with chronic inflammatory bowel disease. In this context, Jang et
al., [118] observed in mice the simultaneous amelioration of colitis
by Bifidobacterium longum and Lactobacillus plantarum, and these
strains inhibited the activation of NF-κB pathway. They may also
diminish the growth of Escherichia coli.
Using a mouse model of experimental colitis induced by the
dextran sodium sulfate, the authors further examined the prebiotic
effects of the flour from peels of P. edulis fruits, which was given
to the female mice (8 mg/mL in the drinking water) [54]. Results of
this study revealed that dietary fibers and polyphenols containing
C-glycosyl flavonoids (isoorientin > vicenin > orientin > vitexin >
isovitexin, lucenin-2, schaftoside, violanthin) downregulated the
pro-inflammatory cytokines IL-1β, IL-6, and IL-17. However, peels
of P. edulis did not affect the TNF-α and IL-12 contrary to previous
studies [97]. Moreover, a biochemical analysis revealed that the
peel’s intake decreased the expression of chemokine MCP-1, the
adhesion molecule ICAM-1, and increased the expression of the
mucin protein MUC-2 and MUC-3, thus leading to improvement of
the epithelial barrier before bacteria, microbial products, and toxins
during the inflammatory process. Another study also exerted that
polyphenolic compounds (i.e. naringenin, naringin) in the diet may
improve the integrity and stabilization of the epithelial barrier [119,
120]. This observation is innovative because there is no cure and
therapies owhich would decrease the inflammatory process and
restore the physiological function of the intestinal barrier [120].
Furthermore, Cazarin et al., [54] observed that peels of P. edulis
decreased the expression of these metalloproteinases (MMP-2 and
MMP-9), which are associated with various physiological proc-
esses.
Other studies have reported that not only P. edulis is an interest-
ing species in this field, but also others such as P. caerulea, which
is a very representative medicinal plant in Brazil. The ethanolic
extract of P. caerulea with identified flavonoids isoorientin, vitexin,
isovitexin, and vicenin-2, was also examined in the experimental
rats model of colitis induced by acetic acid [72]. Results showed
that the extract at a dose of 250 mg/kg, p.o. reduced macroscopic
and microscopic damages of the colon. Besides anti-inflammatory
properties of the extract of P. caerulea, there were also antidiar-
rhoeal and spasmolytic activities.
Recently, it was revealed that also acetone extract from other
species P. subpeltata, prevalent in Mexico, had anti-inflammatory
and protective activity on indomethacin-induced experimental ul-
cerative colitis in rats [51]. This extract contained phenolic and
flavonoid compounds such as gallic acid, apigenin, catechin, luteo-
lin, and quercetin 3-b-D glucoside. Indomethacin (10 mg/kg s.c.)
was administered fortwo days and next, the extract was given to
rats until 11 days. The biochemical study showed that extract at a
dose of 400 mg/kg possessed more effective activity in an experi-
mental model. More detailed information from these studies is
shown in Table 1.
5.1.2. The Activity of Extracts in the Model of Paw Edema and
Air Pouch Inflammation
Currently, Saravanan Shanmugam et al. [95] showed that Passi-
flora leschenaultii growing in India exerted anti-inflammatory ac-
tivity using carrageenan for the induction of paw edema, the cotton
pellet to a model of inflammation and pyrexia model induced by the
suspension of brewer’s yeast in rats. Phytochemical analysis of
various extracts (petroleum ether, chloroform, methanol, acetone,
hot water) from leaves revealed the presence of tannins, phenolics
such as chlorogenic acid, and caffeic acid, and also flavonoids such
as quercetin-3-O-galactoside and rutin. The animals were pre-
treated with the extract 1 h before the application of 0.1 mL of 1%
carrageenan. Assessment of anti-inflammatory properties of the
extracts using doses of 200 and 400 mg/kg b.w. per os, revealed
2586 Current Pharmaceutical Design, 2021, Vol. 27, No. 22 Ożarowski and Karpiński

Table 1. Anti-inflammatory activities of extracts of Passiflora spp.

Passiflora species / Dose and method of Effects on proinflammatory

Pharmacological activities against the pathological status Refs.
preparation administration cytokines

The activity of extracts during the inflammatory process in colitis

- improving the body weight, the weight of proximal

duodenum, distal jejunum, proximal ileum, whole cae-
cum, proximal colon
- reducing the percentage of the damaged area of the
gastrointestinal tract and reducing the number of - suppression of NO and
200 mg/kg
P. subpeltata / extract lesions, necrosis and mucosal infiltrations after a higher TNF-α production in LPS-
400 mg/kg dose of an extract [51]
from leaves induced RAW 264.7 cells,
per os - reduction in the level of neutrophil accumulation after 100 μg/mL of extract
- inhibiting the MPO enzyme levels after a higher dose
of the extract
- decreasing the level of lipid peroxides
- preservation of the enzymes SOD, CAT and GSH
levels

- reduces the expression of

- increasing the expression of the mucin protein MUC-2 chemokine - MCP-1
and MUC-3
8 mg/mL in the - decreasing the ICAM-1
drinking water - the protective effect in the colon mucosa
- reduction in the expres-
P. edulis / flour from (around 40 mg/mice) - decreasing the expression of MMP-2 and MMP-9 sion of IL-1β, Il-6, and IL- [54]
dried peels
per os - promoting the short-chain fatty acids production 17
- enhancing the intestinal protective barrier - no affect on the expression
- revealed prebiotic effects
of the TNF-α and the IL-
12 in the colon

- improving the content of serum proteins, albumin, and

antioxidant status - the five-fold reduction in
1100 µg leaves mL−1 - enhancement of the GSH activity by 1.3- fold and the IL-1β level
P. edulis / extract for 2 weeks GR activity by 1.8-fold in the liver of the tea colitis - the two-fold decrease in
[97]
from leaves per os group compared to the control colitis group IL-6 and TNF-α levels in
- no differences in damage of the colon tissue in macro- the colon intestinal tissue
scopic and microscopic level between the tea colitis of the tea colitis group

group and control colitis group

diets with 50% of the - protection of the colon tissue from lipid peroxidation
cellulose substituted - improving serum antioxidative status and trend to
with dietary fiber enhance the level of the antioxidant enzymes
from passion fruit - increasing the GR activity
P. edulis / peels flour (PFF) for 84 - no studied [53]
- rising the count of Bifidobacterium and Lactobacillus
days
after PFF used in the prevention protocol
per os
- no attenuation of the macroscopic and microscopic
tissue damage in animals with colitis

- reduction in macroscopic and microscopic damages of

colon
P. caerulea / extract 125 mg/kg
- decreasing the MPO level in the colon
from leaves 250 mg/kg
- reduction in the lipid peroxidation - no studied [72]
per os
- reduction in the severity of tissue damage
- antidiarrhoeal (in vivo) and spasmolytic (in vitro)
activities
(Table 1) Contd.....
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2587

Passiflora species / Dose and method of Effects on proinflammatory

Pharmacological activities against the pathological status Refs.
preparation administration cytokines

The activity of extracts in the model of paw edema and air pouch inflammation

- inhibition of the levels of

cytokine-like MIP-2 by
78.0% after aqueous re-
- decreasing the migration of leucocytes by 48% after P. sidual fraction at a dose of
edulis aqueous lyophilized extract at a dose of 100 100 mg/kg (most active)
P. edulis f. flavicarpa 50 mg/kg mg/kg (most active)
- repression in the levels of
/ extract from leaves
100 mg/kg - decreasing the neutrophils by 58.2% after butanolic IL-1β by 74.0% after
and fractions of the [42]
per os fraction at a dose of 50 mg/kg (most active) aqueous residual fraction
extract
- inhibiting the MPO level by 48.2% after butanolic at a dose of 100 mg/kg
fraction at a dose of 50 mg/kg (most active) (most active)
- inhibiting the NO level by
61.7% after aqueous re-
sidual fraction at a dose of
100 mg/kg (most active)

- 200 mg/kg and 400 mg/kg showed 42.07% and 81.37%

inhibition of edema induced by carrageenan, respecti-
vely
P. leschenaultii / 200 mg/kg - 56% and 79.04% granuloma inhibition after 200 mg/kg
extract from leaves 400 mg/kg and 400 mg/kg of an extract, respectively
- no studied [95]
per os - antipyretic activity - decreasing the rectal temperature
after 200 mg/kg and 400 mg/kg of extract by 1.05 and
2.42°C, respectively (after 5h)
- analgesic effect (in additional tests)
- antioxidant activity (in vitro)

- 200 mg/kg and 400 mg/kg presented 47.08% and

81.54% inhibition of edema induced by carrageenan,
P. subpeltata / extract 200 mg/kg respectively
from leaves 400 mg/kg - antipyretic effects - decreasing the rectal temperature
- no studied [48]
per os after 200 mg/kg and 400 mg/kg of extract by 1.68 and
2.55°C, respectively (after 5h)
- analgesic effect (in additional tests)
- antioxidant activity (in vitro)

- 200 mg/kg presented inhibition of edema induced by

P. foetida / extract 100 mg/kg
carrageenan
from leaves 200 mg/kg - no studied [45]
- anti-inflammatory effects against histamine
per os
- analgesic effect (in additional tests)

- reduction in the carrageenan-induced hind paw edema

in mice after all doses

100 mg/kg - reduction in edema induced by histamine after 400

mg/kg dose of the extract
P. cincinnata / extract 200 mg/kg
- reduction in total leukocytes and reduction in neutro- - inhibiting the production [85]
from leaves and stems 400 mg/kg
phil migration after treatment with the 100 and 400 of NO
per os mg/kg doses of the extract
- reduction in the number of mononuclear cells after 200
mg/kg dose of an extract
- analgesic effect (in additional tests)
(Table 1) Contd.....
2588 Current Pharmaceutical Design, 2021, Vol. 27, No. 22 Ożarowski and Karpiński

Passiflora species / Dose and method of Effects on proinflammatory

Pharmacological activities against the pathological status Refs.
preparation administration cytokines

The activity of extracts during the inflammatory process in diabetes

- reduction in the numbers of inflammatory cells in the

pancreatic islets:
- reduction in the proliferation of T lymphocytes at the
doses of 500, 800 and 1000 μg/mL of extract
P. alata / extract from
- decreasing the numbers of CD4+ T and CD8+ T cells
leaves extract in chow diet in the pancreas islets - no studied [126]
(15 g leaves/L water) - reducing the infiltration of CD4+ T and CD8+ T cells
in the pancreatic islets
- decrease of 28.6% in diabetes incidence
- protection of the beta cells
- antioxidant activity: decreasing the lipid peroxidation

- increasing the reduced glutathione concentration

- decreasing numbers of CD4+, CD8+ and CD11c+ cells
P. alata / extract from extract in chow diet
in the pancreas islets
leaves (15 g leaves/L water) - no studied [73]
- reducing the level of insulitis
- antioxidant activity
- decreasing of injury of pancreatic islets

The activity of extracts during inflammation of the pleurae induced by carrageenan

- diminishing the level of

- inhibition of the activity of the MPO (64% of inhibi-
TNF-α (79% of inhibition)
tion) using 250 mg/kg dose of an extract
and IL-1β (59% of inhibi-
- reduction in the leukocyte influx (67% of inhibition) tion) in pleurisy induced
P. edulis var. flavi- 250-500 mg/kg using 250 mg/kg dose of an extract by carrageenan using 250
carpa / extract from mg/kg dose of the extract [43]
intraperitoneal route - decreasing the neutrophils (85% of inhibition) using
leaves
250 mg/kg dose of an extract - inhibiting the level of
- inhibition of the leukocyte migration nitric oxide (47% of inhi-
bition) using 250 mg/kg
dose of the extract

P. alata P. alata
- decreasing the leukocyte migration from ca. 29 to 65% - reducing the C-reactive
- inhibition in the neutrophil influx from 27 to 96% protein level by 64% using
100 mg/kg dose of an
- inhibition of myeloperoxidase by 61% using 100 mg/kg extract
100 – 300 mg/kg of dose
P. alata / extract from P. alata extract P. edulis
leaves - decreasing the adenosine deaminase activity by 57%
intraperitoneal route using 100 mg/kg dose - decreasing the C-reactive
P. edulis / extract protein level by 66% using [44]
from leaves 100 - 1000 mg/kg of P. edulis 250 mg/kg dose of an
P. edulis extract - decreasing the leukocyte migration from 19 to 75% extract
intraperitoneal route - inhibition of the neutrophil influx from 24 to 78%
- inhibition of myeloperoxidase by 49% using 250 mg/kg - no significant changes in
dose nitric oxide levels (P. ala-
- decreasing the adenosine deaminase activity by 77% ta, P. edulis)
using 250 mg/kg dose
Abbreviations (Tables 1 and 2): CAT - catalase, COX-2 - cyclooxygenase-2, GR - reduced glutathione, GSH - glutathione, GSH-Px - glutathione peroxidase,
GST - glutathione S-transferase, HO-1 - heme oxygenase-1, IL-1β, IL-6 – interleukins, iNOS - inducible nitric oxide synthase, ICAM-1 - intercellular adhesion
molecule-1, i.p. - intraperitoneal administration, 5-LOX - 5-lipoxygenase, LPS - lipopolysaccharide, LTB4 - leukotriene, MCP-1 - monocyte chemoattractant
protein-1, MDA - malondialdehyde, MMP-2 - matrix metalloproteinases-2, MMP-9 - matrix metalloproteinases-9, MPO - myeloperoxidase, NF-κB - nuclear
factor kappa-light-chain-enhancer of activated B cells, NO - nitric oxide, Nrf2 - nuclear factor erythroid 2-related factor 2, ox-LDL - oxidized low-density
lipoprotein, PGE2 - prostaglandin E2, PKC - protein kinase C, p.o. - per os administration, ROS - reactive oxygen species, SOD - superoxide dismutase, TGF-
β1- transforming growth factor-β1, TNF-α - tumor necrosis factor-α, TXB2 - thromboxane, VCAM-1 - vascular cell adhesion molecule 1.

that all plant substances showed similar activities in a dose- minished the formation of granuloma by 79% in comparison with
dependent manner. Still, the most active was the acetone extract at a indomethacin. This extract also showed antioxidant, antipyretic,
dose of 400 mg/kg, because it inhibited inflammation during the and analgesic activities. It was discussed that the extract with fla-
late phase (5 h) by 81% in edema induced by carrageenan, and di- vonoids (i.e. quercetin-3-O-galactoside or hyperin) may lead to
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory
anti-inflammatory action by decreasing the mediators of inflamma-
tion through various pathways [121-125].
A similar study was performed earlier by Saravanan Shan-
mugam et al., [48] using the extract from leaves of Passiflora sub-
peltata, which is used in folk medicine in India. The author used the
same test and doses of acetone extract (200 and 400 mg/kg b.w. per
os) in rats. The extract contained flavonoids (apigenin, quercetin,
rutin), and tannin compounds (gallic acid and catechin). The rats
were pre-treated with the extract 1 h before the administration of
0.1 ml of 1% carrageenan. Analysis of pharmacological results
showed that this extract at doses of 200 and 400 mg/kg presented
47.08% and 81.54% inhibition of edema after the administration of
carrageenan. Moreover, the extract exhibited antipyretic effect,
analgesic activity, and the antioxidant potential in vitro, similarly as
acetone extract of Passiflora leschenaultii [95].
Previously, anti-inflammatory properties have also been inves-
tigated for ethanol extract of Passiflora foetida leaves in a model
using 0.1 ml of 1% carrageenan and histamine (in 1% CMC w/v)
for the induction of acute paw edema in rats [45]. Based on other
studies, it was found that the extract may contain rutin, quercetin,
luteolin, hesperidin, and bioflavonoids. The extract, which was
given at a dose of 100 mg/kg b.w., per os, produced a reduction in
inflammatory processes. In contrast, the extract at a dose of 200
mg/kg produced analgesic activity. The anti-inflammatory action of
the extract was observed in both models; however, only on paw
edema induced by histamine, this extract was active as indometha-
cin [45].
In the current study performed by de Lavor et al., [85], the
ethanolic extract from leaves and stems of Passiflora cincinnata
was tested in a similar model of paw edema, which has been in-
duced using carrageenan (20 μl of 1% suspension in 0.9% sterile
saline solution) and histamine (at a concentration of 100
μg/paw).The presence of flavonoids like isoorientin, vitexin, and
isovitexin was indicated in the extract. In this study, three doses of
the extract, 100, 200, and 400 mg/kg, were tested. Pharmacological
results showed that extract inhibited the volume of the edema in
both tests. However, the most effective was the extract in a dose of
400 mg/kg.
Similarly, as a result of Benica’s study [42], the mechanism of
action of this extract was based mainly on the inhibition of the leu-
cocytes migration and the reduction of neutrophils. In addition to
this, the extracts from the leaves of Passiflora edulis f. flavicarpa
containing isovitexin, vitexin, orientin, and isoorientin, has also
been investigated in the model of the air pouch inflammation by
Beninca et al. [42]. The inflammatory process was induced by us-
ing carrageenan, histamine, and substance P in mice. Results
showed similar activity dependent on aqueous extract at a dose of
100 mg/kg, i.p. (AE), butanolic fraction of extract (BuOH: 50
mg/kg, i.p.), and an aqueous residual fraction (AR: 100 mg/kg, i.p.)
used in tests. It was revealed that the extracts diminished the migra-
tion of leucocytes (by 10%-48%), neutrophils (by 29.2%-58.2%).
Moreover, the extracts and fraction decreased levels of cytokines
such as MIP-2 (by 31%-78%) and IL-1β (38.5%-74%).
5.1.3. The Activity of Extracts During the Inflammatory Process
in Diabetes
Figueiredo et al., [126] studied anti-inflammatory and anti-
diabetogenic properties of aqueous extract from the leaf of P. alata
and its effectiveness in non-obese diabetic mice. The objectives of
this study have been justified by the fact that inflammatory cells
occurring in the pancreatic islets can promote the destruction of
beta cells and consequently can decrease the secretion of insulin
during the progression of type 1 diabetes. After the administration
of P. alata extract (containing vitexin, isovitexin, and isoorientin)
for 30 weeks in diet, a tendency towards reduced numbers of in-
flammatory cells in the islets and a decrease of 28.6% in diabetes
incidence were observed. Moreover, the extract of P. alata was able
Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2589
to reduce the proliferation of T lymphocytes, which have been
stimulated by concanavalin A, and decrease the numbers of CD4+
T and CD8+ T cells and their infiltration in the pancreatic islets.
Accordingly, these in vivo findings indicate that anti-inflammatory
properties exerted by P. alata extract containing phenolic com-
pounds protected beta cells. In the previous study of these authors
[73], it was similarly observed that the same aqueous extract (con-
taining vitexin, isovitexin, isoorientin) in diet after 28 weeks de-
creased the injury of pancreatic islets, infiltration of inflammatory
cells, and reduced the incidence of diabetes in non-obese diabetic
mice.
5.1.4. The Activity of Extracts During Inflammation of the Pleu-
rae Induced by Carrageenan
The anti-inflammatory effects of aqueous extract from leaves of
Passiflora edulis var. flavicarpa with a high flavonoid content
(4.4%)at doses 250-500 mg/kg i.p. were previously observed by
Montanher et al., [43]. This study demonstrated several mecha-
nisms of anti-inflammatory effects of extract in the mouse model of
pleurisy induced by a single intrapleural injection of 0.1 mL of
carrageenan. The extract (250 mg/kg) administered 0.5 h before
inflammation, diminished level of pro-inflammatory cytokines such
as TNF-α and IL-1β, inhibited the activity of myeloperoxidase, and
migration of leukocyte and neutrophils. Vargas et al., [44] proved
that not only aqueous extracts from leaves of Passiflora edulis
(with 1.9% w/w of total flavonoid content) but also of Passiflora
alata (with 4.04% w/w of total flavonoid content) inhibited in-
flammation in a mouse model of pleurisy induced by a single intra-
pleural injection of 0.1 ml of carrageenan (1%) through the influ-
ence of this extracts (100 or 250 mg/kg, i.p.) on the migration of
leukocytes and inhibition of myeloperoxidase and adenosine-
deaminase activities, and decreasing C-reactive protein in serum.
Detailed information is shown in Table 1.
5.1.5. Other studies
Apart from the above discussed studies [55], the anti-
inflammatory activity of methanolic extract from fruits of three
species, such as Passiflora edulis var. flavicarpa, P. edulis var.
Sims, P. ligularis var. Juss, was tested using cell culture of colorec-
tal adenocarcinoma (Caco-2). The extracts contain mainly cyanidin
3-rutinoside, (+)-catechin, and ferulic acid in quantifiable amounts.
Additionally, quercetin 3-glucoside was detected only in Passiflora
edulis var. flavicarpa, rosmarinic acid in Passiflora edulis var.
Sims, epigallocatechin, and epigallocatechin gallate in Passiflora
ligularis var. Juss. The study focusing on the impact of extracts on
the dysfunction of the intestinal barrier after application of cytoki-
nes and LPS revealed that the highest inhibitory activity was exhib-
ited by the extract of Passiflora ligularis var. Juss. in comparison
with other extracts at the same concentration at 10 mg/dL. This
extract makes the value of transepithelial electrical resistance to
near 73% of the initial value. The authors concluded that all the
extracts had the ability to inhibit cell barrier dysfunction in in vitro
model used in experiments. Results may show implications of the
extract in the prevention of many inflammatory diseases involving
disorders of the intestinal barrier. At present, several studies have
shown anti-inflammatory properties of polyphenolics using the in
vitro cell model of an inflammatory process in the epithelium of
human intestines [96, 127-132].
6. ANTI-INFLAMMATORY STUDIES OF FLAVONOIDS
There is ample evidence that flavonoids have broad pharmacol-
ogical activities, hence their growing popularity and multipoint
medical use. Many studies have focused on testing of flavonoids for
their not only cardioprotective, neuroprotective, anti-hypertensive,
and anticancer properties but also anti-inflammatory activity [49,
133, 134]. Many flavonoids and phenolic acids present in various
extracts of Passiflora may lead to anti-inflammatory actions by
numerous mechanisms of biological action and by influencing me-
2590 Current Pharmaceutical Design, 2021, Vol. 27, No. 22
diators and effectors of inflammatory processes [48, 49, 50]. The
advancement in the knowledge of molecular mechanisms of fla-
vonoids has been observed for many years. These natural chemical
compounds decreased the concentration of pro-inflammatory pros-
taglandins and leukotrienes by inhibition of the activity of cy-
clooxygenase, lipoxygenase, and phospholipase (Table 2). Moreo-
ver, flavonoids inhibited phosphodiesterases and kinases and re-
duced the expression of cyclooxygenase COX-2 [121, 123]. It is
important to emphasize that flavonoids that have anti-inflammatory
activity can prevent a disorder of the biological structure and
physiological function of the intestinal barrier [55,111].
One of the most investigated flavonoids in this field is quer-
cetin (3,3’,4’,5,7-pentahydroxyflavone), which showed multiple
mechanisms of anti-inflammatory activity in various models such
as in animal and human cell lines, and in vivo model. Lee et al.,
[135] observed that quercetin inhibited in vitro synthase induced by
nitric oxide, production of nitric oxide, and interleukin-6, the nu-
clear translocation of nuclear factor-B (NF-B), which are bio-
markers of inflammation. Other studies showed that quercetin also
inhibited mediators such as MAPK/AP-1 and IKK/NF-B, protein
kinase C vascular superoxide production, and also tyrosine phos-
phorylation [136-138]. Many studies on human cell lines have
shown that quercetin exerted anti-inflammatory action by down-
regulation of vascular cell adhesion molecule 1 [139], by reducing
the gene expression of tumor necrosis factor  and interleukins
such as IL-1, IL-8 and IL-6 [140], and by decreasing the concen-
tration and activity of cyclooxygenase-2 [141] and lipooxygenase
[142, 143]. Lim et al., [144] also observed that quercetin reduced
the induction of metalloproteinase-1, activation of extracellular
signal-regulated protein kinase. Furthermore, Bahareh et al., [77]
showed that quercetin significantly inhibited the productions of the
tumor necrosis factor, nitric oxide, and myeloperoxidase in human
neutrophils.
Another flavonoid, chrysin (5,7-dihydroxyflavone), also ex-
erted anti-inflammatory activity in vitro [145-148]. Previously, it
was shown that this flavonoid inhibited expression cyclooxygenase-
2 via IL-6 signaling [145]. Recently, it was observed that this fla-
vone inhibited the inflammatory process in endothelial cells via the
NF-κB signaling pathway and decreased the levels of pro-
inflammatory mediators [148]. Chrysin also diminished the expres-
sion of vascular cell adhesion molecule-1 in endothelial cells, inhib-
ited nuclear factor-κB, protein kinase activated by p38 mitogen, and
c-Jun N-terminal kinase. Because chrysin decreased the adhesion of
leukocytes to the endothelium, thus this anti-inflammatory effect is
considered as therapeutic potential in the treatment of multiple scle-
rosis and other neurodegenerative disorders [146].
Next, a natural chemical compound such as luteolin (3', 4', 5,7-
tetrahydroxyflavone) at doses of 30 and 50 mg/kg used in rat paw
edema decreased serum levels of proinflammatory cytokines i.e.
tumor necrosis factor-, interleukins (IL-1β, IL-6) and myeloper-
oxidase [67]. These effects were observed previously by Chen et al.
[62]. Also another study [64] showed that luteolin at a concentra-
tion of 0.5 μM inhibited not only TNF-
but also a nuclear factor,
expression of protein-1 in the chemokine monocytes and adhesion
of various molecules to vascular cells. Biochemical results may
suggest that luteolin is a promising molecule that can inhibit in-
flammation by decreasing the signaling pathway of NF-κB and by
improving the function of vascular cells in vitro. Similar effects
were observed in mice fed a diet containing 0.6% luteolin for 3
weeks. Moreover, when luteolin and one of its glycosidic forms -
luteolin-7-O-glucoside (50 mg/kg b.w.) were given daily for 3
weeks to mice with liver injury, it was observed that these natural
compounds protected liver cells by regulation of mediators of in-
flammation and phase II enzymes [66], however, luteolin-7-O-
glucoside only changed the activation of NF-κB [63]. Previously,
Park et al., [63] and Chen et al., [62] showed that luteolin and one
of its glycosidic forms, luteolin-7-O-glucoside, also inhibited the
Ożarowski and Karpiński
synthesis of nitric oxide and prostaglandin E2, diminished the ex-
pression of inducible synthase of nitric oxide and cyclooxygenase-2
in vitro. Moreover, Odontuya et al., [149] observed that luteolin
and their derived C-glycosides inhibited the biosynthesis of throm-
boxane and leukotrienes. Aziz et al., [65] summed up that luteolin
exerts strong anti-inflammatory activity in vitro and in vivo, in
silico and in clinical studies, and its mechanisms of action include
few pathways for the nuclear factor, mitogen-activated protein
kinase, the signal transducer and activator of transcription 3.
Over the years, several investigations have suggested that api-
genin may show beneficial effects in various diseases with inflam-
matory conditions. In recent years, a lot of studies were carried out
to explain the mechanism of the anti-inflammatory activity of api-
genin. The medical database of PubMed contains 280 scientific
articles on this field of 2010 till 2020. Apigenin has been studied in
various models in vitro and in vivo. Many tests were performed
using human cell lines like i.e. human endothelial cells [150], BV2
microglia [151], bronchial epithelial cells [152], lung epithelial
cells [153], human and mouse macrophages [154, 155], and human
pluripotent stem cell model of Alzheimer’s disease [156]. Moreo-
ver, for the assessment of anti-inflammatory effects of apigenin,
few in vivo studies were carried out such as on the model of asth-
matic mice [157], on the model of polycystic ovary syndrome in
rats [158], colonic inflammation in a mouse model of diet-induced
obesity [159], on a rat model of Parkinson's disease [160], on mice
with liver injury [161], on rats model of lung injury [162], on the
model of arthritis in rats [163], and a rat’s model of sepsis [164].
It is well-known that apigenin acts not only as an antioxidant
but also as an anti-inflammatory molecule through inhibition of
mediators and signaling pathways [17]. Several studies have re-
ported that anti-inflammatory mechanism of apigenin action is
based on inhibition/downregulation of the signaling pathways such
as the nuclear factor-kappa B (NF-κB) [143, 154, 162; 165-167],
STAT3-NF-κB [168] the TLR4/NF-κB [169], and P2X7/NF-κB
[163] leading to decreasing cytokines release. Moreover, apigenin
influenced the COX2/PGE2 axis [155, 170], activated the
GSK3β/Nrf2 [151], and the Nrf2 signaling pathways [166]. It was
shown that apigenin subsequently attenuated the synthesis of in-
flammatory cytokines, like TNF-α, IL-1β, and IL-6 [151, 154, 159,
165], and it was revealed that this flavonoid decreased the expres-
sion of pro-inflammatory cytokines and adhesion molecules by 30-
70% [167]. Furthermore, it reduced the expression of LOX-1 and
NLRP3 and inhibited adhesion of leukocytes in vitro [150], and
down-regulated the release of nitric oxide from inflammatory cells
[156]. It should be noted that the anti-inflammatory action of api-
genin was more effective in comparison with the other 13 flavon-
oids tested [152]. Results of studies revealed that apigenin includ-
ing above mechanisms of action, inhibited neuro- [148, 151, 160]
and colonic inflammation [159,171], attenuated atherogenesis [172]
and arthritis [163] and decreased inflammatory processes in the
liver [161], lungs [162], spleen [164] and testicular cells [165].
Based on the above considerations, it can be concluded that api-
genin is a universal molecule with a wide anti-inflammatory effect
observed during many models of disorders, and may be considerate
as an interesting drug candidate to new treatments of not only coli-
tis but also of Parkinson’s and Alzheimer’s disease and many other
diseases occurring with inflammation.
The previous study showed that not only quercetin, luteolin,
and apigenin, but also rutoside (3,3′,4′,5,7-pentahydroxyflavone-3-
rhamnoglucoside; rutin) produced anti-inflammatory activity [173,
174]. Nikfarjam et al., [175] revealed that this compound signifi-
cantly diminished the production of nitric oxide and tumor necrosis
factor- in peripheral blood neutrophils. Moreover, it was observed
that rutoside reduced myeloperoxidase activity in vitro. In the
model of acute and chronic inflammation, this flavonoid (80 mg/kg,
i.p.) inhibited the chronic phase the most in comparison with
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2591

Table 2. Anti-inflammatory activities of flavonoids in various experimental models.

Concentration or dose Effect of flavonoids on inflammatory mediators

Flavonoid Experimental model Refs.
with dosage regimen / other factors / functions

Animal model of inflammation

- decreasing the protein level of TNF-α, IL-1β, and MCP-1 in a

dose-dependent manner
40 mg/kg, p.o., rats with abdominal - reduction in expressions and protein levels of MMP-2 and
aortic aneurysms indu- MMP-9 - max. the inhibitory effect after 40 mg/kg
Apigenin 80 mg/kg, p.o., [143]
ced by 0.5 mol/L of
for 2 months CaCl2 - reduction in phosphorylation of IκB and phosphorylation of
IKKβ
- blocking the activity of NF-κB

- decreasing the percentage of eosinophils, as well as neutrophil

infiltration in the lungs of asthmatic mice
20 mg/kg, p.o. BALF mice with asthma
- down-regulating the expression of NF-κB p65 submit
Apigenin induced by particulate [157]
for 7 days matter (PM2.5) - reducing the levels of total serum immunoglobulin IgE by
about 78% and IL-4 by about 64%, IL-13 by about 33%, IL-17
by about 44.2%

20 mg/kg, p.o. - reducing the TNF-a level by about 28% after apigenin at 20
polycystic ovary syn- mg/kg, and by about 37.3% after apigenin at 40 mg/kg
Apigenin 40 mg/kg, p.o. [158]
drome in the rat model - reducing the IL-6 level by about 32% after apigenin at 20
for 21 days mg/kg and by about 41% after apigenin at 40 mg/kg

- reducing the MDA level by 22.7%

- decreasing the colonic levels of IL-1β by 57% and IL-6 by
10 mg/kg, p.o. C57BL/6J mice fed a
Apigenin 74% [159]
for 8 weeks high-fat diet
- diminishing the eosinophil infiltration
- decreasing the iNOS expression

- inhibiting the release of pro-inflammatory cytokines: TNF-α

by about 18.5%, IL-6 by about 23.5%, NF-κB by about 13%
and pro-inflammatory enzyme iNOS-1 by about 16% after api-
10 mg/kg, i.p. a rotenone-induced rat genin at 10 mg/kg with rotenone
Apigenin 20 mg/kg, i.p. model of Parkinson's [160]
- decreasing the lipid peroxides level, the substantia nigra after
for 14 days disease
apigenin at 10 and 20 mg/kg with rotenone
- increasing the SOD and CAT activity in the striatum after
apigenin at 10 and 20 mg/kg with rotenone

- decreasing the hepatic TNF-α content by about 19% after

apigenin at 100 mg/kg and by about 23.5% after apigenin at
200 mg/kg
100 mg/kg, p.o. d-galactosamine / LPS- - increasing the SOD level by about 23.5% after apigenin at 100
Apigenin 200 mg/kg, p.o. induced liver injury in mg/kg and by 17.6% after 200 mg/kg, CAT level by 15.8% at [161]
mice 200 mg/kg
for 7 day
- increasing the GST level and GR level after apigenin at 200
mg/kg
- reducing the hepatic NF-κ p65 protein expression and level

- reducing the expression in the left lung:

- the TNFα expression by 70% after a single dose and by 71.7%
after double dose apigenin
acute ischemia- - the iNOS expression by 79.4% after a single dose and by 66%
25 mg/kg, i.p.
Apigenin reperfusion double dose apigenin [162]
single or double dose
injury of the lung in rats - the IL-6 expression by 85% after a single dose and by 76.5%
after double dose apigenin
- reducing the NF-κB activation by 40.8% after a single dose
and by 66.1% at double dose apigenin
(Table 2) Contd....
2592 Current Pharmaceutical Design, 2021, Vol. 27, No. 22 Ożarowski and Karpiński

Concentration or dose Effect of flavonoids on inflammatory mediators

Flavonoid Experimental model Refs.
with dosage regimen / other factors / functions

- decreasing the serum concentration of TNF-α by about 24%

after 5 mg/kg, by about 14% at 20 mg/kg, and by about 20.5%
at 40 mg/kg
5 mg/kg, p.o., - decreasing the serum concentration of IL-6 by about 43% (5
20 mg/kg, p.o. Freund’s complete adju- mg/kg), by about 13% (20 mg/kg), by about 30% (40 mg/kg)
Apigenin vant-induced arthritis in [163]
40 mg/kg, p.o. rats - up-regulating the expression of p-NF-κBp65, p- IKKα, P2X7,
for 7 days p-IKKβ, p-IκBα of ankle joint tissue
- protection for synovial inflammatory cell infiltration, articular
cartilage lesion, epithelial cell degeneration, and synovial tis-
sue edema after apigenin at 40 mg/kg

- reducing the proinflammatory cytokine levels:

- TNFα by 7.5%, IL-1β by 15% and IL-6 by 19% after pretreat-
ment with apigenin at 20 mg/kg
20 mg/kg, p.o., polymicrobial sepsis rat
- TNFα by 22.6%, IL-1β by 20.7% and IL-6 by 37% after pre-
model induced by cecal
Apigenin 40 mg/kg, p.o., treatment with apigenin at 40 mg/kg [164]
ligation and puncture
60 mg/kg, p.o. (CLP) - decreasing the lipid peroxidase (LPO) levels by apigenin at 40
mg/kg, and catalase (CAT) levels by apigenin at 20 and 40
mg/kg,
- increasing the SOS activity by all doses

- decreasing the increase of TNF-α by about 30.4% and 32%,

IL-6 by about 37% and 40%, and IL-1β by about 31.7% and
234 mg/kg, p.o. acrylonitrile-induced 33% in rat testes after 234 and 468 mg/kg of apigenin, respec-
Apigenin 468 mg/kg, p.o. inflammation in testicu- tively [165]
for 12 weeks lar cells in rats - decreasing the protein levels of NF-κB by about 45% and
27.4% in rat testes after 234 and 468 mg/kg, respectively
- down-regulating the caspase-3 levels in testicular tissue

- inhibiting the ulcerative colon damage

- inhibiting the production of TNF-α by about 37.5% and 61%,
IL-1β by about 52% and 66.5%, IL-6 by about 38.5% and
200 mg/kg, p.o., ulcerative colitis indu- 60%, MCP-1 by about 41.5% and 63.5% after 200 mg.kg and
Apigenin 300 mg/kg, p.o. ced by dextran sulfate 300 mg/kg of apigenin, respectively [168]
for 20 days sodium in mice - decreasing the expression of COX-2 by about 32% and 53%
after 200 mg/kg and 300 mg/kg of apigenin, respectively
- reducing the MPO activities by about 26% and by 36% after
200 and 300 mg/kg of apigenin, respectively

- reducing the oxidative stress by increasing the level of gluta-

thione (GSH), the activity of glutathione peroxidase (GSH-Px)
117 mg/kg, p.o. after all doses of apigenin
234 mg/kg, p.o. acrylonitrile-induced - increasing the SOD activity after apigenin at 234 mg/kg
Apigenin neuroinflammation in [169]
351 mg/kg, p.o. - downregulating the TLR4/NF-κB signaling pathway
rats
for 28 days - decreasing the concentration of TNF-α and IL-6 after 117
mg/kg
- decreasing the mRNA expression of NF-κB after all doses

- alleviating the injuries such as leukocyte infiltration, eryth-

rocyte aggregation, and interstitial edema after pretreatment of
40 mg/kg, p.o. LPS - induced vascular
Chrysin chrysin at 40 mg/kg and 80 mg/kg [148]
80 mg/kg, p.o. inflammation in mice
- suppressing the leukocyte-endothelial cell adhesion and
inflammation

Isoorientin 15 mg/kg, p.o. carrageenan-induced - inhibiting inflammation between 28-37% (at 15 mg/kg) and
[187]
30 mg/kg, p.o. hind paw edema of mice 36-43% (at 30 mg/kg doses)

(Table 2) Contd....
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2593

Concentration or dose Effect of flavonoids on inflammatory mediators

Flavonoid Experimental model Refs.
with dosage regimen / other factors / functions

- decreasing TNF-α by about 50% (at 50 mg/kg) and 68% (at 100
mg/kg) and I L-6 production by about 43% (at 50 mg/kg) and
70.6% (at 100 mg/kg)
- reducing the MPO activity by about 38% (at 50 mg/kg) and 58%
(at 100 mg/kg), and MDA content by about 51% (at 50 mg/kg)
LPS-induced acute and 68% (at 100 mg/kg)
50 mg/kg, i.p. [177]
Isovitexin lung
100 mg/kg, i.p. - increasing SOD by about 95% (at 100 mg/kg) and GSH levels by
Injury in mice about 90.5% (at 50 mg/kg) and 105% (at 100 mg/kg)
- inhibiting the expression of iNOS by about 28.3% (at 50 mg/kg)
and 56.6% (at 100 mg/kg) and COX-2 by about 32% (at 50
mg/kg) and 54% (at 100 mg/kg)
- diminishing the ROS generation

- reducing the increased circulating levels of MCP-1/JE, KC (the

C57BL/6 mice treated mouse homolog of human MCP-1 and IL-8, respectively), and
Luteolin diet containing 0.6%
with TNF-α at 25 sICAM-1 in mice by 61%, 93%, and 35%, respectively [64]
luteolin
μg/kg (i.p.) - complete blocking of the F4/80-positive monocytes-derived
macrophages

- attenuating the inflammatory cell infiltration and necrosis by the

3-week administration of luteolin
Luteolin galactosamine/LPS-
- attenuating the inflammatory mediators and their transcription
50 mg/kg, p.o. induced hepatitic ICR [66]
factors, NF-κB and AP-1
mice
- ameliorating the increased TNF-α production by about 51% and
COX-2 expression by about 69%

- decreasing the paw edema in dose dependent manner (max.

protective effect after 24 h with 50 mg/kg luteolin)
- decreasing the serum level of TNF-α (from 68.24 ng/mL to 39.28
Luteolin 30 mg/kg, i.p., monosodium urate
ng/mL), IL-1β (from 20.18 ng/mL to 12.07 ng/mL), and IL-6
crystal-induced rats [67]
50 mg/kg, i.p., (from 39.35 ng/mL to 24.72 ng/mL) after 50 mg/kg of luteolin
paw edema
- reduction of lipid peroxidation by 52%, level of glutathione
peroxidase by 40%, level of SOD by 36%, level of CAT by
37.5% after 50 mg/kg of luteolin

- decreasing the edema produced in the acute phase after rutin by

53% and quercetin by 59%
Rutoside adjuvant - carragee-
- decreasing the edema produced in the chronic phase after rutin by
and 80 mg/kg, i.p. nan-induced inflam- [174]
73% after 30 days, but quercetin without significant activity
Quercetin mation in rats
- suppressing the arthrogram scores by 100% after rutin and by
50% after quercetin

Rutoside - the highest anti-inflammatory effect after quercetin = inhibiting

150 mg/kg i.p. of rutin, carrageenan-induced
and the edema by 66% after 1 h and by 63% after 7 h [176]
75 mg/kg i.p. of quercetin paw edema in mice
Quercetin - no significant activity after rutin

Rutoside - decreasing the edema produced in the chronic phase after rutin by
adjuvant arthritis test 53% after 3 h (6 days) and by 61% after 10 days
and 75 mg/kg i.p. [176]
in mice - reducing the edema produced in the chronic phase after quercetin
Quercetin by 59% after 3 h (6 days) and by 70% after 10 days

Rutoside
50 mg/kg s.c. of rutin, cotton pellet granu- - inhibiting the granuloma formation by 24% after rutin
and [176]
25 mg/kg s.c. loma test in rats - inhibiting the granuloma formation by 26% after quercetin
Quercetin

- inhibiting the production of TNF-α by about 36.5%, IL-1β by

about 78%, IL-6 by about 35.5%, IL-33 by about 33%
Vitexin 10 mg/kg, i.p., carrageenan-induced - enhancing the production of anti-inflammatory cytokine (IL-10)
[76]
single dose inflammation in mice by about 77%
- prevention in the carrageenan-induced decrease of GSH levels
(10 mg/kg, i.p.,)
(Table 2) Contd....
2594 Current Pharmaceutical Design, 2021, Vol. 27, No. 22 Ożarowski and Karpiński

Concentration or dose Effect of flavonoids on inflammatory mediators

Flavonoid Experimental model Refs.
with dosage regimen / other factors / functions

5 mg/kg, p.o., carrageenan, zymo-

san LPS-induced - max. inhibitory effects on TNF-α level at the dose of 30mg/kg
15 mg/kg, p.o.,
Vitexin leukocytes migration (69.9%) and IL-1β level at the dose of 15mg/kg (56.4%) [180]
30 mg/kg p.o. to the peritoneal - max. reduction in NO concentration at 15mg/kg (70.9%)
single dose cavity in mice

- decreasing the levels of TNF-α by about 29%, iNOS by about

2 μM, 36.5%, nNOS by about 68.5%, COX-2 by about 26.5%, p-38 by
acrylamide-induced
10 μM, neuroinflammation in about 69% after 10 μM of vitexin
Vitexin [181]
20 μM, zebrafish larvae - up-regulating the nuclear translocation of Nrf2-mediated expressions
(Danio rerio) of SOD by about 66% and CAT by about 50% after 10 μM of vite-
for 24 h
xin

- decreasing the concentrations of TNF-α by about 35%, IL-1β by

10 mg/kg, i.p. LPS- induced acute
Vitexin about 55%, and IL-6 by about 50% [185]
single dose lung injury in mice
- reducing the ROS levels by 44%

- attenuating the migration of eosinophil, neutrophil, and mononuclear

cells and Th2 cytokines level in bronchoalveolar lavage fluid
- reducing the total leukocytes (87%), eosinophils (95%), neutrophils
0.2 mg/kg, murine ovalbumin- (89%), mononuclear cells (79%)
induced allergic
Vitexin 1 mg/kg, - reducing the concentrations of the three cytokines at all doses of [186]
asthma model in
5 mg/kg, mice vitexin with maximum effect for IL-4 (64%) at 1 mg/kg, for IL-5
(96%) at 0.2 mg/kg and for IL-13 (65%) at 1 mg/kg of vitexin
- decreasing the plasma IgE concentration at all doses (79% at 0.2
mg/kg)

Another model for inflammatory processes

- attenuating the increased contents of TNFα by about 34% and 52%,

of IL-1β by about 43.5% and 55.5%, and of IL-6 by about 37.5%
and 50% after 100 μM and 200 μM of apigenin, respectively
human renal epithe- - decreasing the level of MDA by about 32% and 54% after 100 μM
100 μM,
Apigenin lial cell HK-2 incuba- and 200 μM of apigenin, respectively [166]
200 μM ted with D-glucose - increasing the activity of SOD by about 55.5% and 116%, and of
CAT by about 156% and 200% after 100 μM and 200 μM of apige-
nin, respectively
- increasing the mRNA expression of an Nrf2 response gene

- diminishing the leukocyte adhesion and expression of adhesion

ISO-HAS human molecules, i.e. VCAM-1 after 30 μM of apigenin (132%) and 50 μM
10 μM, endothelial cells apigenin (127%), ICAM-1 after 30 μM of apigenin (131%) and 50
Apigenin 30 μM, exposed to trimethy- μM of apigenin (128%) [150]
50 μM lamine-N-oxide
(TMAO) - reducing the protein expression of LOX-1 and NLRP3 after 50 μM
of apigenin

- suppressing the production of these inflammatory cytokines in a

10 μM, LPS-stimulated dose-dependent manner, maximal effect after apigenin at 40 μM:
Apigenin 20 μM, murine BV2 micro- TNF-α by about 83.5%, IL-6 by about 81%, IL-1ß by about 79% [151]
40 μM glial cells - up-regulating the expression of GSK3b, Nrf2, and HO-1
- inhibiting the LPS-induced NF-κB activation

- reducing levels of the IL-6 by about 52.4% after apigenin > by about
40.5% after luteolin
- reducing the level of IL-8 by about 54.5% after luteolin > by about
LPS-stimulated 38.5% after apigenin
Apigenin human bronchial
10-6 - 10-4 M - inhibiting the MCP-1 release by 68% after luteolin > by about 54% [152]
Luteolin epithelial cell line
after apigenin
(BEAS-2B cells)
- decreasing the LPS-induced activity of NF-κB p65 by about 45.5%
after apigenin with LPS
- inhibiting the level of MDA by about 35% after apigenin with LPS
(Table 2) Contd....
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2595

Concentration or dose Effect of flavonoids on inflammatory mediators

Flavonoid Experimental model Refs.
with dosage regimen / other factors / functions

- decreasing the LPS - induced mRNA levels of iNOS and COX-2

in a dose-dependent manner - inhibition in iNOS by 10% and
COX2 by 26% after apigenin at 40 μM
LPS-stimulated human - decreasing the NO production and release in a dose-dependent
Apigenin lung alveolar type II manner
10 μM – 100 μM [153]
epithelial cells (A549 - inhibiting the LPS - induced expression of pro-inflammatory
cells) cytokines (IL-1β, IL-2, IL-6, IL-8, and TNF-α) in a dose-
dependent manner after apigenin at 20 μM and 40 μM
- decreasing the AP-1 proteins: mRNA transcripts of c-Jun, c-Fos,
and JunB in a dose-dependent manner (20 μM and 40 μM)

- inhibiting the IL-6 by about 94% after 25 μM of apigenin and by

6.25 μM, 60% after 12.5 μM of apigenin,
LPS - stimulated human
Apigenin 12.5 μM, - decreasing the IL-1β by about 49% after 25 μM of apigenin and [154]
THP-1 monotypic cells
25 μM by about 37% after 12.5 μM of apigenin,
- reducing the TNF-α by 53% only after 25 μM of apigenin

functional neurons from - promoting a global down-regulation of cytokine and nitric oxide
human induced pluripo- release in inflammatory cells
tent stem cell (iPSC)
5 μM, - protection against apoptosis, neuronal death by apigenin at 50 μM
model,
Apigenin 10 μM, - reducing the caspase-3/7 activity levels by apigenin at 50 μM [156]
RAW264.7 cells,
50 μM - inhibiting the levels of 23 cytokines i.e.
C8B4 cells
IC50 for TNF-α = 75 (RAW264.7), 27 (C8B4), 19 (PM),
primary microglial
(PM) culture IC50 for IL-6 = 46 (RAW264.7), 63 (C8B4), 38 (PM)

human umbilical vein - suppressing the production of ROS (30% relative to control)
endothelial cells using 10 μM of apigenin
Apigenin 0–100 μM (HUVECs) incubated - decreasing the protein expression of proinflammatory cytokines [167]
with glycation end (IL-6, TGF-β1) and adhesion molecules (MCP-1) by 30–70% in a
products (AGEs) dose-dependent manner

- blocking the adhesion of monocytes to bEnd.3 cells exposed to

LPS by 83.9%
- attenuating the IκBα degradation from 29.7% to 94.6% at 100 µM
LPS - stimulated brain - decreasing the phosphorylation of p38 mitogen-activated protein
Chrysin 10 μM –100 µM endothelial cells kinase (MAPK) from 289.8 % to 173.2% at 100 µM [146]
(bEnd.3 cells) - decreasing the phosphorylation of -Jun N-terminal kinase (JNK)
from 240.2% to 92.0% at 100 µM
- reducing the VCAM-1 mRNA expression in a concentration-
dependent manner from 435.8% to 201.4%

- suppressing the increase in mRNA expression and protein levels

human umbilical vein of ICAM-1, VCAM-1, and E-selectin
1 mM, 3 mM, 10 mM,
Chrysin endothelial cells [148]
30 mM - inhibiting the induction of the p-IkBa levels by treatment with 10
(HUVECs)
mM or 30 mM of chrysin

- inhibiting the LTB4 synthesis after 50 µg/mL (33.6%), 100

µg/mL (28.24%)
peritoneal leukocytes of
Isoorientin 25, 50 and 100 µg/mL - inhibiting the TXB2synthesis after 25 µg/mL (54.33%), 50 µg/mL [149]
rats
(56.34%), 100 µg/mL (66.42%)
- inhibiting the COX-2 and 5-LOX activity

- diminishing the AngII-induced increase of the superoxide anion

production in the smooth muscle cells after isorhamnetin (10
Isorhamnetin 1 or 10 mmol/L rings of thoracic aortae mmol/L) [136]
- preventing the in AngII-induced endothelial dysfunction after
incubation with isorhamnetin (10 mmol/L)

- prevention of the endothelin-1 increased intracellular [137]

Isorhamnetin 1 and 10 µM rings of thoracic aortae O2•−production and A23187-stimulated O2•−generation after incu-
bation with 10 µM of isorhamnetin
(Table 2) Contd....
2596 Current Pharmaceutical Design, 2021, Vol. 27, No. 22 Ożarowski and Karpiński

Concentration or dose Effect of flavonoids on inflammatory mediators

Flavonoid Experimental model Refs.
with dosage regimen / other factors / functions

- reducing the NO production with IC50 = 58.5 µM

Isovitexin LPS-stimulated RAW
- inhibiting IKK kinase activity and decreasing the iNOS protein
5 µM - 100 µM 264.7 murine macro- [74]
expression in a dose-depending manner
phages
- preventing the translocation of NF-κB

- reducing the secretion of TNF-α by about 57.5% and IL-6 by

about 54.5% after 50 µg/mL
- decreasing the expression of iNOS by about 93% and COX-2 by
25 μg/mL, LPS-stimulated RAW about 67.7% after 50 µg/mL
Isovitexin 264.7 murine macro- [177]
50 μg/mL - inhibiting the phosphorylation of MAPK, reducing the nuclear
phages
translocation of NF-κB,
- upregulating the expression of Nrf2 and HO-1
- suppressing intracellular ROS generation

- suppressing the LPS-induced gene expressions of TNF- α, IL-6,

iNOS, and COX-2 in a dose-dependent manner
mouse alveolar
macrophages stimula- - reducing the DNA binding activity of NF-κB
Luteolin [62]
5.0 μM – 50 μM ted by LPS (MH-S - blocking the degradation of IκB-α and NF-κB p65 subunit
and RAW 264.7 - attenuating the LPS-mediated protein kinase B
cells)
- attenuating the production of reactive ROS after preincubation
with luteolin (5, 10 and 25 μM)

- suppressing the NO (IC50 = 13.9 μM) and PGE2 (IC50 = 7.4 μM)
Luteolin LPS-stimulated RAW
- inhibiting the LPS-induced expression of iNOS and COX-2 in a
5 μM – 50 μM 264.7 murine macro- [63]
dose-dependent manner
phages
- inhibiting the Akt phosphorylation

- blocking the inflammation-induced adhesion of monocytes to

endothelial cells by luteolin at 20 μM
Luteolin EA.hy926 endothelial - inhibiting the TNF-α-induced gene expression of MCP-1,
0.5 μM – 20 μM [64]
cells VCAM-1, ICAM-1, and chemokine by luteolin at 0.1 μM
- complete prevention of the TNF-α-induced gene expression of
MCP-1, VCAM-1, ICAM-1, and chemokine by luteolin at 2 μM

- inhibiting the LTB4 synthesis after 25 µg/mL (95.29%), 50

25 µg/mL, µg/mL (97.71%), 100 µg/mL (96.27%)
Luteolin peritoneal leukocytes
50 µg/mL, - inhibiting the TXB2 synthesis after 25 µg/mL (39.38%), 50 [149]
of rats
100 µg/mL µg/mL (64.76%), 100 µg/mL (76.88%)
- inhibiting the COX and 5-LOX activity

- decreasing 86.09%, in NO production in the cells during a 4-h

incubation period with quercetin (25 μM)
Quercetin cultured neutrophils [77]
- inhibition of 79.31% in TNF-α production after incubation with
1.0 μM - 100 μM isolated from human
quercetin (25 μM)
blood
- reducing the MPO activities by 83.7% in the cells treated with
quercetin

- reducing the NO production in a dose-dependent manner after

pretreatment with 12.5-25 μM of quercetin
- decreasing the iNOS expression after pretreatment with 6.25-25
LPS - stimulated μM of quercetin
Quercetin
6.25μM - 25 μM RAW264.7 murine - reducing the IL-6 production in a dose-dependent manner after [135]
macrophages pretreatment with 6.25-25 μM of quercetin
- attenuating the nuclear translocation of NF-κB
- no effect on the production of TNF-α, IL-6, and expression of
COX-2
(Table 2) Contd....
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2597

Concentration or dose Effect of flavonoids on inflammatory mediators

Flavonoid Experimental model Refs.
with dosage regimen / other factors / functions

- diminishing the AngII-induced increase of the superoxide anion

production in the smooth muscle cells after quercetin (10
Quercetin 1.0 mmol/L, rings of thoracic mmol/L) [136]
10 mmol/L aortae
- preventing the in AngII-induced endothelial dysfunction after
incubation with quercetin (1 or 10 mmol/L)

- prevention of the endothelin-1 increased intracellular

O2•−production and A23187-stimulated O2•−generation after incu-
Quercetin 1.0 μM, rings of thoracic [137]
bation with 10 µM of quercetin
2.0 10 µM aortae
- inhibition of the increased PKC activity induced by endothelin-1
after incubation with 10 µM of quercetin

- inhibiting the LPS-induced NO production in a concentration-

dependent manner,

Quercetin LPS - stimulated - inhibiting the secretion of PGE2, iNOS, COX-2, TNF-α, IL-1β,
5.0 μM – 20 µM RAW 264.7 murine IL-6, and GM-CSF mRNA and protein expressions at higher con- [138]
macrophages centrations
- inhibiting the LPS-induced NF- κB activation by quercetin in a
time- and dose-dependent manner

- decreasing the expression of VCAM-1 and cluster of differentia-

Quercetin human umbilical vein tion after pretreatment of quercetin at 210 μM
0 - 210 μM endothelial cells [139]
(HUVECs) - the protective effects against oxidative damage at concentrations
of 90-210 μM

- decreasing the mRNA levels of IL-6, IL-8, monocyte chemoat-

tractant protein-1, interferon-γ inducible protein-10, IL-1b, TNF-
Quercetin 0.3 μM, 3.0 μM, human U937 mono- α and cyclooxygenase-2 (COX-2) after the 5-h incubation time [140]
10 μM, 30 μM cytes
- decreasing the phosphorylation of JNK and c-Jun after 2.5 h
pretreatment of quercetin in a dose-dependent manner

- suppression of the arsenite-induced the COX-2 expression mainly

by blocking the activation of the PI3K signaling pathway after
pretreatment with quercetin at a concentration of 10 or 20 μM
10 μM, rat liver epithelial
Quercetin - reduction in the production of PGE2 by quercetin at 10 or 20 μM [141]
20 μM (RLE) cells
- attenuation of the arsenite-induced PI3K activity by binding with
PI3K, and the suppression of activation of Akt, p70S6K, and
ERK

- inhibition of activity of the COX-2 by 68% after quercetin at 100

10 μM, epidermal tissue of μM (IC 50 = 50 μM)
Quercetin [142]
100 μM guinea-pigs - inhibition of activity of the LOX by 61% after quercetin at 100
μM (IC50 = 30 μM) (1%) as

- inhibition of the activity of the MMP-1 (IC50 = 39.6 μM)

- suppression of activation of the transcription factor (AP-1) after
human dermal fibro-
Quercetin 0 – 100 μM 25 and 12.5 μM of quercetin [144]
blast (HDF) culture
- inhibition of extracellular signal-regulated protein kinase (ERK)
and p38 mitogen-activated protein kinase (MAPK) activation

- decreasing the production of NO by about 86%

human peripheral
Rutoside 25 μM - decreasing the production of TNF-α by about 71% [175]
blood neutrophils
- reducing the MPO activity by about 80%

- decreasing 86.74% NO production in the cells after vitexin (25

μM) during a 4-h incubation period
cultured neutrophils
- inhibiting 80.94% TNF-α production after incubation with vitexin
Vitexin 1 μM - 100 μM isolated from human [77]
(25 μM)
blood
- reducing the MPO activities by 87.3% in the cells treated with
vitexin
(Table 2) Contd....
2598 Current Pharmaceutical Design, 2021, Vol. 27, No. 22
Concentration or dose
Flavonoid Experimental model
with dosage regimen
human umbilical vein
Vitexin 1 µM - 50 µM endothelial cells
(HUVECs)
25 μg/ml,
LPS - stimulated
Vitexin 50 μg/ml, RAW 264.7 murine
100 μg/ml macrophages
5 μM, 10 μM,
IL-1β-stimulated
Vitexin 50 μM, 100 μM, chondrocytes from
osteoarthritis patients
for 24 h
quercetin and hesperidin [174]. A similar effect was shown by Ro-
telli et al. [176].
There is evidence that C-glycosylflavonoids, characteristic
chemical compounds detected in extracts from various species of
Passiflora, such as vitexin [76, 77], isovitexin [74, 177], isoorientin
[149, 187], exerted some effects during in vitro and in vivo tests.
Odontuya et al., [149] observed, for example, that isoorientin inhib-
ited the biosynthesis of thromboxane and leukotrienes.
Besides, Lin et al., [74] observed the anti-inflammatory activity
of isovitexin in vitro by interfering IKK phosphorylation, decreas-
ing the NF-kB translocation from the cytoplasm to the nucleus.
Another study showed that isovitexin diminished a few pathways,
such as MAPK, NF-κB, and Nrf2 [178]. However, the most inves-
tigated from C-glycosylflavonoids is vitexin, which possesses anti-
inflammatory properties [179]. Vitexin at a dose of 10 mg/kg b.w.
given to animals was able to decrease the expression of pro-
inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-33), which are
responsible for hyperalgesia induced by the use of carrageenan
[76]. Also, in many studies, it was shown that vitexin significantly
inhibited the productions of the tumor necrosis factor , nitric ox-
ide, and myeloperoxidase in neutrophils [77, 175, 180], and in
macrophages [180]. Vitexin (10 μM) also inhibited processes of
neuroinflammation in experimental conditions after 24 h treatment
by diminishing the CDK5 expression and reduction of the release of
the proinflammatory mediators [181]. Application of vitexin in the
PC12 cell line showed a decline in the generation of free radicals
during oxidative stress and suppression of activation of the caspase-
3 pathway [182]. Next in vitro results showed that vitexin also in-
hibited other signaling pathways like p38, ERK1/2, and JNK, im-
portant in the induction of response of inflammation [181]. In cul-
tured chondrocytes from osteoarthritis patients, vitexin in various
concentrations 24 h after its application decreased the level of nitric
oxide, prostaglandin E2, expression of interleukins such as IL-6 and
TNF-
, and metalloproteinases [183]. A similar study using chon-
drocytes revealed that vitexin also inhibited the pathway of nuclear
factor kappa B and expression of cytokines of inflammation [184].
Lu et al., [185] observed that vitexin (10 mg/kg, i.p.) diminished
the edema of the lungs of mice, and mechanisms of its action in-
clude reduction of free radicals, level of IL-1β, activation of nuclear
factor erythroid-2-related factor 2 and elevated activity of heme
oxygenase. Moreover, it was shown that vitexin (0.2, 1, 1.5 mg/kg
bw p.o.) exerted beneficial effects in mice model of acute allergic
asthma because this flavonoid reduced airway inflammation. In all
doses, it diminished the infiltration of leukocytes such as eosino-
Ożarowski and Karpiński
Effect of flavonoids on inflammatory mediators
Refs.
/ other factors / functions
- inhibiting the ox-LDL-induced overexpression of IL-1β, IL-6,
TNF- α, E-selectin, ICAM1 and VCAM1 after 20 µM of vitexin
- inhibiting the production of ROS and MDA, and by promoting
[179]
the expression of SOD
- increasing the expression of p-AMPK and decreasing the expres-
sion of p-mTOR
- max. inhibitory effects on TNF-α level (26.7%) and IL-1β level
(59.1%) at the concentration of 100 μg/ml of vitexin
- increasing the IL-10 level by 22.8% at 100 μg/ml of vitexin [180]
- decreasing the NO level by 95.1% at 100 μg/ml of vitexin
- max. inhibitory effects on PGE2 by 75.2% at 25 μg/ml of vitexin
- decreasing the IL-1β-induced production of PGE2 and NO (152.6
pg/mL and 72.8 Μmol/L, respectively) after 100 μM of vitexin
[183]
- inhibiting the IL-1β-induced expressions of IL-6, TNF-α,
MMP-1, MMP-3, MMP-13 after 10 μM and 50 μM of vitexin
phils, neutrophils, mononuclear cells, and inhibited the release of
several cytokines [186].
7. ANTIOXIDANT POTENTIAL OF PASSIFLORA SPECIES
It is well known that inflammatory processes with increasing
levels of cytokines such as IL-6, TNF-α are strictly related to the
oxidative stress because it was revealed that the higher production
of reactive oxygen species (ROS) like superoxide anion leads to the
activation of the inflammatory pathway NF-kB and overproduction
of pro-inflammatory cytokines [97, 188, 189]. Many studies re-
vealed a relationship between inflammatory pathogenesis and oxi-
dative stress, and it was shown that the overproduction of ROS
could play a well-known role in the induction and acceleration of
inflammatory processes [189]. Recently, strong evidence showed
that oxidative stress and ROS may occur during many inflammatory
diseases leading to injuries of macromolecules (proteins; lipids;
DNA; RNA), cells and tissues, i.e. during inflammatory bowel dis-
eases [97], type 2 diabetes [7], cardiovascular diseases [189],
neuro-inflammation occurring in Alzheimer diseases [190], and
Parkinson’s diseases [191] and many others.
Recently, it was observed that extracts containing flavonoids
from species of Passiflora exerted not only interesting anti-
inflammatory properties but also valuable antioxidant activity, i.e.
P. subpeltata [41], P. edulis [61, 75, 89, 91, 92, 97, 192-194], P.
alata [49, 73, 75], P. caerulea [49], P. incarnata [49, 56], P.
leschenaultii [95], P. mucronata [99], P. maliformis [91], P. glan-
dulosa [195], P. ligularis [48], P. foetida [20].
There is strong scientific evidence that Passiflora extracts are
healthy food ingredients with antioxidant properties. Many tests for
an estimation of this activity, using well-established in vitro meth-
ods, mainly DPPH (2,2-diphenyl-1-picrylhydrazyl) radical assay
and ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)
radical cation, ferric reducing/antioxidant power assay (FRAP), and
key enzymes for inflammation, were carried out. Saravanan et al.,
[51] showed that the fresh pulp of fruits of P. subpeltata containing
polyphenolic compounds exerted scavenging activities using DPPH
with the value of IC50 = 5.667 μg/mL and ABTS+• (6794.96 μM
Trolox equivalent/g sample). Another study by Saravanan et al.,
[48] revealed that the acetone extract from the leaves of P. subpel-
tata exhibited the highest DPPH (IC50 of 27.9 μg/ml) and ABTS
(10108.91 μM Trolox equivalent/g extract) scavenging activities.
The extract from leaves was more effective in comparison with an
extract from the pulp of fruits. These antioxidant activities may
justify anti-inflammatory activity observed in the animal model
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory
studies carried out by authors. Furthermore, the fractionated extract
from the leaves of P. leschenaultii also showed antiradical capacity
using the standard test in vitro, and it was observed that the pres-
ence of phenolics, flavonoids, and tannins in extracts was responsi-
ble for this effects. Acetone extract caused maximum radical scav-
enging activity using DPPH (IC50 = 29.14 μg/mL), ABTS
(10509.69 μM TEAC/g extract), and FRAP (1511.74 mM Fe (II)
E/g extract) in comparison with petroleum ether, chloroform,
methanol, and hot water extracts [95]. The aqueous extract of P.
alata was investigated in an animal model of diabetes and analyses
of results of the antioxidant study revealed that P. alata reduced the
stable radical DPPH (56%), ABTS (3439 μM Trolox/g) and the
value of FRAP was 226.9 μM FeSO3/g), ORAC (302.1 μM
Trolox/g). Additionally, it was observed that P. alata administered
to animals caused a higher level of glutathione, which is the en-
dogenous enzyme responsible for the elimination of free radicals
[73]. An evaluation of the antioxidant value carried out for hydro-
alcoholic extract from the leaves of P. mucronata [99] using DPPH
radicals showed a value EC50=96.05 μg/ml for extract in compari-
son with EC50=14.61 μg/ml for a fraction of ethyl acetate. Cazarin
et al., [97] observed that the aqueous extract of P. edulis exerted
antioxidant activity in the serum of animals with colitis. Detailed
results showed that the extract decreased peroxidation of lipids in
the colon, liver, and serum. However, it did not change the level of
reduced glutathione, activities of glutathione peroxidase and glu-
tathione reductase. It may be concluded that extract caused a bene-
ficial antioxidant effect together with decreasing the expression and
level of pro-inflammatory cytokines. In another in vivo study, Pan-
elli et al., [61] exerted that the extract from the bark of Passiflora
edulis with carotenoids and phenolics was effective in improving
antioxidant capacity in the plasma, kidney, liver and adipose tis-
sues. Lipid peroxidation and the level of malondialdehyde were
also reduced. Other analyses showed that ethanol extracts from the
fruit peel of P. edulis administered to rats with diabetes increased
the activity of superoxide dismutase and catalase and decreased the
level of thiobarbituric acid reactive species in the heart, liver, and
kidneys of animals [93]. Zeraik et al., [75] studied methanol ex-
tracts from the fruits of Passiflora edulis, pulp of Passiflora alata,
and rinds (epicarp and mesocarp) of P. edulis, using key enzymes in
inflammatory processes like myeloperoxidase of polymorphonu-
clear neutrophils. Extracts of the rind of P. edulis possessed strong
antioxidant activity in vitro because this extract showed a 50%
inhibitory effect at 0.1 mg mL-1 in comparison with the inhibitory
activity of pulp extracts of P. edulis and P. alata (IC50 = 1.0 mg
mL-1). However, isoorientin present in P. edulis, inhibited the activ-
ity of myeloperoxidase with the value of IC50 = 4 µg mL -1.
CONCLUSION
In conclusion, this review provides evidence that various ex-
tracts and flavonoids present in species of Passiflora spp., possess
anti-inflammatory and anti-oxidative activity in many models of
diseases tested in vitro. Moreover, the current studies indicate that
these active substances obtained from various parts of Passiflora
spp.and using various methods of extraction may differ in chemical
composition, however, all tested substances showed pharmacologi-
cal activity. In this context, based on the above presented results of
many studies, it should be concluded that the extracts and flavon-
oids from Passiflora can be a valuable source of anti-inflammatory
and anti-oxidative medications for prevention and treatment of
many diseases which occur with inflammation. However, these
challenges in drug discovery from Passiflora should be tested in
clinical trials.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING

None.

Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2599
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or other-
wise.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Zhong J, Shi G, Eds. Regulation of inflammation in chronic disea-
se. Lausanne: Frontiers Media. 2019. doi: 10.3389/978-2-88945-
916-2
[2] Leyva-López N, Gutierrez-Grijalva EP, Ambriz-Perez DL, Heredia
JB. Flavonoids as cytokine modulators: a possible therapy for
inflammation-related diseases. Int J Mol Sci 2016; 17(6): 921.
[3] Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation:
inflammatory bowel disease and colitis-associated colon cancer.
Front Immun 2012; 3: 107.
[4] Luan YY, Yao YM. The clinical significance and potential role of
C-reactive protein in chronic inflammatory and neurodegenerative
diseases. Front Immunol 2018; 9: 1302.
[5] Sommer C, Leinders M, Üçeyler N. Inflammation in the pathophy-
siology of neuropathic pain. Pain 2018; 159(3): 595-602.
[6] Tasneem S, Liu B, Li B, Choudhary MI, Wang W. Molecular
pharmacology of inflammation: Medicinal plants as anti-
inflammatory agents. Pharmacol Res 2019; 139: 126-40.
[7] de Candia P, Prattichizzo F, Garavelli S, et al. Type 2 diabetes:
How much of an autoimmune disease? Front Endocrinol 2019; 10:
451.
[8] Klein A, Eliakim R. Nonsteroidal anti-inflammatory drugs and
inflammatory bowel disease. Pharmaceuticals 2010; 3: 1084-92.
[9] Vonkeman HE, van de Laar MA. Nonsteroidal anti-inflammatory
drugs: adverse effects and their prevention. Semin Arthritis Rheum
2010; 39(4): 294-312.
[10] Ordas I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ.
Ulcerative colitis. Lancet 2012; 380(9853): 1606-19.
[11] Calabresi E, Petrelli F, Bonifacio AF, Puxeddu I, Alunno A. One
year in review 2018: pathogenesis of rheumatoid arthritis. Clin Exp
Rheumatol 2018; 36(2): 175-84.
[12] Baldassari LE, Fox RJ. Therapeutic advances and challenges in the
treatment of progressive multiple sclerosis. Drugs. 2018; 78(15):
1549-66.
[13] Zadeh AR, Ghadimi K, Ataei A, et al. Mechanism and adverse
effects of multiple sclerosis drugs: a review article (Part 2). Int J
Physiol Pathophysiol Pharmacol 2019; 11(4): 105-14.
[14] Borg-Bartolo SP, Boyapati RK, Satsangi J, Kalla R. Precision
medicine in inflammatory bowel disease: concept, progress and
challenges. F1000Res 2020; 9: F1000 Faculty Rev-54.
[15] Azab A, Nassar A, Azab AN. Anti-inflammatory activity of natural
products. Molecules 2016; 21(10): 1321.
[16] Shal B, Ding W, Ali H, Kim YS, Khan S. Anti-neuroinflammatory
potential of natural products in attenuation of Alzheimer’s disease.
Front Pharmacol 2018; 9: 548.
[17] Ginwala R, Bhavsar R, Chigbu DGI, Jain P, Khan ZK. Potential
role of flavonoids in treating chronic inflammatory diseases with a
special focus on the anti-inflammatory activity of apigenin. Antio-
xidants 2019; 8: 35.
[18] Miroddi M, Calapai G, Navarra M, Minciullo PL, Gangemi S.
Passiflora incarnata L.: Ethnopharmacology,clinical application,
safety and evaluation of clinical trials. J Ethnopharmacol 2013;
150: 791-804.
[19] Cerqueira-Silva CBM, Jesus ON, Santos ESL, Corrêa RX, Souza
AP. Genetic breeding and diversity of the genus Passiflora: pro-
gress and perspectives in molecular and genetic studies. Int J Mol
Sci 2014; 15: 14122-52.
[20] Song Y, Wei XQ, Li MY, et al. Nutritional composition and antio-
xidant properties of the fruits of a Chinese wild Passiflora foetida.
Molecules 2018; 23: 459.
[21] Ożarowski M, Thiem B. Progress in micropropagation of Passiflo-
ra spp. to produce medicinal plants: a mini-review. Rev Brasil
Farmacog 2013; 23(6): 937-47.
2600 Current Pharmaceutical Design, 2021, Vol. 27, No. 22
[22] The Plant List. Passifloraceae. Available from:
http://www.theplantlist.org/1.1/browse/A/Passifloraceae/
[23] Krosnick SE, Porter-Utley KE, Macdougal JM, Jorgensen PM,
Mcdade LA. New insights into the evolution of Passiflora subge-
nus Decaloba (Passifloraceae): phylogenetic relationships and mor-
phological synapomorphies. System Bot 2013; 38(3): 692-713.
[24] Silva EO, Milward-de-Azevedo MA, Sampaio Sá NA, de Sousa
DA, da Conceição GM. New records of Passiflora L. (Passiflora-
ceae) species from Maranhão state and northeastern Brazil. Check
List 2018; 14(2): 347-52.
[25] EMA: Europen Medicine Agency. Assessment report on Passiflora
incarnata L., herba. Committee for Herbal Medicinal Products
(HMPC). EMA/HMPC/669738/2013. 25 March 2014.
[26] Müller SD, Vasconcelos SB, Coelho M, Biavatti MW. LC and UV
determination of flavonoids from Passiflora alata medicinal
extracts and leaves. J Pharm Biomed Anal 2005; 37(2): 399-403.
[27] Thokchom R, Mandal G. Production Preference and importance of
Passion Fruit (Passiflora edulis): a review. J Agricult Engin Food
Technol 2017; 4(1): 27-30.
[28] Faleiro FG, Junqueira NTV, Junghans TG, de Jesus ON, Miranda
D, Otoni WC. Advances in passion fruit (Passiflora spp.) propaga-
tion. Rev Bras Frutic Jaboticabal 2019; 41(2): 1-17.
[29] Correa RCG, Peralta RM, Haminiuk CWI, Maciel GM, Bracht A,
Ferreira IC. The past decade findings related with nutritional com-
position, bioactive molecules and biotechnological applications of
Passiflora spp. (passion fruit). Trends Food Sci Technol 2016; 58:
79-95.
[30] Industry Report. Passion flower extracts market size, share &
trends analysis report by product (organic, conventional), by appli-
cation (pharmaceutical, nutraceutical, personal care, food and beve-
rages), and segment forecasts, 2019-2025. Report ID: GVR-3-
68038-386-7. https://www.grandviewresearch.com/industry-
analysis/passion-flower-extracts-market
[31] Pan SY, Zhou SF, Gao SH, et al. New perspectives on how to
discover drugs from herbal medicines: CAM’s outstanding contri-
bution to modern therapeutics. Evid-Based Complem Altern Med
2013; 2013: ID 627375.
[32] Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, et al. Disco-
very and resupply of pharmacologically active plant-derived natu-
ral products: A review. Biotechnol Adv 2015; 33(8): 1582-614.
[33] Katz L, Baltz RH. Natural product discovery: past, present, and
future. J Ind Microbiol Biotechnol 2016; 43: 155-76.
[34] Kole C, Ed. Wild crop relatives: genomic and breeding resources,
tropical and subtropical fruits. Springer-Verlag Berlin Heidelberg,
2011.
[35] Gaedcke F, Steinhoff B. Herbal medicinal products. Scientific and
regulatory basis for development, quality assurance and marketing
authorization. CRC Press, Washington D.C. 2000.
[36] Domínguez-Rodríguez G, Marina ML, Plaza M. Strategies for the
extraction and analysis of non-extractable polyphenols from plants.
J Chromatogr A 2017; 1514: 1-15.
[37] De Santana FC, de Oliveira Torres LR, Shinagawa FB, et al. Opti-
mization of the antioxidant polyphenolic compounds extraction of
yellow passion fruit seeds (Passiflora edulis Sims) by response sur-
face methodology. J Food Sci Technol. 2017; 54: 3552-61.
[38] Echeverry SM, Medina HI, Costa GM, Aragón DM. Optimization
of flavonoid extraction from Passiflora quadrangularis leaves with
sedative activity and evaluation of its stability under stress condi-
tions. Rev Brasil Farmacogn 2018; 28: 610-7.
[39] Dhawan K, Dhawan S, Sharma A. Passiflora: a review update. J
Ethnopharmacol 2004; 94(1): 1-23.
[40] Da Silva J, Cazarin C, Colomeu T, et al. Antioxidant activity of
aqueous extract of passion fruit (Passiflora edulis) leaves: in vitro
and in vivo study. Food Res Int 2013; 53: 882-90.
[41] Shanmugam S, Gomes IA, Denadai M, et al. UHPLC-QqQ-
MS/MS identification, quantification of polyphenols from Passiflo-
ra subpeltata fruit pulp and determination of nutritional, antioxi-
dant, α-amylase and α-glucosidase key enzymes inhibition proper-
ties. Food Res Int 2018; 108: 611-20.
[42] Beninca JP, Montanher AB, Zucolotto SM, Schenkel EP, Frode TS.
Evaluation of the anti-inflammatory efficacy of Passiflora edulis.
Food Chem 2007; 104: 1097-105.
Ożarowski and Karpiński
[43] Montanher AB, Zucolotto SM, Schenkel EP, Frode TS. Evidence
of anti-inflammatory effects of Passiflora edulis in an inflamma-
tion model. J Ethnopharmacol 2007; 109(2): 281-8.
[44] Vargas AJ, Geremias DS, Provensi G, et al. Passiflora alata and
Passiflora edulis spray-dried aqueous extracts inhibit inflammation
in mouse model of pleurisy. Fitoterapia 2007; 78(2): 112-119.
[45] Sasikala V, Saravanan S, Parimelazhagan T. Analgesic and anti-
inflammatory activities of Passiflora foetida L. Asian Pac J Trop
Med 2011; 4(8): 600-3.
[46] Zucolotto SM, Fagundes C, Reginatto FH, et al. Analysis of C-
glycosyl flavonoids from South American Passiflora species by
HPLC-DAD and HPLC-MS. Phytochem Anal 2011; 23: 232-9.
[47] Xu F, Wang C, Yang L, et al. C-dideoxyhexosyl flavones from the
stems and leaves of Passiflora edulis Sims. Food Chem 2013; 136:
94-9.
[48] Shanmugam S, Arunachalam K, Parimelazhagan T. Antioxidant,
analgesic, anti-inflammatory and antipyretic effectsof polyphenols
from Passiflora subpeltata leaves- A promisingspecies of Passiflo-
ra. Ind. Crops Prod. 2014; 54: 272-280.
[49] Ożarowski M, Piasecka A, Paszel-Jaworska A, et al. Comparison
of bioactive compounds content in leaf extracts of Passiflora
incarnata, P. caerulea and P. alata and in vitro cytotoxic potential
on leukemia cell lines. Rev Brasil Farmacogn 2018; 28: 179-91.
[50] Ożarowski M, Pietrowiak A, Gryszczyńska A, et al. Comparison of
in vitro antioxidative activities of crude methanolic extracts of
three species of Passiflora from greenhouse using DPPH, ABTS
and FRAP methods. Herba Pol 2019; 65(3):10-21.
[51] Shanmugam S, Thangaraj P, Trindade GG, et al. Protective effects
of flavonoid composition rich P. subpeltata Ortega. on indometha-
cin induced experimental ulcerative colitis in rat models of
inflammatory bowel diseases. J Ethnopharmacol 2020; 248:
112350.
[52] Ożarowski M, Mikołajczak P, Kujawski R, et al. Pharmacological
effect of quercetin in hypertension and its potential application in
pregnancy-induced hypertension. Review of in vitro, in vivo and
clinical studies. Evid-Based Complem Altern Med 2018; 2018:
7421489.
[53] Cazarin CB, da Silva JK, Colomeu TC, et al. Passiflora edulis peel
intake and ulcerative colitis: approaches for prevention and treat-
ment. Exp Biol Med (Maywood) 2014; 239(5): 542-51.
[54] Cazarin CB, Rodriguez-Nogales A, Algieri F, et al. Intestinal anti-
inflammatory effects of Passiflora edulis peel in the dextran
sodium sulphate model of mouse colitis. J Funct Foods 2016; 26:
565-76.
[55] Carmona-Hernandez JC, Taborda-Ocampo G, Valdez JC, Bolling
BW, González-Correa CH. Polyphenol extracts from three Colom-
bian Passifloras (passion fruits) prevent inflammation-induced bar-
rier dysfunction of Caco-2 cells. Molecules 2019; 24(24): e4614.
[56] Masteikowa R, Bernatoniene J, Bernatoniene R, Velziene S. Anti-
radical activities of the extract of Passiflora incarnata. Acta Pol
Pharmaceut Drug Res 2008; 65(5): 577-83.
[57] Brown E, Hurd NS, McCall S, Ceremuga TE. Evaluation of the
anxiolytic effects of chrysin, a Passiflora incarnata extract, in the
laboratory rat. AANA J 2007; 75(5): 333-7.
[58] Ingale AG, Hivrale AU. Pharmacological studies of Passiflora sp.
and their bioactive compounds. Afr J Plant Sci 2010; 4(10): 417-
26.
[59] Gavasheli N, Moniavo I, Eristavi L. Flavonoids from Passiflora
incarnata. Chem Nat Compounds 1974; 10(1): 99.
[60] Guseinov MD, Bobkova NV, Svistunov AA, et al. Flavonoids in
Passiflora incarnata L. dry extract of Russian origin. Pharmacog J
2019; 11(5): 1143-7.
[61] Panelli MF, Pierine DT, de Souza SLB, Ferron AJT, Garcia JL, dos
Santos KC. Bark of Passiflora edulis treatment stimulates antioxi-
dant capacity, and reduces dyslipidemia and body fat in db/db
mice. Antioxidants 2018; 7: 120.
[62] Chen CY, Peng WH, Tsai KD, Hsu SL. Luteolin suppresses
inflammation-associated gene expression by blocking NF-kappaB
and AP-1 activation pathway in mouse alveolar macrophages. Life
Sci 2007; 81(23-24): 1602-14.
[63] Park CM, Song YS. Luteolin and luteolin-7-O-glucoside inhibit
lipopolysaccharide-induced inflammatory responses through modu-
lation of NF-κB/AP-1/PI3K-Akt signaling cascades in RAW 264.7
cells. Nutr Res Pract 2013; 7(6): 423-9.
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory
[64] Jia Z, Nallasamy P, Liu D, et al. Luteolin protects against vascular
inflammation in mice and TNF-alpha-induced monocyte adhesion
to endothelial cells via suppressing IΚBα/NF-κB signaling path-
way. J Nutr Biochem 2015; 26(3): 293-302.
[65] Aziz N, Kim MY, Cho JY. Anti-inflammatory effects of luteolin: A
review of in vitro, in vivo, and in silico studies. J Ethnopharmacol
2018; 225: 342-58.
[66] Park CM, Song YS. Luteolin and luteolin-7-O-glucoside protect
against acute liver injury through regulation of inflammatory
mediators and antioxidative enzymes in GalN/LPS-induced hepati-
tic ICR mice. Nutr Res Pract 2019; 13(6): 473-9.
[67] Lodhi S, Vadnere GP, Patil KD, Patil TP. Protective effects of
luteolin on injury induced inflammation through reduction of tissue
uric acid and pro-inflammatory cytokines in rats. J Tradit Complem
Med 2020; 10(1): 60-9.
[68] Zanoli P, Avallone R, Baraldi M. Behavioral characterisation of the
flavonoids apigenin and chrysin. Fitoterapia 2000; 71-81: S117-23.
[69] Gazola AC, Costa GM, Castellanos L, et al. Involvement of
GABAergic pathway in the sedative activity of apigenin, the main
flavonoid from Passiflora quadrangularis pericarp. Rev Brasil
Farmacogn 2015; 25: 158-63.
[70] Foudah AI, Alam P, Kamal YT, et al. Development and validation
of a high-performance thin-layer chromatographic method for the
quantitative analysis of vitexin in Passiflora foetida herbal formu-
lations. Saudi Pharmac J 2019; 27: 1157-63.
[71] Pereira CA, Yariwake JH, Lanças FM, Wauters JN, Tits M, Ange-
not L. A HPTLC densitometric determination of flavonoids from
Passiflora alata, P. edulis, P. incarnata and P. caerulea and com-
parison with HPLC method. Phytochem Anal 2004; 15(4): 241-8.
[72] Anzoise ML, Marrassini C, Bach H, Gorzalczany S. Beneficial
properties of Passiflora caerulea on experimental colitis. J Ethno-
pharmacol 2016; 194: 137-45.
[73] Colomeu TC, Figueiredo D, Cazarin CB, et al. Antioxidant and
anti-diabetic potential of Passiflora alata Curtis aqueous leaves
extract in type 1 diabetes mellitus (NOD-mice). Int Immunophar-
macol 2014; 18: 106-15.
[74] Lin CM, Huang ST, Liang YC, et al. Isovitexin suppresses lipo-
polysaccharide-mediated inducible nitric oxide synthase through
inhibition of NF-kappa B in mouse macrophages. Planta Med 2005;
71(8): 748-53.
[75] Zeraik ML, Serteyn D, Deby-Dupont G, et al. Evaluation of the
antioxidant activity of passion fruit (Passiflora edulis and Passiflo-
ra alata) extracts on stimulated neutrophils and myeloperoxidase
activity assays. Food Chem 2011; 128(2): 259-65.
[76] Borghi SM, Carvalho TT, Staurengo-Ferrari L, et al. Vitexin inhi-
bits inflammatory pain in mice by targeting TRPV1, oxidative
stress, and cytokines. J Nat Prod 2013; 76(6): 1141-9.
[77] Bahareh AN, Farid H, Mohtaram A, Marjan NA. Anti-
inflammatory effects of quercetin and vitexin on activated human
peripheral blood neutrophils. J Pharmacopuncture 2017; 20: 127-
31.
[78] Zhang P, Jiao H, Wang C, Lin Y, You S. Chlorogenic acid amelio-
rates colitis and alters colonic microbiota in a mouse model of dex-
tran sulfate sodium-induced colitis. Front Physiol 2019; 10: 325.
[79] Adamczak A, Ożarowski M, Karpiński TM. Antibacterial activity
of some flavonoids and organic acids widely distributed in plants. J
Clin Med 2020; 9(109); 1-17.
[80] Ayres AS, de Araújo LL, Soares TC, et al. Comparative central
effects of the aqueous leaf extract of two populations of Passiflora
edulis. Rev Brasil Farmacogn 2015; 25: 499-505.
[81] Jawna-Zboińska K, Blecharz-Klin K, Joniec-Maciejak I, et al.
Passiflora incarnata L. improves spatial memory, reduces stress,
and affects neurotransmission in rats. Phytother Res 2016; 30(5):
781-9.
[82] Anusooriya P, Malarvizhi D, Gopalakrishnan VK, Devaki K.
Antioxidant and antidiabetic effect of aqueous fruit extract of Pas-
siflora ligularis Juss. on streptozotocin induced diabetic rats. Int
Sch Res Notices 2014; 2014: 130342.
[83] Salles BCC, da Silva MA, Taniguthi L, et al. Passiflora edulis leaf
extract: evidence of antidiabetic and antiplatelet effects in rats. Biol
Pharm Bull 2020; 43(1): 169-74.
[84] Aman U, Subhan F, Shahid M, et al. Passiflora incarnata attenua-
tion of neuropathic allodynia and vulvodynia apropos GABA-ergic
Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2601
and opioidergic antinociceptive and behavioural mechanisms.
BMC Complement Altern Med 2016; 16: 77.
[85] de Lavor ÉM, Leal AEBP, Fernandes AWC, et al. Ethanolic extract
of the aerial parts of Passiflora cincinnata Mast. (Passifloraceae)
reduces nociceptive and inflammatory events in mice. Phytomedi-
cine 2018; 47: 58-68.
[86] Wasicky A, Hernandes LS, Vetore-Neto A, et al. Evaluation of
gastroprotective activity of Passiflora alata. Rev Bras Farmacogn
2015; 25(4): 407-12.
[87] Nerdy N, Ritarwan K. Hepatoprotective activity and nephroprotec-
tive activity of peel extract from three varieties of the passion fruit
(Passiflora sp.) in the Albino rat. Maced J Med Sci 2019; 7(4):
536-42.
[88] Tal Y, Anavi S, Reisman M, Samach A, Tirosh O, Troen AM. The
neuroprotective properties of a novel variety of passion fruit. J
Funct Foods 2016; 23: 359-69.
[89] Doungue HT, Kengne AP, Kuate D. Neuroprotective effect and
antioxidant activity of Passiflora edulis fruit flavonoid fraction,
aqueous extract, and juice in aluminum chloride-induced Alzhei-
mer’s disease rats. Nutrire 2018; 43: 23.
[90] Calderon A, Salas J, Dapello G, et al. Assessment of antibacterial
and antifungal properties and in vivo cytotoxicity of Peruvian Pas-
siflora mollisima. J Contemp Dent Pract 2019; 20(2): 145-51.
[91] Ramaiya SD, Bujang JS, Zakaria MH. Assessment of total pheno-
lic, antioxidant, and antibacterial activities of Passiflora species.
Sci World J 2014; 2014: ID 167309.
[92] da Silva JK, Cazarin CBB, Batista AG, Marostica M. Effects of
passion fruit (Passiflora edulis) byproduct intake in antioxidant sta-
tus of Wistar rats tissues. LWT Food Sci Technol 2014; 59: 1213-
9.
[93] Kandandapani S, Balaraman AK, Ahamed HN. Extracts of passion
fruit peel and seed of Passiflora edulis (Passifloraceae) attenuate
oxidative stress in diabetic rats. Chinese J Nat Med 2015; 13(9):
680-6.
[94] García-Ruiz A, Girones-Vilaplana A, León P, et al. Banana passion
fruit (Passiflora mollissima (Kunth) L.H. Bailey): microencapsula-
tion, phytochemical composition and antioxidant capacity. Molecu-
les 2017; 22: 85.
[95] Shanmugam S, Murugaiyan I, Lima BS, et al. HPLC-DAD-MS
identification of polyphenols from Passiflora leschenaultii and
determination of their antioxidant, analgesic, anti-inflammatory and
antipyretic properties. Arab J Chem 2019; 12: 760-71.
[96] Aguillón-Osma J, Luzardo-Ocampo I, Cuellar-Nuñez ML, Maldo-
nado-Celis ME, Loango-Chamorro N, Campos-Vega R. Impact of
in vitro gastrointestinal digestion on the bioaccessibility and antio-
xidant capacity of bioactive compounds from Passion fruit (Passi-
flora edulis) leaves and juice extracts. J Food Biochem 2019;
43(7): e12879.
[97] Cazarin CB, da Silva JK, Colomeu TC, et al. Intake of Passiflora
edulis leaf extract improves antioxidant and anti-inflammatory sta-
tus in rats with 2,4,6-trinitrobenzenesulphonic acid induced colitis.
J Funct Foods 2015; 17: 575-86.
[98] Figueiredo D, Colomeu TC, Schumacher NSG, et al. Aqueous leaf
extract of Passiflora alata Curtis promotes antioxidant andanti-
inflammatory effects and consequently preservation of NOD mice-
beta cells (non-obese diabetic). Int Immunopharmacol 2016; 35:
127-36.
[99] de Araujo MH, da Silva IC, de Oliveira PF, et al. Biological activi-
ties and phytochemical profile of Passiflora mucronata from the
Brazilian resting. Rev Bras Farmacogn 2017; 27: 702-10.
[100] Lima GC, Vuolo MM, Batista AG, Dragano NRV, Solon C,
Marostica MR Jr. Passifloraedulis peel intake improves insulin
sensitivity, increasing incretins and hypothalamic satietogenic neu-
ropeptide in rats on a high-fat diet. Nutrition 2016; 32: 863-70.
[101] Aslanargun P, Cuvas O, Dikmen B, Aslan E, Yuksel MU. Passiflo-
ra incarnata Linneaus as an anxiolytic before spinal anaesthesia. J
Anesth 2012; 26: 39-44.
[102] Dantas LP, de Oliveira-Ribeiro A, de Almeida-Souza LM, Groppo
FC. Effects of Passiflora incarnata and midazolam for control of
anxiety in patients undergoing dental extraction. Med Oral Patol
Oral Cir Bucal 2017; 22(1): e95-101.
[103] Rokhtabnak F, Ghodraty MR, Kholdebarin A, et al. Comparing the
effect of preoperative administration of melatonin and Passiflora
2602 Current Pharmaceutical Design, 2021, Vol. 27, No. 22
incarnata on postoperative cognitive disorders in adult patients
undergoing elective surgery. Anesth Pain Med 2016; 7(1): e41238.
[104] Lee J, Jung HY, Lee SI, Choi JH, Kim SG. Effects of Passiflora
incarnata Linnaeus on polysomnographic sleep parameters in sub-
jects with insomnia disorder: a double-blind randomized placebo-
controlled study. Int Clin Psychopharmacol 2020; 35(1): 29-35.
[105] Ngan A, Conduit R. A double-blind, placebo-controlled investiga-
tion of the effects of Passiflora incarnata (passionflower) herbal
tea on subjective sleep quality. Phytother Res 2011; 25(8): 1153-9.
[106] Gibbert J, Kreimendahl F, Lebert J, Rychlik R, Trompetter I.
Improvement of stress resistance and quality of life of adults with
nervous restlessness after treatment with a passion flower dry
extract. Complement Med Res 2017; 24: 83-9.
[107] da Silva JA, Costa MJC, Gonçalves MCR, Braga JEF, Lima CM,
Pordeus LCM. Effects of the single supplementation and multiple
doses of Passiflora incarnata L. on human anxiety: aclinical trial,
double-blind, placebo-controlled, randomized. Int Arch Med 2017;
10(6):1-9.
[108] Farid R, Rezaieyazdi Z, Mirfeizi Z, et al. Oral intake of purple
passion fruit peel extract reduces pain and stiffness and improves
physical function in adult patients with knee osteoarthritis. Nutr
Res 2010;30(9): 601-6.
[109] de Queiroz Mdo S, Janebro DI, da Cunha MA, et al. Effect of the
yellow passion fruit peel flour (Passiflora edulis f. flavicarpa deg.)
in insulin sensitivity in type 2 diabetes mellitus patients. Nutr J
2012; 11: 89.
[110] Market Research Report: Passion flower extracts market size &
trends, Industry Report, 2019-2025. Grand View Research, Inc.
San Francisco, United States. Available from:
https://www.grandviewresearch.com/industry-analysis/passion-
flower-extracts-market
[111] Gil-Cardoso K, Ginés I, Pinent M, Ardévol A, Blay M, Terra X.
Effects of flavonoids on intestinal inflammation, barrier integrity
and changes in gut microbiota during diet-induced obesity. Nutr
Res Rev 2016; 29(2): 234-48.
[112] Costa SL, Silva VD, Dos Santos-Souza C, et al. Impact of plant-
derived flavonoids on neurodegenerative diseases. Neurotox Res
2016; 30(1): 41-52.
[113] Maher P. The potential of flavonoids for the treatment of neurode-
generative diseases. Int J Mol Sci 2019; 20: 3056.
[114] Ayaz M, Sadiq A, Junaid M, et al. Flavonoids as prospective neu-
roprotectants and their therapeutic propensity in aging associated
neurological disorders. Front Aging Neurosci 2019; 11: 155.
[115] Di Paolo M, Papi L, Gori F, Turillazzi E. Natural products in neu-
rodegenerative diseases: a great promise but an ethical challenge.
Int J Mol Sci 2019; 20: 5170.
[116] Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease.
Annu Rev Immunol 2010; 28: 573-621.
[117] Dotan I, Allez M, Danese S, Keir M, Tole S, McBride J. The role
of integrins in the pathogenesis of inflammatory bowel disease:
Approved and investigational anti‐integrin therapies. Med Res Res
2020; 40(1): 245-62.
[118] Jang SE, Jeong JJ, Kim JK, Han MJ, Kim DH. Simultaneous ame-
lioratation of colitis and liver injury in mice by Bifdobacterium
longum LC67 and Lactobacillus plantarum LC27. Sci Rep 2018; 8:
7500.
[119] Singh AK, Cabral C, Kumar R, et al. Beneficial effects of dietary
polyphenols on gut microbiota and strategies to improve delivery
efficiency. Nutrients 2019; 11: 2216.
[120] Vargas-Robles H, Castro-Ochoa KF, Citalán-Madrid AF, Schnoor
M. Beneficial effects of nutritional supplements on intestinal epi-
thelial barrier functions in experimental colitis models in vivo.
World J Gastroenterol 2019; 25(30): 4181-98.
[121] Manthey JA. Biological properties of flavonoids pertaining to
inflammation. Microcirculation 2000; 7(6 Pt 2): S29-34.
[122] Lee S, Jung SH, Lee YS, et al. Antiinflammatory activity of hype-
rin from Acanthopanax chiisanensis roots. Arch Pharm Res 2004;
27(6): 628-32.
[123] Hämäläinen M, Nieminen R, Asmawi MZ, Vuorela P, Vapaatalo
H, Moilanen E. Effects of flavonoids on prostaglandin E2 produc-
tion and on COX-2 and mPGES-1 expressions in activated macro-
phages. Planta Med 2011; 77(13): 1504-11.
[124] Chunzhi G, Zunfeng L, Chengwei Q, Xiangmei B, Jingui Y. Hype-
rin protects against LPS-induced acute kidney injury by inhibiting
Ożarowski and Karpiński
TLR4 and NLRP3 signaling pathways. Oncotarget 2016; 7(50):
82602-8.
[125] Chao CS, Tsai CS, Chang YP, Chen JM, Chin HK, Yang SC.
Hyperin inhibits nuclear factor kappa B and activates nuclear factor
E2-related factor-2 signaling pathways in cisplatin-induced acute
kidney injury in mice. Int Immunopharmacol 2016; 40: 517-23.
[126] Figueiredo DA, Pordeus LC, Paulo LL, et al. Effects of bark flour
of Passiflora edulis on food intake, body weight and behavioral
response of rats. Rev Brasil Farmacogn 2016; 26: 595-600.
[127] Sergent T, Piront N, Meurice J, Toussaint O, Schneider Y-J. Anti-
inflammatory effects of dietary phenolic compounds in an in vitro
model of inflamed human intestinal epithelium. Chem-Biol Interact
2010; 188: 659-67.
[128] Martin DA, Bolling BW. A review of the efficacy of dietary poly-
phenols in experimental models of inflammatory bowel diseases.
Food Funct 2015; 6(6): 1773-86.
[129] Kaulmann A, Bohn T. Bioactivity of polyphenols: preventive and
adjuvant strategies toward reducing inflammatory bowel diseases-
promises, perspectives, and pitfalls. Oxid Med Cell Longev 2016;
2016: 9346470.
[130] Santino A, Scarano A, De Santis S, De Benedictis M, Giovinazzo
G, Chieppa M. Gut microbiota modulation and anti-inflammatory
properties of dietary polyphenols in IBD: new and consolidated
perspectives. Curr Pharm Des 2017; 23(16): 2344-51.
[131] Nunes S, Danesi F, Del Rio D, Silva P. Resveratrol and inflamma-
tory bowel disease: the evidence so far. Nutr Res Rev 2018; 31(1):
85-97.
[132] Valdez JC, Bolling BW. Anthocyanins and intestinal barrier func-
tion: A review. JFB 2019; 31: 18-30.
[133] Grotewold E. The science of flavonoids. Springer Science + Busi-
ness Media, LLC. New York, 2008.
[134] Brodowska K. Natural flavonoids: classification, potential role, and
application of flavonoid analogues. Eur J Biol Res 2017; 7(2): 108-
23.
[135] Lee HN, Shin SA, Choo GS, et al. Anti-inflammatory effect of
quercetin and galangin in LPS-stimulated RAW264.7 macrophages
and DNCB-induced atopic dermatitis animal models. Int J Mol
Med 2018; 41(2): 888-98.
[136] Sanchez M, Lodi F, Vera R, et al. Quercetin and isorhamnetin
prevent endothelial dysfunction, superoxide production, and ove-
rexpression of p47phox induced by angiotensin II in rat aorta. J
Nutr 2007; 137(4): 910-5.
[137] Romero M, Jiménez R, Sánchez M, et al. Quercetin inhibits vascu-
lar superoxide production induced by endothelin-1: role of NADPH
oxidase, uncoupled eNOS and PKC. Atherosclerosis 2009; 202(1):
58-67.
[138] Endale M, Park S-C, Kim S, et al. Quercetin disrupts tyrosine-
phosphorylated phosphatidylinositol 3-kinase and myeloid diffe-
rentiation factor-88 association, and inhibits MAPK/AP-1 and
IKK/NF-B-induced inflammatory mediators production in
RAW264.7 cells. Immunobiology 2013; 218(12): 1452-67.
[139] Yang D, Liu X, Liu M, Chi H, Liu J, Han H. Protective effects of
quercetin and taraxasterol against H2O2-induced human umbilical
vein endothelial cell injury in vitro. Exp Ther Med 2015; 10(4):
1253-60.
[140] Overman A, Chuang C-C, McIntosh M. Quercetin attenuates
inflammation in human macrophages and adipocytes exposed to
macrophage-conditioned media, Int J Obesity 2011; 35(9): 1165-
72.
[141] Lee KM, Hwang MK, Lee DE, Lee KW, Lee HJ. Protective effect
of quercetin against arsenite-induced COX-2 expression by targe-
ting PI3K in rat liver epithelial cells. J Agricult Food Chem 2010;
58(9): 5815-20.
[142] Kim HP, Mani I, Iversen L, Ziboh VA. Effects of naturally-
occurring flavonoids and biflavonoids on epidermal cyclooxygena-
se and lipoxygenase from guinea-pigs. Prostaglandins Leukot
Essent Fatty Acids 1998; 58(1): 17-24.
[143] Li D, Ma J, Wang L, Xin S. Apigenin prevent abdominal aortic
aneurysms formation by inhibiting the NF-κB signaling pathway. J
Cardiovasc Pharmacol 2019. doi: 10.1097/FJC.0000000000000785
[144] Lim H, Hyun PK. Inhibition of mammalian collagenase, matrix
metalloproteinase-1, by naturally-occurring flavonoids. Planta Med
2007; 73(12): 1267-74.
Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory
[145] Woo KJ, Jeong YJ, Park-kwon TK. Chrysin induced apoptosis is
mediated through caspase activation and akt inactivation in U937
leukemia cell. Biochem Biophys Res Commun 2004; 325-334:
1215-22.
[146] Lee BK, Lee WJ, Jung YS. Chrysin attenuates VCAM-1 expression
and monocyte adhesion in lipopolysaccharide-stimulated brain
endothelial cells by preventing NF-κB signaling. Int J Mol Sci
2017; 18(7): e1424.
[147] Chylińska-Wrzos P, Lis-Sochocka M, Jodłowska-Jędrych B. Chry-
sin and its potential antineoplastic effect. Eur J Biol Res 2017; 7(3):
245-54.
[148] Zhao S, Liang M, Wang Y, et al. Chrysin suppresses vascular
endothelial inflammation via inhibiting the NF-κB signaling path-
way. J Cardiovasc Pharmacol Ther 2019: 24(3): 278-87.
[149] Odontuya G, Hoult JR, Houghton PJ. Structure-activity relationship
for anti-inflammatory effect of luteolin and its derived glycosides.
Phytother Res 2005; 19: 782-6.
[150] Yamagata K, Hashiguchi K, Yamamoto H, Tagami M. Dietary
apigenin reduces induction of LOX-1 and expression, leukocyte
adhesion, and acetylated low-density lipoprotein uptake in human
endothelial cells exposed to trimethylamine-n-oxide. J Cardiovasc
Pharmacol 2019; 74(6): 558-565.
[151] Chen P, Huo X, Liu W, Li K, Sun Z, Tian J. Apigenin exhibits anti-
inflammatory effects in LPS-stimulated BV2 microglia through
activating GSK3β/Nrf2 signaling pathway. Immunopharmacol
Immunotoxicol 2020; 42(1): 9-16.
[152] Zhang P, Mak JC, Man RY, Leung SW. Flavonoids reduces lipo-
polysaccharide-induced release of inflammatory mediators in
human bronchial epithelial cells: Structure-activity relationship.
Eur J Pharmacol 2019; 865: 172731.
[153] Patil RH, Babu RL, Naveen Kumar M, et al. Anti-inflammatory
effect of apigenin on LPS-induced pro-inflammatory mediators and
AP-1 factors in human lung epithelial cells. Inflammation 2016;
39(1): 138-147.
[154] Zhang X, Wang G, Gurley EC, Zhou H. Flavonoid apigenin inhi-
bits lipopolysaccharide-induced inflammatory response through
multiple mechanisms in macrophages. PLoS One 2014; 9(9):
e107072.
[155] Makanjuola SBL, Ogundaini AO, Ajonuma LC, Dosunmu A. Api-
genin and apigeninidin isolates from the Sorghum bicolor leaf tar-
gets inflammation via cyclo-oxygenase-2 and prostaglandin-E2
blockade. Int J Rheum Dis 2018; 21(8):1487-1495.
[156] Balez R, Steiner N, Engel M, et al Neuroprotective effects of api-
genin against inflammation, neuronal excitability and apoptosis in
an induced pluripotent stem cell model of Alzheimer's disease. Sci
Rep 2016; 6: 31450.
[157] Pang L, Zou S, Shi Y, Mao Q, Chen Y. Apigenin attenuates
PM2.5-induced airway hyperresponsiveness and inflammation by
down-regulating NF-κB in murine model of asthma. Int J Clin Exp
Pathol 2019; 12(10): 3700-9.
[158] Darabi P, Khazali H, Natanzi MM. Therapeutic potentials of the
natural plant flavonoid apigenin in polycystic ovary syndrome in
rat model: via modulation of pro-inflammatory cytokines and
antioxidant activity. Gynecol Endocrinol 2019; doi:
10.1080/09513590.2019.1706084.
[159] Gentile D, Fornai M, Colucci R, et al. The flavonoid compound
apigenin prevents colonic inflammation and motor dysfunctions
associated with high fat diet-induced obesity. PLoS One 2018;
13(4): e0195502.
[160] Anusha C, Sumathi T, Joseph LD. Protective role of apigenin on
rotenone induced rat model of Parkinson's disease: Suppression of
neuroinflammation and oxidative stress mediated apoptosis. Chem
Biol Interact 2017; 269: 67-79.
[161] Zhou RJ, Ye H, Wang F, Wang JL, Xie ML. Apigenin inhibits d-
galactosamine/LPS-induced liver injury through upregulation of
hepatic Nrf-2 and PPARγ expressions in mice. Biochem Biophys
Res Commun 2017; 493(1): 625-30.
[162] Bougioukas I, Didilis V, Emmert A, et al. Apigenin Rreduces NF-
κB and subsequent cytokine production as protective effect in a
rodent animal model of lung ischemia-reperfusion injury. J Invest
Surg 2018; 31(2): 96-106.
[163] Chang X, He H, Zhu L, et al. Protective effect of apigenin on
Freund's complete adjuvant-induced arthritis in rats via inhibiting
P2X7/NF-κB pathway. Chem Biol Interact 2015; 236: 41-6.
Current Pharmaceutical Design, 2021, Vol. 27, No. 22 2603
[164] Karamese M, Erol HS, Albayrak M, Findik-Guvendi G, Aydin E,
Aksak-Karamese S. Anti-oxidant and anti-inflammatory effects of
apigenin in a rat model of sepsis: an immunological, biochemical,
and histopathological study. Immunopharmacol Immunotoxicol
2016; 38(3): 228-37.
[165] Dang Y, Li Z, Wei Q, Zhang R, Xue H, Zhang Y. Protective effect
of apigenin on acrylonitrile-induced inflammation and apoptosis in
testicular cells via the NF-κB pathway in rats. Inflammation 2018;
41(4): 1448-59.
[166] Zhang J, Zhao X, Zhu H, Wang J, Ma J, Gu M. Apigenin protects
against renal tubular epithelial cell injury and oxidative stress by
high glucose via regulation of NF-E2-related factor 2 (Nrf2) path-
way. Med Sci Monit 2019; 25: 5280-8.
[167] Zhou Q, Cheng KW, Gong J, Li ETS, Wang M. Apigenin and its
methylglyoxal-adduct inhibit advanced glycation end products-
induced oxidative stress and inflammation in endothelial cells. Bio-
chem Pharmacol 2019; 166: 231-41.
[168] Ai XY, Qin Y, Liu HJ, et al. Apigenin inhibits colonic inflamma-
tion and tumorigenesis by suppressing STAT3-NF-κB signaling.
Oncotarget 2017; 8(59): 100216-26.
[169] Zhao F, Dang Y, Zhang R, et al. Apigenin attenuates acrylonitrile-
induced neuro-inflammation in rats: Involved of inactivation of the
TLR4/NF-κB signaling pathway. Int Immunopharmacol 2019; 75:
105697.
[170] Okla M, Al-Madani JO, Chung S, Alfayez M. Apigenin reverses
interleukin-1β-induced suppression of adipocyte browning via
COX2/PGE2 signaling pathway in human adipocytes. Mol Nutr
Food Res 2020; 64(1): e1900925.
[171] Ali F, Rahul, Naz F, Jyoti S, Siddique YH. Health functionality of
apigenin: A review. Int J Food Propert 2017; 20(6): 1197-238,
[172] Zeng P, Liu B, Wang Q, et al. Apigenin attenuates atherogenesis
through inducing macrophage apoptosis via inhibition of AKT
Ser473 phosphorylation and downregulation of plasminogen acti-
vator inhibitor-2. Oxid Med Cell Longev 2015; 2015: 379538.
[173] Calixto JB, Beirith A, Ferreira J, Santos AR, Cechinel Filho V,
Yunes RA. Naturally occurring antinociceptive substances from
plants. Phytother Res 2000; 14: 401-18.
[174] Guardia T, Rotelli AE, Juarez AO, Pelzer LE. Anti-inflammatory
properties of plant flavonoids. Effects of rutin, quercetin and hespe-
ridin on adjuvant arthritis in rat. Farmaco 2001; 56(9): 683-7.
[175] Nikfarjam BA, Adineh M, Hajiali F, Nassiri-Asl M. Treatment
with rutin - a therapeutic strategy for neutrophil-mediated inflam-
matory and autoimmune diseases: anti-inflammatory effects of
rutin on neutrophils. J Pharmacopuncture 2017; 20(1): 52-6.
[176] Rotelli AE, Guardia T, Juárez AO, de la Rocha NE, Pelzer LE.
Comparative study of flavonoids in experimental models of
inflammation. Pharmacol Res 2003; 48(6): 601-6.
[177] Lv H, Yu Z, Zheng Y, et al. Isovitexin exerts anti-inflammatory
and anti-oxidant activities on lipopolysaccharide-induced acute
lung injury by inhibiting MAPK and NF-κB and activating HO-
1/Nrf2 pathways. Int J Biol Sci 2016; 12(1): 72-86.
[178] He M, Min JW, Kong WL, He XH, Li JX, Peng BW. A review on
the pharmacological effects of vitexin and isovitexin. Fitoterapia
2016; 115: 74-85.
[179] Zhang S, Guo C, Chen Z, Zhang P, Li J, Li Y. Vitexin alleviates
ox-LDL-mediated endothelial injury by inducing autophagy via
AMPK signaling activation. Mol Immunol 2017; 85: 214-21.
[180] Rosa SI, Rios-Santos F, Balogun SO, Martins DT. Vitexin reduces
neutrophil migration to inflammatory focus by down-regulating
pro-inflammatory mediators via inhibition of p38, ERK1/2 and
JNK pathway. Phytomedicine 2016; 23(1): 9-17.
[181] Krishnan M, Kang SC. Vitexin inhibits acrylamide-induced neu-
roinflammation and improves behavioral changes in zebrafish lar-
vae. Neurotoxicol Teratol 2019; 74: 106811.
[182] Chen L, Zhang B, Shan S, Zhao X. Neuroprotective effects of
vitexin against isoflurane-induced neurotoxicity by targeting the
TRPV1 and NR2B signaling pathways. Mol Med Rep 2016; 14(6):
5607-13.
[183] Yang H, Huang J, Mao Y, Wang L, Li R, Ha C. Vitexin alleviates
interleukin-1β-induced inflammatory responses in chondrocytes
from osteoarthritis patients: Involvement of HIF-1α pathway.
Scand J Immunol 2019; 90(2): e12773.
[184] Xie CL, Li JL, Xue EX, et al. Vitexin alleviates ER-stress-activated
apoptosis and the related inflammation in chondrocytes and inhibits
2604 Current Pharmaceutical Design, 2021, Vol. 27, No. 22
the degeneration of cartilage in rats. Food Funct 2018; 9(11): 5740-
9.
[185] Lu Y, Yu T, Liu J, Gu L. Vitexin attenuates lipopolysaccharide-
induced acute lung injury by controlling the Nrf2 pathway. PLoS
One 2018; 13(4): e0196405.
[186] Venturini CL, Macho A, Arunachalam K, et al. Vitexin inhibits
inflammation in murine ovalbumin-induced allergic asthma. Bio-
med Pharmacother 2018; 97: 143-51.
[187] Küpeli E, Aslan M, Gürbüz I, Yesilada E. Evaluation of in vivo
biological activity profile of isoorientin. Z Naturforsch C J Biosci
2004; 59(11-12): 787-90.
[188] Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-
κB signaling. Cell Res 2011; 21(1): 103-15.
[189] Hussain F, Mittal S, Joshee N, Parajuli P. Application of bioactive
compounds from Scutellaria in neurologic disorders. Adv Neuro-
biol 2016; 12: 79-94.
[190] Gross AL, Walker KA, Moghekar AR, et al. Plasma markers of
inflammation linked to clinical progression and decline during pre-
clinical AD. Front Aging Neurosci 2019; 11: 229.
Ożarowski and Karpiński
[191] Adams B, Nunes JM, Page MJ, et al. Parkinson’s disease: a syste-
mic inflammatory disease accompanied by bacterial inflammagens.
Front Aging Neurosci 2019; 11: 210.
[192] Zeraik ML, Yariwake JH, Wauters J-N, Tits M, Angenot L. Analy-
sis of passion fruit rinds (Passiflora edulis): Isoorientin quantifica-
tion by HPTLC and evaluation of antioxidant (radical scavenging)
capacity. Química Nova 2012; 35: 541-5.
[193] Lourith N, Kanlayvattanakul M. Antioxidant activities and pheno-
lics of Passiflora edulis seed recovered from juice production resi-
due. J Oleo Sci 2013; 62(4): 235-40.
[194] da Silva Morrone M, de Assis AM, da Rocha RF, et al. Passiflora
manicata (Juss.) aqueous leaf extract protects against reactive oxy-
gen species and protein glycation in vitro and ex vivo models. Food
Chem Toxicol 2013; 60: 45-51.
[195] Lima-Neto ABM, Marques MM, Mendes FN, Vieira IG, Diniz DB,
Guedes MI. Antioxidant activity and physicochemical analysis of
passion fruit (Passiflora glandulosa Cav.) pulp native to Cariri
region. Acta Sci Biol Sci 2017; 39(4): 417- 22.