Various Promising Biological Effects of Cranberry Extract: A Review

Abstract

Cranberry is a well-known natural occurring product that has been used for centuries in traditional medicine to promote urinary tract health. Besides that, Cranberry has shown promising biomedicinal activity in the prevention and treatment of many human disorders. The presence of polyphenolic entities such as proanthocyanidins, anthocyanins, flavonols, and other chemo-constituents is commonly linked to the positive effects of this natural product on human health. Cranberry and its extract were developed and marketed as nutraceutical supplements, and their antioxidant, antibacterial, anti-inflammatory, and anticancer properties allow them to be used for managing a variety of ailments, including microbial infections, metabolic syndrome elements, and cancer. The focus of this paper is on some of the recent studies which explore the potential pharmacological activities of Cranberry extract. Ultimately, this study concluded that cranberry extract can offer a feasible and prospective phytochemical option for treating many disorders affecting human health.

Full text

Hybrid Open AccessReview Article
Clinical Schizophrenia & Related Psychoses
Clin Schizophr Relat Psychoses
Volume 15: S6, 2021
Doi: 10.3371/CSRP.KRET.113021
Various Promising Biological Effects of Cranberry Extract: A
Review
Abstract
Cranberry is a well-known natural occurring product that has been used for centuries in traditional medicine to promote urinary tract health. Besides
that, Cranberry has shown promising biomedicinal activity in the prevention and treatment of many human disorders. The presence of polyphenolic
entities such as proanthocyanidins, anthocyanins, avonols, and other chemo-constituents is commonly linked to the positive eects of this natural
product on human health. Cranberry and its extract were developed and marketed as nutraceutical supplements, and their antioxidant, antibacterial,
anti-inammatory, and anticancer properties allow them to be used for managing a variety of ailments, including microbial infections, metabolic
syndrome elements, and cancer. The focus of this paper is on some of the recent studies which explore the potential pharmacological activities of
Cranberry extract. Ultimately, this study concluded that cranberry extract can oer a feasible and prospective phytochemical option for treating many
disorders aecting human health.
Keywords: Cranberry •Cranberry extract •Antimicrobial •Antioxidant •Anti-inammatory
Raghad Riyadh Khalil*, Eman Tareq Mohammed and Yasser Fakri Mustafa
Department of Pharmaceutical Chemistry, University of Mosul, Mosul, Iraq
*Corresponding Author:
Raghad Riyadh Khalil, Department of Pharmaceutical Chemistry, University of Mosul, Mosul, Iraq; Email: raghadalbarhawi@uomosul.edu.iq
Copyright: © 2021 Khalil RR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received date: 04 August, 2021; Accepted date: 18 August, 2021; Published date: 25 August, 2021
Introduction
Nature, predominately through plants, has always been an inexhaustible
source of bioactive compounds. In many different cultures, phytotherapy
has had a well-known effect on the treatment and prevention of various
diseases [1]. According to the World Health Organization (WHO), about
eighty percent of the world's population, primarily in developing countries,
relies on conventional plant-derived medicines for primary health care,
while plant products continue to play a significant, albeit indirect role in
the health care systems of the developed countries [2]. Better compatibility
with the human body and relatively fewer side effects of botanical-based
medicine, in comparison with synthetic compounds, may shift the global
trend of synthetic drugs, in the past few decades, to herbal medicines, that
intimates a return to nature to treat different ailments [3-5].
North American Cranberry (Vaccinium macrocarpon), which belongs to
the Ericaceae family is a woody, low-growing, vining perennial plant native
to northeastern North America, extending from eastern Canada to North
Carolina in the United States. This edible red fruit is one of the economically
significant North American fruits [6], while Vaccinium oxycoccus is the
European variety, which is grown in portions of central Europe, Germany,
and Finland. Vaccinium oxycoccus is a smaller fruit with slightly different
acid profiles and anthocyanin than the North American variant [7]. Native
Americans employed the Vaccinium macrocarpon as a food source and
natural deterrent against bladder and kidney disorders. Furthermore, during
ocean trips, American sailors used Cranberries as an antiscorbutic agent
[6,8].
The promising health potential of V. macrocarpon, which received the
most attention for its advantageous effects on human health dating back
to the 17th century, led within the last few decades to the popularity of
Cranberry's dietary supplements as an alternative and convenient dietary
source of Cranberry phytochemicals. These supplements profess to
be manufactured from concentrated Cranberry extracts, freeze-dried
Cranberry powders, or Cranberry phenolic isolate products and advertised
for their high equivalence values to the fresh fruit and a variety of putative
health advantages, including urinary tract health support [9-12].
Chemo-constituents of cranberry and its cultivars
Cranberries are a varied and abundant source of phytochemicals. More
than one hundred fifty phytochemicals have been discovered and studied
in Cranberry and its cultivars so far. However, more ingredients can be
discovered as analytical techniques developed [13].
Flavonoids seem to be the most predominant chemo-constituent
phenotype. Also, other chemo-constituents have been recognized,
such as Anthocyanins, which give Cranberries their bright red color;
proanthocyanidins, which protect against urinary tract infections; flavonols,
the secondary yellowish pigments; terpene; and pectins; While the sour
and astringent flavor of Cranberries is due to catechins, organic acids, and
resveratrol [13].
Anthocyanins
Anthocyanins are arguably the most investigated phytoconstituent and are
responsible for the fruit's characteristic red color. Anthocyanins are found
mainly in the colored bodies of the exocarp layer of the fruit's pericarp,
and they increase as the fruit matures [14-16]. Whole, raw Cranberry fruits
contain substantial albeit inconsistent quantities of anthocyanins, ranging
from 13.6 to 140 mg/100 g depending primarily on the cultivar, place of
growth, fruit size, climatic, genetic, environmental, and other factors [13,16].
Chemically, anthocyanins consisting of an anthocyanidin backbone
attached to a single or multiple sugar moieties. V. macrocarpon is one of
the rare foods that muster glycosides of six aglycones of the anthocyanidin
family: petunidin, cyanidin, delphinidin, pelargonidin, peonidin, and
malvidin (Figure 1). The prevalent anthocyanins are 3-O-arabinosides and
3-O-galactosides of peonidin and cyanidin; a total of thirteen anthocyanins,
mainly 3-O-monoglycosides, have been discovered [7,17,18].
Viskelis et al. Investigated four American Cranberry cultivars and reported
that the average composition of the anthocyanins in these cultivars was
as the following: peonidin-3-galactoside (32.7% ± 1.2%), cyanidin-3-
galactoside (20.5% ± 1.8%), cyanidin-3-arabinoside (19% ± 3.3%),
peonidin-3-arabinoside (6.7% ± 1.2%) peonidin-3-glucoside (3.5% ± 1.3%),
and cyanidin-3-glucoside (2.3% ± 0.3%) [19]. However, recent analyzes

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Khalil RR, et al.
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have revealed a difference in the anthocyanin content of different processed
Cranberry products and supplements [20–22].
O
+
HO
OH
OH
R1
OH
3
R2
cyanidin: R1=OH, R2=H
delphinidin: R1=R2=OH
peonidin: R1=OCH
3
, R2=H
pelargonidin: R1=R2=H
malvidin: R1=R2=OCH
3
petunidin: R1=OCH
3
, R2=OH
Figure 1. The general chemical structure of the Cranberry’s
anthocyanidins (18).
Flavonols
Flavonols are found in a multitude of Cranberry fruits, mostly in glycosylated
forms of myricetin, quercetin, and to a lesser extent, kaempferol. Quercetin
glycosides (mainly quercetin 3-O-galactoside) (Figure 2) forming about 75%
of the Cranberry flavonols. A wide range of flavonols was detected, many
of which are found in low concentrations, such as quercetin, myricetin,
myricetin 3-O-arabinofuranoside, myricetin 3-O-galactoside, myricetin
3-O-xylopyranoside, myricetin 3-O-arabinopyranoside, and myricetin
3-O-rhamnoside [14,23–27].
O
O
HO
OH
O
OH
OH
O
HO
OH
OH
OH
4
Figure 2. The chemical backbone of quercetin-3-galactoside (28).
Flavan-3-ols are significant metabolites of Cranberry. They possess the
flavonoid scaffold as flavonols but without the C4 carbonyl group. They arise
naturally in the plant as aglycons of epicatechin and catechin. Unlike other
flavonoids, their good solubility allows them to stay in the vacuole with no
need for glycosylation [7,13]. Flavonols and flavan-3-ols have received a lot
of researchers' interest due to their supposed beneficial health properties
[23].
Proanthocyanidins
One of the exceptional properties of Cranberries is their diverse group of
proanthocyanidins (PACs) content, also referred to as non-hydrolysable
condensed tannins,that exhibit several unique structural characteristics.
The flavan-3-ols mostly epicatechin and catechin are the monomeric units
used by the plant to assemble oligomeric or polymeric structures known as
PACs.
Although the mechanism by which this condensation occurs in the plant
is not fully understood, two types of this chemical process have been
identified. In the less commonly type named B, the condensation occurs via
an inter-flavan bond between the flavan-3-ol units, where these monomeric
units coupled primarily by bonds between C-4 and C-8, though connections
between C-4 and C-6. On the other hand, type-A proanthocyanidins are
characterized by an additional bond between C-2 and C-7 of the underlying
flavan-3-ol units (Figure 3) [29-31].
Figure 3. Chemical backbones of the PAC trimers and dimers isolated
from Cranberries. (A) epicatechin- (4-6)-epicatechin-(4-8,2-O-7)-
epicatechin, (B) epicatechin-(4-8,2-O-7)-epicatechin- (4-8)-epicatechin, (C)
epicatechin-(4-8)- epicatechin-(4-8,2-O-7)-epicatechin,(D) epicatechin-(4-
8,2-O-7)-epicatechin, (E) epicatechin- (4-8)-epicatechin (13).
The degree of PAC polymerization (DP) is determined by the source and
processing of the fruit. PACs with DP equal to 23 and 26 have been detected
in Cranberries using mass spectroscopy. These structural characteristics
of PACs are responsible for their various and interesting bioactivities
[29,32,33].
According to Gardana et al., the PAC content of different Cranberry
cultivars ranging from 1471 mg/100 g-6563 mg/100 g of dry weight [34],
while commercial extracts are standardized to 15% and 33% PAC. Because
of this high content, Cranberry is considered as an expensive natural
extract. Unfortunately, this has resulted in the adulteration of Cranberry-
based products when inexpensive sources of PACs are employed and not
disclosed on the label [13,34,35].
Other chemo-constituents
In the American version of the cranberry fruit, derivatives of the ursane
type of triterpenoids, such as betulinic acid, oleanolic acid, and ursolic acid,
were identified. In a study of six American Cranberry cultivars, Oszmia´nski
et al. discovered that ursolic acid, the pentacyclic triterpene, was the most
abundant triterpenoid (ranging from 50%-37%), followed by oleanolic acid
(ranging from 28%-35%), and betulinic acid (ranged from 19%-28%) [36].
In addition, Cranberry contains phenolic acids, including hydroxycinnamic
and hydroxybenzoic acid derivatives. The former is the most abundant.
The foremost phenolic acids in Cranberry are caffeic acid, chlorogenic
acid, ferulic acid, gallic acid, p-coumaric acid, protocatechuic acid,
3-hydroxybenzoic acid, 3-hydroxyphenylpropionic acid, 4-hydroxybenzoic
acid, and 4-hydroxyphenylacetic [37].
Cranberry supplements may show ingredients profile that is somewhat
different from that found in the other Cranberry products. Ursolic acid and
oleanolic acid are found primarily in the fruit peel, which may not be used
in supplements manufacturing. In most cases, there is no clear information
on the label about the sources and forms used, whether whole fruit, juice,
or extract. The reduced PAC content in most supplements could be due to

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the peel removal during the manufacturing process. The fruits are often
squeezed or pressed during the Cranberries processing, and the residual
pomace is dumped as a waste product. Furthermore, any fruit processing
that requires extended exposure to light and heat has the potential to
destroy the existing anthocyanin molecules [22,38].
Biomedical Activities
Anti-pathogenic potentials
Antiviral effect: With the rise in antiviral resistance and the emergence of
new viral pathogens, there is an urgent need for antiviral medications that
are commonly available, inexpensive and have few adverse effects. Many
traditional medicines, which contain various plant metabolites, exhibited
significant antiviral properties are now validated as new antivirals. Recently,
studies have increasingly harangued the suitability of Cranberry extracts as
promising antiviral agents [39,40].
Non-Dialyzable Materials (NDM) of high molecular weight isolated from
Cranberry juice were reported to reduce influenza virus adhesion and
infectivity; probably by preventing viral adsorption onto the cells [41]. Where
Weiss et al. discovered that low NDM concentrations, which are twenty-
fold lower than those found in Cranberry juice, inhibits hemagglutination
of RBCs induced by both influenza virus B and the A subtypes (H3N2 and
H1N1). Pre-incubation of Madine-Darby Canine Kidney (MDCK) cells with
NDM (250 g/ml) considerably reduced the infectivity of the influenza A and
B subtypes, as evidenced by the lack of cytopathic effect on MDCK cells
and hemagglutination activity in the medium of infected cells. Suggesting
it hinders viral offspring generated by infected cells from adsorbing onto
new cells [42].
Because Hemagglutinin (HA) and Neuraminidase (NA), the influenza virus
surface glycoproteins, are crucial for the replication and infection of the
virus, Oiknine-Djian et al. Examined the NDM's effect on neuraminidases,
as these are the target of most marketed anti-influenza medications. They
found that the enzymatic activity of NA of both influenza virus A and B
strains in addition to that of Streptococcus pneumoniae can be inhibited
by NDM. The NDM's anti-NA activity was found to be promising against
different influenza virus strains and moderately active against Streptococcus
pneumoniae NA. This finding is significant in light of the increasing
prevalence of influenza isolates resistant to antiviral medicines, which has
reached 90% in some areas. In addition to the therapeutic potential against
both A and B influenza virus infections, this study suggested that cranberry
constituents might also stymie the development of subsequent secondary
bacterial complications [43].
In this context, V. macrocarpon extracts may give prospective chemicals
capable of preventing viral attachment to the target cells basing on their
known anti-adhesive actions against bacteria [44].
Oximacro, traditionally available Cranberry extract containing a high
concentration of PACs type-A, has been shown to have a significant dose-
dependent antiviral effect against influenza A and B viruses, according
to Luganini et al. Mechanistic experiments have demonstrated that the
extract may inhibit the binding and penetration of influenza virus into
target cells plus its virucidal properties. It was discovered that the extract
may interact with the ectodomain of the viral hemagglutinin glycoprotein,
implying interference with hemagglutinin activities and, as a result, loss of
influenza virus particle infectivity. Fluorescence spectroscopy and in silico
docking simulations confirmed the in-vitro findings, indicating that PAC-A2
(Dimeric catechin) is the predominant anti-influenza virus component
among the several ingredients of this extract. The involvement of PAC-A2
in anti-influenza virus action was further verified when it was shown that
it suppressed influenza virus reproduction. Overall, these findings point
to Cranberry extracts as a promising candidate for developing innovative
natural antiviral medicines to prevent influenza virus infections [45].
Hydrogen bonding, electrostatic interactions, van der Waals, as well
as covalent bond formation, are expected to play a major role in the
development of protein-PAC complexes. In this context, Terlizzi et al. found
that the PACs type-A of Oximacro extract may protect against Herpes
Simplex Type 1 (HSV-1) and Herpes Simplex Type 2 (HSV-2) infection
through a similar biochemical process. This route involving changes in the
envelope glycoproteins essential for entrance, such as gB and gD. The
antiadhesive activity of this extract on HSV is attributable to direct contacts
with the virion surface, as evidenced by interaction studies between PACs
and either HSV particles or the ectodomain of pure gD protein.
Moreover, Cranberry extract may inhibit the in vitro replication of these
DNA viruses. Even at acidic pH values (3.0- 4.0) and in the presence
of 10% human serum proteins, this extract was maintained its anti-HSV
activity, simulating the physiological features of the vagina as a prospective
therapeutic location [46].
Overall, these findings point to Cranberry extract as a promising candidate
for developing innovative natural antiviral medicines to prevent and treat
RNA and DNA viruses' infections. The antiviral activity of Cranberry extract
against human norovirus surrogates, Feline Calicivirus (FCV-F9), Murine
Norovirus (MNV-1), and bacteriophage MS2 has been also investigated
[47-49].
Based on the aforementioned studies, the proposed mechanism of the
Cranberry extract could be associated with the direct binding between
procyanidins and viral capsid proteins. This interaction can afford viral
particle aggregation, which cause significant structural and morphological
changes in the viral capsid and/or blocking of antigenic binding sites,
resulting in reduced overall viral infectivity [50-52]. The integrity of the
rotavirus capsid appears to be compromised by Cranberry's PACs. Direct
viral testing indicates not only the absence of viral antigen but also a
PAC-related inhibition or alteration of the rotavirus antigenic attachment
determinants. These events appear to significantly lower the rotavirus
infectivity [52-54].
Based on the findings of the studies involved in this review, Cranberry extract
appears to have the potential as a natural antiviral remedy for treating and
preventing foodborne and other virus infections. Also, the Covid-19 crisis
highlighted the urgent need for improving the currently-available therapeutic
facilities and exploring the antiviral potentials of various natural occurring
products [40,55].
Antibacterial effect: Cranberry extract has been shown to have an
antimicrobial activity against various pathogenic bacteria, including
Staphylococcus aureus, E. coli, Helicobacter pylori, Campylobacter, and
Salmonella. This would explain the apparent significance of the extract to
prevent certain infectious diseases, such as Urinary Tract Infections (UTIs),
stomach ulcers, and tooth decay [19].
UTI is one of the most prevalent bacterial illnesses in humans, with
Escherichia coli being the most common cause. UTI affects up to 40%–50%
of women at some point during their lives. The high frequency of UTIs, as
well as the alarming growth in the antibiotic resistance among uropathogens,
highlight the need for novel approaches to treat and prevent UTIs [56,57].
For too many years, Cranberry juice is being used as a remedy to treat and
avert UTIs. Spanned to the present of some evidence that Cranberry juice
can reduce the number of symptomatic urinary tract infections over one
year, especially in women who have recurrent UTIs. These findings led the
French Food Safety Authority to make the first-ever health claim on berry
phenolics in 2004: A daily intake of 36 mg of Cranberry proanthocyanidins
helps reduce the adherence of certain E. coli bacteria to the epithelium of
the urinary tract [19,56].
Thereby, many studies have demonstrated the effectiveness of PAC-
standardized Cranberry supplements against bacterial adhesion and
virulence in the urinary tract. Thus, these supplements can offer a means
to cure and prevent UTIs [56,58]. Oral supplementation of a 120 mg
capsule of Cranberry extract, standardized to 36 mg proanthocyanidins,
for sixty days provided a prophylaxis in young, healthy subjects suffering
from recurrent UTIs [59]. Furthermore, oral Cranberry supplementation
reported to be effective in preventing UTI recurrence in healthy women [60].

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Postmenopausal women, pregnant as well as lactating women, elderly men
with benign prostatic hyperplasia, and children [61-64].
It is believed that the PACs, particularly type A phenotype, may act on
the initial step of infection by inhibiting E. coli from the adherence to
uroepithelial cells in a dose-dependent manner. PAC can bind to the E. coli
and render bacteria non-adherent, probably by binding to fimbrial tips and
compressing them, reducing adhesive forces and consequently influencing
the first stage of infection. Also, PAC can decrease the number of fimbriae
in E. coli in addition to compressing them. Because these mechanisms do
not kill bacteria, there is a lower chance of resistant bacterial strains being
selected. PAC derived from Cranberries may inhibit the multi-drug resistant
E. coli strains from adhering to uroepithelial cells by 70% [29,58].
Another mechanism postulated is that quinic acid enhances the excretion of
hippuric acid in the urine, which has an antibacterial effect, thus prevents the
bacterial infection. Another explanation is that fructose inhibits fimbriated E.
Coli from adhering to uroepithelial cells. While another theory proposed that
Cranberry can affect the concentration of Tamm-Horsfall glycoproteins in
urine, preventing E. coli from adherence to the human kidney [65,66].
Helicobacter pylori is a spiral-shaped Gram-negative bacteria that infect
over half of the world's population. Chronic gastritis, peptic ulcer disease,
mucosa-associated lymphoid tissue lymphoma, and gastric cancer are
all thought to be caused by H. pylori infection in the stomach. It's difficult
enough to choose the optimal treatment regimens for eradicating H. pylori
infection. The most common causes of treatment failure are antibiotic
resistance caused by frequent and unregulated usage, as well as a high
prevalence of antibiotic side effects. To increase the rate of H. Pylori
eradication, a variety of approaches are developed, such as prolonging the
treatment period, utilizing new antibiotics, or including natural anti-H. Pylori
food products like Cranberry in the treatment [67,68].
The anti-H. pylori characteristics of Cranberry may be accomplished through
multiple modes of action, such as bacterial growth inhibition, enzyme
inhibition such as urease as well as proline dehydrogenase, anti-adhesion
activity, morphological changes, and inhibition of inflammatory cytokines
secretion including IL-8 from gastric cells induced by H. pylori [68,69].
According to a study conducted in Gorgan, Iran, the addition of Cranberry to
the proton pump inhibitor-based triple therapy for H. pylori had a significant
and greater rate of eradication than the usual regimen alone. H. pylori
positive patients with peptic ulcer disease were randomly assigned to one of
two groups: the first one received a two weeks triple therapy consisting of 30
mg lansoprazole bid, 0.5 g clarithromycin bid, and 1 g amoxicillin bid, while
the second group received two weeks 0.5 g Cranberry capsules bid along
with the same triple therapy. Bacterial eradication has been assessed using
a 13C-urea breath test six weeks after the completion of the treatment. In
the first group, H. pylori eradication was achieved in 74% while the percent
was 89% in the second group [67].
Dental caries is a multifactorial ailment induced by acid-producing bacteria
that are entrenched in the biofilm of dental plaque and ferment dietary
carbohydrates like sucrose [70]. Enamel demineralization occurs when
the pH of the tooth's surface falls below 5.5, resulting in tooth decay.
Due to its aciduric, acidogenic, and adhesion capabilities, Gram-positive
bacteria phenotype, primarily the mutant versions of streptococci mainly
Streptococcus mutans and Streptococcus sobrinus is thought to be the
primary causative organism of dental caries [71,72].
The influence of Cranberry's PACs on the formation, persistence, and
development of dental biofilm has been studied. Cranberry PACs' capacity
to suppress the activity and synthesis of Glucosyl Transferase (GTF)
and Fructosyl Transferase (FTF), which are involved in the formation of
exopolysaccharides by S. mutans, has been attributed to their ability
to prevent sucrose-dependent biofilm development [73]. Furthermore,
Cranberry PACs can prevent bacterial coaggregation, diminish bacterial
hydrophobicity, and change cell surface molecules to hinder non-sucrose-
dependent biofilm formation [74]. In a human trial, it is concluded that the
daily usage of Cranberry-containing mouthwash for six weeks can reduce
counts of the mutant streptococcal versions in saliva [75].
Another study conducted on children; Gupta et al. revealed that the
presence of NDM in the mouthwash can significantly reduce the
Streptococcal count in the oral environment [72]. Cranberry PACs have
also shown a promise role in the prevention and treatment of periodontal
diseases involving gingivitis and periodontitis. Cranberry extract has been
demonstrated to diminish periodontopathogen-induced inflammation by
lowering inflammatory cytokines, including IL-1, IL-6, IL-8, as well as TNF-α
in macrophages [65,74].
Antifungal effect: Fungal infections are becoming more common at an
alarming rate, posing a significant challenge to the healthcare providers.
This rise is directly linked to the growing number of immune compromised
people in addition to the changes in medical practice, such as the use of
immunosuppressive medicines and intense chemotherapy. The health
problems attributed to pathogenic fungi have also been exacerbated by HIV
and other disorders that produce immunosuppression. In addition, many
fungal phenotypes are becoming more resistant to traditional antifungal
drugs like fluconazole and amphotericin B. These two factors deepen the
need for finding potent alternatives, primarily from natural sources [76,77].
Cranberry's capacity to suppress the growth of opportunistic human fungal
pathogens that cause oral, respiratory, cutaneous, and systemic infections
has recently gotten more attention [78]. Isolated Cranberry proanthocyanidin
oligomers can suppress the growth of a variety of human pathogenic fungus
species. Candida krusei, Candida glabrata, Cryptococcus neoformans, and
Candida lusitaniae all showed vulnerability to micromolar quantities of PAC
fractions extracted from Cranberry fruit. Higher antifungal activity was seen
as PAC oligomers concentration increased, which could be attributed to an
increase in the number of free hydroxyl groups available for interaction with
proteins involved in organism development and viability (79).
Furthermore, Rane and his colleagues reported a remarkable in-vitro action
of Cranberry PACs against the formation of C. albicans biofilm in artificial
urine. Where anti-adherence characteristics, iron chelation, or both are
thought to be responsible for the Cranberry PAC action against C. albicans
biofilm development [78]. In the context of dental caries, Cranberry extract
has reported to suppress cariogenic pathogenicity features of S. mutans
and C. albicans dual-species biofilms in an in-vitro model [80].
Metabolic syndrome relieving potential
Metabolic syndrome is a complex disorder characterized by a cluster
of cardiovascular risk factors, including central obesity, dyslipidemia,
hypertension, impaired glucose metabolism, and associated with a hepatic
manifestation represented as Non-Alcoholic Fatty Liver Disease (NAFLD).
Consequently, increasing the risk of coronary heart diseases and type 2
diabetes mellitus [81].
Consumption of Cranberry and its-based products may have favorable
effects on metabolic syndrome, influencing one or more of its components,
a multitude of inflammatory biomarkers, and oxidative stress, as revealed
by observational and interventional studies in humans [82].
Through a clinical trial, Lee et al. investigated the effect of Cranberry extract
on lipid profiles in Type 2 diabetic patients. The patients who received
Cranberry extract supplement, one capsule of 500 mg Cranberry powder
after each meal for 12 weeks, exhibited lowering in the atherosclerotic
cholesterol profiles. Total cholesterol, Low-Density Lipoprotein (LDL)
cholesterol, and the total High-Density Lipoprotein (HDL) cholesterol ratio
all decreased considerably in the Cranberry supplemented patients as
compared to the placebo patients. Also, Cranberry supplements have a
neutral effect on glycemic control in Type 2 diabetic subjects taking oral
glucose-lowering agents [83].
The increasing prevalence of metabolic syndrome has been linked to
a hepatic manifestation known as Non-Alcoholic Fatty Liver Disease
(NAFLD). For instance, a veterinary study was conducted to estimate the
hepatoprotective effect of Cranberry using a model, in which, the non-
alcoholic fatty liver disease was induced in rats administered either or both

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Khalil RR, et al.
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of high fat cholesterol diet and Cranberry bulk supplement (50 and 100 mg/
kg/day, three times a week orally for eight weeks). Cranberry supplement
dramatically decreased oxidative stress, hepatic steatosis, inflammatory
state by lowering the expression of IL-6, TNF-α, and NF-kB. This nutraceutical
also enhanced insulin sensitivity and markedly increased the expression
of adiponectin. Most importantly, this study revealed that Cranberry may
increase Nrf-2 expression in hepatic tissues and considerably reduce
collagen formation and expression of fibrotic markers (TGF-β and α-SMA)
in a NAFLD model, indicating that Cranberry can significantly reduce liver
fibrosis development [84].
Parallel results have been found through a randomized clinical trial conducted
by Hormoznejad et al., suggesting that 288 mg of Cranberry extract, which
is equivalent to 26 g of dried Cranberry, might improve the management of
NAFLD. This is attributable in part to the improvement of insulin resistance
and the reduction of serum levels of alanine aminotransferase [85].
In a scope similar to the previous studies, many clinical trials found that
eight weeks of Cranberry juice consumption may improve the antioxidant
status and reduce the cardiovascular disease risk factors. This can be
achieved by enhancing gluco-regulation with a positive impact on the insulin
resistance homeostasis model. In addition, Cranberry was ably down-
regulating inflammatory biomarkers, increasing HDL cholesterol, lowering
fasting serum triglycerides, decreasing serum C-reactive protein, and
lowering diastolic blood pressure. Accordingly, it has been concluded that
Cranberry juice consumption can resolve some cardiovascular risk factors
in the disorder named metabolic syndrome [86-89].
On the other hand, Cranberry anthocyanins can modulate the plasma
lipoprotein profile by lowering total plasma cholesterol, non-HDL cholesterol
and non-HDL cholesterol/HDL-cholesterol ratio. The cholesterol-lowering
effect of Cranberry anthocyanins is primarily mediated by the increased
excretion of total neutral and acidic faecal sterols [90,91].
According to Xie et al., Cranberry anthocyanins can possess an effective
pancreatic lipase inhibiting activity, a well-known target of orlistat. In this
study, ultrafiltration was offered as an efficient approach for screening
pancreatic lipase inhibitors. Four Cranberry anthocyanins involving cyanidin-
3-O-arabinoside, peonidin-3-O-arabinoside, cyanidin-3-O-galactoside
and, peonidin-3-O-galactoside were identified as potent pancreatic lipase
inhibitors. The results gathered from molecular dynamics, molecular
docking, circular dichroism spectroscopy, and fluorescence spectroscopy
illustrated that the aforementioned Cranberry anthocyanins could interact
with the active site of pancreatic lipase. Hinting that Cranberry supplement
can be exploited to prevent the absorption of lipids and facilitate the
treatment and prevention of obesity [92].
Antioxidant potential
The lack of equilibrium, between the incidence of Reactive Species (ROS/
RNS) and the organism's ability to counteract their induced damage via
the antioxidative defence systems, was characterized as oxidative stress.
This overwork is caused by an increase in the ROS/RNS production or a
decrease in the antioxidant protection capacity. As a result, endogenous
systems' ability to combat oxidative attacks directed at target biomolecules
is diminished [93].
Specific factors that cause oxidative damage in cells may be triggered by
oxidative stress, such as the formation of mutagenic compounds, over-
expression of oncogenes, inflammation, or promotion of atherogenic activity.
Consequently, the risk of cardiovascular diseases, neurodegeneration,
carcinogenesis, diabetes, liver diseases, and kidney diseases increased
[94,95].
Antioxidants are bioactive molecules that can delay or prevent oxidative
damage. They are effective when they prevent oxidative damage by
blocking free radical-initiated chain reactions and eliminating them. Aside
from the endogenous antioxidant enzymes including catalase, glutathione
reductase, superoxide dismutase, and glutathione peroxidase, the
antioxidant consumption through the diet or supplements is an additional
protective element in maintaining cellular redox homeostasis. To quench
the damaging free radicals, the endogenous and exogenous antioxidant
defense systems can interact and operate synergistically [96].
Cranberries have been shown to exhibit a beneficial effect on oxidative
stress-related disorders. Using HepG2 cells, Martín and coworkers
investigated the hepatoprotective effect of Cranberry juice and powdered
Cranberry extract in the face of oxidative stress. Pre-treatment of HepG2
cells with the powders for twenty hours resulted in a significant reduction
of cellular damage induced by tert-butyl hydroperoxide (t-BOOH). Both
powders have considerably reduced the over-activated glutathione
peroxidase, glutathione reductase, and Malondialdehyde (MDA). Although
the juice powder has a lower antioxidant activity than the extract, it can
modulate protein signaling pathways at the molecular level to prevent cell
damage. Manifesting that, Cranberry chemo-constituents may preserve
hepatocytes from oxidative stress by altering GSH levels, antioxidant
enzyme activity, MDA plus ROS production, and cell signaling pathways
[97].
Another study that looked at the protective effects of Cranberry extract
against iron-induced hepatic toxicity in rats found that the extract
possesses potent hepatoprotective properties against iron sulfate-induced
liver injury. These benefits could be attributed to Cranberry's membrane
protective action via antioxidant and free radical scavenging activities [98].
Furthermore, the results of a study carried out by Kim and colleagues
indicated that Cranberry powder may supply adequate antioxidants to
help hypercholesterolemic rats exposed to lipopolysaccharide regain their
antioxidant capacity [99].
These findings imply that Cranberry and its based products can be used
to serve as a springboard for the development of newer, safer, and more
effective free radical scavenging agents.
Anti-inflammatory potential
Inflammation is the body's defence mechanism against infections, chemicals,
and toxins. If inflammation becomes a chronic condition, it may play a
crucial role in the evolution of various chronic noncommunicable diseases,
including cardiovascular disease, metabolic syndrome, neurodegenerative
diseases, and some malignancies [100-103]. The nuclear factor-κB (NF-
κB) plays an important part in the signal transduction pathways that are
involved in the inflammatory disorders, in addition to other mediators [104].
A recent study carried out by Yu et al. revealed that PAC-rich Cranberry
extract can inhibit the lipopolysaccharide-induced inflammatory responses
in the macrophages of mouse bone marrow and RAW264.7. In both cell
phenotypes, the extract significantly reduced the production of pro-
inflammatory mediators COX-2, iNos, Il-6, TNF-α, and Mcp-1. The suggested
potential mechanisms include the inhibition of NF-B p65 phosphorylation and
acetylation levels of histone H4 in both cell types, as well as an increase in
HDAC3 protein production (105). In an earlier study, Denise and colleagues
concluded similar results. The Caco-2/15 intestinal cells pre-incubated with
Cranberry extract were found to have a reduced pro-inflammatory mediator
TNF-α and IL-6 in addition to a lowered NF-ĸB activation rate [106].
Antitumor potential
Despite ongoing breakthroughs in chemotherapy research, cancer continues
to be a crucial challenge for modern medicinal chemistry, necessitating
increased global efforts to produce more effective anticancer medicines
with fewer side effects to battle this disease [107].
Natural products have been demonstrated promising chemotherapeutic
properties in the treatment of a variety of cancers. phytochemicals or their
derivatives are already used in the management of different types of cancer.
Cranberry and its based products are thought to have anticancer potential
due to their high phytochemicals content including the anthocyanins,
flavonoids, and phenolic acids [108,109].
Khairnar et al. investigated the anticancer activity of Cranberry extract
against KB (Nasopharyngeal carcinoma) and AW13516 (low to moderately

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Khalil RR, et al.
Page 6 of 9
differentiated squamous cell carcinoma of the tongue). The authors found
that the extract exhibited good anti-proliferative properties against the KB
cell line with no remarkable activity against AW13516 cell line [110].
In the case of ovarian carcinoma, highly pure PAC isolated from Cranberry
extract has been reported to inhibit angiogenesis and ovarian cancer viability
in vitro. Chemotherapy-resistant human ovarian adenocarcinoma (SKOV-
3) cells were treated with PAC that arrested the cell cycle and induced
apoptosis. PAC-1 also inhibited VEGF (Vascular Endothelial Growth Factor)
function in endothelial cells in addition to the suppression of pro-survival
Pi3K/AKT signaling in both ovarian cancer and endothelial cells, which was
favorably linked with the prevention of endothelial tube formation.
Using DU145 (human prostate adenocarcinoma) cells, some studies
reported that apoptosis could be induced in these cells in response to the
cranberry extract treatment, MacLean and colleagues found that Cranberry-
induced in vitro apoptosis of DU145 cells can be accomplished through
increased caspase-8 and -9 activities [111,112]. Likewise, a researcher and
his team found that the daily consumption of 1500 mg powdered Cranberry
fruit for a mean of one month lowered serum PSA (prostate-specific antigen)
in patients with prostate cancer as Cranberry constituents can regulate the
expression of androgen-responsive genes [113].
Conclusion
Several centuries ago, Vaccinium macrocarpon received significant
attention for its advantageous effects on humans. The dietary supplements
of cranberry have been developed in recent decades as an alternate
and convenient dietary source of its phytochemicals. Various Cranberry
products contain numerous phytoconstituents such as proanthocyanidins,
anthocyanins, flavonols, organic acids, and phenolic acids. The antioxidant,
antimicrobial, anti-inflammatory, and antitumor activities found in different
in vitro, in vivo, and clinical studies seem to be due to this diverse and rich
array of cranberry phytochemicals. Reviewed data in this study strongly
imply that cranberry supplements consumption can help manage metabolic
syndrome components and protect against cardiovascular diseases,
malignancies, microbial infections affecting oral health, urinary tract, and
Helicobacter pylori-induced ulcers. Overall, this paper concluded that
cranberry extract can be exploited as a viable and promising tool to combat
a wide range of human diseases.
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How to cite this article: Khalil Raghad Riyadh, Eman Tareq Mohammed
and Yasser Fakri Mustafa. “Various Promising Biological Effects of Cranberry
Extract: A Review” Clin Schizophr Relat Psychoses 15S(2021). Doi: 10.3371/
CSRP.KRET.113021.