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53 Imran et al.
Int. J. Biosci. 2020
RESEARCH PAPER OPEN ACCESS
CITRUS PEEL POLYPHENOLS: RECENT UPDATES AND
PERSPECTIVES
Muhammad Imran, Shahnai Basharat, Sidra Khalid, Maria Aslam, Fatima Syed,
Shaista Jabeen, Hafsa Kamran, Muhammad Zia Shahid*, Tabussam Tufail, Faiz-ul-
Hassan Shah, Awais Raza
University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, University
of Lahore, Lahore-Pakistan
Key words: Citrus peel, Polyphenols, Anti-oxidants, Health benefits, Toxicity.
http://dx.doi.org/10.12692/ijb/16.2.53-70
Article published on February 05, 2020
Abstract
Enormous amount of agro-wastes is producing annually during the processing of fruits and vegetables. These by-
products are prominent and promising source of bioactive compounds which exhibits health endorsing
perspectives such as prevention from cancer insurgence, diabetes preventive, and protection from cardiovascular
complications, anti-aging, and prevention from oxidative stress due to their strong antioxidant potential. Among
these agro-wastes,citrus peels are rich source of polyphenols as flavanones, flavones, flavonols and anthocyanins
and have health protective effect and act as a potential nutraceutical in the treatment of various non-
communicable diseases. These bioactive moieties act as antioxidant thereby scavenging free radical activity and
reducing oxidative stress which is cause of burden of diseases. Polyphenols has been used as prebiotic in
mitigating gut microbiome and a solution for gastrointestinal disorders. Citrus polyphenols exert health
promoting effect in regulating lipid metabolism and treating neurodegenerative diseases.
* Corresponding Author: Muhammad Zia Shahid [email protected]
International Journal of Biosciences | IJB |
ISSN: 2220-6655 (Print), 2222-5234 (Online)
http://www.innspub.net
Vol. 16, No. 2, p. 53-70, 2020
54 Imran et al.
Int. J. Biosci. 2020
Introduction
Polyphenols are secondary plant metabolites that act
as prebiotic and have disease protective benefits in
certain form of cancers, cardiovascular diseases,
diabetes associated oxidative stress and most
importantly protecting the DNA against oxidative
damage(Kawabata et al., 2019).Among these, citrus
fruits peels contain phenolic and flavonoids
compounds which have health protective effect. These
flavonoids have various types as
flavanones, flavones, flavonols. Citrus peel contains
anthocyanins in the form of hydroxycinnamic
andhydroxybenzoic acids (Belisteri et al., 2019).
Naringenin is a flavanone as polyphenol and has
many therapeutic benefits in reducing and
eliminating inflammation, oxidative stress and other
neurological disorders(Joshi et al., 2018).A study
conducted by Casacchiaand their co-workers, they
explored that citrus peel polyphenols have inhibitory
action on human enzyme amylase and lipaseto treat
and manage human disorders due to their antioxidant
potential(Casacchia et al., 2019).
Polyphenols are obtained from different varieties of
citrus fruits. They include gallic acid, quercetin,
sinapic acid, chlorogenic acid,ferulic acid, myricetin,
and kaempferol including the new compounds of
tetra-O-methylscutella and heptamethoxy flavone are
new compounds derived fromkaempferol, chlorogenic
acid sinapic acid, myricetin,ferulic acid, quercetin,
and gallic acid as well as nutritional flavonoids like
naringin, hesperidin, total flavones, glycosyl (Ahmed
et al., 2019).Citrus by-products are promising and
prominent source of bioactive compounds such as
(431–4131 mg/100 g DW) andhesperidin (131–
5433 mg/100 g DW), (Thieme et al., 2019).In dose
dependent manner, citrus polyphenols significantly
suppressed the formation of micronuclei and lowered
the micronucleated polychromatic erythrocytes in
bone marrow cells of rats (Chandrappa et al., 2017).
Flavonoids found in citrus plants are beneficial for
lipid metabolism. Su et a l(2019) carried out a study
to find the lipid lowering effect of poly phenols in
human hepatoma cell line. Citrus peel flavonoids
extracts (CPFE) and flavonoid compounds;
tangeretin, hesperidin, and nobiletin, citrus flavonoid
purity mixture (CFPM), have lipid-lowering effects on
oleic acid-induced lipid accumulation in HepG2 cells.
CPFE and CFPM suppressed miR-122 and miR-33
expression, increase in the
carnitinepalmitoyltransferase 1α (CPT1α) gene and,
decrease in fatty acid synthase (FAS) gene in oleic
acid-treated HepG2 cells by regulating lipid
metabolism, (Su et al., 2019). Bioactive compounds
can be produced by recycling of agro-industrial waste.
Phytochemical constituents found in Citrus peels of
lemon, grapefruit, and mandarin exerts antigenotxic,
antiproliferation, anticancer and antioxidant
activities. Ethanol 98% was used for extraction of
three peels of lemon, grapefruit, and mandarin to
assess total flavonoid content (TFC), total polyphenol
content (TPC), and antioxidant activity using DPPH
(1, 1-diphenyl-2-picrylhydrazyl). Results revealed that
TPC was found highest in lemon peel, TFC in
mandarin peels and antioxidant activity was greater
in lemon peel exerting radical scavenging activity by
DPPH at 50% effective concentration(EC50= 42.97 µg
extract/ mL) and Trolox equivalent antioxidant
capacity (TEAC=0.157). Moderate cytotoxic activity
(IC50 = 77.8 µg/mL) was observed in Mandarin peel
against human leukemia HL-60 cells, (Diab, 2016).
A study conducted by He, Li, Peng, He, & Pan, to
determine the anti-melanogenic and anti-oxidant
effects of peel derived from pomelo cv. Guan Xi
named as pomelo peel essential oil (PPEO). Analysis
of PPEO exposed volatile chemical components as β-
pinene (3.16%), limonene (55.92%), and β-myrcene
(31.17%). Effects of PPEO on the B16 melanoma cell
system showed concentrations below50 μg/mL
decrease the melanin content and inhibiting
tyrosinase (TYR) activity. PPEO antioxidant activity is
showed against superoxide anion free radicals, 2,2′-
azinobis-(3-ethylbenzthiazoline-6-sulphonate(ABTS),
and 2,2-diphenyl-2-picryhydrazyl (DPPH) (He, Li,
Peng, He, & Pan, 2019).
Citrus polyphenols have cardioprotective effect but
because of poor bioavailability its hypolipidemic
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effects are not properly achieved. Mollace et al.,
conducted a Double Blind, randomized, Placebo-
Controlled Study to evaluate Hypolipemic and
Hypoglycemic effects of standard bergamot
polyphenolic fraction (BPF®) as well as of its
phytosomal formulation (BPF Phyto) in diabetic and
hyperlipemic patients. Results revealed hypolipemic
effect by increasing HDL level, reducing LDL
atherogenic particles and overall reduction in fasting
plasma glucose exerting hypoglycemic effect,
(Mollace, et al., 2019).
Health endorsing perspectives
Diabetes prevention
Ernawita and colleagues, 2016, using HPLC analysis
examined that Violaxanthin (Z)- and violaxanthin
(all-E)- were the basic carotenoids of the peel, while
the major carotenoids of the pulp of jeruktakengon
were (all-E) β-cryptoxanthin and (Z)-violaxanthin.
The peel extract showed increased antioxidant
activity as compared to the pulp extract, and this
activity was further enhanced by the process
saponification. Peel extracts due to their qualities of
antioxidant, antibacterial and α-amylase inhibitory
activity, showed biological potential, (Ernawita et al.,
2016).Sathiyabama and fellow researchers, 2018,
studied fruit peel of Citrus sinensis (CSMe), rats were
given CSMe (50 and 100 mg/kg) and results showed
decreased levels of plasma insulin (22.9% and 32.7%,
respectively) and blood glucose of fasting (56.1% and
55.7%, respectively) in comparison to rats with
untreated diabetic control. Peel of citrus invert the
biochemical abnormalities and also showed an
increase in the strength of the positive
immunoreactions for insulin in pancreatic islets and
their cytoprotective activity in diabetic rats. Peel of
citrus dose augmented the activity of PPARγ in the
adipose tissue and insulin receptor and signaling
molecules GLUT4, (Sathiyabama et al., 2018).
Fayeket al., 2017, analyzed the antidiabetic and
hypocholesterolemic activities of four citrus peels
agro wastes. Mandarin peels aqueous homogenate
and its hexane fraction (59.3% and 56.8%) and
reference drug (54.7%) had given the same effect as it
decreased the cholesterol level. Almost, all samples
reduced triacylglyceride (36%–80.6%) than reference
drug (35%), also, glucose was reduced (71.1%–82.8
and 68.6%–79.6%) mainly by the aqueous
homogenates and alcoholic extracts of Citrus fruits
peels better than the reference drug used (by 68.3%).
All the extracted pectin, from the four types, has
marked effect on the three parameters. For the first
time these findings confirmed the comparative HPLC
quantification of nobiletin and biological studies of
different citrus peels varieties as agro-waste products,
(Fayeket al., 2017).
Wahyuono and co fellows, 2017, analyzed the citrus
peel and pulp samples from Indonesia and reported
antioxidant property, inhibition of α-amylase and
antibacterial activities of sample. Most of the extract
contained lower doses of α-carotene, β-carotene and
β-cryptoxanthin, zeaxanthin, and lutein. The extract
also enclosedhesperidin, naringin,polymethoxylated,
sinensetinneohesperidin, quercetin and tangeretin. L-
TEAC (lipophilic trolox equivalent antioxidant
capacity) test used for the extract of peel showed
higher antioxidant activity in comparison to extract of
pulp. All the extracts showed α-amylase inhibitory
activity; extract of pulp showed increased inhibitory
activity then the extract of peel, (Wahyuono et al.,
2017).
Alu'datt and colleagues, 2107, investigatedselective
plants of the citrus family by their phenolic
compounds which showed antioxidant and phenolic
extract-mediated inhibitory activities using
spectrophotometry for α-glucosidase and α-amylase.
A large amount of free phenolic content was explored
for sample (85.43-92.82% of TPC) in comparison to
the bounded form (7.18-14.57% of TPC).
The main phenolic compounds in lemon and red
blood orange was 38 Hs (hesperidin)in bounded
form, while in clementine, shamouti and pummel,
ferulic acid was found. The highest inhibitory activity
of α-glucosidase from the extracted phenolics in
lemon were associated with free phenolic extracts
acquired at the temperature 30 ºC with values of
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complete inhibition. Extracted phenolic compounds
in bounded form after acid base hydrolysis from all 43
selected samples of the Citrus showed induced
activation of the ACE and α-amylase enzymes. In
contrast free phenolic extract at 30 ºC in red blood
orange marked the highest α-amylase inhibition
activity (32.3%), (Alu'datt et al., 2017).
Table 1. Protective effects of citrus peel polyphenols.
Citrus peel polyphenols Mechanism Disease protective effect Reference
Nobiletin Anti-tumor
Antiproliferative
Chemopreventive role
inhibited the expression of poly(ADP‐ribose),
polymerase‐2 (PARP‐2)
Zeng et al., 2019
Tangeretin Antimicrobial role
Anti-allergic
Suppress OVA induced allergic inflammation
T cell differentiation either in vivo or in vitro
Xu et al., 2019
Hesperidin antioxidant
anticancer
anti-inflammatory
Liet al., 2019
Citrus Peel Flavonoid Extracts
CPFE
Suppress miR-122 and miR-33 expression
carnitinepalmitoyltransferase 1α (CPT1α) gene was
markedly increased
fatty acid synthase (FAS) gene was significantly decreased
Lipid lowering effect on oleic acid-induced
lipid accumulation in HepG2 cells
Su et al., 2019
Citrus olive oils COOs increased presence of tyrosol and hydroxytyrosol Inhibition of neurodegenerative diseases as the
Parkinson’s disease.
Ascrizzi et al., 2019
Bergamot Polyphenolic Fraction
(BPF®)
Significant reduction of fasting plasma glucose, serum LDL
cholesterol and triglycerides accompanied by increased HDL
cholesterol was observed. This effect was linked with significant
reduction of small dense atherogenic LDL particles
Cardiometabolic disorders
Mollace et al., 2019
Tacle® enzyme amylase and lipase inhibition Metabolic disorders as obesity and diabetes Casacchia et al., 2019
PPEO
Limonene (55.92%)
β-myrcene (31.17%) β-pinene
(3.16%)
Act against 2,2-diphenyl-2-picryhydrazyl (DPPH), 2,2′-
azinobis-(3-ethylbenzthiazoline-6-sulphonate (ABTS) and
superoxide anion free radicals
Anti-oxidant potential He et al., 2019
Inhibiting tyrosinase (TYR) activity on B16 melanoma cell
system
Anti-melanogenic effects
Guo et al., 2016, examined the effect of chenpi (dry
peel of Citrus) extract using high fat diet to induced
obesity and diabetes mouse model in improving their
metabolic features. Oral consumption of 0.25% and
0.5% extract in food for more than 15 weeks showed
obesity, hepatic steatosis, and symptoms of diabetes.
The favorable consequence was associated with
activation of 5'-adenosine monophosphate-activated
protein kinase in adipose tissue. The findings
declared that 5-demethylated polymethoxyflavones
(5-OH PMFs) enriched chenpi extract worked in
controlling obesity and type 2 diabetes, and its effect
cam also be linked with activation of AMPK pathway,
which leads to improvement in lipid metabolism,
(Guo et al., 2016). Navel orange hydroethanolic
extract and its flavonoids naringin and naringenin
were studied by Ahmed and co-fellows, to assess their
anti-hyperglycemic and the anti-hyperlipidemic
effects and anti-oxidant activities on nicotineamide
induced type-II-diabetic rats. The NA-induced type 2
diabetic rats were orally treated for 4 weeks with the
extract of sample, naringin and narengenin at dose
level of 100 mg/Kg/day. The treatments with peel
extract, they possiblyimproved the dropped serum
insulin and C-peptide concentrations, the reduced
liver glycogen amount, the increased liver glucose-6-
phosphatase and glycogen phosphorylase working,
serum lipid profile, and the suppressed liver
antioxidant defense system of NA-induced type 2
diabetic rats. The study concluded that peel extract
had potent antidiabetic effects in NA -induced type 2
diabetic rats due to the insulin-tropic effects and
insulin improving action which in result could
mediated through adiponectin expression in adipose
tissue and enhancing insulin receptor, GLUT4,
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(Ahmed, et al., 2017).
Homayouni et al., 2018, inspected the concequences
of hesperidin supplement on inflammation, blood
pressure and type II diabetes. For 6 weeks, 64
patients were unsystematically given 500 mg/day
hesperidin or placebo capsules. In the hesperidin
group, SBP, mean arterial blood pressure, IL‐6, and
hs‐CRP decreased whereas TAC increased in
comparison to the standards. Mean percent change of
SBP, diastolic blood pressure, mean arterial blood
pressure, serum TAC, and inflammatory markers
(tumor necrosis factor alpha, IL‐6, and hs‐CRP)
significantly improved between hesperidin and
control groups following intervention in adjusted
models (p < .05). According to findings hesperidin act
as antihypertensive and anti‐inflammatory effects in
type-II-diabetes, (Homayouni et al., 2018).
Table 2. Acceptable doses of citrus peel polyphenols.
Polyphenols Trial Dose acute
oral toxicity (AOT)
Dose sub-chronic
toxicity
Low Observed Adverse
Effect Level (LOAEL)
Median lethal
dose (LD50)
References
Hesperidin
73% methanolic extract
Animal Sprague-
Dawley rats
5000mg/kg 250mg/kg
500mg/kg
1000mg/kg 4837.5 mg/kg Bodhankar et al.,
2019
Effects 10% mortality No abnormalities in
body weight
Good safety profile
Anti-obesity
It has been examined through the study conducted in
two thousands and seventeen by Guo and fellows,
exhibited the impact of aged citrus peel excerpt on
discerning three T three-Lone parts of cells. It has
been observed that 2 kinds of excerpts of aged citrus
peel excerpts differentiating in Five-OH- poly
methoxy flavones substances constantly decreases the
deposition of oil and fat with in the cell deprived of
suggestively disturbing the feasibility and
propagation of cell.it has been noted that deprivation
in deposition of oil and fat was associated with
Adenosine-monophosphate initiated protein
formation process (AMPK) initiation and reduction in
cellular response to the deposition of fat and oils at
the fatty tissues arrangement features and lipid
formation DNA fragments. It has been observed that
aged citrus leaf excerpt exert the straight impact of
lipid formation at the fatty tissues in body and the
parts of five-OH poly methoxy flavones possibly exert
the lipolysis effect through against the process of lipid
formation effect of aged citrus peel excerpts, (Guo et
al., 2017).
It has been observed through a study conducted in
two thousands and sixteen by researchers Nakajima
and co-workers to study the deprivation of the lipid
formation feature of excerpt of flavonoids from the
citrus foods (that are enriched with vitamin C
content) acquire the from the reminder of citrus food
at manufacturing cite of some pigmented compounds
of flavones that are actually reduced in amount. It has
been observed through the consequences that excerpt
from the citrus peel that has been acquired next the
metabolism of citrus peel was actually a better basis
of two compounds hesperitin and naringenin;
pigmented compounds that have no foundation of
formation on a huge basis, just as it has been used
drugs and adjunction. Now, the consequences show
that whole excerpt of citrus peel should be used in the
management of overweight. It has been noted that
actual excerpt “In Nature” is valuable to decreases the
innovative fatty cells formation and deposition of
fatty acids and oil, it also has been noted that excerpt
that produced commercially, (metabolites of excerpt)
may be used to bring the metabolism of lipids at the
fatty cells, (Nakajima et al., 2016).
It has been noted through the study conducted in two
thousands and sixteen by Baba et al., that explain the
reduction of the expression of fatty cells formation
through the Citrus limonoidkihadanin B and insistent
on its compact process in rats at the three-T-three-L
one fatty tissues formation. The compounds from the
immature citrus peel known as Kihadanin B was
cleaned and refined from the immature citrus peel
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Int. J. Biosci. 2020
excerpt suppresses the deposition of lipid through the
decreases the manifestation of fatty cells formation
and lipid formation DNA fragments, however it did
not apply any impact on lipid resolution and
metabolism of lipid at the fatty cells. Addition of
phosphate in adenosine triphosphate and other
regulatory factors of and a reduction of PPAR-gemma
was decreased by immature citrus peel (kihadanin B.
Moreover, immature citrus peel excerpt kihadanin B
enlarged the tie of transcriptional factors to the
PPAR-gemma DNS fragments at the fatty cells. The
consequences exhibited that compound obtained
from the immature citrus peel decreases the
formation of adipose cells through the reduction of
deposition of fats and oils through the reduction of
Akt-FOXO1-PPAR-gemma axis in three-T three L one
fatty acids formation, (Baba et al., 2016).
A research was conducted in two thousands and
eighteen written by Kang and fellow researchers, to
find out the effect of excerpt of citrus unshiu peel
pellet on the adipose tissues and fatty cells and on
lipid levels. In this research one hundred and
eighteen persons with BMI is greater than twenty
three that has been included the excerpt of citrus
inshiu pellet for four week duration, biochemical
analysis and changes in biochemical profile is
calculated formerly and next of introduction of citrus
inshiu peel pellet in their daily routine. It has been
noted through the consequences that a considerable
reduction in body mass index was noted in all
experimental persons after management with citrus
inshiu peel pellet and sixty five point three percent of
these patients lose their weight from one kilogram to
zero point kilogram of weight next of four week of
duration of management with CUPP. Whole lipid and
cholesterol stage was considerably reduced from two
hundred and four milligram per deciliter to one
hundred and ninety three milligram per deciliter.
Considerable reduction in stages of cholesterol of low
density, lipid profile, and triglycerides level was
examined, (Kang et al., 2018).
It has been examined in research conducted in two
thousand and seventeen written by Pan et al.,
examined the impact of SlimTrym (a thing that has
been formed that include the excerpt of PMFs, green
tea and lychee) on the food-prompted overweight and
related NAFLD in male rat, the consumed the normal
healthy food, high lipid food that contain the
SlimTrym in the quantity of zero point one to zero
point five percent for 16 weeks of duration. When
SlimTrym is included in the diet of these persons, it
has been seen that considerable decreases of weight
and consequent fatty cells present around the gonads,
behind the peritoneum and around the mesenteric
region and parallel dimension of fat cells in high fat
diet-fed rats. It has been noted that adjunction of
SlimTrym too considerably reduced the fatty liver and
fat accumulation at liver and blood stages of GOT,
GPT, triglycerides and whole cholesterol. Reduced the
expression of PPAR-gemma, SREBP-One, and
regulation of adenosine monophosphate–regulatory
protein activation indicating through the Slim Trym
in parallel of fatty cells and hepatic that are actually
answerable for the weight reduction impact in
experimental subjects, (Pan et al., 2017).
It has been examined in a study conducted in two
thousands and sixteen written by Kim et al to
observed the impact of weight reduction in
experimental animals by the reduction and stoppage
effect of Diospyros kaki fruit and Citrus unshiu peel
combination excerpt (PCM) on the lipid metabolic
enzymes of lipid of pancreas through the lipid profile
calculation from the high fat diet rats in the
procedure outside the body. Citrus unshiu peel
combination excerpt was inculcate at the amount of
fifty to two hundred milligram per kilogram of body
weight for six week of duration through mouth.
Excerpt of combination of citrus unshiu peel showed
the reduction impact on lipid formation bustle with
minimum inhibitory concentration amount is five
hundred and seven point zero one microgram per
milliliter. Furthermore, it has been noted the amount
and profile of triglycerides, cholesterol and outer
body fat on weight in blood were considerably
decreases parallel to high fat diet normal rats in
excerpt of combination of peel inshiu than rats that
consumed the two hundred milligram per kilogram
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Int. J. Biosci. 2020
managed rats. The consequences exhibited that
combination of excerpt of citrus inshiu peel inculcate
has a great potential against the weight gain, as an
effect anti-obesity cause for the decrease of fat
digestion through the stoppage of release of lipids
enzymes released from the pancreas, (Kim et al.,
2016).
A study was conducted in two thousands and eighteen
written by Tung and co-workers, to find out the
impact of 2 kinds of excerpts of citrus peel just like
PMF acquired from the (SCFE) against the weight
gain in which A type of poly methoxy flavones with
the reduced amount of poly methoxy flavones and
HOPMFs. The A-type of poly methoxy flavones and B
type of poly methoxy flavones were included through
mouth for sixteen weeks of duration to the improved
and enlarged amount of fat in the food or diet –
prompted overweight rats. The consequences
exhibited that B-type of poly methoxy flavones are
collectively exert more considerable effect than that
B-type of poly methoxy flavones. Similar effect of A
and B type of poly methoxy flavones shown that they
decreases the mass of fat cells around the gonads in
distinct manner by reducing the stages of fat fragment
and sizes perilipin one protein, SRE BP-one effect.
Relating to the effect of high lipid fed diet cluster, B
type poly methoxy flavones modify the increased
amount of microbes present inside their intestines
through improving the gram negative bacteria
pervotella and reducing the rc4-4 bacteria. The
alteration in the arrangement of microbes present in
intestines, the population of diseases causing bacteria
and health bacteria may also be answerable for the
weight reduction procedure, (Tung et al., 2018).
Anti-inflammatory role
Swelling whether it exist for long duration or short
duration is defined as non-causative type of defense
system reaction of the organism’ body against any
other kind infection and of damages whether are
occurring outside the body or inside the body likewise
reactions of disease causing germs, plague, reaction of
defense system. Short term swelling initiated and
grown in fast manner and is provoked through the
multiple ways like wounds formation, effect of
pathogens, poisonous effect of anybody or reaction of
defense system against any pathogens. Long time
swelling typically persists for the longer period of
duration and consequently from the effect of retain of
short term swelling and when swelling cannot remove
properly, diseases of immune system, effect of variety
of disease causing germs and in the environment at
which diseases causing bacteria are present in an
abundant amount. Excluding the wound and injury
by personal error, it has been observed that direct and
straight association exist between the long term
swelling and variety of typically hospital based
ailments like problem of neurons and other illnesses
of heart and metabolism. It has been seen that PMF
has been a novel and effective in the management of
obstructive activities with in the body concerning the
variety of physiological and defense system disorders
including swelling, (Wang et al., 2018).
Polypethoxyflavons also mitigate the harmful effects
of oxidative by neutralizing and scavenging the effects
of free radicals. Polymethoxyflavones have been
found to prevent from the enhancement in the
concentrations of antioxidant enzymes such as
glutathione, catalase, superoxide dismutase induced
by carbon tetrachloride (Wang et al., 2018).It also has
been directed that protection of degenerative diseases
of neurons as well as defense from the disorders of
neurons besides the toxicity of neurons that is
activated by Amyloid beta-protein (Kuo et al., 2017).
It has been noted that high blood sugar level prompts
swelling and effect of reactive oxygen species are the
risk factors of excessive harm and impairment in the
mind region. A study was conducted in two thousand
and eighteen written by Okuyama et al., 2018 and
they demonstrated the reduction of swelling and
various impact of desiccated sprinkles of citrus outer
most covering on the experimental subjects like rats
as well as the occurrence of type two sugar at which
high blood sugar levels is prompts by hyper glycemic
agents (streptozotocin). It has been noted that peel of
citrus demonstrated many hold up activities of many
hormones and molecules at the different brain region
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Int. J. Biosci. 2020
of rat model. Also, it has been seen that citrus peel
included hold up the initiated of abnormal rate of
replication of astrocyte at the brain region and
excessive phosphate deposition at the region of two
hundred and thirty-one region of threonine and three
hundred and ninety six of serine at the brain region
and it also has been noted that it decreases the
destruction of neurons formation at the different
regions of brain in type two sugar prompt rats , so, it
has been briefly concluded that desiccated sprinkles
of citrus family utilizes the anti-swelling and
protection from neurons at the mind region,
(Okuyama et al., 2018).
A research was conducted in 2017 by Chen and fellow
researchers to find out the holdup activities from the
different varieties of Citrus peel likewise desiccated
outer most covering of citrus from America and from
the china that has enhanced amount of different
compounds of citrus fruits as well as excerpt of outer
covering of orange that had enhanced quantity of
PMF besides they have enhanced capability to hold up
activities of reactive oxygen species, like nitrogen
oxide .it has been noted that excerpt of outer covering
of orange has enhanced amount of nitrogen oxide,
hold up the activated NOS as well as cyclooxygenase –
two rather than conventional cluster of pigmented
compounds. it has been see that from the excerpt pf
outer covering of orange a compounds known as
nobiletin that are actually great chemical agent to
induce the anti-swelling impact in body. It has been
noted that desiccate outer covering of citrus had more
advantageous for the human body than that of
traditional foundations of outer covering of peel
(Chen et al., 2017).
A research was directed in two thousand and eighteen
and written by Son et al., to find out the reduction of
swelling impact and the molecular procedure of
pigmented compound that are actually antioxidant
and plant metabolite quercetogetin (QUE) against the
LPS prompted RAW two hundred and sixty fours
point seven cells. Antioxidant metabolite of plant
QUE hold up the formation of nitrogen oxide and
inflammatory factors E-two through the reduction of
lipopolysaccharides- prompted activation of initiated
NOS and COX-2 at the transcriptional and
translational stage. It has been noted that
quercetogetin reduces the formation of variety of
compounds released because of swelling like IL-1 and
others. Quercetogetin also hold up the modification of
place of NF-kB and a distinct component of
biomarkers, p-sixty five with in the main unit through
the interferences of phosphate transferring of
inhibitory k-B and α with in the lipopolysaccharides
prompt RAW two hundred and sixty four point seven
cell (basic unit), (Son et al., 2018).
Antimicrobial role
Citrus sinensis commonly known as sweet oranges
have beneficial effects against dental pathogens.
Dental pathogens include Streptococcus mutans and
Lactobacillus acidophilus. Sapna, et al. in 2016
observed the antimicrobial role of Citrus sinensison
dental pathogens. The 5mg per mL, 10mg per mL,
15mg per mL, 20mg per mL and 25mg per mL
concentrations of hot and cold ethanol concentrations
of Citrus orange were incubated at 37ºC for 24 hours.
25mg per mL concentration of hot and cold
concentrations of orange peel reduced the dental
caries pathogens with the mean zone of inhibition i.e.
9.5 mm to 10.9 mm. The hot ethanolic extract of
Citrus sinensiswas more operative than the cold
extracts of Citrus sinensiswith an increase in the zone
of inhibition against Streptococcus mutans and
Lactobacillus acidophilus, (Sapna et al., 2016).
The most popular of all is the Citrus limon peel
commonly known as lemon has many antimicrobial
properties of its peel and essential oil extracted from
it. The lemon peel extract has a high potential
antimicrobial role against the activities of Escherchia
coli. In a study to check the effect of lemon peel
extracts against the activities of Escherchia coli, the
citrus lemon peel was extracted by using 96% ethanol
by using maceration extraction method. The 25%,
50%, 75% and 100% ethanolic citrus peel extracts
have a strong antimicrobial activity against the
average inhibition zone of 15.03mm, 16,17 mm, 15, 83
mm, 18, 77mm of Escherchia coil. The ethanolic
61 Imran et al.
Int. J. Biosci. 2020
citrus peel extracts inhibits the specific enzymetic
activity by distrupting the bacterial membrane and
damage the lipids and proteins layers of microbes,
(Alohi et al., 2018).
Anti-aging
It has been noted that Citrus junos has been used in
variety of body activities like it can be used in the
treatment of influenza in winter season and for
different blood disorders. Though, the full activation
of different characteristics of Citrus junosare now
been searching. A study was conducted by Shim et al.,
2019, established an extracted procedure to find out
the amount of stimulated and full mature
components of outer covering of Citrus junos. Warm
water and excerpt of Citrus junosin ethanol were
formed and their laboratory and other types of test
are done. Eighty percent of excerpt of ethanol
exhibited the higher oxidative effect and composition
of phenols rather the one hundred percent of excerpt
of ethanol had an authority of holdup action of
xanthine Hot water and ethanolic extracts of C.
junos peel were prepared and their chemical profiles
and biological activities were evaluated xanthine
oxidase enzyme. Thus it is concluded that enrich
excerpt of citrus junos had been used in the
management of different type body or health ailments
and high level of nitrogen in blood although the
excerpt in H2O resolvable of Citrus junoscan be used
in the management of variety of age related disorders
(Shim et al., 2019).
A trial by Shimizu et al., 2019 demonstrated the
impact of polyphenol of outer covering of lemon on
the age related ailments like age related activities,
motor action, judgmental and thinking activity as
well as microbes present in gut region in age related
degradation enhanced in rats that are more
susceptible to it (SAMP1) and age related
degradation enhancement inhibited in rats (SAMR1.
Entire rats given desired amount of H2O (P-one
group SAMR-one) or zero point one percent of LPP.
In this experiment, polyphenols in lemon peel
amount enhance the life duration by around three
weeks of duration and reduces the intensifications
of age-associated actions. Water cluster-P one
exhibited excess quantity of modifications in gut
region (in its microbes figure) but R-one and Pone-
LPP does not shown any changes. Different types of
chemicals (phylum Bacteroidetes/Formicates)
which are related to overweight and weight gain in
the P one-water cluster was considerably in little
and greater than that in the P one-polyphenols in
lemon peel and resistant cluster-one accordingly.
Though, it has been noted that he cumulative
frequency of friendly bacteria (Lactobacillus) are
more increase in similar cluster P one cluster with
aging disorders and P one –polyphenols in lemon
peel cluster exhibited the considerable a slight
enhancement than that of P one –H2o cluster. So it
is concluded that polyphenol of lemon peel has
reduction in age associated modifications in the
climate of gut and on the physical expression (Igase
et al., 2018; Shimizu et al., 2019).
A study was done by Lee and fellows to find out the
effectivity of citrus peel compound (hesperidin)
alongside the age related effect on upper skin side
upon the rats (that re six weeks of age) that are
without hair. The rats are separated into the 3
clusters (one group has seven rats); first is normal
group without any intervention and disease, and
second is ultraviolent B managed cluster and third is
ultra-violent Blight treated with citrus compound.
Ultra-violent light B destructed mice treated with
citrus peel compound were given zero milter of H2O
mixing one hundred milligram per kilogram of BW of
citrus peel compound.
It has been the enhancement of betterment wrinkles
upon the skin of rats that are managed with ultra-
violent B hesperidin cluster that considerably reduces
the enhancement of in the outer covering of skin
layering and increasing the size of outer covering of
skin. Compound of peel of citrus reduces the
dehydration between the skin layers. Ultra-violent B
radiated outer covering enhances the demonstration
of swelling biomarkers although citrus compounds
treated rats demonstrated the decreases appearance.
It has been described that compound of citrus peel
62 Imran et al.
Int. J. Biosci. 2020
demonstrate the effective age related skin problems
through the maintenance of MMP-nine action via the
reduction of MAPK- contingent expressive routes
(Lee et al., 2018).
An investigation by Kim et al., 2018 inspected the
skin security and skin lightening impact of normal
outer covering of citrus fruit in personal experimental
subjects. To increase the value in the hospital based
trial, it included two things one is water soluble
micronutrients (Vitamin C) for the reduction of
oxidative stress and other is L-cysteine for the
reduction of formation of melanin. Entire types of
persons should give the one tablet as attest subjects
(one hundred milligram of excerpt of citrus peel and
one hundred and twenty five milligram of water
soluble vitamin C and sixty milligram of L-cysteine)
or conventional cluster for 2 months of duration.
It has been seen that melanin composition were
considerably reduced in test group parallel to the
conventional cluster next to four week of duration.
Additionally, AP-BF02-consumed cluster had
considerable enhancement in the effectiveness in
texture and texture at the finish of test duration.
Subsequently, adjunction through mouth with AP-BF
zero two can lighten the outer covering of
experimental subjects in normal females deprived of
bad impact and side effects, (Kim et al., 2018).
Apraj and Pandita, demonstrated the effect of age
related problems that is reduced by excerpt of C.
reticulata Blanco outer most covering usage in outer
side of body: reduction of oxidative stress and against
the enzymes methods. It has been seen through the
procedure that reactive oxygen components has the
ability of digestion and adsorbents for the warm
excerpt of alcohol of Citrus reticulate and excerpt of
ice of alcohol Citrus reticulatewere originated to one
hundred and forty three and one hundred and sixty
three micromoles of six- hydroxyl-two, five, seven,
and eight tetra methyl chromane-two-carboxylic acid
correspondent per gram of material correspondingly
warm excerpt of alcohol of Citrus
reticulatedemonstrated the potential against the
collagen and against the elastase than cold excerpt of
alcohol Citrusreticulate. Since, warm excerpt of
alcohol citrus reticulate demonstrated the enhanced
effect of oxidation process and effect against enzymes
of cold excerpt of Citrus reticulate. Correspondingly,
it is seen that Citrus reticulateouter covering can be
applied against the skin problems (wrinkles) in the
skin care products, (Apraj and Pandita, 2016).
Anti-hypertensive
Obho et al., in 2017 evaluated the effect of oils from
the peels of orange and lemon fruits on α-amylase
and α-glucosidase in patients with type-II-diabetes
and enzyme of angiotensin-I-converting enzyme
(ACE) in hypertensive patients. Both the enzymes
reduced the activities of ACE. 26.17 μg per mL of
lemon peel showed positive effects on inhibition as
compared with 31.79 µg per mL of orange peel
whereas 8.16µg/mL and 7.56 µg per mL of lemon peel
have strong positive effects on the actions of α-
amylase and α-glucosidase when compared with the
11.51 µg per mL and 11.53 µg per mL of orange peel
extracts, (Oboh et al., 2017).
Gui et al., 2018 determined the consequences of
polymethoxyflavones obtained from orange peel oil in
hypertensive rats. The orange peel oil contains eight
polymethoxyflavones. The polymethoxyflavones
present in orange peel oil are sinensetin,
hexamethoxyflavone, tetramethyl-O-isoscutellarein,
nobiletin, tetramethyl-O-scutellarein,
heptamethoxyflavone, 5-demethylnobiletin and
tangeretin.
The rats were divided into the normal group, control
group, low concentration of orange peel oil group,
high concentration of orange peel oil (OPO-H) group,
the group containing limonene and group treated
with captopril; total 6 groups. 5mL per kg and 10 mL
per kg dose of orange peel oil was given to these
groups for 61 days. The results showed significant
improvements in systolic and diastolic blood pressure
after the treatment and the nitric oxide contents of
serum, cardic, functions of liver and kidney were also
improved. A high dose or 10mL/kg of body weight has
63 Imran et al.
Int. J. Biosci. 2020
beneficial effects in hypertensive rats. A high dose
reduces the Malondialdehyde levels and ET-1, VEGF
and E-selectin serum levels were also reduced. The
high concentration of orange peel oil of 10 mL per kg
treatment showed greater positive effects than the
dose of 5mL per kg of orange peel oil. The high dose
of orange peel oil reduced the blood pressure by 15/16
mmHg as compared to other groups (Gui, et al.,
2018).
Hepatoprotective role
Alam et al., 2018carried out a study to find out the
protection of liver through the phenols released by
the citrus fruit via the measurement of amount of
hepatic enzymes (ALT, AST, ALP, and other oxidative
damage of hepatic organ). Inclusion of carbon tetra
chloride is enhanced the hepatic enzymes in blood
like ALT, AST, ALP and excessive oxidation of hepatic
region although it reduces the oxidative damage at
the cell level and provide the security against
oxidative damage as well as it decreases the oxidative
enzymes in mice that are reached at the regular and
moderate level when we dealing with the mice with C.
marcoptera.
It is observed that C. marcoptera has a considerable
reasonable quantity of variety of compounds like
caffeic acid and flavonoids; epicatechins and others. It
has been noted that C. marcoptera prompt the action
of protection of hepatic region through the improving
the anti-oxidant system alongside the carbon tetra
chloride-prompted hepatic destruction through
oxidation (Alam et al., 2018).
A study was conducted by Setyawati and Anggraeni,
2018, to find out the efficiency of excerpt of outer
covering of orange (Citrus sinensis) to enhancing the
action of hepatic organ of experimental subjects
(mice) that are promoted to cigarette smoke. Twenty
five mice of white in color of wistar strain are
separated into the five cluster; first cluster is negative
or minus normal, second group is optimize normal,
third group given excerpt of outer most covering of
sweet orange fruit in the quantity of thirty seven point
five milligram per kilogram of body weight, fourth
group given excerpt of outer most covering of sweet
orange in the amount of seventy five milligram per
kilogram of body weight and fifth cluster excerpt of
outer most covering of sweet orange fruit in the
amount of 112.5 mg/Kg of body weight . Considerable
variations is noted and reduction of enhancement of
alkaline phosphatase and ALT, AST in fifth cluster
can efficiently enhance the hepatic actions of the
experimental subjects promoted by the usage of
cigarette (Setyawati and Anggraeni, 2018).
A study by Gao et al., 2018, inspected security of liver
through the coumarin present in the outer most covering
of citrus fruits like grape fruits alongside of thioacetamide
prompted inflammation and stones of hepatic organ of
experimental subjects (mice). Coumarine of outer most
covering of citrus fruit was novel compound to give the
security alongside the damage of hepatic organ that are
prompted through the thioacetamide in the experimental
subjects and regulate the normalization of secretion of
hepatic enzymes through the maintenance of forsanide X
reacted mark DNA fragments and their parts. Moreover,
coumarin present in the outer most covering of citrus
fruits hold up the initiation of cells of hepatic stellate
through reducing the activation of Total Growth Factor-
beta one and alpha-SMA and demonstrated the anti-
swelling action via the decrease the secretion of nuclear
factor-keppa B, tumor necrosis factor-alpha and
interleukin-one beta. Though, the modifications in these
DNA fragments and at the point of translation as well as
it reduces the liver cells through the Coumarine of outer
most covering of citrus fruit. Briefly, it was observed that
the citrus peel induces the protection in the
thioacetamide prompted liver inflammation and liver
destruction because of decrease of poisonous excretion of
liver enzymes and the reduction of initiation of liver
stellate basic units and swelling that are related with
initiation of FXR (Gao et al., 2018).
Han et al., 2019 studied the medicinal impact of C.
auarntiumexcerpt (that contains the reasonable
amount of PMF compounds and compound extracted
from citrus family) upon the liver ailment of non-
alcoholic to the experimental animal that digest the
enlarge quantity of aft in their food in the
64 Imran et al.
Int. J. Biosci. 2020
experimental subjects that are more prone to emerge
the ailment of liver that are non-alcoholic.
Overweight rats were arbitrarily carried into the 4
clusters in which each cluster conatin 8 rats (high fat
diet alone, high fat fed diet with the silymarin, high
fat fed diet with fifty microgram per kilogram of C.
auarntium excerpt, high fat fed diet with one
hundred microgram per kilogram of C. auarntium
excerpt approximately in the duration of eight weeks.
It has been concluded that C. auarntium excerpt
including in the treatment regime of experimental
animals considerably decreases the high fat fed diet –
prompted non-alcoholic fatty liver disease.as it has
been observed through the reduction of lipid profile
in blood and reduced hepatic ailment. Variety of
pathways that promoted through the oxidative stress
is reduced with the treatment of C. auarntium excerpt
because it decreases the oxidative stress in these
experimental subjects. Furthermore, in comparison to
the non-managed mice, C. auarntiumexcerpt
managed rats demonstrated the reduced activation of
anti-swelling activation. The consequences described
that C. auarntiumexcerpt holdup the high fed fat diet
–prompted nan-alcoholic fatty liver disease through
decreasing the stage of TG and TC and reduces the
level of lipid in blood, (Han et al., 2019).
Kim and fellow researchers, 2016 investigated the
defensive efficiency of excerpt ofC. auarntiumL.
alongside the short and long term poisonous of liver
organ prompted by carbon tetra chloride. Male rats
were given H2O, silymarin (optimize control, two
hundred milligram per kilogram) and C.
auarntiumexcerpt (fifty and two hundred milligram
per kilogram) for three days of duration before the
carbon tetra chloride treatment (one milliliter per
kilogram, fifty percent volume by volume in fat of
olive through the injection.
In the case of long term swelling example, the
experimental subjects are managed for the
continuously twenty eight days and carbon
tetrachloride (one milliliter per kilogram, twenty
percent) was given 2 times per week.it is noted that
short and long term duration of swelling cases,
carbon tetra chloride induces the oxidative damage
and destruction in mice and modification in the cell
level of hepatic organ. Alongside, it is noted that C.
auarntiumexcerpt management normalize the
changes in the diseased condition and corrected the
oxidative damage through the improving the enzymes
that reducing the oxidation process and decreasing
the oxidation of fat and oil with in the body of
experimental subjects. Also, C. auarntiumExcerpt
increasing the Nrf-two and it associated defense at
cellular level pathways, briefly, it is concluded that C.
auarntiumexcerpt induce the defensive impact
alongside the carbon tetra chloride-promoted
poisoning hepatic region along its protection against
oxidative stress , anti-swelling and cell death within
the experimental subjects (Kim et al., 2016).
An investigation by Lin et al., formed the 3 main
components of C. outer most covering to find out the
defensive role of liver in which include excerpt of
H2O, excerpt of ethanol, and H2O released remaining
ethanol excerpt. Between these excerpts, the third
excerpt (one hundred milligram per milliliter) can
efficiently improve the nuclear related factor-
auarntium excerpt cycle in hepatic cell of G two-C
eight cell line that is suitable to reactive with C.
auarntiumexcerpt.
The third excerpt (fifty milligram per milliliter) also
demonstrate the considerable defense mechanism
upon the rats cells of liver effect on the mouse
AML12taht are prone to damage by the poisonous
chemical. It is more demonstrated that the third
excerpt improves the action of also improves the anti-
oxidants level and reduces the oxidation damage in
these cell lime of hepatic organ. It is advantageous to
defense liver from the destruction of reactive oxygen
species via the maintenance of anti-oxidants enzymes
and it also induces the alteration at the DNA level
(Lin et al., 2017).
Safety and toxicity
An innovative approach to transform waste nature of
citrus peels to form neutracueticals for health
promotion. Ascrizzi et al., 2019extracted essential oils
65 Imran et al.
Int. J. Biosci. 2020
from the peels of two Tuscany Citrus of the Massa by
cryomaceration and further pressing with olives to
produce Citrus olive oils (COOs). Functional
compounds as naringenin, minor phenolics, and
carotenoids found in COOs have therapeutic potential
for the treatment of neurodegenerative diseases, for
promoting health and wellbeing, (Ascrizzi et al.,
2019).Nishad et al., 2019conducted a comparative
study to evaluate Citrus paradisi L. peels extraction
technologies. Grapefruit peel phenolics were
extracted by enzyme-assisted extraction (EAE) and
ultrasound assisted extraction (UAE) and enzyme-
assisted extraction (EAE). Total phenolic content
(TPC) and total flavonoid content (TFC) were
extracted through optimization. The UAE, EAE
extracts were compared with conventional solvent
extraction for availability of phenolic compounds TPC
and TFC. Results revealed that EAE is the best
technology for polyphenols extraction, (Nishad, et al.,
2019).
Hesperidin(glycoside hesperetin-7-rhamnoglucoside)
is found in Citrus sinensis which has anticancer,
anti-inflammatory and antioxidant potential. Li et al.,
conducted an experimental trial in Sprague Dawley
rats to determine acute and chronic toxicity of
hesperidin from Citrus sinensis peel. For this
purpose, by using methanolic extract dried peel
polyphenol Hesperidin (73%). Hesperidin at dose of
5000 mg/kg to Sprague-Dawley ratsdepicts 10%
mortality in acute oral toxicity (AOT) and for sub-
chronic toxicity Hesperidin at dose of 250 and
500 mg/kg did not show any functional and
physiological abnormality and exerts good safety
profile at a dose of 4837.5 mg/kg for both genders of
Sprague-Dawley rats(Bodhankar, et al., 2019).
Conclusion
It is concluded that citrus peel polyphenols exert
health protective effects on human beings. It has as
such no toxic effects. It's a new approach in
enhancing bioavailability and pharmacokinetic
potential in reducing disease burden and enhancing
longevity. Citrus peels are a cheaper source of
antioxidants and potential bioactive compounds as
naringenin, hesperidin and other flavonoids have less
toxic effects and regarded as safe for consumption.
Further research should be conducted to detect the
toxic effects of citrus peel polyphenols.
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