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 Zia.Shahid@dnsc.uol.edu.pk

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

55 Imran et al.

Int. J. Biosci. 2020

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

56 Imran et al.

Int. J. Biosci. 2020

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,

57 Imran et al.

Int. J. Biosci. 2020

(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

58 Imran et al.

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

59 Imran et al.

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

60 Imran et al.

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.

References

Abe H, Ishioka M, Fujita Y, Umeno A,

Yasunaga M, Sato A, Yoshida Y. 2018. Yuzu

(Citrus junos Tanaka) peel attenuates dextran sulfate

sodium-induced murine experimental colitis. Journal

of oleo science, ess17184.

https://doi.org/10.5650/jos.ess17184

Apraj VD, Pandita NS. 2016. Evaluation of skin

anti-aging potential of Citrus reticulatablanco

peel. Pharmacognosy research 8,

160.

https://dx.doi.org/10.4103%2F09748490.182913

Ahmed OM, Hassan MA, Abdel-Twab SM,

Azeem MNA. 2017. Navel orange peel

hydroethanolic extract, naringin and naringenin have

anti-diabetic potentials in type 2 diabetic rats.

Biomedicine & Pharmacotherapy 94, 197-205.

https://doi.org/10.1016/j.biopha.2017.07.094

Alam MA, Sagor AT, Tabassum N, Ulla A, Shill

MC, Rahman GMS, Reza HM. 2018. Caffeic acid

rich Citrus macroptera peel powder supplementation

prevented oxidative stress, fibrosis and hepatic

damage in CCl 4 treated rats. Clinical Phytoscience 4,

14.

https://doi.org/10.1186/s40816-018-0074-y

Alu'datt MH, Rababah T, Alhamad MN, Al-

Mahasneh MA, Ereifej K, Al-Karaki G,

Ghozlan KA. 2017. Profiles of free and bound

phenolics extracted from Citrus fruits and their roles

in biological systems: content, and antioxidant, anti-

diabetic and anti-hypertensive properties. Food &

function 9, 3187-3197.

Ahmed W, Azmat R, Qayyum A, Khan SU,

Khan SM, Ahmed S, Moin S. 2019. Extraction of

diverse polyphenols in relation with storage periods

66 Imran et al.

Int. J. Biosci. 2020

of Citrus paradisi CV. Shamber through HPLC–DAD

technique using different solvent. Journal offood

science and technology 56, 384-390.

https://doi.org/10.1007/s13197-018-3499-x

Ascrizzi R, Taglieri I, Sgherri C, Flamini G,

Macaluso M, Sanmartin C, Zinnai A. 2019.

Nutraceutical Oils Produced by Olives and Citrus Peel

of Tuscany Varieties as Sources of Functional

Ingredients. Molecules 24, 65.

https://doi.org/10.3390/molecules24010065

Alhoi HH, Edy FI, Nyoman EL. 2018.

Antimicrobial Activity of Lemon (Citrus limon) Peel

Extract Against Escherichia coli. ASRJETS. 1.

http://asrjetsjournal.org/

Ballistreri G, Fabroni S, Romeo FV.

Timpanaro N, Amenta M, Rapisarda P. 2019.

Anthocyanins and Other Polyphenols in Citrus

Genus: Biosynthesis, Chemical Profile, and Biological

Activity Polyphenols in Plants. Elsevier 195-215

Baba S, Ueno Y, Kikuchi T, Tanaka R,

Fujimori K. 2016. A limonoidKihadanin B from

immature Citrus unshiu peels suppresses

adipogenesis through repression of the Akt-FOXO1-

PPARγ axis in adipocytes. Journal of agricultural and

food chemistry 64, 9607-9615.

https://doi.org/10.1021/acs.jafc.6b04521

Castro VL, Alañón ME, Rodríguez RV, Pérez

MS, Hermosín GI, Díaz MC, Jordán J, Galindo

MF, Arroyo J. 2016 Bioactive flavonoids,

antioxidant behaviour, and cytoprotective effects of

dried grapefruit peels (Citrus paradisiMacf.).

Oxidative Medicine and Cellular Longevity.

http://dx.doi.org/10.1155/2016/8915729

Chaabane M, Elwej A, Ghorbel I, Boudawara

T, Zeghal N, Soudani N. 2017. Citrus aurantium L.

peel extract mitigates hexavalent chromium-induced

oxidative stress and cardiotoxicity in adult rats 8, 18.

http://dx.doi.org/10.29252/pbr.3.2.8

Chandrappa CP, Smitha BM, Chandrasekar N,

Govindappa M. 2017. Effect of Citrus medica L

Fruit Peel Extract on Genotoxicity Induced by

Cyclophosphamide in Mice Bone Marrow

Cells. International Journal of Microbiological

Research 8, 43-47.

http://dx.doi.org/10.5829/idosi.ijmr.2017.43.47

Chen XM, Tait AR, Kitts DD. 2017. Flavonoid

composition of orange peel and its association with

antioxidant and anti-inflammatory activities. Food

chemistry 218, 15-21.

https://doi.org/10.1016/j.foodchem.2016.09.016

Casacchia T, Occhiuzzi MA, Grande F, Rizzuti

B, Granieri MC, Rocca C, Statti G. 2019. A pilot

study on the nutraceutical properties of the Citrus

hybrid Tacle® as a dietary source of polyphenols for

supplementation in metabolic disorders. Journal of

Functional Foods 52, 370-381.

https://doi.org/10.1016/j.jff.2018.11.030

Diab KA. 2016. In Vitro Studies on Phytochemical

Content, Antioxidant, Anticancer,

Immunomodulatory, and Antigenotoxic Activities of

Lemon, Grapefruit, and Mandarin Citrus Peels. Asian

Pacific Journal of Cancer Prevention 17, 3559-3567.

http://dx.doi.org/10.14456/apjcp.2016.134/APJCP.2

016.17.7.3559

Ernawita WR, Hesse J, Hipler UC, Elsner P,

Böhm V. 2016. Carotenoids of indigenous citrus

species from Aceh and its in vitro antioxidant,

antidiabetic and antibacterial activities. European

Food Research and Technology 242, 1869-1881.

http://dx.doi.org/10.1007/s00217-016-2686-0

Fayek NM, El-Shazly AH, Abdel-Monem AR,

Moussa MY, Abd-Elwahab SM, El-Tanbouly

ND. 2017. Comparative study of the

hypocholesterolemic, antidiabetic effects of four agro-

waste Citrus peels cultivars and their HPLC

standardization. Revista Brasileira de Farmacognosia.

27, 488-494.

https://doi.org/10.1016/j.bjp.2017.01.010

67 Imran et al.

Int. J. Biosci. 2020

Gao X, Wang C, Ning C, Liu K, Wang X, Liu Z,

Meng Q. 2018. Hepatoprotection of auraptene from

peels of citrus fruits against thioacetamide-induced

hepatic fibrosis in mice by activating farnesoid X

receptor. Food & function 9, 2684-2694.

Guo J, Cao Y, Ho CT, Jin S, Huang Q. 2017.

Aged citrus peel (chenpi) extract reduces lipogenesis

in differentiating 3T3-L1 adipocytes. Journal of

Functional Foods 34, 297-303.

https://doi.org/10.1016/j.jff.2017.04.042

Guo J, Tao H, Cao Y, Ho CT, Jin S, Huang Q.

2016. Prevention of obesity and type 2 diabetes with

aged citrus peel (Chenpi) extract. Journal of

agricultural and food chemistry 64, 2053-2061.

https://doi.org/10.1021/acs.jafc.5b06157

Gui L, Wang J, Yu C, Xiang T, Yu Z, Qiang W,

Fang G, Guang L, Xin Z, Hua W. 2018.

Prophylactic Effects of Polymethoxyflavone-Rich

Orange Peel Oil on Nω-Nitro-L-Arginine-Induced

Hypertensive Rats. Applied Sciences 8, 752.

https://doi.org/10.3390/app8050752

Han HY, Lee SK, Choi BK, Lee DR, Lee HJ,

Kim TW. 2019. Preventive Effect of Citrus

aurantium Peel Extract on High-Fat Diet-Induced

Non-alcoholic Fatty Liver in Mice. Biological and

Pharmaceutical Bulletin 42, 255-260.

https://doi.org/10.1248/bpb.b18-00702

Homayouni F, Haidari F, Hedayati M,

Zakerkish M, Ahmadi K. 2018. Blood pressure

lowering and anti‐inflammatory effects of hesperidin

in type 2 diabetes; a randomized double‐blind

controlled clinical trial. Phytotherapy research 32,

1073-1079.

https://doi.org/10.1002/ptr.6046

He W, Li X, Peng Y, He X, Pan S. 2019. Anti-

Oxidant and Anti-Melanogenic Properties of Essential

Oil from Peel of Pomelo cv. Guan Xi. Molecules 24,

242.

https://doi.org/10.3390/molecules24020242

Igase M, Okada Y, Ochi M, Igase K, Ochi H,

Okuyama S, Ohyagi Y. 2018. Auraptene in the

peels of Citrus kawachiensis (Kawachibankan)

contributes to the preservation of cognitive function:

a randomized, placebo-controlled, double-blind study

in healthy volunteers. The journal of prevention of

Alzheimer's disease 5, 197-201.

http://dx.doi.org/10.14283/jpad.2017.47

Joshi R, Kulkarni YA, Wairkar S. 2018.

Pharmacokinetic, pharmacodynamic and

formulations aspects of Naringenin: an update. Life

sciences 215, 43-56.

https://doi.org/10.1016/j.lfs.2018.10.066

Kang S, Song S, Lee J, Chang H, Lee S. 2018.

Clinical investigations of the effect of Citrus unshiu

peel pellet on obesity and lipid profile. Evidence-

Based Complementary and Alternative Medicine.

https://doi.org/10.1155/2018/4341961

Kim GN, Shin MR, Shin SH, Lee AR, Lee JY,

Seo BI, Roh SS. 2016. Study of antiobesity effect

through inhibition of pancreatic lipase activity of

Diospyros kaki fruit andCitrusunshiu peel. BioMed

research international.

http://dx.doi.org/10.1155/2016/1723042

Kim JK, Park NH, Hwang JS, Baek JH, Jeong

HW. 2018. Effect of Oral Intake of A Mixture

Containing Natural Citrus Peel Extract, Vitamin C,

and L-Cystine on Skin Brightness in Healthy

Women. Journal of Food and Nutrition Research 6,

655-659.

http://dx.doi.org/10.12691/jfnr-6-10-6

Kim TW, Lee DR, Choi BK, Kang HK, Jung JY,

Lim SW, Suh JW. 2016. Hepatoprotective effects of

polymethoxyflavones against acute and chronic

carbon tetrachloride intoxication. Food and Chemical

Toxicology 91, 91-99.

https://doi.org/10.1016/j.fct.2016.03.004

Kuo PC, Liao YR, Hung HY, Chuang CW.

Hwang TL, Huang SC, Wu TS. 2017. Anti-

68 Imran et al.

Int. J. Biosci. 2020

inflammatory and neuroprotective constituents from

the peels of Citrus grandis. Molecules 22, 967.

https://doi.org/10.3390/molecules22060967

Kawabata K, Yoshioka Y, Terao J. 2019. Role of

intestinal microbiota in the bioavailability and

physiological functions of dietary polyphenols.

Molecules 24, 370.

https://doi.org/10.3390/molecules24020370

Lee HJ, Im AR, Kim SM, Kang HS, Lee JD,

Chae S. 2018. The flavonoid hesperidin exerts anti-

photoaging effect by downregulating matrix

metalloproteinase (MMP)-9 expression via mitogen

activated protein kinase (MAPK)-dependent signaling

pathways. BMC complementary and alternative

medicine 18, 39.

https://doi.org/10.1186/s12906-017-2058-8

Lin ZH, Luo WT, Chan YF, Su ZY. 2017.

Chemopreventive effect of aged citrus peel (Chenpi)

extracts against tumor initiator acetaminophen-

induced hepatotoxicity through regulating Nrf2

pathway. In CANCER RESEARCH 77, 615.

http://dx.doi.org/10.1158/15387445.AM2017-LB-177

Li Y, Kandhare AD, Mukherjee AA,

BodhankarS L. 2019. Acute and sub-chronic oral

toxicity studies of hesperidin isolated from orange

peel extract in Sprague Dawley rats. Regulatory

Toxicology and Pharmacology.

https://doi.org/10.1016/j.yrtph.2019.04.001

Mollace V, Scicchitano M, Paone S, Casale F,

Calandruccio C, Gliozzi M, Nucera S. 2019.

Hypoglycemic and Hypolipemic Effects of a New

Lecithin Formulation of Bergamot Polyphenolic

Fraction: A Double Blind, Randomized, Placebo-

Controlled Study. Endocrine, Metabolic & Immune

Disorders-Drug Targets (Formerly Current Drug

Targets-Immune, Endocrine & Metabolic Disorders)

19, 136-143.

https://doi.org/10.2174/187153031966618120315151

3

Nakajima VM, Madeira Jr JV, Macedo GA,

Macedo JA. 2016. Biotransformation effects on anti

lipogenic activity of citrus extracts. Food chemistry.

197, 1046-1053.

https://doi.org/10.1016/j.foodchem.2015.11.109

Nishad J, Saha S, Dubey AK, Varghese E, Kaur

C. 2019. Optimization and comparison of non-

conventional extraction technologies for Citrus

paradisi L. peels: a valorization approach. Journal of

food science and technology 56, 1221-1233.

https://doi.org/10.1007/s13197-019-03585-0

Okuyama S, Shinoka W, Nakamura K, Kotani

M, Sawamoto A, Sugawara K, Furukawa Y.

2018. Suppressive effects of the peel of Citrus

kawachiensis (Kawachi Bankan) on astroglial

activation, tau phosphorylation, and inhibition of

neurogenesis in the hippocampus of type 2 diabetic

db/db mice. Bioscience, biotechnology, and

biochemistry 82, 1384-1395.

https://doi.org/10.1080/09168451.2018.1469396

Onuma W, Asai D, Tomono S, Miyamoto S,

Fujii G, Hamoya T, Wakabayashi K. 2017.

Anticarcinogenic effects of dried citrus peel in colon

carcinogenesis due to inhibition of oxidative

stress. Nutrition and cancer 69, 855-861.

https://doi.org/10.1080/01635581.2017.1339096

Oboh G, Olasehinde TA, Ademosun AO. 2017.

Inhibition of enzymes linked to type-2 diabetes and

hypertension by essential oils from peels of orange

and lemon. International Journal of Food Properties

20, 586–594.

http://dx.doi.org/10.1080/10942912.2017.13037s09

Pan MH, Yang G, Li S, Li MY, Tsai ML, Wu JC,

Lai CS. 2017. Combination of citrus

polymethoxyflavones, green tea polyphenols, and

Lychee extracts suppresses obesity and hepatic

steatosis in high‐fat diet induced obese

mice. Molecular nutrition & food research 61,

1601104.

https://doi.org/10.1002/mnfr.201601104

69 Imran et al.

Int. J. Biosci. 2020

Sathiyabama RG, Gandhi GR, Denadai M,

Sridharan G, Jothi G, Sasikumar P, Ramos

AGB. 2018. Evidence of insulin-dependent signalling

mechanisms produced by Citrus sinensis (L.) Osbeck

fruit peel in an insulin resistant diabetic animal

model. Food and Chemical Toxicology 116, 86-99.

https://doi.org/10.1016/j.fct.2018.03.050

Selmi S, Rtibi K, Grami D, Sebai H, Marzouki

L. 2017. Protective effects of orange (Citrus sinensis

L.) peel aqueous extract and hesperidin on oxidative

stress and peptic ulcer induced by alcohol in

rat. Lipids in health and disease 16, 152.

https://doi.org/10.1186/s12944-017-0546-y

Setyawati I, Anggraeni R. 2018. Effectiveness of

Sweet Orange Peel Extract (Citrus sinensis) on The

Improvement of Liver Functions of Animal Trials

Induced by Cigarette Smoke. Journal of Young

Pharmacists 10, 132.

Shan Y. 2016. Chapter 1–Functional Components of

Citrus Peel. In: Comprehensive Utilization of Citrus

By-Products. Academic Press, 1-17

Shim JH, Chae JI, Cho SS. 2019. Identification

and Extraction Optimization of Active Constituents in

Citrus junosSeib ex TANAKA Peel and Its Biological

Evaluation. Molecules 24, 680.

https://doi.org/10.3390/molecules24040680

Shimizu C, Wakita Y, Inoue T, Hiramitsu M,

Okada M, Mitani Y, Nabeshima T. 2019. Effects

of lifelong intake of lemon polyphenols on aging and

intestinal microbiome in the senescence-accelerated

mouse prone 1 (SAMP1). Scientific reports 9, 3671.

https://doi.org/10.1038/s41598-019-40253-x

Smeriglio A, Cornara L, Denaro M, Barreca D,

Burlando B, Xiao J, Trombetta D. 2019.

Antioxidant and cytoprotective activities of an ancient

Mediterranean citrus (Citrus lumiaRisso) albedo

extract: Microscopic observations and polyphenol

characterization. Food chemistry 279, 347-355.

https://doi.org/10.1016/j.foodchem.2018.11.138

Son ES, Park J, Park HR, Han W, Yun DE,

Kwon OC, Lee CS. 2018. Anti-Inflammatory

Activity of Quercetogetin Isolated from Citrus Unshiu

Peel Involves Suppression of NF-κB and MAPK

Signaling Pathways in LPS-induced RAW 264(7),

Macrophages.

https://doi.org/10.20944/preprints201811.0229.v1

Sapna B, Shetty Prabu Mahin SI, Shaji V, Bibin

TG, Pathinettam KT, Deepak B, Shaista H,

Sreeja S, Darshan DD. 2016. Antimicrobial effects

of Citrus sinensis peel extracts against dental caries

bacteria: An in vitro study. Journal of Clinical and

Experimental Dentistry 8, 71–77.

https://dx.doi.org/10.4317%2Fjced.52493

Su D, Liu H, Qi X, Dong L, Zhang R, Zhang J.

2019. Citrus peel flavonoids improve lipid

metabolism by inhibiting miR-33 and miR-122

expression in HepG2 cells. Bioscience, biotechnology,

and biochemistry. 1-9.

https://doi.org/10.1080/09168451.2019.1608807

Thieme C, Westphal A, Malarski A, Böhm V.

2019. Polyphenols, Vitamin C, in Vitro Antioxidant

Capacity, α-Amylase and COX-2 Inhibitory Activities

of Citrus Samples from Aceh,

Indonesia. International Journal for Vitamin and

Nutrition Research.

https://doi.org/10.1024/0300-9831/a000481

Tung YC, Chang WT, Li S, Wu JC, Badmeav V,

Ho CT, Pan MH. 2018. Citrus peel extracts

attenuated obesity and modulated gut microbiota in

mice with high-fat diet-induced obesity. Food &

function 9, 3363-3373.

Wahyuono R, Hesse J, Hipler UC, Elsner P,

Böhm V. 2017. In vitro lipophilic antioxidant

capacity, antidiabetic and antibacterial activity of

citrus fruits extracts from Aceh,

Indonesia. Antioxidants 6, 11.

https://doi.org/10.3390/antiox6010011

Wang M, Meng D, Zhang P, Wang X, Du G,

70 Imran et al.

Int. J. Biosci. 2020

Brennan C, Zhao H. 2018. Antioxidant protection

of nobiletin, 5-demethylnobiletin, tangeretin, and 5-

demethyltangeretin from citrus peel in

Saccharomyces cerevisiae. Journal of agricultural and

food chemistry 66, 3155-3160.

https://doi.org/10.1021/acs.jafc.8b00509

Wang X, Li S, Wei CC, Huang J, Pan MH,

Shahidi F, Ho CT. 2018. Anti-inflammatory effects

of polymethoxy-flavones from citrus peels: a review.

Journal of food bioactives 3, 76-86.

https://doi.org/10.31665/JFB.2018.3150

Xua S, Konga GY, Jiaoa ER. 2019. Tangeretin

promotes regulatory T cell differentiation by

inhibiting Notch1/Jagged1 signaling in allergic

rhinitis. International Immunopharmacology 72,

402-412.

https://doi.org/10.1016/j.intimp.2019.04.039

Zheng DG, Hu PJ, Chao XY, Zhou Y, Yang JX,

Chen ZB, Yu YX, Cai Y. 2019. Nobiletin induces

growth inhibition and apoptosis in human

nasopharyngeal carcinoma C666‐1 cells through

regulating PARP‐2/SIRT1/AMPK signaling pathway.

Food Science and Nutrition 7, 1104-1112.

https://doi.org/10.1002/fsn3.953