TUGAS PENGGANTI UTS FARMAKOLOGI MOLEKULER

Senyawa 6-shogaol Pada Tanaman Jahe Sebagai Antiinflamasi

Dosen Pengampu : Apt.Fifteen Aprila Fajrin, S.Farm., M.Farm.

Disusun Oleh
Nama :
Sukma Anora Wahyunia 162210101019
Saragoza Oktaviana M 162210101057
Guspa Gayatri Azmi 162210101133

FAKULTAS FARMASI
UNIVERSITAS JEMBER
2021
 Jahe (Zingiber officinale Roscoe) merupakan tumbuhan yang berasal dari famili
Zingiberaceae,. Bagian tanaman yang biasa digunakan yaitu pada bagian akanya untuk mengobati
beberapa penyakit umum, seperti sakit kepala, masuk angin, mual, dan muntah. Tanaman ini
memiliki beberapa senyawa bioaktif yang terkandung didalamnya, seperti senyawa fenolik dan
terpene. Senyawa fenolik diantaranya yaitu gingerol, shogaols, dan paradol, yang berperan dalam
berbagai bioaktivitas jahe. Selain itu jahe memiliki aktivitas biologis, seperti aktivitas antioksidan,
anti-inflamasi, antimikroba, dan antikanker. Dan juga jahe memiliki potensi untuk mencegah
beberapa penyakit, seperti penyakit neurodegeneratif, penyakit kardiovaskular, obesitas, diabetes
melitus, mual dan emesis yang diinduksi oleh kemoterapi, dan gangguan pernapasan.

Pada suatu studi ilmiah menunjukkan bahwa jahe memiliki efek karminatif dan dapat
membantu mengurangi tekanan pada esofagus bagian bawah, mengurangi kram usus, mencegah
dispepsia, atulensi dan kembung. Studi klinis menunjukkan bahwa konsumsi jahe dapat
meningkatkan relaksasi esofagus bagian bawah, untuk menurunkan kecepatan kontraksi esofagus.
Studi ultra-sound yang dilakukan setelah mengkonsumsi jahe pada interval yang sering
menunjukkan bahwa ada kecenderungan kontraksi antral yang lebih banyak, sementara tidak ada
perubahan yang diamati pada dimensi fundus atau gejala gastrointestinal, dan juga pada
konsentrasi peptida usus GLP-1, motilin dan ghrelin dalam bentuk serum. Selain itu, ada studi
klinis pada jahe yang memvalidasi bahwa jahe dapat melindungi terhadap penundaan yang
disebabkan cisplatin dan pyrogallol dalam pengosongan lambung, Jahe adalah agen anti emetik
yang efektif, Jahe dapat mencegah tukak lambung dan lain-lain. Berikut adalah senyawa fitokimia
penting yang ada pada jahe dan telah divalidasi.
 Jahe memiliki banyak bahan aktif, seperti senyawa fenolik dan terpene. Senyawa fenolik
dalam jahe terutama adalah gingerol, shogaols, dan paradol. Pada jahe, gingerol merupakan
polifenol utama, seperti 6-gingerol, 8-gingerol, dan 10-gingerol. Dengan dipanaskan atau
penyimpanan lama, gingerol dapat diubah menjadi shogaol yang sesuai. Setelah hidrogenasi,
shogaols dapat diubah menjadi paradol. Sehingga dapat dikatakan bahwa 6- shogaols hasil dari
senyawa 6- gingerol yang telah disimpan cukup lama. Telah banyak penelitian yang menyatakan
bahwa jahe dan senyawa bioaktif yang dimiliki, mempunyai aktivitas antiinflamasi, yang dapat
melindungi dari penyakit terkait peradangan seperti kolitis. Sifat anti-inflamasi jahe telah dikenal
selama berabad-abad. Penemuan asli efek penghambatan jahe pada biosintesis prostaglandin di
awal tahun 1970-an telah berulang kali dikonfirmasi. Laporan sebelumnya menunjukkan pada
pasien Rheumatoid Arthritis, penggunaan jahe bubuk selama 3 bulan hingga 2,5 tahun,
mengurangi rasa sakit serta peradangan sampai 75%. Gingerol dan shogaol adalah dua unsur
paling aktif dari tumbuhan jahe. Kedua nya dilaporkan menunjukkan aktivitas biologis salah
satunya yakni antiinflamasi.

studi yang dilakukan di masa lalu menunjukkan bahwa peradangan memainkan peran
utama dalam berbagai proses patofisiologis dan dimediasi oleh TNF-a, NF-kb, i-NOS dan COX-
2, dan peningkatan pembentukan eisonaoid proinflamasi. Jahe dan senyawanya telah dipelajari
secara rinci untuk efek anti inflamasi dan penelitian telah menunjukkan jahe dapat menekan
sintesis prostaglandin dengan menghambat COX-1, COX-2 dan biosintesis leukotriene dengan
menghambat 5-LOX. Penemuan lainnya juga mengidentifikasi jahe sebagai produk obat herbal
yang memiliki kesamaan sifat farmakologis dengan obat antiinflamasi nonsteroid. Mekanisme
jahe sebagai antiinflamasi yaitu dengan cara penghambatan siklooksigenase-1 dan
siklooksigenase-2 (COX-1 dan COC-2), serta menekan biosintesis leukotriene degan menghambat
5-lipooksigenase. Hal tersebut yang membedakan jahe dengan obat antiinflamasi nonsteroid.
Penemuan ini memiliki profil terapeutik yang lebih baik serta memiliki efek samping yang lebih
sedikit dibanding obat antiinflamasi nonsteroid. Senyawa 6-shogaol yang berperan dalam
antiinflamasi untuk mengobati peradangan tanpa mengganggu fungsi makrofag yang
menyebabkan antigen. Efek antiinflamasi terutama terkait dengan phoshatidylinositol-3-kinase
(PI3K), protein kinase B (Akt), dan peningkat rantai ringan faktor inti kappa dari sel B yang
diaktifkan (NF-κB). Secara umum, jahe dan senyawa aktifnya terbukti efektif dalam meredakan
peradangan, terutama pada penyakit radang usus. Mekanisme anti-inflamasi jahe terkait dengan
penghambatan aktivasi Akt dan NF-κB, peningkatan sitokin anti-inflamasi, dan penurunan sitokin
proinflamasi. Khususnya, penerapan nanopartikel jahe berpotensi meningkatkan pencegahan dan
terapi penyakit radang usus.

Mekanisme dari 6-shogaol sebagai antiinflamasi yaitu dengan menunjukkan adanya efek
perlindungan terhadap disfungsi penghalang usus yang diinduksi oleh faktor nekrosis tumor α
(TNF-α) dalam sel usus manusia. Hal ini juga mencegah peningkatan regulasi Claudin-2 dan
pembongkaran Claudin-1 melalui penekanan pada jalur pensinyalan yang terlibat dengan PI3K
atau Akt dan NF-κB. Selain itu, ekstrak jahe menghambat aktivasi NF-κB dan menurunkan tingkat
IL 1β di usus besar tikus, yang mengurangi kolitis yang diinduksi oleh 2, 4, 6 asam sulfonat
trinitrobenzene. Jahe juga melindungi terhadap enteritis yang diinduksi oleh antibodi anti-CD3
pada tikus, dan juga jahe dapat mengurangi produksi TNF-α serta aktivasi Akt dan NF-κB. Selain
itu, nanopartikel yang berasal dari jahe (GDNPs 2) dapat mencegah peradangan usus dengan
meningkatkan kadar sitokin antiinflamasi seperti interleukin-10 (IL-10) dan IL-22 serta
menurunkan kadar sitokin proinflamasi seperti TNF-α , IL-6, dan IL-1β pada tikus dengan kolitis
akut dan kolitis kronis. Dan juga, nanopartikel 6-shogaol untuk menipiskan gejala kolitis dan
meningkatkan perbaikan luka kolitis pada tikus dengan kolitis yang diinduksi natrium sulfat
dekstran. Selain itu, microRNA dari nanopartikel mirip eksosom jahe (GELN) memperbaiki kolitis
tikus dengan menginduksi produksi IL-22, faktor peningkatan fungsi penghalang.
 Sifat anti-inflamasi jahe telah dikenal selama berabad-abad. Penemuan asli efek
penghambatan jahe pada biosintesis prostaglandin di awal tahun 1970-an telah berulang kali
dikonfirmasi. Laporan sebelumnya menunjukkan pada pasien Rheumatoid Arthritis, penggunaan
jahe bubuk selama 3 bulan hingga 2,5 tahun, mengurangi rasa sakit serta peradangan sampai 75%.
Gingerol dan shogaol adalah dua unsur paling aktif dari tumbuhan jahe. Kedua nya dilaporkan
menunjukkan aktivitas biologis salah satunya yakni antiinflamasi.

Penemuan ini mengidentifikasi jahe sebagai produk obat herbal yang memiliki kesamaan sifat
farmakologis dengan obat antiinflamasi nonsteroid. Mekanisme jahe sebagai antiinflamasi yaitu
dengan cara penghambatan siklooksigenase-1 dan siklooksigenase-2 (COX-1 dan COC-2), serta
menekan biosintesis leukotriene degan menghambat 5-lipooksigenase. Hal tersebut yang
membedakan jahe dengan obat antiinflamasi nonsteroid. Penemuan ini memiliki profil terapeutik
yang lebih baik serta memiliki efek samping yang lebih sedikit dibanding obat antiinflamasi
nonsteroid. Senyawa 6-shogaol yang berperan dalam antiinflamasi untuk mengobati peradangan
tanpa mengganggu fungsi makrofag yang menyebabkan antigen. ((((((Kumar dkk., 2013)

Haniadka R, Saldanha E, Sunita V, Palatty PL, Fayad R, Baliga MS. A review of the
gastroprotective effects of ginger (Zingiber officinale Roscoe). Food Funct. 2013
Jun;4(6):845-55. doi: 10.1039/c3fo30337c. Epub 2013 Apr 24. PMID: 23612703.
Kumar, S., K. Saxena, I. Uday, N. Singh, R. Saxena, dan U. N. Singh. 2013. Anti-inflammatory action of
ginger: a critical review in anemia of inflammation and its future aspects. International Journal of
Herbal Medicine. 1(4):16–20.
Mao, Q. Q., Xu, X. Y., Cao, S. Y., Gan, R. Y., Corke, H., & Li, H. B. (2019). Bioactive
compounds and bioactivities of ginger (Zingiber officinale Roscoe). Foods, 8(6), 185.
 Food & Function
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REVIEW View Journal | View Issue

A review of the gastroprotective effects of ginger

(Zingiber officinale Roscoe)
Published on 24 April 2013. Downloaded by University of Queensland on 08/09/2013 18:24:06.

Cite this: Food Funct., 2013, 4, 845

Raghavendra Haniadka,a Elroy Saldanha,b Venkatesh Sunita,a Princy L. Palatty,c

Raja Fayadd and Manjeshwar Shrinath Baliga*a

Received 26th November 2012
Accepted 15th March 2013
DOI: 10.1039/c3fo30337c
www.rsc.org/foodfunction
The rhizomes of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger is an important kitchen
spice and also possess a myriad health benefits. The rhizomes have been used since antiquity in the various
traditional systems of medicine to treat arthritis, rheumatism, sprains, muscular aches, pains, sore throats,
cramps, hypertension, dementia, fever, infectious diseases, catarrh, nervous diseases, gingivitis, toothache,
asthma, stroke and diabetes. Ginger is also used as home remedy and is of immense value in treating various
gastric ailments like constipation, dyspepsia, belching, bloating, gastritis, epigastric discomfort, gastric
ulcerations, indigestion, nausea and vomiting and scientific studies have validated the ethnomedicinal uses.
Ginger is also shown to be effective in preventing gastric ulcers induced by nonsteroidal anti-inflammatory
drugs [NSAIDs like indomethacin, aspirin], reserpine, ethanol, stress (hypothermic and swimming), acetic acid
and Helicobacter pylori-induced gastric ulcerations in laboratory animals. Various preclinical and clinical
studies have also shown ginger to possess anti-emetic effects against different emetogenic stimuli. However,
conflicting reports especially in the prevention of chemotherapy-induced nausea and vomiting and motion
sickness prevent us from drawing any firm conclusion on its effectiveness as a broad spectrum anti-emetic.
Ginger has been shown to possess free radical scavenging, antioxidant; inhibition of lipid peroxidation
and that these properties might have contributed to the observed gastroprotective effects. This review
summarizes the various gastroprotective effects of ginger and also emphasizes on aspects that warranty
future research to establish its activity and utility as a gastroprotective agent in humans.

a
Department of Research, Research and Development, Father Muller Medical c
Department of Pharmacology, Father Muller Medical College, Kankanady,
College, Kankanady, Mangalore, Karnataka, India 575002. E-mail: msbaliga@ Mangalore, Karnataka, India 575002
gmail.com; Fax: +91-824-2437402; +91-824-2436352; Tel: +91-824-2238331 d
Department of Exercise Science, Arnold School of Public Health, University of South
b
Department of General Surgery, Father Muller Medical College, Kankanady, Carolina, Columbia, SC 29208, USA
Mangalore, Karnataka, India 575002

Dr Raghavendra Haniadka is a Dr Elroy Saldanha is a current

postgraduate student in the
Department of Anesthesiology &
Critical Care at the prestigious
Postgraduate Institute of Medical
Education and Research, Chan-
digarh, India. He did his under-
graduate degree in Father Muller
Medical College Mangalore and
worked as a student assistant to
Dr MS Baliga on the mechanisms
responsible for the chemo-
preventive and chemoprotective
effects of ginger. Dr Haniadka is a recipient of the prestigious research
fellowship (STS 2008) from the Indian Council of Medical Research
and has published four text book chapters and seven papers in
international journals of repute.
postgraduate student in the
Department of General Surgery
at Father Muller Medical
College and is working as a
senior student assistant to Drs
PL Palatty and Baliga. He is
recipient of the prestigious
research fellowship (STS 2005)
from the Indian Council of
Medical Research and worked
under the mentoring of Dr Pal-
atty. Dr Saldanha's interests are
in the area of gastric surgery and have published three papers in
international journals of repute.

This journal is ª The Royal Society of Chemistry 2013 Food Funct., 2013, 4, 845–855 | 845

Food & Function
1 Introduction
The stomach, the muscular, hollow, dilated part located
between the esophagus and the small intestine of the alimen-
tary canal, is a vital organ functioning under the control of the
neuro-hormonal system. The principal function of the stomach
is to secrete proteolytic enzymes and powerful acids to ensure
the chemical digestion of macerated food (bolus) that has
arrived from the oral cavity and to then send the partially
digested food (chyme) to the small intestine for further diges-
Published on 24 April 2013. Downloaded by University of Queensland on 08/09/2013 18:24:06.
tion and absorption, thereby making it an important organ for
sustenance and healthy living for the individual.1 The stomach
is a sensitive organ and may be affected by various factors both
of endogenous and exogenous origins. Ailments like dyspepsia,
belching, bloating, gastritis and epigastric discomfort are
considered to be mild, while gastric ulcers and cancer cause
severe morbidity and mortality.1 A number of pharmaceutical
drugs are available for the treatment of various gastric ailments/
Ms Sunitha Venkatesh is a nal
year medical undergraduate
student in Father Muller
Medical College and is working
as a student assistant to Dr
Baliga. She is the recipient of the
prestigious research fellowship
(STS 2012) from the Indian
Council of Medical Research and
worked under the mentoring of
Dr Baliga.
Dr Princy L Palatty is a professor
in the Department of Pharma-
cology at Muller Medical
College. She has over twenty
years of experience in clinical
and experimental pharma-
cology. She is a recognised guide
for the MD curriculum and has
been an examiner for both
undergraduate and post-
graduate courses in the medical
curriculum. She has been a
principal investigator in
national projects and has published over 25 publications in peer
reviewed journals and text books. Currently she is the chair person
of the prestigious UNESCO BIOETHICS unit of South India.
846 | Food Funct., 2013, 4, 845–855
View Article Online
Review
diseases, but their repeated use is associated with untoward
side effects and negates the therapeutic benet.1 In view of
these observations the need for agents that are both effective
and devoid of side effects are required.
2 The kitchen spice ginger as a
gastroprotective agent
Dietary agents have been a source of medicine and the rhizomes
of Zingiber officinale, colloquially known as ginger is arguably
the most important gastroprotective agent in the various
traditional systems of medicine.2 Ginger belongs to the family
Zingiberaceae and is supposed to be indigenous to South-East
Asia (today's Northeast India). However, today the plants are
cultivated and found growing in many tropical and subtropical
regions of the world like Nigeria, Sierra Leone, Indonesia,
Bangladesh, Australia, Fiji, Jamaica, Nepal, Haiti, Mexico and
Hawaii.3 The rhizomes are the most important part and are
Dr Raja Fayad is a medical
doctor and a tenure-track assis-
tant professor in the Applied
Physiology Division at the
University of South Carolina.
His background research is in
gastroenterology and mucosal
immunology. Particularly, his
research is focused on chronic
inammation induced colon
cancer in adiponectin, a protein
produced by fat cells, deciency
status. He is a target PI at Colon
Cancer Center at the University of South Carolina and was a PI on
several recently completed grants from the Crohn's and Colitis
Foundation of America and Broad Foundation. He has published
over 25 articles concerning inammation related diseases.
Dr Manjeshwar Shrinath Baliga
is a senior scientist at Father
Muller Medical College and
Hospital. He obtained his PhD
from Manipal University, India,
and postdoctoral training at the
University of Alabama at Bir-
mingham, USA, and University of
Illinois at Chicago, USA. Dr
Baliga is a recipient of several
prominent fellowships including
the Commonwealth to UK in
1992 and Indian National
Academy of Sciences in 2008. He is a life member of numerous
professional societies, editorial board member/reviewer of several
peer-reviewed journals. He has been a principal investigator in
national projects and has published over 70 publications in peer
reviewed journals.
This journal is ª The Royal Society of Chemistry 2013
 View Article Online

Review Food & Function

Table 1 The different vernacular names of ginger in India and other parts of the shogaols, paradols and zingerone render pungency to ginger
world and are responsible for the warm pungent sensation in the
mouth.3,6,7 Fresh ginger also contains gingerols, a series of
Language Names
chemical homologs differentiated by the length of their
Scientic name Zingiber officinale Roscoe unbranched alkyl chains; [3–6]-, [8]-, [10]-, and [12]-gingerols
English Ginger and having a side-chain with 7–10, 12, 14, or 16 carbon atoms,
respectively as the major active components. Of all the ginger-
Indian languages
Assamese Ada
ols, the compound 6-gingerol is the most abundant.3–8 Ginger-
Bengali Ada ols are thermolabile and undergo dehydration to form the
Gujarati Adu corresponding shogaols rapidly. Shogaols may be further con-
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Hindi Adrak verted to paradols by hydrogenation.6,7 The other constituents

Kannada Shunti present are neral, capsaicin, gingediol, galanolactone, ginge-
Konkani Shunti, Alae
Malayalam Inji
sulfonic acid, galactosylglycerols, gingerglycolipids, diary-
Manipuri Shing lheptanoids and phytosterols.5–7 Some of the chemical
Marathi Aale structures are represented in Fig. 1.
Mizo Thingpuidum
Oriya Ada
Pali Singivera
4 Traditional uses of ginger
Punjabi Adaraka
For centuries, ginger has been extensively used as both medic-
Sanskrit Ardraka
Tamil Inji inal and dietary agent in Southeast Asia. It is a crucial ingre-
Telugu Allam dient in the various Chinese, Ayurvedic, Unani, Tibetan,
Urdu Adrak Srilankan, Korean, Arabic, Greek, Roman and also in the
various folk systems of medicines all over the world. In the
Other languages
Ayurvedic system of medicine, ginger is called “maha aushadhi”,
Arabic Zanjbeel
Burmese Sif meaning the great medicine and is used to treat wide array of
Dutch Gember ailments. It also nds wide applications in other traditional and
Filipino Luya folk systems of medicine (Table 2).3–7 Ginger has been an inte-
French Gingembre gral ingredient for managing digestive disorders and has been
German Ingwer
used as a carminative and digestive, and to prevent nausea and
Italian Zenzero
Javanese Jahe vomiting, motion sickness, stomach ache, stomach ulcers,
Khmer Khnyyi bacterial dysentery and dyspepsia. In the following section
Malay Halia these aspects will be addressed in details.
Nepali Sano Adwa
Russian Imbir
Sinhala Inguru 5 Validate scientific studies
Spanish Jengibre 5.1 Ginger prevents epigastric discomfort and dyspepsia
Swahili Tangawizi
Thai Kľng Ginger is a frontline dietary agent to possess carminative effect
Tibetan Sga skya and offers relief by decreasing pressure on lower esophagus,
reducing intestinal cramping, preventing dyspepsia, atulence
and bloating.4,5 Clinical studies have shown that consumption of
used as both medicinal and culinary agent.3–5 The vernacular ginger enhances relaxation of the lower esophageal sphincter, to
name of ginger in various Indian and other international decrease esophageal contraction velocity, and that these activi-
languages is enlisted in Table 1. ties possibly mediate the anti-atulent effects of ginger.9 Addi-
tionally, double blind studies carried out in patients with
functional dyspepsia have also shown that, when compared to
3 Phytochemistry of ginger the patients who have had received placebo, the gastric emptying
was more rapid in the cohorts that had received ginger.10 Ultra-
Ginger is one of the highly investigated dietary agents for its
sound studies at frequent intervals post ginger consumption has
chemical constituents and studies have shown it to contain a
showed that there was a trend for more antral contractions, while
wide variety of volatile and non-volatile compounds, and also
no alterations were observed in the fundus dimensions or
that their concentration varies with growing conditions,
gastrointestinal symptoms, and also in the concentrations of the
temperature, harvesting and processing.3–7 The characteristic
gut peptides GLP-1, motilin and ghrelin in the serum.10
aroma of ginger is credited to be due to the presence of volatile
compounds like camphene, b-phellandrene, curcumene,
cineole, geranyl acetate, terphineol, terpenes, borneol, geraniol, 5.2 Ginger protects against cisplatin and pyrogallol-induced
limonene, b-elemene, zingiberol, linalool, a-zingiberene, b- delay in gastric emptying
sesquiphellandrene, b-bisabolene, zingiberenol and a-farm- Cisplatin and pyrogallol causes severe nausea and vomiting,
esene.3–7 The non-volatile molecules like the gingerols, accompanying gastrointestinal symptoms such as abdominal

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Food & Function
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Fig. 1 Important phytochemicals present in ginger.
discomfort and delay in gastric emptying time.11–13 Labora-
tory studies with rats have shown that the oral pretreatment
with acetone and 50% ethanolic extract of ginger (100, 200
and 500 mg kg
1) and ginger juice (2 and 4 ml kg
1)
reversed cisplatin-induced delay in gastric emptying.12
Additionally studies have also shown that the acetone extract
of ginger (100, 250 and 500 mg kg
1) reversed the pyrogallol-
induced delay in gastric emptying.13 Together, all these
observations clearly indicate the potential of ginger in
improving symptoms such as abdominal discomfort, bloat-
ing and emesis.13
5.3 Ginger is an effective anti-emetic agent
Ginger has been used as an anti-emetic agent in various tradi-
tional systems of medicine since antiquity and scientic studies
have shown ginger to be efficacious in preventing nausea and
vomiting in various conditions.3–8,14 Ginger is shown to be
effective in ameliorating nausea and vomiting during early
pregnancy15–19 and without increasing pregnancy-related
complications, the pregnancy outcome and congenital abnor-
malities.18,20 Ginger is also reported to prevent post-operative
nausea and vomiting.21–23 Preclinical studies with experimental
848 | Food Funct., 2013, 4, 845–855
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animals have also shown that ginger juice produces antimotion
sickness action, and that this action was possibly due to its
effect on the central and peripheral cholinergic, histaminergic
and serotonergic pathways.24 However, human studies have
shown divergent results with certain reports indicating it to be
benecial,25,26 while others were contradicting the usefulness.27
However studies have equivocally shown ginger to be effective
in reducing the sea sickness in human volunteers and naval
cadets indicating its usefulness in maritime endeavors and
work.28,29
Ginger is also shown to be effective in preventing radio-
therapy and chemotherapy-induced nausea and vomiting.
Seminal studies by Arora and co investigators30,31 have shown
that the intraperitoneal administration of the hydroalcoholic
extract of ginger one hour before exposure to 2 Gy of g irradi-
ation was effective in blocking the saccharin avoidance
response. The optimal effective dose was observed to be 200 mg
kg
1 b wt in males,29 and 250 mg kg
1 in female rats31 respec-
tively. Ginger is also shown to be effective in preventing
cisplatin-induced emesis in the healthy mongrel dogs. The
acetone extract was more valuable than the ethanolic extract but
was less effective than granisetron.32 The acetone, 50% etha-
nolic extract and fresh ginger juice were also effective in
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Table 2 Traditional uses of ginger rhizome in different countries3–6
Country Pharmacological property
Arabian nations Aphrodisiac, anti-emetic, stomachic, carminative;
cold, headaches, nausea, stomach upset, motion
sickness and morning sickness, diarrhea, help
digestion, treat arthritis, rheumatological
conditions, muscular discomfort, carminative and
anti-atulence
Burma Anti-u agent, anti-emetic, rheumatological
conditions, carminative, cold, nausea, motion
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sickness and morning sickness and stomach upset
China anti-emetic, antitussive, expectorant, diaphoretic,
antihypertensive, arthritis, rheumatological
conditions, muscular discomfort, motion sickness
and morning sickness, carminative and antiatulent
Congo Against common cold, anti-emetic, arthritis,
rheumatological conditions, carminative,
antiatulent, cold, nausea and stomach upset
Europe anti-emetic, digestive aid, carminative, antiatulent,
cold, nausea
Germany anti-emetic, digestive aid, preventing motion
sickness
Greece Digestive aid, anti-emetic, rheumatological
conditions, motion sickness and morning sickness
India Antispasmodic, antiinammatory, anti-emetic,
aphrodisiac, astringent, digestive aid, motion
sickness and morning sickness. Antithrombotic and
antiarthritic
Indonesia Improving fatigue, antihypertensive, digestive aid,
antirheumatic, carminative, antiatulent, cold,
nausea
Japan anti-emetic, antitussive, expectorant, diaphoretic,
carminative, antiatulent, cold, nausea
Srilanka Carminative, diaphoretic, antispasmodic,
expectorant, peripheral circulatory stimulant,
astringent, appetite stimulant, anti-inammatory
agent, diuretic and digestive aid
Tibetan Carminative, diaphoretic, antispasmodic,
expectorant, peripheral circulatory stimulant,
astringent, appetite stimulant, anti-inammatory
agent, diuretic and digestive aid
United States of Carminative, stomachic, antispasmodic,
America diaphoretic, against motion sickness and morning
sickness
preventing cisplatin-induced delayed gastric emptying in rats.32
The reversal produced by ginger juice was better than the 5-HT3
receptor antagonist ondansetron, while that of the acetone
extract was similar to it.12
Gingerol, the active principle of raw ginger, was also
reported to possess anti-emetic property against cisplatin
and the effect was similar to that of ondansetron, used as
positive control.33 Mechanistic studies suggest that gingerol
caused a dose-dependent suppression in the levels of
substance P and NK1 receptors in the area postrema and
ileum and suggest its action to be similar to that of apre-
pitant.33 Additionally, studies have also shown that [6]-, [8]-
and [10]-gingerol and [6]-shogaol exert their anti-emetic
effect at least in part by acting on the 5-HT(3) receptor ion–
channel complex, probably by binding to a modulatory site
distinct from the serotonin binding site. This may include
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Food & Function
indirect effects via receptors in the signal cascade behind the
5-HT(3) receptor channel complex such as substance P
receptors and muscarinic receptors.34 The activity can be
summarized as 5-HT(3) antagonist, NKI antagonist, antihis-
taminic and prokinetic effects, and was devoid of any
adverse effects.
Although ginger was effective in preventing chemotherapy-
induced nausea in animals, the clinical observations have
been contradictory. Double-blinded crossover studies with
gynecologic cancer patients receiving cisplatin have shown
that ginger when combined with standard anti-emetic
regimen was ineffective in reducing chemotherapy-induced
nausea and vomiting in the acute phase of cisplatin-induced
emesis, while it was as effective in the delayed phase and the
effect was similar to that of the conventionally used meto-
clopramide.35 Subsequent studies have shown it to be effec-
tive in reducing CINV stimulated by cyclophosphamide
containing anticancer drug regimens, with the effect being
equal to that of metoclopramide but inferior to ondanse-
tron.36 Additionally combining high protein meals with ginger
is also shown to reduce the chemotherapy-induced delayed
nausea and the use of standard anti-emetic medications in
cancer patients.37
Series of reports published in the recent past have also
shown that combining the conventionally used anti-emetics the
5-HT(3) receptor antagonists and dexamethasone with ginger
offered better effects in reducing the CINV in children and
young adults being treated for sarcoma of the bone38 and
women for breast cancer.39 Additionally, ginger supplementa-
tion at a daily dose of 0.5–1.0 g along with 5-HT(3) receptor
antagonist anti-emetic on day 1 of all cycles is also shown to
reduce the severity of acute chemotherapy-induced nausea in
adult cancer patients indicating its usefulness.40 However, the
observations of Zick et al.,41 contradict the previous reports and
indicate that ginger offers no benecial effects in reducing the
prevalence or severity of acute or delayed CINV when combined
with 5-HT3 receptor antagonists and/or aprepitant. Addition-
ally, the authors also reported that the cohorts receiving both
ginger and aprepitant had more severe acute nausea than
participants on aprepitant only suggesting a possible
antagonism.41
5.4 Ginger prevents gastric ulcerations
Gastric ulcers are one of the most important causes of human
morbidity and ginger has been shown to offer benecial effects
against ulcerogens. In the following sections the gastro-
protective effects of ginger against various stresses will be
accordingly addressed.
5.4.1 Ginger protects against indomethacin-induced ulcer
in rat. Prolonged consumption of high doses of the analgesic
indomethacin, causes gastric ulcers by generating free radicals,
inhibiting prostaglandin synthesis and increasing the expres-
sion of IL-1 and TNF-a.8,38,42 Preclinical studies have shown that
oral administration of 500 mg kg
1 ginger extract produced
signicant anti-ulcerogenic activity in rats subjected to indo-
methacin administration.43
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Food & Function
5.4.2 Ginger protects against aspirin-induced ulcer in rat.
Aspirin, a nonselective cyclooxygenase inhibitor is one of the
most commonly used analgesic-antipyretic in clinics. The
chronic use of aspirin causes mucosal damage by interfering
with prostaglandin synthesis, increasing acid secretion and
back diffusion of H+ ions.44 Experiments have shown that oral
administration of ginger oil (0.5 and 1 g kg
1) ameliorates
aspirin alone and aspirin plus pylorus ligation-induced gastric
ulceration in rats by decreasing gastric acid secretion and
increase in mucus wall thickness.45
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5.4.3 Ginger protects against reserpine-induced ulcer in
rat. Reserpine is a potent gastric ulcerogen and causes gastric
ulcerations by generating free radicals, inhibiting mucus
release and triggering the breakdown of surface mucus by
stimulating b-adrenoceptor.46,47 Preclinical studies have shown
that pretreatment with 500 mg kg
1 of ginger extract pre-
vented the occurrence of reserpine-induced gastric
ulceration.45
5.4.4 Ginger protects against hypothermic restraint stress-
induced ulcer in rat. Hypothermic restraint is physical form of
stress and causes mucosal erosion and peptic ulcer At a cellular
level hypothermic restraint stress causes generation of free
radicals, lipid peroxidation, alteration in the levels of prosta-
glandin and histamine release, disturbances of gastric mucosal
circulation and abnormal gastric motility,48 and alteration of
gastric secretion,49 all of which have been shown to contribute
towards stress-induced gastric mucosal damage and depletion
of gastric mucus. Animal studies have shown that pretreatment
with 500 mg kg
1 of ginger extract signicantly inhibited the
gastric juice secretion and thus prevented the occurrence of
ulcer caused by hypothermic restraint stress.43
5.4.5 Ginger protects against pyloric ligation-induced
gastric ulcer in rat. Pyloric ligation-induced model of gastric
ulceration is an important preclinical model study. The lesions
are induced through histamine-2 receptors (H2R), by triggering
the secretion of acid (HCl) into the stomach lumen through the
cAMP/protein kinase pathway.50,51 Studies with rats have shown
that the pretreatment with ginger extract (500 mg kg
1)
decreases gastric acid secretion and to inhibit ulcer formation.43
Additionally, studies have also shown that ginger oil (0.5 and 1 g
kg
1) was effective in preventing against pyloric-ligation
induced gastric ulceration and to mediate these effects by
inhibiting gastric acid secretion, by increasing mucus wall
thickness and reducing the levels of serum g-GTT.45
5.4.6 Ginger protects against ethanol-induced ulcer in rat.
Ethanol is an important gastric ulcerogen and causes ulcers by
generating free radicals.52 Animal studies with laboratory rats
have shown that oral administration of acetone extract of ginger
(1000 mg kg
1), zingiberene (100 mg kg
1) and 6-gingerol
signicantly inhibited gastric lesions induced by HCl/ethanol.53
Animal studies have shown that oral pretreatment with ginger
extract (500 mg kg
1) orally exert signicant cytoprotection
against 80% ethanol, 0.6 M HCl, 0.2 M NaOH and 25% NaCl
induced gastric lesions.43 Aqueous extract of ginger rhizome
(200 mg kg
1) is also reported to protect ethanol stress-induced
ulcers in rats by recovering gastric mucus damage.54
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Additionally, recent studies also indicate that rats fed with
spicy diet containing ginger (0.05% for 8 weeks) were protected
against ethanol-induced gastric and intestinal mucosal injury
by signicantly enhancing the activities of antioxidant enzymes
SOD, CAT, GPrx and GST.55 The ginger phytochemicals like b-
sesquiphellandrene, b-bisabolene, ar-curcumene and 6-shogaol
have also been shown to possess gastroprotective effect against
HCl/ethanol-induced gastric lesions.53
5.4.7 Ginger protects against swim stress-induced ulcer in
rat. Stresses resulting from physiological and psychological
factors are shown to cause gastric ulcers by affecting gastroin-
testinal defense and increasing accumulation of acid in the
lumen. Pretreatment with aqueous extract of ginger (200 mg
kg
1) protected rats against the gastric ulcers induced by swim
stress by aiding recovery of gastric mucus damage and
normalizing the depleted antioxidant enzymes.54
5.4.8 Ginger protects against acetic acid-induced ulcer in
rat. Acetic acid (50–60%) is an important experimental ulcer-
ogen and has been regularly used to study the gastroprotective
effects of investigatory molecules. Administration of acetic acid
increases the XO activity, platelet aggregating factor formation
and ROS all of which contribute to the pathological events.56,57
Ko and Leung,58 investigated the gastroprotective effects of
ginger against the acaetic acid-induced ulcerogenesis and
observed that the cohorts pretreated with ginger extract had
reduced gastric ulcer area. Dose-dependent protective effects
were seen and biochemical studies showed to be mediated by
attenuation of XO and MPO and reducing the levels of MDA in
the ulcerated mucosa.58
5.4.9 Effect of ginger against Helicobacter pylori infection.
Helicobacter pylori a microaerophilic bacterium is categorized as
a group I carcinogen59 and a major contributor (70–80%) for
peptic ulcer and gastric cancer.59,60 Innumerable preclinical
studies have shown the various extracts of ginger, the oil of
ginger, gingerol containing fractions were effective in inhibiting
the growth of H. pylori,61–64 including against the highly virulent
CagA+ strains.61 Seminal studies by Siddaraju and Dharmesh64
have also shown that the ginger-free phenolic and hydrolysed
phenolic fractions inhibited H. pylori growth and the effect to be
better than that of lansoprazole.64 The ginger-free phenolic and
ginger-hydrolysed phenolic fractions are also reported to
possess inhibitory effects on the growth of H. pylori, to scavenge
free radicals, possess reducing power abilities, protects DNA
and to inhibit lipid peroxidation.64 Laboratory studies have also
shown that the pretreatment with the standardized ginger
extract (100 mg kg
1) decreased H. pylori load, and reduced
both acute and chronic muscosal and submucosal inamma-
tion, cryptitis, as well as epithelial cell degeneration and erosion
induced by H. pylori in mice.65
6 Effect of ginger on hyperglycaemia-
induced gastric dysrhythmias
In people with diabetes, dyspepsia and other gastric ailments
due to gastropathy are common and these disturbances affect
their quality of life. The pathogenesis of diabetic gastropathy is
multifactorial and is predominantly characterized by motor
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Review
disturbances such as delayed gastric emptying, reduced antral
contractions, decreased fundic tone, pylorospasm, etc. In
people with diabetes, the degree of glycaemic control can
inuence the magnitude of gastric motor and myoelectric
dysfunction. During periods of hyperglycaemia gastric
emptying is delayed and gastric slow wave dysrhythmias
become prominent.66 Double blind, placebo controlled studies
with healthy volunteers have shown, when compared to a
placebo, the cohorts receiving ginger had decreased the
induction of tachygastria in response to acute hyperglycaemia.66
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Additionally, administering ginger did not affect the slow wave
disruptions elicited by 400 mg of misoprostol. These observa-
tions clearly indicate that ginger mediates its antidysrhythmic
effects by preventing the production of prostaglandin during
periods of hyperglycaemia.66
7 Mechanism/s of action
7.1 Ginger scavenges free radicals
Free radicals like the ROS and RNS which contain one or more
unpaired electrons are extremely reactive and initiates/
contributes to the pathogenesis and toxic effects of radiation
and xenobiotic compounds.67–72 Experiments have shown that
ginger extracts and its phytochemicals possess free radical
scavenging effects and to scavenge, superoxide, hydroxyl, nitric
oxide and ABTS*+ radicals in cell free assays.67,68 The phyto-
chemical zingerone was observed to scavenge superoxide,69
peroxyl,70 peroxynitrite71 and to inhibit the formation of perox-
ynitrite-mediated tyrosine nitration.71 Another important
phytochemical of ginger,6-gingerol scavenged peroxyl radi-
cals,70 and caused a dose-dependent inhibition of NO produc-
tion and signicant reduction of iNOS in LPS-stimulated
J774.1 cells.72
7.2 Ginger prevents oxidative damage to lipids
Free radicals induce damage to membrane lipids, proteins and
DNA. Of the various lipid constituents the PUFA are highly
vulnerable to peroxidative attack and damage to these mole-
cules alters the cell membrane structure, properties and func-
tions.70 Ginger and its phytochemicals 6-gingerol and zingerone
have been shown to prevent/inhibit lipid peroxidation
in vitro.70,73–75 Additionally, previous studies have also shown
that the polyphenols prevents lipid peroxidation of the food and
to inhibit the absorption of the lipotoxin MDA into the blood
stream and, thereby also prevent atherogenesis.76 It is quite
possible that ginger mediates its protective effects on both
stomach and the vascular system through this mechanism and
offers additional benet to the individual.76
7.3 Ginger enhances antioxidant defense systems in vivo
Eukaryotic cells also contain certain molecules (glutathione,
vitamin C, uric acid, albumin, bilirubin, vitamin E, carotenoids
and ubiquinone) and enzymes (SOD, GSH-Px and CAT) to
detoxify the free radicals.77,78 Previous studies have shown that
ginger reduces the oxidative stress by promoting antioxidant
mechanisms.79–81 Ginger extract is shown to ameliorate ethanol-
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Food & Function
induced gastric injury,55 indomethacin-induced gastric ulcera-
tions43 and acetic acid-induced gastric inammation82 by
enhancing the levels of antioxidant molecules and enzymes.
7.4 Ginger possesses anti-inammatory effects
Seminal studies carried out in the recent past indicate that
inammation plays a cardinal role in various pathophysiolog-
ical processes and that it is mediated by TNF-a, NF-kb, i-NOS
and COX-2, and increased generation of proinammatory
eisonaoids.83 Ginger and its compounds have been studied in
detail for its anti-inammatory effects and studies have shown
it to suppress synthesis of prostaglandin by inhibiting COX-1,
COX-2 and the biosynthesis of leukotriene by inhibiting 5-
LOX.84,85 The phytochemicals 8-paradol and 8-shogaol are also
reported to possess strong inhibitory effects on COX-2 enzyme
activity in vitro.86 Ginger and its phytochemicals are also shown
to decrease the levels of pro-inammatory cytokines (TNF-a, IL
1b, IL-6 and interferon-g) and to reduce the elevated expression
of NFkB.87 Ginger extract inhibited the activity of COX-2, NF-kB
and to inhibit the release of IL-1b, IL-6, IL-8, and TNF-a from
LPS-stimulated human peripheral blood mononuclear cells in
combating H. pylori infection.65
7.5 Ginger modulates detoxifying enzymes
The enzymes belonging to the Phase I (Cyto P450, Cyto b5 etc.)
and Phase II (GST, UDPGT etc.) categories are important in the
detoxication of xenobiotic compounds that have entered the
system.88,89 Experimental studies have shown that feeding
ginger increases the levels of microsomal cytochrome P 450-
dependent aryl hydroxylase, Cyto P450, Cyto b5, GST, UGT, aryl
hydrocarbon and quinone reductase in liver.88–92 Studies have
also shown that ginger oil also possesses benecial effects and
to increase the activity of AHH and GST in mouse liver.92
7.6 Ginger modulates muscarinic and 5HT receptors and
enhances gastric motility
Muscarinic receptor (M1 and M2) and 5HT are an integral part
of the enteric nervous system and inuences GI motility. Ex vivo
studies with the rat stomach fundus have shown that the
hydromethanolic extract of dried ginger was effective in
reversing the spasmogenic effects of Zo$Cr.93 Ginger and its
phytochemical gingerol mediated the anti-spasmogenic activity
by inhibiting the butyrylcholinesterase and enhancing the
muscaranic activity. Additionally experiments have also shown
that ginger possess calcium antagonistic activity leading to
spasmolyis. The enhanced spasmolytic activity prevents the
possible gastric damage and ulcerogenesis by reducing the
gastric emptying time and decreasing the contact time of acidic
gastric contents with the mucosa.93 Ginger also stimulates
synthesis and secretion of mucin which acts as a buffer and
thereby prevents the corrosive damage of HCl on the walls of the
pyloric end of the stomach. Together all these observations
indicate that ginger, by stimulating the muscarinic receptors
and inhibiting 5-HT(3) receptors, mediates gastroprotective
effects.
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8 Conclusions
Preclinical studies have shown that ginger is effective as a gas-
troprotective agent. However, the clinical data is insufficient to
draw rm conclusions especially against motion and chemo-
therapy-induced nausea and vomiting which may be due to the
variations in the bioactive compounds as these studies were
performed in different countries. In view of these observations
it is imperative that some quality control is established for the
presence of active phytochemicals at the required levels. Addi-
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 foods
Review
Bioactive Compounds and Bioactivities of Ginger
(Zingiber officinale Roscoe)
Qian-Qian Mao 1 , Xiao-Yu Xu 1 , Shi-Yu Cao 1 , Ren-You Gan 2, * , Harold Corke 2 , Trust Beta 3,4
and Hua-Bin Li 1, *
1 Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of
Public Health, Sun Yat-sen University, Guangzhou 510080, China; maoqq@mail2.sysu.edu.cn (Q.-Q.M.);
xuxy53@mail2.sysu.edu.cn (X.-Y.X.); caoshy3@mail2.sysu.edu.cn (S.-Y.C.)
2 Department of Food Science & Technology, School of Agriculture and Biology, Shanghai Jiao Tong University,
Shanghai 200240, China; hcorke@sjtu.edu.cn
3 Department of Food & Human Nutritional Sciences, University of Manitoba, Winnipeg,
MB R3T 2N2, Canada; Trust.Beta@umanitoba.ca
4 Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg,
MB R3T 2N2, Canada
* Correspondence: renyougan@sjtu.edu.cn (R.-Y.G.); lihuabin@mail.sysu.edu.cn (H.-B.L.);
Tel.: +86-21-3420-8517 (R.-Y.G.); +86-20-873-323-91 (H.-B.L.)




Received: 12 May 2019; Accepted: 28 May 2019; Published: 30 May 2019


Abstract: Ginger (Zingiber officinale Roscoe) is a common and widely used spice. It is rich in various
chemical constituents, including phenolic compounds, terpenes, polysaccharides, lipids, organic
acids, and raw fibers. The health benefits of ginger are mainly attributed to its phenolic compounds,
such as gingerols and shogaols. Accumulated investigations have demonstrated that ginger possesses
multiple biological activities, including antioxidant, anti-inflammatory, antimicrobial, anticancer,
neuroprotective, cardiovascular protective, respiratory protective, antiobesity, antidiabetic, antinausea,
and antiemetic activities. In this review, we summarize current knowledge about the bioactive
compounds and bioactivities of ginger, and the mechanisms of action are also discussed. We hope
that this updated review paper will attract more attention to ginger and its further applications,
including its potential to be developed into functional foods or nutraceuticals for the prevention and
management of chronic diseases.

Keywords: phytochemicals; antioxidant; antinausea; antiobesity; anticancer; anti-inflammatory

1. Introduction
Ginger (Zingiber officinale Roscoe), which belongs to the Zingiberaceae family and the Zingiber
genus, has been commonly consumed as a spice and an herbal medicine for a long time [1]. Ginger root
is used to attenuate and treat several common diseases, such as headaches, colds, nausea, and emesis.
Many bioactive compounds in ginger have been identified, such as phenolic and terpene compounds.
The phenolic compounds are mainly gingerols, shogaols, and paradols, which account for the various
bioactivities of ginger [2]. In recent years, ginger has been found to possess biological activities, such
as antioxidant [3], anti-inflammatory [4], antimicrobial [5], and anticancer [6] activities. In addition,
accumulating studies have demonstrated that ginger possesses the potential to prevent and manage
several diseases, such as neurodegenerative diseases [7], cardiovascular diseases [8], obesity [9],
diabetes mellitus [10], chemotherapy-induced nausea and emesis [11], and respiratory disorders [12].
In this review, we focus on the bioactive compounds and bioactivities of ginger, and we pay special
attention to its mechanisms of action.

Foods 2019, 8, 185; doi:10.3390/foods8060185 www.mdpi.com/journal/foods

Foods 2019, 8, 185 2 of 21

2. Bioactive Components and Bioactivities of Ginger

2.1. Bioactive Components

Ginger is abundant in active constituents, such as phenolic and terpene compounds [13].
The phenolic compounds in ginger are mainly gingerols, shogaols, and paradols. In fresh ginger,
gingerols are the major polyphenols, such as 6-gingerol, 8-gingerol, and 10-gingerol. With heat treatment
or long-time storage, gingerols can be transformed into corresponding shogaols. After hydrogenation,
shogaols can be transformed into paradols [2]. There are also many other phenolic compounds in
ginger, such as quercetin, zingerone, gingerenone-A, and 6-dehydrogingerdione [14,15]. Moreover,
there are several terpene components in ginger, such as β-bisabolene, α-curcumene, zingiberene,
α-farnesene, and β-sesquiphellandrene, which are considered to be the main constituents of ginger
essential oils [16]. Besides these, polysaccharides, lipids, organic acids, and raw fibers are also present
in ginger [13,16].

2.2. Antioxidant Activity

It has been known that overproduction of free radicals, such as reactive oxygen species (ROS),
plays an important part in the development of many chronic diseases [17]. It has been reported that a
variety of natural products possess antioxidant potential, such as vegetables, fruits, edible flowers,
cereal grains, medicinal plants, and herbal infusions [18–24]. Several studies have found that ginger
also has high antioxidant activity [14,25].
The antioxidant activity of ginger has been evaluated in vitro via ferric-reducing antioxidant power
(FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,20 -azinobis-(3-ethylbenzothiazoline-6-sulfonic
acid) (ABTS) methods. The results revealed that dried ginger exhibited the strongest antioxidant
activity, because the number of phenolic compounds was 5.2-, 1.1-, and 2.4-fold higher than that of
fresh, stir-fried, and carbonized ginger, respectively. The antioxidant activity of different gingers
had a tendency to be the following: dried ginger > stir-fried ginger > carbonized ginger > fresh
ginger. This was mainly associated with their polyphenolic contents. When fresh ginger was heated,
dried ginger with higher antioxidant activity was obtained, because fresh ginger contains a higher
moisture content. However, when dried ginger was further heated to obtain stir-fried ginger and
carbonized ginger, the antioxidant activity decreased, because the processing could change gingerols
into shogaols [26]. Additionally, a fraction of the dried ginger powder abundant in polyphenols
showed high antioxidant activity based on data from FRAP, oxygen radical absorbance capacity,
and cellular antioxidant activity assays [27]. Besides, the type of extraction solvent could have an effect
on the antioxidant activity of ginger. An ethanolic extract of ginger showed high Trolox-equivalent
antioxidant capacity and ferric-reducing ability, and an aqueous extract of ginger exhibited strong free
radical scavenging activity and chelating ability [16]. Moreover, ethanolic, methanolic, ethyl acetate,
hexane, and water extracts of ginger respectively inhibited 71%, 76%, 67%, 67%, and 43% of human
low-density lipoprotein (LDL) oxidation induced by Cu2+ [28]. Results from a xanthine/xanthine
oxidase system showed that an ethyl acetate extract and an aqueous extract had higher antioxidant
properties than ethanol, diethyl ether, and n-butanol extracts did [3].
Several studies have indicated that ginger was effective for protection against oxidative
stress. The underlying mechanisms of antioxidant action were investigated in cell models [14,29].
Ginger extract showed antioxidant effects in human chondrocyte cells, with oxidative stress mediated
by interleukin-1β (IL-1β). It stimulated the expression of several antioxidant enzymes and reduced
the generation of ROS and lipid peroxidation [30]. Additionally, ginger extract could reduce the
production of ROS in human fibrosarcoma cells with H2 O2 -induced oxidative stress [31]. In stressed
rat heart homogenates, ginger extract decreased the content of malondialdehyde (MDA), which was
related to lipid peroxidation [29]. Ginger and its bioactive compounds (such as 6-shogaol) exhibited
antioxidant activity via the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway
(Figure 1) [32]. In human colon cancer cells, 6-shogaol increased intracellular glutathione/glutathione
 Foods 2019, 8, 185 3 of 21

disulfide (GSH/GSSG) and upregulated Nrf2 target gene expression, such as with heme oxygenase-1
Foods 2019, 8, x FOR PEER REVIEW 3 of 21
(HO-1), metallothionein 1 (MT1), aldo-keto reductase family 1 member B10 (AKR1B10), ferritin light
chain(FTL),
chain (FTL), and
and γ-glutamyltransferase-like
γ-glutamyltransferase-like activity
activity44(GGTLA4).
(GGTLA4).Besides,
Besides,6-shogaol
6-shogaol also
alsoenhanced
enhanced the
expression of genes involved in glutathione synthesis, such as the glutamate-cysteine
the expression of genes involved in glutathione synthesis, such as the glutamate-cysteine ligase ligase catalytic
subunit (GCLC)
catalytic subunitand the glutamate-cysteine
(GCLC) ligase modifier
and the glutamate-cysteine subunit
ligase (GCLM).
modifier Further(GCLM).
subunit analysis Further
revealed
that 6-shogaol
analysis revealedand its metabolite
that 6-shogaol andactivated Nrf2 via the
its metabolite alkylation
activated Nrf2ofviacysteine residues of
the alkylation ofKelch-like
cysteine
ECH-associated protein 1 (Keap1) [33]. Moreover, ginger phenylpropanoids
residues of Kelch-like ECH-associated protein 1 (Keap1) [33]. Moreover, ginger phenylpropanoidsimproved Nrf2 activity
and enhanced
improved Nrf2 the levelsand
activity of glutathione
enhanced the S-transferase P1 (GSTP1) S-transferase
levels of glutathione as well as the P1downstream
(GSTP1) aseffector
well asof
the downstream effector of the Nrf2 antioxidant response element in foreskin fibroblast cells [15].stem
the Nrf2 antioxidant response element in foreskin fibroblast cells [15]. In a human mesenchymal In
acell model,
human ginger oleoresin
mesenchymal stem was investigated
cell model, gingerfor its effectswas
oleoresin on investigated
injuries that were
for itsinduced
effects onby injuries
ionizing
radiation.
that The treatment
were induced of oleoresin
by ionizing could
radiation. Thedecrease
treatment theoflevel of ROScould
oleoresin by translocating
decrease theNrf2 leveltoofthe
ROScell
nucleus and activating the gene expression of HO-1 and NQO1 (nicotinamide
by translocating Nrf2 to the cell nucleus and activating the gene expression of HO-1 and NQO1 adenine dinucleotide
phosphate (NADPH)
(nicotinamide adenine quinone dehydrogenase
dinucleotide 1) [14].
phosphate (NADPH) quinone dehydrogenase 1) [14].

Figure1.1.The
Figure The potential
potential mechanism
mechanism forfor
thethe antioxidant
antioxidant action
action of 6-shogoal:
of 6-shogoal: 6-shogoal
6-shogoal leadsleads
to theto
the translocation
translocation ofinto
of Nrf2 Nrf2theinto the nucleus
nucleus and increases
and increases the expression
the expression of Nrf2
of Nrf2 target genestarget genes by
by modifying
modifying
Keap1 Keap1 and Nrf2
and preventing preventing Nrf2 from proteasomal
from proteasomal degradation.degradation. Thus,ofthe
Thus, the level GSHlevel of GSH increases,
increases, and the
level of ROS decreases. Abbreviations: Nrf2, nuclear factor erythroid 2-related factor 2; Keap1,factor
and the level of ROS decreases. Abbreviations: Nrf2, nuclear factor erythroid 2-related Kelch-2;
Keap1,
like Kelch-like ECH-associated
ECH-associated protein
protein 1; NQO1, 1; NQO1, nicotinamide
nicotinamide adenine dinucleotide
adenine dinucleotide phosphate
phosphate (NADPH)
(NADPH)
quinone quinone dehydrogenase
dehydrogenase 1; HO-1,
1; HO-1, heme heme oxygenase-1;
oxygenase-1; GCLC, glutamate-cysteine
GCLC, glutamate-cysteine ligase
ligase catalytic
catalytic subunit; GCLM, glutamate-cysteine ligase modifier subunit; Trx1, thioredoxin
subunit; GCLM, glutamate-cysteine ligase modifier subunit; Trx1, thioredoxin 1; TrxR1, thioredoxin 1; TrxR1,
thioredoxin
reductase 1; AKR1B10, 1; AKR1B10,
reductase Aldo-keto Aldo-keto
reductase reductase
family familyB10;
1 member 1 member B10; FTL,
FTL, ferritin lightferritin
chain; light chain;
GGTLA4,
GGTLA4, γ-glutamyltransferase-like activity 4; ROS, reactive oxygen species; GSH,
γ-glutamyltransferase-like activity 4; ROS, reactive oxygen species; GSH, glutathione; ARE, glutathione; ARE,
antioxidantresponse
antioxidant responseelement.
element.

An animal model has also been used to investigate the antioxidant properties of ginger and
An animal model has also been used to investigate the antioxidant properties of ginger and its
its bioactive compounds in vivo. There, 6-shogaol exhibited antioxidant potential by inducing the
bioactive compounds in vivo. There, 6-shogaol exhibited antioxidant potential by inducing the
expression of Nrf2 target genes such as MT1, HO-1, and GCLC in the colon of wild-type mice, but not
expression of Nrf2 target genes such as MT1, HO-1, and GCLC in the colon of wild-type mice, but not
Nrf2−/−−/− mice [33]. In addition, rats with a gastric ulcer induced by diclofenac sodium were treated
Nrf2 mice [33]. In addition, rats with a gastric ulcer induced by diclofenac sodium were treated
with the butanol extract of ginger. It could prevent an increase in the level of MDA and a decrease in
with the butanol extract of ginger. It could prevent an increase in the level of MDA and a decrease in
catalase activity as well as the level of glutathione [34]. Moreover, the 6-gingerol-rich fraction from
catalase activity as well as the level of glutathione [34]. Moreover, the 6-gingerol-rich fraction from
ginger could reduce the levels of H2 O2 and MDA, enhance antioxidant enzyme activity, and increase
ginger could reduce the levels of H2O2 and MDA, enhance antioxidant enzyme activity, and increase
glutathioneininrats
glutathione ratswith
withoxidative
oxidativedamage
damageinduced
inducedbybychlorpyrifos
chlorpyrifos[25].
[25].Furthermore,
Furthermore,treatment
treatmentwith
with
ginger extract elevated the contents of antioxidants and testosterone in serum and protected rat
ginger extract elevated the contents of antioxidants and testosterone in serum and protected rat testestestes
frominjuries
from injuriesininchemotherapy
chemotherapywith
withcyclophosphamide
cyclophosphamide[35].
[35].
Overall, in vitro and in vivo studies have demonstrated that ginger and its bioactive compounds,
such as 6-shogaol, 6-gingerol, and oleoresin, possess strong antioxidant activity (Table 1). Moreover,
the activation of the Nrf2 signaling pathway is crucial to the underlying mechanisms of action. It
should also be pointed out that the overproduction of ROS in the human body is considered to be a
Foods 2019, 8, 185 4 of 21

Overall, in vitro and in vivo studies have demonstrated that ginger and its bioactive compounds,
such as 6-shogaol, 6-gingerol, and oleoresin, possess strong antioxidant activity (Table 1). Moreover,
the activation of the Nrf2 signaling pathway is crucial to the underlying mechanisms of action.
It should also be pointed out that the overproduction of ROS in the human body is considered to be
a cause of many diseases. Theoretically, antioxidants should be effective. However, several factors,
such as health conditions, individual differences, the lifestyles of people, other dietary factors, and the
dosage, solubility, and oral intake of antioxidants could affect the bioaccessibility and bioavailability of
antioxidants, leading to low blood concentrations overall, which probably could explain why most
antioxidants do not work in the real world.

2.3. Anti-Inflammatory Activity

A series of studies showed that ginger and its active constituents possessed anti-inflammatory
activity (Table 2), which could protect against inflammation-related diseases such as colitis [4,36].
The anti-inflammatory effects were mainly related to phoshatidylinositol-3-kinase (PI3K), protein
kinase B (Akt), and the nuclear factor kappa light chain-enhancer of activated B cells (NF-κB).
In addition, 6-shogaol showed protective effects against tumor necrosis factor α (TNF-α)-induced
intestinal barrier dysfunction in human intestinal cell models. It also prevented the upregulation
of Claudin-2 and the disassembly of Claudin-1 via the suppression of signaling pathways involved
with PI3K/Akt and NF-κB [37]. In addition, 6-dehydroshogaol was more potent than 6-shogaol
and 6-gingerol in reducing the generation of proinflammatory mediators such as nitric oxide (NO)
and prostaglandin E2 (PGE2 ) in mouse macrophage RAW 264.7 cells [36]. Besides, ginger extract
and zingerone inhibited NF-κB activation and decreased the level of IL-1β in the colons of mice,
which alleviated colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid [38]. Ginger also protected
against anti-CD3 antibody-induced enteritis in mice, and ginger could reduce the production of
TNF-α as well as the activation of Akt and NF-κB [39]. Moreover, nanoparticles derived from edible
ginger (GDNPs 2) could prevent intestinal inflammation by increasing the levels of anti-inflammatory
cytokines such as interleukin-10 (IL-10) and IL-22 and decreasing the levels of proinflammatory
cytokines such as TNF-α, IL-6, and IL-1β in mice with acute colitis and chronic colitis [4]. In addition,
nanoparticles loaded with 6-shogaol were found to attenuate colitis symptoms and improve colitis
wound repair in mice with dextran sulfate sodium-induced colitis [40]. Moreover, microRNAs of
ginger exosome-like nanoparticles (GELN) ameliorated mouse colitis by inducing the production of
IL-22, a barrier function improvement factor [41]. Additionally, a fraction rich in 6-gingerol prevented
an increase in inflammatory markers such as myeloperoxidase, NO, and TNF-α in the brain, ovaries,
and uterus of rats treated with chlorpyrifos [25]. Furthermore, 28 male endurance runners consumed
capsules of 500 mg of ginger powder. The results showed that the treatment could attenuate the
post-exercise elevation of several cytokines that promote inflammation, such as plasma IL-1β, IL-6,
and TNF-α [42].
In general, ginger and its active compounds have been found to be effective in alleviating
inflammation, especially in inflammatory bowel diseases. The anti-inflammatory mechanisms of
ginger are probably associated with the inhibition of Akt and NF-κB activation, an enhancement in
anti-inflammatory cytokines, and a decline in proinflammatory cytokines. Notably, the application
of ginger nanoparticles has the potential to improve the prevention of and therapy for inflammatory
bowel disease.
Foods 2019, 8, 185 5 of 21

Table 1. The antioxidant activity and potential mechanisms of ginger.

Constituent Study Type Subjects Dose Potential Mechanisms Ref.

Increasing the intracellular GSH/GSSG ratio;
HCT-116 human colon cancer decreasing the level of ROS;
In vivo 20 µM
6-shogaol cells upregulating the expression of AKR1B10, FTL, GGTLA4, [33]
HO-1, MT1, GCLC, and GCLM genes
Wild-type and Nrf2−/−
In vitro 100 mg/kg Upregulating the expression of MT1, HO-1, and GCLC
C57BL/6J mice
Reducing ROS production;
Human mesenchymal stem
Ginger oleoresin In vitro 100 µg/mL inducing the translocation of Nrf2 to the cell nucleus; [14]
cells
activating HO-1 and NQO1 gene expression
Ginger phenylpropanoids In vitro BJ foreskin fibroblasts 40 µg/mL Increasing Nrf2 activity and the level of GSTP1 [15]
Reducing the levels of H2 O2 and MDA;
6-gingerol-rich fraction In vivo Female Wistar rats 50 and 100 mg/kg increasing the activities of antioxidant enzymes and the [25]
level of GSH
Reducing the level of MDA;
In vivo Male Wistar albino rats 100 mg/kg preventing the depletion of catalase activity and GSH [34]
content
Ginger extract
C28I2 human chondrocyte Increasing the gene expression of antioxidant enzymes;
In vitro 5 and 25 µg/mL [30]
cells reducing the content of ROS and lipid peroxidation
HT1080 human fibrosarcoma
In vitro 200 and 400 µg/mL Reducing the generation of ROS [31]
cells
In vitro Rat heart homogenates 78–313 µg/mL Decreasing the level of MDA [29]
GSSG, glutathione disulfide; MT1, metallothionein 1; GSTP1, glutathione S-transferase P1; MDA, malondialdehyde; Ref, reference.
Foods 2019, 8, 185 6 of 21

Table 2. Anti-inflammatory activity and potential mechanisms of ginger.

Constituent Study Type Subjects Dose Potential Mechanisms Ref.

HT-29/B6 and Caco-2
6-shogaol In vitro human intestinal 100 µM Inhibiting the PI3K/Akt and NF-κB signaling pathways [37]
epithelial cells
6-shogaol and 6-gingerol, RAW 264.7 mouse
In vitro 2.5, 5, and 10 µM Inhibiting the production of NO and PGE2 [36]
6-dehydroshogaol macrophage cells
6-gingerol-rich fraction In vivo Female Wistar rats 50 and 100 mg/kg Increasing the levels of myeloperoxidase, NO, and TNF-α [25]
Female C57BL/6 Increasing the levels of IL-10 and IL-22;
GDNPs 2 In vivo 0.3 mg [4]
FVB/NJ mice decreasing the levels of TNF-α, IL-6, and IL-1β
Ginger extract and Inhibiting NF-κB activation and decreasing the level of
In vivo Female BALB/c mice 0.1, 1, 10, and 100 mg/kg [38]
zingerone IL-1β
Inhibiting the production of TNF-α;
Ginger extract In vivo C57BL6/J mice 50 mg/mL [39]
Activating Akt and NF-κB
NO, nitric oxide; PGE2 , prostaglandin E2 ; TNF-α, tumor necrosis factor α; GDNPs 2, nanoparticles derived from edible ginger.
Foods 2019, 8, 185 7 of 21

2.4. Antimicrobial Activity

The spread of bacterial, fungal, and viral infectious diseases has been a major public threat
due to antimicrobial resistance. Several herbs and spices have been developed into natural effective
antimicrobial agents against many pathogenic microorganisms [43]. In recent years, ginger has been
reported to show antibacterial, antifungal, and antiviral activities [44,45].
Biofilm formation is an important part of infection and antimicrobial resistance. One result
found that ginger inhibited the growth of a multidrug-resistant strain of Pseudomonas aeruginosa by
affecting membrane integrity and inhibiting biofilm formation [46]. In addition, treatment with ginger
extract blocked biofilm formation via a reduction in the level of bis-(30 -50 )-cyclic dimeric guanosine
monophosphate (c-di-GMP) in Pseudomonas aeruginosa PA14 [47]. Moreover, a crude extract and
methanolic fraction of ginger inhibited biofilm formation, glucan synthesis, and the adherence of
Streptococcus mutans by downregulating virulence genes. Consistent with the in vitro study, a reduction
in caries development caused by Streptococcus mutans was found in a treated group of rats [48].
Furthermore, an in vitro study revealed that gingerenone-A and 6-shogaol exhibited an inhibitory
effect on Staphylococcus aureus by inhibiting the activity of 6-hydroxymethyl-7, 8-dihydropterin
pyrophosphokinase in the pathogen [49].
The compounds in ginger essential oil possess lipophilic properties, making the cell wall as
well as the cytoplasmic membrane more permeable and inducing a loss of membrane integrity in
fungi [50]. An in vitro study revealed that ginger essential oil effectively inhibited the growth of
Fusarium verticillioides by reducing ergosterol biosynthesis and affecting membrane integrity. It could
also decrease the production of fumonisin B1 and fumonisin B2 [51]. In addition, ginger essential
oil had efficacy in suppressing the growth of Aspergillus flavus as well as aflatoxin and ergosterol
production [50]. Moreover, the γ-terpinene and citral in ginger essential oil showed potent antifungal
properties against Aspergillus flavus and reduced the expression of some genes related to aflatoxin
biosynthesis [44]. Furthermore, fresh ginger was found to inhibit plaque formation induced by human
respiratory syncytial virus (HRSV) in respiratory tract cell lines. Ginger was effective in blocking
viral attachment and internalization [52]. In a clinical trial, ginger extract decreased hepatitis C virus
(HCV) loads, the level of α-fetoprotein (AFP), and markers relevant to liver function, such as aspartate
aminotransferase (AST) and alanine aminotransferase (ALT), in Egyptian HCV patients [53].
Therefore, ginger has been demonstrated to inhibit the growth of different bacteria, fungi,
and viruses. These effects could be mainly related to the suppression of bacterial biofilm formation,
ergosterol biosynthesis, and viral attachment and internalization (Table 3).

Table 3. Antimicrobial activity and potential mechanisms of ginger.

Constituent Study Type Subjects Dose Potential Mechanisms Ref.

Reducing ergosterol biosynthesis;
500, 1000, 2000, 3000, affecting membrane integrity;
Ginger In vitro Fusarium verticillioides [51]
4000, and 5000 µg/mL decreasing the production of fumonisin B1
essential oil
and fumonisin B2
Reducing ergosterol biosynthesis;
5, 10, 15, 20, 25, 50, 100,
In vitro Aspergillus flavus affecting membrane integrity; [50]
and 150 µg/mL
inhibiting the production of aflatoxin
Inhibiting the activity of
Gingerenone-A
In vitro Staphylococcus aureus 25, 50, and 75 µg/mL 6-hydroxymethyl-7, 8-dihydropterin [49]
and shogaol
pyrophosphokinase
50, 100, 150, and 200 Affecting membrane integrity;
In vitro Pseudomonas aeruginosa [46]
µg/mL inhibiting biofilm formation
Ginger extract
8, 16, 32, 64, and 128 Inhibiting biofilm formation, glucan
In vitro Streptococcus mutans [48]
µg/mL synthesis, and adherence
HEp-2 human larynx
epidermoid carcinoma
10, 30, 100, and 300 Blocking viral attachment and
In vitro cells and A549 human [52]
µg/mL internalization
lung carcinoma cells
with HRSV
HRSV, human respiratory syncytial virus.
Foods 2019, 8, x FOR PEER REVIEW 8 of 21

cells and A549 human

lung carcinoma cells
with HRSV
Foods 2019, 8, 185 8 of 21
HRSV, human respiratory syncytial virus.

2.5.
2.5.Cytotoxicity
Cytotoxicity
Cancer
Cancerisisdocumented
documentedtotobebea dominant
a dominantcause
causeofof
death, and
death, and there were
there wereapproximately
approximately9.6 9.6million
million
cases
casesofofdeath
deathinin
2018 [54].
2018 Several
[54]. research
Several works
research workshave demonstrated
have demonstrated thatthat
natural products
natural suchsuch
products as
fruits and medicinal plants possess anticancer activity [55,56]. Recently, ginger has
as fruits and medicinal plants possess anticancer activity [55,56]. Recently, ginger has been widely been widely
investigated
investigatedforforitsitsanticancer
anticancerproperties
propertiesagainst
againstdifferent
differentcancer
cancertypes,
types,such
suchasasbreast,
breast,cervical,
cervical,
colorectal,
colorectal,and
andprostate
prostatecancer
cancer[4,57,58].
[4,57,58].The
Thepotential
potentialmechanisms
mechanismsofofaction
actioninvolve
involvethe
theinhibition
inhibitionofof
proliferation
proliferationand
andthetheinduction
inductionofofapoptosis
apoptosisinincancer
cancer(Figure
(Figure2)2)[59,60].
[59,60].

Several
Figure2.2.Several
Figure signaling
signaling pathways
pathways are
are involved
involved ininthe
theanticancer
anticancermechanisms
mechanisms ofof6-gingerol.
6-gingerol.CDK:
CDK:
Cyclin-dependentkinase;
Cyclin-dependent kinase;PI3K:
PI3K:Phosphoinositide
Phosphoinositide3-kinase;
3-kinase;Akt:
Akt:Protein
Protein kinase
kinase B;B; mTOR:
mTOR: Mammalian
Mammalian
targetof
target of rapamycin;
rapamycin;AMPK:AMPK: 5’adenosine
5’adenosinemonophosphate-activated
monophosphate-activated protein kinase;kinase;
protein Bax: Bcl-2-associated
Bax: Bcl-2-
X protein; Bcl-2: B-cell lymphoma 2.
associated X protein; Bcl-2: B-cell lymphoma 2.

Severalinvestigations
Several investigationshave havedemonstrated
demonstratedthat thatginger
gingerand anditsitsbioactive
bioactivecompounds
compoundscan caninterfere
interfere
with the carcinogenic processes of colorectal cancer. It was observed in an in vitro
with the carcinogenic processes of colorectal cancer. It was observed in an in vitro study that a fraction study that a fraction
richininthe
rich thepolyphenols
polyphenolsofofdrieddriedginger
gingerpowder
powdersuppressed
suppressedthe theproliferation
proliferationofofcolorectal
colorectalcancer
cancercells
cells
and gastric adenocarcinoma cells [27]. Besides, treatment with ginger extract promoted apoptosis byby
and gastric adenocarcinoma cells [27]. Besides, treatment with ginger extract promoted apoptosis
decreasingthe
decreasing theexpression
expressionof of genes
genes involved
involvedwith withthe
theRas/extracellular
Ras/extracellularsignal-regulated
signal-regulated kinase
kinase(ERK)
(ERK)and
PI3K/Akt
and PI3K/Akt pathways, suchsuch
pathways, as theasv-Ki-ras2 Kirsten
the v-Ki-ras2 rat sarcoma
Kirsten viral oncogene
rat sarcoma homolog
viral oncogene ERK, Akt,
(KRAS),(KRAS),
homolog
and B-cell lymphoma-extralarge (Bcl-xL). It also increased the expression
ERK, Akt, and B-cell lymphoma-extralarge (Bcl-xL). It also increased the expression of caspase 9, of caspase 9, which promoted
apoptosis
which in HT-29
promoted colorectal
apoptosis in cancer
HT-29 cells [60]. In
colorectal rats with
cancer cells1,2-dimethylhydrazine-induced colon cancer,
[60]. In rats with 1,2-dimethylhydrazine-
induced colon cancer, ginger extract loading with coated alginate beads increased the activities and
ginger extract loading with coated alginate beads increased the activities of NADH dehydrogenase of
succinate dehydrogenase [61]. In addition, GDNPs 2 treatment decreased
NADH dehydrogenase and succinate dehydrogenase [61]. In addition, GDNPs 2 treatment decreased tumor numbers and tumor
loads numbers
tumor in mice with and colitis-associated
tumor loads in mice cancer
withinduced by azoxymethane
colitis-associated and dextran
cancer induced sodium sulfate.
by azoxymethane
The levels of proinflammatory cytokines were decreased, and intestinal epithelial
and dextran sodium sulfate. The levels of proinflammatory cytokines were decreased, and intestinal cell proliferation was
inhibitedcell
epithelial [4]. proliferation
In a pilot, randomized,
was inhibited and [4].
controlled trial,randomized,
In a pilot, ginger extractand supplementation
controlled trial, decreased
ginger
proliferation and increased apoptosis in the colonic mucosa of patients
extract supplementation decreased proliferation and increased apoptosis in the colonic mucosa with a high risk of colorectal
of
cancer. with
patients Ginger extract
a high risksupplementation
of colorectal cancer. induced
Ginger a decrease in the expressioninduced
extract supplementation of two markers
a decrease of cell
in
proliferation, telomerase reverse transcriptase (hTERT) and MIB-1 (epitope
the expression of two markers of cell proliferation, telomerase reverse transcriptase (hTERT) and of Ki-67), and increased the
expression of pro-apoptotic gene Bcl-2-associated X (Bax) [6]. In subjects with
MIB-1 (epitope of Ki-67), and increased the expression of pro-apoptotic gene Bcl-2-associated X (Bax) a high risk of colorectal
cancer,
[6]. ginger supplementation
In subjects with a high decreased cyclooxygenase-1
risk of colorectal cancer,(COX-1)
ginger expression, a key enzyme
supplementation in the
decreased
production of PGE2 , which indicated the preventive potential of ginger in colorectal cancer [62].
The cytotoxic effects and underlying mechanisms of ginger in prostate cancer were evaluated
both in vivo and in vitro. It was found that 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol
Foods 2019, 8, 185 9 of 21

showed an antiproliferative effect on human prostate cancer cells via a downregulation of the
protein expression of multidrug resistance associated protein 1 (MRP1) and glutathione-S-transferase
(GSTπ) [59]. In addition, binary combinations of ginger phytochemicals, such as 6-gingerol, 8-gingerol,
10-gingerol, and 6-shogaol, synergistically inhibited the proliferation of PC-3 prostate cancer cells [63].
An in vivo study investigated the effect of ginger on athymic nude mice with human prostate tumor
xenografts. A natural ginger extract showed a 2.4-fold higher inhibitory effect on the growth of tumors
than an artificial mixture of 6-shogaol, 6-gingerol, 8-gingerol, and 10-gingerol [64]. Additionally,
6-shogaol could be more significant than 6-gingerol and 6-paradol in reducing cell survival and inducing
apoptosis in human and mouse prostate cancer cells. It worked mainly through the suppression of
signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling. It also decreased the
expression of cyclinD1, survivin, c-Myc, and B-cell lymphoma 2 (Bcl-2), and enhanced Bax expression [56].
Ginger also exhibits cytotoxic activity against other types of cancer, such as breast, cervical, liver,
and pancreatic cancer. An in vitro study revealed that 6-gingerol could inhibit the growth of HeLa
human cervical adenocarcinoma cells, and it induced cell cycle arrest in the G0 /G1 -phase by decreasing
the protein levels of cyclin A and cyclin D1. Apoptosis in Hela cells was induced by increasing
the expression of caspase and inhibiting mammalian target of rapamycin (mTOR) signaling [65].
Besides, ginger extract protected against breast cancer in mice through the activation of 5’adenosine
monophosphate-activated protein kinase (AMPK) and the downregulation of cyclin D1. The extract
promoted apoptosis via an increase in the expression of the tumor suppressor gene p53 and a decrease
in the level of NF-κB in tumor tissue [58]. Additionally, 10-gingerol was found to be potent in inhibiting
human and mouse breast carcinoma cell growth. It reduced cell division and induced S phase cell
cycle arrest and apoptosis [66]. Moreover, fluorescent carbon nanodots (C-dots) prepared from ginger
effectively controlled tumor growth in nude mice, where the tumor was caused by HepG2 human
hepatocellular carcinoma cells. The in vitro experiment found that C-dots increased the content of ROS
in the HepG2 cells, which upregulated the expression of p53 and promoted apoptosis [67]. Furthermore,
ginger extract and 6-shogaol suppressed the growth of human pancreatic cancer cells and led to
ROS-mediated and caspase-independent cell death. Ginger extract suppressed tumor growth from
pancreatic cancer in both a peritoneal dissemination model and an orthotopic model of mice without
serious adverse effects [68].
Experimental studies have demonstrated that ginger can prevent and treat several types of cancer,
such as colorectal, prostate, breast, cervical, liver, and pancreatic cancer (Table 4). The anticancer
mechanisms mainly involve the induction of apoptosis and the inhibition of the proliferation of cancer cells.

2.6. Neuroprotection
Some individuals, especially elderly people, have a high risk for neurodegenerative diseases, such
as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [69]. Recently, many investigations have
revealed that ginger positively affects memory function and exhibits anti-neuroinflammatory activity,
which might contribute to the management and prevention of neurodegenerative diseases [70,71].
The results from a lipopolysaccharide (LPS)-activated BV2 microglia culture model revealed that
10-gingerol was responsible for the strong anti-neuroinflammatory capacity of fresh ginger. It inhibited
the expression of proinflammatory genes by blocking NF-κB activation, which led to a decline in the
levels of NO, IL-1β, IL-6, and TNF-α [7]. Additionally, in mice with scopolamine-induced memory
deficits, ginger extract could ameliorate the cognitive function of mice, which was assessed by a
novel object recognition test. Further experiments in mouse hippocampi and rat C6 glioma cells
revealed that ginger extract promoted the formation of synapses in the brain through the activation
of extracellular signal-regulated kinase (ERK) induced by nerve growth factor (NGF) and cyclic
AMP response element-binding protein (CREB) [69]. Another study found that 6-shogaol exhibited
neuroprotective activity by activating Nrf2, scavenging free radicals, and elevating the levels of several
phase II antioxidant molecules, such as NQO1 and HO-1, in neuron-like rat pheochromocytoma PC12
Foods 2019, 8, 185 10 of 21

cells [32]. In addition, 6-dehydrogingerdione exhibited cytoprotection against neuronal cell damage
induced by oxidative stress. It could effectively scavenge various free radicals in PC12 cells [72].

Table 4. Cytotoxic activity and potential mechanisms of ginger.

Constituent Study Type Subjects Dose Potential Mechanisms Ref.

Inducing apoptosis;
LNCaP, DU145,
inhibiting STAT3 and NF-κB signaling;
6-shogaol In vitro and PC-3 human 10, 20, and 40 µM [57]
downregulating the expression of cyclin
prostate cancer cells
D1, survivin, c-Myc, and Bcl2
Inducing cell cycle arrest in the
G0 /G1 -phase;
HeLa human cervical decreasing the levels of cyclin A, cyclin
6-gingerol In vitro 60, 100, and 140 µM [65]
adenocarcinoma cells D1, and cyclin E1;
increasing the expression of caspase;
inhibiting the mTOR signaling pathway
Inhibiting cell growth;
Human and mouse reducing cell division;
10-gingerol In vitro 50, 100, and 200 µM [66]
breast carcinoma cells inducing S phase cell cycle arrest and
apoptosis
6-gingerol,
Inhibiting prostate cancer cell
10-gingerol, PC-3 human prostate
In vitro 1,10, and 100 µM proliferation; downregulating the [59]
6-shogaol, cancer cells
expression of MRP1and GSTπ
and 10-shogaol
Suppressing the expression of cyclin D1;
GDNPs 2 In vivo Female C57BL/6 mice 0.3 mg inhibiting intestinal epithelial cell [4]
proliferation
Promoting apoptosis;
HT29 human colorectal upregulating the caspase 9 gene;
In vitro 2–10 mg/mL [60]
Ginger extract adenocarcinoma cells downregulating KRAS, ERK, Akt,
and Bcl-xL
Activating AMPK;
Female Swiss albino decreasing the expression of cyclin D1
In vivo 100 mg/kg [58]
mice and the level of NF-κB;
increasing the expression of p53
Ginger extract Increasing the activity of NADH
with alginate In vivo Male Wistar rats 50 mg/kg dehydrogenase and succinate [61]
beads dehydrogenase
Ginger
extract-based HepG2 human Increasing the level of ROS;
fluorescent In vitro hepatocellular 1.11 mg/mL upregulating the expression of p53; [67]
carbon carcinoma cells promoting apoptosis
nanodots
STAT3, signal transducer and activator of transcription 3; Bcl-2, B-cell lymphoma 2; mTOR, mammalian target of
rapamycin; MRP1, multidrug resistance associated protein 1; GSTπ, glutathione-S-transferase; AMPK, 5’adenosine
monophosphate-activated protein kinase; NF-κB, nuclear factor kappa light chain-enhancer of activated B cells.

In a mouse model of AD induced by amyloid β1–42 plaque, fermented ginger ameliorated memory
impairment by protecting neuronal cells in mouse hippocampi, and it increased the levels of presynaptic
and postsynaptic proteins [71]. In addition, ginger extract had protective effects against AD in rats, and a
high dose of ginger extract decreased latency in showing significant memory deficits, as well as the levels
of NF-κB, IL-1β, and MDA [73]. Moreover, 6-shogaol could alleviate cognitive dysfunction in mice with
AD by inhibiting inflammatory responses, upregulating the level of NGF, and enhancing synaptogenesis
in the brain [74]. Furthermore, in rat mesencephalic cells treated with 1-methyl-4-phenylpyridinium
(MPP+ ), 6-shogaol improved the amount of tyrosine hydroxylase-immunoreactive (TH-IR) neurons
and inhibited the levels of TNF-α and NO. Treatment with 6-shogaol ameliorated motor coordination
and bradykinesia in vivo in PD [70].
The above studies found that ginger and its bioactive compounds, such as 10-gingerol, 6-shogaol,
and 6-dehydrogingerdione, exhibited protective effects against AD and PD. The antioxidant and
anti-inflammatory activities of ginger contributed to neuroprotection.

2.7. Cardiovascular Protection

Cardiovascular diseases have been considered to be a leading cause of premature death,
and 17.9 million people die per year [75]. Dyslipidemia and hypertension are known to be risk
Foods 2019, 8, 185 11 of 21

factors for cardiovascular diseases, including stroke and coronary heart disease [8,76]. A series of
studies has shown that ginger can decrease the levels of blood lipids and blood pressure [77,78],
contributing to protection from cardiovascular diseases.
Ginger extract reduced the body weight of rats fed a high-fat diet and enhanced the level of
serum high-density lipoprotein-cholesterol (HDL-C), a protective factor against coronary heart disease.
Besides, ginger extract increased the levels of apolipoprotein A-1 and lecithin-cholesterol acyltransferase
mRNA in the liver, which was related to high-density lipoprotein (HDL) formation [79]. Additionally,
total cholesterol (TC) and LDL concentrations were decreased by ginger extract in rats fed a high-fat
diet, and the level of HDL increased through the combined application of aerobic exercise and ginger
extract [76]. Moreover, ginger extract could reduce the levels of plasma TC, triglyceride (TG), and very
low-density lipoprotein (VLDL) cholesterol in high-fat diet rats. The mechanism was related to higher
liver expression of peroxisome proliferator-activated receptors (PPARα and PPARγ), which were
related to atherosclerosis [78].
Vascular smooth muscle cell proliferation is a process in the pathogenesis of cardiovascular
diseases. In an in vitro study, 6-shogaol exerted antiproliferative effects through increasing the number
of cells in the G0 /G1 phase and activating the Nrf2 and HO-1 pathways [80]. In addition, ginger
decreased the activities of angiotensin-1 converting enzyme (ACE) and arginase and increased the
level of NO, a well-known vasodilator molecule. Thus, blood pressure decreased in hypertensive
rats pretreated with ginger [8]. Besides, ginger protected against hypertension-derived complications
by decreasing platelet adenosine deaminase (ADA) activity and increasing the level of adenosine,
which prevented platelet aggregation and promoted vasodilation in hypertensive rats [77]. Moreover,
ginger extract exhibited vasoprotective effects on porcine coronary arteries by suppressing NO
synthase and cyclooxygenase [81]. Furthermore, a cross-sectional study found that the probability of
hypertension and coronary heart disease declined when a daily intake of ginger was increased [82].
Generally, ginger has exhibited cardiovascular protective effects by attenuating hypertension and
ameliorating dyslipidemia, such as in the improvement of HDL-C, TC, LDL, TG, and VLDL.

2.8. Antiobesity Activity

Obesity is a risk factor for many chronic diseases, such as diabetes, hypertension,
and cardiovascular diseases [83]. Several studies have reported that ginger is effective in the
management and prevention of obesity [9,84].
In 3T3-L1 preadipocyte cells, gingerenone A exhibited a greater inhibitory effect on adipogenesis
and lipid accumulation than gingerols and 6-shogaol. Gingerenone A could also modulate fatty acid
metabolism via the activation of AMPK in vivo, attenuating diet-induced obesity [9]. In cultured
skeletal muscle myotubes, 6-shogaol and 6-gingerol could increase peroxisome proliferator-activated
receptor δ (PPARδ)-dependent gene expression, and this resulted in the enhancement of cellular fatty
acid catabolism [83]. In addition, both ginger and orlistat reduced the body weight and lipid profile
of high-fat diet rats, while ginger had a greater effect on increasing the level of HDL-C than orlistat
did [84]. In a randomized, double-blind, and placebo-controlled study, obese women receiving 2 g
of ginger powder daily had a decreased body mass index (BMI) [85]. Moreover, the intake of dried
ginger powder could reduce respiratory exchange ratios and promote fat utilization by increasing fat
oxidation in humans [86].
Ginger and its bioactive constituents, including gingerenone A, 6-shogaol, and 6-gingerol,
have shown antiobesity activity, with the mechanisms mainly related to the inhibition of adipogenesis
and the enhancement of fatty acid catabolism.

2.9. Antidiabetic Activity

Diabetes mellitus is known as a severe metabolic disorder caused by insulin deficiency and/or
insulin resistance, resulting in an abnormal increase in blood glucose. Prolonged hyperglycemia could
accelerate protein glycation and the formation of advanced glycation end products (AGEs) [87].
Foods 2019, 8, 185 12 of 21

Many research works have evaluated the antidiabetic effect of ginger and its major active
constituents [88].
An in vitro experiment resulted in both 6-shogaol and 6-gingerol preventing the progression
of diabetic complications, and they inhibited the production of AGEs by trapping methylglyoxal
(MGO), the precursor of AGEs [87]. Additionally, 6-gingerol reduced the levels of plasma glucose
and insulin in mice with high-fat diet-induced obesity. Nε-carboxymethyl-lysine (CML), a marker of
AGEs, was decreased by 6-gingerol through Nrf2 activation [88]. In 3T3-L1 adipocytes and C2C12
myotubes, 6-paradol and 6-shogaol promoted glucose utilization by increasing AMPK phosphorylation.
In addition, in a mouse model fed a high-fat diet, 6-paradol significantly reduced the level of
blood glucose [10]. In another study, 6-gingerol facilitated glucose-stimulated insulin secretion and
ameliorated glucose tolerance in type 2 diabetic mice by increasing glucagon-like peptide 1 (GLP-1).
Besides, 6-gingerol treatment activated glycogen synthase 1 and increased cell membrane presentation
of glucose transporter type 4 (GLUT4), which increased glycogen storage in skeletal muscles [89].
Furthermore, the consumption of ginger could reduce the levels of fasting plasma glucose, glycated
hemoglobin A (HbA1C ), insulin, TG, and TC in patients with type 2 diabetes mellitus (DM2) [90].
Moreover, ginger extract treatment improved insulin sensitivity in rats with metabolic syndrome,
which might have been relevant to the energy metabolism improvement induced by 6-gingerol [91].
In addition, ginger extract alleviated retinal microvascular changes in rats that had diabetes induced
by streptozotocin. Ginger extract could reduce the levels of NF-κB, TNF-α, and vascular endothelial
growth factor in the retinal tissue [92]. In a randomized, double-blind, and placebo-controlled trial,
the ingestion of ginger decreased the levels of insulin, low-density lipoprotein cholesterol (LDL-C),
and TG; decreased the homeostasis model assessment index; and increased the quantitative insulin
sensitivity check index in patients with DM2 [93].
The studies have demonstrated that ginger and its bioactive compounds could protect against
diabetes mellitus and its complications, probably by decreasing the level of insulin, but increasing the
sensitivity of insulin.

2.10. Antinausea and Antiemetic Activities

Ginger has been traditionally used to treat gastrointestinal symptoms, and recent research has
demonstrated that ginger could effectively alleviate nausea and emesis [11,94,95].
In a clinical trial, inhaling ginger essence could attenuate nausea intensity and decrease emesis
episodes two and six hours after a nephrectomy in patients [96]. In addition, dried ginger powder
treatment reduced episodes of intraoperative nausea in elective cesarean section patients [97]. Moreover,
nausea and emesis are common side effects of chemotherapy [98]. The activation of vagal afferent
mediated by serotonin (5-HT) is crucial in the mechanism of emesis. An in vitro experiment revealed
that 6-shogaol, 6-gingerol, and zingerone inhibited emetic signal transmission in vagal afferent neurons
by suppressing the 5-HT receptor, and 6-shogaol had the strongest inhibitory efficacy [99]. Furthermore,
ginger extract alleviated chemotherapy-induced nausea and emesis by suppressing the activation
of 5-HT receptors in enteric neurons [11]. In a double-blind, randomized, and placebo-controlled
trial, supplementation with ginger could improve the nausea-related quality of life in patients after
chemotherapy [94]. Moreover, ginger alleviated the nausea induced by antituberculosis drugs and
antiretroviral therapy, and it reduced the frequency of mild, moderate, and severe episodes of nausea
in patients [100,101].
Previous results have shown that ginger could attenuate pregnancy-induced nausea and emesis
and motion sickness, while recent studies have focused on the preventive efficacy of ginger on
postoperative and chemotherapy-induced nausea and emesis [102].
Foods 2019, 8, 185 13 of 21

2.11. Protective Effects against Respiratory Disorders

Natural herbal medicines have a long history of application in the treatment of respiratory
disorders such as asthma, and ginger is one of these remedies [12,103]. Ginger and its bioactive
compounds have exhibited bronchodilating activity and antihyperactivity in several studies [104].
Ginger induced significant and rapid relaxation in the isolated human airway smooth muscle.
In results from guinea pig and human tracheas models, 6-gingerol, 8-gingerol, and 6-shogaol could
lead to the rapid relaxation of precontracted airway smooth muscle. The nebulization of 8-gingerol
attenuated airway resistance via a reduction in Ca2+ influx in mice [12]. In another study, 6-gingerol,
8-gingerol, and 6-shogaol promoted β-agonist-induced relaxation in human airway smooth muscle
via the suppression of phosphodiesterase 4D [103]. In addition, ginger ameliorated allergic asthma
by reducing allergic airway inflammation and suppressed Th2-mediated immune responses in mice
with ovalbumin-induced allergic asthma [105]. Moreover, the water-extracted polysaccharides of
ginger could decrease times of coughing, which was induced through citric acid in guinea pigs [106].
Besides, ginger oil and its bioactive compounds, including citral and eucalyptol, inhibited rat tracheal
contraction induced by carbachol in rats [104]. Furthermore, in patients with acute respiratory distress
syndrome (ARDS), an enteral diet with rich ginger contributed to gas exchange and reduced the
duration of mechanical ventilation [107].
The above results indicate that ginger and its bioactive constituents, including 6-gingerol,
8-gingerol, 6-shogaol, citral, and eucalyptol, have protective effects against respiratory disorders,
at least mediating them through the induction of relaxation in airway smooth muscle and the attenuation
of airway resistance and inflammation.

2.12. Other Bioactivities of Ginger

Apart from the bioactivities mentioned above (Figure 3), ginger has other beneficial effects, such as
hepatoprotective and antiallergic effects [108,109].
In a rat nephropathy model induced by gentamicin, gingerol dose-dependently ameliorated renal
function and reduced lipid peroxidation and nitrosative stress. Gingerol also increased the levels of
GSH and the activity of superoxide dismutase (SOD) [110]. Additionally, ginger extract ameliorated
histological and biochemical alterations in the radiation-induced kidney damage of rats through
antioxidant and anti-inflammatory activities [111]. Furthermore, liver histological results showed
that ginger essential oil reduced lipid accumulations in the liver of obese mice fed a high-fat diet.
Ginger essential oil could protect against steatohepatitis by enhancing antioxidant capacity and reducing
inflammatory responses in the liver [109]. In another study with mice fed an alcohol-containing liquid
diet, ginger essential oil ameliorated alcoholic fatty liver disease by decreasing the levels of AST, ALT,
TG, and TC and increasing liver antioxidant enzyme activity, such as catalase and SOD [112]. To our
knowledge, there has been no literature reporting the liver toxicity of ginger up to now. Additionally,
in a mouse model of allergic rhinitis induced by ovalbumin (OVA), a ginger diet attenuated the severity
of sneezing and nasal rubbing and inhibited the infiltration of mast cells into nasal mucosa as well as
the secretion of serum immunoglobulin E. The in vitro study indicated that 6-gingerol could alleviate
allergic rhinitis by reducing cytokine production for T cell activation and inhibiting the activation of B
cells and mast cells [108]. Moreover, treatment with ginger could reduce blood loss in women with
heavy menstrual bleeding [113]. In a double-blinded randomized clinical trial, treatment with ginger
powder alleviated a common migraine attack and had fewer clinical adverse effects than the clinical
medicine sumatriptan [114].
 Foods 2019, 8, 185 14 of 21
Foods 2019, 8, x FOR PEER REVIEW 14 of 21

Figure
Figure3.3.An
Anoverview
overviewofofthe
thebioactivities
bioactivitiesofofginger.
ginger.

ItItisis interesting
interestingtoto note
note that
that several
several plants
plants in
in Zingiberaceae
Zingiberaceae have have also
also attracted
attracted increasing
increasing
attention,such
attention, Curcumalonga
suchasasCurcuma longaL.L.(turmeric), Zingiberofficinale
(turmeric),Zingiber officinaleRoscoe
Roscoe(ginger),
(ginger),and Alpiniazerumbet
andAlpinia zerumbet
(shell ginger) [115]. In a previous paper, we reviewed the bioactivities of curcumin
(shell ginger) [115]. In a previous paper, we reviewed the bioactivities of curcumin (main active (main active
componentofofCurcuma
component Curcumalonga)
longa)[116],
[116],andand a comparison
a comparison between
between ginger
ginger andand shell
shell ginger
ginger is given
is given in
in Table 5. Shell ginger has exhibited similar biological activities to ginger, including
Table 5. Shell ginger has exhibited similar biological activities to ginger, including antioxidant, anti- antioxidant,
anti-inflammatory,
inflammatory, antimicrobial,
antimicrobial, anticancer,
anticancer, cardiovascular
cardiovascular protective,
protective, antiobesity,and
antiobesity, andantidiabetic
antidiabetic
activities [115]. Differently,
activities Differently,ginger hashas
ginger alsoalso
beenbeen
reported to havetoneuroprotective,
reported respiratory
have neuroprotective, protective,
respiratory
antinausea, and antiemetic activities, while shell ginger might contribute to longevity.
protective, antinausea, and antiemetic activities, while shell ginger might contribute to longevity. In In particular,
shell ginger
particular, hasginger
shell been found
has beento play
foundantoimportant contributory
play an important role in therole
contributory longevity of peopleofin
in the longevity
Okinawa
people [115].
in Okinawa [115].

Thecomparison
Table5.5.The
Table comparisonbetween
betweenginger
gingerand
andshell
shellginger.
ginger.

Items Items GingerGinger ShellGinger

Shell Ginger Ref.
Ref.
Scientific
Scientific name name ZingiberZingiber officinale
officinale Roscoe Roscoe Alpinia
Alpinia zerumbet(Pers.)
zerumbet (Pers.)B.L.
B.L. Burtt
Burtt &
&R.M.
R.M.Sm.Sm. [115,117]
[115,117]
Family Zingiberaceae
andand genus Zingiberaceae familyfamily and Zingiber
and Zingiber
Family Zingiberaceae family and Alpinia genus [115,117]
genus Zingiberaceae family and Alpinia genus [115,117]
genusEdible parts
genus Rhizomes Leaves and rhizomes [8,115]
Edible parts Rhizomes Leaves and rhizomes
Dihydro-5,6-dehydrokawain, [8,115]
Gingerols, shogaols, paradols,
Bioactive compounds Dihydro-5,6-dehydrokawain, 5,6-
5,6-dehydrokawain, essential oils, [2,44,115]
Bioactive and essential
Gingerols, shogaols, paradols, oilsand
dehydrokawain,and flavonoids
essential oils, and [2,44,115]
compounds essential oils
Antioxidant, anti-inflammatory,
flavonoids
Antioxidant, anti-inflammatory,
antimicrobial, anticancer, cardiovascular
antimicrobial, anticancer, cardiovascular
Biological activities Antioxidant, anti-inflammatory,
protective, antiobesity, antidiabetic, [3–12,115]
protective, antiobesity, antidiabetic activities,
antimicrobial,
neuroprotective,anticancer,
respiratory protective, Antioxidant, anti-inflammatory,
longevity
Biological antinausea,
cardiovascular and antiemetic
protective, activities
antiobesity, antimicrobial, anticancer, cardiovascular
[3–12,115]
activities antidiabetic, neuroprotective, protective, antiobesity, antidiabetic activities,
3. Conclusions respiratory protective, antinausea, and longevity
antiemetic activities
In conclusion, ginger contains diverse bioactive compounds, such as gingerols, shogaols,
3.and
Conclusions
paradols, and possesses multiple bioactivities, such as antioxidant, anti-inflammatory,
andInantimicrobial
conclusion,properties. Additionally,
ginger contains diverse ginger hascompounds,
bioactive the potentialsuch
to beas
thegingerols,
ingredientshogaols,
for functional
and
foods or nutriceuticals, and ginger could be available for the management and
paradols, and possesses multiple bioactivities, such as antioxidant, anti-inflammatory, prevention of several
and
diseases suchproperties.
antimicrobial as cancer, cardiovascular
Additionally, diseases,
ginger hasdiabetes mellitus,toobesity,
the potential be theneurodegenerative diseases,
ingredient for functional
nausea,
foods emesis, and respiratory
or nutriceuticals, and gingerdisorders.
could be In the future,
available more
for the bioactive compounds
management in ginger
and prevention could
of several
be isolated and clearly identified, and their biological activities and related mechanisms
diseases such as cancer, cardiovascular diseases, diabetes mellitus, obesity, neurodegenerative of action
should benausea,
diseases, further emesis,
investigated. Notably, well-designed
and respiratory disorders. Inclinical trials ofmore
the future, ginger and its various
bioactive bioactive
compounds in
compounds are warranted to prove its efficacy against these diseases in human beings.
ginger could be isolated and clearly identified, and their biological activities and related mechanisms
of action should be further investigated. Notably, well-designed clinical trials of ginger and its
Foods 2019, 8, 185 15 of 21

Author Contributions: Conceptualization, Q.-Q.M., R.-Y.G., and H.-B.L.; writing—original draft preparation,
Q.-Q.M. and X.-Y.X.; writing—review and editing, X.-Y.X., S.-Y.C., R.-Y.G., H.C., T.B., and H.-B.L.; supervision,
R.-Y.G. and H.-B.L.; funding acquisition, R.-Y.G., H.C., and H.-B.L.
Funding: This study was supported by the National Key R&D Program of China (2017YFC1600100),
the Shanghai Basic and Key Program (18JC1410800), the Agri-X Interdisciplinary Fund of Shanghai Jiao Tong
University (Agri-X2017004), and the Key Project of the Guangdong Provincial Science and Technology Program
(2014B020205002).
Conflicts of Interest: The authors declare no conflicts of interest.

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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

ISSN 2321-2187
IJHM 2013; 1 (4): 16-20
© 2013 AkiNik Publications
Received: 03-10-2013
Accepted: 14-10-2013
Subodh Kumar
Department of Biochemistry, Major S
D Singh Medical College & Hospital,
Fatehgarh (U.P.), India
Kiran Saxena
Department of Biochemistry, Chirayu
Medical College & Hospital, Bhopal
(M.P.) India
Uday N. Singh
Department of Biochemistry, Major S
D Singh Medical College & Hospital,
Fatehgarh (U.P.), India
Ravi Saxena
Department of Biochemistry, Chirayu
Medical College & Hospital, Bhopal
(M.P.) India
Correspondence:
Subodh Kumar
Department of Biochemistry, Major
S D Singh Medical College &
Hospital, Fatehgarh (U.P.), India
Email: somya2011.dsk@gmail.com
Tel: 7607879471
International Journal of Herbal Medicine 2013; 1 (4): 16-20
Anti-inflammatory action of ginger: A critical
review in anemia of inflammation and its
future aspects
Subodh Kumar, Kiran Saxena, Uday N. Singh, Ravi Saxena
ABSTRACT
Anti-inflammatory action of ginger has been confirmed by various scientists, but there is very few
review article published till date on inflammation associated diseases. Inflammation is mainly, culprit
of anemia and inflammation associated disorder (like- Pulmonary diseases, Cardiovascular diseases,
Diabetes Type-2, cancer, Arthritis, Alzheimer, Neurological diseases and Autoimmune diseases).Since
Infection (bacterial/ viral), activate Nuclear factor –-κB, which is a major mediator of inflammation in
most of the disease. Zinger has been established potent NF–ƙB inhibitory action via the suppression of
pro-inflammatory cytokine, TNF-α and also provides a molecular link between the innate and adaptive
immune system. This review takes the Zinger bioactive components, property, Chemical composition,
Mechanism of action, function, side effects, current research and their potential application in modern
medicine. The present study demonstrates that ginger showed broad spectrum action in which Anti-
inflammatory action is one of them. So the present study concludes that ginger and its bioactive
components have the potential for development of modern medicine in the treatment of anemia and
various diseases in near future.
Keywords: Bioactive component of ginger, Anti-inflammatory action, Anemia, Anemia of inflammation,
Modern Medicine.
1. Introduction
Anemia of inflammation is considered a major contributor to anemia observed in developing
countries [1] and anemia of inflammation may even be associated with asymptomatic and
subclinical infection [2]. The only effective treatment of chronic inflammation is correction of
the underlying disorder [3]. NF-κB is a pleiotropic transcription factor. It is involved in the
transcriptional activation of numerous genes leading to a cumulative immunogenic response,
provides a molecular link between the innate and adaptive immune system, whilst playing
regulatory roles in haemapoiesis and lymphoid organogenesis. NF-κB activation seems to be a
key early event in a variety of cell & animal model systems developed to elucidate the
pathobiology of lung disease including Systemic inflammatory [4].
Ginger is extensively used as a spice & food preservative in India, China and South East Asia
and probably originated in India. [5, 58] Ginger obtained from the underground stems of rhizomes
of Zingiber officinale Rosc.), an herbaceous tropical perennial belonging to the family
Zingiberaceae. It has been used in Ayurvedic Medicine since ancient times with various
biological applications. Different constituents of ginger has been established its role in
medicine to treat various ailments from time immemorial in different parts of the world [6].
Recent years have seen an increased enthusiasm in treating various diseases with natural
products. Ginger (Zingiber officinale) is a non-toxic highly promising natural antioxidant
compound having a wide spectrum of biological function (antimicrobial, anti-inflammatory,
antioxidant, immunomodulatory, anticarcinogenic). Safety evaluation studies indicate that
Zingiber officinale are well tolerated even at a very high dose without any toxic effects [7].
Thus ginger and its bioactive components have the potential for development of modern
medicine in the treatment of anemia and inflammation associated diseases
~ 16 ~ 
  
International Journal of Herbal Medicine

(like- Pulmonary diseases, cardiovascular diseases, Diabetes Type-
2, cancer, Arthritis, Alzheimer, Neurological diseases and
autoimmune diseases) in near future cost effectively, the main aim
of the present review.
2. Review of Literature
2.1 Chemistry of zinger
In the fresh ginger rhizome, the gingerols were identified as the
major active components and [6] gingerol [5-hydroxy-1-(4-hydroxy-
3-methoxy phenyl) decan-3-one is the most abundant constituent in
the gingerol series (Table 1). The powdered rhizome contains 3-6%
fatty oil, 9% protein, 60-70% carbohydrates, 3-8% crude fiber,
about 8% ash, 9-12% water and 2-3% volatile oil. The volatile oil
consists of mainly mono and sesquiter–penes; camphene, beta-
phellandrene, curcumene, cineole, geranyl acetate, terphineol,
terpenes, borneol, geraniol, limonene, linalool, alpha-zingiberene
(30-70%), beta-sesquiphellandrene (15-20%), beta-bisabolene (10-
15%) and alpha-farmesene. In dried ginger powder, shogaol a
dehydrated product of gingerol, is a predominant pungent
constituent upto [8-10].

Table 1: Structure of active component of ginger with IUPAC name

1. 6-gingerol (S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone
2. 8- gingerol (5S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) dodecan-3-one
3. 10-gingerol (E)-1-(4-hydroxy-3-methoxyphenyl) dec-4-en-3-one
4. 6-shogaol (E)-1-(4-Hydroxy-3- methoxyphenyl) dec-4-en-3-one

2.2 Chemical Composition of ginger: Nutritional data for 100
gm. Dry ginger is as follows
Water–9.4 gm, Protein–9.1gm, Fat–6.0gm, Total carbohydrate–
70.8 gm, Food energy–374 kcal, Fibre–5.9 gm, ash–4.8 gm, iron–
12 mg, magnesium–184 mg, Phosphorous- 148 mg, potassium-
1342 mg, sodium-32 mg, zinc–5 mg and niacin-5mg [11].
2.3 The percentage of vitamin in ginger rhizome powder is as
follows
Thiamine–0.035%, Riboflavin–0.015%, Niacin–0.045%,
Pyridoxin–0.056%, Vitamin C–44%, vitamin A-Traces, vitamin E-
Traces, Total-44.15% [12].
2.4 Ginger: safety, dose, side effect and drug interactions
Safety: Ginger is recommended in U.S. Food and Drug
Administration’s GRAS (generally recognized as safe) list.The
British Herbal Compendium documents no adverse effects of
ginger [13]. Ginger appears to be relatively safe except in pregnancy
[14]
. the observation that ginger also suppresses leukotriene biosynthesis
Dose: A dose of 0.5–1.0 g of ginger powder ingested 2-3 times for
periods ranging from 3 months to 2.5 years did not cause any
adverse effects [15]. Most of the research has been done with 1-2
grams of ginger powder, but in India the average intake is around
8-10 grams per day.
Side effect: Ginger is quite safe in therapeutic doses. For anti-
inflammatory purpose, the dose of ginger is 3–6 grams two to three
times per day. In experimental animals, the doses of 2.5 gram/kg
body weight were tolerated without any mortality. However, when
the dose was increased to 3–3.5 gram/kg body weight then there
was 10–30 % mortality [16].
Drug interaction: Few ginger–drug interactions have been
reported in the literature. Ginger does not interact with the anti-
coagulant drug warfarin in rats or man [17- 18].
2.5 Functional property of Ginger: Ginger, as an antimicrobial
[19-21]
, anti-inflammatory [22-29], antioxidant [30--32] and
immunomodulatory role [26] have been established.
2.6 Mechanism of action of ginger
Ginger is considered to exert its anti-inflammatory activity by
inhibiting COX-2 and LOX pathways [33-34]. Recently, it has been
observed that two labdanum-diterpene like dialdehides isolated
from Ginger extracts act as in vitro inhibitors of the human 5-
lipooxygenase [35]. In one study curcumin has been shown to
suppress the expression of COX2, 5-LOX, and iNOS, most likely
through the downregulation of NF-κB activation [36]. The other
study reported that 6-gingerol, a natural analog of curcumin
derived from the root of ginger (Zingiber officinalis), exhibits a
biologic activity profile similar to that of curcumin [37].
2.7 Anti-inflammatory action of ginger
The anti-inflammatory properties of ginger have been known and
valued for centuries. The original discovery of ginger's inhibitory
effects on prostaglandin biosynthesis in the early 1970s has been
repeatedly confirmed. This discovery identified ginger as an herbal
medicinal product that shares pharmacological properties with non-
steroidal anti-inflammatory drugs. Ginger suppresses prostaglandin
synthesis through inhibition of cyclooxygenase-1 and
cyclooxygenase-2. An important extension of this early work was
by inhibiting 5-lipoxygenase. This pharmacological property
distinguishes ginger from nonsteroidal anti-inflammatory drugs.
This discovery preceded the observation that dual inhibitors of
cyclooxygenase and 5-lipoxygenase may have a better therapeutic
profile and have fewer side effects than non-steroidal anti-
inflammatory drugs. The characterization of the pharmacological
properties of ginger entered a new phase with the discovery that a
ginger extract (EV.EXT.77) derived from Zingiberofficinale
(family Zingiberaceae) and Alpinagalanga (family Zingiberaceae)
inhibits the induction of several genes involved in the
inflammatory response. These include genes encoding cytokines,
chemokines, and the inducible enzyme cyclooxygenase-2. This
discovery provided the first evidence that ginger modulates
biochemical pathways activated in chronic inflammation. The
earlier report suggested that in Rheumatoid arthritis (RA) and
Osteoarthritis (OA) patients, use of powdered ginger for 3-month
to 2.5-year period, reduce pain and inflammation in 75% patients
without any adverse effect and suggested ginger is an anti-
inflammatory agent [24]. 6-gingerol acts as an anti-inflammatory
compound that may be useful to treat inflammation without
interfering with antigen presenting function of macrophages [38]. It
has been also recently observed that Synergistic effect of Ginger
with anti-tuberculosis treatment were more beneficial effect rather
than only ATT (anti-tuberculosis treatment) in anemic Pulmonary

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International Journal of Herbal Medicine
tuberculosis Patients and concluded that ginger supplementation in
such patients not only increases absorption of iron but also
significant decreases in CRP, Ferritin and significant increase in
Fig 1: Synergetic effect of anti- tubercular treatment (ATT) with ginger supplementation a new approach to cure TB with better outcome.
2.8 Antimicrobial Action
Investigation of ginger rhizome (Zingiber officinale) afforded three
lipophilic analogues 6-gingerol [39], 8-gingerol [40] and 10- gingerol
[41]
that exhibited antimicrobial activity. The lipophilic analogues
Fig 2: NF-ƙB activating agen
2.9 Pathophysiological Mechanism underlying Anemia of
inflammation
Anemia of inflammation Pathophysiology is like Anemia of
Chronic disease (ACD) [60]. During inflammation, hepcidin (an
acute phase protein) production is stimulated and iron entry into
plasma is inhibited, causing the hypoferremia and anemia of
inflammation [42]. Acute Phase Proteins are a class of diverse
Proteins whose blood plasma concentrations increase (positive
acute phase protein), or decreases (negative acute phase protein)
during the response to inflammation in the acute phase. They are
produced within a few hours by the liver, responding to
inflammatory cytokines such as IL-1, TNF-α and in particular IL-6
[43-44, 59]
. It has been observed that during infection, there is an
increase in cytokine levels (IL-6) which is responsible for
activation of NF-κB & endotoxins which in turn increase the
synthesis and release of CRP from hepatocytes. Raised level of
CRP is marker of inflammation which causes blunted
erythropoietin resistance resulting anemia.
2.10 Various disorders linked with anemia of inflammation
Inflammation is considered to play an important role in the
Pathophysiology of various disorders. However, when
inflammation becomes chronic or lasts too long, it can be harmful.
The diagnosis of inflammation and its biomarkers are not fully
understood; however, pro-inflammatory cytokines, chemokines,
adhesion molecules and the inflammatory enzymes have been
linked to chronic inflammation [45]. Chronic inflammation has been
~ 18 ~
serum iron, total iron binding capacity, which in turn correct
anemia [29].
(8-gengerol and 10 gingerol) were more active, with MIC values of
25–50 μg/ ml exhibited towards M. tuberculosis H37Rv and M.
avium [40, 41].
found to mediate a wide variety of diseases including
cardiovascular diseases, diabetes, arthritis, Alzheimer’s disease,
pulmonary diseases and autoimmune diseases. Chronic
inflammation has also been associated with various steps involved
in carcinogenesis as well as cellular transformation, promotion,
survival, proliferation, invasion, angiogenesis and metastasis [46-47].
Many pro-inflammatory cytokines can activate the transcriptional
factor NF-κB, while some of the effects of pro-inflammatory
cytokines may be mediated through the NF-κB pathway [48-50].
2.11 Role of Bioactive component of Zinger
The 6-gingerol and 6-paradol have been reported to possess a
strong anti-inflammatory activity and to suppress the TNF-α
production in TPA-treated female ICR-mice and rats [51, 52]. The
activation of the TNF-α gene causes the release of pro-
inflammatory cytokines, and this would activate the transcriptional
factor NF-κB. Activation of NF-κB would activate the expression
of other inflammatory cytokines such as COX-2, LOX-2, other
chemokines and iNOS, which would lead to inflammation and
related diseases. Ginger (Zingiber officinale) is widely used all
over the world as a spice and condiment in daily cooking. It is a
natural food component with many active phenolic compounds
such as shagaol and gingerol, and it has been shown to have broad
anti-inflammatory action. It is apparent that ginger may act as an
anti-cancer and anti-inflammatory agent by blocking the activation
of NF-κB via the suppression of pro-inflammatory cytokine, TNF-
α [53]. Other, similar reports have also shown the inhibitory effect of
 

International Journal of Herbal Medicine
ginger on the NF-κB pathway: topical application of 6-gingerol
inhibited TPA-induced COX-2 expression and suppressed NF-κB
DNA binding activity in mice skin [51, 54]. The 6-gingerol and 6-
paradol have been reported to possess a strong anti-inflammatory
activity and to suppress the TNF-α production in TPA-treated
female ICR-mice and rats [51, 52]. Inhibiting the activity of NF-κB,
will subsequently inhibit inflammation and inflammation
associated disorder. The natural active compounds in ginger
(gingerols and zerumbone) have been found to be potent inhibitors
for NF-κB and pro-inflammatory cytokine TNF-a. Ginger may
block any one or more steps in the NF-κB signaling pathway, such
as the signals that activate the NF-κB signaling cascade,
translocation of NF-κB into the nucleus, DNA binding of dimers or
interactions with the basal transcriptional machinery [55].
Ginger extract significantly reduced the elevated expression of NF-
κB and TNF-α in rats with liver cancer. Ginger may act as an anti-
cancer and anti-inflammatory agent by inactivating NF-κB through
the suppression of the pro-inflammatory TNF-α [56].
2.12 Zinger future perspective
As a source of potential chemotherapeutic agent continues. Natural
products and their derivatives represent more than 50% of all the
drugs in clinical use in the world today. Phytomedicine have more
beneficial effect than their synthetic counterparts through being
safer, acceptable, affordable, culturally compatible and suitable for
Fig 3: Ginger Supplement inhibits both COX- 2 & LPO expression by suppressing NF- ƙB activity via TNF – α
This review article concludes that ginger and its bioactive
components have the potential for development of modern
medicine in the treatment of various diseases in near future because
it controls the molecular mechanism of inflammation. Further trials
in humans are required to determine the efficacy of ginger (one or
more of its constituents) and to study what, if any, beneficial or
adverse effects are observed if consume over a long period of time.
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