Turmeric's Health Benefits and Applications

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY
FACULTY OF CHEMICAL TECHNOLOGY

DEPARMENT OF FOOD TECHNOLOGY
SERMINAR
FUNCTIONAL FOOD
TURMERIC (CURCUMA LONGA L)

FUNCTINALITY AND APPLICATIONS
Student name:
Hoang Lan
13110563
Vo Thi Hong Linh 13110564

Supervisors:
Dr. Dong Thi Anh Dao
Tp.HCM, 4-2014
Tumeric (Curcuma Longa L.): Functionality and Apllication
TABLE OF CONTENTS
INTRODUCTION............................................................................................................7
CHAPTER 1: LITERATURE REVIEW..........................................................................9
1.1Tumeric (Curcuma Longa L.) plant..................................................................9
1.1.1. Introduction.................................................................................................9
1.1.2. Cultivation.................................................................................................10
1.1.3. Chemical composition of tumeric..............................................................11
1.1.4. Pharmacology activities of tumeric............................................................12
1.1.5. Tumerics production and consumption in the world.................................13
1.1.6. Tumeric in Vietnam...................................................................................13
1.2. Essential and Oleoresin.................................................................................14
1.2.1. Essential oil...............................................................................................14
1.2.2. Tumeric oleoresin......................................................................................16
1.3. Curcuminoids...............................................................................................17
CHAPTER 2: TUMERIC FUNCIALITYS RESEARCH.............................................21
2.1. Tumeric as a traditional medicine.................................................................21
2.2. Tumeric as a modern medicine.....................................................................22
2.2.1 In vitro studies with Tumeric......................................................................22
2.2.2. In vivo studies with Tumeric.....................................................................25
2.2.3. Clinical studies using Tumeric...................................................................33
CHAPTER 3: MECHANISM OF TUMERIC FUNTIONALITY..................................36
3.1. Curcumin: Antioxidant mechanism..............................................................36
3.2. Anti- inflammatory property of curcumin.....................................................37
3.2.1. Effect of Curcumin on Cyclooxygenases and Lipoxygenases...................37
3.2.2. Effect of Curcumin on Inducible Nitric Oxide Synthase...........................39
3.2.3. Effect of Curcumin on Nuclear Factor-B.................................................40
3.2.4. Effect of Curcumin on Tumor Necrosis Factor..........................................41
3.3. Therapeutic use of curcumin.........................................................................42
3.3.1 Cancer.........................................................................................................42
3.3.2 Atherosclerosis...........................................................................................43
3.3.3 Neurodegenerative disease..........................................................................44
3.3.4 Diabetes......................................................................................................45
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3.3.5 Aids............................................................................................................46
3.3.6 Autoimmune disease...................................................................................46
3.3.7 Psoriasis......................................................................................................47
3.4. Cancer chemopreventive effects of Curcumin..............................................47
3.4.1. Inhibition of carcinigen activition..............................................................49
3.4.2. Suppression of pro- inflammatory signaling..............................................50
3.5. Curcumin as an inhibitor of angiogenesis.....................................................51
3.6. Radioprotection and radiosensitization by Curcumin...................................53
3.7. Curcumin and angiogenes in skin diseases...................................................55
3.8. Cardioprotective effects of Curcumin...........................................................56
CHAPTER 4: PRODUCTIONS AND APPLICATION.................................................57
4.1. Fresh turmeric rhizome.................................................................................57
4.2. Dried tumeric rhizome..................................................................................57
4.3. Tumeric powder............................................................................................57
4.4. Tumeric essential oil.....................................................................................58
4.5. Tumeric oleoresin.........................................................................................59
4.6. Curcumin powder.........................................................................................59
4.7. Application of Tumeric in Food ..................................................................63
....................................................................................................................................... 66
CONCLUSION..............................................................................................................67
LIST OF TABLES
Table1.1: Tumeric (Curcuma Longa L.) Nutritive Value per.........................................11
Table1.2: Chemopreventive and anticancer effects of curcumin....................................20
Table 2.1 In Vivo Effect of Turmeric against Development of Various
Diseases/Disorders.........................................................................................................23
Diseases/Disorders.........................................................................................................25
Table3.1: Summary of chemopreventive effects of curcumin and underlying
mechanisms.................................................................................................................... 49
Table 4.1 MIC of Curcumin and Nanocurcumin against Different Microbes ................60
Table 4.2 MIC of Curcumin and Nanocurcumin against Different Microbes ................61
LIST OF FINGURES
Fingue 1.1: Tumeric plant, flower and fhizome................................................................9
Fingue 1.2: Structure and therapeutic application of curcumin......................................13
Fingue 1.3: Essential oil constituents..............................................................................15
Fingue 1.4: Structures and Physical characteristics of tumerone and artumerone .......16
Fingue 1.6: Potentional uses of curcumin based on modern technology........................19
Fingue 2.1: Inhibition of tumor growth in mice by turmeric extracts in a dose-dependent
manner. .......................................................................................................................... 28
Mice were injected with Daltons lymphoma cells (1 million) intraperitoneally. After
randomization, turmeric was given to the mice (n= 8) at indicated concentration for 10
days. Controlled animals received saline only. (a) Percent of tumor formation after 30
days. (b) Number of animals surviving at 30 days and 60 days. (Redrawn from Kuttan,
R., P.Bhanumathy, K.Nirmala,and M.C.George.1985.Cancer Lett 29:197202)...........28
Fingue 2.2: Inhibition of tumor growth in mice by turmeric extracts in a dose-dependent
manner............................................................................................................................ 34
Figure 3.1: Effects of curcumin in turmeric on multistage carcinogenesis.....................48
Figure 3.2: Suppression of angiogenesis pathway by curcumin.....................................52
Figure 2.5: Mechanism of radiation-induced damage.....................................................54
Figure 3.3: Mechanism of radioprotection by curcumin. indicates increase or
upregulationand indicates decrease or inhibition............................................................55
Fingue 4.1: Dried tumeric...............................................................................................57
Fingue 4.2: Tumeric powder...........................................................................................58
Fingue 4.4: Size characterization of curcumin nanoparticles: (left)................................60
TEM image, and (right) SEM image..............................................................................60
Fingue 4.5: (a) Antibacterial activity of nanocurcumin (water) andcurcumin (DMSO)
solutions at a concentration of 200 g/mL (b) Zone of inhibition of B. subtilis.............61
Fingue 4.7 Total phenolic contents (A) and antioxidant activities (B) of breads
containing turmeric powder. Control, TB2, TB4, TB6 and TB8 are breads prepared with
0%, 2%, 4%, 6% and 8% replacement of wheat our with turmeric powder,
respectively. Bars represent standard error of means (n = 3) and means with different
letters are signicantly different (P < 0.05)....................................................................64
Fingue 4.8 Cross-sections of the breads prepared with turmeric powder replacement for
wheat our. Control, TB2, TB4, TB6 and TB8 are breads prepared with 0%, 2%, 4%,
6%and 8% replacement of wheat our with turmeric powder, respectively...................65
Cross-sectional views of different breads prepare with turmeric powder are presented in
Fig. 3. The change in bread crumb colour is quite evident and with the increase of
turmeric powder in bread, crumb colour became darker and yellower. We may explain
that a daily intake of 50 g or two slices of turmeric bread having 4% wheat oor
substitution with turmeric powder can deliver approximately 4.6 mg of curcumin and
40.12 mg GAE of total phenolic compounds which can render additional health benets
to human body. The data on exact recommended dosage of these phytochemicals is not
available however different in vitro and in vivo studies have been carried out to analyse
their biological effects. ..................................................................................................65
INTRODUCTION
Antioxidants play an important role in human health due to their ability to
prevent or reduce the oxidative damage which contributes to health problems such as
heart disease, macular degeneration, diabetes, cancer, etc. Endogenous antioxidants such
as vitamin E, C, -carotene and some enzyme will trap free radicals which are produced
from metabolic processes of our body. However, the large numbers of free radicals
increase because of effect of UV rays from sunlight, cigarette smoke, inflammation
inside the body. Thus, the endogenous antioxidants are not enough to balance and it is
needed to supply exogenous antioxidants for the purpose of disease prevention, health
promotion and anti-aging. It is actually not hard to find exogenous antioxidants from
natural sources such as vegetable, fresh fruits, and some herbs. Beside that; spice is the
rich and abundant source of materials providing a large number of high quality
antioxidants which are known as essential oils and oleoresins. Essential oils include
aromatic volatile oil while oleoresin contains both aromatic compound and pungent
compound. Ginger, garlic, chili, pepper, turmeric, etc. are used as the main materials to
produce essential oils and oleoresin in the world market. Prominently, turmeric
(Curcuma Longa L.) showed high oxidation resistance and found usage in many other
significant applications.
Turmeric is native to tropical and subtropical regions of South-East Asia, and is
now extensively cultivated from India to Bangladesh, Indonesia, Sri Lanka, Taiwan, part
of China and Jamaica (Krishnamurthy, 1976). Vietnam has tropical monsoon climate
which is favorable condition for the development of turmeric. Therefore, it is cultivated
throughout country to provide spice and drugs. Curcumin, which gives the yellow color
to turmeric, was first isolated almost two centuries ago, and its structure as
diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 bc)
numerous therapeutic activities have been assigned to turmeric for a wide variety of
diseases and conditions, including those of the skin, pulmonary, and gastrointestinal
systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within
the last half century has proven that most of these activities, once associated with
turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti7
inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a
potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimers
disease, and other chronic illnesses. These effects are mediated through the regulation of
various transcription factors, growth factors, inflammatory cytokines, protein kinases,
and other enzymes. Curcumin exhibits activities similar to recently discovered tumor
necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular
endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor
receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker
(e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted
therapy is better than monotargeted therapy for most diseases, curcumin can be
considered an ideal Spice for Life.
CHAPTER 1: LITERATURE REVIEW

1.1 Tumeric (Curcuma Longa L.) plant
1.1.1. Introduction
Taxonomic position of turmeric is as follow:
Class: Liliopida
Subclass: Commelinids
Order: Zingiberales
Family: Zingiberaceae
Genus: Curcuma
Species: Curcuma Longa
Fingue 1.1: Tumeric plant, flower and fhizome

Turmerics scientific name is Curcuma Longa Linn (Curcuma domestica Lour)
which belongs to Zingiberaceae family. It is also called Rhizoma Curcumiae Longae or
Radix Curcumae Longae. Turmeric is a perennial plant which is known as a stemless
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rhizomatous herb and can reach up to 1m high. It has oblong, ovate, short-branched,
brown-skin rhizomes with bright orange and scented flesh. The rhizomes contain the
mother rhizome and fingers. Light green leaves sprout directly from the rhizomes with
elliptical shape and can measure up to 1.2m in length. Its flowers are yellow, funnelshaped and about 10-15m in length. They group together in dense inflorescences which
arise though the pseudostem. The curved bracts are pale green and like as large pouch
with yellow flowers in the lower part. There are no flowers in the upper part where the
bracts are white and green or pink. The flowers bloom at the end of spring and until
middle of summer. However, it is said that there are no fruits for this plant. Turmeric is
originated from Asiatic countries and cultivated mainly in India and China that are
known tropical and subtropical regions of the world. In India, it is popularly known as
"Haldi", and has been well studied due to its economic importance (Araujo and Leon,
2001). Turmeric has warm, bitter taste and golden color, so it is commonly used as a
food additive to improve palatability of food. In addition, turmeric is also used in fabric
dyes and preservative.
1.1.2. Cultivation
Turmeric is known as plant originated from Asiatic countries, so it is easily
grown in diverse tropical conditions from sea level to 1500m elevation, at a temperature
range of 20-35OC. However, Herbs, spices and essential oils Posth-harvest operations
in developing countries (2005) reported that the optimum temperature varies with crop.
High heat (30-35C) is needed to encourage sprouting, 25-30C during tillering, 2025C as rhizomes appear and 18-20C during enlargement. Rhizome yield and the target
product are significantly affected by soil moisture. Therefore, an optimum rainfall is
annually 1500mm, under natural rainfall or irrigated condition. Utpala Parthasarthy
(2006) reported that though turmeric can be grown on different types of soils, it thrives
best in well-drained sandy or clay loam soil, which has adequate soil moisture. Although
turmeric plant does not produce seeds for propagation, we use fresh turmeric root to
start the plant. After two months from planting, turmeric shoots appear. When the leaves
and stems become dry in about seven to ten month after planting, the rhizome can be
harvested.
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1.1.3. Chemical composition of tumeric

The composition of turmeric depends on some factors: habitat, maturity of
cultivars.
Table1.1: Tumeric (Curcuma Longa L.) Nutritive Value per
Principle
Nutrient Value
Energy
354 Kcal
Carbohydrates
64.9 g
Protein
7.83 g
Total Fat
9.88 g
Cholesterol
0 mg
Dietary Fiber
21 g
Vitamins
Folates
39 g
Niacin
5.140 mg
Pyridoxine
1.80 mg
Riboflavin
0.233 mg
Vitamin A
0 IU
Vitamin C
25.9 mg
Vitamin E
3.10 mg
Vitamin K
13.4 g
Electrolytes
Sodium
38 mg
Potassium
2525 mg
Minerals
Calcium
183 mg
Copper
603 g
Iron
41.42 mg
Magnesium
193 mg
Manganese
7.83 mg
Phosphorus
268 mg
Zinc
4.35 mg
(Source: USDA National Nutrient data base)
More than 100 components have been isolated from turmeric. The main
component of the root is a volatile oil, containing turmerone, and there are other
coloring agents called curcuminoids in turmeric. Curcuminoids consist of curcumin
demethoxycurcumin, 5-methoxycurcumin, and dihydrocurcumin, which are found to be
natural antioxidants (Ruby et al. 1995; Selvam et al. 1995). In a standard form, turmeric
contains moisture (>9%), curcumin (56.6%), extraneous matter (<0.5% by weight),
mould (<3%), and volatile oils (<3.5%). Volatile oils include d--phellandrene, dsabinene, cinol, borneol, zingiberene, and sesquiterpenes (Ohshiro, Kuroyanag, and
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Keno 1990). There are a variety of sesquiterpenes, like germacrone; termerone; ar-(+)-,
-, and -termerones; -bisabolene; -curcumene; zingiberene; -sesquiphellanderene;
bisacurone; curcumenone; dehydrocurdione; procurcumadiol; bis-acumol; curcumenol;
isoprocurcumenol; epiprocurcumenol; procurcumenol; zedoaronediol; and curlone,
many of which are specific for a species. The components responsible for the aroma of
turmeric are turmerone, arturmerone, and zingiberene. The rhizomes are also reported to
contain four new polysaccharides-ukonans along with stigmasterole, -sitosterole,
cholesterol, and 2-hydroxymethyl anthraquinone (Kapoor 1990; Kirtikar and Basu
1993). Nutritional analysis showed that 100 g of turmeric contains 390 kcal, 10 g total
fat, 3 g saturated fat, 0 mg cholesterol, 0.2 g calcium, 0.26 g phosphorous, 10 mg
sodium, 2500 mg potassium, 47.5 mg iron, 0.9 mg thiamine, 0.19 mg riboflavin, 4.8 mg
niacin, 50 mg ascorbic acid, 69.9 g total carbohydrates, 21 g dietary fiber, 3 g sugars,
and 8 g protein (Balakrishnan 2007). Turmeric is also a good source of the -3 fatty
acid and -linolenic acid (2.5%; Goud, Polasa, and Krishnaswamy 1993).
1.1.4. Pharmacology activities of tumeric
Turmeric is known as popular spice as well as herb that is used for many
different purpose. Particularly it is widely used as traditional panacea in India and many
countries. Turmeric is a natural, conventional, powerful and familiar drug such as
stomachic, carminative, tonic, blood purifier and an antiseptic that are most commonly
use in every house. Long known for its anti-inflammatory properties, turmeric is
revealed as a natural wonder that contributes to treatment of many different health
conditions from cancer to Alzheimer's disease. Turmeric is useful not only to promote
wound healing, it also brings many advantagous and valuable effects, especially for
human health thank to its benifical properties. In addition, turmeric can not only lower
cholesterol but also prevent blood clot and reduce blood pressure. Besides, it is known
for anti-cancer activity such as cataracts, breast cancer, colon cancer, and lymphoma.
Turmeric helps digest fat by stimulating the production of bile which is needed for fat
metabolism and helps in weight management. Furthermore, it is also used to treating
diarrhea by killing salmonella bacteria and protozoa. Moreover, Turmeric is useful drug
to treat arthritis and rheumatoid arthritis thanks to its potent natural anti-inflammatory
properties without the side effects.
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Fingue 1.2: Structure and therapeutic application of curcumin

1.1.5. Tumerics production and consumption in the world
India is considered as the major producer as well as consumer of its own turmeric
production in over the world, because turmeric is a part of Indian's culture. Devi and
Sangamithra (2011) reported that turmeric is annual produced around 892,213 tones
with a culture area of 194,358 ha. Parthasarathy et al. (2008) reported that 80% of the
world production of turmeric is from India, even though the crop is grown in several
countries such as Paistan, Malaysia, Myanmar, Vietnam, Thailand, the Philippines,
Japan, China, Korea, Sri Lanka, the Caribbean Islands and Central America. In India,
turmeric is produced from 230 districts in 22 states (Chempakam and Parthasarathy,
2008); that cause India to become a largest exporter in the world. From 1990 to 1995,
turmeric oil and oleoresin exports rose from 0.5t to 4.0t and 150t to 250t, respectively
(Anna Plotto, 2004). Asian countries consume much of their own turmeric production,
except for Japan and Sri Lanka (ASTA, 2002).
1.1.6. Tumeric in Vietnam
Vietnam has a tropical monsoon climate, the natural conditions favorable for the
development of turmeric. In Vietnam, turmeric is a very familiar species, which is not
only easy to grow and find, but it is also effective and safe to use. Therefore, it is
cultivated throughout country to provide spice and drugs. Turmeric is used widely in
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food for its flavor and color as well as traditional medicine to treat stomachache,
jaundice, hepatic disorder, menstrual difficulties, scabies, pimple, etc. In addition,
Vietnamese use turmeric to speeds up wound healing and assist in remodeling of
damaged skin. Moreover, women, especially women in confinement, use it as cosmetic
to prevent acne and have smooth and soft skin. Its flower bloom from March to May.
In the South of Vietnam, turmeric is harvested in November or December, but a little
late in the North. o Nhung (2005) reported that turmeric brought higher income for
famers than rice in Chi Tan (Hung Yen). So, the farmer annual enlarge cultivated area to
meet the satisfaction of market demand. At Cam My (Dong Nai), total area used for
cultivating turmeric up to 100 ha that bring the farmer large profit in 2010 (Thuy Hang,
2011).
1.2. Essential and Oleoresin
1.2.1. Essential oil
An essential oil which is known as volatile oil is a concentrated hydrophobic
liquid containing volatile aroma compounds from plants. The term essential mean that
the oil carries distinctive scent of the plant. Essential oil can be generally distilled from
the leaves, stems, flowers, bark, roots or other elements from various parts of plants
Essential oils make up the characteristic odor of many plants, although they just
represent as a small fraction of a plants composition. Makgwane (2006) reported that
essential oils are composed of different chemical groups of terpenic hydrocarbons and
their oxidized derivatives such as aldehydes, esters, ketones and alcohols. Hydrocarbon
terpenes (monoterpenes, sesquiterpenes, sesquiterpene lactones, Di- terpenes, etc.)
represent a large percentage of the components of essential oils of plants that do not
contribute much to flavor, fragrance or odour of the oil. In contrast, oxygenated
compounds are responsible for the characteristic odors and favors. Figure 2-5 shows the
TUMER essential oils carry the essence of a plant, the identifiable aroma, flavor or other
characteristics that may have some practical use in the pharmaceuticals, food and
fragrance industries.
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The essential oils can be extracted from plant by variety of methods such as
steam distillation, aqueous infusion, solvent extraction, cold or hot expression and
supercritical fluid extraction (SFE) with carbon dioxide.
Fingue 1.3: Essential oil constituents

Turmeric essential oil
Turmeric rhizome contains 3-5% volatile oil, which is obtained by steam
distillation of turmeric powder for about 8-10h (Sasikumar, 2001). The turmeric
essential oil is pale yellow to orange-yellow in color, with peppery and aromatic odor
(Krishnamurthy et al, 1976). Turmeric essential oil is useful in aromatherapy and in
perfumery. The oil can use to treat wound.
Yongxiang Yu (2006) reported that the different cultivars, different soil and
climate, and age of plants that influenced the composition of turmeric oils. Thus, there is
a tremendous variation in published compositions of turmeric essential oils (Anne
Plotto, 2004). Yongxiang Yu (2006) reported that among these are terpenes and oxygen
derivative terpenoids that are believed to contribute turmeric flavor. Other minor aromas
include short chain alcohols, ketones, and fatty acids, which are degraded products of
fatty acids. It was found that the aroma of turmeric essential oil was due to mixture of
turmerone and ar-turmerone (Rupe et al., 1934). Turmeric oil contains nearly 100
compounds and most of them are sesquiterpenes (Yongxiang Yu, 2006). Govindarajan
(1980) also reported that ar-turmerone and turmerone account for nearly 50% of the oil.
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Ar-turmerone is a colorless oily chemical and; in contrast, turmerone is a pale yellow

oily chemical. Their structures and physical characters are shown in Figure 2.6
(Yongxiang Yu, 2006).
Fingue 1.4: Structures and Physical characteristics of tumerone and artumerone

1.2.2. Tumeric oleoresin
Oleoresins are the flavor extracts obtained by the solvent extraction of the ground
spices. They contain the essential oil plus other non-volatile components which
characterize the flavor, color and other aspects of the starting raw material. They have
aroma of spice and possess the attributes which contribute to the taste such as pungency.
Spice oleoresins are a liquid, semi-solid or solid residue and possessing the full
character of nature spices. The physical characteristics of oleoresins range from viscous
oils to thick, tacky pastes (Devi and Sangamithra, 2011).
Turmeric oleoresin is a mixture of curcumin, volatile oil, non-volatile fatty and
resinous material, and other active ingredients, which are extracted from powdered or
comminuted rhizome with organic solvents (Govindarajan, 1980). The author also
reported that the process yields (about 12%) depend on the solvent used for extraction
and on the turmeric type and cultivar. Sasikumar (2001) demonstrated that acetone is a
good solvent for oleoresin extraction. Turmeric oleoresin is in orange-red color and
consists of an upper oily layer and a lower crystalline layer. Anna Plotto (2004) reported
16
that the major compounds of turmeric oleoresin are the curcuminoid (40-50%) and the
volatile oils (15-20%). The content of curcuminoid determines the quality of turmeric
oleoresin. Turmeric oleoresin is the industrial starting material to produce pigment
curcumin (Jayaprakasha, 2006).
1.3. Curcuminoids
Curcuma Longa L. extracts contain a mixture of three different naturally occuring
curcuminoids,
curcumin
hydroxycinnamoyl,
(diferuloylmethane),
feruloylmethane)
and
demethoxy-curcumin
bisdemethoxycurcumin
(p(di-p-
hydroxycinnamoylmethane) (Jayaprakasha et al, 2002). In 1815, Curcumin that has been

first isolated by Vogel and Pelletier is a bright yellow, oil-soluble pigment obtained by
solvent extraction of turmeric rhizome (Aggarwal et al., 2006). Curcumin, C 21H22O6, has
a molecular weight of 368.37 with the melting point at 184OC.
IUPAC name of curcumind is (1E, 6E) 1, 7-bis (4-hydroxy-3-metoxyphenyl)
-1, 6-heptadien-3, 5-dion. Ahsan et al (1999) reported that curcumin made up to 77% of
commercial curcumin, but quite low percentage in demethoxy-curcumin (10-20%),
bisdemethoxycurcumin (less than 5%).
Curcumin is soluble in ethanol, alkalis, ketone, acetic acid and chloroform; but
insoluble in water (Araujo and Leon, 2001). The curcumin molecule and the related
curcuminoid family contain a conjungated section with phenyl rings. Curcumin are
placed in the category of phenolic antioxidant due to its carbonyl, methoxy and hydroxyl
groups (Wright, 2002).
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Fingue 1.5: Structures of Curcumin, Demethoxycurcumin, BisDemethoxycurcumin

Activity of Curcuminoids
Curcuminoids is known as an important active component of turmeric, which has
several biological effects, including: anti-inflammatory, antioxidant, anti-protozoal
activity, nematocidal activity, anti-bacterial activity, anti-venom activity, anti-HIV, antitumor activity (Araujo and Leon, 2001). However, the most popular activities of
curcuminoids include anti-inflammatory and antioxidant activity in which antioxidant
activity is widely applied in life and science. Oliver Schulz (2008) reported that the
main features of curcuminoids are the two conjugated groups that play an important role
in reactions with proteins, and the two phenolic hydroxyl groups, which convey the
antioxidative properties to curcumin. Thus, it is considered that the antioxidant activity
is one of the most significant properties of curcuminoids. Curcuminoids were
demonstrated that it is capable of scavenging oxygen free radicals such as superoxide
anions and hydroxyl radicals, which are the initiators of lipid peroxidation (Reddy and
Lokesh, 1992). The authors also showed that turmeric could lower lipid peroxidation by
maintaining the activities of antioxidant enzymes like superoxide dismutase, catalase
and glutathione peroxidase at higher levels. These enzymes play an important role in the
regulation of lipid peroxidation, which has a main role in the inammation, in heart
diseases, and in cancer. Unnikrishnan and Rao (1992) studied the antioxidative
properties of curcuminoids that was demonstrated to protect (52%) hemoglobin from
nitrate-induced oxidation to methemoglobin at 400mM concentration. In addition,
Kapoor and Priyadarsini (2001) have recognized curcuminoids as a powerful antioxidant that can repair both oxidative and reductive damage caused to proteins by
radiation. Araujo and Leon (2001) reported that the phenolic and the methoxy group on
the phenyl ring and the 1, 3-diketone system seems to be important structural features
that can contribute to antioxidant effects of curcuminoids.
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Fingue 1.6: Potentional uses of curcumin based on modern technology
19
Table1.2: Chemopreventive and anticancer effects of curcumin.
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CHAPTER 2: TUMERIC FUNCIALITYS RESEARCH

2.1. Tumeric as a traditional medicine
In folk medicine, turmeric has been used in therapeutic preparations over the
centuries in different parts of the world. In Ayurvedic practices, turmeric is thought to
have many medicinal properties including strengthening the overall energy of the body,
relieving gas, dispelling worms, improving digestion, regulating menstruation,
dissolving gallstones, and relieving arthritis. Many South Asian countries use it as an
antiseptic for cuts, burns, and bruises, and as an antibacterial agent. In Pakistan, it is
used as an anti-inflammatory agent, and as a remedy for gastrointestinal discomfort
associated with irritable bowel syndrome and other digestive disorders. In Pakistan and
Afghanistan, turmeric is used to cleanse wounds and stimulate their recovery by
applying it on a piece of burnt cloth that is placed over a wound. Indians use turmeric, in
addition to its Ayurvedic applications, to purify blood and remedy skin conditions.
Turmeric paste is used by women in some parts of India to remove superfluous hair.
Turmeric paste is applied to the skin of the bride and groom before marriage in some
parts of India, Bangladesh, and Pakistan, where it is believed to make the skin glow and
keep harmful bacteria away from the body. Turmeric is currently used in the formulation
of several sunscreens. Several multinational companies are involved in making face
creams based on turmeric.
In Ayurvedic medicine, turmeric is a well-documented treatment for various
respiratory conditions (e.g., asthma, bronchial hyperactivity, and allergy), as well as for
liver disorders, anorexia, rheumatism, diabetic wounds, runny nose, cough, and sinusitis
(Araujo and Leon 2001). In traditional Chinese medicine, it is used to treat diseases
associated with abdominal pain (Aggarwal, Ichikawa, and Garodia 2004). From ancient
times, as prescribed by Ayurveda, turmeric has been used to treat sprains and swelling
(Araujo and Leon 2001). In both Ayurvedic and traditional Chinese medicine, turmeric
is considered a bitter digestive and a carminative. Unani practitioners also use turmeric
to expel phlegm or kapha, as well as to open blood vessels in order to improve blood
circulation. It can be incorporated into foods, including rice and bean dishes, to improve
digestion and reduce gas and bloating. It is a cholagogue, stimulating bile production in
21
the liver and encouraging excretion of bile via the gallbladder, which improves the
bodys ability to digest fats. Sometimes, turmeric mixed with milk or water is taken to
treat intestinal disorders as well as colds and sore throats.
2.2. Tumeric as a modern medicine
Although modern medicine has been routinely used in treatment of various
diseases, it is less than 100 years old. Traditional medicine, in comparison, has served
mankind for thousands of years, is quite safe and effective. The mechanism or the
scientific basis of traditional medicine, however, is less well understood.
2.2.1 In vitro studies with Tumeric
Throughout the Orient, turmeric is traditionally used for both prevention and
therapy of diseases. Modern in vitro studies reveal that turmeric is a potent antioxidant,
anti-inflammatory, antimutagenic, antimicrobial, and anticancer agent (Table 3.1).
Turmeric, used in cooking and in home remedies, has significant antioxidant abilities at
different levels of action. Studies indicate that sufficient levels of turmeric may be
consumed from curries in vivo to ensure adequate antioxidant protection. (Tilak et
al.2004). As an antioxidant, turmeric extracts can scavenge free radicals, increase
antioxidant enzymes, and inhibit lipid peroxidation. Turmeric (100g/mL) inhibits lipid
peroxidation in renal cells against hydrogen peroxide-induced injury when incubated
with cells for 3 hours (Cohly et al. 1998). Using Salmonella typhimurium strains TA 100
and TA 1535, a mutagenicity study showed that turmeric inhibits the mutagenicity
produced by direct-acting mutagens such as N-methyl N-nitro-N-nitrosoguanidine and
sodium azide. Turmeric extracts were found to inhibit microsomal activation-dependent
mutagenicity of 2-acetamidofluorene (Soudamini et al. 1995).
22

Diseases/Disorders.
Numerous lines of evidence suggest that turmeric exhibits anti-inflammatory

activity. In one study, crude organic extracts of turmeric were found to inhibit
lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)- (median
inhibitory concentration [IC50] value = 15.2 g/mL) and prostaglandin E2 (PGE2; IC 50
value = 0.92 g/mL) from HL-60 cells. A combination of several fractions that
contained the turmeric oils was more effective than curcuminoids in inhibiting PGE2
production (Lantz et al. 2005). A hydroethanolic extract of turmeric was recently found
to inhibit activation of human dendritic cells in response to inflammatory cytokines
(Krasovsky et al. 2009).
23
Besides these properties, turmeric has strong antimicrobial properties. The

growth of histamine-producing bacteria (Vibrio parahaemolyticus, Bacillus cereus,
Pseudomonas aeruginosa, and Proteus mirabilis) was inhibited by garlic and turmeric
extracts at a 5% concentration (Paramasivam, Thangaradjou, and Kannan 2007).
Turmeric was also found to inhibit histamine production in Morganella morganii
(potent histamine-producing bacteria). However, inhibition of histamine production and
histidine decarboxylase activity of turmeric is less than that of clove and cinnamon
(Shakila, Vasundhara, and Rao 1996). Turmeric extract was found to inhibit growth of
the foodborne pathogen V. parahaemolyticus with good sensitivity (Yano, Satomi, and
Oikawa 2006). A methanolic extract of turmeric inhibited the growth of different strains
of Helicobacter pylori with a minimum inhibitory concentration range of 6.2550.0
g/mL (Mahady et al. 2002). Among the various plant extracts that killed H. pylori,
such as cumin, ginger, chili, borage, black caraway, oregano, and licorice, turmeric was
found to be the most efficient (OMahony et al. 2005).
Ethanolic extracts of C. longa have good antifungal activity against Trichophyton
longifusus (Khattak et al. 2005). Tests using the agar disc diffusion method for detecting
antifungal activity showed that a crude ethanolic extract of turmeric killed all 29 tested
clinical strains of dermatophytes. This extract exhibited an inhibition zone range of 6.1
26.0 mm (Wuthi-udomlert et al. 2000).
The anticancer activities of turmeric include inhibiting cell proliferation and
inducing apoptosis of cancer cells. Ar-turmerone, which is isolated from turmeric,
induced apoptosis in human leukemia Molt 4B and HL-60 cells by fragmenting DNA to
oligonucleosome-sized fragments, a known step in the process of apoptosis
(Aratanechemuge et al. 2002). Moreover, the nucleosomal DNA fragmentation induced
by ar-turmerone was associated with induction of Bax and p53 proteins, rather than B
cell lymphoma 2 (Bcl-2) and p21, and activation of mitochondrial cytochrome c and
caspase-3 (Lee 2009). This study showed that turmeric extract repressed the production
and secretion of hepatitis B surface antigen from HepG 2.2.15 cells, an activity that is
mediated through the enhancement of cellular accumulation of p53 protein by
transactivating the transcription of the p53 gene as well as increasing the stability of the
p53 protein (Kim et al. 2009).
24
2.2.2. In vivo studies with Tumeric

Both the preventive and therapeutic effects of turmeric have been examined in
animal models (Table 13.4). These studies report that this yellow spice exhibits
anticancer (Azuine and Bhide 1994; Deshpande, Ingle, and Maru 1997; Garg, Ingle, and
Maru 2008), hepatoprotective (Miyakoshi et al. 2004), cardioprotective (Mohanty, Arya,
and Gupta 2006), hypoglycemic (Kuroda et al. 2005; Honda et al. 2006), and
antiarthritic properties (Funk et al. 2006).
Diseases/Disorders.
25
26
AP = alkaline phosphatase; ALT = alanine aminotransferase; LDH = lactate

dehydrogenase; AST = aspartate aminotransferase; CYP = cytochrome enzymes; GGT =
gamma glutamyl transpeptidase; GSH = glutathione; LDL = low-density lipoprotein;
LPO = lipid peroxidation; NC = not clear; VEGF = vascular endothelial growth factor;
VSMC = vascular smooth muscle cell. ( a Mice;
Guinea pig;
Chicks;
Turmeric powder;
Hamster;
Rat;
Rabbit;
Aqueous extract of turmeric;
Dog;
Ethanolic
extract of turmeric; k Methanolic extract of turmeric; L Not clear)

In various models, turmeric has been reported to exhibit activity against the
development of skin cancer (Villaselor, Simon, and Villanueva 2002), breast cancer
(Deshpande, Ingle, and Maru 1998a), oral cancer (Azuine and Bhide 1992a), and
stomach cancer (Azuine and Bhide 1992b). It prevents carcinogenesis at various steps,
including inhibiting mutation (Polasa et al. 1991), detoxifying carcinogens (Thapliyal,
Deshpande, and Maru 2001), decreasing cell proliferation, and inducing apoptosis of
tumor cells (Garg, Ingle, and Maru 2008). Turmeric extract prevents animal tumors
induced by Daltons lymphoma (Kuttan et al. 1985). In this study, mice were injected
with Daltons lymphoma cells intraperitoneally and treated with turmeric extract (1040
mg/animal) for 10 days. After 30 days, the authors found up to 80% decrease in tumor
formation in comparison with nontreated mice (Figure 3.1a). They also observed that up
to 75% of animals survived after 30 days and 50% after 60 days of treatment (Figure
3.1b). In a 7, 12-dimethylbenz (a) anthracene (DMBA)-induced hamster buccal pouch
model of carcinogenesis, dietary turmeric (1%) decreased tumor burden and multiplicity
and enhanced the latency period in parallel. The mechanisms of anticarcinogenesis were
mediated through inhibition of DMBA-induced expression of the ras oncogene product,
induction of p21 and its downstream targets, mitogen-activated protein kinases, and
reduction of proliferating cell nuclear antigen and Bcl-2 expression. Turmeric also
enhanced apoptosis (increased expression of Bax, caspase-3, and apoptotic index),
decreased inflammation (levels of cyclooxygenase [COX]-2, the downstream target of
activator protein-1/nuclear factor KB [NF-KB], and PGE2), and induced aberrant
expression of known differentiation markers, that is, cytokeratins (Garg, Ingle, and
Maru 2008).
27
Fingue 2.1: Inhibition of tumor growth in mice by turmeric extracts in a

dose-dependent manner.
Mice were injected with Daltons lymphoma cells (1 million)
intraperitoneally. After randomization, turmeric was given to the mice (n= 8)
at indicated concentration for 10 days. Controlled animals received saline
only. (a) Percent of tumor formation after 30 days. (b) Number of animals
surviving at 30 days and 60 days. (Redrawn from Kuttan, R., P.Bhanumathy,
K.Nirmala,and M.C.George.1985 .Cancer Lett 29:197202).
Topical application of turmeric was found to decrease multiplicity and onset of
skin tumors (Villaseor, Simon, and Villanueva 2002). Dietary administration of 1%
turmeric per 0.05% ethanolic turmeric extract was found to inhibit DMBA-induced
mammary tumorigenesis in female SpragueDawley rats (Deshpande, Ingle, and Maru
1998a). Dietary turmeric inhibited ethyl (acetoxymethyl) nitrosamine-induced oral
carcinogenesis in Syrian hamsters. However, the inhibitory effect of a combination of
turmeric and betel leaf extract was found to be higher than that of the individual
constituents (Azuine and Bhide 1992a). Administration of turmeric extract at a dose of 3
mg/animal 18 hours prior to intraperitoneal (i.p.) injection of benzo[a]pyrene (BaP; 250
mg/kg) significantly inhibited bone marrow micronuclei formation in female Swiss
mice. Moreover, the incidence and multiplicity of BaP-induced forestomach tumors in
28
female Swiss mice were significantly inhibited by turmeric extract (Azuine, Kayal, and
Bhide 1992). Chandra Mohan, Abraham, and Nagini (2004) also showed that
pretreatment with turmeric alone and in combination with tomato and garlic extract
significantly lowered the frequencies of DMBA-induced bone marrow micronuclei, as
well as the extent of lipid peroxidation. They revealed that these changes may be
mediated by the antioxidant-enhancing effects of the dietary agents. Combined
treatment of urethane, a well-known mutagen, and turmeric displayed an inhibition of
the genotoxic effect of urethane by turmeric (el Hamss et al. 1999). Decrease in
tumorigenesis caused by turmeric is also associated with inhibition of DNA adduct
formation. Turmeric inhibited the levels of BaP-induced DNA adducts in the livers of
rats. Inclusion of turmeric at 0.1%, 0.5%, and 3.0% in the diet for 4 weeks significantly
decreased the level of BaPDNA adducts, including the major adduct dG-N2-BaP,
formed within 24 hours in response to a single i.p. BaP injection (Mukundan et al.
1993). Irrespective of whether turmeric was included in the diet or applied locally, it
significantly decreased DMBA-induced DNA adducts at the target site and consequently
lowered the number of tumors and tumor burden in the studied animals (Krishnaswamy
et al. 1998). Turmeric contains several substances capable of inhibiting chemical
carcinogenesis. It enhanced the xenobiotic-metabolizing enzymes in the hepatic tissue of
rats fed with 0.51.0% turmeric in the diet. Detoxifying enzymes such as uridine
diphosphate (UDP), glucuronyl transferase, and glutathione-S-transferase significantly
increased in turmeric-fed mice as compared with control animals (Goud, Polasa, and
Krishnaswamy 1993).
Ethanolic turmeric extract was found to have opposing actions on murine
lymphocytes and on Ehlrich ascitic carcinoma cells. Turmeric enhances lymphocyte
viability and blastogenesis, but induces formation of cytoplasmic blebs and plasma
membrane disintegration of tumor cells. Thus, it is suggested that turmeric is a
conducive agent for lymphocytes and inhibitory as well as apoptosisinducing for tumor
cells (Chakravarty and Yasmin 2005). A comparative study of edible plants like C.
longa and F. caraica, and herbaceous plants like Gossypium barbadense and Ricinus
communis extracts for their antitumor activities showed that the edible plant extracts
exhibited higher antitumorigenic activities. Thus, edible plants that show in vivo
29
antitumor activities may be recommended as safe sources of antitumor compounds

(Amara, El-Masry, and Bogdady 2008).
Turmeric showed antioxidant potential by lowering oxidative stress in animals. A
study showed that a diet containing 0.1% turmeric fed for 3 weeks to retinol-deficient
rats lowered lipid peroxidation rates by 22.6% in liver, 24.1% in kidney, 18.0% in
spleen, and 31.4% in brain (Kaul and Krishnakantha 1997). A study conducted on mice
showed that turmeric extract inhibited membrane phospholipid peroxidation and
increased liver lipid metabolism, which indicates turmeric extract has the ability to
prevent the deposition of triacylglycerols in the liver. Dietary supplementation for one
week (1% w/w of diet) with a turmeric extract showed lower phospholipids
hydroperoxide level in mice red blood cells (RBC). The liver lipid peroxidizability
induced with Fe2+/ascorbic acid was effectively suppressed by dietary supplementation
with turmeric (Asai, Nakagawa, and Miyazawa 1999). Oral administration of a
nutritional dose of turmeric extract decreased susceptibility to oxidation of erythrocyte
and liver microsome membranes in vitro. When turmeric hydroalcoholic extract (1.66
mg/kg of body weight) was given to rabbits fed a high-fat diet, oxidation of erythrocyte
membranes was found to be significantly lower than that in membranes of control
animals. Levels of hydroperoxides and thiobarbituric acid-reactive substances in liver
microsomes were also low (Mesa et al. 2003). Turmeric also seems beneficial in
preventing diabetes-induced oxidative stress. In diabetic rats, an AIN93 diet containing
0.5% turmeric was found to control oxidative stress by inhibiting increases in
thiobarbituric acid-reactive substances and protein carbonyls and reversing altered
antioxidant enzyme activities without altering the hyperglycemic state (Arun and Nalini
2002; Suryanarayana et al. 2007). This diet also inhibited expression of vascular
endothelial growth factor in diabetic rats (Mrudula et al. 2007). Further, it suppressed
increase in blood glucose level in type 2 diabetic KK-Ay mice. A dose of 0.2 or 1.0 g of
ethanol extract, 0.5 g of hexane extract, and 0.5 g of hexane-extraction residue per 100 g
of diet in the mice feed suppressed significant increase in blood glucose levels. The
ethanol extract of turmeric also stimulated human adipocyte differentiation, and it
showed human peroxisome proliferator-activated receptor-gamma (PPAR-) ligandbinding activity (Nishiyama et al. 2005). Further, turmeric appeared to minimize
30
osmotic stress. Most importantly, aggregation and insolubilization of lens proteins due
to hyperglycemia was prevented by turmeric, indicating that it prevents or delays the
development of cataracts (Suryanarayana et al. 2005).
Turmeric has been reported to be hepatoprotective. Diets containing turmeric
extract suppressed increases in lactate dehydrogenase (LDH), alanine aminotransferase
(ALT), and aspartate aminotransferase (AST) levels caused by D-galactosamineinduced liver injury in rats (Miyakoshi et al. 2004). A 5% turmeric extract decreased
carbon tetrachlorideinduced increases in serum levels of bilirubin, cholesterol, AST,
ALT, and alkaline phosphatase (ALP) in mice (Deshpande et al. 1998b). In female
Wistar
rats
fed
diet
containing
0%,
0.2%,
1.0%,
or
5.0%
turmeric,
nitrosodiethylamineinduced hepatocarcinogenesis was inhibited. This effect was

detected by measuring the numbers of -glutamyl transpeptidasepositive foci, a marker
of hepatocarcinogenesis (Thapliyal et al. 2003).
Turmeric is also effective against neuronal, cardiac, and kidney disorders. The
effect of turmeric on myocardial apoptosis and cardiac function was examined in an
ischemia and reperfusion model of myocardial injury. Turmeric at 100 mg/kg
administered for 1 month afforded significant cardioprotection and functional recovery
that was attributed to reduction in cell death (Mohanty, Arya, and Gupta 2006).
Turmeric is also useful against depression (Yu, Kong, and Chen 2002; Xia et al.
2006; Xia et al. 2007). Its ethanolic extract markedly attenuated swim stressinduced
decreases in serotonin, 5-hydroxyindoleacetic acid, and noradrenaline and dopamine
concentrations, as well as increases in serotonin turnover. Also, this extract significantly
reversed swim stressinduced increases in serum corticotropin-releasing factor and
cortisol levels and thus regulated neurochemical and neuroendocrine systems in mice
(Xia et al. 2007). In another study, administration of aqueous extracts of turmeric to
mice (140560 mg/kg for 14 days) reduced immobility in the tail suspension test and the
forced swimming test (Yu, Kong, and Chen 2002). The effects of 560-mg/kg turmeric
were found to be more potent than those of the antidepressant fluoxetine. The extracts
significantly inhibited brain monoamine oxidase (MAO)-A activity at a low dose, but at
a higher dose, they inhibited brain MAO-B activity. In comparison, fluoxetine showed
31
only a tendency to inhibit MAO-A and -B activity in animal brains. These results
demonstrate that turmeric has specific antidepressant effects in vivo. However, since
curcumin is not water soluble, the agent in aqueous extracts of turmeric responsible for
this activity is not clear.
The antiarthritic effects of turmeric include inhibition of joint inflammation and
periarticular joint destruction. In vivo treatment with turmeric extract prevented local
activation of NF-B and the subsequent expression of NF-B-regulated genes mediating
joint inflammation and destruction, including chemokines, COX-2, and the receptor
activator of NF-B ligand (RANKL). It also inhibited inflammatory cell influx, joint
levels of PGE2, and periarticular osteoclast formation in rats (Funk et al. 2006).
Turmeric was found to be effective against carrageenan-induced edema in rats
(Yegnanarayan, Saraf, and Balwani 1976), and water extracts of turmeric were more
active than alcohol extracts in the inhibition of carrageenan-induced edema. Turmeric
extract, when given intraperitoneally, was found to be more active than hydrocortisone
(Ghatak and Basu 1972). The yellow powder of turmeric is known to have potent
vasorelaxant activity and to decrease the atherogenic properties of cholesterol. A study
showed that supplementation of turmeric in the diet controlled arterial blood pressure in
animals and enhanced vasorelaxant responses to adenosine, acetylcholine, and
isoproterenol (Zahid Ashraf, Hussain, and Fahim 2005). Turmerics antiatherosclerotic
effect is associated with inhibition of low-density lipoprotein oxidation, prevention of
lipoperoxidation, and reduction in levels of cholesterol (Quiles et al. 1998; RamrezTortosa et al. 1999). A study showed that feeding an ethanolic extract of turmeric to rats
elevated the high-density lipoprotein (HDL)-cholesterol/total cholesterol ratio. The
extract also caused a significant decrease in the ratio of total cholesterol/phospholipids.
Turmeric extract exhibited better cholesterol and triglyceride lowering (85% and 88%,
respectively) as compared to Nardostachys jatamansi extract in tritoninduced
hyperlipidemic rats (Dixit, Jain, and Joshi 1988). Turmeric suppresses Freunds
adjuvantinduced arthritis and acute edema in rats, and it has also been reported that oil
extract of turmeric is more active than cortisone (Chandra and Gupta 1972).
Another interesting property of turmeric is its wound-healing ability. Gujral,
Chowdhury, and Saxena (1953) found that turmeric has the property of healing wounds
32
and ulcers in rats and rabbits. Other studies in rabbits revealed that stimulation of mucin
secretion could protect the stomach from ulcer (Mukerji, Zaidi, and Singh 1961).
Besides causing these effects, addition of turmeric to the diet significantly
improved weight gain of broiler chicks and reduced their relative liver weight. Turmeric
also ameliorated the adverse effects of aflatoxin on some serum chemistry parameters
(total protein, albumin, cholesterol, calcium) in broiler chicks and restored antioxidant
functions in terms of level of peroxides, superoxide dismutase activity, and total
antioxidant concentration in their livers (Gowda et al. 2008).
Turmeric acts as a digestive stimulant. As a dietary supplement, it favorably
enhanced the activities of pancreatic lipase, chymotrypsin, and amylase. Moreover,
turmeric mixed with other spices such as coriander, red chili, black pepper, and cumin
brought about a pronounced stimulation of bile flow and bile acid secretion (Platel et al.
2002). Mukerji, Zaidi, and Singh (1961) showed that turmeric increases the mucin
content of gastric juice in rabbits. Studies conducted by Farnsworth and
Bunyapraphatsara (1992), Supniewski and Hano (1935), and Prucksunand et al. (2001)
explain that turmeric has local anesthetic action. After eating turmeric, secretion of
gastrin hormone from the antrum of the stomach may be inhibited. Turmeric may
possess local membrane-anesthetizing activity at the antrum of the stomach, which then
inhibits secretion of gastrin in the same way as oxethazaine, the active ingredient of
strocain (Masuda 1973). This is the reason turmeric is administered before meals.
2.2.3. Clinical studies using Tumeric
Turmeric has been tested against various diseases in humans (Table 3.2). In one
study, the antimutagenic effects of turmeric were examined in 16 chronic smokers
(Polasa et al. 1992). Turmeric was given in doses of 1.5 g/day for 30 days, and this was
found to significantly reduce the urinary excretion of mutagens in these smokers. In six
nonsmokers, on the other hand, no change in urinary excretion of mutagens was noted.
These results suggest that dietary turmeric is an effective antimutagen and may be useful
in chemoprevention. In another study, the effect of turmeric was examined on patients
with irritable bowel syndrome. When 1 or 2 tablets of a standardized turmeric extract
were given daily for 8 weeks, the prevalence of irritable bowel syndrome was
33
significantly decreased, as was the abdominal pain/discomfort score (Bundy et al. 2004).
Alcoholic extract of turmeric offered protection against BaP-induced increase in
micronuclei in circulating lymphocytes of healthy individuals (Hastak et al. 1997). In a
subsequent study, the authors treated patients suffering from oral submucous fibrosis
(OSF) with turmeric extract (3 g/day) for 3 months. The number of micronuclei from
oral exfoliated cells of OSF patients before and after treatment with turmeric extract was
recorded. They found that the number of micronuclei in oral exfoliated cells decreased
substantially and was comparable with that of normal, healthy individuals (Figure 2.2).
Table 2.3 Human Studies with Turmeric.
Fingue 2.2: Inhibition of tumor growth in mice by turmeric extracts in

a dose-dependent manner
34
Inhibition of micronuclei formation in oral submucous fibrosis (OSF) patients:

(a) Incidence of micronuclei in exfoliated buccal mucosal cells of OSF patients before
and after treatment with turmeric and of normal healthy individuals. (b) Incidence of
micronuclei in circulating lymphocytes of OSF patients before and after turmeric
treatment. (n = 10). The symbol * indicates statistical significance when compared with
untreated pretreatment group (p < .001). The symbol ** indicates statistical significance
when compared with benzo[a]pyrene-treated pretreatment group (p < .001). (Redrawn
from Hastak, K., N. Lubri, S. D. Jakhi et al. 1997. Cancer Lett 116:2659.)
Turmeric was also found useful in healing peptic ulcers. In a phase II clinical
trial, 45 patients with peptic ulcer received capsule-filled turmeric orally in the dose of 2
capsules (300 mg each) five times daily. After 4 weeks of treatment, ulcers were found
to be absent in 48% of cases. After 12 weeks of treatment, ulcer-free cases increased to
76% (Prucksunand et al. 2001). A double-blind trial found turmeric to be helpful for
people with indigestion and for people with stomach or intestinal ulcers, but it was
shown to be less effective than antacids (Kositchaiwat, Kositchaiwat, and Havanondha
1993). An ethanol extract of turmeric was found to produce remarkable symptomatic
relief in patients with external cancerous lesions. In a study of 62 patients, reduction in
smell was noted in 90% of the cases and reduction of itching in almost all cases. Some
patients (10%) had a reduction in lesion size and pain (Kuttan, Sudheeran, and Joseph
1987).
A study on eight healthy subjects showed that the presence of turmeric in curry
increases bowel motility and activates hydrogen-producing bacterial flora in the colon,
thereby increasing the concentration of breath hydrogen (Shimouchi et al. 2008).
Turmeric paste is used to heal wounds or to protect against infection. In certain parts of
Bangladesh, turmeric is the most common application on the cut umbilical cord after
delivery (Alam et al. 2008).
35
CHAPTER 3: MECHANISM OF TUMERIC FUNTIONALITY

3.1. Curcumin: Antioxidant mechanism
The antioxidant mechanisms of curcumin have recently been the focus of interest
of free radical chemists and biologists.
Curcumin is known to protect biomembranes against peroxidative damage.
Peroxidation of lipids is known to be a free-radical-mediated chain reaction, leading to
the damage of the cell membranes, and the inhibition of peroxidation by curcumin is
mainly attributed to the scavenging of the reactive free radicals involved in the
peroxidation. Most of the antioxidants have either a phenolic functional group or a diketone group. Curcumin is an unique antioxidant, which contains a variety of
functional groups, including the - diketone group, carboncarbon double bonds, and
phenyl rings containing varying amounts of hydroxyl and methoxy substituents.
The central argument is whether the phenolic or the central methylenic hydrogen
in the heptadienone moiety is responsible for its antioxidant activity. Curcumin is a
superb H-atom donor by donating the H-atom from the central methylenic group rather
than from the phenolic group in acidic and neutral aqueous and acetonitrile solutions.
On the other hand, Curcumin is a classical phenolic chain-breaking antioxidant,
donating H-atoms from the phenolic group, phenolic group is essential for the freeradical-scavenging activity and that the presence of the methoxy group further increased
the activity.
Theoretical calculations by the density functional theory demonstrated that the
enol form of curcumin is significantly more stable than the diketo form and that the
bond dissociation enthalpy (BDE) of the phenolic O: H bond is significantly lower than
the BDE of the central O: H bond, suggesting that the hydrogen atom abstraction takes
place in the phenolic group. It was also pointed out that the relative contribution of the
phenolic group and the central methylenic group on the antioxidant activity depends on
the activity of attacking radical and the reaction medium. Scientists recently compared
the rate constants of the reaction of 1,1-Diphenyl-2-picrylhydrazyl radical with
curcumin in ionizing solvents and nonionizing solvents and resolved the curcumin
antioxidant controversy by the mechanism of sequential proton loss electron transfer;
36
that is, in solvents that support ionization, curcumin reacts with electrophilic radicals
initially at ionized keto-enol moiety and the resulting neutral radicals lose a phenolic
photon, thus yielding the same phenoxyl radical, as would have been formed by H-atom
transfer from the phenolic hydroxyl group of the curcumin anion to the radicals.
However, in nonionizing solvent, the sequential proton loss electron transfer mechanism
cannot occur and the reactions involve only H-atom transfer from a phenolic hydroxyl
group of the neutral curcumin to the radical.
Another important mechanism is that curcumin can degrade into trans- 6-(4hydroxy-3-methoxyphenyl)-2, 4-dioxo-5-hexanal, ferulic acid, ferruloylmethane, and
vanillin at basic pH within 30 min. Among these, ferrulic acid and vannilin are wellestablished antioxidants.
3.2. Anti- inflammatory property of curcumin
Curcumin was found to have a miraculous power in anti-inflammatory response.
The natural anti-inflammatory activity of curcumin is on a par with steroidal drugs and
nonsteroidal drugs as indomethacin and phenylbutazone, which have dangerous side
effects. Its anti-inflammatory property appears to be mediated through the inhibition of
induction of COX-2, LOX, iNOS and production of cytokines such as interferon- and
tumor necrosis factor, and activation of transcription factors like NF-B, and AP-1.
3.2.1. Effect of Curcumin on Cyclooxygenases and Lipoxygenases
The anti-inflammatory properties of curcumin have been attributed, at least in
part, to suppression of prostaglandins (PGs) synthesis. The involvement of PGs and
other eicosanoids in the development of human cancer has been known for over two
decades. Importantly, an increase in PG synthesis might influence tumor growth in
human beings and experimental animals, and numerous studies have illustrated the
effect of PG synthesis on carcinogen metabolism, tumor cell proliferation, and
metastatic potential.21 Cyclooxygenase (COX) is a key enzyme responsible for the
conversion of arachidonic acid to PGs. It consists of two different isoforms, designated
Cyclooxygenase 1 (COX 1) and Cyclooxygenase 2 (COX 2). COX 1 is a
constitutive isoform present in most tissues and is generally regarded as a
housekeeping enzyme and its inhibition results in serious effects such as peptic
ulceration or impairment of renal blood flow. In contrast, COX 2 is constitutively
37
expressed only in brain and spinal cord tissue and it can also be induced in a wide
variety of normal tissues by the hormones of ovulation and pregnancy, cytokines,
growth factors, oncogenes, and tumor promoters. COX-2 overexpression has been
implicated in the carcinogenesis of tumors of the colon, rectum, breast, head and neck,
lung, pancreas, stomach, and prostate. There is growing evidence that inhibitors of
COX-2 activity are useful for treating inflammation and preventing or treating cancer.
Therefore, agents that interfere with the signaling mechanisms governing the
transcription of COX-2 should also inhibit inflammation and tumorigenesis. Further
investigations suggest that arachidonic acid (AA) metabolites derived from
lipoxygenase (LOX) pathways play an important role in growth-related signal
transduction, implying that intervention through these pathways should be useful for
arresting cancer progression.
An expanding body of evidence suggests that curcumin inhibits the expression of
COX-2. The scientists have demonstrated that dietary curcumin significantly inhibits
phospholipase A2 in colonic mucosa and tumors, leading to the release of arachidonic
acid from phospholipids, alters COX and LOX activities, and modifies PGE 2 levels.
Unlike selective COX-2 inhibitors, which inhibit the catalytic activity of the COX
enzyme, curcumin decreases COX-2 expression at the transcriptional level. Several lines
of evidence also indicate that the mechanism of action of curcumin is not limited to PG
inhibition. They have also observed that dietary curcumin inhibits LOX activity and the
production of the LOX metabolites in the colonic mucosa and in tumors. LOX
metabolites have also been shown to promote tumor cell adhesion, stimulate the
spreading of tumor cells, and augment metastatic potential.
In one study, Zhang and colleagues from the Cornell University campus in New
York City, exposed gastrointestinal cells to two known tumor promoters: bile acids
(BA) and phorbol esters (PMA). The team found COX-2 to be induced in several of the
cell lines, accompanied by a 10-fold increase in the synthesis of inflammatory-causing
PGE2. However, dose-dependent treatment of the cells with curcumin suppressed both
BA- and PMA-mediated induction of COX-2 protein, genetic COX-2 expression (as
measured by mRNA), and the synthesis of PGE2. Most impressive, however, was the
discovery that curcumin directly inhibited the enzymatic activity of COX-2.
38
An additional study presented at the 1999 American Association for Cancer

Research (AACR) conference also examined the pain-relieving properties of curcumin.
Researchers at the University of California, San Diego and the Veterans Administration
Medical Center, San Diego investigated whether curcumin could suppress COX-2
expression in human colon cancer cells. After exposing such cells to curcumin, the
researchers found the compound not only inhibited cell growth but also reduced the
expression of COX-2 mRNA in a time- and dose-dependent manner. Therefore,
curcumin would appear to be a safe, natural COX-2 inhibitor in humans, given its safety
profiles and demonstrated anti-inflammatory activity.
3.2.2. Effect of Curcumin on Inducible Nitric Oxide Synthase
Another enzyme that plays a pivotal role in mediating inflammation is inducible
nitric oxide synthase (iNOS). iNOS catalyzes the oxidative deamination of l-arginine to
produce NO, a potent pro-inflammatory mediator. NO has multifaceted roles in
mutagenesis and carcinogenesis. In addition to acting as an initiator of carcinogenesis,
NO is involved in the promotional stage of tumorigenesis or neoplastic transformation.
NO is also known to affect tumor progression by regulating the angiogenesis, possibly
by stimulating the production of vascular endothelial growth factor (VEGF). NO reacts
rapidly with superoxide anion to produce the extremely powerful oxidant peroxynitrite
(ONOO). Peroxynitrite can cause various DNA modifications and other types of
cellular injury, contributing to genotoxicity or initiation of multistage carcinogenesis.
One of the secondary processes that might follow DNA damage by NO or peroxynitrite
includes activation of the tumor suppressor gene p53 or the DNA repair enzyme poly
(ADP-ribose) polymerase (PARP). It is known that activation of p53 or PARP is often
associated with apoptotic cell death. There are numerous reports on the NO- or
peroxynitrite-induced apoptosis. Increased expression of iNOS and/or its catalytic
activity has been observed in several human tumor tissues and also in chemically
induced animal tumors as well as in inflammatory disorders. Human breast tumor
biopsies in higher grades exhibited elevated levels of iNOS, compared with those in
lowergrade ones. Thus, aberrant or excessive expression of iNOS, as in the case of
COX-2, is considered to be implicated in the pathogenesis of cancer, and compounds
that can selectively inhibit abnormal expression of iNOS can act as a potential candidate
39
for chemoprevention. iNOS has been shown to be involved in the regulation of COX-2
and, hence, the subsequent production of pro-inflammatory PGs.
In addition to COX-2, iNOS also appears to be a target for the anti-inflammatory
effect of curcumin. Curcumin is reported to inhibit the NO production and expression of
iNOS protein and mRNA in RAW 264.7 cells stimulated with lipopolysaccharides
(LPSs) or interferon-.40 Downregulation of the iNOS gene by curcumin in RAW 264.7
cells might be attributed to suppression of c-Jun/AP-1 activation, because it is a known
fact that the consensus AP-1-binding sequence is present in the promoter region of the
iNOS gene and it can be attenuated by curcumin.40 Chan et al.41 have reported that
curcumin can inhibit the iNOS gene expression in isolated BALB/c mouse peritoneal
macrophages and in the livers of LPS-injected mice.
3.2.3. Effect of Curcumin on Nuclear Factor-B
One of the most ubiquitous eukaryotic transcription factors that regulate
expression of genes involved in controlling cellular proliferation/growth, inflammatory
responses, cell adhesion, and so forth is nuclear factor-B (NF-B). The functionally
active NF-B exists mainly as a heterodimer consisting of subunits of the Rel, which is
normally sequestered in an inactive cytoplasmic complex by binding to an inhibitory
protein, IB. Exposure of cells to such external stimuli as mitogens, inflammatory
cytokines, ultraviolet radiation, ionizing radiation, viral proteins, bacterial LPSs, and
ROS causes rapid phosphorylation of IB with subsequent degradation by proteosomes.
Dissociation of IB from NF-B allows the activated free dimer to translocate to the
nucleus, where it induces, through binding the cis-acting B element, the transcription
of a large variety of target genes that normally encode cytokines, cell adhesion
molecules, growth factors, and so forth. The transcriptional activity of NF-B is
regulated via an elaborate series of intracellular signal transduction events in response to
external stimuli. In addition to its central roles in mediating inflammation, NF-B is
important in control via cell proliferation, oncogenesis, and cell transformation.44 Thus,
aberrant constitutive activation of NF-B/Rel has been observed in an array of human
and experimentally induced tumors and transformed cells in culture. There is increasing
evidence that constitutive activation of this transcription factor is associated with the
proliferation and survival of certain tumor cells and causes resistance to apoptosis.
40
The data from experimental studies have demonstrated that curcumin inhibits the
activation of NF-B in different cancer cell lines. It has been found that oxidative stress
activates NF-B DNA-binding activity. Because curcumin has been known as an
antioxidant, its inhibitory effects on oxidative stress might be mediated through the
suppression of NF-B DNA-binding activity. It has been reported that curcumin
inhibited IKB kinase (IKK), suppressed both constitutive and inducible NF-B
activation and potentiated tumor necrosis factor (TNF)-induced apoptosis. Curcumin
treatment reduced the amount of phosphorylated IKK, which ultimately prevents the
translocation of NF-B to the nucleus. Curcumin also showed strong antioxidant and
anticancer properties through regulating the expression of genes that require the
activation of activator protein (AP1) and NF-B.
3.2.4. Effect of Curcumin on Tumor Necrosis Factor
Tumor necrosis factor (TNF) has been shown to mediate tumor initiation,
promotion, and metastasis. Moore et al. have reported that TNF-deficient mice have
been shown to be resistant to skin carcinogenesis. The induction of pro-inflammatory
genes by TNF has been linked to most diseases. The proinflammatory effects of TNF
are primarily due to its ability to activate NF-B. Almost all cell types, when exposed to
TNF, activate NF-B, leading to the expression of inflammatory genes. These include
COX-2, LOX-2, cell adhesion molecules, inflammatory cytokines, chemokines, and
iNOS. TNF has been found to be a growth factor for most tumor cells.
Because of the critical role of TNF in mediating tumorigenesis, agents that can
suppress TNF activity have the potential for therapy of TNF-linked diseases. Curcumin
was found to have a spellbound effect in the suppression of TNF production. The
constitutive activation of NF-B in mantle cell lymphoma (MCL) cells is due to
autocrine expression of TNF. TNF mRNA is constitutively expressed in the MCL cell
lines; curcumin inhibits the expression of both TNF mRNA and TNF protein in MCL
cell lines. Suppression of TNF by curcumin led to inhibition of NF-B and cell
proliferation, as was the case when TNF secretion was neutralized using anti-TNF
antibody.
41
Thus, curcumin exerts a protective role against inflammatory diseases through

the suppression of COX, LOX, iNOS, NF-B, TNF and some other inflammatory
mediators.
3.3. Therapeutic use of curcumin
3.3.1 Cancer
Curcumin has proved its credentials as a wonderful chemopreventive agent
against a variety of cancers. Oxidative stress induced by ROS has been linked to tumor
promotion in mouse skin and other tissues. Hydrogen peroxide promotes the
transformation of chemically initiated mouse epidermal cells. When different types of
tumor promoter were applied topically to mouse skin, there was a distinct increase in the
production of hydrogen peroxide in the epidermis, which correlated with their
promoting potential. Superoxide anion radicals were also formed in keratinocytes
stimulated with the tumor promoter such as 12-Otetradecanoylphorbol-13-acetate
(TPA). Further support for the association between pro-oxidant status and tumor
promotion derives from the observation that many structurally unrelated antioxidants
and radical scavengers exert antipromotional activity. Exogenous superoxide dismutase
(SOD) inhibited the promotion by TPA of JB6 mouse epidermal cell transformation,
providing additional evidence for a critical role of ROS in tumor promotion. Similarly,
the lipophilic biomimetic SOD cupric 3,5-diidopropylsalicylic acid inhibited tumor
promotion in mouse epidermis.58 Ornithine decarboxylase (ODC), a rate-limiting
enzyme in polyamine biosynthesis, has been utilized as a biochemical marker for tumor
promotion. ODC induction was found to be suppressed by SOD and catalase in murine
mammary tumor cells and by butylated hydroxytoluene in mouse epidermal cells,
suggesting the intermediacy of Reactive oxygen intermediates (ROIs) in the tumor
promotion.
Persistent, local inflammation has been considered to contribute to multistage
carcinogenesis. ROS produced during the inflammatory tissue damage can trigger a
series of reactions responsible for malignant transformation, particularly in the stage of
promotion.52. There is accumulating evidence that ROS influence the intracellular
signaling cascades mediating cell proliferation. Activity or expression of several protein
kinases have been shown to be regulated by the pro-oxidant state of cells.ROSare typical
42
by-products of eicosanoid metabolism.59 ROSare released from the cells of the

inflammatory skin infiltrate. A correlation exists between the ability of a compound to
induce PG release in vitro and its ability to promote papilloma formation in mouse skin
in vivo. Verma et al.60 suggests that PGs play a crucial role in the induction of ODC
activity and mouse skin tumor promotion by TPA. Both ROI generation by
inflammatory cells and skin tumor promotion are efficiently inhibited by protease
inhibitors, indicating an interrelationship between the two processes. Chemopreventive
properties of curcumin have been extensively investigated and well documented.61,62
One of the most plausible mechanisms underlying the chemopreventive effects of
curcumin involves suppression of tumor promotion. Thus, topical application of
curcumin strongly inhibited TPA-induced inflammation, hyperplasia, proliferation,
ODC activity, ODC mRNA expression, generation of ROIs, oxidized DNA base
modification, and papilloma formation in mouse skin.62-63 Curcumin inhibited COX-2
and LOX activities in TPA-treated mouse epidermis.20 Treatment of several human
gastrointestinal cell lines with curcumin suppressed expression of COX-2 protein and
mRNA, PGE2 production, and AP-1 DNA binding induced by TPA or
chenodeoxycholate.27 Suppression of TPA-induced activation of c-Jun/AP-1 in cultured
NIH3T3 cells has been proposed to be responsible for the antitumor-promoting activity
that curcumin retains.
In conclusion, the anticancer potential of curcumin stems from its ability to
suppress proliferation of a wide variety of tumor cells, downregulate transcription
factors NF-B, AP-1, and Egr-1, downregulate the expression of COX-2, LOX, iNOS,
MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules, and cyclin D1,
downregulate growth factor receptors (such as EGFR and HER2), and inhibit the
activity of c-Jun N-terminal kinase, protein tyrosine kinases, and protein
serine/threonine kinases. It also influences the free-radical production during the
activation of carcinogen and helps in detoxification of carcinogens.
3.3.2 Atherosclerosis
The most common form of heart disease is atherosclerosis. Atherosclerosis
involves the deposition of fatty substances, cholesterol, complex carbohydrates and
fibrin (a clotting material in the blood), and so forth in the inner lining of the major
43
artery. The deposition that results (referred to as plaque) can partially or totally block
the flow of blood through the artery. This can lead to the formation of a blood clot
(thrombus) on the surface of the plaque. If either of these events occurs and blocks the
coronary artery, a heart attack might result. Some controllable mechanisms that are
involved in the development of atherosclerosis are oxidation of low-density lipoproteincholesterol (LDL-C), abnormal platelet aggregation, and inflammation. Curcumin has
gained importance because of its antioxidant and antiplatelet aggregating qualities.
Curcumins ability to control platelet aggregation appears directly to be related to
thromboxane inhibition (a promoter of aggregation) and an increase in prostacyclin
activity, an inhibitor of aggregation. Curcumin, being a powerful antioxidant, quenches
free radicals, thereby decreasing the cellular damage. It also helps in reducing blood
lipid levels, particularly cholesterol. Rats fed 0.1% curcumin, along with a cholesterol
diet, had about one-half of the blood cholesterol as rats fed equal amounts of cholesterol
but without curcumin.
Curcumin, with its potent anti-inflammatory activity, reduces the inflammation,
promotes fibrinolysis, and inhibits the leukotriene formation, which are important steps
in the prevention of atherosclerosis.
3.3.3 Neurodegenerative disease
Oxidative stress has been implicated in mechanisms leading to neuronal cell
injury in various pathological states of the brain. Alzheimers disease (AD) is a
progressive disorder with cognitive and memory decline, speech loss, personality
changes, and synapse loss. Many approaches have been undertaken to understand AD,
but the heterogeneity of the etiologic factors makes it difficult to define the clinically
most important factor determining the onset and progression of the disease. However,
increasing evidence indicates that factors such as oxidative stress and disturbed protein
metabolism and their interaction in a vicious cycle are central to AD pathogenesis.
Increasing interest has been focused on identifying dietary compounds that can
inhibit, retard, or reverse the multistage pathophysiological events underlying AD
pathology. AD, in fact, involves a chronic inflammatory response associated with both
brain injury and -amyloid associated pathology. All of the above evidence suggests that
44
stimulation of various repair pathways by mild stress has significant effects on delaying
the onset of various age-associated alterations in cells, tissues, and organisms.
Curcumin has emerged as a strong inducer of the heat shock response. In light of
this finding, curcumin supplementation has recently been considered an alternative,
nutritional approach to reduce oxidative damage and amyloid pathology associated with
AD.
The potential neuroprotective action of curcumin was discovered during a
screening of its potential to protect against the adverse effects from high doses of
alcohol, which revealed positive results. Since then, studies have indicated potential
benefits forADand Parkinsons disease, based on laboratory animal models; clinical
work is now beginning. In addition, studies in animal models of AD indicate a direct
effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of
curcumin as a food additive and relatively small short-term studies in humans suggest
safety, curcumin is a promising agent in the treatment and/or prevention of AD. Just as
in AD, inflammation and oxidative damage play a strong role in the neurodegenerative
process of Hodgkins disease (HD): Oxidative damage helps to degrade nerve cells in
the basal ganglia and cerebral cortex an chronic inflammation in the brains of people
with HD is believed to play a significant role in the progression of the disease. As
shown previously, curcumin was able to reduce inflammation and oxidative damage in
mouse models of AD.
3.3.4 Diabetes
Environmental factors play an important role in the etiology and management of
diabetes, and antioxidants in food and medicinal plants are potential modulators of
diabetes onset, progression, and complications. Among the naturally occurring
compounds, curcumin has received the most attention as an antidiabetic compound.
Oxidative stress as a consequence of hyperglycemia and changes in energy metabolism
and inflammatory mediators play an important role in the pathophysiology of diabetes in
association with depleted cellular antioxidant defense systems and enhanced production
of ROS. Oxidative stress associated with hyperglycemia impairs cellular function and
alters vascular and neural function. High glucose concentrations promote free-radical
production via the following three biochemical pathways: advanced glycation end
45
products (AGEs), protein kinase C activation, and aldose reductase pathway. Another
important factor that increases ROS is TNF; it forms a possible connection between
obesity and diabetes and has been linked to insulin resistance and diabetic
complications.
Curcumin generally improves oxidative status, protects and enhances endogenous
defenses, and directly mediates various mechanics of pathology. Many studies have
shown that curcumin prevents AGE-induced complications in rats. Curcumin might act
by sparing or enhancing the function of the endogenous antioxidants. Antioxidant
activities of curcumin might occur synergistically with glucose-lowering activity. The
antidiabetic action of curcumin seems to be mediated through stimulation of the
pancreas to produce and secrete insulin, interference with dietary glucose absorption,
insulin-sparing action of the constituent bioactive compounds, and antioxidant and antiinflammataory properties of curcumin.
3.3.5 Aids
More recently, curcumin has been shown to inhibit HIV replication and currently
it is in clinical trials. Mazumder et al. have shown that curcumin inhibits p24 antigen
production and Tat-mediated transcription. They also shown that curcumin inhibits
purified HIV-l integrase, suggesting that the anti-HIV activity of curcuma could be due
to several mechanisms. Energy minimization studies suggest that theanti-integrase
activity of curcumin could be due to an intramolecular stacking of two phenyl rings that
brings the hydroxyl groups into close proximity (antioxidant property). The present data
suggest that HIV-l integrase inhibition might contribute to the antiviral activity of
curcumin. These observations suggest new strategies for antiviral drug development that
could be based on curcumin as a lead compound for the development of inhibitors of
HIV-l integrase.
3.3.6 Autoimmune disease
The immune system has evolved to discriminate self from nonself antigens,
thereby protecting the host from microbial pathogens and malignant tumors.
Nevertheless, a breakdown in this fundamental immunoregulatory process often results
in the development of chronic infectious diseases, malignant tumors, and organspecific
autoimmune diseases. Recent studies have used nutraceuticals (human diets of plant
46
origin, containing many hundreds of biologically active compounds called

nutraceuticals) to successfully target organ-specific autoimmune diseases. The
pathogenesis of autoimmune diseases involves complex immune mechanisms in which
the pro-inflammatory cytokines contribute to manifestation of the diseases.
The anti-inflammatory action of curcumin is associated with its ability to inhibit
reactive-oxygen-generating enzymes such as COX, LOX, xanthine dehydrogenase, and
iNOS. The involvement of interleukin (IL)-12 in the pathogenesis of rheumatoid
arthritis and myocarditis has been well established, and inhibition of IL-12 has
decreased the clinical symptoms of these autoimmune diseases. In view of the central
role played by IL-12 in Th1 differentiation, the IL-12/Th1 axis has become a novel
molecular target in the treatment of Th1 cell-mediated autoimmune diseases.
Many studies suggest that nutraceuticals ameliorate autoimmune diseases by
blocking Th1 cell-mediated inflammation and/or by promoting the progenitor cell
growth and differentiation in the repair process.
3.3.7 Psoriasis
Curcumin, by its immune-modulating, anti-inflammatory, and antioxidant
properties, shows a favorable effect on a mouse model of psoriasis. Heng et al. showed
that topical treatment with curcumin results in resolution of the psoriatic activity as
assessed by clinical, histological, and immunological criteria in patients. According to
them, this antipsoriatic effect is linked to a curcumin-caused modulation of
phosphorylase-
kinase
(Phk)
activity
that
integrates
multiple
calcium/calmodulindependent signaling pathways. These pathways are coupled to

glycogenolysis and ATP-dependent phosphorylation, thus ensuring the required energy
supply for cell proliferation and migration.
3.4. Cancer chemopreventive effects of Curcumin
The aforementioned chemopreventive effects of curcumin are likely to be the
sum of several distinct mechanisms. The plausible mechanisms by which curcumin
exerts its inhibitory effects on multistage carcinogenesis are described below and
summarized in Table 2.1.
47
Figure 3.1: Effects of curcumin in turmeric on multistage carcinogenesis.

Curcumin inhibits tumor initiation by blocking the metabolic activation of
carcinogens or by stimulating their detoxication. It also exerts antitumor-promoting
effects by suppressing inammatory signaling mainly mediated by COX-2 and iNOS
that are under the control of NF-B and other transcription factors. Curcumin also acts in
the progression stage of carcinogenesis by inhibiting metastasis and angiogenesis, which
are crucial for the survival and spread of tumor cells. Furthermore, curcumin has
antiproliferative effects that are attributed to its capability to induce apoptosis of
precancerous and malignant cells or inhibit the cell cycle progression. The mechanistic
basis for the aforementioned chemopreventive effects of curcumin is summarized in
Table 2.1.
48
Table3.1: Summary of chemopreventive effects of curcumin and underlying

mechanisms.
3.4.1. Inhibition of carcinigen activition

Modulation of enzymes involved
in
metabolic
activation
and
detoxification/excretion of carcinogens is one of the representative mechanisms of

chemopreventive agents.100 Phase I enzymes, including those that belong to the
cytochromes P450 (CYP450) superfamily, are intended, in general, to facilitate the
elimination of toxic xenobiotics by the addition of functional groups, rendering these
compounds more water soluble. Although phase I functionalization reaction might be
necessary for efficient detoxification, induction of phase I xenobiotic metabolizing
enzymes might also be detrimental, as it can produce ultimate electrophilic species
capable of reacting with DNA, thereby initiating carcinogenesis. The effects of turmeric
and curcuminoids on the formation of B[a]P-derived DNA adducts were studied in vitro
by employing the mouse liver postmitochondrial S9 fraction. A dose-dependent
49
decrease in binding of B[a]P metabolites to calf thymus DNA was observed in the
presence of turmeric and curcumin. Demethoxycurcumin and bis-demethoxycurcumin
also inhibited the B[a]PDNA adduct formation dosedependently.
When MCF-7 human mammary epithelial carcinoma cells were treated with 1
M of DMBA for 24 h, there was an increase in CYP1A1 enzyme activity. Curcumin
competitively inhibited the DMBA-induced CYP1A1 activity in these cells. The
CYP1A1 activity of microsomes isolated from DMBA-treated cells was inhibited by
50% with 1 M curcumin treatment. Curcumin also blocked the metabolic activation of
DMBA, as measured by the formation of DMBADNA adducts and decreasedDMBAinduced cytotoxicity.50 Thapliyal and Maru investigated the effects of curcumin,
demethoxycurcumin, and bis-demethoxycurcumin on the activities of isozymes of
CYP1A1, CYP1A2, and CYP2B1, which are predominantly involved in the metabolism
of B[a]P. In vitro incubation of rat liver microsomes with each of the compounds
showed a dose-dependent decrease in carbon monoxide binding to microsomes and also
inhibited CYP1A1, CYP1A2, and CYP2B1 activity, which were induced by B[a]P and
NNK. Pretreatment of SpragueDawley rats with1%turmeric through the diet resulted in
a significant decrease in B[a]P-induced CYP1A1 and CYP1A2 and phenobarbitone
(PB)-induced CYP2B1 in the liver, lung, and stomach, although the extent of the
inhibition was different. A similar inhibition was also reported in female A/J mice.
Thus, the administration of 2% curcumin in the diet to female A/J mice for 2 weeks
produced a 25% decrease in the CYP1A catalytic activity but not protein levels. Female
Swiss Webster mice given curcumin (200 mg/kg or 400 mg/kg, p.o.) for 2 weeks
displayed a 25% decrease in the hepatic CYP1A catalytic activity, whereas the activities
of ovarian aromatase, hepatic catechol-O-methyltransferase and hepatic UDPglucuronosyltransferase (UGT) were not altered. Additionally, there was a 20% decrease
in the catalytic activity and a 28% decrease in polypeptide levels of CYP3A following 2
weeks of curcumin treatment at 400 mg/kg.
3.4.2. Suppression of pro- inflammatory signaling
Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are
important enzymes that mediate inflammatory processes. Improper upregulation of
COX-2 and iNOS has been associated with the pathophysiology of certain types of
50
human cancer as well as inflammatory disorders. Because chronic inflammation is

closely linked to tumor promotion, substances with potent anti-inflammatory activities
are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the
promotion stage.
The ability of curcumin to inhibit both activity and induced expression ofCOX-2
has been demonstrated in various cell lines and animal models. Topical application of
curcumin strongly inhibited the activities of COX-2 and lipoxygenase, two key enzymes
involved in arachidonic acid cascades and in mouse epidermal microsomes and cytosol,
respectively Treatment of several human gastrointestinal cell lines with curcumin
suppressed the expression of COX-2 protein and mRNA as well as PGE2 production
induced by TPA or chenodeoxycholate. Curcumin inhibited nitric oxide (NO)
production and the expression of iNOS protein and mRNA in RAW264.7 cells
stimulated with bacterial lipopolysaccharide (LPS) or interferon (IFN).
3.5. Curcumin as an inhibitor of angiogenesis
Angiogenesis inhibitors can be divided into two classes. The first class, or direct
angiogenesis inhibitors, are relatively specific for endothelial cells and have little effect
on tumor cells. Indirect inhibitors might not have direct effects on endothelial cells, but
they downregulate the production of angiogenesis stimulators. Curcumin has been
shown by Arbiser et al.7 to be a direct inhibitor of angiogenesis and also plays an
important role in the downregulation of proangiogenic protein. Curcumins
antiangiogenic effect is also in part due to its inhibitory effect on the production of
cytokines relevant to tumor growth such as tumor necrosis factor and its antiapoptotic
effect: its inhibitory effect on endothelial cell attachment, motility and proliferation.
51
Figure 3.2: Suppression of angiogenesis pathway by curcumin.

The angiogenic switch, which is essential for angiogenesis, is mediated by
angiogenic oncogenes, which upregulate the expression of proangiogenic proteins such
as VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor)
and reduced the expression of angiogenesis inhibitors. Among the proangiogenic
proteins, VEGF and bFGF are crucial factors in pathological angiogenesis. VEGF-A is
considered the most important of the five isoforms. VEGF mediates angiogenic signals
through its VEGFR-1, -2, and -3 receptors, which initiate signaling events that begins
with dimerization and transautophosphorylation of TK residues in the receptors, which,
in turn, activate phospholipase C-, phospho-inositide 3 (PI3) kinase (PI3-K), GTPase
activating protein (GAP), mitogen-activated protein kinase (MAPK), and others. Cui et
al. showed that VEGF secretion by U937 and Raji cells is increased by tumor necrosis
factor- (TNF-) treatment and suppressed by curcumin treatment.11 TNF- augments
the expression of VEGF165 and VEGF121 mRNA and curcumin reduces the
expression. Angiogenesis was tested by network formation of endothelial cells on
Matrigel and no networks or cords formed in control and curcumin groups and there was
tube formation on matrigel in the supernatants of the Raji culture group and the
supernatants groups treated by the VEGF group and TNF- in Raji cells. The study
concluded that expressions of VEGF mRNA in U937 and Raji cells were increased by
TNF- and suppressed by curcumin. VEGF and TNF- can induce angiogenesis, and
52
curcumin can inhibit angiogenesis in ECV304 cells and can, therefore, inhibit potential
mechanisms controlling tumor neovascularization.
3.6. Radioprotection and radiosensitization by Curcumin
Ionizing radiations like X-rays and -rays, particles, particles, and neutrons
have sufficient energy to knock out an electron and ionize atoms of the medium. The
ability to ionize radiations to produce ionization is responsible for biological damage.
Ionizing radiations interact with the biological molecules in two ways: the direct effect
and the indirect effect. High-LET (linear energy transfer) radiations interact with
biological systems by directly producing free radicals in the biomolecules and causing
cellular damage. Because biological systems contain 7590% water, the predominant
effect by which ionizing radiations cause damage to the important biomolecules is
through radiolysis of water (the indirect effect; Figure 2.5), where ionizing radiation
interacts with water molecule(s) to produce a wide range of reactive oxygen species
(ROS) such as eaq, OH, H, OH, +H, O2, and peroxides.1 Among these hydroxyl
(OH) and hydrogen (H) radicals are free radicals (containing an unpaired electron in
the outermost orbit and are highly reactive). The OHradical is a highly reactive and
oxidizing species that can react virtually with all cell constituents at diffusion-controlled
rates. Among the entire cell constituents, DNA, lipids, and proteins are the principal
targets for the attack of OH radicals.4 As a result of the interaction of OH radicals with
the cellular genome, a cascade of events is initiated leading to various
pathophysiological disorders and eventually to cell death.
53
Figure 2.5: Mechanism of radiation-induced damage.

It is a well-established fact that radiation induces ROS that follows a cascade of
events leading to DNA damage that includes single- or double-strand breaks (dsb), base
damage, and DNADNA or DNAprotein cross-links, and these lesions cluster as
complex, local, multiply-damaged sites. The DNA dsbs are considered the most lethal
events after ionizing radiation and have been found to be the main target of cell killing
by radiation. The putative mechanisms of radioprotection by curcumin are shown in
Figure 2.6. The radioprotective activity of curcumin might not be due to a single
mechanism but to several mechanisms. The scavenging of radiation-induced free
radicals and the elevation of cellular antioxidants by curcumin in irradiated systems
could be one of the main leading mechanisms. Upregulation of enzymes like catalase,
glutathione transferase (GST), glutathione peroxidase (GSHpx), superoxide dismutase
(SOD), and their mRNAs might be another mechanism of radioprotection by curcumin.
Reduction in lipid peroxidation and elevation in glutathione (GSH) and increase in
sulphydryl groups might also contribute to some extent for its radioprotective activity.
Inhibition of activation of PKC, MAPK, and NO by curcumin might also provide
protection against radiation-induced damage. Curcumin has been reported to scavenge
free radicals, increase antioxidant status, inhibit lipid peroxidation, and elevate GST,
54
GSHpx, SOD, GSH, and sulphydryl groups.25,26,6065 Curcumin has been reported to
enhance GSH content and acid-soluble sulphydryl groups.
Figure 3.3: Mechanism of radioprotection by curcumin. indicates increase

or upregulationand indicates decrease or inhibition.
3.7. Curcumin and angiogenes in skin diseases
Angiogenesis, the formation of new blood vessels, plays a significant role in
physiological processes like growth and development, wound-healing and reproductive
functions in adults. Contrary to these beneficial effects, angiogenesis can be detrimental
in several pathological conditions, which include malignant diseases like skin cancer as
well as nonmalignant conditions like psoriasis, atopic dermatitis and diabetic
retinopathy. Astonishingly, VEGF, a proangiogenic factor is overexpressed in the skin
of patients with SSc despite insufficient angiogenesis. Angiogenesis appears to be a
fundamental inflammatory response early in pathogenesis, and significant abnormalities
of vascular morphology and angiogenic growth factors have been described in psoriasis.
Proteasome inhibitors have been recently investigated for treating psoriasis and other
inflammatory disorders. Compounds like curcumin, which not only inhibit angiogenesis
but also inhibit proteasome activity, might provide a suitable alternative to treat
psoriasis Antiangiogenic therapies represent a powerful addition to traditional cancer
therapies and other skin diseases. Curcumin is found to hamper tumor angiogenesis74
55
and it might be a reason in part for its activity in inhibiting carcinogenesis in skin.
Endothelial cell proliferation and differentiation are sequential events involved in
capillary formation. The growth of human umbilical vein endothelial cells (HUVECs)
stimulated with fibroblast growth factor (FGF) and endothelial cell growth supplement
(ECGS) was found to be inhibited by curcumin, wherein it effectively blocked cell cycle
progression during the S phase by inhibiting the activity of TK enzyme.75 Curcumin
treatment resulted in inhibiting tube formation as well as reduced the migration of
endothelial cells in a Matrigel plug model, thus showing their inhibitory nature on
angiogenic differentiation of endothelial cells. All of the cited experimental evidence
indicate the antiangiogenesis effect of curcumin and its potential as a valuable
therapeutic agent. However, curcumin has shown a beneficial effect as a pro angiogenic
agent in wound-healing by inducing TGF-. During the inflammation that follows injury,
TGF- induces both the angiogenesis and accumulation of the ECM, which continue
through the remodeling phase of wound repair. Moreover TGF- can attract inflammatory
and connective tissue cells, which, in turn, control angiogenesis. The preclinical
evidence suggests that curcumin might exert a dual effect in angiogenesis and its action
mainly depends on the environment in which it is acting.
3.8. Cardioprotective effects of Curcumin
Curcumin exhibits a variety of beneficial effects and appears to have a significant
potential in the treatment of multiple diseases that are a result of oxidative stress106
(Figure 3). These protective effects of curcumin are attributed mainly to its antioxidant
properties and should be further exploited to develop novel drugs. In most of these
disease states, a long-term treatment will be necessary. Thus, oral administration of
turmeric/curcumin with minimal acute or chronic toxicity will be of great value in
combating these chronic illnesses.
56
CHAPTER 4: PRODUCTIONS AND APPLICATION

4.1. Fresh turmeric rhizome
Both fresh and dried form of turmeric has been used as food additive and
traditional medicine. Fresh turmeric is crushed and extracted juice that is then taken
either raw or mixed with honey. It is believed that turmeric juice enhance health and acts
as a blood purifier. Besides, fresh turmeric has been used as herbal cosmetic for beauty
care since ancient times and is still used in modern times. The juice of raw turmeric is
applied to the skin as a paste in order to add glow to the skin and produce a soft, smooth
skin and fairer complexion. It also helps reduce acne and other skin related problems.
Fresh turmeric paste is applied to cuts and burns as it has antiseptic effects and promotes
healing. In addition, fresh turmeric is able to treat psoriasis and other inflammatory skin
condition.
4.2. Dried tumeric rhizome
Dried turmeric is mostly used to make turmeric powder or extract oleoresin and
essential. Rhizome quality is judge by a clean and smooth skin, uniform skin and flesh
color, and a clean snap when broken. Bulk rhizomes which are graded into fingers,
bulbs and splits, are stored in a cool and dry environment, away from direct sunlight.
The fingers are the secondary branches from the bulb (or mother rhizome) and the splits
are the bulbs cut into halves or quarters before curing.
Fingue 4.1: Dried tumeric

4.3. Tumeric powder
Ground turmeric, which is mostly used on the retail market, is made by milling
the clean, dry rhizomes to approximately 60-80 mesh particle size. The quality of
57
grinding turmeric is not loss much from oxidation (Govindarajan, 1980; Sasikumar,
2001). It is important to pack ground turmeric in a UV protective packaging and
appropriately stored because of its color constituents that deteriorate with light and to a
lesser extent, under heat and oxidative conditions (Anne Plotto, 2004). Anne Plotto
(2004) also reported that turmeric power is mostly used not only in cooking as spices
but also in food industry as colorant and flavor. Turmeric powder is the major
component (about 40-50%) of curry powder, which is a blend of a number of spices and
herbs (Sasikumar, 2001).
Fingue 4.2: Tumeric powder

4.4. Tumeric essential oil
Anna Plotto (2004) reported that turmeric essential oil has little interest in the
Western food industry. Turmeric essential oil is obtained by distillation and it is also a
byproduct of curcumin industry (Saju, 1998). Furthermore, it has less commercial value,
as opposed to oleoresin, so the chemistry of turmeric oil has not received much attention
(Jayaprakasha et al., 2005). However, Jayaprakasha et al., (2001) showed that the
turmeric essential oil contributed to some medicinal activities of turmeric.
Fingue 4.3: Tumeric essential oil
58
4.5. Tumeric oleoresin

Turmeric oleoresin is the organic extract which is obtained by the solvent
extraction of the ground turmeric with organic solvents. Turmeric oleoresin is used as a
spice and coloring agent that is added to meat and fish products. Otherwise, it is
essentially used in certain products such as mustard, pickles and relish formulae, butter
and cheese (Chempakam and Parthasarathy, 2008).
4.6. Curcumin powder
The most interested compounds in turmeric oleoresin are curcuminoids, which
consist of mostly curcumin, demethoxycurcumin, and bisdemetoxycurcumin. Curcumin
powder that is obtained by purifying and crystallizing turmeric oleoresin will be used in
products where the turmeric flavor is undesirable, such as cheese, ice cream, beverages
and baked products (ASTA, 2002). Curcumin is a highly potent, nontoxic, bioactive
agent found in turmeric and has been known for centuries as ahousehold remedy to
many ailments. The only disadvantage that it suers is of low aqueous solubility and
poor bioavailability. Bhawana et ell, 2011 developed a method for the preparation of
nanoparticles of curcumin with a view to improve itsaqueous-phase solubility and
examine the eect on its antimicrobial properties. Nanoparticles of curcumin
(nanocurcumin) were prepared by a process based on a wet-milling technique and were
found to have a narrow particle size distribution in the range of 2-40 nm. The detailed
preparation and characterization of Curcumin Nanoparticles was: Curcumin (100 mg,
0.27 mmol) was taken in dichloromethane (20 mL), and 1 mL of this solution was
sprayed into boiling water (50mL) dropwise with a flow rate of 0.2 mL/min in 5 min
under ultrasonic conditions, with an ultrasonic power of 100 W and a frequency of 30
kHz. After sonication for 10 min, the contents were stirred at 200-800 rpm at room
temperature for about 20 min when a clear orange-colored solution was obtained. The
solution was concentrated under reduced pressure at 50 0C and then freeze-dried to
obtain an orange powder. A co-TLC of the powdered sample with standard curcumin
showed both to have the same Rf values. Further, H NMR and ultraviolet (UV) spectra
of the lyophilized powder confirmed it to be curcumin. The choice of the solvent was
crucial because spraying of curcumin solution prepared in other organic solvents, such
asmethanol or acetone, resulted in particle aggregation and nanoparticles could not be
59
isolated. Further, maintaining the dropflow was significant for both the formation of
nanoparticles and maintaining a uniformity in their size. It was seen that the addition of
the entire curcumin solution to water in one lot led to particle aggregation.
Unlike curcumin, nanocurcumin was found to be freely dispersible in water in the
absence of any surfactants. The chemical structure of nanocurcumin was the same as
that of curcumin, and there was no modication during nanoparticle preparation.
Aminimum inhibitory concentration of nanocurcumin was determined for a variety of
bacterial and fungal strains and was compared to that of curcumin. It was found that the
aqueous dispersion of nanocurcumin was much more eective than curcumin against
Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa,
Penicillium notatum, and Aspergillus niger. The results demonstrated that the water
solubility and antimicrobial activity of curcuminmarkedly improved by particle size
reduction up to the nano range.
Fingue 4.4: Size characterization of curcumin nanoparticles: (left)

TEM image, and (right) SEM image.
For the selected microorganisms, the activity of nanocurcumin was more
pronounced against Gram-positive bacteria than Gram-negative bacteria. Furthermore,
its antibacterial activity was much better than antifungal activity.
Table 4.1 MIC of Curcumin and Nanocurcumin against Different Microbes
60
Fingue 4.5: (a) Antibacterial activity of nanocurcumin (water) andcurcumin

(DMSO) solutions at a concentration of 200 g/mL (b) Zone of inhibition of
B. subtilis.
Table 4.2 MIC of Curcumin and Nanocurcumin against Different Microbes
Taken together, the results indicated that the selected Gram-positive bacteria had
higher sensitivity than the selected Gram-negative bacteria. This could be due to
differences in their cell membrane constituents and structure. It is known that Grampositive bacteria contain an outer peptidoglycan layer, while Gram-negative bacteria
containThe mechanism of antibacterial action of curcumin nanoparticles was
investigated by transmission electronmicrograph (TEM) analysis, which revealed that
61
these particles entered inside the bacterial cell by completely breaking the cell wall,
leading to cell death. an outer phospholipidic membrane, both of which undergo
different types of interaction when encountered by curcumin. MIC of nanocurcumin and
curcumin examined for the two fungal strains showed these compounds to be ineffective
against P. notatum even at high concentrations up to 1000 g/mL. They, however,
showed some antifungal activity for A. niger (350 g/ mL for nanocurcumin), although
the MIC (minimum inhibitory concentration) value was higher than the MIC range (100200 g/mL) for the bacteria tested (Table 5.1).
Fingue 4.6 TEM images of (A) an unexposed (control) cell of S. aureus, (B) S. aureus
treated with curcumin nanoparticles, with anchoring of curcumin nanoparticles at the
cell wall, and (C) attack of curcumin nanoparticles, disruption of the cell wall
(peptidoglycan layer), an penetration of nanocurcumin inside the cell
Figure 5.6 shows the TEMimage of an isolated cell of S. aureus with a diameter
of 700-800 nm. It was seen that, during the growth of the bacteria in the presence of
curcumin nanoparticles, these nanoparticles (2-40 nm), which can be seen as dark,
electron-dense spheres anchored at the cell wall of the bacterial cell, broke the
peptidoglycan layer and penetrated inside the cell, thereby causing disruption of the
structure of cell organelles and killing the cell through lysis. Their results are in
agreement with earlier reports where nano-sized particles of different chemistries have
been shown to mobilize inside the cell. The other studies carried out on B. subtilis have
shown that the mechanism of antibacterial activity of curcumin involves perturbing the
GTPase activity of FtsZ protofilaments, which are known to play a critical role in
bacterial cytokinesis. This perturbation becomes lethal to the bacteria and inhibits
bacterial cell proliferation by inhibiting the assembly dynamics of FtsZ in the Z ring.
62
The authors however mentioned that the membrane structure of the bacteria is not
perturbed by curcumin in any way. In another study, it has been shown that curcumin
inhibits bacterial surface protein sortase A and prevents cell adhesion to fibronectin,
thereby acting as an antibacterial agent against S. aureus. In the present scenario, the
mechanism through which curcumin nanoparticles are believed to manifest antibacterial
properties is by anchoring to the cell wall of the bacterial cell, breaking it, then
penetrating inside the cell, and disrupting the structure of cell organelles.
However, it is not easy to use in food processes and products destined to longterm storage because of its sensitivity to light, alkaline pH, heat and chemical oxidants
(Buescher and Yang, 2000). Moreover, curcumin powder is also used to treat diseases
due to its curing characteristics.
4.7. Application of Tumeric in Food
Antioxidants are used as food additives in order to prevent the oxidative
deterioration of fats and oils in processed foods. However, due to limitation on the use
of synthetic antioxidants and enhanced public awareness of health issues, there is an
increasing need of health-promoting natural antioxidants in foods, such as in bakery
products (Nanditha & Prabhasankar, 2009). Current researches have conrmed that
foods rich in antioxidants play an essential role in the prevention of cardiovascular
diseases, cancers and neurodegenerative diseases, as well as inammation and problems
caused by cell and cutaneous aging (Fan, Zhang, Yu, & Ma, 2006). So that the
objectives of H.S. Lim et als study in 2011 were to evaluate the physicochemical,
sensory and antioxidant properties of wheat breadsmade with different levels of turmeric
powder. Turmeric (Curcuma longa L.) powder was used to substitute 0%, 2%, 4%, 6%
and 8% of wheat our for making turmeric wheat breads. Proximate composition,
physical quality, functional components (curcumin and total phenols) and antioxidant
properties of breads containing turmeric were analysed and compared with those of
wheat bread.
63
Fingue 4.7 Total phenolic contents (A) and antioxidant activities (B) of
breads containing turmeric powder. Control, TB2, TB4, TB6 and TB8 are
breads prepared with 0%, 2%, 4%, 6% and 8% replacement of wheat our
with turmeric powder, respectively. Bars represent standard error of means (n
= 3) and means with different letters are signicantly different (P < 0.05).
The total phenolic contents of turmeric powder and bread samples were also
analysed and results are shown in Fig. 2(A). Bread prepared with wheat our only (no
turmericadded) had 30.9 mg GAE/100 g of phenolic compounds, whereasthe bread
prepared with 8% turmeric powder had 150.5 mg GAE/100 g of those, showing a
signicant increase in total phenolics in bread. The phenolic content of turmeric powder
was 2195 mg GAE/100 g (data not shown). The comparison of the measured total
phenol content in turmeric breads with the expected values suggests that some
degradation may have occurred. Reduction of total phenol contents of turmeric powder
in turmeric bread were observed following bread making, whereby the reduction extent
was 3254%. However, despite the loss of total phenol content after baking, all breads
containing turmeric showed signicantly higher phenolic compounds and antioxidant
activities when compared with the control. The antioxidant activities of breads prepared
with different levels of substitution of wheat our with turmeric powder were analysed
using the b-carotene bleaching assay and results are shown in Fig. 2(B). The antioxidant
activities of breads also increased signicantly with increase in turmeric powder
substitution. They also determined the antioxidant activity of turmeric powder alone
using the b-carotene bleaching assay (Velioglu et al., 1998) and it showed 79.8 0.6%
antioxidant activity. Turmeric curcuminoids are reported to have better stability and
64
heating dose not affect the concentration of individual curcuminoids. The Maillard
reaction products also possess the antioxidant activities howeverantioxidants formed
during Maillard reaction were found to beunstable when exposed to air. The results
showed that addition of turmeric powder greatly enhanced the antioxidant activity of
bread. The improved antioxidant activity of turmeric bread might be due to the
incorporation of phenolic compounds including curcumin, which had been shown to
possess strong antioxidant activity).
Fingue 4.8 Cross-sections of the breads prepared with turmeric powder

replacement for wheat our. Control, TB2, TB4, TB6 and TB8 are breads
prepared with 0%, 2%, 4%, 6%and 8% replacement of wheat our with
turmeric powder, respectively.
Cross-sectional views of different breads prepare with turmeric powder
are presented in Fig. 3. The change in bread crumb colour is quite evident
and with the increase of turmeric powder in bread, crumb colour became
darker and yellower. We may explain that a daily intake of 50 g or two slices
of turmeric bread having 4% wheat oor substitution with turmeric powder
can deliver approximately 4.6 mg of curcumin and 40.12 mg GAE of total
phenolic compounds which can render additional health benets to human
body. The data on exact recommended dosage of these phytochemicals is not
available however different in vitro and in vivo studies have been carried out
to analyse their biological effects.
They observed that bread with 4% level of turmeric powder can have
signicantly higher antioxidant activity (33.7%) than the normal wheat bread (9.9%) as
analysed by -carotene bleaching assay.
65
A 4% substitution of wheat our with turmeric powder showed acceptable

sensory scores which were comparable to wheat bread. Breads containing turmeric
powder can thus be developed as a health-promoting functional food.
They also reported that turmeric was more effective than BHA and BHT in
preventing the oxidative shelf-life in processed cakes and those containing turmeric
resisted mould growth up to 3 weeks whereas cakes without turmeric showed mould
growth after just 1 week. As breads are lower in fat, the addition of turmeric powder is
expected to have profound effects of on the shelf-life of bread.
66
CONCLUSION
Turmeric has medicinal properties due to its bioactive components. One of the
important components of turmeric is its volatile oil. Turmeric oil inhibits Trichophytoninduced dermatophytosis in guinea pigs. Studies of the antiviral effects of the zedoary
turmeric oil spray in the respiratory tract showed that whereas influenza virus,
parainfluenza viruses I and III, respiratory syncytial virus, and adenoviruses 3 and 7
were inhibited slightly, parainfluenza virus II was significantly inhibited by this turmeric
compound (Huang et al. 2007). Curcuma oil ameliorated the ischemia-induced
neurological functional deficits and the infarct and edema volumes in rats. It
downregulated inducible nitric oxide (NO) synthase (iNOS)-derived NO produced
during ischemic injury, which coincided with an increased survival rate of neurons
(Dohare et al. 2008).
The neuroprotective activity of curcuma oil against cerebral ischemia is
associated with its antioxidant activities. Further, cucurma oil attenuated delayed
neuronal death via a caspase-dependent pathway. Thus, curcuma oil appears to be a
promising agent for the treatment of not only cerebral stroke but also other disorders
associated with oxidative stress (Rathore et al. 2008). A study revealed that ingestion of
turmeric oleoresin and essential oil inhibits the development of increased blood glucose
and abdominal fat mass in obese, diabetic rats (Honda et al. 2006).
Turmeric volatile oil is effective against disorders of the respiratory tract. The
volatile oil is active in removing sputum, relieving cough, and preventing asthma. Thus,
turmeric volatile oil may be an efficacious drug in the treatment of respiratory diseases
(Li et al. 1998). This oil acts as a repellent against both day- and night-biting mosquitoes
(Tawatsin et al. 2001).
Hexane extracts of C. comosa, an indigenous plant of Thailand that is
traditionally used for the treatment of uterine inflammation, at concentrations of 0.1, 0.5,
and 1 M were found to significantly decrease LPS-induced NO and PGE2 production.
It also decreased the expression of iNOS and COX-2 (Thampithak et al. 2009).
The use of turmeric as a spice and as a household remedy has been known to be
safe for centuries. To date, no studies in either animals or humans have discovered any
67
toxic effects associated with the use of turmeric (Lao et al. 2006), and it is clear that
turmeric is not toxic even at very high doses. The U.S. Food and Drug Administration
(FDA) has conducted its own clinical trials with turmeric and published a 300-page
monograph. The FDA has declared turmeric and its active component curcumin as
GRAS (generally regarded as safe). Thus, in the United States, turmeric and its
components are currently being used in mustard, cereals, chips, cheese, butter, and other
products (http://www.kalsec.com/products/color). In a phase I clinical study on the
safety and tolerance of turmeric oil use, the oil was administered orally to healthy
volunteers for 3 months. No side effects of turmeric oil intake were observed in 3
months on body weight, blood pressure, and hematological, renal, or hepatic toxicity
(Joshi et al. 2003).
The beneficial effects of turmeric are traditionally achieved through dietary
consumption, even at low levels, over long periods of time. A precise understanding of
effective dose, safety, and mechanism of action is required for the rational use of
turmeric in the treatment of human diseases. Further clinical studies are warranted if
turmeric is to be employed in meeting human needs and improving human welfare. The
activities of turmeric include antibacterial, antiviral, anti-inflammatory, antitumor,
antioxidant,
antiseptic,
cardioprotective,
hepatoprotective,
nephroprotective,
radioprotective, and digestive activities. Phytochemical analysis of turmeric has

revealed a large number of compounds, including curcumin, volatile oil, and
curcuminoids, which have been found to have potent pharmacological properties.
68
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HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY

FACULTY OF CHEMICAL TECHNOLOGY

TURMERIC (CURCUMA LONGA L)

Vo Thi Hong Linh 13110564

Dr. Dong Thi Anh Dao

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

CHAPTER 1: LITERATURE REVIEW

Fingue 1.1: Tumeric plant, flower and fhizome

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

1.1.3. Chemical composition of tumeric

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Fingue 1.2: Structure and therapeutic application of curcumin

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Fingue 1.3: Essential oil constituents

Tumeric (Curcuma Longa L.): Functionality and Apllication

Ar-turmerone is a colorless oily chemical and; in contrast, turmerone is a pale yellow

Fingue 1.4: Structures and Physical characteristics of tumerone and artumerone

Tumeric (Curcuma Longa L.): Functionality and Apllication

hydroxycinnamoylmethane) (Jayaprakasha et al, 2002). In 1815, Curcumin that has been

Tumeric (Curcuma Longa L.): Functionality and Apllication

Fingue 1.5: Structures of Curcumin, Demethoxycurcumin, BisDemethoxycurcumin

Tumeric (Curcuma Longa L.): Functionality and Apllication

Fingue 1.6: Potentional uses of curcumin based on modern technology

Tumeric (Curcuma Longa L.): Functionality and Apllication

Table1.2: Chemopreventive and anticancer effects of curcumin.

Tumeric (Curcuma Longa L.): Functionality and Apllication

CHAPTER 2: TUMERIC FUNCIALITYS RESEARCH

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Table 2.1 In Vivo Effect of Turmeric against Development of Various

Numerous lines of evidence suggest that turmeric exhibits anti-inflammatory

Tumeric (Curcuma Longa L.): Functionality and Apllication

Besides these properties, turmeric has strong antimicrobial properties. The

Tumeric (Curcuma Longa L.): Functionality and Apllication

2.2.2. In vivo studies with Tumeric

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

AP = alkaline phosphatase; ALT = alanine aminotransferase; LDH = lactate

Aqueous extract of turmeric;

extract of turmeric; k Methanolic extract of turmeric; L Not clear)

Tumeric (Curcuma Longa L.): Functionality and Apllication

Fingue 2.1: Inhibition of tumor growth in mice by turmeric extracts in a

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

antitumor activities may be recommended as safe sources of antitumor compounds

Tumeric (Curcuma Longa L.): Functionality and Apllication

nitrosodiethylamineinduced hepatocarcinogenesis was inhibited. This effect was

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Tumeric (Curcuma Longa L.): Functionality and Apllication

Fingue 2.2: Inhibition of tumor growth in mice by turmeric extracts in

Tumeric (Curcuma Longa L.): Functionality and Apllication