REVIEW

published: 25 March 2022

doi: 10.3389/fphar.2022.820806

A Comprehensive Review on the

Therapeutic Potential of Curcuma
longa Linn. in Relation to its Major
Active Constituent Curcumin
Shivkanya Fuloria 1†, Jyoti Mehta 2†, Aditi Chandel 2, Mahendran Sekar 3†,
Nur Najihah Izzati Mat Rani 4, M. Yasmin Begum 5, Vetriselvan Subramaniyan 6,
Kumarappan Chidambaram 7, Lakshmi Thangavelu 8, Rusli Nordin 6, Yuan Seng Wu 9,
Kathiresan V. Sathasivam 10, Pei Teng Lum 3, Dhanalekshmi Unnikrishnan Meenakshi 11,
Edited by:
Vinoth Kumarasamy 6,12, Abul Kalam Azad *,1 and Neeraj Kumar Fuloria 1,8*†
Mohd Farooq Shaikh, 1
Faculty of Pharmacy, AIMST University, Kedah, Malaysia, 2Faculty of Applied Sciences and Biotechnology, Shoolini University of
Monash University, Malaysia
Biotechnology and Management Sciences, Solan, India, 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy and
Reviewed by: Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Malaysia, 4Faculty of Pharmacy and Health
Sadiq Umar, Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Malaysia, 5Department of Pharmaceutics, College of
University of Illinois at Chicago, Pharmacy, King Khalid University, Abha, Saudi Arabia, 6Faculty of Medicine, Bioscience and Nursing, MAHSA University,
United States Selangor, Malaysia, 7Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi Arabia, 8Center for
Seyed Zachariah Moradi, Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical
Kermanshah University of Medical and Technical Sciences, Saveetha University, Chennai, India, 9Department of Biological Sciences and Centre for Virus and
Sciences, Iran Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, Malaysia, 10Faculty of Applied Sciences,
AIMST University, Kedah, Malaysia, 11College of Pharmacy, National University of Science and Technology, Muscat, Oman,
*Correspondence: 12
Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Perak, Malaysia
Neeraj Kumar Fuloria
neerajkumar@aimst.edu.my
Abul Kalam Azad
curcumin is a chemical in tumeric
Curcuma longa Linn. (C. longa), popularly known as turmeric, belongs to the Zingiberaceae family
azad2011iium@gmail.com
†
and has a long historical background of having healing properties against many diseases. In Unani
These authors have contributed
equally to this work and Ayurveda medicine, C. longa has been used for liver obstruction and jaundice, and has been
treat tumor/ cancer
aspects through NPS
applied externally for ulcers and inflammation. Additionally, it is employed in several other ailments
Specialty section: such as cough, cold, dental issues, indigestion, skin infections, blood purification, asthma, piles,
This article was submitted to
Ethnopharmacology, bronchitis, tumor, wounds, and hepatic disorders, and is used as an antiseptic. Curcumin, a major
a section of the journal constituent of C. longa, is well known for its therapeutic potential in numerous disorders. However,
Frontiers in Pharmacology
there is a lack of literature on the therapeutic potential of C. longa in contrast to curcumin. Hence,
Received: 23 November 2021
the present review aimed to provide in-depth information by highlighting knowledge gaps in
Accepted: 27 January 2022
Published: 25 March 2022 traditional and scientific evidence about C. longa in relation to curcumin. The relationship to one
Citation: another in terms of biological action includes their antioxidant, anti-inflammatory, neuroprotective,
Fuloria S, Mehta J, Chandel A, anticancer, hepatoprotective, cardioprotective, immunomodulatory, antifertility, antimicrobial, Large
Sekar M, Rani NNIM, Begum MY, amounts
Subramaniyan V, Chidambaram K, antiallergic, antidermatophytic, and antidepressant properties. Furthermore, in-depth in tumeric
Thangavelu L, Nordin R, Wu YS, discussion of C. longa on its taxonomic categorization, traditional uses, botanical description,
Sathasivam KV, Lum PT,
phytochemical ingredients, pharmacology, toxicity, and safety aspects in relation to its major
Meenakshi DU, Kumarasamy V,
Azad AK and Fuloria NK (2022) A compound curcumin is needed to explore the trends and perspectives for future research.
Comprehensive Review on the Considering all of the promising evidence to date, there is still a lack of supportive evidence
Therapeutic Potential of Curcuma
longa Linn. in Relation to its Major especially from clinical trials on the adjunct use of C. longa and curcumin. This prompts further
Active Constituent Curcumin. preclinical and clinical investigations on curcumin.
Front. Pharmacol. 13:820806.
doi: 10.3389/fphar.2022.820806 Keywords: Curcuma longa, curcumin, phytochemical, pharmacology, toxicology
Future research is needed!!

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 Fuloria et al. Therapeutic Potential of Curcuma Longa

GRAPHICAL ABSTRACT |

INTRODUCTION found in several regions of the globe. Curcuma longa Linn.

(C. longa) is the common tall herb that flourishes in tropical as
Herbs and natural products have long been exploited by humans well as in other Indian regions and is referred to as “Indian
Goal to to combat numerous diseases since the dawn of time. The Indian saffron or The Golden Spice of India” because of its use in a
combine subcontinent boasts diverse flora, including both aromatic and broad range of diseases in Indian homes as a spice, food
natural
remedies
therapeutic species. After all, contributions should be made to preservative, and coloring source. C. longa belonging to the
with modern analyze, standardize, and confirm Unani and Ayurvedic Zingiberaceae (ginger) family is a perennial plant commonly
administratio
n procedures
medication for potential, safety, and effectiveness prior to planted in Asian nations. It is among the oldest spices of India
actually introducing them to the market as first-line drug that have been used in Western and Southern parts for
delivery. Plant-based therapies are being used across all centuries, and is a significant part of Ayurvedic medicine.
civilizations. Plant-based medicines are already extensively In Ayurveda, the therapeutic effects of C. longa have been well
utilized, and several countries invest 40%–50% of their total established and are discussed in Dashemani Lekhaniya
health budget to produce novel drugs. Herbal medicines are (emaciating), Kusthagna (anti-dermatosis), and Visaghna
assumed to have a beneficial effect on health without any side (anti-poisonous) texts. It is known by many distinct names
effects. REDUCE CYTO/OVERALL such as Haridra in Sanskrit, Haldi in Hindi, Jianghuang
TOXICITY
The genus Curcuma has been employed from many years (yellow ginger in Chinese), manjal in South India, and
back due to its medicinal applications; it is composed of Kyoo or Ukon in Japanese, which means an effective
approximately 133 species worldwide. C. longa (Haridra), medication for jaundice (Sharma, 2000). C. longa is also
C. aromatica Salisb (Vana Haridra), C. angustifolia Roxb., extensively described in Indian material medica
C. zanthorrhiza Roxb., C. amada Roxb (Amaragandhi (Dravyaguna Shastra) and is used in the beauty regimen of
Haridra), C. caesia Roxb (Kali Haridra), and C. zedoaria Hindu girls where it is applied daily on their foreheads. The
Rosc (Zedoary) are common species of genus Curcuma bride is smeared with a C. longa paste, which is a key aspect of

Look into other species?

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Fuloria et al. Therapeutic Potential of Curcuma Longa

FIGURE 1 | Important parts of C. longa. (A) C. longa in natural habitat, (B) medicinally important part of C. longa (rhizome), and (C) powder of dried rhizome of C.
longa (used as a coloring agent in food).

Grind myself?? Order online

Utilize this in pure form

FIGURE 2 | The taxonomic classification and nutritional profile of C. longa.

Possible oral administration to
parents

Hindu tradition (Paranjpe and Pranjpe, 2001). It is well C. longa is formed has a coarse and segmented skin. In the
recognized by the Chinese, Japanese, and Korean ground soil, the rhizomes mature underneath the foliage. The
Pharmacopoeias, and its application spans a broad range of matured rhizomes have a yellowish-brown color with a dull
medical conditions. In China, it is being used to relieve orange from inside. Small pointed or tapered tubers sprout off
urticaria, dermatitis, hepatitis infection, inflammatory the main rhizome measuring 2.5–7.0 cm (1–3 inches) in
joints, sore throat, and wounds. It was mentioned in Hindu length and 2.5 cm (1 inch) in diameter (Prasad and
Mythology manuscripts as an aromatic stimulant and Aggarwal, 2011). The dry rhizome is ground into a yellow
carminative. Turmeric powder combined with calcium powder form that has a bitter, yet sweet taste. A yellow-
hydroxide is indeed a popular home remedy for treating colored substance derived from the rhizome is curcumin
sprains and swelling induced by wounds or might be (1,7-bis[4-hydroxy-3- methoxyphenyl]-1,6-heptadiene-3,5-
applied directly over the injury site. Traditional medicine dione), a combined form of resin and oil. Rhizome powder
has exploited dried curcumin powder to treat illnesses in is supposed to flavor various cuisines and treat numerous
history. C. longa is said to have antitoxic, anticancer, disorders, including inflammation, flatulence, jaundice,
antibacterial, anti-inflammatory, and antioxidant effects menstrual troubles, hematuria, and hemorrhage. It is also a
(Ghotaslou et al., 2017). The tuberous rhizome from which useful ointment to treat several skin disorders. Curcumin or

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Use this and dissolve into NPS
 Fuloria et al. Therapeutic Potential of Curcuma Longa

Useful for organic drug

alternatives FIGURE 3 | Benefits of curcumin in various conditions. Utilizing this health benefit aspect

diferuloylmethane and numerous volatile oils. C. longa of bioavailability and overcome all the disadvantages in relation to
India is particularly popular when compared with those drug delivery. Proposed but never tested I WIKL
from other countries due to its high curcumin TEST WOOHOO
concentration, which is the most essential and active
biological ingredient responsible for its therapeutic Botanical Description, Geographical
potential (Verma et al., 2018). Curcumin is a flavonoid Distribution, and Cultivation of C. longa
having a lipophilic affinity that is practically water- C. longa is a perennial herb with no stem and rootstock. Their
insoluble (Dave et al., 2017) yet quite stable at the leaves are 1 m long, lanceolate or oblong, dark green from the
stomach’s acidic pH. C. longa and curcumin show upper surface and pale green from beneath. The petiole and
antioxidant features close to vitamins C and E in both sheath are about the same length as the blade. Spike makes its
aqueous and fat-soluble extracts. appearance before the leaves. Flowers are sterile, pale yellow with
Curcumi Due to shortcomings in the earlier published review articles, a reddish covering, and flowering bract is green with a deep
n needs such as a lack of information on the therapeutic potential of C. ferruginous purplish color. It has a 2-m-long, erect leafy shoot
to do longa in relation to its major compound curcumin, we have (pseudostems) (Rajkumari and Sanatombi, 2017) bearing 8–12
diluted attempted to provide in-depth information by highlighting leaves and is commonly grown in rural backyard gardens. Its
in some knowledge gaps in traditional and scientific evidence about C. medicinally important parts are presented in Figure 1. The
sort of longa in relation to the therapeutic potential of curcumin against rhizomes have a balmy smell and bitter in taste (Puteri et al.,
acid in numerous disorders. This review mainly focuses on the 2020). The taxonomic classification of C. longa is shown in
order to distribution, cultivation, botany, nutritional composition, Figure 2.
be able phytochemistry, toxicology, traditional and medicinal properties, Turmeric is believed to have originated from South or
to and safety aspects including the pharmacological activities of C. Southeast Asia, more likely in Vietnam, China, or western
longa in relation to its major compound curcumin. This review will India. It is only identified as a domesticated plant and has not
dissolve
further discuss the current advances in C. longa and curcumin, been found in the wild. India is the biggest producer, consumer,
into the
such as the utilization of nanocarriers to increase curcumin and supplier, but it is also cultivated extensively in Cambodia,
silver
NPs
SOURCE FROM INDIAN SELLER!?

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 Fuloria et al. Therapeutic Potential of Curcuma Longa

TABLE 1 | The main products of C. longa, their appearance, chemical constituents, and use.

Product name Appearance Chemical constituents Uses

Whole rhizome Orange-brown, red-yellow, or 3%–15% curcuminoids, and 1.5%–5% essential oils Medicinal purposes
(dried form) pale yellow
Ground C. longa Yellow or red-yellow Curcuminoids and essential oils may be reduced during the processing, Used as a condiment, dye, medicine,
as well as by light exposure. The powder must be stored in a UV-resistant and dietary supplement
container
C. longa oil Yellow to brown oil Monoterpenes and sesquiterpenes are predominated in essential oils of Used as a spice, medicine, and dietary
leaves and rhizomes, respectively supplement
C. longa oleoresins Dark yellow, reddish-brown 25% of essential oil and 37%–55% of curcuminoids Used as a food dye, medicine, and
viscous fluid dietary supplement
Curcumin Yellow to orange-red colored Curcumin and its bisdemethoxy and demethoxy derivatives. The three Used as medicine and dietary
crystalline powder primary curcuminoids may account for up to 90% of the total supplement
curcuminoids. Oils and resins may make up a small percentage of the
total composition.

How to purify? Need pure form

Nanocrystal tech utilization?

Bangladesh, Nepal, Indonesia, Thailand, Cambodia, Malaysia, antiseptic, an anti-inflammatory agent, and a preservative (Ayati
West Bengal, Madagascar, Tamil Nadu, Maharashtra, Madras et al., 2019).
Indonesia, and Philippines (Royal Botanic Gardens Kew, 2021). C. longa is also developed in Thailand, Philippines, Sri Lanka,
Could grow The turmeric plant requires an average temperature from 20 to and Malaysia and is considered an ethnomedicinally important
myself but it
would take 30°C and a good annual rainfall to grow. Plant species can reach plant in Indonesia and Malaysia. Its poultice, when rubbed to the
too long... 1 m in height and have long, oblong leaves. Turmeric can be perineum, ensures the healing of any birth canal lesions. C. longa
found in both tropical and subtropical regions. This will thrive is also used to relieve dental issues and digestive troubles like
best in the dark if not overcrowded, but somehow it also develops discomfort or pain in the upper abdomen and acidity, indigestion,
larger and better rhizomes when exposed to sunlight. Turmeric gas, and ulcers, as well as mitigate the hallucinogenic effects of
usually grows in a humid environment. Harvest time usually lasts hashish and other psychoactive drugs. The tribes of Jhalda,
from January to March–April. Early types are ready in 7–8 Parulia District of West Bengal, apply rhizome paste to the
months, while medium types mature in 8–9 months. After the body to relieve physical pain. Assamese tribal women apply a Using this
formation of yellow colored leaves, they begin to dry and the crop fresh rhizome paste for skin infection and also to improve their aspect through
is ready to be harvested (Soudamini and Kuttan, 1989). Upon complexion. Rhizome in addition to other ingredients cures loose nanoparti
ripening, cutting of the leaves are done nearer to the soil surface, stools in cattle. It is considered as a source of various problems cles delivery
the ground is ploughed, and the rhizomes are collected by hand such as blood purification, brain and heart tonic, asthma,
picking or carefully lifting the clusters with a spade. The turmeric leucoderma, piles, bronchitis, spleen enlargement, tumor,
plant needs a rich and friable soil with just a little sand content. It biliary disorders, anorexia, cough, rheumatism, sinusitis,
grows in irrigated and rain-fed areas on light black, ashy loam, tuberculous glands in the neck, diabetic wounds, hepatic
and red soils to stiff loams. Total irrigation for turmeric will be disorders, leucorrhea, and gonorrheal secretion. It helps to
defined by the climatic and soil conditions. Based on the soil types lower blood clotting and blood sugar level (Zhang et al.,
and rainfall, 15–25 irrigations are provided in medium heavy 2013). Curcumin is now regarded as a promising “new
soils, and 35–40 irrigations are needed in light texture red soils. medicine” that is being utilized as a supplement in a number
Rhizomes are typically piled under trees for shade or in well- of countries, namely, India, Japan, Thailand, Korea, China,
ventilated shelters and finally wrapping is done with turmeric Malaysia, and Pakistan; it is added to curry, tea, cosmetics,
leaves. Matured rhizomes as a seed could be kept in sawdust pits and drinks, and used as a colorant, antiseptic, and anti-
(Aggarwal et al., 2004). inflammatory agent to treat gastrointestinal discomfort. It is
also used as a component in cheese, butter, mustard sauce,
and chips, and as a preservative and a dyeing agent in the Could make
Traditional and Medicinal Properties of C. it cheaper
United States. Curcumin is commercially available in multiple and more
longa forms, including capsules, energy drinks, soaps, tablets, available to
people in
C. longa rhizome is also consumed as an herbal infusion with ointments, and cosmetics. Goud et al. (1993) found out that general,
conventionally produced gin called “ogogoro” by the native C. longa is the best source of ω-3 fatty acid and α-linolenic also maybe
more within
individuals of Delta State, Nigeria, with the notion that it heals acid (2.5%). my budget
various ailments. It is used to preserve and flavor food and is also Rhizomes are being added to other plants to develop
used as a condiment in Nigeria. It is used for wound-healing and traditional remedies for a range of infections, such as
pimples in Pakistan and is widely consumed as folk medicine tonsillitis, snake bites and stings, headaches, wounds, sprains,
(Wahono et al., 2017). In Bhutanese traditional medicine, it is and fractured bones. Turmeric has been applied as a home
named Yung-ba, and it is employed as a tonic, an antidote, an remedy to heal wounds and also facilitates the treatment for

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 Fuloria et al. Therapeutic Potential of Curcuma Longa

Different types? Look into

if other ones are more
effective

FIGURE 4 | Chemical structure of phytoconstituents present in C. longa.

digestive dysfunction, hepatic problems, leukemia, moisture (>9%), curcumin (5–6.6%), extraneous matter
atherosclerosis, osteoarthritis, menstrual problems, bacterial (<0.5%), mold (<3%), and volatile oils (<3.5%).
infections, and eye problems. Turmeric has a role in Monoterpenes dominate the essential oils of flowers and
preventing inflammation in the mucous membranes that line leaves, while sesquiterpenes dominate the oils of roots and
the throat, stomach, intestine, and lungs (Figure 3). rhizomes. The oil constituents contain 25% tumerone, 11.5%
Maybe use for myself lol
curdine, and 8.55% ar-turmerone (Nisar et al., 2015). C. longa
oil contains anti-mutagenic qualities and is also capable of
GENERAL HEALTH BENEFITS preventing the development and excretion of urinary
mutagens in those who smoke cigarettes. According to the Prevent
Evidence suggests the benefits of turmeric in relieving acne, latest analysis, essential oil content in the rhizome was mutations
as well?!
inflammation, joint pain, asthma, eczema, and tonic and acute approximately 3.97%, with ar-turmerone (40%), α-turmerone Use to
allergies; in wound healing; in maintaining a balanced mood and (10%), and curlone (23%) being the major components analyzed prevet tnbc
recurrence
blood sugar levels; and in immunomodulation (Ammon and by gas chromatography (Guimarães et al., 2020). The ar- as well?
Wahl, 1991; Reddy and Rao, 2002). turmerone has been employed as a repellant for insects, and
its mosquitocidal ability has been revealed in the leaf extract. C.
longa is a rich source of polyphenolic curcuminoids like
PHYTOCHEMISTRY OF C. LONGA curcumin (about 80%), demethoxycurcumin (about 12%),
Again! Consider oral and bisdemethoxycurcumin (Ashraf, 2018), as well as
administration??
C. longa contains carbohydrates, fiber, certain proteins and proteins, volatile oils (tumerone, atlantone, and zingiberone),
lipids (no cholesterol), vitamin C, pyridoxine, magnesium, sugars, and resins. Curcumin, which makes up 0.3%–5.4% of
phosphorus, potassium, and calcium, which makes it a raw C. longa, is the well-studied active ingredient. Table 1
nutritionally rich natural food ingredient. The nutritional illustrates the principal C. longa products, their appearance, .. Oh may
be
profile of C. longa is shown in Figure 2 (Pradeep et al., chemical contents, and use. The C. longa plant is known to expensive
1993). To date, 719 constituents have been isolated and possess acidic polysaccharides (which include ukonan A, B, C, sin e
maybe c
recognized from 32 Curcuma species, including terpenoids, and D), 4.2% volatile oils (which include turmerone, ar- long
Can u
derive
flavonoids, phenylpropene derivatives, alkaloids, turmerone, curcumene, germacrone, and ar-curcumene as needs to
be used to
this in diphenylalkanoids, steroids, and other compounds (Sun et al., main constituents), and 5.8% essential oils (which include derive
its pure
form?
2017). The rhizome was found to contain over 235 0.6% sabinene, 0.5% borneol, 1% α-phellandrene, 1% cineole, curcumin
phytoconstituents, the majority of which are polyphenols and 53% sesquiterpines, 25% zingiberene, and 3%–4% curcumin)
terpenoids. Curcuminoids are made up of 80% curcumin and (Chattopadhyay et al., 2004). Phenolic diketone curcumin
are the most common polyphenols. There are 109 provides yellow color, and consists of curcumin I (94%),
sesquiterpenes, 68 monoterpenes, 22 diarylheptanoids and curcumin II (6%), and curcumin III (0.3%). Protein (6.3%),
diarylpentanoids, eight phenolics, five diterpenes, four sterols, fat (5.1%), minerals (3.5%), carbohydrates (69.4%), and
three triterpenoids, two alkaloids, and 14 remaining moisture (13.1%) were reported by Liao et al. (2011). The
constituents. In a standard form, C. longa consists of main phytocompounds are presented in Figure 4.

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Fuloria et al. Therapeutic Potential of Curcuma Longa

FIGURE 5 | Modulation of antibodies by curcumin. Curcumin assists in the modulation of antibodies that react with endothelium and causes hyperacute graft
rejection. Blocking the expression of pro-inflammatory cytokines and transcription factors linked to inflammation and fibrosis may help to prevent dead grafts.

PHARMACOLOGICAL PROPERTIES OF C. cosmetic ingredient (Paranjpe and Pranjpe, 2001). In human

LONGA trials, curcumin is suggested to be effective and safe, and the U.S.
Food and Drug Administration has certified it as “generally
C. longa claims to offer a wide range of therapeutic properties. C. regarded as safe”.
longa was reported to contain curcuminoids, glycosides,
terpenoids, and flavonoids. Haridra rhizome has been Gastrointestinal Disorders
employed by healthcare professionals for diabetes, cholesterol, C. longa has long been used to treat digestive problems, and
inflammation, diarrhea, liver problems, asthma, and cancer with clinical investigations have verified its therapeutic advantages. Its
minimal cytotoxicity to normal cells, and has been used as a anti-inflammatory action has been established in preclinical

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Fuloria et al. Therapeutic Potential of Curcuma Longa

research to potentially protect the gastrointestinal tract. It has also disturbance in healthy participants who are overweight (Uchio
been shown to increase gastrin, secretin, and bicarbonate et al., 2021). Researchers discovered that curcumin has anti-
secretion, as well as gastric wall mucus and pancreatic enzyme inflammatory properties by inhibiting the pro-inflammatory
(Ammon and Wahl, 1991), as well as inhibit intestinal spasms transcription factor (NF-κB) in 1995. They also discovered the
and ulcer formation caused by stress, alcohol, indomethacin, molecular mechanism that underlies this inhibition (Singh and
pyloric ligation, and reserpine (Rafatullah et al., 1990) and Aggarwal, 1995). TNF-α quickly activates NF-κB, which consists
improve dyspeptic patients’ condition. The activity of of the p50 and p65 subunits in human myeloid ML-1 cells, while
curcumin against inflammation and its therapeutic effect on curcumin prevented this activation. Curcumin also inhibits the
gastrointestinal illnesses such as dyspepsia, Helicobacter pylori binding of activator protein 1 (AP-1) binding factors, but the Sp1
infection, Crohn’s disease, gastric ulcer, acidity, and ulcerative binding factor remained unaffected. Curcumin inhibits the
colitis in the form of fresh juice are thought to be antihelmintic. activation of NF-κB by phorbol ester and hydrogen peroxide,
Curcumin inhibits nuclear factor (NF)-κB and reduces gastric in addition to TNF-α. Furthermore, curcumin suppresses the NF-
mucosal damage in rats suffering from NSAID-induced κB activation pathway after the convergence of multiple stimuli
gastropathy, leukocyte adhesions, intercellular adhesion but before human I kappa B alpha phosphorylation. The capacity
molecule 1, and tumor necrosis factor (TNF)-α (Thong-Ngam of C. longa to suppress both inflammatory prostaglandin
et al., 2012). Between baseline and 8 weeks of treatment, C. longa derivative of arachidonic acid and neutrophil activity during
tablet dramatically reduced irritable bowel syndrome (IBS) inflammation may also indicate its anti-inflammatory
prevalence and abdominal pain/discomfort score, and IBS activities. Curcumin is frequently used with bromelain to
quality of life scores showed considerable improvement improve absorption and anti-inflammatory activity. Curcumin
(Rahimi and Abdollahi, 2012). In male mice with liver is equally efficacious as cortisone or phenylbutazone when given
damage, curcumin protects against acetaminophen-induced orally in acute inflammation. C. longa given orally to reduce
hepatitis by lowering oxidative stress and liver injury, and also inflammatory edema considerably. Curcumin’s therapeutic effect
restores glutathione levels (Somanawat et al., 2013). in sepsis appears to be achieved by activation of peroxisome
proliferator-activated receptor gamma (PPAR-γ), which leads to
Respiratory Disorders inhibition of pro-inflammatory cytokine along with expression
C. longa and its constituents have a relaxing impact on tracheal and release of TNF-α (Jacob et al., 2008). One trial evaluated 43
smooth muscles, suggesting a possible bronchodilatory influence kidney transplant patients; 480 mg of curcumin and 20 mg of
in individuals with obstructive lung disease. They also have a quercetin per capsule were observed to be potent during delayed
protective benefit in an animal model of respiratory disorders, graft rejection. Significant lower serum creatinine after transplant
involving effects on inflammatory cells and mediators, lung was attained in 43% of control patients and 71% of low-dose-
pathological alterations, airway responsiveness, and treated participants. Induction of the hemeoxygenase enzyme,
immunomodulatory responses (Boskabady et al., 2020). proinflammatory cytokines, and free radical scavenger associated
Curcumin has been shown in both in vivo and in vitro with tissue injury possibly caused the enhanced early
investigations to have antiasthmatic properties. Curcumin performance of transplanted kidneys (Figure 5) (Shoskes
therapy during OVA sensitization exhibited significant et al., 2006). Majority of the benefits seemed to be due to the
protective effects in an OVA-induced asthma paradigm in anti-inflammatory and antioxidant properties of curcumin, while
guinea pigs, attenuating bronchial constriction and the quercetin in the molecule was negligible.
hyperreactivity (Ram et al., 2003). Bronchitis is treated with
fresh rhizome juice. C. longa is boiled in milk and combined Diabetes Mellitus
with jiggery and used internally for rhinitis and cough. In cases of In diabetes mellitus, C. longa rhizome powder is particularly
catarrhal cough and painful throat with infection, a rhizome beneficial when added to amla juice and honey. Curcuminoids,
decoction is gargled, and a piece of the rhizome is slightly burned the active component in the rhizome, reduce lipid peroxidation by
and chewed. Turmerones, curcuminoids, curcumin, and keeping superoxide dismutase, catalase, and glutathione peroxidase
tetrahydrocurcumin are chemical compounds of C. longa that active at higher levels. Curcuminoids have been demonstrated in
have anti-asthmatic properties, and Haridradhumvarti (fumes diabetes mellitus type 2 patients to improve insulin resistance, reduce
wick) fumes are used in asthma and congestion. glucose and insulin levels, enhance adiponectin secretion, and lower
levels of leptin, resistin, interleukin (IL-6, IL-1β), and TNF-α (Hajavi
Inflammatory Disorders et al., 2017). According to the findings, C. longa ethanolic extract
Inflammatory markers include C-reactive protein (CRP), containing both curcuminoids and sesquiterpenoids is more
complements, and fibrinogen, all of which are induced by hypoglycemic than curcuminoids or sesquiterpenoids alone
inflammatory cytokines in response to stimulation. According (Nishiyama et al., 2005). C. longa extracts examined under in
to Sandur et al. (2007), curcumin, demethoxycurcumin, and vivo conditions towards type 2 diabetes in mice models predict
bisdemethoxycurcumin are the active compounds in C. longa that it has a hypoglycemic impact by reducing blood glucose levels
that inhibit TNF-induced NF-κB activation. The methoxy groups (Ponnusamy et al., 2012). C. longa has a low impact on postprandial
on the phenyl ring were discovered to be responsible for their plasma glucose and insulin in healthy individuals; it was found that
actions. C. longa extract was examined to improve serum consumption of 6 g of C. longa had no noticeable effect on the
inflammatory markers and mental health and mood glycemic level. The change in insulin was substantially greater 30 and

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Fuloria et al. Therapeutic Potential of Curcuma Longa

60 min after the oral glucose tolerance test (OGTT) with C. longa. (Park et al., 2000). Karamalakova et al. (2019) investigated the
Following the OGTT, the insulin area under the curve was likewise decrease in the level of plasma bilirubin and gamma glutamyl
considerably greater after consuming C. longa. Curcumin and its transpeptidase, and the decrease in lipid peroxidation and
three derivatives (dimethoxy curcumin, bisdemethoxycurcumin, provided significant hepatic protection against bleomycin
and diacetyl curcumin) were reported for their antioxidant toxicity by decreasing reactive oxygen species (ROS), which
capabilities (Faizal et al., 2009). C. longa dried rhizome powder improves superoxide dismutase, catalase, and malondialdehyde
diluted in milk has antidiabetic, hypolipidemic, and hepatoprotective levels. Curcumin is said to increase apoptosis in injured
properties, according to the scientific and systemic investigation, and hepatocytes while also reducing inflammatory effects, hepatic
could be used as an efficient and safe antidiabetic dietary supplement fibrogenesis, and substantially liver injury. The hepatoprotective
with great potential (Rai et al., 2010). Both isopropanol and acetone attribute of C. longa and curcumin might be due to direct free
extract of C. longa inhibited human pancreatic amylase enzyme, radical scavenging mechanisms, boosting glutathione levels, and
which reduces starch hydrolysis, resulting in lower glucose levels assisting in liver detoxification. Aflatoxin-induced biliary
(Ponnusamy et al., 2010). hyperplasia, lipid alterations, and necrosis were likewise cured
by C. longa and curcumin. Sodium curcuminate is a salt of
Cardiovascular Diseases curcumin that has choleretic effects, boosting biliary excretion
Cardiovascular diseases (CVDs) seem to be a global health issue of bile salts, cholesterol, bilirubin, and bile solubility, thus helping
that is linked to high disease and death rates. Anti- to prevent and treat cholelithiasis. This could be related to the
hypercholesterolemic, anti-atherosclerotic (Gao et al., 2019), antioxidant capacity of curcumin’s phenolic groups. Tacrine is
and protective capabilities against cardiac ischemia and well-known for its hepatotoxic and T-cell-destructive properties.
reperfusion (Wang et al., 2018) of curcumin have been proven Curcumin was over ten times more efficient than standard
in preclinical and clinical trials. Curcumin has anti-CVD therapy, ascorbic acid, in research involving human
potential by improving the lipid profile of patients, and it hepatocytes cells that had been disrupted by tacrine (Song
might be administered alone or as a dietary supplement to et al., 2001).
traditional CV medicines (Qin et al., 2017). Curcumin is also
seen in many studies to protect against coronary heart disease (Li Neuroprotective Activity
H. et al., 2020) and also possesses anticoagulant properties. CV Curcuma oil lowers ischemia’s negative effect by decreasing
preventive characteristics of C. longa include reduction in the nitrosative and oxidative stress. Ischemia collapses the
level of cholesterol and triglycerides, decrease in the vulnerability membrane potential of the mitochondria, cytochrome c
of low-density lipoprotein (LDL) to lipid peroxidation, and releases, Bax:Bcl-2 protein ratio changes, and caspase-
platelet aggregation prevention, which helps to defend against activated, which leads to the apoptotic initiation in a
atherosclerosis according to animal studies and also inhibits sequential manner, which was considerably inhibited by
thromboxane formation. Curcumin increases VLDL cholesterol Curcuma oil. As a result, there is evidence for the action of
trans-protein plasma, causing increased levels and mobilization Curcuma oil in neuroprotection with a wide therapeutic window
of α-tocopherol from adipose tissue that protects against for the reduction in ischemic brain injury (Dohare et al., 2008).
oxidative stress that occurs during atherosclerosis. However, In an Alzheimer’s disease transgenic mouse, curcumin
the fatty acids in the animals were less susceptible to oxidation decreased oxidative stress and repaired amyloid pathology.
in the blood vessel. It was suggested that oral intake of 500 mg/ Antioxidant and anti-inflammatory features of curcumin
day curcumin for a week leads to a significant reduction in serum helped to minimize the manifestation of Alzheimer’s disease,
lipid peroxide (33%) and total serum cholesterol (12%) levels which is characterized by inflammation and oxidation.
while increasing HDL cholesterol (29%). Curcumin may reduce Parkinson’s disease (PD) is found to be the second most
chronic heart failure by boosting p38 MAPK, JNK, and ASK1, common neurodegenerative disease following Alzheimer’s
according to Cao et al. (2018). Curcumin and its components disease, which affects dopaminergic neurons of the substantia
were used in recent research to determine the utility of nigra pars compacta (SNpc) and decreases dopamine (DA) in
nanotechnology-based medication delivery systems in CVD their striatal terminals. Curcumin is suggested to be an effective
patients (Salehi et al., 2020). therapeutic and nutraceutical agent for PD treatment.
Interestingly, curcumin was found to inhibit the synthesis of
Hepatoprotective MOA-B enzyme (Khatri and Juvekar, 2016), which would lead to
In jaundice, rhizome powder added to amla juice is utilized. an increase in the level and availability of DA in the brain.
Jaundice is also cured by combining corriliyum (Anjana) with Neuroprotective effects of curcumin in a 6-hydroxydopmine
Haridra, Red ochre (Gairika), and Amalaki (Emblica officinalis animal model of PD (El Nebrisi et al., 2020) indicated an
Gaertn.) (Tripathi, 2009). C. longa’s hepatoprotective abilities increase in the survival of striatal TH fibers and SNpc
have been proven in studies against several hepatotoxic ailments, neurons, decreased abnormal turning behavior, and exerted
including carbon tetrachloride, galactosamine, and neuroprotective properties. These findings provide evidence
acetaminophen (paracetamol) (Rao et al., 1995). The ethanolic that α7-nicotinic acetylcholine receptors could be a potential
crude extract of rhizomes was detected with curcumin, tumerone, therapeutic target and curcumin would be the first natural
atlantone, and zingiberene, which had substantial source that is found to modulate nicotinic receptors in PD.
hepatoprotective ability at an oral dose of 250 and 500 mg/kg Curcumin can be a future therapy for various neurological

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Fuloria et al. Therapeutic Potential of Curcuma Longa

illnesses including major depression, involuntary movement, as 1 (AP-1), β-catenin, and signal transducer and activator of
well as diabetic neuropathy (Kulkarni and Dhir, 2010). Ethanol transcription (STAT) proteins, and to act as a partial agonist
extract of C. longa was found to show neuroprotective effects on of the PPAR-γ, a ligand-activated transcription factor involved in
neuronal loss induced by dexamethasone treatment in rat both neuroprotective and anti-inflammatory signaling pathways
hippocampus (Issuriya et al., 2014). In 2018, an in vivo study (Chen et al., 2015; Kunnumakkara et al., 2017). Curcumin has
revealed that administration of C. longa extract at a dose of been demonstrated to help with a variety of diseases, including
200 mg/kg in trimethyltin (TMT)-treated Sprague–Dawley rats multiple sclerosis (MS) (Mohajeri et al., 2015). Curcumin-D-
with neurotoxic damage seems to prevent the deficits in the monoglucuronide (curcumin monoglucuronide, CMG) was
spatial memory performance and partially inhibit the decrease in developed as a prodrug form of curcumin due to its low
the number of CA2–CA3 region pyramidal neurons. Therefore, bioavailability in the body. CMG is deemed to be safe for use
the anti-inflammatory as well as antioxidant effects of C. longa and can be injected intravenously, revealing an anticancer impact
were observed (Yuliani and Mustofa, 2018) Furthermore, Yuliani on mice implanted with human colorectal cancer cells by
and Mustofa (2019) examined the neuroprotective effects of achieving a 1,000-fold higher blood concentration of free-form
ethanolic C. longa extract at 200 mg/kg in an in vivo analysis curcumin than curcumin administered orally (Ozawa et al.,
via preventing oxidative stress by decreasing the plasma and brain 2017). In mouse xenograft models, CMG given
malondialdehyde levels and increasing the superoxide dismutase, intraperitoneally appears to have antitumor effects on
catalase, and glutathione peroxidase enzyme activities and oxaliplatin-resistant colon cancer with minimal toxicity
glutathione levels in the brain on TMT-exposed (Ozawa-Umeta et al., 2020). After CMG delivery, the
Sprague–Dawley rats. Terrestrial animals and aquatic animals microbiota changes, which may be linked to
are also required to be used for research purposes. An aquatic immunopathology suppression in an autoimmune model for
environment serves as a sink for environmental contaminants MS (Chearwae and Bright, 2008) and experimental
including Benzo[a]pyrene (B[a]P), and research on the fish model autoimmune encephalomyelitis (EAE). The gut microbiota has
is also needed to understand the influence of B[a]P on oxidative been suggested to play a major role in the development and
stress-induced neurotoxicity and anxiety-like behavioral severity of MS. When compared to healthy controls, MS patients
responses in aquatic animals (Billiard et al., 2006; Satpathy L. had an increased number of bacteria from the genera
and Parida S. P., 2021). B[a]P is important in the mechanical Akkermansia, Blautia, and Pseudomonas, as well as a lower
aspects of oxidative stress to lipid membranes, nucleic acids, and number of bacteria from the genera Prevotella and
proteins, as well as changes in antioxidant capacity. Curcumin Parabacteroides (Chen et al., 2016; Park et al., 2017; Tsunoda,
has a potential to act as a co-supplement by reducing anti-anxiety 2017).
behavioral response and altering antioxidant activity with a
significant increase in pyknotic neuronal counts in the Antioxidant Properties
periventricular gray zone of the optic tectum that regulates C. longa and its curcumin constituent have significant antioxidant
anxiety against B[a]P-induced neurotoxicity in adult zebrafish activity, equivalent to both vitamin C and vitamin E, in both
(Satpathy L. and Parida S., 2021). water- and fat-soluble extracts. Curcumin can help the body rid
Banji et al. (2021) demonstrated the neuroprotective and itself of hydroxyl radicals, singlet oxygen, superoxide radicals,
antioxidant activity of C. longa extract in synergy with nitrogen dioxide, and NO. Curcumin pretreatment was proven to
essential oil against neurotoxicity mediated by aluminum. reduce ischemia-induced mutations in the heart (Dikshit et al.,
Detection of free curcumin and its metabolites in the brain 1995). The efficiency of curcumin on endothelial heme
and plasma has increased bioavailability and tissue oxygenase-1 (inducible stress protein) employing bovine aortic
distribution, implying that it could be used in endothelial cells was discovered in an in vitro investigation that
neurodegenerative illnesses. resulted in increased cellular resistance to oxidative stress.
Another neurodegenerative disease, amyotrophic lateral Curcumin can also help Caenorhabditis elegans live longer by
sclerosis (ALS), causes a selective loss of motor neurons in the lowering intracellular ROS and lipofuscin levels during aging
spinal cord, brainstem, and motor cortex. Curcumin was (Liao et al., 2011). Previous research into the potential of C. longa
studied to determine if it could help ALS patients, to sustain hippocampal cells of male Wistar rats from lead-
particularly those with bulbar involvement, survive longer induced damage and reduces lipid peroxidation caused by
(Ahmadi et al., 2018). Curcumin therapy reduced the toxic heavy metals. Resveratrol and curcumin alleviate and
development of ALS and oxidative damage in a double- synergistically repair oxidative stress to the tissues by
blind therapeutic trial (Chico et al., 2018). Curcumin-based enhancing antioxidant response through free radical
drug delivery systems are beneficial for the treatment of ALS, scavenging (Al-Basher et al., 2020). In one of the earlier
according to a study (Tripodo et al., 2015), although studies, the anti-inflammatory and antioxidant capability of
Rakotoarisoa and co-workers pointed out that curcumin curcumin was detected to be synergistically enhanced with
has chemical instability, low oral bioavailability, and low quercetin, and a synergistic protective effect was also
water solubility rate in the ALS disease condition demonstrated in diazinon-induced rats (Abdel-Diam et al.,
(Rakotoarisoa and Angelova, 2018). 2019). The anti-inflammatory impact of berberine and
The ability of curcumin to interact indirectly with a diverse curcumin may decrease oxidative stress, liver inflammation,
array of transcription factors, including NF-κB, activator protein and lipid metabolism (Feng et al., 2018), and the berberine

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Fuloria et al. Therapeutic Potential of Curcuma Longa

FIGURE 6 | Curcumin’s mechanism of action in reducing inflammation, anabolism, and apoptosis. By inhibiting the pro-inflammatory transcription factor (NF-κB),
and activation of PPAR-γ, curcumin aids in anabolism and apoptosis, suppression of pro-inflammatory cytokines, as well as the expression and release of TNF-α.
Abbreviations: TLR, Toll-like receptors; TNFR, Tumor necrosis factor receptor; ROS, Reactive oxygen species; TRADD, Tumor necrosis factor receptor type 1-
associated death domain protein; CYLD, CYLD lysine 63 deubiquitinase; cIAP1/2, Cellular inhibitor of apoptosis protein 1/2; TRAF 2/5, Tumor necrosis factor
receptor-associated factor 2/5; RIPK1, Receptor-interacting serine/threonine-protein kinase 1; LUBAC, Linear ubiquitin chain assembly complex; SPATA2,
Spermatogenesis-associated protein 2; NEMO, NF-κB essential modulator; TAB2/3, TGF-beta activated kinase 1 (MAP3K7) binding protein 2; TAK1, Transforming
growth factor-β-activated kinase 1; IKKα, IKKβ, and IKKγ, Inhibitory kappa b kinase alpha, beta, and gamma; IkB, Inhibitor of nuclear factor kappa Bv; PPAR-γ,
Peroxisome proliferator-activated receptor gamma; P13K, Phosphoinositide 3-kinases; Akt, Ak strain transforming; ERK, Extracellular-signal-regulated kinase; JNK, Jun
N-terminal kinase; Bax, Bcl-2-associated X-protein; AP-1, Activated protein-1; MMP-9, Matrix metallopeptidase 9; COX-2, Cyclooxygenase 2; IL-6 and 1β, Interleukin 6
and 1 beta; TNF-α, Tumor necrosis factor alpha; MCP-1, Monocyte chemoattractant protein-1.

combination also reduced inflammatory and oxidative stress tumor volume in dimethyl benz[a]anthracene (DMBA)-
responses in the cortex and hippocampus of rats (Lin et al., 2020). initiated and 12,O-tetradecanoylphorbal-13-acetate (TPA)-
promoted skin tumors (Huang et al., 1988). Kuttan and his
Anticancer Activity colleague’s work was the first to demonstrate curcumin’s anti-
Annapurna et al. (2011) evaluated the ability of C. longa cancer potential in both in vitro and in vivo experimental models
prophylactically and therapeutically, i.e., pre-induction (Kuttan et al., 1985). Curcumin activates DNA damage response,
treatment and post-induction treatment via oral and topical laying the foundation for the therapeutic use of these
application to modulate the N-methyl-N-nitrosourea-induced nutraceuticals in prostate cancer chemoprevention (Horie,
mammary cancer in rats for 24 weeks. Prophylactic topical 2012). The general anti-carcinogenic effect of curcumin
application given at 200 mg/kg of C. longa has significantly involves mechanisms like induction of apoptosis and
reduced the mean tumor volume compared with therapeutic inhibition of cell-cycle progression in rat aortic smooth muscle
topical application. This was the first report to show the cells (Chen and Huang, 1998). The antiproliferative effect is
anticancer activity of C. longa with topical application in a regulated partly through hindrance of protein tyrosine kinase
breast cancer model. In an in vivo research involving the activity and c-myc mRNA expression, while the apoptotic effect
topical application of curcumin in CD-1 mice and dietary may partly be mediated via preventing the functioning of protein
administration of 1% C. longa, 0.05% of its ethanol extract tyrosine kinase, protein kinase C, and expressions of c-myc
significantly reduced tumor incidence, tumor burden, and mRNA and bcl-2 mRNA (Chen and Huang, 1998). Curcumin

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Fuloria et al. Therapeutic Potential of Curcuma Longa

FIGURE 7 | Mechanism of curcumin in regulation of cancer proliferation. TGF-β1/smad3, IGF, PI3K/Akt, Wnt/β-catenin, and vascular endothelial growth factor
(VEGF) are some of the signaling pathways and molecular targets that curcumin modulates to inhibit cancer. Blocking these receptors has the potential to reduce chronic
inflammation and oxidative damage. DSH and AXIN are recruited once the WNT binds to LRP 5/6, producing the β-catenin destruction complex. β-catenin that has
escaped into the nucleus promotes the transcription of genes including cyclin D1 and P13k, which promote cell proliferation and growth. IGF-1R, Insulin-like growth
factor 1 receptor; TGF-β1, Transforming growth factor beta 1; WNT, Wingless/integrated; LRP 5/6, Low-density lipoprotein receptor-related protein 5/6; Smad, small
mothers against decapentaplegic; Ras, Rat sarcoma virus; Raf, Rapidly Accelerated Fibrosarcoma; MEK 1/2, Mitogen-activated protein kinase 1/2; ERK ½,
Extracellular-signal-regulated kinase ½; P13K, Phosphoinositide 3-kinases; Akt, Ak strain transforming; mTOR, mammalian target of rapamycin; TCF/LEF, T-cell factor/
lymphoid enhancer factor; FZD, Frizzled; DSH, Dishevelled; AXIN, Axis Inhibitor; APC, Adenomatous polyposis coli; GSK-3β, Glycogen synthase kinase-3 beta; CK-1,
casein kinase 1.

inhibits the transcription factor NF-κB (Figure 6) and various well as anticancer activity of the nanoparticulate emulsion (Nair
downstream gene products like c-myc, Bcl-2, COX-2, nitric oxide et al., 2012). Curcumin also has an impact on numerous growth
synthase (NOS), Cyclin D1, TNF-α, ILs, and matrix factor receptors and adhesion molecules that are implicated in
metallopeptidase 9 (MMP-9) and has anti-proliferative tumor growth, angiogenesis, and metastasis (Wilken et al., 2011)
activities in a diversity of malignancies. Curcumin could be and exerts antitumor action in cancer cells by the suppression of
used to avoid colorectal cancer (CRC) in diabetics with type 2 NF-κB and signal transducers and activators of the transcription
diabetes by lowering leptin blood levels and increasing 3 (STAT3) pathways (Jiménez-Flores et al., 2014).
adiponectin levels. Poloxamer 407 can be employed as a A study on in vitro and in vivo models revealed that both C.
polymer to expand the colorectal medicine liberation longa and curcumin exhibited the ability to lessen the impacts
mechanism for curcuminoids in CRC treatment, according to of numerous known causative agents of mutation and cancer
the study of Chen et al. (2012). in different body tissues. Curcumin (50 μM) initiates
A novel approach in adjuvant treatment for osteosarcoma is by destruction in the human kidney cells and causes the
combining a synthetic counterpart of the natural chemical colorectal HT-29 cancerous cells to grow larger, which is
pancratistatin with curcumin (Ma et al., 2011). One controlled most probably due to cell cycle arrest (Kössler et al., 2012).
study found that employing poly-lactic-co-glycolic acid to create Curcumin also triggers programmed cell death in colon
and characterize nano-curcumin improves the water solubility as cancerous cells and inhibits micro-inflammation in the

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Fuloria et al. Therapeutic Potential of Curcuma Longa

gastrointestinal system linked to inflammatory bowel illnesses, exact molecular mechanism of this activity against HCC is
according to laboratory research (Nita, 2003). Okanlawon unknown.
et al. (2020) determine the influence of the inclusion of Curcumin therapy of Burkitt’s lymphoma cell lines in
powdered C. longa on carcass yield and intestinal increase combination with ionizing radiation shows that it boosts
in rabbit production. Farombi et al. (2007) explored the lymphoma cells’ susceptibility to ionizing radiation-induced
combined effects of curcumin and kolaviron (a bioflavonoid apoptosis and improves cell cycle arrest at the G2/M phase.
extracted from Garcinia kola seeds) on DBP-induced testicular Curcumin and L-ASP show synergism in patients with blood
injury in rats. Curcumin treatment of mice infected with and bone marrow malignancy (Jiang et al., 2015). Curcumin
human prostate cancer cells resulted in a lowered also hinders the cellular growth of uterine leiomyosarcoma
microvessel density, cell proliferation, an improvement in and reduces the spread of castrate-resistant disease and
apoptosis. Endothelial cells derived from bovine aorta human leiomyosarcoma cells via modulating the AKT-
exposed to curcumin (5–15 μM) under normoxic (oxygen mammalian target of rapamycin pathway for inhibition
tensions within 10–21%) or hypoxic (oxygen tensions (Wong et al., 2011). Curcumin or C. longa extract’s
within 1–5%) conditions were reported to increase heme potential in decreasing tumors induced chemically was
oxygenase activity and resistance to oxidative stress. investigated. It was documented that curcumin and crude
Consumption of alcohol sensitizes the pancreas to give an extract of C. longa is useful in reducing papilloma
inflammatory response through NF-κB activation via protein development throughout carcinogenesis and progression.
kinase C epsilon. One pilot study concluded that an oral About 0.2% and 1.0% of dietary curcumin can reduce the
dosage of 500 mg of curcumin with 5 mg of piperine could number of papilloma by acting on 7,12-dimethyl benz[a]
restore lipid peroxidation in patients suffering from tropical anthracene (DMBA) and 12,0-tetradecanoylphorbol-13-
pancreatitis (Durgaprasad et al., 2005). acetate (TPA) that promoted skin tumor, which was
EGFR-, miRNA-, autophagy-, and cancer stem cell-based explored by Limtrakul et al. (2001) as ras-p21 and fos-p62
treatments with curcumin could be proven as potential oncogene expression was decreased dose-dependently by
processes and targets for tackling lung cancer (Ye et al., 2012). curcumin. Mohanty et al. (2006) examined the potency of
Curcumin also seems to promote tumor progression, reducing C. longa on apoptosis of myocardial cells in experimentally
the efficiency of docetaxel in lung cancer patients. Meanwhile, produced myocardial ischemic–reperfusion injury because it
synchronized curcumin and docetaxel treatment causes minor exhibited considerable anti-apoptotic effects that lead to the
toxicity in normal organs, as well as the bone marrow and liver preservation of cardioprotective characteristics and heart
(Yin et al., 2012). In vivo curcumin lessens the migratory and function. Aqueous C. longa extract exhibited antimutagenic
invasive capabilities of A549 cells and inhibited adiponectin activity against mutagens and also inhibited the progression
expression thought to be mediated through the NF-κB/MMP of forestomach tumors induced by benzo[a]pyrene against
pathways and has been proposed as an adjuvant in lung Salmonella typhimurium strains.
malignancy (Tsai et al., 2015). Insulin-like growth factor-binding protein-3 (IGFBP-3) is a
Yu and his colleagues evaluated the role of curcumin in high-affinity binding protein that alters the mitogenic functions
inhibiting the human hepatoma SMMC-7721 cells significantly of IGFs while also having anti-proliferative and proapoptotic
by promoting apoptosis via modulation of Bax/bcl-2 (Yu et al., characteristics. Apoptosis is induced by transfection of IGFBP-3
2011). Apoptosis was associated with increases in p53 levels as cDNA into breast cancer cell lines expressing either mutant
well as its DNA-binding ability, along with protein expression of (T47D) or wild-type p53 (MCF-7). IGFBP-3 results in a
Bax. Phosphorylation of CDC27 (cell division cycle 27) is the higher ratio of pro-apoptotic to anti-apoptotic Bcl-2 family
main mechanism of anticancer efficacy of curcumin by members. Curcumin induced cell apoptosis in MCF-7 via a
obstructing cell growth and proliferation in an apoptotic p53-dependent pathway and could offer therapeutic promise
pathway, leading to the death of the cells (Lee and Langhans, in patients with breast cancer (Choudhuri et al., 2002). In the
2012). It has been discovered that circulating miR-21 is elevated mouse model, the combination of curcumin and
in patients with hepatocellular carcinoma (HCC); it can be cyclophosphamide negated the efficacy of cyclophosphamide
exploited as a diagnostic marker and therapeutic target for and then hindered the reduction of tumor size. Curcumin
HCC, and is being linked to distant metastasis (Zhang et al., causes DNA fragmentation and base degradation in the
2019). According to Li and his colleagues, in human hepatoma presence of copper and cytochrome p450 isoenzymes.
cell lines such as HepG2 and HCCLM3, suppression of miR-21 Furthermore, Frank et al. (2003) demonstrated that curcumin
improved anticancer action of curcumin like cell growth bonded to copper did not suppress spontaneous hepatic tumor
suppression, apoptosis via upregulated target gene, and TIMP3 growth in a rat model of liver cancer. The enhanced toxicity and
expression, and the mechanism may refer to TGF-β1/smad3 oxidative stress may be explained by the excess load of copper.
signaling pathway inhibition (Li J. et al., 2020). Curcumin Curcumin can limit the absorption and effectiveness of irinotecan,
inhibits cancer through modulating several signaling pathways a chemotherapy medication used in colon cancer. Curcumin in
and molecular targets, including TGF-β1/smad3, IGF, PI3K/Akt, combination with paclitaxel (Taxol) effectively decreased breast
Wnt/β-catenin, and vascular endothelial growth fact (VEGF) cancer dissemination to the lung in a xenograft mouse model of
(Figure 7) (Mohebbati et al., 2017). Although several reasons human breast cancer, relative to either curcumin or paclitaxel alone
for curcumin’s antitumor potential have been hypothesized, the (Frank et al., 2003). Curcumin reduces T cells significantly, but a low

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Fuloria et al. Therapeutic Potential of Curcuma Longa

dosage of curcumin boosts T cells retrieved from mice with the 3LL Pregnancy/Neonates
tumor. Consequently, increased CD8+ T cells demonstrated C. longa and curcumin caused a considerable increase in hepatic
improved IFN-γ secretion and proliferation, especially against 3LL glutathione S-transferase (GST) and sulfhydryl (SH),
tumor cells (Han et al., 2014). C. longa extracts (containing Cytochrome b5, and cytochrome P450 levels, implying that C.
curcuminoids, volatile oil, and water-soluble polysaccharides) longa and/or curcumin metabolites can be passed down through
could be employed as an adjuvant supplement for cancer patients the milk supply. C. longa and curcumin are nontoxic and non-
who have their immune systems impaired by chemotherapy and saw mutagenic during pregnancy in animals, although additional
an improvement in the expansion of peripheral blood mononuclear research in humans is needed (Soleimani et al., 2018).
cells and the composition of cytokines. In vitro and in vivo analyses
have indicated that aromatic-turmerone exhibits anti-angiogenic Irritable Bowel Syndrome
abilities on human endothelial cells (Yue et al., 2015). IBS patients have far more inflammatory cells in the mucosa of
Dietary substances such as curcumin and docosahexaenoic the colon and ileum part of the intestine. Ng et al. (2018) looked
acid (DHA) have varying antiproliferative abilities among into the possibility that curcumin can aid in IBS manifestation.
multiple breast cell lines and indicated synergism in SK-BR-3 Crohn’s disease (CD) and ulcerative colitis (UC) are the two
(human breast cancer cell line) cells, which might be due to DHA primary forms of inflammatory bowel disease (IBD),
elevation of cellular curcumin absorption and, thus, an characterized by abdominal pain, bloating, altered bowel
occurrence unique to the combined action of substances habits, and increased stool frequency. Holt et al. (2005) carried
(Altenburg et al., 2011). The study shows the synergistic out a pilot study to see how curcumin therapy affected IBD
interaction between curcumin and garcinol in pancreatic patients who had earlier received standard UC or CD therapy.
cancer cells (BxPC-3 and Panc-1) in a dose-dependent manner Curcumin with standard treatment exerts more beneficial effects
(Parasramka and Gupta, 2012). In vitro screening is carried out than placebo plus conventional UC treatment in maintaining
on human multiple myeloma cell lines (U266) by Ghoneum and recovery, according to Hanai et al. (2006). Bundy et al. (2004)
Gollapudi (2011) to explain the synergistic apoptotic potency of examined that abdominal pain or discomfort score was lowered
arabinoxylan rice bran (MGN-3/Biobran) and curcumin (C. significantly by 22% and 25% in the one- and two-tablet group
longa) in the United States. volunteers, respectively, and revealed the role of C. longa on IBS
pathology.
Anti-Allergic Activity
Curcumin inhibited the degranulation and release of histamine Dyspepsia and Gastric Ulcer
from rat peritoneal mast cells caused by compound 48/80. Six hundred milligrams of curcumin five times a day for 12 weeks
Calcium uptake measurements and cAMP tests in mast cells to individuals with peptic ulcers could prevent ulcer development
were used to investigate the mechanism of action. In an animal but also cause symptomatic erosions, dyspepsia, and gastritis in
model, curcumin dramatically reduced the mast cell-mediated some patients. Abdominal pain along with other symptoms has
passive cutaneous anaphylactoid reaction. Curcumin enhanced greatly decreased with curcumin within 1–2 weeks. Kim et al.
intracellular cAMP levels and inhibited both nonspecific and (2005) found that orally administered ethanolic C. longa extract
selective mast cell-mediated allergy reactions (Choi et al., 2010). decreased stomach acid, gastric juice secretion, and ulcer
Curcumin significantly reduced IgE/Ag-induced PSA (passive initiation in male rats by inhibiting H2 histamine receptors,
systemic anaphylaxis), as measured by serum-dependent which is similar to the effects of ranitidine. Similarly, the
leukotriene C4, dependent prostaglandin D2, and histamine antiulcer action of C. longa ethanolic extract was seen as it
levels, indicating that it might be useful to produce drugs for lowers ulcer index in addition to stomach acidity significantly.
allergic inflammatory illnesses (Li et al., 2014). Curcumin can C. longa extract also suppressed hypothermic-restraint stress
suppress expression of CD80, CD86, and class II antigens by depletion of stomach wall mucus and diminished the severity
dendritic cells and blocks the release of inflammatory cytokines of necrotizing agent-induced lesions.
like IL1β, IL-6, and TNF-α from LPS-stimulated dendritic cells.
Antidepressant Properties
Antidermatophytic Activity Rats suffering from chronic mild stress (CMS) lead to much less
Rhizome juice is utilized as an antiparasitic in the therapeutics of sucrose intake; increased IL-6, TNF-α, CRF, and cortisol levels;
numerous skin problems, and rhizome powder is added to cow’s smaller medulla oblongata; and reduced splenic NK cellular
urine to relieve internal itching and dermatitis (Paranjpe and activity. The condition created in CMS was cured with
Pranjpe, 2001). Leaves hold great potential against human ethanolic extract, which even caused the medulla oblongata to
pathogenic fungi on account of their various in vitro and in be lower than normal. C. longa has antidepressant potential
vivo antifungal activities, for instance, strong fungicidal ability, because it tends to hinder monoamine oxidase accumulation
long shelf life, high inoculum density tolerability, thermostability, in the central nervous system (Yu et al., 2002). Curcumin has a
a large number of antidermatophytic effects, and lack of any side wide range of characteristics that are important to depression
effects. Curcumin has been proven to have antimutagenic, pathogenesis. The ethanolic C. longa extract prevented the
antioxidant, free radical scavenging, anti-inflammatory, and decrease in serotonin, noradrenalin, and dopamine
anti-carcinogenic abilities, allowing it to protect the skin from concentrations while increasing serotonin turnover, cortisol
detrimental UV-induced impacts (Binic et al., 2013). levels, and serum corticotrophin-releasing factor levels (Xia

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Fuloria et al. Therapeutic Potential of Curcuma Longa

et al., 2007). The consequences of orally administered curcumin curcumin component, and oil fraction of C. longa revealed
seem on behavior under chronic stress or depression condition in antibacterial activity and suppresses H. pylori, Streptococcus,
the rat model. Curcumin administration showed a similar impact Staphylococcus, and Lactobacillus species (Mahady et al.,
to imipramine, a known antidepressant drug, and it has been 2002).
indicated by various authors to be a feasible alternative source in
depression condition (Mohammed et al., 2019; Qi et al., 2020). Synergistic Interaction
Curcumin has been identified to have synergistic effects but not
Curcumin Prevents Drug Resistance antagonistic effects when combined with antibiotics such as
Curcumin possesses a powerful anti-drug resistance agent. It has oxacillin, ampicillin, ciprofloxacin, gentamicin, amikacin,
a novel capacity to suppress adriamycin-induced elevation of polymyxin B, and norfloxacin, and anti-inflammatory effects
P-glycoprotein and its mRNA, and this ability is linked to when combined with a certain cytotoxic agent, with
increased intracellular drug accumulation, thereby increasing chemotherapy (Lin et al., 2007), or with a polyphenol
ADM lethality (Xu et al., 2011). Curcumin blocks NF-κB derivative-containing diet (Strimpakos and Sharma, 2008).
activation, which results in chemosensitivity in drug-resistant Various researchers have employed different extracts prepared
cancer cells. Furthermore, curcumin and tamoxifen co-therapy from medicinal plants to treat MDR bacteria (Mehta and Jandaik,
has also been illustrated to expose tamoxifen-resistant breast 2016; Urmila Jandaik et al., 2016; Mehta et al., 2021; Mehta et al.,
cancer cells, suggesting that it could be a viable method for 2022a), which has been recognized as a global concern. A mixture
either minimizing tamoxifen resistance or re-sensitizing of C. longa, galanga powder, and essential oil of lemongrass
refractory illness to tamoxifen therapy (Mimeault and Batra, slowed the deterioration of raw white hard clam muscle,
2011). which improved the seafood quality during preservation
(Nguyen, 2020).
Antimicrobial and Synergistic Property
The essential oil as well as extracts of C. longa can suppress a Antifungal Activity
diverse range of bacteria, infectious fungus, and parasites. Curcumin was shown to improve the activity of common azole
and polyene anti-fungal (Sharma et al., 2010). Another study
Antibacterial Activity indicated that C. longa oil suppressed dermatophytes and
Some of the researchers assessed the antimicrobial activity of pathogenic fungus when applied externally on guinea pigs
curcumin against different bacterial strains such as Salmonella infected with dermatophytes, molds, and yeast. The guinea
paratyphi, Trichophytongypseum, Staphylococcus aureus, pigs with dermatophytes and fungal infected lesions improved,
Streptococci mutans, and Mycobacterium tuberculosis and the lesions become invisible after 7 days of C. longa
(Tajbakhsh et al., 2008; Maghsoudi et al., 2017). The extract administration. The antifungal, antibacterial, phytotoxic,
showed antimicrobial activity towards Trichophyton cytotoxic, and insecticidal activities of a C. longa ethanolic
longifusus, Microsporum canis, and S. aureus while toxicity extract were explored by Khattak et al. (2005). Ether,
was indicated against Lemna minor. The C. longa-treated chloroform, and ethanol extracts of C. longa along with its
rabbit group had a significantly greater mean value for oil possess antifungal effect against Aspergillus flavus,
wound contraction, and therefore, wounds revealed Aspergillus parasiticus, Fusarium moniliforme, and
decreased inflammation and a rising tendency in collagen Penicillium digitatum, as suggested by several authors
formation. The extract of C. longa in ethanol was active for (Wuthi-Udomlert et al., 2000; Jayaprakasha et al., 2001). C.
Shigella flexneri, Staphylococcus epidermis, Klebsiella longa methanolic extract exhibited antifungal action for
pneumoniae, Lactobacillus, Pseudomonas aeruginosa, Vibrio Cryptococcus neoformans and Candida albicans, which
cholerae, and Salmonella typhi (Oghenejobo and Bethel, 2017). indicates minimum inhibitory concentration (MIC) values
Drug combinations can cause powerful or reductive of 128 and 256 g/ml, respectively. Curcumin has antifungal
pharmacokinetic effects, which may enhance or diminish action over all Candida test strains, at MICs varying from 250
the clinical efficiency of one another via regulation of to 2,000 g/L, but is less efficacious than fluconazole, according
absorption, distribution, metabolism, and excretion (Chou, to a recent analysis. It could be attributable to changes in
2006). Another study revealed the synergistic combinatorial membrane-associated ATPase activity, ergosterol production,
impact of copper metal ions with aqueous extracts of C. longa or proteinase secretion (Neelofar et al., 2011).
against Paenibacillus popilliae, a known food spoilage
bacterium, and detected the phytoconstituents including Antiviral and Antiparasitic Activity
alkaloid, flavonoid, anthocyanin, steroids, and coumarin in Curcumin has antiviral potential (von Rhein et al., 2016) even for
C. longa extracts (Jassal et al., 2015). C. longa aqueous extract HIV; inhibiting HIV-1 LTR promoter directed gene expression
and chitosan possess significant synergism and antibacterial with no effect on cell viability (Ashraf, 2018). Curcumin had
potency at 512 μg/ml and 1,024 μg/ml against MDR pathogens moderate effectiveness towards Plasmodium falciparum and
such as methicillin-resistant S. aureus, carbapenem-resistant Leishmania organisms. The ethanol extracts exhibit anti-
Pseudomonas, carbapenem-resistant Enterobacteriaceae and Entamoeba histolytica activity while curcumin has anti-P.
AmpC-producing Enterobacteriaceae, and antibiofilm falciparum and anti-Leishmania effect in vitro. Curcumin
producers (Etemadi et al., 2021). The aqueous extract, seems to have its antiviral activity for Epstein–Barr virus and

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Fuloria et al. Therapeutic Potential of Curcuma Longa

TABLE 2 | Curcumin of C. longa with immunomodulating activity and their mechanisms of action.

Main Subjects Study Immunomodulatory Modulation in References

constituent design activities parameters/mediators affected

Curcumin Healthy albino mice In vivo White blood cell production and weight Stimulates lymphoid organs and white Afolayan et al.
lymphoid organs blood cells (2018)
Dendritic cells In vitro Surface molecule expression Suppresses expression of CD80, CD86, Kim et al. (2005)
MHC class II, and IL-1
Dendritic cells In vitro Cytokine production Decreases production of IL-6, IL-12, and Kim et al. (2005)
TNF-α
Dendritic cells In vitro Phosphorylation of mitogen-induced protein Inhibition of LPS-induced MAPK activation Kim et al. (2005)
kinases (MAPKs) and NF-κB p65 translocation and nuclear translocation of NF-κB p65
Bronchoalveolar of In vivo Allergic response Decreases number of eosinophils Ravikumar and
Balb/c mice Kavitha (2020)
Bronchoalveolar of In vivo Cytokine production Decreases level of IL-4 Ravikumar and
Balb/c mice Kavitha (2020)
PBMCs In vitro T-cell proliferation Inhibit the proliferation of lymphocyte Yadav et al. (2005)
PBMCs In vitro Cytokine production Inhibits the production of IL-2 and TNF-α Yadav et al. (2005)
PBMCs In vitro NF-κB Inhibit lipopolysaccharide-induced NF-κB Yadav et al. (2005)
Erythroleukemic cell In vitro Cytotoxicity Increases NK cell cytotoxicity Yadav et al. (2005)
line K562
Lupus BALB/c mice In vivo Adaptive immune response Decreases the percentage of Th1, Th2, Kalim et al. (2017)
and Th17
Lupus BALB/c mice In vivo Antinuclear antibody (ANA) levels Decreases level of ANA Kalim et al. (2017)
Monocytes and liver In vivo ROS production Increased the production of ROS Inzaugarat et al.
macrophages (2017)
Monocytes and CD4+ In vivo TNF-α and IFN-γ production Enhanced the production of TNF-α in Inzaugarat et al.
cells monocytes and IFN-γ in CD4+ cells (2017)
Fish In vivo Immune response Increased the expression of antimicrobial Alambra et al.
peptides (2012)

HIV (Taher et al., 2003). An extract of C. longa in both aqueous manufactured antifertility medicines. Parkes mouse strain
and ethanol is used in aquaculture as a treatment for bacterial was given aqueous rhizome extract of C. longa via the oral
infections (Sahu et al., 2005). Curcumin exerts anti-parasitic route (600 mg/kg body weight/day for 8 and 12 weeks), which
action against African trypanosomes, has schistosomicidal causes reversible spermatogenesis, decreased seminiferous
activities against Schistosoma mansoni adult worms, and has tubules diameter, and loosening of germinal epithelium,
anti-malarial in addition to nematocidal effects. Diets thus indicating its potential in male fertility. Hembrom
supplemented with C. longa reduced small intestine lesion et al. (2015) also examined the influence of an aqueous C.
scores and boosted weight gain in chicks infected with the longa rhizome extract in sperm count, spermatozoa motility,
cecal protozoan, Eimeria maxima. Curcumin fits well to the and seminal pH in Swiss Albino male mice leading to
active site of the protease, according to in silico modeling infertility. The combined action of curcumin and
studies (Vajragupta et al., 2005) and proved to be a powerful andrographolide significantly suppressed the number of
inhibitor of HIV integrase, as it can bind acidic residues in the implants and litter size in female Sprague–Dawley rats,
integrase’s catalytic site, limiting it from interacting with its changed the duration of phases involved in the estrus cycle,
substrates. Molecular docking analysis revealed that and lowered the number of ovarian follicles (Shinde et al.,
particularly the keto-enol and terminal o-hydroxyl group of 2015). Petroleum ether in addition to aqueous extract of
curcumin are tightly linked to the integrase’s binding region rhizome shows antifertility impact on rats via oral
formed by residues such as Glu92, Thr93, Asp116, Ser119, Asp64, administration and results in complete inhibition of
His67, Thr66, Asn120, and Lys159 (Vajragupta et al., 2005). implantation. Curcumin also reduces human sperm
Recent analysis has also shown the therapeutic potential of C. motility, suggesting its usage as intravaginal contraceptive
longa against coronavirus disease 2019 (COVID-19) (Emirik, and its antispermatogenic activity.
2020), and its ability to modulate cytokine storm in COVID-
19 patients (Valizadeh et al., 2020; Mehta et al., 2022b) has Immunomodulatory
produced formidable renewed interest in C. longa. In the management and therapy of diseases caused by immune
system malfunctioning, immune response modulation is
Antifertility necessary. The most commonly used immunosuppressant in
Traditional medicine has been recommended by the World transplant rejection is cyclosporin A, a microbial peptide
Health Organization as a cost-effective substitute to (Elgert, 2009); however, cyclosporin A exhibited toxicities

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Fuloria et al. Therapeutic Potential of Curcuma Longa

FIGURE 8 | Curcumin must be modified/improved prior to future research due to its extremely low bioavailability. Due to the quick elimination of curcumin in the
systemic circulation as a result of enzyme metabolism, conjugating curcumin to adjuvants or other delivery systems may be beneficial in order to increase its half-life and
bioavailability.

and adverse effects like nephrotoxic activity and gingival Curcumin inhibits lymphoma B-cell proliferation by lowering
hypertrophy. Unfortunately, the majority of commercially the potency of c-MYC, BCL-XL, and NF-κB. Curcumin has also
available medications include adverse effects. The main been demonstrated to suppress the production of ROS in
important side effects of NSAIDs include injury to the macrophages. Curcumin also stimulates NK cell apoptosis by
stomach and intestinal mucosa. Corticosteroids, an modulating the NF-κB pathway and inhibiting BCL-XL and
immunosuppressive medicine, have several negative health Cyclin D. Curcumin inhibits IL-1 and IL-6 inflammatory
risks, including decreased bone marrow and skin fragility. cytokines such as from LPS-stimulated dendritic cells and
Natural products continue to be a valuable source of suppresses the expressions of CD80, CD86, and MHC class
innovative and safe anti-inflammatory compounds (Elgert, II by dendritic cells. Curcumin also causes reduced LPS-induced
2009). Due to the existence of bioactive metabolites, many MAPK activation and NF-κB p65 translocation in dendritic cells
Curcuma species, including C. longa, C. zanthorrhiza Roxb., (Nair et al., 2017) along with impaired activation of Th1
C. amada Roxb., C. manga Valeton & Zijp, C. aeruginosa Roxb., responses. Curcumin significantly suppressed the formation
and C. zedoaria Rosc., have been shown to have a variety of of IL-6, IL-8, TNF-α, and MCP-1 from higher glucose-
immunomodulatory effects. Several recent analyses on the cultured monocytes, according to Jain et al. (2009).
phytochemistry, biological, and pharmacological action of the Curcumin decreased NOS activity and macrophages’ ability
Curcuma genus have been published (Rajkumari and to secrete nitric oxide (NO) at low doses. Curcumin has been
Sanatombi, 2017; Sun et al., 2017; Mahadevi and Kavitha, revealed to be linked to the viral S1 protein, which is required for
2020; USDA, 2021). Curcumin can inhibit the expansion of SARS-CoV-2 entry in an in silico approach; thus, it may inhibit
T cells triggered by plant lectin concanavalin A (Con A), cytokine storm in the severe stage of COVID-19 (Pawitan,
according to a report on the role of the genus Curcuma and 2020). Table 2 shows the immunomodulating activity of
its bioactive metabolites to control the immunological response. curcumin with its mechanisms of action.

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Fuloria et al. Therapeutic Potential of Curcuma Longa

FIGURE 9 | Curcumin safety, toxicity profiles, and solution to overcome it. Curcumin safety, toxicity profiles, and a way to circumvent it. Despite its recognized
safety, certain investigations have highlighted unprecedented side effects of curcumin, including gastrointestinal problems, chronic inflammations, and others. To
address this issue, fewer additives should be utilized, and curcumin microencapsulation should be tailored.

TABLE 3 | Clinical uses of C. longa and its major compound curcumin (https://clinicaltrials.gov/).

S. Clinical use Condition Intervention Status

No.

1. Curcumin as nutraceutical in patients of depression Major depressive disorder Dietary Supplement: Curcumin Drug: Fluoxetine Completed
2. Premedication with curcumin on post-endodontic pain Acute pulpitis Drug: Curcumin Completed
Dietary Supplement: 400 mg starch
3. Curcumin during the off treatment periods in patients with Prostate cancer Dietary Supplement: Curcumin and placebo Completed
prostate cancer undergoing intermittent androgen
deprivation therapy
4. Curcumin and function in older adults Older adults, physical Drug: Curcumin or microcrystalline cellulose Completed
function, and cognitive
function
5. Turmeric on new onset primary dysmenorrhea Primary dysmenorrhea Drug: Naproxen Completed
Dietary Supplement: Turmeric
6. Turmeric and exercise-induced muscle damage and Muscular injury Dietary Supplement: Turmeric strength for joint and Completed
oxinflammation placebo
7. Topical application of commercially available Curcuma Chronic periodontitis Drug: Topical application of Curenext gel Completed
longa gel on superoxide dismutase and malondialdehyde Dietary Supplement: Placebo
levels in saliva of chronic periodontitis patients
8. Turmeric on oxidative modulation in ESRD (end-stage renal End-stage renal failure Drug: Turmeric Completed
disease) patients Dietary Supplement: Placebo
9. Turmeric in gingival massaging and adjunct to scaling and Chronic periodontitis Procedure: Tooth brushing with dentifrice, turmeric Completed
root planing in chronic periodontitis patient massaging, scaling, and root planing with turmeric
massaging
10. Turmeric and turmeric-containing tablets and sebum Skin inflammation Dietary Supplement: Turmeric or turmeric-containing Completed
production combination tablet or placebo tablets

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Fuloria et al. Therapeutic Potential of Curcuma Longa

FIGURE 10 | Future perspective of curcumin-loaded gold nanoparticles functionalized with Ty1 and bevacizumab in a patient infected with SARS-CoV-2
(COVID-19).

NANO-FORMULATIONS AND GREEN Integrating curcumin into nanocarriers is an effective and

SYNTHESIS OF C. LONGA AND ITS efficient way to improve curcumin’s biological features, such
as bioavailability and solubility, long-term circulation, and
RELATED COMPOUNDS long-term retention in the body, as well as overcome
In the last few years, the use of nanoformulation antibiotics has curcumin’s physiological challenges (Das et al., 2010; Li et al.,
become increasingly popular in improving pharmacological 2013; Fonseca-Santos et al., 2016). It can also limit unintentional
therapeutic benefits. Nanomedicine is a relatively new field toxicity to neighboring normal cells/tissues by dispersing the
that is rapidly expanding in conjunction with nanotechnology intended tissues. Curcumin encapsulated in poly(lactic-co-
and pharmaceutical disciplines (Caster et al., 2017). glycolic acid) nanoparticles showed a ninefold increase in
Nanopharmaceuticals, on the other hand, confront numerous nano curcumin when compared to natural curcumin (Shaikh
hurdles, including improved characterization, toxicity issues, et al., 2009). Experiments demonstrate that nanoforms of
regulatory standards, high expenses, and healthcare warnings. curcumin are effective in the treatment of liver and heart
Curcumin’s practical applications are frequently limited by problems (Shimatsu et al., 2012), cancer (Mohanty and Sahoo,
factors such as poor water solubility and physicochemical 2010), and brain tumors (Mohanty and Sahoo, 2010; Lim et al.,
instability, poor bioactive absorption, rapid metabolization, 2011). Moreover, curcumin nanoformulation exhibited threefold
low pharmacokinetics, bioavailability, penetration and higher anti-HIV activity in comparison with its free form;
targeting efficacy, sensitivity to metal ions, alkaline conditions, obstructed the HIV-1-triggered expression of interleukin-1β
heat, and light, among others (Flora et al., 2013). These barriers (IL-1β), Topo II α, and cyclooxygenase 2 (COX-2); and
are being overcome by encapsulating curcumin in blocked the synthesis of viral complementary DNA (cDNA)
nanoformulations (nano curcumin) (Yallapu et al., 2012). (Gandapu et al., 2011).

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Fuloria et al. Therapeutic Potential of Curcuma Longa

Moreover, metal-based green synthesis is gaining importance amylovora, which could be useful for nano-drug delivery
due to its chemical, optical, photochemical, and electronic applications (Gaurav, 2021). Curcumin’s bioavailability was also
properties (Mohanpuria et al., 2008). Among several metals, discussed in Figure 8, as well as a method for dealing with it.
silver has gained huge attention for the green synthesis of NPs
because of its numerous applications in various industries,
particularly because of its nonlinear optical, biolabeling, and Side Effects, Contraindications,
antibacterial capacity. Silver nanoparticles (AgNPs) are widely Precautions, and Safety Aspects of C. longa
used in various fields like in drug delivery (Basu et al., 2018), Facts suggest that excessive turmeric consumption may trigger
nanomedicine (Carabineiro, 2017), agriculture, and cosmetics, and uterine contraction in pregnancy, and may hinder iron
most importantly, they are used as an antimicrobial agent (Zhang absorption (and so must be used with caution in iron-deficient
et al., 2017). However, many scientists report that AgNPs also cause individuals). Turmeric has been reported to reduce testosterone
toxicity (McGillicuddy et al., 2017), but still, they play a major role levels and sperm movement in men (when administered orally) and
as a disinfectant and as a antimicrobial agent. An emergence of delay blood clotting (and so its use must be terminated at least
nanotechnology that helps in the production of AgNPs has served 2 weeks before a scheduled surgery). According to some reports,
as a new therapeutic modality. Because of their characteristic broad- turmeric should not be consumed if one has gallbladder and bleeding
spectrum antimicrobial ability, AgNPs have gained increasing problems (Deshpande et al., 1998; Park et al., 2000). Figure 9 depicts
attention in biomedical applications including wound curcumin’s safety and toxicity profiles, and a way to manage them
management (Parveen et al., 2018; Ahsan and Farooq, 2019; (Cheng et al., 2001; Perkins et al., 2002; Rithaporn et al., 2003; Liddle
Ravindran et al., 2019), but the hydrophobic nature of curcumin et al., 2006; Sharma et al., 2007; Vareed et al., 2008; Dance-Barnes
limits its biomedical applications. Hydrogels are in natural or et al., 2009). In addition, Table 3 summarizes the clinical uses of C.
synthetic forms including bacterial cellulose as one of the longa and its major component curcumin.
promising synthetic candidates used in wound dressings because
of its ability to maintain a moist microclimate at the wound site,
which has been proven to facilitate healing (Tao et al., 2019; Xue CONCLUSION
et al., 2019). The hydrophobicity of curcumin was overcome by its
microencapsulation in cyclodextrins. A combination of AgNP with C. longa with its various pharmacological features has been
curcumin in the biosynthetic bacterial cellulose is used for the characterized as a universal panacea among herbal remedies, as per
preparation of hydrogel dressings that exhibit antimicrobial activity the literature survey. This plant is regarded as a potent medicinal plant
against wound-infecting pathogenic microbes like S. aureus, P. with a wide range of potent pharmacological properties due to the
aeruginosa, and Candida auris (Gupta et al., 2020). Among presence of numerous chemical components including starch, essential
several different approaches to synthesizing AgNP, the use of elements, proteins, vitamins, volatile oils, curcumin, and curcuminoids.
extracts from natural plant sources has received wide research Curcumin has a long history of use as a culinary spice and food color, as
consideration because of the safe and eco-friendly procedure well as a component of Ayurvedic and Chinese medicine. Curcumin
(Alsammarraie et al., 2018; Hemmati et al., 2019; Ravindran has a variety of beneficial effects on humans, according to science.
et al., 2019; Keshari et al., 2020). The antibacterial action of Curcumin is still utilized as a cooking ingredient today, but modern
nano formed curcumin against a wide range of microorganisms, technology has made it possible to use it in a range of food- and health-
including fungi, bacteria, and viruses, has been carried out by related applications. Curcumin’s efficacy, safety, and pharmacokinetics
researchers. Curcumin-modified AgNPs, for example, are utilized have all been examined extensively in clinical studies over the last
to inhibit respiratory syncytial virus (RSV) infection cells and 50 years (Gupta et al., 2013; Subramani et al., 2018). The development
reduce viral loads while having no deleterious side effects (Yang of innovative nanomedicine formulations to increase curcumin
et al., 2016). Naseri et al. then investigated the antiviral effects of targeting, pharmacokinetics, efficacy, and cellular uptake has been
curcumin nanomicelles on the attachment and entrance of hepatitis prompted by a significant therapeutic limitation (Salehi et al., 2020a;
C virus (HCV) infection, finding out that the viral load in HCV cells Salehi et al., 2020b). Cancer, CVD, arthritis, atherosclerosis, diabetes,
treated with curcumin nanomicelles was reduced (Naseri et al., gastric illness, IBD, psoriasis, acquired immunodeficiency syndrome,
2017). Nanocurcumin was shown to exhibit improved antibacterial and other inflammatory disorders are all examples of pleiotropic
activity compared to curcumin because of its enhanced aqueous- activities. Several studies in this review discovered the anti-
phase solubility and simple dispersibility. An efficient antibacterial inflammatory effects of C. longa and curcumin, including decreased
potential was found against Bacillus subtilis, H. pylori, S. aureus, and white blood cell, neutrophil, and eosinophil numbers, as well as
P. aeruginosa (Basniwal et al., 2011). An aqueous extract from C. protective effects on serum levels of inflammatory mediators like
longa-coated cotton fabrics, as well as formulated metallic AgNPs, phospholipase A2 and total protein in various inflammatory
also exhibited noticeable antimicrobial potency against S. aureus, P. disorders. Curcumin has anticancer properties by interfering with
aeruginosa, S. pyogenes, and C. albicans, and even AgNP-loaded many cellular systems and inhibiting/inducing the production of
cotton fabrics displayed potent wound healing activity in fibroblast multiple cytokines, enzymes, or IκKβ, TNF-α, STAT3, COX-2,
(L929) cells (Maghimaa and Alharbi, 2020). Moreover, recently, it PKD1, NF-κB, epidermal growth factor, and MAPK, among others.
has been found that the combination of AgNP with the rhizome Under oxidative stress conditions, C. longa extracts and curcumin
extract of C. longa showed antimicrobial effect towards plant decreased MDA and NO levels while increasing thiol, SOD, and
affecting bacteria such as Xanthomonas axonopodis and Erwinia catalase levels. Curcumin also influenced the lifespan of organisms

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Fuloria et al. Therapeutic Potential of Curcuma Longa

by regulating important signaling pathways such as the mTOR, PKA, investigate the possibilities of practical clinical applications as
and FOXO signaling pathways. In conditions where the immune well as the details of hidden and untold areas in order to
system was disturbed, treatment with C. longa and curcumin enhanced maximize its utility for the benefit of humanity. It is suggested
IgE, IL-4, TGF-β, IL-17, IFN-γ, and the Th1/Th2 ratio. The to inhibit cytokine storm in the severe stage of COVID-19. So, we
pharmacological effects of C. longa extracts and curcumin on can further work on it to get out of this pandemic situation of
respiratory, allergy, and immunologic problems suggest that C. COVID-19 mutations. For the rational usage of turmeric and
longa and curcumin may have a possible therapeutic effect on curcumin in the therapies of human diseases especially COVID-
these illnesses. C. longa extracts and curcumin delay the onset of 19, an accurate knowledge of effective dose, safety, and mode of
diabetes, improve β-cell functioning, prevent β-cell death, and reduce action is necessary.
insulin resistance in animal models. Curcumin’s use has been limited
due to its low water solubility, which can result in poor chemical
stability, oral bioavailability, and cellular uptake. Other strategies that AUTHOR CONTRIBUTIONS
have been aggressively studied include delivering medications at a
controlled rate, slow delivery, and targeted delivery. Curcumin Writing—original draft: JM, AC, SF, MS, and NF;
nanoformulations have been produced to improve the solubility Conceptualization: JM and AC; Resources: SF, JM, AC, MS,
and bioavailability of the compound. Curcumin’s medicinal NR, MB, VS, KC, LT, RN, YW, KS, PL, DM, VK, AA, and
applications and clinical efficacy could be expanded if NF; Data curation: SF, JM, AC, MS, NR, MB, VS, KC, LT, RN,
biotechnology and nanotechnology were used to address the YW, KS, PL, DM, VK, AA, and NF; Writing—review and editing:
current limitations. SF, JM, AC, MS, NR, MB, VS, KC, LT, RN, YW, KS, PL, DM, VK,
This review adds to the growing body of evidence supporting the AA, and NF. All authors have read and agreed to the published
use of turmeric as a preventative and therapeutic strategy. We believe version of the manuscript.
that more progress in the development of strategies incorporating
natural products can be exploited to be used against COVID-19 in the
upcoming years. Hence, this paper also suggests the use of gold FUNDING
nanoparticles in combination with neutralizing antibody Ty1, which
may assist selectively in the receptor binding domain of the SARS- This study was funded by the Deanship of Scientific Research
CoV-2 spike, directly hindering angiotensin-converting enzyme 2 through Research Group (Small) (project number RGP.1/330/
interaction. The inclusion of curcumin and bevacizumab further 42) of the King Khalid University, Abha 61421, Saudi Arabia.
enhanced the efficacy of the proposed strategy as both may target The authors extend their appreciation to the Deanship of
and potently neutralize VEGF, thereby decreasing and slowing tumor Scientific Research at King Khalid University for funding
growth (Figure 10). this work through Research Group (Small) (project number
RGP.1/330/42). All the authors of this manuscript are thankful
to their respective Departments/Universities for successful
FUTURE DIRECTIONS completion of this study. The figures in this manuscript
were created with the support of https://biorender.com
C. longa entailed extensive research and development work to under a paid subscription (Ref: C08A1A0B-0002; 3
fully exploit its medicinal value, and efforts should be made to November 2021).

Alambra, J. R., Alenton, R. R. R., Gulpeo, P. C. R., Mecenas, C. L., Miranda, A. P.,
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