ArticlePDF AvailableLiterature Review


Curcumin, a natural polyphenolic and yellow pigment obtained from the spice turmeric, has strong antioxidative, anti-inflammatory, and antibacterial properties. Due to these properties, curcumin has been used as a remedy for the prevention and treatment of skin aging and disorders such as psoriasis, infection, acne, skin inflammation, and skin cancer. Curcumin has protective effects against skin damage caused by chronic ultraviolet B radiation. One of the challenges in maximizing the therapeutic potential of curcumin is its low bioavailability, limited aqueous solubility, and chemical instability. In this regard, the present review is focused on recent studies concerning the use of curcumin for the treatment of skin diseases, as well as offering new and efficient strategies to optimize its pharmacokinetic profile and increase its bioavailability.
Received: 23 February 2018
Accepted: 28 June 2018
DOI: 10.1002/jcp.27096
Evidence of curcumin and curcumin analogue effects in skin
diseases: A narrative review
Yunes Panahi
Omid Fazlolahzadeh
Stephen L. Atkin
Muhammed Majeed
Alexandra E. Butler
Thomas P. Johnston
Amirhossein Sahebkar
Chemical Injuries Research Center, Systems
Biology and Poisonings Institute, Baqiyatallah
University of Medical Sciences, Tehran, Iran
Department of Chemistry, Faculty of Science,
K. N. Toosi University of Technology, Tehran, Iran
Weill Cornell Medicine Qatar, Doha, Qatar
Sabinsa Corporation, East Windsor, New Jersey
Life Sciences Research Division, AntiDoping
Laboratory Qatar, Doha, Qatar
Division of Pharmaceutical Sciences, School
of Pharmacy, University of MissouriKansas
City, Kansas City, Missouri
Biotechnology Research Center, Pharmaceutical
Technology Institute, Mashhad University of
Medical Sciences, Mashhad, Iran
Neurogenic Inflammation Research Center,
Mashhad University of Medical Sciences,
Mashhad, Iran
School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran
Omid Fazlolahzadeh, Department of Chemistry,
Faculty of Science, K. N. Toosi University of
Technology, 163151618, Tehran, Iran.
Amirhossein Sahebkar, Department of Medical
Biotechnology, School of Medicine, Mashhad
University of Medical Sciences, Mashhad
9177948564, Iran.
Curcumin, a natural polyphenolic and yellow pigment obtained from the spice turmeric, has
strong antioxidative, antiinflammatory, and antibacterial properties. Due to these
properties, curcumin has been used as a remedy for the prevention and treatment of
skin aging and disorders such as psoriasis, infection, acne, skin inflammation, and skin
cancer. Curcumin has protective effects against skin damage caused by chronic ultraviolet
B radiation. One of the challenges in maximizing the therapeutic potential of curcumin is its
low bioavailability, limited aqueous solubility, and chemical instability. In this regard, the
present review is focused on recent studies concerning the use of curcumin for the
treatment of skin diseases, as well as offering new and efficient strategies to optimize its
pharmacokinetic profile and increase its bioavailability.
curcumin, dermatology, inflammation, skin, topical use
J Cell Physiol. 2018;114. © 2018 Wiley Periodicals, Inc.
Abbreviations: 5LOX, 5lipoxygenase; AAPK, autophosphorylationactivated protein kinase; AATF1, arylamine Nacetyltransferases 1; AHR, aryl hydrocarbon receptor; AP1, activating
protein 1; AR, androgen receptor; Bcl2, Bcell lymphoma protein 2; Ca
PK, Ca
dependent protein kinase; CKCR4, chemokine (CXC motif) receptor 4; COX2, cyclooxygenase 2; CREBBP,
CREBbinding protein; CTGF, connective tissue growth factor; DFF40, DNA fragmentation factor 40 kDa subunit; DNA Pol, DNA polymerase; DR5, death receptor 5; EGF, epidermal growth
factor; EGFR, EGF receptor; EGFRK, EGF receptor kinase; ELAM1, endothelial leukocyte adhesion molecule 1; EPCR, endothelial protein C receptor; ERE, electrophile response element; ERK,
extracellular receptor kinase; ERα, estrogen receptorα; FAK, focal adhesion kinase; FGF, fibroblast growth factor; FPT, farnesyl protein transferase; FR, Fas receptor; GCL, glutamyl cysteine
ligase; GST, gluthathioneStransferase; H2R, histamine (2) receptor; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; HIF1, hypoxiainducible factor 1; HO,
hemeoxygenase 1; HSP70, heatshock protein 70; IAP1, inhibitory apoptosis protein 1; ICAM1, intracellular adhesion molecule 1; IL1, interleukin 1; IL12, interleukin 12; IL18, interleukin
18; IL1R AK, IL1 receptorassociated kinase; IL2, interleukin 2; IL5, interleukin 5; IL6, interleukin 6; IL8 R, interleukin 8 receptor; IL8, interleukin 8; iNOS, inducible nitric oxide synthasel;
IR, integrin receptor; JAK, janus kinase; JNK, cjun Nterminal kinase; LDLR, low density lipoproteinreceptor; MaIP, macrophage inflammatory protein; MAPK, mitogenactivated protein
kinase; MCP, monocyte chemoattractant protein; MDRP, multidrug resistance protein; MIP, migration inhibition protein; MMP, matrix metalloproteinase; NFκB, nuclear factor κlightchain
enhancer of activated B cells; NGF, nerve growth factor; NQO1, NAD(P)H: quinoneoxidoreductase 1; Nrf, nuclear factor 2related factor; ODC, ornithine decarboxylase; PAK, protamine
kinase; PCNA, proliferating cell nuclear antigen; PDGF, plateletderived growth factor; PhPD, phospholipase D; PKA, protein kinase A; PKB, protein kinase B; PKC, prorein kinase C; Pp60ctk,
pp60csrc tyrosine kinase; PPARγ, peroxisome preoliferatoractivated receptorγ; PTK, protein tyrosine kinase; Src2, Src homology 2 domaincontaining tyrosine phosphatase 2; STAT1,
signal transducers and activators of transcription 1; STAT3, signal transducers and activators of transcription 3; STAT4, signal transducers and activators of transcription 4; STAT5, signal
transducers and activators of transcription 5; TF, tissue factor; TGFβ1, transforming growth factorβ1; TMMP3, tissue inhibitor of metalloproteinase 3; TNFα, tumor necrosis factor α; uPA,
urokinasetype plasminogen activator; VCAM1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; WTG1 , Wilmstumor gene 1.
This review focuses on curcumin, the compound that imparts the yellow
color to turmeric and that is used to flavor food. For centuries, turmeric
has been used as a remedy for multiple conditions including dyspepsia,
liver disorders, flatulence, jaundice, urinary tract diseases, colds, biliary
disorders, rheumatism, sinusitis, chronic otorrhea, diabetic ulcers, cough,
and various skin conditions (Hewlings & Kalman, 2017). Turmeric
possesses more than 300 different components, including phenolic
compounds and terpenoids (B. B. Aggarwal, Yuan, Li, & Gupta, 2013).
Turmeric contains three naturally occurring curcuminoids: Curcumin or
diferuloylmethane (75%), demethoxycurcumin (20%), and bisdemethox-
ycurcumin (5%; Akbik, Ghadiri, Chrzanowski, & Rohanizadeh, 2014).
Chemically, curcumin is a lipophilic molecule (1,7bis(4hydroxy3
methoxyphenyl)1,6heptadiene3,5dione) and a natural polyphenol. Its
chemical structure includes ketoenol tautomerism (depending on
whether curcumin resides in an acidic or alkaline medium). The molecule
rapidly permeates cell membranes and acts on multiple targets in various
cellular pathways to elicit various therapeutic actions in a variety of
diseases. Due to variable efficacy and the side effect profiles of many
modern medications, it is an appropriate time to assess the therapeutic
usefulness of ancient and traditional medications, including curcumin
(Kocaadam & Sanlier, 2017). Curcumins simple molecular structure,
along with its varied therapeutic effectsanditsuseinmanydisease
conditions has attracted much attention (Cheppudira et al., 2013;
Kunnumakkara et al., 2017). Curcumin can be used as an effective
treatment in several diseases by targeting different molecular targets and
with minimal toxicity to both humans and animals (Cheppudira et al.,
2013; Kocaadam & Sanlier, 2017; Kunnumakkara et al., 2017).
Curcumin is well known to exert therapeutic effects against a variety
of pathological conditions including cancer (Iranshahi et al., 2010;
Momtazi et al., 2016; Teymouri, Pirro, Johnston, & Sahebkar, 2017),
chemotherapyinduced adverse reactions (Mohajeri & Sahebkar, 2018;
Rezaee, Momtazi, Monemi, & Sahebkar,2017),metabolicsyndrome
(Panahi et al., 2015; Panahi, Khalili, Hosseini, Abbasinazari, & Sahebkar,
2014), osteoarthritis (Panahi, Rahimnia, et al., 2014; Sahebkar & Henrotin,
2016), dyslipidemias (Cicero et al., 2017; Ganjali et al., 2017; Sahebkar,
2014; Sahebkar et al., 2016; SimentalMendia et al., 2017), diabetes
(Hajavi et al., 2017; Panahi et al., 2017, 2018), nonalcoholic fatty liver
disease (Rahmani et al., 2016), endothelial dysfunction (Karimian, Pirro,
Johnston, Majeed, & Sahebkar, 2017), hyperuricemia (Panahi et al., 2016),
respiratory diseases (Lelli, Sahebkar, Johnston, & Pedone, 2017; Panahi,
Ghanei, Bashiri, Hajihashemi & Sahebkar, 2015; Panahi, Ghanei,
Hajhashemi & Sahebkar, 2016), and autoimmune diseases (Abdollahi,
Momtazi, Johnston, & Sahebkar, 2018; MomtaziBorojeni et al., 2018).
According to the literature, turmeric has been orally and topically used in
the prevention and treatment of skin diseases, which include parasitic
skin infections, infected wounds, premature aging, inflammation, and
psoriasis (Vaughn, Branum, & Sivamani, 2016).
Skin is the largest organ of the human body and is responsible for
covering, separating, and protecting the body from the external
environment, receiving sensory stimuli, and regulating body
temperature. Premature aging of the skin may be related to extrinsic
factors and personal lifestyle choice such as smoking, solar radiation
exposure, low air humidity, poor diet, and excess alcohol intake, as
well as systemic diseases such as diabetes mellitus. According to the
literature, curcumin possesses significant therapeutic effects for
various skin conditions, including antiinflammatory properties (B. B.
Aggarwal et al., 2013), ultraviolet (UV) protection (H. Li et al., 2016),
antioxidant effects (Xie et al., 2015), chemopreventive and che-
motherapeutic activity (Jiang, Jiang, Li, & Zheng, 2015; Lelli, Pedone,
& Sahebkar, 2017; Qiu et al., 2014; Toden et al., 2015), wound
healing benefits (Akbik et al., 2014), and antimicrobial effects (Krausz
et al., 2015). Due to its freeradical scavenging and antiinflammatory
properties, topical application of curcumin has allowed new
therapeutic avenues for wound healing, protection against oxidative
skin damage, skin cancer treatment (Qiu et al., 2014), control of pain
resulting from dermal burns (J. Kim et al., 2016; Mehrabani et al.,
2015), androgendependent skin disorders (Liao et al., 2001), and
decreasing skin irritation and reducing the symptoms of autoim-
munerelated skin disorders such as psoriasis (Kang et al., 2016).
However, recent studies have highlighted curcumins poor
bioavailability, low aqueous solubility, chemical instability, rapid
degradation, and rapid systemic elimination as major limitations for
its use in clinical practice (Kharat, Du, Zhang, & McClements, 2017).
This review aims to provide recent evidence for the usefulness of
curcumin in dermatology, as well as to suggest strategies to increase
its effectiveness and stability in vivo.
Exposure of human skin to solar radiation, chemical pollutants, and
mechanical stress results in the generation of free radicals. Free
radicals, like reactive oxygen species (ROS), are unstable chemical
entities that are highly reactive, cause skin damage through
inflammation, and may result in skin cancer. The resultant destruc-
tion of proteins, collagen, and elastic fibers is reflected in the signs of
skin aging (Poljsak & Dahmane, 2012). Antioxidants are compounds
that are protective by quenching free radical activity. The antioxidant
system in the skin includes superoxide dismutases (SOD), catalases,
and peroxidases (seleniumdependent glutathione peroxidases [GPx],
for example). Aging and prolonged exposure to ROSgenerating
factors, which include poor nutrition, alcohol intake, UV radiation,
stress, and environmental pollution, result in ROS accumulation,
which in turn damages the skin (Lee et al., 2013).
While most of the antioxidants have either a phenolic functional
group or adiketone group, there are different functional groups including
the Bdiketo group, carboncarbon double bonds, and phenyl rings
containing varying amounts of hydroxyl and methoxy entities that make
curcumin a unique and potent antioxidant. Curcumins antioxidant
activity is attributed to its diketone and phenol moieties (diferuloyl
methane portion of the molecule), which are free radical quenchers (Lee
et al., 2013). Masuda et al. (2001) proposed that the antioxidant
mechanism of curcumin includes an oxidative coupling reaction at the 3ʹ
position of the curcumin structure with lipid and a subsequent
intramolecular DielsAlder reaction. Curcumin functions as a mediator
in the regulation of genes related to the generation of proteins with
antioxidant characteristics such as heme oxygenase1, transcription and
growth factors, and inflammatory cytokines (Kou et al., 2013; OToole
et al., 2016). Curcumin also regulates antioxidant enzymes, scavenges
hyperglycemiainduced ROS, and profoundly increases the intracellular
antioxidant, reduced glutathione (GSH), which serves to decrease lipid
peroxidation. Studies have also shown strong protective effects of
curcumin against damage to the keratinocytes and fibroblasts in the skin
induced by H
(Phan, See, Lee, & Chan, 2001). Tetrahydrocurcumi-
noids obtained by hydrogenating cucuminoids (Prakash & Majeed, 2009)
are one of the major colorless metabolites of curcumin, in the form of its
glucuronide conjugate in bile. This conjugate compound has been shown
to have enhanced antioxidant properties with superior free radical
scavenging, free radical formation prevention, and increased lipid
peroxidation inhibition compared to curcumin and vitamin E (Prakash &
Majeed, 2009).
Therefore, the literature suggests that curcumin and its deriva-
tives may be promising and effective antioxidants that can be used
both orally and topically.
Acute and chronic inflammation are part of the bodys defense
mechanisms and involve immune cells, blood vessels, and molecular
mediators in response to harmful stimuli such as pathogens or
irritants. Pain, redness, immobility, swelling, and heat are the
hallmark signs of skin inflammation. Cytokines and hormonelike
polypeptide mediators like tumor necrosis factor α(TNFα, a key
proinflammatory cytokine) induce proinflammatory cytokines such as
interleukins 1, 6, 8, 10, and 21 and result in the activation of nuclear
factor κlightchainenhancer of activated B cells (NFκB), cJun
terminal kinase, and mitogenactivated protein kinase (MAPK)
in the skin. These factors play a major role in the pathogenesis of
many inflammatory skin diseases and in the immunoregulatory
responses. Most inflammatory skin disorders are associated with
the overproduction of cytokines, dysregulation of cytokines, or
alterations in cytokine receptors (Figure 1).
Curcuminsantiinflammatory properties have been unequivocally
established (R. Agrawal, Sandhu, Sharma, & Kaur, 2015; Koop, de Freitas,
de Souza, Savi, & Silveira, 2015) in several different organs such liver and
skin through modulation of autoimmune disease and prevention of injury
to these organstissues (R. Agrawal et al., 2015). The primary mechanism
by which curcumin modulates inflammation is by reducing the expression
of the two main cytokines that are released by monocytes and
macrophages (Figure 1; Akbik et al., 2014; Kang et al., 2016). These
molecules are interleukin 1 (IL1) and TNFα, which have important roles
in the regulation of the inflammatory response. Also, curcumin inhibits
the activity of the proinflammatory transcriptional factor, NFκB, which is
responsible for the regulation of many genes involved during the initial
onset of the inflammatory response. A variety of kinases (AKT, PI3K, and
IKK) activate NFκB (Jagetia & Rajanikant, 2015). Suppression of NFκB
activation causes downregulation of cyclooxygenase2andinducible
nitric oxide synthase, and prevents upregulation of vascular endothelial
FIGURE 1 Activation of NFκB plays a
major role in the pathogenesis of many
inflammatory skin diseases. NFκB: nuclear
factor κlightchainenhancer of activated
B cells [Color figure can be viewed at]
growth factor (VEGF) messenger RNA and microvascular angiogenesis
during inflammatory conditions. Curcuminsantiinflammatory actions
can be utilized to control inflammation of the skin resulting from different
skin diseases. For example, Arunraj et al. (2014) studied the anti
inflammatory actions of curcumin and curcumin nanospheres (CNSs) to
prevent denaturation of bovine serum albumin and compared it with
diclofenac sodium (a nonsteroidal antiinflammatory drug) both in vitro
and ex vivo. The results of in vitro stability testing for heattreated
albumin at physiological pH showed that CNSs had a greater anti
inflammatory effect in comparison with curcumin and diclofenac across a
dose range (251,000 μg/ml).
Skin is an essential protective organ for the body against the
environment. Chronic injuries in skin cause the body to initiate a
dynamic and multistep process of repair to regain tissue integrity. Four
processes are involved during the wound healing process: hemostasis,
inflammation, proliferation, and remodeling (Hussain, Thu, Ng, Khan, &
Katas, 2017; Margolis et al., 2011). At the initiation of the injury, rapid
aggregation of platelets via hemostasis causes clot formation. Migration
of neutrophils and macrophages to the wound site and release of
cytokines, thereby promoting fibroblast migration, results in inflamma-
tion at the wound site. Reepithelialization, generation of new blood
vessels (termed angiogenesis or neovascularization), and extracellular
matrix protein deposition by fibroblasts (collagen fibers, granulation
tissue, for example) occur to protect cell ingrowth. Collagen is used as
the building block during this proliferation phase (Hussain et al., 2017;
Margolis et al., 2011). The collagen remodeling and formation of scar
tissue is the final phase of wound healing. Inflammation, part of the acute
injury response, attracts neutrophils to the injured site resulting in the
release of inflammatory mediators such as TNFαand IL1(Arunrajetal.,
2014). Neutrophils in the wound area are associated with high levels of
destructive proteases and ROS molecules, which cause inflammation and
result in tissue damage, as well as prolonging the inflammatory phase.
The ROS molecules, bacterial infection, and protracted inflammation are
the major reasons for delays in wound healing (Guo & Dipietro, 2010;
Sorg, Tilkorn, Hager, Hauser, & Mirastschijski, 2017). Therefore,
curcumins potent antioxidant, antiinflammatory, and antiinfectious
actions can play a healing role in the process of wound resolution (Akbik
et al., 2014; Mohanty & Sahoo, 2017). Topical application of curcumin
has been shown to promote reepithelialization in burn wound areas to
increase the rate of wound healing (Kulac et al., 2013; LopezJornet,
CamachoAlonso, JimenezTorres, OrdunaDomingo, & GomezGarcia,
2011). Clinical studies have indicated an increased rate of epidermal
growth, increased thickness of the cuticular layer, and significant
improvement in wound healing in curcumintreated subjects when
compared to untreated subjects (Kulac et al., 2013; J. Li, Chen, & Kirsner,
2007; Wen, Wu, Chen, Yang, & Fu, 2012).
Kulac et al. (2013) reported that topical treatment with curcumin at a
concentration of 100 mg/kg body weight on burn wound healing in rats
enhanced the healing process compared to the control group, with a
decrease in inflammatory cells, and enhanced collagen deposition,
angiogenesis, granulation tissue formation, and epithelialization. Castan-
gia et al. (2014) used curcumin nanovesicles for wound healing in chronic
cutaneous pathologies in both in vivo and in vitro studies. They showed
that nanoentrapped curcumin prevented the formation of skin lesions
and inhibited the biochemical processes that normally lead to epithelial
damage. Based upon epidemiological evidence, they recommended the
daily topical application of curcuminloaded nanovesicles for patients at a
higher risk of skin wound infection to afford better protection. Using
liposomes and penetration enhancer-containing vesicles (PEVs) showed
an additional benefit by enhancing skin penetration. Krausz et al. (2015)
showed that topical use of curcuminencapsulated nanoparticles in an in
vivo murine wound model enhanced granulation tissue, reepithelializa-
tion and decreased wound area after 14 days of treatment leading to
improved wound healing. The results showed statistically significant
acceleration of wound healing in mice treated with curcuminencapsu-
lated nanoparticles (curcnp) compared to untreated, silver sulfadiazine,
coconut oil, control, control np, and curcumin (curc). Topical curcumin
used in breastfeeding women suffering lactationinduced mastitis showed
that curcumin effectively decreased mastitisrelated pain, breast tender-
ness, and erythema. This reduction in inflammation occurred within 72 hr
of administration without any side effects showing the efficacy of
curcumin in this situation (Afshariani, Farhadi, Ghaffarpasand, &
Roozbeh, 2014).
Psoriasis is an epidermal hyperproliferative and autoimmune dermal
chronic inflammatory disease caused by genetic and immunologic
factors and normally affects the skin and joints (Lowes, SuarezFarinas,
& Krueger, 2014). Psoriasis shows triggering of intraregional
Tlymphocytes that prime basal stem keratinocytes to proliferate
excessively. Enhanced cell proliferation results in an excessive buildup
of cells on the surface of the skin and rapidly forms scales and red
patches that are itchy, inflamed, and sometimes painful. External
triggers like stress, alcohol, injury, infection, and medications may
initiate new psoriasis lesions. Psoriasis initiates from the premature
maturation of keratinocytes induced by an inflammatory cascade in the
dermis by dendritic cells, macrophages, and T cells. These immune cells
move from the dermis to the epidermis and secrete inflammatory
chemical signals (cytokines) such as IL 36γ,interferonγ(IFNγ), TNFα,
IL17, IL6, IL8, and IL22, that stimulate keratinocytes to proliferate.
Consequently, skin cells are replaced every 35 days rather than the
usual 2830 days, resulting in scales on the surface of skin.
Reports suggest that the antiinflammatory effect of curcumin
may allow it to act as an antipsoriasis agent (H. Liu, Danthi, &
Enyeart, 2006; Sun et al., 2017). Some reports on the inhibitory
activity of curcumin suggest that its action on the potassium
channel subtype Kv1.3 in T cells plays a central role in psoriasis
(Kang et al., 2016; H. Liu et al., 2006). Recently, Kang et al. (2016)
showed that generation of Tcell inflammatory factors, such as
IL17, IL22, IFNγ,IL2, IL8, and TNFα,decreasedby3060% in
mice with psoriasislike diseases after 20 days of oral curcumin.
Over 50% of Tcell proliferation was interrupted by application
of a 100μM curcumin preparation, and curcumin significantly
decreased the signs of psoriasis and improved the condition of the
skin. Curcumin (10 μM) reduced the generation of inflammatory
agents (IL17, IL22, IFNγ,IL2, IL8, and TNFα)invitroin
Tcellsby3060%. Sun et al. (2017) studied different formulations
of curcumin (dose: 0.25 mg·day
) and tacrolimus (dose:
0.1 mg·day
) on the imiquimod (IMQ)induced psoriasis
like mouse model both in vitro and in vivo, compared to a placebo
vehicle as control. Their results showed that treatment using
tacrolimus and 50 nm CurNPs gel reduced the white scale
thickness and the pink hue in inflamed skin. Also, they demon-
strated that encapsulation of curcumin into a poly(lacticco
glycolic) acid (PLGA)based nanoparticlecontaining hydrogel fa-
cilitated penetration through the skin and into the circulation (Sun
et al., 2017). In fact, this formulation had a superior performance
when compared to curcumin hydrogel in this imiquimod (IMQ)
induced psoriasislike mouse model, significantly improving the
antipsoriasis activity of curcumin.
Solar radiation induces both an acute and chronic reaction in animal and
human skin. One of the most important agents causing ROS production in
the body is UVB irradiation, which causes oxidative modification of
cellular lipids, proteins, and nucleic acids and can lead to inflammation,
gene mutation, and immunosuppression (Dupont, Gomez, & Bilodeau,
2013; Natarajan, Ganju, Ramkumar, Grover, & Gokhale, 2014). High
levels of UV radiation kill most of the skin cells in the upper skin layer,
and cells that are not killed are damaged. In its mildest form, sunburn
leads to erythema on skin; however, severe sunburn may cause the skin
to blister and peel, which is not only painful but also leaves the new skin
unprotected and more prone to UV damage. Excessive UV radiation
damages the skins cellular DNA, producing genetic mutations that can
lead to precancers like actinic keratoses, and to skin cancers including
melanoma. UVB (290320 nm) radiation is highly mutagenic and
carcinogenic in animal experiments compared to UVA (320400 nm)
Recently, several research groups have studied curcumins
protective effects against skin damage caused by chronic UVB
irradiation (Khandelwal et al., 2016). They showed that curcumin
exhibited photoprotective activity against acute UVB irradiation
induced photo damage. Topical application of curcumin before
chronic UV irradiation delayed the appearance of dermal tumors,
inflammation, and skin aging. H. Li et al. (2016) demonstrated that
shortterm topical application of emulsified curcumin (2 mg/ml
curcumin was prepared in 0.5% carboxymethyl cellulose sodium
[CMCNa]) protected against acute UVB irradiationinduced
inflammation and photoagingassociated damage in mouse skin
without any adverse effects. They show that curcumin attenuated
lactate dehydrogenase release induced by acute UVB irradiation in
HaCaT cells. The photoprotective effect of curcumin can be
attributed to its antioxidant properties and inhibition of UVB
induced oxidative damage by regulating the Nrf2 signaling path-
way in mouse skin and HaCaT cells (Khandelwal et al., 2016; H. Li
et al., 2016). Curcumin inhibited the generation of metallopro-
teases and NFκB in human dermal fibroblasts, which play a key
role in UVB exposureinduced skin damage.
Chopra et al. (2016) encapsulated curcumin with a biodegradable
polymer, PLGA (150 nm size range), and termed this formulation
preparation PLGACurNPs. They studied the protective effect of
curcumin in mouse fibroblasts (NIH3T3) and human keratinocytes
(HaCaT) against UV rays in vitro. They demonstrated sustained
release of curcumin at a low level from the PLGACurNPs and
suggested that this formulation could be an effective agent to protect
skin from exposure to UV irradiation. The results of this study
suggest that slow release of curcumin from PLGACurNPs could
counteract the adverse effects of photodegradation on curcumin
formulations upon exposure to UVA and UVB irradiation. UVB
exposure can induce cyclobutane pyrimidine dimers, leading to DNA
damage and skin cancer. According to various studies, considerable
DNA damage occurred with free curcumin, whereas this was not the
case with PLGACurNPs (Chopra et al., 2016).
Preclinical studies (Elad et al., 2013; H. Kim, Park, Tak, Bu, & Kim, 2014;
Kuttan, Sudheeran, & Josph, 1987; Phillips et al., 2013, 2011) on
curcumin have established its anticancer properties in breast, cervical,
skin, and pancreatic cell lines. However, rapid systemic clearance, low
aqueous solubility, poor physicochemical stability, and low cellular
uptake have limited the applications of curcumin. Recently, use of
nanotechnology for encapsulation of curcumin has improved its
therapeutic index, delivery, and bioavailability (Mangalathillam et al.,
2012). One of the most lethal skin cancers is melanoma, a result of
carcinogenic transformation of melanocytes (the pigmentcontaining
cells of the skin). The DNA damage caused by UV light exposure is
central to the development of melanoma in people with low levels of
skin pigment (Autier & Dore, 1998). Studies showed that cytokine
expression can support the growth and metastasis of melanoma cells.
Elias et al. reported that over 80% of human melanoma cell lines
produce excessive levels of several cytokines and growth factors, such
as transforming growth factor β(TGFβ), IL8, IL6, IL1α, VEGF, platelet
derived growth factorAA, and osteopontin (OPN), that are capable of
stimulating tumor growth, invasion, and angiogenesis.
Jiang et al. (2015) studied the human melanoma cell lines A375, MV3,
and M14 and the human normal lung fibroblast cell line MRC5invitro,
and showed that the viability of melanoma cells decreased with
increasing concentrations of curcumin from 5 to 50 μm. They demon-
strated that curcumin suppresses proliferation and induces double strand
break, suppressing the activation of NFκB (involved in tumor cell
proliferation) and causing apoptosis in melanocytes. Curcumin also
suppresses Bcell lymphoma protein 2 (Bcl2) and myeloid cell leukemia1
(Mcl1) expression and upregulates the expression of Bax (a p53), which
are primary drivers for apoptosis. Following curcumin treatment, the
tbax to Bcl2 ratio increased, demonstrating that curcumin induced
apoptosis. The regulation of Bax, Bcl2, and Mcl1 expressions indicates
that mitochondrial pathways play a key role in curcumininduced
apoptosis; thus, curcumin may provide antitumor efficacy and may offer
hope to those with melanoma. Additionally, Huang et al. (1997) showed
that topical application of very low doses (13,000 nM) of curcumin on
mouse epidermis inhibited the mean values of the 12Otetradecanoyl-
phorbol13acetateinduced epidermal oxidized DNA base 5hydroxy-
methyl29deoxyuridine and, hence, tumor promotion. Jose, Labala,
Ninave, Gade, and Venuganti (2018) studied the synergistic effect of
encapsulated curcumin in 1,2-dioleoyl-3-trimethylammonium-propane
(DOTAP)based cationic liposomes, as well as complexed with signal
transducers and activators of transcription 3 (STAT3) small interfering
RNA (siRNA); they demonstrated that in an animal model of melanoma
skin cancer, liposomal encapsulation of curcumin and STAT3siRNA
significantly inhibited tumor weight and volume progression when
compared with either liposomal curcumin or STAT3 siRNA alone.
Consequently, these data suggest that curcumin may inhibit skin cancer
and may provide adjuvant therapy without side effects in skin cancer
The in vivo study on male Wistar rats (Bala et al., 2006) showed that
curcumin can significantly decrease the normal agingrelated factors such
as lipid peroxidation, lipofuscin concentration, and intraneuronal lipofus-
cin accumulation, and enhance the enzymes SOD, GPx, and Na(+), K(+)
adenosine triphosphatase. Curcumin prevents premature aging of skin by
quenching free radicals and reducing inflammation, and has antiproli-
ferative properties through inhibition of NFkB, TNFα,andMAPK
pathway inhibition, as well as suppression of TGFβ(Tsai et al., 2012).
Curcumin also partially prevents UV damage that may decrease the
development of skin tumors and be an effective factor for prevention of
premature aging (Bala et al., 2006).
Infectious diseases are a global issue and a wide range of synthetic
semisynthetic antibiotics have been developed for their treatment.
The development of multidrug resistant bacteria is an evolving health
problem and a major concern; hence, the need for new antibacterial
agents. The major drawbacks of many of these new drugs are their
expense, limited therapeutic window, mode of delivery, rapid
bacterial resistance and their side effects. Minimal or limited side
effects associated with natural products has led to an increasing
research focus to further investigate their use in this scenario.
Curcumins antimicrobial effects have been demonstrated in
several studies (Krausz et al., 2015; Luer, Troller, Jetter, Spaniol, &
Aebi, 2011). Krausz et al. (2015) studied the effect of curcnp as
antimicrobial agents on wound healing. According to this study, curc
np exhibited a significant antimicrobial effect against methicillin
resistant Staphylococcus aureus strain (MRSA) and Pseudomonas
aeruginosa (97.0% reduction of MRSA growth and 59.2% reduction
of P. aeruginosa growth by colony-forming unit (CFU) quantification)
from 8 hr onwards, in comparison to both untreated control and
control np (p0.0001). They showed that curcumin decreases the
bundling of FtsZ protofilaments (which are associated with binding
ability to the cellular proteins FtsZ32 and sortase A). As a result,
cytokinesis and cellular adhesion are interrupted, which also
interferes with the formation of a biofilm. Curcumins antibacterial
mechanisms involve suppression of bacterial cell proliferation due to
the inhibition of assembly dynamics of FtsZ (FtsZ polymerization) in
the Zring, which subsequently leads to interruption of prokaryotic
cell division. Also, Tortik, Steinbacher, Maisch, Spaeth, & Plaetzer
(2016) showed that curcumin has high photo killing efficiency against
microorganisms and a high photobleaching effect using a photo-
dynamic inactivation technique. This technique combines a harmless
visible light and a photosensitizer to kill pathogens through ROS
generation. Natural photoactive compounds, like curcumin, are cost
effective and provide excellent biocompatibility for most conceivable
applications. Consequently, the photosensitivity of human skin due to
prolonged exposure is decreased. According to several studies, it is
notable that the antibacterial effect of curcumin is greater against
Grampositive rather than Gramnegative species (due to less
interaction with Gramnegative bacterial cell membranes; Afshariani
et al., 2014; Bhawana, Basniwal, Buttar, Jain, & Jain N., 2011; Krausz
et al., 2015; Luer et al., 2011; Tortik et al., 2016). To increase the
antimicrobial effect of curcumin on Gramnegative species like
Escherichia coli, Tortik et al. (2016) added calcium chloride to increase
permeability of the Gramnegative bacterial cell membranes.
Curcumin can also work synergistically with antibiotics (Bhawana
et al., 2011; Mun et al., 2013), such as penicillin, ampicillin, oxacillin,
and norfloxacin, against the MRSA. Curcumins poor solubility in
water can be improved by the preparation of polyvinylpyrrolidone
curcumin (Tortik et al., 2016), which is efficacious against liquid
cultures of Grampositive S. aureus as well as Gramnegative E. coli
after in vitro permeabilization is enhanced with the inclusion of
. Izui et al. (2016) studied the effect of curcumin against
homotypic and heterotypic biofilm formation. Their results showed
that curcumin prevented Porphyromonas gingivalis OMZ314 homo-
typic biofilm formation and that this effect was dosedependent,
inhibition surpassing 70% and 80% using 10 and 20 μg/ml of
curcumin, respectively. The effect of curcumin in preventing the
formation of heterotypic biofilm formation using P. gingivalis
OMZ314 and Streptococcus gordonii G9B showed curcumins inhibi-
tion of heterotypic biofilm formation was again dosedependent,
curcumin inhibiting biofilm formation by 55%, 80%, and 90% using
5, 10, and 20 μg/ml, respectively. Consequently, the antiinfective
properties of curcumin make it a promising natural agent for wound
healing, acne treatment and treatment of skin infections.
Acne vulgaris is a longterm and cutaneous pleomorphic skin
disease of the pilosebaceous unit involving abnormalities in
TABLE 1 Studies of curcumins effects in dermatological diseasesIn vivo
application Formulation Test model
Duration of
treatment References
2 mg/ml curcumin in 0.5%
CMCNa (topical) 10 mM for the
treatment of HaCaT cells
Hairless mice and HaCaT
In vivo, in vitro 14
days; 24 hr
Curcumin is an active agent for
preventing and treating UV radiation
induced acute inflammation and
photoaging due to antioxidant defenses
and inhibition of oxidative damages via
regulating Nrf2 signaling pathway
H. Li et al. (2016)
1030 μM curcumin Human foreskin (human
dermal fibroblasts)
In vitro 24 hr Curcumin inhibit the UVBinduced
expression of MMPs and blocks ROS
production and the MAPK/NFjB/AP1
signalling pathway in human dermal
fibroblasts (HDFs). Therefore, an
effective therapeutic candidate for
preventing and treating of skin
Phillips et al. (2013)
10 μmol/L curcumin Murine epidermal In vitro 24 hr Prevent UVBinduced both mTOR and
FGFR2 signaling potentially leading to
a new therapeutic candidate for
advanced cancer with dual pathway
et al. (2016)
Skin cancer
25 μM curcumin Melanoma cell culture In vitro 24 hr Curcumininduced melanoma cell
death by associated with mPTP
Qiu et al. (2014)
15 mg/100 µl (topical and oral) SKH1 hairless mice In vivo Curcumin inhibits UV radiation
induced skin cancer and prolong time
to tumor onset
Phillips et al. (2013)
0.02% wt/wt (oral) Mouse In vivo 114 weeks Curcumin present high
anticarcinogenic activity in skin
cancer through the inhibition of IGF1
H. Kim et al. (2014)
5 and 15 mg/day (oral) SCID mice In vivo 24 days Curcumin inhibit skin squamous cell
carcinoma growth and blocks tumor
progression by inhibiting pS6 and
mTOR pathway
Phillips et al. (2011)
0.11.0 mg/ml CCNGs Human melanoma cell,
human dermal fibroblast,
and porcine skin
In vitro 624 hr Effective transdermal penetration of
CCNGs could leading to specific
advantage for the treatment of
et al. (2012)
Curcumin nanoniosome gel
(3.15 ± 0.086 drug loading;
Swiss albino mice In vivo 7 weeks Effective transdermal penetration of
curcumin nanoniosome significantly
inhibit proliferation of squamous cell
carcinoma in DMBAtreated animals
R. Agrawal
et al. (2015)
TABLE 1 (Continued)
application Formulation Test model
Duration of
treatment References
Antimicrobial 0.00030.0004 g/L curcumin
loaded nanocubosomal hydrogel
Escherichia coli In vitro 24 hr Enhance bioavailability of curcumin
able to increase curcumin
antibacterial activity in topical drug
et al. (2014)
50 or 100 μM curcuminbound to
Staphylococcus aureus,E. coli Ex vivo
(porcine skin
24 hr Increase water solubility of curcumin
and highly efficient against S. aureus
an antibacterial against E. coli
Tortik et al. (2016)
510 mg/ml curcumin
encapsulated nanoparticles
Pseudomonas aeruginosa,
methicillinresistant S.
aureus strain
In vitro 24 hr Inhibit growth of Grampositive and
Gramnegative organisms
Krausz et al. (2015)
100400 μg/ml curcumin
S. aureus, Bacillus subtilis, E.
coli, P. aeruginosa,
Penicillium chrysogenum,
Aspergillus niger
In vitro 24 hr Higher aqueous solubility and more
effective antimicrobial activity of
curcumin nanoparticle compare to
et al. (2011)
7250 μg/ml curcumin S. aureus In vitro 24 hr Curcumin has synergistic effect in
combination with antibiotics
Mun et al. (2013)
Wound healing 2 g/L curcumin in chloroform
including dissolved
polyvinylpyrrolidone and ethyl
cellulose (topical)
Rat In vivo 21 days A combination of polyvinylpyrrolidone
and ethyl cellulose significantly
improve the permeation of curcumin
transdermal patch leading to
acceleration of wound healing and
Gadekar, Saurabh,
Thakur, and
Saurabh (2012)
Curcumin cream (200 mg per
pump; topical)
Breastfeeding women with
lactational mastitis
Clinical 72 hr Topical application of curcumin
significantly decrease the signs of
lactational mastitis such as pain,
breast tension, and erythema
et al. (2014)
2% concentration curcumin
ointment (topical)
Rat In vivo 21 days A decrease in size of the burn wounds
and a reduction in inflammation after
14th day
et al. (2015)
200 mg/cm
of curcumin (topical) Minipig In vivo 35 days Reduce expression of cyclooxygenase
2 and NFkB, and decrease the
epithelial desquamation lead to
stimulation of wound healing
J. Kim et al. (2016)
10 mg/ml quercetin and curcumin
loaded phospholipid liposome
nanovesicles (topical)
Newborn pig skin, mice In vitro, in vivo 1 day,
4 days
Increase drug bioavailability and
prevent the formation of skin lesion
et al. (2014)
100 mg/kg body weight (topical) Wistaralbino rats In vivo 12 days Rise in the hydroxyproline levels and
expression of PCNA in skin
tissuesbytopical application of
curcumin leading much faster wound
et al. (2011)
TABLE 1 (Continued)
application Formulation Test model
Duration of
treatment References
Encapsulated curcumin loaded in
polymeric micelles in thermo
sensitive hydrogel composite
SpragueDawley albino rat In vivo 7 days Very good wound healing activity
present in both linear incision and
fullthickness excision wound model
in rats
Krausz et al. (2015)
Curcuminloaded hydrogel of
xanthan and galactomannan
Rat In vitro, in vivo 12 hr,
21 days
Curcumin loaded into xanthan
galactomannan hydrogels present
good skin permeation and topical
inflammation inhabitor
Koop et al. (2015)
2 g/L of curcuminloaded vesicular
system (topical)
Female Laca mice and male
Wistar rats
Ex vivo, in vitro 24 hr Improve the skin permeability of
curcumin and bioavailability leading
to significant inflammatory
R. Agrawal
et al. (2015)
0.145% wt/wt nanocurcumin gel
Wistar rat In vivo 12 days High shelf life and effective anti
AlRohaimi (2015)
40 mg/kg curcumin (oral) Mice In vivo 20 days Depress expression of cytokines and
Tcell proliferation though Kv1.3
channelinhabitation lead to a great
therapeuticeffect without obvious
side effects.
Kang et al. (2016)
Tablets containing 100 mg of
standardized Curcuma longa
extract with 12 mg of curcumin
per tablet (oral)
Patient male and female Clinical 75 days Combination of the oral curcuma
extract and UVA or visible light
irradiation improve treatment rate of
moderatetosevere plaque psoriasis
et al. (2015)
10 μM of curcumin (oral) Mouse In vivo 20 days Significantly inhibited secretion of
inflammatory factors including
interleukins, TNFαin T cells and a
great potential to treat psoriasis
without toxicity to kidney
Kang et al. (2016)
Encapsulation of curcumin in poly
(lacticcoglycolic acid)
nanoparticles (topical)
Mice In vivo 7 days Significantly increase curcumin
dispersion, sustainedrelease,
accumulation, skin penetration and
entrance the blood circulation, which
improves antipsoriasis activity
Sun et al. (2017)
sebum production that occurs when hair follicles are clogged with
dead skin cells and oil from the skin. Five important factors in the
pathophysiology of acne generation are (a) excess sebum
secretion from sebaceous glands, (b) bacterial infection (Propio-
nibacterium acnes), (c) follicular epidermal hyperproliferation, (d)
inflammation, and (e) genetics (Beylot et al., 2014; Williams,
Dellavalle, & Garner, 2012). Different gene candidates have been
proposed, including certain variations in TNFα,IL1α,and
CYP1A1 genes, among others. Acne can create either nonin-
flammatory or inflammatory lesions, mostly affecting the face but
also the back and chest. Although the use of antibiotics is a
currently acceptable method to treat acne, the side effects of
antibiotics and development of antibiotic resistance in Staphylo-
coccus epidermidis demonstrates the need for nontraditional
antimicrobial agents in the treatment of acne vulgaris.
Curcumins antiinflammatory and antimicrobial properties make
it an ideal candidate for acne treatment. C. H. Liu & Huang (2012)
developed a curcuminloaded myristic acid microemulsion which was
shown to be an excellent vehicle for delivering curcumin and
inhibiting S. epidermidis (a bacteria involved in acne). Thus, curcumin
is a promising therapeutic agent for the topical treatment of acne
vulgaris. Also, in other studies by C. H. Liu & Huang (2013)), an
emulsion of curcuminloaded lauric acid lipid vehicles showed
antibacterial activity against propionibacteria species (the primary
agent involved in inflammatory acne). The effectiveness of this
emulsion was considerably increased by the nanosized vehicle due to
enhanced effective contact with the bacteria and increased cell
membrane penetration.
In spite of these numerous advantages, the limitations to the use of
curcumin, which include bioavailability challenges, low stability, low
skin penetration, limited water solubility, and instability following
exposure to light in the UVvisible range, has meant that this
bioactive compound has found limited use as a pharmaceutical
ingredient (Jafari, Sabahi, & Rahaie, 2016; Liang, Friedman, &
Nacharaju, 2017). Notably, reports (Arunraj et al., 2014) have
shown that curcumins antioxidant and antiinflammatory proper-
ties are not only decreased following light exposure but, in
addition, it can induce oxidative stress, apoptosisnecrosis, cell
injury, and cell death. In fact, the phototoxic and photosensitizing
effects of crude curcumin are controversial. According to the
literature (Mondal, Ghosh, & Moulik, 2016), the absorption spectra
of curcumin falls in the UVvisible range, indicating its photo-
degradability. Additionally, poor bioavailability of curcumin (W. Liu
et al., 2016; Prasad, Tyagi, & Aggarwal, 2014) makes it a class II
drug in the biopharmaceutics classification system. In the last
couple of decades, nanotechnology has been used to increase the
stability of drugs, decrease side effects, and improve their delivery
(Arunraj et al., 2014; Rachmawati, Budiputra, & Mauludin, 2015).
Recently, to overcome some of the limitations of curcumin,
TABLE 1 (Continued)
application Formulation Test model
Duration of
treatment References
Acne treatment 0.43 µg/ml of Curcumin Pig skin In vitro 24 hr Combined curcuminlauric acid in the
nanosized vehicles significantly inhibit
the growth of Propionibacterium acnes
and present a treatment of acne
C. H. Liu and
Huang (2013)
100 mg/kg curcumin (oral) Mouse In vivo 20 days Significant raise the glutathione
concentration and activities of GPx
and SOD enzymes in skin, whereas
lipid peroxidation declined
significantly meaning to antioxidant
status of Curcumin
Jagetia and
Rajanikant (2015)
Note.AP1: activating protein 1; CCNG: curcuminloaded chitinnanogel; DMBA: 7,12Dimethylbenz[a]anthracene; FGFR2: Fibroblast growth factor receptor 2; GPx: glutathione peroxidase; IGF1: Insulinlike
growth factor 1; MAPK: mitogenactivated protein kinase; mPTP: 1methyl4phenyl1,2,3,6tetrahydropyridine; mTOR: mammalian target of rapamycin; NFkB: nuclear factor κlightchainenhancer of
activated B cells; PCNA: proliferating cell nuclear antigen; ROS: reactive oxygen species; SOD: superoxide dismutase; TNFα: tumor necrosis factor α; UVB: ultraviolet B.
different curcumin encapsulated formulations on a nanosize
and microsize scale, including liposomesphospholipid (Manconi
et al., 2017), nanogels (Mangalathillam et al., 2012), monooleine
aqueous dispersion (Puglia et al., 2013), nanostructured lipid
carriers (Chanburee & Tiyaboonchai, 2017), nanoemulsions (Kumar
et al., 2016), polymeric micelles (M. Li et al., 2016) and polymeric
nanoparticles (Yin, Zhang, Wu, Huang, & Chen, 2013), elastic
vesicular systems (R. Agrawal et al., 2015), and lamellar and
hexagonal mesophases (FonsecaSantos, Dos Santos, Rodero,
Gremiao, & Chorilli, 2016) have been investigated and have
demonstrated improved aqueous solubility, bioavailability, and
increased targeting potential. Additionally, continuous, lowlevel
release of curcumin from encapsulated formulations should protect
encapsulated compounds (including curcumin) from airinduced
oxidation and may afford longterm activity and stability. As an
example, AlRohaimi (2015) has shown that the permeation rate,
drug release parameters, shelflife, and antiinflammatory activity
of curcumin noticeably improved by using amorphous NanoCur as
the source of curcumin, which was then incorporated into a
nanoemulsion (o/w) using a water titration method and subse-
quently evaluated for topical drug delivery. Also, some research
groups (Jeengar, Rompicharla, et al., 2016; Jeengar, Shrivastava,
Mouli Veeravalli, Naidu, & Sistla, 2016) have introduced the use of
emu oil as a carrier for topical curcumin application due to
increased solubility and improved skin penetration, resulting in a
synergistic antiinflammatory effect. It should, however, be noted
that the use of emu oil as an antiinflammatory agent is
controversial. On the other hand, ethanol, dimethyl sulfoxide, and
propylene glycol were used as solvents for curcumin in aqueous
formulations such as curcumin gels. Menthol has been proposed as
a penetration enhancing agent in preparations of curcumin gels for
topical application due to enhanced percutaneous flux and
transdermal absorption of curcumin (Patel, Patel, & Patel, 2009).
Also, some polymers, such as carbopol, hydroxypropyl methylcel-
lulose, and sodium alginate have been introduced into formulations
to serve as gelling agents and have shown enhanced bioavailability
and dermal permeation of curcumin (Patel et al., 2009).
Curcumin exhibits a variety of important properties and holds
promise for the treatment of dermatological diseases as summarized
in Table 1. Recently, clinical research and preclinical scientific studies
have demonstrated curcumins remarkable antioxidant, antiinflam-
matory, and antibacterial activities, which can be effectively
utilized to treat acne, psoriasis, dermal wounds, sun burn, premature
aging, melanoma, and ROS agglomeration.
Finally, it would appear that the limitations of poor bioavailability
and low stability of curcumin can be overcome using nanotechnology,
including liposomesphospholipid, nanogels, nanostructured lipid
carriers, nanoemulsions, polymeric micelles, and various polymeric
nanoparticulate methods, though further studies are needed to
clarify the utility of curcumin.
The authors are thankful to the Clinical Research Development Unit
of the Baqiyatallah Hospital (Tehran, Iran).
Muhammed Majeed is the Founder and Chairman of Sabinsa
Corporation and Sami Labs Limited. For remaining authors, there
are no conflicts of interest.
Stephen L. Atkin
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How to cite this article: Panahi Y, Fazlolahzadeh O, Atkin SL,
et al. Evidence of curcumin and curcumin analogue effects in
skin diseases: A narrative review. J Cell Physiol. 2018;114.
... This natural polypheno lic compound has widely been used as a dietary pigment, spice, food preservative and medicine in China (3). According to many recent studies curcumin shows different therapeutic properties such as anti-cancer, anti-inflammatory, antioxidant and wound-healing activities (4,2,5). The beneficial effects of curcumin in cardiovascular, respiratory and neurodegenerative diseases, diabetes and metabolic syndrome is also well documented (6)(7)(8). ...
... Chemical skeleton of curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadie ne-3,5-dione] determines its lipophilic properties and the different tautomeric forms (8,4). ...
... Lipophilic properties allow this compound to cross cellular membranes easily and act on multiple targets in various cellular pathways, which plays an important role in the pharmacological and biological action of curcumin in a wide range of diseases (4). Moreover, diketone and phenol moieties (diferuloylmethane part of the molecule) have an important role in antioxidant activity of curcumin since they are free radical quenchers (11,4). ...
Curcumin is a plant‐derived yellow‐orange compound widely used as a spice, dye and food additive. It is also believed to have therapeutic effects against different disorders. On the other hand, there are data showing its phototoxicity against bacteria, fungi and various mammalian cells. Since the mechanism of its phototoxic action is not fully understood, we investigated here the phototoxic potential of curcumin in liposomal model membranes and in HaCaT cells. First, detection of singlet oxygen (1O2) luminescence proved that curcumin generates 1O2 upon blue light irradiation in organic solvent and in liposomes. Then, HPLC‐EC(Hg) measurements revealed that liposomal and cellular cholesterol is oxidized by 1O2 photogenerated by curcumin. Enrichment of liposome membranes with curcumin significantly increased the oxygen photo‐consumption rate compared to the control liposomes as determined by EPR oximetry. Cytotoxicity measurements, mitochondrial membrane potential analyzes and protein hydroperoxides detection confirmed strong phototoxic effects of curcumin in irradiated HaCaT cells. These data show that since curcumin is advertised as a valuable dietary supplement, or a component of cosmetics for topical use, caution should be recommended especially when skin is exposed to light.
... CUR has been shown to modulate signal transducers and transcription activators like JAK-STAT, Nrf2, Notch-1 and nuclear factor kappa B (NF-kB) as well as the protein kinases Akt and MAPK [16,17]. The anti-inflammatory effects of CUR are used to target and control skin inflammation in different skin diseases; its mechanism of action involves reducing the expression of cytokines released by immune cells [18]. ...
... Studies on mechanisms involved on the inhibition activity of CUR suggested a targeted action on the potassium channels of immune cells, which have a central role in chronic immune pathologies such as psoriasis [58]. For this reason, it has been suggested that CUR may be considered antipsoriatic due to these anti-inflammatory effects [18,20]. ...
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This work focuses on the development and evaluation of a dual nanostructured lipid carrier (NLC)/Carbopol®-based hydrogel system as a potential transporter for the topical delivery of curcumin to the skin. Two populations of different sized negatively charged NLCs (P1, 70–90 nm and P2, 300–350 nm) were prepared and characterized by means of dynamic light scattering. NLCs presented an ovoid platelet shape confirmed by transmission electron microscopy techniques. Curcumin NLC entrapment efficiency and release profiles were assessed by HPLC (high pressure liquid chromatography) and spectrophotometric methods. Preservation and enhancement of curcumin (CUR) antioxidant activity in NLCs (up to 7-fold) was established and cell viability assays on fibroblasts and keratinocytes indicated that CUR-NLCs are non-cytotoxic for concentrations up to 10 μM and exhibited a moderate anti-migration/proliferation effect (20% gap reduction). CUR-NLCs were then embedded in a Carbopol®-based hydrogel without disturbing the mechanical properties of the gel. Penetration studies on Franz diffusion cells over 24 h in CUR-NLCs and CUR-NLCs/gels demonstrated an accumulation of CUR in Strat-M® membranes of 22% and 5%, respectively. All presented data support the use of this new dual CUR-NLC/hydrogel system as a promising candidate for adjuvant treatment in topical dermal applications.
... Nevertheless, there are a vast number of studies conducted with curcumin to investigate anti-inflammatory, antioxidant, anti-carcinogenic, antiviral, and anti-infection activities. Owing to its antibacterial, antioxidant, anti-inflammatory, and antiseptic properties, curcumin has been proven useful in treating several skin diseases, such as psoriasis, infection, acne, skin inflammation, and skin cancer [180] . Curcumin controlled the in vitro growth of Staphylococcus aureus and Pseudomonas aeruginosa in an in vivo murine wound model, and topical administration accelerated healing [181] . ...
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The unending morbidity and mortality that results from cancer, as well as adverse reactions due to chemotherapy and the enormous economic burden of treatment and hospitalization, advocates for the necessity of chemopreventive measures. Cancer chemoprevention refers to the use of agents capable of reversing, reducing, or slowing down the pathology of cancer at various stages. Fortunately, a few therapeutic drugs with relatively low toxicity (e.g., tamoxifen, finasteride), and a sparse number of vaccines (hepatitis B, HPV), are used to prevent specific cancers. In the general population, however, therapeutic options for cancer prevention are not common. Nonetheless, it is generally agreed that diet affects the genesis of cancer, and phytochemicals have the capacity of functioning as cancer chemoprevention agents. This is supported by epidemiological studies and clearly documented with animal models designed to mimic human carcinogenesis. Additionally, some public health strategies, such as recommendations for greater consumption of fruits and vegetables, reflect the merits of cancer chemoprevention. Here, we focus on some well-established natural product cancer chemopreventive agents, including resveratrol (grapes), epigallocatechin-3-gallate (green tea), sulforaphane (cruciferous vegetables), anthocyanins (grapes and berries), curcumin (turmeric), silibinin (milk thistle), and lycopene (tomatoes). As aptly demonstrated by genomic analysis and other methods, the mechanistic underpinning is variable and complex. In addition, responses may be mediated through indirect mechanisms, such as interaction with the microbiome. Furthermore, ancillary applications of chemopreventive agents are worthy of consideration, such as management of sequelae induced by chemotherapy. Recognizing the loss of millions of cancer patients every year, it is obvious that negating malignant metastatic conditions remains of paramount importance. In meeting this objective, cancer chemoprevention offers great promise.
... There is no consensus on the definition of the best concentration of curcumin for topical treatments of skin diseases, with concentrations of curcumin ranging generally from 1% to 2% (w/w) in topical formulations. In this sense, in the research effort entertained herein, biopolysaccharide gels were produced integrating 1.0, 1.5 and 2.0% (w/w) of pure curcumin (Kim and Lio, 2020;Panahi et al., 2019;Vollono et al., 2019). The pharmaceutical form ''gel" was therefore used to evaluate the effectiveness of CAGE-IL in enhancing the delivery of curcumin via the transdermal route. ...
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The transdermal permeation of curcumin aided by choline and geranic acid ionic liquid (CAGE-IL) was addressed as a potential treatment for skin diseases. An in-depth analysis of the effect of CAGE-IL concentration in the enhancement of transdermal permeation of curcumin was performed, and the results were modelled via nonlinear regression analysis. The results obtained showed that a low percentage of CAGE-IL (viz. 2.0%, w/w) was effective in disrupting the skin structure in a transient fashion, facilitating the passage of curcumin dissolved in it.
Curcumin [1,7‐bis(4‐hydroxy‐3‐methoxyphenyl) ‐1,6‐heptadiene‐3,5‐dione] is pharmacologically active polyphenol isolated from rhizome Curcumin longa L and is a versatile molecule known for its various biological properties including anti-inflammatory, antioxidant, antibacterial, including antibacterial, anticancer, arthritis, allergies and other various chronic diseases. In recent years this compound has attracted considerable attention due to multimodal effects. In this endeavor, novel curcumin derivatives have also been synthesized and tested against different models of human disease. The current chapter is a compilation of existing information from many recent studies utilizing curcumin in various disease conditions and the new drug delivery approach to tackle bioavailability issues have also been discussed. Further the ongoing clinical studies on curcumin in various disease conditions are also reviewed in this chapter.
Practical application of versatile nanomaterials to food engineering is desirable. In this study, highly encapsulated curcumin‐loaded shellac (Cur@Lac) nanoparticles are efficiently prepared via a rotating packed bed (RPB). In this modified co‐precipitation process, the morphology of Cur@Lac nanoparticles is systematically investigated under experimental parameters involving the high‐gravity level, the volume of antisolvent and the concentration of shellac. By virtue of the highly structured polymeric ester matrices of shellac and adequate supersaturation brought from RPB on a microscale, the obtained Cur@Lac nanoparticles with uniform size exhibit high encapsulation efficiency of over 96%. After 2 months of storage at room temperature, the aqueous Cur@Lac nanodispersions exhibit long‐term stability with no agglomeration or sedimentation, and the final retention rate of curcumin was over 85%. Colored drinks of fruit syrup (pH = 4.0), fruit soda (pH = 6.0), and soda water (pH = 8.3) are prepared by using the Cur@Lac as the colorant, which possessed orange‐yellow color. The nanocomposites of alkali‐sensitive indicators based on cellulose paper and gelatin film demonstrated in the work show promising application value for sensing of alkaline solution and gas of perishable food. Curcumin‐loaded shellac nanoparticles are successfully prepared by modified co‐precipitation method in a rotating packed bed. As the amphipathic matrix, biopolymer (shellac) encapsulates a sensitive multifunctional material (curcumin) with high encapsulation efficiency and stability. The composite nanoparticles can be used as natural colorants dispersed in daily drinks and applied for sensing of alkaline solution and gas of perishable food.
Treatment of leishmaniasis by conventional synthetic compounds has faced a serious challenge worldwide. This study was performed to evaluate the effect and modes of action of aromatic Turmerone on the Leishmania major intra-macrophage amastigotes, the causative agent of zoonotic cutaneous leishmaniasis in the Old World. In the findings, the mean numbers of L. major amastigotes in macrophages were significantly decreased in exposure to Turmerone plus meglumine antimoniate (Glucantime®; MA) than MA alone, especially at 50 µg/mL.In addition, Turmerone demonstrated no cytotoxicity as the selectivity index (SI) was 21.1; while it induced significant apoptosis in a dose-dependent manner on L. major promastigotes. In silico molecular docking analyses indicated an affinity of Turmerone to IL-12, with the MolDock score of -96.8 kcal/mol; which may explain the increased levels of Th1 cytokines and decreased level of IL-10. The main mechanism of action is more likely associated with stimulating a powerful antioxidant and promoting the immunomodulatory roles in the killing of target organism.
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The rapid spread of antibiotic resistance and lack of effective drugs for treating infections caused by multi-drug resistant bacteria in animal and human medicine have forced us to find new antibacterial strategies. Natural products have served as powerful therapeutics against bacterial infection and are still an important source for the discovery of novel antibacterial drugs. Curcumin, an important constituent of turmeric, is considered safe for oral consumption to treat bacterial infections. Many studies showed that curcumin exhibited antibacterial activities against Gram-negative and Gram-positive bacteria. The antibacterial action of curcumin involves the disruption of the bacterial membrane, inhibition of the production of bacterial virulence factors and biofilm formation, and the induction of oxidative stress. These characteristics also contribute to explain how curcumin acts a broad-spectrum antibacterial adjuvant, which was evidenced by the markedly additive or synergistical effects with various types of conventional antibiotics or non-antibiotic compounds. In this review, we summarize the antibacterial properties, underlying molecular mechanism of curcumin, and discuss its combination use, nano-formulations, safety, and current challenges towards development as an antibacterial agent. We hope that this review provides valuable insight, stimulates broader discussions, and spurs further developments around this promising natural product.
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Organogels (ORGs) are remarkable matrices due to their versatile chemical composition and straightforward preparation. This study proposes the development of ORGs as dual drug-carrier systems, considering the application of synthetic monoketonic curcuminoid (m-CUR) and lidocaine (LDC) to treat topical inflammatory lesions. The monoketone curcuminoid (m-CUR) was synthesized by using an innovative method via a NbCl5–acid catalysis. ORGs were prepared by associating an aqueous phase composed of Pluronic F127 and LDC hydrochloride with an organic phase comprising isopropyl myristate (IPM), soy lecithin (LEC), and the synthesized m-CUR. Physicochemical characterization was performed to evaluate the influence of the organic phase on the ORGs supramolecular organization, permeation profiles, cytotoxicity, and epidermis structural characteristics. The physico-chemical properties of the ORGs were shown to be strongly dependent on the oil phase constitution. Results revealed that the incorporation of LEC and m-CUR shifted the sol-gel transition temperature, and that the addition of LDC enhanced the rheological G′/G″ ratio to higher values compared to original ORGs. Consequently, highly structured gels lead to gradual and controlled LDC permeation profiles from the ORG formulations. Porcine ear skin epidermis was treated with ORGs and evaluated by infrared spectroscopy (FTIR), where the stratum corneum lipids were shown to transition from a hexagonal to a liquid crystal phase. Quantitative optical coherence tomography (OCT) analysis revealed that LEC and m-CUR additives modify skin structuring. Data from this study pointed ORGs as promising formulations for skin-delivery.
Herein, a simple, novel, and cost-effective biosensor array is developed for the differentiation of carrier proteins (i.e. human serum albumin (HSA), bovine serum albumin (BSA), transferrin (TRF), immunoglobulin G (IgG), fibrinogen (Fb) and casein (Cas) based on fading nanocurcumin in alkaline solutions. We found that the carrier proteins show different inhibitory effects with diverse extents on the alkaline decomposition of nanocurcumin. In the other words, in the presence of carrier proteins, the biosensor array produces fingerprint-like absorbance patterns to identify each carrier protein. The absorbance patterns of this biosensor array can be analyzed by linear discrimination analysis (LDA) and hierarchical cluster analysis (HCA). The six carrier proteins have been well discriminated in different concentrations levels. Furthermore, complex mixtures of HSA and TRF with a total concentration of 25 µM and different mole ratios are also discriminated without errors. Also, the HSA as an example of carrier proteins has been well determined in the range of 5-75 µM. The results revealed that the biosensor array shows high selectivity to the carrier proteins in the presence of other interfering substances. The analytical performance of the biosensor array is examined by the differentiation of carrier proteins in human urine and serum biofluids. It should be noted that the biosensor array is very simple, label-free, and selective, and only restricted sensor elements are required for attaining a high differentiation capability of carrier proteins.
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Introduction Curcuminoids have been shown to reduce glycemia and related complications in diabetes. In the present study, we evaluated the impact of curcuminoids plus piperine administration on glycemic, hepatic and inflammatory biomarkers in type 2 diabetes (T2D) patients. Methods T2D patients aged 18–65 years were enrolled in a randomized double-blind placebo-controlled trial and randomly allocated to standard-of-care treatment and dietary advises plus either curcuminoids (daily dose of 500 mg/day co-administered with piperine 5 mg/day) or placebo for a period of 3 months. Glycemic, hepatic and inflammatory parameters were measured at baseline and final conditions. Results A total of 100 subjects (50 in each group) completed the 3-month period of trial. A significant reduction was found in serum levels of glucose (−9±16 mg/dL vs. −3±11 mg/dL in curcuminoids and placebo groups, respectively; p=0.048), C-peptide (−0.6±0.8 ng/mL vs. 0.02±0.6 ng/mL; p<0.001) and HbA1c (−0.9±1.1% vs. −0.2±0.5%; p<0.001) after curcuminoids supplementation versus placebo group. Additionally, participants in the intervention group showed lower serum alanine aminotransferase (−2±6 vs. −1±5; p=0.032) and aspartate aminotransferase (−3±5 vs. −0.3±4; p=0.002) levels compared with the placebo group. Finally, no significant differences in high-sensitivity C-reactive protein (hs-CRP) concentrations were observed between curcuminoids and placebo groups (p>0.05). Conclusion The results of the present trial revealed a beneficial effect of curcuminoids plus piperine supplementation on glycemic and hepatic parameters but not on hs-CRP levels in T2D patients.
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Doxorubicin (DOX)-induced toxicity and resistance are major obstacles in chemotherapeutic approaches. Despite effective in the treatment of numerous malignancies, some clinicians have voiced concern that DOX has the potential to cause debilitating consequences in organ tissues, especially the heart. The mechanisms of toxicity and resistance are respectively related to induction of reactive oxygen species (ROS) and up-regulation of ATP-binding cassette (ABC) transporter. Curcumin (CUR) with several biological and pharmacological properties is expected to restore DOX-mediated impairments to tissues. This review is intended to address the current knowledge on DOX adverse effects and CUR protective actions in the heart, kidneys, liver, brain, and reproductive organs. Coadministration of CUR and DOX is capable of ameliorating DOX toxicity pertained to antioxidant, apoptosis, autophagy, and mitochondrial permeability.
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Turmeric, a spice that has long been recognized for its medicinal properties, has received interest from both the medical/scientific world and from culinary enthusiasts, as it is the major source of the polyphenol curcumin. It aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia. It may also help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and performance in active people. In addition, a relatively low dose of the complex can provide health benefits for people that do not have diagnosed health conditions. Most of these benefits can be attributed to its antioxidant and anti-inflammatory effects. Ingesting curcumin by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. There are several components that can increase bioavailability. For example, piperine is the major active component of black pepper and, when combined in a complex with curcumin, has been shown to increase bioavailability by 2000%. Curcumin combined with enhancing agents provides multiple health benefits. The purpose of this review is to provide a brief overview of the plethora of research regarding the health benefits of curcumin.
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In recent years there has been a growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies nutraceuticals might help to obtain the theraputic lipid goals and reduce the cardiovascular residual risk. Some nutraceuticals have essential lipid lowering-properties confirmed in studies, some might have also possible positive effects on non-lipid cardiovascular risk factors and have proven to improve early markers of vascular health such as endothelial function and pulse wave velocity. However the clinical evidence supporting the use of single or a combination of lipid-lowering nutraceuticals is largely variable and for many of them very limitted and therefore often debatable. The purpose of this Position Paper is to provide consensus-based recommendations for optimal management of lipid-lowering nutraceuticals in patients with dyslipidemia still not being on statin therapy, on statin or combination therapy without lipid goals achieved, and for those with statin intolerance. This statement is intended for physicians and other health care professional that are engaged in the diagnosis and management of patients with lipid disorders, especially in the setting of primary care. Key words: dyslipidemia, lipid, nutraceuticals, position paper, recommendations.
Objective: The aim of this systematic review and meta-analysis was to determine and clarify the impact of curcuminoids on serum lipid levels. Methods: Randomized controlled trials (RCTs) investigating the effects of curcuminoids on plasma lipids were searched in PubMed-Medline, Scopus, Web of Science databases (from inception to April 3rd, 2017). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on lipid concentrations. Results: A meta-analysis of 20 RCTs with 1427 participants suggested a significant decrease in plasma concentrations of triglycerides (WMD: -21.36 mg/dL, 95% CI: -32.18, -10.53, p < 0.001), and an elevation in plasma HDL-C levels (WMD: 1.42 mg/dL, 95% CI: 0.03, 2.81, p = 0.046), while plasma levels of LDL-C (WMD: -5.82 mg/dL, 95% CI: -15.80, 4.16, p = 0.253) and total cholesterol (WMD: -9.57 mg/dL, 95% CI: -20.89, 1.75, p = 0.098) were not altered. The effects of curcuminoids on lipids were not found to be dependent on the duration of supplementation. Conclusion: This meta-analysis has shown that curcuminoid therapy significantly reduces plasma triglycerides and increases HDL-C levels.
Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune complexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1 (Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory effects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant cytokines that participate in SLE.
Oxidative damage and inflammation have been identified, through clinical and preclinical studies, as the main causes of nonhealing chronic wounds. Reduction of persistent chronic inflammation by application of antioxidant and anti-inflammatory agents such as curcumin has been well studied. However, low aqueous solubility, poor tissue absorption, rapid metabolism and short plasma half-life have made curcumin unsuitable for systemic administration for better wound healing. Recently, various topical formulations of curcumin such as films, fibers, emulsion, hydrogels and different nanoformulations have been developed for targeted delivery of curcumin at wounded sites. In this review, we summarize and discuss different topical formulations of curcumin with emphasis on their wound-healing properties in animal models.
The aim of the present study was to evaluate the effectiveness of iontophoretic co-delivery of curcumin and anti-STAT3 siRNA using cationic liposomes against skin cancer. Curcumin was encapsulated in DOTAP-based cationic liposomes and then complexed with STAT3 siRNA. This nanocomplex was characterized for the average particle size, zeta-potential, and encapsulation efficiency. The cell viability studies in B16F10 mouse melanoma cells have shown that the co-delivery of curcumin and STAT3 siRNA significantly (p < 0.05) inhibited the cancer cell growth compared with either liposomal curcumin or STAT3 siRNA alone. The curcumin-loaded liposomes were able to penetrate up to a depth of 160 μm inside the skin after iontophoretic (0.47 mA/cm²) application. The in vivo efficacy studies were performed in the mouse model of melanoma skin cancer. Co-administration of the curcumin and STAT3 siRNA using liposomes significantly (p < 0.05) inhibited the tumor progression as measured by tumor volume and tumor weight compared with either liposomal curcumin or STAT3 siRNA alone. Furthermore, the iontophoretic administration of curcumin-loaded liposome-siRNA complex showed similar effectiveness in inhibiting tumor progression and STAT3 protein suppression compared with intratumoral administration. Taken together, cationic liposomes can be utilized for topical iontophoretic co-delivery of small molecule and siRNA for effective treatment of skin diseases.
Curcumin, the bioactive component of turmeric, has been used for the treatment of several diseases including diabetes and its complications. Curcumin has been shown to exert pleiotropic effects by modulating different signaling molecules, including transcription factors, chemokines, cytokines, and adipokines. Disturbed regulation of adipokines, which include adiponectin, leptin, resistin, and visfatin, are implicated in the development of insulin resistance and Type 2 Diabetes. Here, we review the findings of in vitro, in vivo, and clinical studies on the modulating effects that curcumin treatment exerts on adipokines. Additionally, we examine the potential beneficial effects of the activity of curcumin in the prevention and treatment of diabetes and its comorbidities.
Aiming at improving the nebulization performances and lung antioxidant protection of curcumin, chitosan or hyaluronan-coated liposomes were prepared and their characteristics and performances were compared with that of uncoated liposomes. Curcumin loaded liposomes displayed a diameter lower than 100 nm, the coating with both polymers led to a small increase of vesicle size around 130 nm and the zeta potential turned to positive values using chitosan while remained negative using hyaluronan. Chitosan allowed the formation of more lamellar and stiffer vesicles with a higher bilayer thickness (dB ∼ 59 Ǻ) with respect to the uncoated liposomes, whereas hyaluronan allowed the interdigitation of the bilayers (dB ∼ 47 Ǻ) due to the polymer intercalation between phospholipid head groups resulting in vesicles mainly organized in uncorrelated bilayers. Both polymer coatings, especially hyaluronan, greatly improved the stability of the vesicles, especially during the nebulization process, promoting the deposition of the phytodrug in the furthest stages of the impactor in high amount (≥50%). Polymer coated vesicles were biocompatible and improved the curcumin ability to protect A549 cells from the oxidative stress induced by hydrogen peroxide, restoring healthy conditions (cell relative metabolic activity 100%). In particular, a synergic effect of curcumin and hyaluronan was observed resulting in a proliferative effect and a subsequent further enhancement of cell relative metabolic activity up to 120%.