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Skin color disorders can be caused by various factors, such as excessive exposure to sunlight, aging and hormonal imbalance during pregnancy, or taking some medications. Kojic acid (KA) is a natural metabolite produced by fungi that has the ability to inhibit tyrosinase activity in synthesis of melanin. The major applications of KA and its derivatives in medicine are based on their biocompatibility, antimicrobial and antiviral, antitumor, antidiabetic, anticancer, anti-speck, anti-parasitic, and pesticidal and insecticidal properties. In addition, KA and its derivatives are used as anti-oxidant, anti-proliferative, anti-inflammatory, radio protective and skin-lightening agent in skin creams, lotions, soaps, and dental care products. KA has the ability to act as a UV protector, suppressor of hyperpigmentation in human and restrainer of melanin formation, due to its tyrosinase inhibitory activity. Also, KA could be developed as a chemo sensitizer to enhance efficacy of commercial antifungal drugs or fungicides. In general, KA and its derivatives have wide applications in cosmetics and pharmaceutical industries.
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Biomedicine & Pharmacotherapy
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Kojic acid applications in cosmetic and pharmaceutical preparations
Majid Saeedi
, Masoumeh Eslamifar
, Khadijeh Khezri
Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
Department of Environmental Health Engineering, Faculty of Health, Mazandaran University of Medical Sciences, Sari, Iran
Student Research Committee, Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
Health brightening products
Kojic acid
Skin color disorders can be caused by various factors, such as excessive exposure to sunlight, aging and hormonal
imbalance during pregnancy, or taking some medications. Kojic acid (KA) is a natural metabolite produced by
fungi that has the ability to inhibit tyrosinase activity in synthesis of melanin. The major applications of KA and
its derivatives in medicine are based on their biocompatibility, antimicrobial and antiviral, antitumor, anti-
diabetic, anticancer, anti-speck, anti-parasitic, and pesticidal and insecticidal properties. In addition, KA and its
derivatives are used as anti-oxidant, anti-proliferative, anti-inammatory, radio protective and skin-lightening
agent in skin creams, lotions, soaps, and dental care products. KA has the ability to act as a UV protector,
suppressor of hyperpigmentation in human and restrainer of melanin formation, due to its tyrosinase inhibitory
activity. Also, KA could be developed as a chemo sensitizer to enhance ecacy of commercial antifungal drugs
or fungicides. In general, KA and its derivatives have wide applications in cosmetics and pharmaceutical in-
1. Introduction
Skin is one of the most important organs of the body which consists
of several layers including the stratum corneum (SC), viable epidermis,
and dermis. The SC is selectively permeable to specic material such as
drugs [1,2]. The major obstacle for transdermal absorption in percu-
taneous Drug Delivery System (PDDS) is predominance of the SC bar-
rier. Several systems have been developed to enhance drug permeation
through the skin. Chemical transdermal enhancers and prodrugs are the
main paths for conquest of the SC barrier. A new intracellular screening
method in delivery of biologically active ingredients is using a protein
transduction system with a topical delivery enhancer. The combination
of naturally derived melanogenesis inhibition peptide and protein
transdermal delivery system is very useful for whitening peptides that
could be applied in cosmetics and pharmaceutical industry [3,4].
Over the past few decades, the skin has been considered as an im-
portant route in drug delivery. However, it is identied as a signicant
and eective barrier [5] and is associated with some transdermal pro-
blems in drug delivery. A major advance to solving this problem, is the
novel drug delivery methods which is designed for topical, local, and
systemic treatments. Nevertheless, few number of drugs have been re-
cognized and they need to pass eectively through the layer of stratum
corneum to achieve eective blood concentration levels. Dierent
methods have been developed to enhance the transdermal absorption of
drugs, including drug derivatives, drug saturation systems, and che-
mical and physical enhancers. All these facilitate the penetration of
drugs through the stratum corneum layer [6,7]. Drug resistance is a big
problem in systemic chemotherapy in cancer. Therefore, delivery of
chemotherapeutic agents and anti-apoptotic genes possess advantages
to overcome this problem. The nano-carrier system prepared from kojic
acid shows eective deliveries of anti-cancer drugs, signicantly in-
hibits cell proliferation and also reduces tumor growth [8,9].
Skin brighteners are a kind of therapy methods that can be used for
the treatment of skin disorders caused by hyperpigmentation. They may
inhibit the synthesis of melanin [10]. Melanin is a pigment that is
produced inside the melanocytes. They synthesize from thyrosine in a
complex process in the presence of thyrosinase and after packaging in
melanosomes immigrate to keratinocytes, the main epidermal cells
[11]. When these pigment productions are more than usual situation or
their distribution are not normal, development of skin hy-
perpigmentation occurs [12]. The use of chemical products to reduce
skin hyperpigmentation by several mechanisms such as reducing the
concentration of melanin is known as whitening of the skin. Nowadays,
brightening the skin is one of the most common procedures to improve
the hyper pigmented parts of the skin [13]. KA and its derivatives are
used to block the formation of pigment by melanocytes as one of the
most popular lightener in cosmetic products [2,1416].
The kojic acid scaold has an excellent structure in medicinal
Received 20 September 2018; Received in revised form 25 November 2018; Accepted 2 December 2018
Corresponding authors at: Mazandaran University of Medical Science, Sari, Iran.
E-mail addresses: (M. Saeedi), (M. Eslamifar), (K. Khezri).
Biomedicine & Pharmacotherapy 110 (2019) 582–593
0753-3322/ © 2018 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license
chemistry research, due to its vast biological activities. Unnatural
amino acids, that occur either naturally or synthesized chemically, are
widely used in ligand design. They represent a powerful tool in drug
discovery when incorporated into therapeutic peptidomimetics and
peptide analogs. The incorporation of unnatural amino acids could
enhance the resistance of peptides to enzymatic degradation and in-
crease peptides structural diversity as well as bioactivity. Synthesis of
novel hybrid molecules containing variety of natural products, such as
novel kojic acid amino acid hybrid natural products has made re-
markable progress over the last few years, opening new paths in
pharmacological approaches. These new amino acid derivatives con-
taining kojic acid have several reaction centers for oxidation, reduction,
alkylation, acylation, and peptide coupling reaction. Also, these com-
pound will nd perfect application as tyrosinase inhibitor [17]. Tran-
scription factors, are involved in important cellular processes of some
diseases like cancers, autoimmune and inammatory diseases [18].
Accumulation of tyrosinase and melanin in cells lead to melasma
and hyperpigmentation. Tyrosinase is the central enzyme in melanin
biosynthesis. Therefore, illumination of the molecules and pathways
that regulate tyrosinase activity could identify target areas for the de-
velopment of compounds to treat hyperpigmentation in vitro. A major
transcription factor for tyrosinase is the microphthalmia-associated
transcription factor (MITF) that increases tyrosinase expression when
upregulated and is involved in the pigmentation, proliferation, and
survival of melanocytes. Transcription factors are a class of proteins
that regulate gene expression by binding to specic DNA sequences.
Factors such as ultraviolet radiation, metal ions, free radicals, have
signicantly stimulate transcription of tyrosinase gene. the inhibitory
eect of melanin formation and tyrosinase activity of kojic acid and
kojic acid esters was evaluated in B16F1 melanoma cells [1921].
Kojic acid showed the potential inhibition of cellular NF-κB activity
in human keratinocytes. NF-κB activation is probably involved in kojic
acid induced anti-melanogenic eect [18,22].
During the past decades, uorescent metal nanoclusters have been
widely studied because of their good photo stability, adjustable light
emission wavelength, and low bio toxicity. In particular, DNA template
uorescent metal nanoclusters have been the center of interest [23].
Luminescent transition metal complexes have also attracted a great deal
of interest for the detection of biomolecules in scientic projects [9].
Hybrid probes are highly ecient tools used for locating biological
molecules and signals in living cells. They have great advantages based
on small molecules or uorescent proteins and are reported to be of
great benet in live-cell analyses of epigenetic disorders. Yet several
hybrid probes have been utilized by using that uorescence property in
response to pH, metal ions, or gas molecules. But, there is paucity of
information on the use of hybrid probes for detecting live cells in bio
macromolecules. Particularly, there is still unsatised demand for
probes for direct visualization of membrane dynamics of live cells
Several substituents are combined into kojic acid at its 2-hydro-
xymethyl group. Some kojic acid derivatives are synthesized and
evaluated for their ability to inhibit D-amino acid oxidase (DAAO).
These analogs act as benecial molecular probes to explore the sec-
ondary binding site, which could be used in designing more potent
inhibitors [27].
Human skin exposure to ultraviolet light can cause many skin le-
sions, such as sunburn, skin cancer, and oxidative stress, all of which
depend on the intensity and amount of UV light [28,29]. KA can be
used as a UV protector, with the ability to restrict hyperpigmentation
tyrosinase inhibitory eect [2,3036]. Side eects of hydroquinone
(HQ) as a popular skin lightener has made KA a suitable substitution in
cosmetic products [2,37]. This review describes and discusses the ap-
plication and high capacity of KA, as a lightening agent in cosmetic and
health care preparations.
2. Investigating the background and chemical structure of KA
The KA (the name kojic acidwas derived from Koji) is a chemical
product that is obtained from various types of fungi such as A. avus, A.
oryzae, A. tamarii, and A. parasiticus (Table 1). It is also produced from
the fermentation of some Asian foods (e.g soy sauce and rice wine),
which acts as a primer for fungus or inoculum [3844]. kojic Acid was
rst marketed in 1955. The Charles Pzer and Company, USA, was the
rst company to try to build this product. In recent years, kojic acid-
producing companies include two in China and three companies in
Japan, Switzerland, and the USA. Rapid growth of industries and dis-
covery of the potential uses of kojic acid and its derivatives, generated
great demands for this product. KA (Fig. 1) is classied in the group of
organic acids, which is obtained from dierent types of fungi during
aerobic fermentation process. The common names of KA are presented
in Fig. 2 [39,41,43,4551].
Its chemical structure is identied as 5-hydroxy-2-hydroxymethyl-γ-
pyron [3844]. Some of these species are capable of producing KA in
Table 1
Natural sources of kojic acid from dierent isolates belonging to various species
of fungi [5255].
Family Genus Organisms type species
Pleosporaceae Alternaria Alternaria alternata
Pleospora P. herbarum
Pleospora Pleospora allii
Chaetomiaceae Chaetomium Chaetomium globosum
Microascaceae Microascus Microascus brevicaulis
Stachybotryaceae Stachybotrys Stachybotrys chartarum
Stachybotrys Stachybotrys theobromae
Torulaceae Torula Torula herbarum
Hypocreaceae Trichoderma Trichoderma hamatum,Trichoderma
koningii,T. longibrachiatum,T.
Acremonium Acremonium strictum
Nectriaceae Fusarium Fusarium aquaeductuum,
F. chlamydosporum
F. equiseti, F. lateritium
F. moniliforme, F. oxysporum
F. proliferatum, F. solani
F. subglutinans, F. tricinctum
Cunninghamellaceae Cunninghamella Cunninghamella echinulata
Mucoraceae Mucor Mucor circinelloides,
Mucor. fuscus
Syncephalastraceae Syncephalastrum Syncephalastrum racemosum
Trichocomaceae Penicillium P. Capsulatum, P. lividum, P. spinulosum
P. funiculosum, P. purpurogenum,
P. rugulosum, P. albidum, P.
atramentosum, P. aurantiogriseum
P. janthinellum, P. citrinum,
P. corylophilum, P. camemberti
P. chrysogenum, P. cyaneofulvum
P. cyclopium, P. digitatum, P. expansum
P. frequentans, P. godlewski,
P. nigricans, P. somniferum, P.
Trichocomaceae Aspergillus A. Candidus, A. phoenicis, A. melleus
A. Ochraceus, A. sclerotiorum
A. Sulphureus, A. fumigatus
A. avus, A. avus var. columnaris
A. Oryzae, A. Parasiticus
A. tamarii, A. wentii, A. aculeatus
A. niger, A. terreus, A. avipes
A. Janus, A. sydowii A. versicolor,
Fig. 1. Chemical structure of KA.
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
large amounts, but genetic modications could alter their ability to
greater performance [56]. As mentioned earlier, KA as a skin
whitening, skin lightener or depigmenting agent is used in cosmetic
formulations. It is naturally produced by various species of Penicillium
and Acetobacter and various species of acetic acid bacilli [5760].
Several methods are suggested for the analysis of KA in various
industries, including voltammetry, spectrophotometry, column chro-
matography with ultraviolet detection, thin-layer chromatography, gas
chromatography with or without ame ionization, mass spectrometry
detection, bio gel P-2 column chromatography [61], and high-perfor-
mance liquid chromatography with photodiode-array or ultraviolet
detection [58,6173].
3. Melanin synthesis steps and its role in making pigmentation
Melanin is synthesized by melanocytes at the lower layer of epi-
dermis. Melanocytes are classied in the category of specialized den-
dritic cells that are located among epidermal keratinocytes and they
play the primary role of melanin production within an organelle called
melanosomes, and thus spread to surrounding keratinocytes. Each
melanocyte makes contact with melanosomes in dierent stages of the
dendritic cells and is distributed in many keratinocytes. Melanins are
complex polymers that are derived from tyrosine and other inter-
mediates. They change into black-brown eumelanin and yellow-red
pheomelanin through a multi-stage process of oxidation and complex
reactions that cause variations of color in human population [74,75].
Tyrosinase contain copper ion in the active site. When exposed to UV
rays, the copper ion commands the tyrosinase to become more active.
KA captures the copper ion, preventing that from activating the tyr-
osinase. By inhibiting the activities of tyrosinase, KA can also prevent
creating melanin (Figs. 3 and 4)[76].
More than 80 genes are involved in producing and regulating mel-
anin. Biosynthesis of melanin is controlled by various extracellular
signaling pathways, thus signals are transmitted as a cascade.
Fibroblasts are reported to be involved in this signaling. The early
stages of melanin production can occur in the skin by complex genetic
mechanisms, internal and external factors such as aging and ultraviolet
radiation and it can lead to considerable changes in synthesis of pure
melanin [77,78].
4. Transdermal penetration, depigmentation and development of
The topical absorption of KA according to pharmacokinetic ab-
sorption studies in rats and human skin, is estimated to be
0.030.06 mg/kg/day. The genotoxic risk of KA as a skin lightening
agent for humans is less. The in vitro percutaneous absorption values of
KA in human skin resulted in 17%, and the maximum potential human
systemic exposure dose (SED) would be 1.7 mg or 0.028 mg/kg/day for
a 60 kg adult human. This SED range is based on the application area of
hands and face [79].
The results of an oral/topical pharmacokinetic study in rats showed
18% of systemic exposure after topical application. Pharmacokinetic
studies in rats after oral and subcutaneous administration to rats,
showed that KA was rapidly absorbed and metabolized. The percuta-
neous absorption of KA in human skin was investigated in vitro and
C-equivalents (%) were determined by liquid scintillation
counting in the skin excess (%75.8 ± 9.3), stratum corneum
(%3.7 ± 2.2), epidermis + dermis (%9.2 ± 4.3) and the receptor
uid (7.8 ± 6.8). KA showed a signicant tendency to penetrate into
the dermis and epidermis (penetration rate of 16.98 ± 10.28%, cor-
responding to 3.58 ± 2.38
of treated skin area) [80].
Percutaneous absorption of KA in six healthy postmenopausal
Japanese women was measured before and after applying a cream
containing 1% KA. All the concentrations in plasma were only slightly
above the quantitation limit of 1 ng/ml. So, it was proved that KA had
not the potential role for transdermal penetration into the blood [81].
The inhibition of Eumelanin (black brown) production is usually
Fig. 2. Schematic diagram of Trade Names,Technical Names and Trade Name of KA.
Fig. 3. Tyrosinase inhibitory mechanism of KA in melanin biosynthesis for creating melanin by KA.
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
considered the main mechanism for depigmentation agents. Cultured B-
16 melanoma cells are excellent material for conrming the melano-
genesis inhibition in vitro. Cultivation of B-16 cells in eagles MEM
containing 10% fetal bovine serum and inserting several concentrations
of depigmenting agents is one of the evaluation methods. After 5 days,
the cells are xed by formalin and stained by ammoniacal silver nitrate,
then premelanosome stained in black. When the cells are alive, and
premelanosome stain is negative with the presence of depigmenting
agents, melanogenesis have been successfully inhibited. The eects of
melanogenesis inhibition have been established when a depigmenting
agent such as KA was added to the water in which black goldsh were
kept. After 12 months the black goldsh turned to yellowish brown
(Fig. 5). Later the goldsh was kept in water without KA, and it turned
back to its original black color. Therefore, KA as a highly eective and
safe ingredient inhibited melanogenesis without damaging cells nor its
function. This demonstrated that melanogenesis was inhibited [82].
5. Cellular and molecular mechanisms of kojic acid
Cosmetic performance that use skin-lightening agents to treat pig-
ment abnormalities are popular worldwide. Yet the molecular and
cellular mechanisms of these agents are mainly unknown. There are
only few skin-lightening compounds with the ability to inhibit tyr-
osinase in addition to activating or inhibiting intracellular signal
leading to the transcriptional inhibition of melanin synthesis genes.
Evidence suggest that most skin-lightening compounds reduce the
synthesis of melanin by inhibiting tyrosinase enzyme activity with low
toxicity on melanocytes. Some skin-lightening agents are believed to
regulate intracellular signaling pathways, leading to a decrease in
melanin synthesis, or increase in melanocyte cell death [85].
Malignant melanoma generally develops from the transformation
and proliferation of melanocytes in the basal cell layer of the epidermis.
The melanocytes may spread to other organs in the body (metastasis),
and disrupt the function of that organ. To better understand the mo-
lecular and cellular mechanisms of melanoma, human malignant mel-
anoma cells have been extensively used as a skin model for in vitro
examinations because they are highly reproducible, quantiable and
facility to cultivate. It is a structural cell model that closely equals the
progression of melanoma in vivo, and also a cost-eective alternative to
clinical testing. The anti-apoptotic mechanisms regulating cell death
are involved in drug resistance in tumor cells. Therefore, further
knowledge on the signal transduction pathways leading to tumor cell
death could result in identication of new target molecules to combat
drug resistance and improve melanoma therapy. Tyrosinase catalyzes
three distinct reactions in the melanogenic pathway: hydroxylation of
monophenol (L-tyrosine), dehydrogenation of catechol (L-DOPA), and
dehydrogenation of dihydroxyindole. By contrast, catalase is a potent
inhibitor of tyrosinase that regulates the removal of H2O2. Also, per-
oxidase in the presence of H2O2 and copper ions enhance the conver-
sion of monomers to eumelanin polymers. Thus, enzymatic changes
such as modications in protein and gene expression, aect melano-
genesis in melanomas. The complex regulatory control of the bio-
synthesis system in melanogenesis includes receptor-mediated path-
ways activated by hormones, neurotransmitters, cytokines, and growth
factors. The biological eects of kojic acid on gene and protein ex-
pression proles of A375 human melanoma cells and cancer therapy
have been researched. The tumorigenic potential and some genotoxic
eects of kojic acid on human skin cell lines have been widely studied,
Fig. 4. Inhibiting the activities of tyrosinase by KA.
Fig. 5. Black goldsh was kept in water containing Kojic Acid,
its color tone fadedIn an initial clinical study, the cream
containing 1% KA had better therapeutic properties than the
cream containing 2.3% KA because KA in the latter crystal-
lized gradually and the eect of the improvement reduced. In
that study, cases of melasma were treated with 1% KA cream
for 6 months. Hyperpigmentation in melasma patient de-
creased signicantly after the treatment period. But the
symptoms of melasma returned with exposure to sunlight
[83]. The KA as an iron chelator is applied in treatment of
depigmentation and skin aging. Nanotechnology-based drug
delivery systems, such as liquid crystalline systems (LCSs), can
improve drug permeation through the skin and ecacy of
therapeutic response for a prolonged time [84].
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
but its eect on gene and protein expression levels in many biological
functions of human skin has not been exactly reported. Investigating
the genes and proteins involved in melanoma may consequently im-
prove the development of early diagnostic and therapeutic applications
Melanogenesis is a process that is regulated by tyrosinase and tyr-
osinase related protein-1 and -2 (TRP-1 and TRP-2). Tyrosinase plays an
ecient role in melanin generation by the hydroxylation of tyrosine
into dihydroxyphenylalanine (DOPA) followed by further oxidation of
DOPA into DOPA Quinone. Therefore, inhibition of tyrosinase as a
common method could help in achieving skin hypopigmentation. In
addition, tyrosinase, TRP-1 and TRP-2 are transcriptionally regulated
by a microphthalmia-associated transcription factor (MITF). Skin pig-
mentation is regulated by dierent types of extrinsic and intrinsic fac-
tors. In particular, extracellular signal-regulated kinase (ERK) nega-
tively regulates melanogenesis in melanoma cells. It is also an eective
regulator of the activation of MITF [87].
The transcriptional level is the rst step by which the expression of
tyrosinase and related melanogenic enzymes may be regulated.
Important factor in this process are the microphthalmia-associated
transcription factor (MITF) is a basic helix-loop-helix leucine zipper
transcription factor that regulates cellular melanocyte as well as the
transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2)
and melanosome structural proteins (MART-1 and PMEL17). There
have been substantial advances in our understanding on the cellular
and molecular mechanisms in pigment biology and the processes
causing skin pigmentation. This has led to the development of many
skin lightening agents to reduce skin hyperpigmentation. There has
been an increased interest in alternative hypo pigmenting mechanisms
and need for a standardized streamlined protocol to screen melanogenic
regulatory compounds. Cellular recognition between melanocytes and
keratinocytes is an important event involved in melanosome transfer,
because of their inuence on cellular processes including intracellular
tracking, endocytosis, and cell-cell recognition [88].
6. Chemical characterizations and applications of KA in various
KA is known as a multi-agent molecule with a reactive gamma-
pyrone ring that has poor acidity. KA is reactive on its own ring in any
situation, therefore, it could be used in production of some products
with industrial value, including metal chelates, pyridones, pyridines,
ethers, azodyes, mannich base, and the products of cyanoethylation.
Many functional chemical reactions of KA have been investigated over
several decades after its separation. The hydroxyl group in the carbon 5
position from the γ-pyrene ring gives a weak acidic property to the KA
molecule, which leads to the formation of salt by some metals such as
sodium, zinc, copper, calcium, nickel, and cadmium [4850].
Kojic acid is well-known for its wide application in various in-
dustries such as food, pharmaceuticals, cosmetics, agriculture, and en-
vironment. It is distributed naturally in traditional Asian food.
Moreover, the most striking benet of kojic acid and its derivatives is
found in human and animal medicines as biological active compounds
(Fig. 6 and Table 2).
7. Hyperpigmentation disorders and their causes in human skin
Genetic factors, endocrine abnormalities, injuries, skin cancers,
Fig. 6. Diagrams of the key function of kojic acid and its derivatives in dierent industries [55,129131].
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
birth control pills, pregnancies, and medications that aect melanin
production, such as chlorpromazine and hydroxychloroquine, are
amongst the eective factors for hyperpigmentation [132]. Many other
factors can also contribute to the development of hyperpigmentation.
These conditions can be very complicated and may require dierent
stages of treatment. In more acute cases, surgery or laser therapy may
be the only solution; but stains, melasma, spots, and small patch of light
brown color on the skin caused by post inammatory hyperpigmenta-
tion can be eectively treated with topical products and also with
cosmetic treatment through the use of skin-whitening products. These
products are made from compounds such as KA and Arbutin, and other
substances with bleaching properties of the skin [132]. Melasma is a
Table 2
Applications of KA in various industries.
Functions Fields References
tyrosinase inhibitor (to inhibit melanin formation) Cosmetic [89]
Anti-inammatory Cosmetic [17]
Radio protective Cosmetic [90]
Skin-lightening agent in skin creams, lotions, soaps, products Cosmetic [91]
UV protector Cosmetic [92]
Decrease the appearance of scars Cosmetic [93]
Anti-aging eect Cosmetic [94]
Antidermatophytic Cosmetic [94]
Skin whitening or depigmenting agent in cosmetics Cosmetic [79]
Radical scavenging activity Cosmetic [95]
An antioxidant Food and cosmetic [79,96]
Anti-biolm Food and medical [97]
Anti-convulsant Medical [98]
Anti- HIV Medical [98,99]
Antimicrobial Medical [97]
An inhibitor of the growth of Gram-negative bacteria Medical [100]
antiviral Medical [101]
Biocompatibility Medical [102]
Antitumor Medical [89]
Antidiabetic Medical [103,104]
Anticancer Medical [105]
Antispeck Medical [106,107]
Anti-parasite Medical [108]
Chemo sensitizer to enhance ecacy of commercial antifungal drugs or fungicides Medical [109,110]
Pain killer Medical [55,100]
Anti-proliferative Medical [111]
Antileishmanial activity against Leishmania (L.) amazonensis both in vitro and in vivo Medical [89]
Inducing the activation of murine peritoneal macrophages by increasing reactive oxygen species (ROS)
production without causing cytotoxic eects
Medical [112]
Dental care Dentistry [113]
In the preparation of novel derivatives of kojic acid Chemistry and
Adhesives between metals and organic materials Chemistry [122]
Metal-adsorbents removing contaminating metals from water or chemicals produced by metal-catalyzed
Chemistry [122]
In chelate-forming resins Chemistry [123]
A metal chelating agent Chemistry [124]
An intermediate in synthesis Chemistry [55]
The prevention of discolouration of crustacean, meat, and fresh (0.2%) vegetables at 1.0% Food [123]
As a preservative Food [125]
As an antioxidant for fats and oils Food [126]
In avourings at 0.2% to add luster Food [123]
In our production at 0.1% Food [107]
In syrup at 0.05% Food [123]
Pesticide and insecticide Agriculture [127,128]
As a plant growth regulating agent to increase production Agriculture [123]
Table 3
Melasma therapies using KA alone and in various combinations (Main ingredients of bleaching or depigmenting formulas for melasma and other disorders: GA
(Glycolic acid), KA (Kojic acid), HQ (Hydroquinone), and VC(vitamin C) [135139].
Treatment formulation given patients Duration Results Reference
2% KA, 5% GA 39 patients 3 months Highly eective in reducing the pigment in melasma patients [140]
2% KA, 10% GA, 2% HQ 40 12 weeks 60% improvement [133]
KA (0.75%),
VC (2.5%),
4% HQ
60 patients 12 weeks 4% HQ and 0.75% KA + vitamin c 2.5% are eective topical hypo pigmenting agents in the treatment of
facial melasma
1% KA
2% HQ
80 patients 12weeks 71.87 %
2% KA
2% HQ
50 3 months HQ was more suitable than KA for the treatment of melasma [143]
4% KA
2% HQ
100 women three month KA 4% was found to be more suitable in the treatment of melasma [144]
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
common hyper pigmentation skin problem on the face which generally
happens in women. One of the most common treatments for melasma is
long-term treatment with topical agents that are used alone, or in
combinations. KA (5-hydroxy-2-hydroxymethyl-4-pyrone) is usually
combined with other agents at a concentration of 14% for its skin-
lightening property. The mechanism of its eect might be due to re-
ducing melanin formation in melanocytes by tyrosinase inhibition
[133].Several studies suggested the use of KA with other drugs in
melasma (Table 3). Combination of KA with other agents was also
found to be better than the monotherapy. KA combined with Hydro-
quinone (HQ) 2% showed signicantly better results compared with
other formulations. In summary, ecacy of KA in melasma therapies is
yet to be understood due to lack of studies with standard drugs used in
melasma. More detailed and extensive studies on KA remain a necessity
8. Characteristics and applications of KA in cosmetic and
pharmaceutical preparations
The most important applications of KA are as follows:
a Bleaching properties and skin protection in contrast to ultraviolet
light in cosmetic products
b Dental care products
In some studies, melanogenic inhibitory properties of KA has been
proven in vitro. Due to the carcinogenicity of HQ and its prohibition in
Asia, the FDA has introduced KA as an alternative for HQ. Recently,
chelates of KA and manganese and zinc metals have been introduced as
protective agents against gamma and radio rays [14,15,37,145]. In
many studies, various derivatives of KA such as KA ester, KA laureate,
KA dipalmitate and, KA ethyl phosphonate with aldehyde have been
reported to be more eective than KA [145,146]. A schematic of cos-
metic applications of KA is shown in Fig.7. Moreover, due to the pre-
sence of a pyron ring in the structure of KA, it is used to assess iron in
mineral stones. KA metal chelates are used in controlled release in drug
delivery and catalysts.
Several studies have reported that KA acts as an antibiotic against
human tubercle bacilli,gram-negative and gram-positive microorganisms in
in vitro. In addition, the derivatives of KA called azidometalkojates are
reported to act as antifungal and antibacterial agents on several species
of Bacillus,Staphylococcus,Saccharomyces,Aspergillus,Rhizopus, and
Fusarium [147,148]. Also, zinc derivatives of azidometalkojates have
cytotoxic activity on the hella tumor cells. In addition, other derivatives
of KA act as antifungal agent on several species of Phythium graminicola,
Fusarium oxysporum, and Rhizoctonia solani. In other studies, insecticidal
properties of KA has been shown on Heliothis zea,Spodoptera frugiperda,
Musca domestica, and Drosophila melanogaster insects. It also causes
sterility in male and female species [149153].
KA and its derivatives have become increasingly important due to
various biological activities, including antimicrobial and antiviral
[101], antitumor [154], antidiabetic [103], anticancer [105], anti-
speck [107], anti-parasitic [108], and pesticidal and insecticidal ac-
tivities [155]. In addition, KA and its derivatives are used as anti-oxi-
dant, anti-proliferative, anti-inammatory, radio protective and skin-
lightening agent in drug and cosmetic products, due to their tyrosinase
inhibitory activity [37,156158]. Furthermore, KA could be developed
as a chemo sensitizer to enhance ecacy of commercial antifungal
drugs or fungicides [109].
Potential application of KA and its derivatives has been studied in
veterinary medicine, cosmetic and chemical industry (Table 46).
9. Safety assessment of KA in cosmetics
Several studies are performed to evaluate the mechanisms of de-
pigmentation and safety of KA [193]. They suggested that the best
range of concentrations for KA topical preparation is 1% or less because
in these ranges, KA melts show eective and safe properties. Clinical
studies have shown eectiveness of 1% KA cream therapy for 6 months
in photo-hypersensitive melasma patients [193,194]. High epidermal
diusion of KA signicantly decreased its remaining in viable epi-
dermis. The absorption was modied by altering the topical preparation
base. Melasma patients who had used 1% KA cream were followed for 2
years and no signicant side eect or adverse reaction was observed.
Nowadays, new depigmentation agents such as KA are known as com-
mercial cosmeceutical products and other compounds may be oered in
the future [83,195,196].
Fig. 7. Schematic diagram of cosmetic applications of KA.
Table 4
Antifungal Activities of KA.
Properties Antifungal
drugs or fungicides
Species Disease or
Antifungal and anti-parasite activities KA Pathogenic yeasts and
Filamentous fungi
Human invasive aspergillosis [109]
Acrylate monomers
based on KA
Candida kefyr Candida infections-
Nosocomial Bloodstream Infections
Chloro KA derivatives Candida albicans
C. parapsilosis
Invasive and non-invasive fungal infections [101]
Amino Acid and Peptide Derivatives of KA Pythium graminicola, Fusarium
Oxysporum,Rhizoctonia solani
blight, fusarium wilt and sheath blight,
KA derivatives Dermatophytic
Skin disease [188]
KA L. amazonensis Leishmaniasis [108]
Chitosan oligosaccharide/ KA grafts Aspergillus niger
Saccharomyces cerevisiae
Crohn's disease
food-borne diseases
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
KA is found to be rapidly absorbed and distributed in oral admin-
istration in rats; but, its transdermal administration showed that KA is
slowly absorbed and distributed [79]. In other studies, tyrosinase in-
hibitory activity was evaluated and KA was seen to have a tyrosinase
inhibitory eect in positive control tests [3036]. In some researches,
KA 1 and 2% not show any allergenic or ocular sensitivity [197199].
The International Agency for research on cancer introduced KA as a
group 3 carcinogen [200202] based on in vivo studies on genetic
toxicity of mammals [203210]. Also, the FDA has not approved KA for
use in pharmaceutical products without prescription, but European
Commission's Scientic Committee has announced that:
1 The dose of KA should be 1% in the formulation of skin care.
2 KA is not a toxicant in acute, chronic, generative, and genotoxicity
form [79,211215].
10. Eectiveness and risks of KA as a lightening agent
The lightening eect on visible sun damages, age spots, or scars that
lead to anti-aging outcomes on the skin are the main therapeutic eect
of KA. It is also safe to be used in cosmetics in concentration of 1%
according to the Cosmetic Ingredient Review Expert Panel (CIREP).
Besides, KA has exhibited antimicrobial properties that can eradicate
some common types of bacterial strains (E.g. acne caused bacteria) even
in small dilutions. Studies also have shown that KA has potentially
antifungal eect. Furthermore, the treating of yeast infections, candi-
diasis, and ringworm have been reported too.
Some adverse reactions and disadvantages are associated with KA in
cosmetic application. Contact dermatitis (especially for sensitive skins)
is the main side eect of KA which is accompanied by irritation, rashes,
inamed skin, itchiness, and pain. These side eects can be observed
with a higher concentration more than 1% of KA. Another adverse re-
action may appear in long-term use of KA, such as sunburn in sensitive
skin. KA could also result in skin cancer on damaged skins. But, further
studies are needed to identify other potential benets or risks of KA.
Table 7. shows some main applications and risks of KA as a lightening
11. New applications of KA
Dierent types of technology including various nanoparticles such
as polymeric micelles, noisome, dendrimers, liposomes, carbon nano-
tubes, and metal-based nanoparticles are being eectively used in drug
delivery systems. Nanoparticles coated with polymers have been ap-
plied in dierent biomedical elds. Biocompatible compounds for drug
delivery systems can also provide the potential to develop new medi-
cines aiming at increased bio-availability, biocompatibility, biode-
gradability, lower toxicity, higher eciency, and controlled release. KA
products have been studied in combination with polymeric nano-
particles and liposomes. Recently, KA liposomal nano carriersdelivery
system were designed to enhance the chemotherapeutic ecacy in
tumor cell line. Despite its wide benets, there are some challenges,
including fast elimination by the reticuloendothelial system, toxicity,
and inammation of delivery systems [8,222]. In Nano chemical
Table 5
Some commercial applications of KA as an antimicrobial agent.
Properties Compounds Species of bacteria References
bacterial activities
Acrylate monomers based on KA Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi [186]
KA crystals Proteus, Staphylococcus, Streptococcus, Pseudomonas, Bacillus, Corynebacterium, Clostridium,
Aerobacter, Escherichia,Klebsiella,
Natural KA Pseudmonas aeuroginosa; E. coli, Proteus vulgaris
Staphylococcus aureus; Streptococcus
pneumoniae, Bacillus subtilis
Metal Chelation of KA analogs S. aureus, E. coli and Ps. uorescens [161]
Natural KA S. typhimurium, E. coli [80]
Chitosan oligosaccharide/ KA grafts Staphylococcus aureus, Escherichia coli [189]
Table 6
Anticancer and Anti proliferative activity of KA.
Properties Compounds Function Type of cancer cell References
Anticancer activities Pyrone-derived ligands from KA Inhibit dimer formation,
sucient stability in aqueous solution.
Metastatic tumor cell lines [192]
Selenocyanatomethyl derivatives of
Induce cellular biological changes, act as an
immunomodulatory agent, modulatory action on human
Human skin carcinoma (A431) and
human breast carcinoma (MCF7) cells
KA derivatives,
including RHS-0110
anti-oxidative, modulate glioma cell proliferation
and Toll-like receptor
tumors C6 glioma and SYF cells
KA Anti-proliferative activity Breast cancer cell line, MDA MB435S
cell lines
(Breast cancer)
KA ATPase, protein binding
anti-apoptosis, hetero dimerization activity
A375 human malignant melanoma
Table 7
Some main benets and risks of KA as a lightening agent.
Advantages Lighten eect on visible sun damages, age spots [56]
Anti-aging outcomes [216]
Antimicrobial possessions [125]
Antifungal belongings [217]
Anti-acne properties [218]
Benecial in treating yeast infections, candidiasis, and ringworm
Disadvantages Contact dermatitis (especially in sensitive skins) [220]
Long-term use of KA may make skin more susceptible to sunburn
Using KA on damaged or broken skins can result in cancer
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
promotion, liposomes are used as a minute capsule having a particle
size of 100 nm because of its superior biocompatibility and biode-
gradability. It seems to be an ideal DDS in skin and cells. The eciency
of drug delivery is inuenced by the interaction between cell and li-
posome [223225]. The penetration of kA through skin is found to
improve using HTCC-coating liposomes. The aim of this protocol was to
improve the eciency of fusion of liposome with cell membrane in
order to increase the absorption of drug [226].
Researchers are trying to improve the disadvantages and challenges
of this system by developing biocompatible products and bio ther-
apeutics. Drug discovery and drug delivery nanoparticles not only in-
crease the eectiveness of active compounds but also improve infection
control, particularly when organisms show multidrug resistant. Coated
magnetic nanoparticles loaded with anticancer drugs such as bio-
compatible product can localize and reduce tumor cells with low side
eects. KA is a poly functional compound without any hazardous side
eects that approve the development of biologically natural compounds
and pharmaceuticals. KA-coated liposome could be used in drug de-
livery in melanoma to its higher fusion ability with cell membrane, high
water solubility and lower toxicity. These liposomal nano carriers can
be applicable for transdermal drug delivery, cancer chemotherapy, and
gene delivery [226,227]. Further researches are suggested to focus on
application of drug-delivery systems with bio therapeutics that include
delivery of several types of nucleic acids such as plasmids, nucleotides
or RNA, antibodydrug conjugates and combination of KA derivate and
liposome, to develop new type of nano carriers for drug delivery in the
12. Conclusion
Generally, KA is popular for its applications in various purposes
such as pharmaceuticals, cosmetics, agriculture, food, and chemical
industry. The most signicant advantage of KA is its wide applications
in cosmetics and medical industry. It acts as a brightening ingredient in
whitening creams, skin lotions, and bleaching soaps, and also in dental
and medical care products. In conclusion, and today with massive
growth in this industry, its supply and demand is increasing con-
siderably. Therefore, more clinical studies are needed for designing and
developing new products based on KA.
This study is a research project and involves receiving a research
score with approval number 86, supported by Student Research
Committee of the Mazandaran University of Medical Sciences.
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... Tyrosinase is the enzyme responsible for melanin production. This enzyme is found in melanocytes, which are located in the basal layer of the epidermis [40]; therefore, for melanogenesis inhibition to occur, KDP must reach melanocytes and inhibit tyrosinase. Figure 4 shows the amount of KDP from 1 and 2 mg/mL KDP nanoemulsions (NERO1KDP and NERO2KDP, respectively) that permeated the receptor medium after 12 h of contact with the membrane, as well as the amount of the compound found in the stratum corneum (after removal of excess formulation), epidermis, and dermis. ...
... KDP did not permeate the full thickness skin after 12 h, as well as it was not possible to quantify the amount of active ingredient in the dermis. These findings are indicative of the safety of the nanoemulsions, as the molecule is expected to act in the viable epidermis, where melanocytes are found [40], and not have systemic action. ...
... Therefore, it is usually a target of melanogenesis inhibitors and skin-depigmenting agents [43]. Tyrosinase catalyzes the hydroxylation of tyrosine into dihydroxyphenylalanine (DOPA) and then the oxidation of DOPA into dopaquinone, which is spontaneously converted to dopachrome [40]. In the analysis, dopachrome is quantified under UV light at 405 nm [26]. ...
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Melasma is a hard-to-treat hyperpigmentation disorder. Combined incorporation of kojic dipalmitate (KDP), the esterified form of kojic acid, and rosehip oil, an oil with antioxidant and skin-regenerating properties, into nanocarrier systems appears to be a suitable strategy to develop high-performance formulations. A high-energy method (Ultra-Turrax®) was used to develop nanoemulsions containing up to 2 mg/mL KDP, 5% rosehip oil, and 7.5% surfactant. Formulations were characterized regarding droplet size, size distribution, pH, density, morphology, KDP content, incorporation efficiency, and stability under different temperature conditions. A scale-up study was conducted. Skin permeation, antioxidant potential, and tyrosinase inhibitory activity were assessed in vitro. Cell viability studies were also performed. Results showed that nanoemulsions containing 1 and 2 mg/mL KDP had incorporation efficiencies greater than 95%, droplet size smaller than 130 nm, suitable size distribution, zeta potential of approximately −10 mV, and good stability over 30 days of refrigerated storage. The nanoemulsion containing 1 mg/mL KDP was chosen for further evaluation because it had lower nanocrystal formation, greater scale-up feasibility and allowed KDP permeation up to the epidermis similarly than observed for 2 mg/mL KDP. This formulation (1 mg/mL KDP) showed antioxidant and depigmenting efficacy, close to that of 1 mM ascorbic acid. No cytotoxicity was observed in formulations concentrations ranging from 0.06% to 1%.
... Kojic acid (KA) inactivates tyrosinase by chelating copper, which is the prosthetic group for this enzyme; it is effective in concentrations ranging from 1% to 4% (117). The maximum potential human systemic exposure dose (SED) of KA is 0.028 mg/kg/day. ...
... The maximum potential human systemic exposure dose (SED) of KA is 0.028 mg/kg/day. KA reduces the synthesis of melanin and is less toxic to melanocytes (117). ...
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Hyperpigmentation is a common complication in patients with burn injuries during wound healing; however, the mechanisms underlying its occurrence and development remain unclear. Recently, postinflammatory hyperpigmentation (PIH) was found to result from overproduction of melanin. Local or systemic inflammatory responses are often observed in patients who develop hyperpigmentation. However, we lack studies on the relationship between PIH and burn injury. Therefore, we comprehensively reviewed the existing literature on the melanogenesis of the skin, inflammatory mechanisms in pigmentation, and local or systemic alteration in inflammatory cytokines in patients suffering from burn trauma to elucidate the relationship between PIH and burn injury. We believe that this review will guide further research on regulating melanin production in the burn management process.
... According to our literature review of the properties and the general structures of antioxidant compounds, several compounds contained in X. granatum extracts have potential as antioxidants. These compounds mostly belong to the phenolics and polyphenols groups, including catechol [26], pyrogallol [24], 3-hydroxybenzoate, 4-hydroxybenzoic acid, 4-hydroxyphenylacetic acid, 3,4-dihydroxybenzoate [27], kojic acid [28], quinic acid [29], p-coumaric acid, gallic acid, ferulic acid, caffeic acid [30], epicatechin, epigallocatechin, and kaempferol [23]. ...
... Quinic acid is a carboxylic acid with many hydroxy groups (-OH), with potential as an antioxidant by inhibiting oral pathogens [29]. Kojic acid, on the other hand, is widely used in cosmetic products, especially as a skin-lightening agent [28,33]. ...
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The potential application of Xylocarpus granatum, a mangrove species, as traditional medicine has been widely linked to its high secondary metabolite and antioxidant contents. However, few studies have been reported to identify and classify active metabolites responsible for such excellent biological activities. Therefore, the aim of this work was to determine the antioxidant activity, identify the metabolite profiles, and predict the metabolites acting as antioxidants in X. granatum extract using a gas chromatography–mass spectrometry (GC-MS)-based metabolomics approach. The seeds, stems, fruit peel, pulp, leaves, and twigs of X. granatum were macerated with ethanol. Each extract was analyzed with GC-MS, and the data were processed using mass spectrometry data-independent analysis (MS-DIAL) software to identify the metabolites. The IC50 value of plant parts of X. granatum ranged from 7.73 to 295 ppm. A total of 153 metabolites were identified and confirmed in the X. granatum extracts. Among the identified metabolites, epicatechin and epigallocatechin were the two most abundant in the stem extracts and are expected to have the greatest potential as antioxidants. Principal component analysis (PCA) succeeded in grouping all parts of the plant into three groups based on the composition of the metabolites: group 1 (stems, fruit peel, and twigs), group 2 (seeds and pulp), and group 3 (leaves).
... It can be used as a preservative for cosmetics, without one-time or cumulative irritation to the skin, and in a variety of foods, where it is added to prevent enzymatic browning [4]. It can strongly absorb ultraviolet rays and can be used alone or in combination with various sunscreen products and soaps [5]. It also can treat and prevent the formation of skin pigmentation, such as liver spots [6]. ...
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Co-crystallization of kojic acid (HKA) with silver(I), copper(II), zinc(II), or gallium(III) salts yielded three 1D coordination polymers and one 0D complex in which kojic acid was present as a neutral or anionic terminal or bridging ligand. All reactions were conducted mechanochemically via ball milling and manual grinding, or via slurry. All solids were fully characterized via single-crystal and/or powder X-ray diffraction. As kojic acid is a mild antimicrobial compound that is widely used in cosmetics, and the metal cations possess antibacterial properties, their combinations were tested for potential antibacterial applications. The minimal inhibition concentrations (MICs) and minimal biocidal concentrations (MBCs) for all compounds were measured against standard strains of the bacteria P. aeruginosa, S. aureus, and E. coli. All compounds exerted appreciable antimicrobial activity in the order of silver, zinc, copper, and gallium complexes.
... quality (5)(6)(7). Recent research indicated that kojic acid, widely used for skin whitening and hyperpigmentation preventing, would lead to skin irritation and mutagenic effect on human skin (8)(9)(10). Thus, searching for safe tyrosinase inhibitors of nature origin has attracted increasing attention in cosmetic and medicinal industries (11). ...
Background: Essential oils (EOs), derived from aromatic plants, exhibit properties beneficial to health, such as anti-inflammatory, anti-oxidative, antidiabetic, and antiaging effects. However, the effect of EOs and their interaction in binary combinations against tyrosinase is not yet known. Objective: To evaluate the underlying mechanisms of EOs and their interaction in binary combinations against tyrosinas. Design: We explored to investigate the inhibitory effect of 65 EOs and the interaction among cinnamon, bay, and magnolia officinalis in their binary combinations against tyrosinase. In addition, the main constituents of cinnamon, bay, and magnolia officinalis were analyzed by gas chromatography-mass spectrometry (GC-MS). Results: The results showed that the most potent EOs against tyrosinase were cinnamon, bay, and magnolia officinalis with IC50 values of 25.7, 30.8, and 61.9 μg/mL, respectively. Moreover, the inhibitory mechanism and kinetics studies revealed that cinnamon and bay were reversible and competitive-type inhibitors, and magnolia officinalis was a reversible and mixed-type inhibitor. In addition, these results, assessed in mixtures of three binary combinations, indicated that the combination of cinnamon with bay at different dose and at dose ratio had a strong antagonistic effect against tyrosinase. Magnolia officinalis combined with cinnamon or bay experienced both antagonistic and synergistic effect in anti-tyrosinase activity. Conclusion: It is revealed that natural EOs would be promising to be effective anti-tyrosinase agents, and binary combinations of cinnamon, bay, and magnolia officinalis might not have synergistic effects on tyrosinase under certain condition.
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Kojic acid has gained its importance after it was known worldwide that the substance functions primarily as skin-lightening agent. Kojic acid plays a vital role in skin care products, as it enhances the ability to prevent exposure to UV radiation. It inhibits the tyrosinase formation which suppresses hyperpigmentation in human skin. Besides cosmetics, kojic acid is also greatly used in food, agriculture, and pharmaceuticals industries. Conversely, according to Global Industry Analysts, the Middle East, Asia, and in Africa especially, the demand of whitening cream is very high, and probably the market will reach to $31.2 billion by 2024 from $17.9 billion of 2017. The important kojic acid-producing strains were mainly belongs to the genus Aspergillus and Penicillium. Due to its commercial potential, it continues to attract the attention for its green synthesis, and the studies are still widely conducted to improve kojic acid production. Thus, the present review is focused on the current production processes, gene regulation, and limitation of its commercial production, probable reasons, and possible solutions. For the first time, detailed information on the metabolic pathway and the genes involved in kojic acid production, along with illustrations of genes, are highlighted in the present review. Demand and market applications of kojic acid and its regulatory approvals for its safer use are also discussed. Key points • Kojic acid is an organic acid that is primarily produced by Aspergillus species. • It is mainly used in the field of health care and cosmetic industries. • Kojic acid and its derivatives seem to be safe molecules for human use.
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Background: Kojic acid (KA) is a widely used compound in the cosmetic, medical, and food industries, and is typically produced by Aspergillus oryzae. To meet increasing market demand, it is important to optimize KA production through seeking alternatives that are more economic than current A. oryzae-based methods. Results: In this study, we achieved the first successful heterologous production of KA in Aspergillus niger, an industrially important fungus that does not naturally produce KA, through the expression of the kojA gene from A. oryzae. Using the resulting KA-producing A. niger strain as a platform, we identified four genes (nrkA, nrkB, nrkC, and nrkD) that negatively regulate KA production. Knocking down nrkA or deleting any of the other three genes resulted in a significant increase in KA production in shaking flask cultivation. The highest KA titer (25.71 g/L) was achieved in a pH controlled batch bioreactor using the kojA overexpression strain with a deletion of nrkC, which showed a 26.7% improvement compared to the KA titer (20.29 g/L) that was achieved in shaking flask cultivation. Conclusion: Our study demonstrates the potential of using A. niger as a platform for studying KA biosynthesis and regulation, and for the cost-effective production of KA in industrial strain development.
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Kojic acid (KA) is a fungal metabolite and has a variety of applications in the cosmetics and food industries. Aspergillus oryzae is a well-known producer of KA, and its KA biosynthesis gene cluster has been identified. In this study, we showed that nearly all section Flavi aspergilli except for A. avenaceus had complete KA gene clusters, and only one Penicillium species, P. nordicum, contained a partial KA gene cluster. Phylogenetic inference based on KA gene cluster sequences consistently grouped section Flavi aspergilli into clades as prior studies. The Zn(II)2Cys6 zinc cluster regulator KojR transcriptionally activated clustered genes of kojA and kojT in Aspergillus flavus. This was evidenced by the time-course expression of both genes in kojR-overexpressing strains whose kojR expression was driven by a heterologous Aspergillus nidulans gpdA promoter or a homologous A. flavus gpiA promoter. Using sequences from the kojA and kojT promoter regions of section Flavi aspergilli for motif analyses, we identified a consensus KojR-binding motif to be an 11-bp palindromic sequence of 5′-CGRCTWAGYCG-3′ (R = A/G, W = A/T, Y = C/T). A CRISPR/Cas9-mediated gene-targeting technique showed that the motif sequence, 5′-CGACTTTGCCG-3′, in the kojA promoter was critical for KA biosynthesis in A. flavus. Our findings may facilitate strain improvement and benefit future kojic acid production.
Melanin is a pigment produced from the amino acid L-tyrosine in melanosomes. The CNC-family transcription factor Nrf3 is expressed in the basal layer of the epidermis, where melanocytes reside, but its melanogenic function is unclear. Here, we show that Nrf3 regulates macropinocytosis and autophagy to coordinate melanogenesis cascade. In response to an exogenous inducer of melanin production, forskolin, Nrf3 upregulates the core melanogenic gene circuit, which includes Mitf, Tyr, Tyrp1, Pmel, and Oca2. Furthermore, Nrf3 induces the gene expression of Cln3, an autophagosome-related factor, for melanin precursor uptake by macropinocytosis. Ulk2 and Gabarapl2 are also identified as Nrf3-target autophagosome-related genes for melanosome formation. In parallel, Nrf3 prompts autolysosomal melanosome degradation for melanocyte survival. An endogenous melanogenic inducer αMSH also activates Nrf3-mediated melanin production, whereas it is suppressed by an HIV-1 protease inhibitor, nelfinavir. These findings indicate the significant role of Nrf3 in the melanogenesis and the anti-melanogenic potential of nelfinavir.
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Although the antimicrobial properties of kojic acid have been recognized, the subcellular mechanism of bacterial inactivation caused by it has never been clearly elucidated. In the present study, the antibacterial and anti-biofilm activity of kojic acid was evaluated against five foodborne pathogens including Listeria monocytogenes, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Salmonella typhimurium. The antibacterial activity was determined by minimum inhibitory concentration, minimum bactericidal concentration, and the time-kill assay. Among them, the susceptibility of Escherichia coli was significant with the lowest minimum inhibitory concentration and minimum bactericidal concentration values of 10 and 20 mM, respectively. Subcellular mechanism of bacterial inactivation related to kojic acid was revealed through comprehensive factors including cell morphology, membrane permeability, K⁺ leakage, zeta potential, intracellular enzyme, and DNA assay. Results demonstrated that bacterial inactivation caused by kojic acid, especially for Gram-negative bacteria, was primarily induced by the pronounced damage to the cell membrane integrity. Leakage of intracellular enzyme to the supernatants implied that the cell membrane permeability was compromised. Consequently, the release of K⁺ from the cytosol leads to the alterations of the zeta potential of cells, which would disturb the subcellular localization of some proteins and thereby cause the bacterial inactivation. The free −CH2OH group at the C-2 of kojic acid could play more significant role in the antimicrobial performance of kojic acid against Gram-negative bacteria. Moreover, remarkable interaction with DNA was also observed. Kojic acid at sub-minimum inhibitory concentration inhibited biofilm formation by these bacteria.
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Cosmetic practices that use skin-lightening agents to obtain desired skin tones or treat pigment abnormalities have been popular worldwide. However, the molecular and cellular mechanisms of these agents are still largely unknown. Here we identified a family of compounds, with the lead compound named A11, that exhibited strong pigment reduction in developing zebrafish embryos. The pigment inhibition lasted for several days and is effective both before and after melanogenesis. By comparison with several known skin-lightening compounds, A11 appeared to be more potent and caused slower pigment recovery after withdrawal. A11, however, did not inhibit tyrosinase or cause apoptosis in melanocytes. We further found that A11 suppressed proliferation in melanocytes and reduced the number of differentiated melanocytes by activating MAPK (mitogen-activated protein kinase) and Akt. Finally, A11 also caused melanin reduction in mammalian melanocytes. Together, A11 might be a potent skin-lightening agent with novel mechanisms.
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Fungal synthesis of kojic acid has gained more interest in these days as an alternative way to chemical synthetic. The aspect of the microbial fermentation process is to develop a suitable culture medium to obtain the maximum amount of kojic acid using statistical methods. In this study; different selected three isolates of Aspergillus flavus (No 1, 2 and 3) were screened for their ability to produced kojic acid and the isolate No 3 was the highest kojic acid producer one. The capability of A. flavus No 3 to produce kojic acid was improved using Plackett- Burman design. From ten different agro-industrial wastes cane molasses recorded the highest kojic acid productivity with 2.24 g/l-1 day-1 and was the most effective parameter plays a crucial role in Plackett- Burman design. Maximum kojic acid production (24.65 g/l) by A. flavus (No. 3) obtained under the fermentation conditions: incubation temperature at 25oC, incubation time 9 days, pH 3, inoculum size 0.5%, shaking rate at 150 rpm and medium constituents: Cane molasses 60 g/l, yeast extract 7 g/l, KH2PO4 2 g/l, ZnSO4·7H2O 100 μg/l and MgSO4·7H2O 1 g/l with regression analysis (R2) 99.45% and 2.33-fold increase in comparison to the production of the original level (10.6 g/l).
Cultivation of the fungal species Aspergillus parasiticus led to the isolation of Kojic acid (KA), an important secondary metabolite, but unstable under some conditions. In order to improve the pharmacokinetic potential of KA for biotechnological applications in pharmaceutical and cosmetic formulations, KA was immobilized in mesoporous nanomaterials based on silica (MSN). This kind of inorganic support has been intensively studied as candidates for controlling-release drugs, due to its high surface area, high ordering of mesopores and pore size in nanometer scale. In this way, mesoporous silica nanoparticles have been synthesized and were chemically modified by post-synthesis with 3-aminopropyltriethoxysilane (MSNAPTES) and the influence of functionalization of the matrix on the loading rate of KA was studied. Nanoparticles were physicochemical characterized by SAXS, SEM, CHN, TGA, N2 adsorption, photon correlation spectroscopy and zeta potential analysis. Bactericidal efficacy of these nanoparticles was tested against different microorganisms, and these new kojic acid nanoparticles showed high bactericidal efficiency. In relation to acetylcholinesterase (AChE) inhibition test, used to screen drugs active to treat Alzheimer’s disease patients, MSNAPTES KA nanoparticles showed to be as efficient as the free-acid. KA loading showed also tyrosine inhibitory property preserved. The results points that, although free-kojic acid amount in MSNAPTES KA is thirty times lower, biological activity of this nanoparticle is as high as the activity of free-kojic acid, being, therefore, a highly and multi-active nano-system for kojic acid delivery with improved pharmacokinetic skills and a wide scope of industrial applications.
Dopamine has been shown interact strongly with Cu²⁺ to form a stable complex and inhibit the formation of polythymine-templated copper nanoclusters. Based on these findings, a label-free sensing strategy has been designed for the detection of dopamine using polythymine-templated copper nanoclusters as fluorescence probes. The fluorescent method exhibits sensitive and selective detection of dopamine with a linear range from 1 nM to 50 µM and a detection limit of 0.5 nM. In addition, the method was successfully applied for the determination of dopamine in dopamine hydrochloride injection samples. Thus, this approach holds considerable potential for the construction of a simple, rapid, and sensitive fluorescent assay for the determination of dopamine.
A series of novel kojic acid fused furans have been synthesized by domino cyclization‐elimination reactions of a kojic acid derivative with (Z)‐bromonitroalkenes. In the presence of a bifunctional thiourea‐tertiary amine organocatalyst and sodium bicarbonate, the reactions provided the products in up to quantitative yields. Domino reactions of a kojic acid derivative with (Z)‐bromonitroalkenes promoted by a bifunctional thiourea‐tertiary amine organocatalyst and sodium bicarbonate provided various novel fused furans in up to quantitative yields.
Monocytes are mononuclear phagocytes in peripheral blood that can differentiate into macrophages and dendritic cells. Macrophages play a specific role in the inflammatory process and are essential for the innate response. Given the important role of monocytes/macrophages in the immune response, this study aimed to evaluate the activity of kojic acid (KA), a natural product of certain fungal species, on human peripheral blood monocytes in vitro. Purified monocytes isolated from human blood were incubated with KA (50 μg/mL for 48 h) and analyzed by light microscopy, scanning electron microscopy, transmission electron microscopy and flow cytometry. Host cell cytotoxicity was measured by the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. KA treatment induced morphological alterations in monocytes, such as increased cell size, as well as numerous cellular projections. Furthermore, flow cytometry revealed increased labeling of cell surface EMR1-F4/80 but decreased labeling of CD11b and CD14. KA also promoted increased IL-6 cytokine production but did not cause cytotoxic effects in monocytes. In conclusion, our results show that KA promotes the differentiation of monocytes into macrophages and can act as an immunomodulatory agent.