Multiplicative Effects of Essential Oils and Other Active Components on Skin Tissue and Skin Cancers

Naturally derived essential oils and their active components are known to possess various properties, ranging from anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, and anti-cancer activities. Numerous types of essential oils and active components have been discovered, and their permissive roles have been addressed in various fields. In this comprehensive review, we focused on the roles of essential oils and active components in skin diseases and cancers as discovered over the past three decades. In particular, we opted to highlight the effectiveness of essential oils and their active components in developing strategies against various skin diseases and skin cancers and to describe the effects of the identified essential-oil-derived major components from physiological and pathological perspectives. Overall, this review provides a basis for the development of novel therapies for skin diseases and cancers, especially melanoma.


Introduction
Essential oils (EO)s are natural oils secreted as secondary metabolites or concentrated plant extracts from many parts of aromatic plants (especially the bark, fruits, and flowers) [1].EOs and their active components possess many biological properties, including anti-bacterial, anti-virus, anti-fungal, anti-inflammatory, and anti-cancer properties [2,3].The skin is the first barrier that protects against external stimuli and microorganisms.Moreover, the skin possesses unique characteristics, such as its stratified structure, various cell types, and the pigmentation process, which are distinct from other tissues.Notably, EOs are used to treat several diseases, including skin diseases such as eczema, psoriasis, dermatitis, and skin cancers.In this review, we aimed to highlight the benefits of various EOs and several plant oils (POs) in terms of skin reactivity and the treatment of skin cancers, especially melanoma, with a PubMed-based selection of studies published in the last three decades which address the effects of EOs/POs on skin diseases and skin cancers.Overall, a summary of the effectiveness of EOs would help alleviate skin diseases and promote the development of therapeutic strategies against various skin diseases and skin cancers.

Anti-Inflammatory Role of EOs 2.1. Citrus limetta Peel Essential Oil (Cl-EO)
Citrus limetta (C.limetta) Risso peels exhibit various medicinal activities, such as antioxidant and anti-inflammatory activities [4], due to the presence of large quantities of flavonoids [5].EO, a widely used ingredient in cosmetic and pharmaceutical products, is an important product of citrus fruit peels [6,7].EOs and their constituents from citrus fruits exhibit anti-inflammatory activities in vitro by inhibiting the biosynthesis of inflammatory cytokines [8].Inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, are found to be dose-dependently reduced by treatment with C. limetta peel EO (Cl-EO) in the lipopolysaccharide (LPS)-exposed primary macrophages or the 12-Otetradecanoylphorbol-13-acetate (TPA), used as protein kinase C (PKC) activator, -exposed mouse ear [9].In addition, Cl-EO is found to inhibit, dose-dependently, oxidative stress in hydrogen peroxide (H 2 O 2 )-exposed primary macrophages and TPA-exposed mice [9].

Baccharis dracunculifolia Essential Oil (BD-EO)
Baccharis dracunculifolia (B.dracunculifolia) is a domestic plant which is widely used as an immunomodulator and an anti-bacterial and anti-diabetic agent, but it possesses many other properties [10,11].Several studies have evaluated the medicinal actions of B. dracunculifolia, especially its anti-microbial effects [12][13][14].Dos Santos et al. reported the anti-inflammatory effects of B. dracunculifolia leaves extract on a paw edema model, which is induced by carrageenan and formalin [15].Additionally, B. dracunculifolia leaf extract is found to exhibit an inhibitory effect on LPS-challenged murine macrophages by inhibiting the biosynthesis of IL-6 and IL-10 [16,17].Ear edema, infiltration, and proliferation/differentiation of keratinocytes, as well as the activities of myeloperoxidase and N-acetylglutamate synthase, are downregulated by BD-EO administration in a TPAinduced acute and chronic inflammatory mouse model [18].

Perilla frutescens L. Britt Essential oil (PF-EO)
Perilla frutescens (P.frutescens) L. Britt is a herbaceous plant that plays a critical role in Chinese medicine and is used to treat various pathological symptoms, including abdominal pain, nausea, cold, constipation, food poisoning, and cough [19].The EOs from P. frutescens have been noted to possess anti-bacterial, anti-inflammatory, and anti-oxidant properties [20,21].In addition, psoriasis symptoms, such as erythema, scaling, and epidermal thickening, have previously found to be alleviated by treatment with P. frutescens L. Britt EO (PF-EO) in a mouse model of imiquimod (IMQ)-induced psoriasis [22].Inflammationrelated factors, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, IL-1, IL-6, and neutrophil proliferation, are downregulated by PF-EO treatment in the full skin and epidermis of an IMQ-induced psoriasis in mouse [22].IMQ induces dendritic cell activation, which is related to the activation of macrophages and T-lymphocytes [23][24][25].The upregulated mRNA expression levels of IL-17, IL-22, IL-23, interferon (IFN)-α, and IFN-γ due to IMQ administration are found to be reduced by PF-EO treatment in the skin [22].The production of psoriasis-development-associated cytokines, such as IL-1, IL-6, IL-17, IL-23, and nuclear factor kappa B (NF-κB), are downregulated by PF-EO treatment in the serum of an IMQ-induced mouse [22] (Figure 1).

Baccharis dracunculifolia Essential Oil (BD-EO)
Baccharis dracunculifolia (B.dracunculifolia) is a domestic plant which is widely used as an immunomodulator and an anti-bacterial and anti-diabetic agent, but it possesses many other properties [10,11].Several studies have evaluated the medicinal actions of B. dracunculifolia, especially its anti-microbial effects [12][13][14].Dos Santos et al. reported the anti-inflammatory effects of B. dracunculifolia leaves extract on a paw edema model, which is induced by carrageenan and formalin [15].Additionally, B. dracunculifolia leaf extract is found to exhibit an inhibitory effect on LPS-challenged murine macrophages by inhibiting the biosynthesis of IL-6 and IL-10 [16,17].Ear edema, infiltration, and proliferation/differentiation of keratinocytes, as well as the activities of myeloperoxidase and N-acetylglutamate synthase, are downregulated by BD-EO administration in a TPA-induced acute and chronic inflammatory mouse model [18].

Perilla frutescens L. Britt Essential oil (PF-EO)
Perilla frutescens (P.frutescens) L. Britt is a herbaceous plant that plays a critical role in Chinese medicine and is used to treat various pathological symptoms, including abdominal pain, nausea, cold, constipation, food poisoning, and cough [19].The EOs from P. frutescens have been noted to possess anti-bacterial, anti-inflammatory, and anti-oxidant properties [20,21].In addition, psoriasis symptoms, such as erythema, scaling, and epidermal thickening, have previously found to be alleviated by treatment with P. frutescens L. Britt EO (PF-EO) in a mouse model of imiquimod (IMQ)-induced psoriasis [22].Inflammation-related factors, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, IL-1, IL-6, and neutrophil proliferation, are downregulated by PF-EO treatment in the full skin and epidermis of an IMQ-induced psoriasis in mouse [22].IMQ induces dendritic cell activation, which is related to the activation of macrophages and T-lymphocytes [23][24][25].The upregulated mRNA expression levels of IL-17, IL-22, IL-23, interferon (IFN)-α, and IFN-γ due to IMQ administration are found to be reduced by PF-EO treatment in the skin [22].The production of psoriasis-development-associated cytokines, such as IL-1, IL-6, IL-17, IL-23, and nuclear factor kappa B (NF-κB), are downregulated by PF-EO treatment in the serum of an IMQ-induced mouse [22] (Figure 1).

Oregano Essential Oil (O-EO)
Origanum vulgare (O.vulgare), also known as oregano, is a ubiquitous aromatic plant of the Lamiaceae family and a typical Mediterranean flora [51].Assuming no toxicity, O. vulgare is used not only in therapeutic regimens [52][53][54] but also in the food, agricultural, and veterinary fields [55,56].Moreover, oregano EOs (O-EOs) exhibit a unique function in the prevention of neurodegenerative disorders [57].The major components of O-EO are carvacrol (CRV) and thymol [51], which exhibit anti-oxidant, immunomodulatory, anticancerous, anti-melanogenesis, anti-inflammatory, and anti-microbial activities [52,54,58].The anti-cancer effects of the EOs, such as their effects against melanoma, are discussed in Section 3. O-EO is found to reduce ROS production, DNA damage, and the expression of inflammatory factors, such as inter-cellular adhesion molecule (ICAM)-1, iNOS, and COX-2, in IFN-γ/histamine-induced NCTC254 cells, a normal human keratinocyte cell line [51].In addition, the expression levels of extracellular matrix (ECM) agents-such as matrix metalloproteinase (MMP)-1 and MMP-12-and cell proliferation are found to be reduced by O-EO treatment in IFN-γ/histamine-induced NCTC254 cells [51].

Matricaria chamomilla Essential Oil (MC-EO)
Matricaria chamomilla L., also known as German chamomile, is a member of the Compositae family [70].Matricaria chamomilla (M.chamomilla) is reported as possessing traditional uses; it is used in the treatment of gastrointestinal conditions [71] and has antiinflammatory [72] and anti-spasmodic properties [73].In addition, it is reported that M. chamomilla EO (MC-EO) promotes wound healing and repairs the wounded skin barrier [74].Moreover, Wang et al. found that MC-EO decreased the pro-inflammatory factors such as TNF-α and IL-6 during eczema [75].The major component of MC-EO is azulene [70].The inflammatory cytokines-IL-1β, IL-6, and TGF-β-are attenuated by via MC-EO treatment through downregulation of phosphorylated (p)-Akt, the p-mammalian target of rapamycin (p-mTOR), and the p-p38 pathway in IL-22, TNF-α, or LPS-stimulated HaCaT cells [70].In addition, not only the clinical symptoms of psoriasis, such as erythema, thickening, and scaling, but also the skin inflammation cytokines are alleviated through the downregulation of p-phosphoinositide 3-kinase (PI3K) and p-mTOR by treatment with MC-EO in a mouse model of IMQ-induced psoriasis [70].Moreover, treatment with MC-EO decreases scratch frequency and serum levels of immunoglobulin (Ig)E, IgG, and histamine in a mouse model of 2,4-dinitrochlorobenzene (DNCB)-stimulated atopic dermatitis (AD) [76].Moreover, the symptoms of eczema, such as skin erythema, exudation, thickening, rough surface, and swelling, are reduced by treatment with MC-EO in a DNCB-induced eczema mouse model [75].The serum levels of IL-6, IL-17, and TNF-α are also downregulated through the downregulation of mitogen-activated protein kinase (MAPK) and the NF-κB pathway by treatment with MC-EO in a DNCB-induced eczema mouse model [75].

Helianthus annuus Plant Oil (HA-PO)
Helianthus annuus (H.annuus), also known as common sunflower, belongs to the Asteraceae family [77].The major components of H. annuus plant oil (HA-PO) are oleic and linoleic acids [77].The HA-EO moisturizes and protects damaged skin barriers.In particular, ozonated HA-PO is an active-components mixture obtained from the partial ozonation of HA-PO.Ozonated HA-PO possesses an anti-inflammatory effect on the skin diseases of mice and humans [78].The symptoms of AD, such as scaling, excoriation, erythema, edema, epidermal thickness, infiltration of mast cell, serum levels of IgE, and spleen weight and lymph node length are decreased by treatment with ozonated HA-PO in an oxazolone (Oxz)-induced AD mouse model [79].In addition, skin hydration function and FLG are recovered by treatment with ozonated HA-PO through the downregulation of IL-4/signal transducers and activators of the transcription (STAT) 3/extracellular signalregulated kinase (ERK) pathway in an Oxz-induced AD mouse model [79].Moreover, the levels of nitrite oxide (NO) and iNOS are inhibited by treatment with ozonated HA-PO through downregulation of IL-1β and TNF-α via MAPK and the NF-κB pathway in serum and skin tissues in an Oxz-induced AD mouse model [79].

Mentha arvensis Essential Oil (MA-EO)
Mentha arvensis (M.arvensis), commonly known as mint, belongs to Lamiaceae family and is a flowering plant species [80].Mentha species are native to Asia, Europe, Africa, Australia, and North America [81].M. arvensis has been commonly used in many medicines for its anti-inflammatory and anti-oxidant activities [82].The major components of M. arvensis EO (MA-EO) are menthol, menthone, and piperitone [80].The inflammation mediators, such as PGE2 and NO, IL-1β, and IL-6, are decreased by treatment with MA-EO through the downregulation of iNOS and COX-2 in LPS-exposed HaCaT keratinocytes [80].In addition, the clinical symptoms of AD, such as erythema, edema, and ear thickness, as well as the scoring AD index, are improved by treatment with MA-EO in a DNCB-induced AD mouse model [80].Moreover, infiltration of mast cell and epidermal layer thickness are attenuated by treatment with MA-EO in a DNCB-induced AD mouse model [80].Furthermore, the formation of the nucleotide-binding oligomerization-domain-like receptor (NLR) family pyrin-domain-containing 3 (NLRP3) inflammasome is attenuated by treatment with MA-EO in the macrophage of a DNCB-induced AD mouse [83].

Rosmarinus officinalis Essential Oil (RO-EO)
Rosmarinus officinalis (R. officinalis) L., also known as rosemary, is a perennial evergreen shrub [84].Rosemary is often used to treat digestive problems, the nervous system, and allergies in Morocco [85].Takaki et al. assessed the anti-inflammatory effect of R. officinalis EO (RO-EO) and reported that RO-EO treatment reduced effusion volume and leukocyte migration in a carrageenan-stimulated rat model [86].The major components of RO-EO are camphor and eucalyptol [84].The symptoms of AD are improved by treatment with RO-EO in a DNCB-induced AD mouse model [84].In addition, serum levels of IL-6 and TNF-α are attenuated by treatment with RO-EO through regulation of the Janus kinase (JAK)/STAT/MAPK pathway in a DNCB-induced AD mouse model [84].

Curcuma longa Essential Oil (Cl-EO)
Curcuma longa (C.longa), is a member of the Zingiberaceae family and is grown mainly in Asia and India [87].The skin penetration effects of the rhizome extracts, molecules, and EO of Curcuma species in skin diseases are reported, assuming no toxicity [88].The major components of C. longa EO (Cl-EO) are terpinolene and α-phellandrene [89].The levels of inflammatory cytokines, including, IL-6, IL-1β, and TNF-α, are downregulated by treatment with Cl-EO in LPS-or TPA-stimulated HaCaT cells [89].In in vivo systems, the levels of IL-1β, IL-6, and TNF-α are decreased by treatment with Cl-EO in the serum of a TPA-induced inflammatory mouse model [89].In addition, ear edema and leucocyte infiltration are reduced by treatment with Cl-EO in a TPA-induced inflammatory mouse model [89].

Lavender-Essential Oil (L-EO)
Lavandula angustifolia, also known as lavender, belongs to the Labiatae family and has been used as either a form of dried plant or for its volatile oils due to its diverse therapeutic and cosmetic properties [100].Lavender EO (L-EO) has been reported to possess numerous biological properties, including anxiolytic [101], neuroprotective [102], anti-oxidant [103], analgesic [103], anti-inflammatory [103,104], anti-microbial [105,106], wound healing [107], and anti-joint-pain properties [108].The symptoms of psoriasis, such as thickness, erythema, and scaling, and the inflammatory cytokines levels of T-helper (Th)-17-specific cells, such as IL-17 and IL-22, and Th-1-specific cells, such as TNF-α and IL-1β, are reduced by treatment with L-EO in an IMQ-induced psoriasis mouse model [109].In addition, the major compounds of L-EO are linalool and linalyl acetate [107], which represent the alleviation effects of psoriasis, such as the reduction of erythema, thickness, scaling, keratin, pigmentation, and curvature, as well as the inflammatory cytokines levels of Th-17-and Th-1-specific cells by downregulating C-C motif chemokine receptor (CCR) 6 and IL-17 expression in an IMQ-induced psoriasis mouse model [109].In addition, linalool and linalyl acetate exhibit an anti-inflammatory effect against a carrageenan-induced edema model [110].

Zanthoxylum coreanum Essential Oil (ZC-EO)
The Zanthoxylum species belongs to the Rutaceae family and has been used as a source of spices in Asian cuisine and traditional Asian medicine [111,112].Zanthoxylum coreanum (Z.coreanum) has been shown to have anti-viral activity against picornaviruses [113].The major components of Z. coreanum EO (ZC-EO) are β-Ocimene and α-pinene [114].The AD-like skin lesions, such as large ulcers, ear swelling, and hyperkeratosis, the thickness of the epidermis and dermis, and inflammatory cell infiltration, are inhibited by treatment with ZC-EO through the downregulation of NF-κB and the phosphorylated MAPK pathway in a DNCB-induced AD mouse model [114].

Anti-Cancer Effect of EOs
EOs are concentrated hydrophobic liquids from aromatic plants that exert anti-cancer effects on various cellular targets [115].Melanogenesis is a pivotal process in melanocytes, which possess melanosomes to synthesize and store melanin pigment [116].This process is tightly regulated by several enzymes, including tyrosinase and tyrosinase-related proteins (TRPs)-1 and -2 [117].These enzymes are responsible for initiating and regulating melanogenesis [117].In addition, these enzymes contribute to the completion of the process and act as modifiers to regulate pathway velocity [118].Among melanogenesis-associated enzymes, TRP-1 and TRP-2 stabilize tyrosinase activity and maintain the structural integrity of melanosome [118].Moreover, melanogenesis is associated with H 2 O 2 production through the enzymatic and non-enzymatic reactions and subsequently induces oxidative stress in melanocytes [119,120].ROS production is derived by α-melanocyte, stimulating hormone (MSH)-induced melanogenesis [121].Treatment of several ROS scavengers and ROS inhibitors reduces the UV-induced melanogenesis [122,123].Therefore, the development of melanogenesis inhibitors, anti-oxidants, and ROS scavengers has been revealed to be beneficial in the treatment of hyperpigmentation in skin care fields.This section is focused on EO's anti-cancer effects, including their anti-melanoma effects.

Artemisia capillaris Grass Clumps Essential Oil (AC-EO)
The ethanol extract and ethyl acetate fraction of Artemisia capillaris (A.capillaris) possess anti-cancer [156] and anti-oxidant functions [157], respectively.Treatment with A. capillaris grass clumps EO (AC-EO) is found to reduce both intracellular and extracellular melanin contents via the downregulation of TRP-1 signaling in melanoma B16F10 melanoma [118].The skin is exposed to various external stresses, such as ROS, which induce various deleterious effects and the apoptosis of keratinocytes [158,159].AC-EO treatment is found to upregulate the proliferation of H 2 O 2 -exposed B16F10 melanoma [118].

Origanum syriacum (OS) and Origanum Ehrenbergii (OE)
Origanum syriacum (OS) and Origanum ehrenbergii (OE) are two naturally growing plants in Lebanon that belong to the Lamiaceae family [57].These plants are used in maceration for rheumatism and neuralgic treatments [169].The major components of OS and OE are aromatic terpenoids, quinones, and CRV [170].The cell viability of B16-F1 melanoma is found to be dose-dependently decreased following treatment with OS-EO and OE-EO [171].Melanin levels are downregulated by treatment with OS-EO, OE-EO, or CRV without any alterations to tyrosinase activity in B16-F1 melanoma [171].These results indicate that both EOs and CRV exhibit anti-melanogenic activity by competing with tyrosine as a tyrosinase substance.

Cinnamomum cassia Essential Oil (CC-EO)
Cinnamomum cassia (C.cassia) Presl is broadly grown in China [167].Assuming no toxicity, the dried form of C. cassia stem bark is known to exhibit multiple biological activities, such as anti-bacterial [183], anti-inflammatory [184], and anti-diabetic properties [185], and its traditional uses are reviewed in [186].Additionally, it has been found that the extraction of C. cassia twigs suppresses tyrosinase activity [187].The C. cassia EO (CC-EO) is known to possess hypouricemic [188] and anti-fungal activities [189].The major components of CC-EO are cis-2-methoxycinnamic acid and cinnamaldehyde [167].Melanin content is reduced by treatment with CC-EO or its major components through the inhibition of tyrosinase activity and its expression in α-MSH-induced B16 melanoma [167].α-MSH-mediated oxidative stress and lipid peroxidation are attenuated by treatment with CC-EO or cinnamaldehyde through the regulation of GSH level and CAT activity in α-MSH-induced B16 melanoma [167].

Chrysanthemum boreale MAKINO Essential Oil (CB-EO)
Chrysanthemum boreale (C.boreale) MAKINO is a perennial herbaceous plant and is a member of the Compositae family [194].The C. boreale species, including C. boreale MAKINO, are broadly grown in East Asia, including Korea, China, and Japan [195,196], and, assuming no toxicity, they are widely used as medicinal plants due to their biological properties, such as anti-inflammation and anti-bacterial action, skin-regenerative properties, and wound healing properties [194,196,197].The major compounds of CB-EO are camphor, germacrene-D, and β-thujone [196].Moreover, treatment with C. boreale MAKINO EO (CB-EO) from the flower reduces melanogenesis through the downregulation of tyrosinase via the ERK and MAPK pathway in α-MSH-stimulated B16BL6 melanoma [198].

Artemisia argyi Essential Oil (AA-EO)
The anti-inflammatory activity of AA-EO has been addressed in Section 2.12.Melanogenesis is attenuated by treatment with AA-EO through the downregulation of tyrosinase activity or oxidative stress in α-MSH-stimulated B16F10 cells [91].

Acorus macrospadiceus Essential Oil (AM-EO)
Plants of the Acorus species belong to the Acoraceae family and are distributed in India, Europe, and Asia [224].Assuming non-toxicity, the biological activities of the EOs extracted from Acorus species are reported.The volatile oils from Acorus (A.) calamus rhizomes possess diverse biological properties, including anthelmintic activities [225] and acetylcholinesterase-inhibitory activities [226].In addition to Acorus calamus, the volatile oil from A. gramineus rhizomes possesses a neuroprotection function [227].The major components of A. macrospadiceus EO (AM-EO) are chavicol methyl ether and nootkatone [228].Melanogenesis is reduced by treatment with AM-EO through the downregulation of tyrosinase activity or oxidative stress in α-MSH-stimulated B16F10 cells [228].

Modulation of Skin Proliferation
Wound healing is complex physiological process which consists of three dynamic steps, including an inflammatory step, a proliferative step, and a maturation step involving the development of cellular connective tissue and the formation of newly generated epithelial tissue [229,230].The cellular connective tissue is supported by the presence of collagen [231].In addition, dysregulated keratinocyte growth and differentiation lead to aberrant cellular processes, including hyperproliferation, abnormal differentiation, and inflammatory infiltration [232].The hyperproliferation of epidermal keratinocytes leads to the pathogenesis of several cutaneous disorders, such as psoriasis and AD [233].These diseases are characterized by dysregulated epidermal homeostasis, which causes disordered skin proliferation and differentiation [234].This section is focused on the effects of EOs on skin proliferation and regeneration in maintaining epidermal homeostasis.

Pistacia lentiscus L. Plant Oil (PL-PO)
Pistacia lentiscus L., which is known as the lentisk or mastic tree in Greece, belongs to the Anacardiaceae family [243].Pistacia lentiscus PO (PL-PO) is mainly used as a flavor agent in cuisines but is also administered as an ointment to treat wounds [244].The major components of PL-PO are oleic, palmitic, linoleic acids, and phenolic compounds, including tocopherols, carotenoids, and anthocyanins [245,246].PL-PO possesses several biological activities, including anti-bacterial, anti-oxidant, proliferation, and wound healing effects [247][248][249][250]. Treatment with PL-PO liposomes induces the proliferation of HaCaT keratinocytes [251] and enhances the migration of HaCaT keratinocytes [251].The application of liposomes with PL-PO might be a useful approach in the field of cosmetics.

Lavender-Essential Oil (L-EO)
L-EO is derived from the blossoms of Lavandula angustifolia [252].As described in Section 2.13, the major components of L-EO are linalool and linalyl acetate [107].Based on various reports, L-EO is expected to exhibit beneficial effects in wound healing [253][254][255][256]. Wound area is found to be rapidly reduced by treatment with L-EO compared with that of the control in a rat model [107].The synthesis of type-III collagen (Col III) a1, an essential component for the formation of granulation tissue in the early phase of wound healing, is upregulated by L-EO treatment in rat wound lesions [107].In addition, the mRNA levels of Col IIIa1 and Col Ia2 are enhanced by L-EO treatment in a wounded rat model [107].TGF-β is known to induce the fibroblasts proliferation and production of both Col I and Col III [257].The level of TGF-β is upregulated by L-EO treatment in the wound lesions of rats [107].In addition, TGF-β induces the differentiation of fibroblasts to myofibroblasts in wound granulation tissue [258].Differentiation into myofibroblasts and wound contraction are observed in rat wound lesions treated with L-EO [107].

Calophyllum inophyllum Plant Oil (CI-PO)
Calophyllum inophyllum (C.inophyllum), a member of the mangosteen family, is a large, evergreen tree of South India, Malaysia, Africa, Polynesia, and the Philippines [259].C. inophyllum PO (CI-PO; syn: Tamanu oil) is a plant oil acquired from the seeds of the C. inophyllum tree [260].CI-PO possesses anti-inflammatory [261], anti-microbial [262,263], and anti-fungal [263].The components of C. inophyllum are calophyllolide, calophyllic acid, inophyllum, and polyphenols that possess wound healing and anti-oxidant properties [264].Wound area is reduced by treatment with CI-PO through the enhancement of mature granulation and the density of fibrosis and collagen in wounded skin in a rat model [265].Parrotiopsis jacquemontiana (P.jacquemontiana) belongs to the Hamamelidaceae family [266] and is reported to possess medicinal properties such as anti-microbial [266] and anti-cancer properties [267].The major compounds of P. jacquemontiana PO (PJ-PO) are 2, 6-dimethyl-8-oxoocta-2, 6-dienoic acid, syringol, and catechol [268].Wound contraction is inhibited by treatment with PJ-PO through collagen synthesis in wounded skin in a rat model [268].In addition, the thickness of the epidermis layer is accompanied by faster fibroblast cells migration from the dermal layer to the epidermal layer in the treated groups [268].

Summary
Naturally derived EOs and other plant-based active components are believed to possess various biological pharmacological properties and are used as raw materials in drug development.Owing to the various functions of EOs and their active components in the skin, they are considered to be potential treatments for different diseases (Table 1).Although EOs have various and positive effects not only on the skin but also on other tissues and organs, EOs are associated with several drawbacks, such as hypersensitivity reactions, appropriate doses, individual reaction differences, toxicity, and side effects.Because of the stratified structure, various cell types, and the presence of pigmentation in the skin tissue, research on the modulation of skin homeostasis should be dealt with in particular.Thus, scientific evidence pertaining to EOs, such as the identification of the biological and physiological mechanisms of EOs, should be developed and reinforced for skin safety concerns.Moreover, it is necessary to overcome skin cancer and skin diseases, including psoriasis, eczema, and fungal infections, through the discovery of numerous potential EO substances as alternatives to synthetic drugs.Leaf, rhizome, and stem (camphor, camphene, β-pinene, p-cymene, α-pinene, and D-limonene) [191][192][193] Chrysanthemum boreale MAKINO EO Anti-melanogenesis, anti-inflammatory, anti-bacterial, skin regeneration, and wound healing C. boreale Flower [194,196,197] Vitex negundo EO Anti-melanogenesis, anti-nociceptive, anti-convulsant, anti-inflammatory, and analgesic V. negundo leaves and roots (sesquiterpene and monoterpene) [199][200][201][202][203][204] Achillea millefolium EO Anti-melanogenesis, alleviation of inflammatory, gastrointestinal disorders, hepatobiliary conditions, overactive cardiovascular, and respiratory infection

Figure 1 .
Figure 1.Schematic of the alleviation effect of PF-EO treatment in an imiquimod-mediated mouse model of psoriasis.PF-EO treatment induces the downregulation of psoriasis symptoms, such as erythema, scaling, and epidermal thickening, and the expression of inflammatory factors and psoriasis-related factors [22].The red arrow indicates downregulated expression in the epidermis of a

Figure 1 .
Figure 1.Schematic of the alleviation effect of PF-EO treatment in an imiquimod-mediated mouse model of psoriasis.PF-EO treatment induces the downregulation of psoriasis symptoms, such as erythema, scaling, and epidermal thickening, and the expression of inflammatory factors and psoriasis-related factors [22].The red arrow indicates downregulated expression in the epidermis of a PF-EO-treated mouse.PF-EO: Perilla frutescens L. Britt essential oil; IL: interleukin; iNOS: inducible nitric oxide synthase; COX-2: cyclooxygenase-2; IFN: interferon.

Table 1 .
Different functions of essential oils in the skin and their natural sources.