Promising Natural Products in New Drug Design, Development, and Therapy for Skin Disorders: An Overview of Scientific Evidence and Understanding Their Mechanism of Action

Introduction

The skin, which is the largest organ in the body, consists of several layers, including the epidermis, dermis, and hypodermis. The skin plays an important role by conferring protection and acting as a barrier to the body. It also regulates body temperature and facilitates sensation. The most common concern with regards to the skin is skin disorders or skin disease. In fact, 50% of the adult population have suffered from some type of skin disorder at one point in their lives, with one in three having the chronic or mild condition.¹ According to Kassab et al,² skin disorders remain one of the biggest challenges that affect the quality-of-life of adults and teenagers alike.

Skin

Being the largest organ in the body, skin protects the internal organs from various external insults, such as invading pathogens (bacteria, fungi, viruses, parasites, and mites), exogenous physical stresses, chemicals, and others. Besides, it has an essential role in regulating temperature, electrolytes, water, and others, and providing essential vitamins to the whole body, ie, Vitamin D. Unlike other mucosal epithelia, skin possesses a dry (due to lipids) and a formidable layer of epithelia, which prevent the ease of access of microorganism entry. Despite other routes of pathogen entry, the skin plays an important role in protecting from pathogens. Besides, skin cells also produce many chemicals, such as fatty acids and defensins (antibacterial peptides), to destroy the pathogens. As such, skin is composed of three different major layers, which harbor several types of cells, including immune cells, that perform various functions (Figure 1).³ Considering this high amount of immune niches in the skin, it is regarded as “skin immune system” or “tertiary lymphoid structures” (TLS) or “tertiary lymphoid organs” (TLO).^4,5

Figure 1 Skin anatomy in health. The skin structure is mainly divided into the epidermis, dermis, and subcutaneous/hypodermis. The epidermis is further divided into the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. The epidermis contains specialized cells, such as Langerhans cells (LCs), CD8+ T-cells, melanocytes, and others. Although skin appendages (hair, hair follicles, sweat glands, and sebaceous glands) are the main entry points for microorganisms, they are useful in transportation (from outside to inside and vice versa), prevention from mechanical damage, keeping skin dry, regulating temperature changes, protecting from ultraviolet light, and other. The dermis is the place where the majority of skin immunological interventions take place. The dermis is composed of fibroblasts, tissue-resident T-cells (TRM; including CD4+ T-cells [Th1, Th2, and Th17 cells] CD8+ T-cells, γδT cells, NKT cells), dendritic cells (including plasmacytoid DCs, tissue-resident DCs), tissue-resident macrophages, mast cells and others, and dense extracellular matrix (ECM). ECM is composed of collagen and elastin fibres, which occupies the extracellular space. The ECM provides a basement structure for the blood vessels, lymphatic vessel, and neurons through which transportation of immune cells and sensory functions are carried out, respectively. Beneath the dermis, a fatty layer which protects the host is the subcutaneous layer, also called subcutaneous adipose tissue. Along with the dermis, the subcutaneous layer also harbors a variety of immune cells, including T-cells, B-cells, macrophages, and others, and thus is collectively called the stromal vascular fraction (SVF). Despite immune cells function, adipocytes tissue secretes several bioactive proteins, collectively called adipokines (such as leptin, resistin, and adiponectin). These adipokines have various functions, including metabolic, inflammation, coagulation, vascular homeostasis, and others. Besides adipokines, adipocytes also secrete other molecules, such as IL-6, TGF-β, IGF-1, and others. Dermal DCs and LCs, which carry self/non-self-antigens (from PAMPs or DAMPs), migrate to lymph nodes and become antigen-presenting cells and present the antigens to the lymph node resident T-cells. The antigen-experienced T-cells differentiated into T-helper cells and migrate to the injured skin scite. Similarly, B-cells produce antibodies against self/non-self-antigens. The stratum corneum is the outermost layer (10–30 µm) in the skin, which is formed majorly from dead keratinocytes (also called denucleated keratinocytes; corneocytes), intracellular lipids (providing the hydrophobic nature to the skin), and others. The stratum lucidum is a very thin layer of dead cells in the skin after the stratum corneum that can appear as a translucent layer under a microscope. The stratum granulosumis composed of 3–5 layers of cells, which are composed of dark clumps of cytoplasmic granules. The stratum spinosum,also known as the prickle cell layer, originated from the keratinocytes that were differentiated and moved from the stratum basale. The stratum basale is a single layer of undifferentiated keratinocytes, which is the source of the stratum spinosum, and composed of melanocytes (Pigment melanin secreting cells). More information on skin anatomy can be found in excellent reviews.3,10,11,210 Created with BioRender.com.  Abbreviations: DAMPs, damage-associated molecular patterns; IGF, Insulin-like growth factor; NKT, natural killer T-cells; PAMPs, pathogen-associated molecular pattern; TGF, transforming growth factor, IL, interleukin.

Dysregulations in the skin-associated lymphoid system lead to chronic, inflammatory, and hyperproliferative skin diseases (Table 1). In addition, damaged or tender skin is the best route of entry for many microorganisms. Therefore, regulation of immune responses in the skin is at most important. The skin-associated lymphoid system is composed of tightly coordinated innate and adaptive arms of the immune system. Despite the innate immune system, humoral immunity (also called antibody-mediated immunity) in the adaptive immune system is also critical for regulating immune homeostasis in the skin. B-cells and their subtypes in the skin have been implicated in antibody-mediated protective immunity. However, the type of antibody production (either self-reactive or non-self-reactive) depends on the type of antigen (self or foreign) exposed, and may drive or suppress the inflammatory response. Therefore, B-cells are implicated in both homeostatic and pathogenic mechanisms in the skin. Although information about localized skin-resident B-cells is inadequate, their migration, via expressing cutaneous lymphocyte-associated antigen (CLA) and chemokine receptors, to the skin during the inflammatory diseases is well established.⁶

Table 1 List of Skin Diseases or Disorders

Several autoimmune skin diseases are positively correlated with the infiltrating B-cell subsets.^6–9 Moreover, the skin-homing B-cells respond to local antigens and produce antibodies, which is devoid of primary and secondary lymphoid organs. These antibodies play a crucial role in autoimmune diseases. Some B-cell-mediated autoimmune diseases are mostly by autoreactive B-cells that are possibly devoid of T-cell involvement. The precise source of the autoreactive B-cells in the skin is unknown and is debatable. It is assumed that autoreactive B-cells are generated from either bone marrow or secondary lymphoid organs. However, how these cells are produced by escaping the central or peripheral tolerance checkpoints is still an unanswered question. Once autoreactive B-cells differentiate into memory B-cells and plasma cells in the germinal centers, they become culprits for systemic secretion of autoantibodies. Once the plasma cells are generated, it’s their innate nature to reach bone marrow and become a reservoir for a long time (even lifelong) of autoantibody secretion, upon antigen encounter. In skin-associated or cutaneous autoimmune diseases, the presence of autoantibodies is considered a unique diagnostic method. The skin resident autoreactive B-cells amplify or aggravate the autoimmune disease via antibody secretion (IgM, IgG, and IgA), antigen-presentation, T-cell stimulation, pro- and anti-inflammatory cytokine secretion (IL-6, IL-10, and TGF-β), and growth factors secretion (platelet-derived growth factor, basic fibroblast growth factor) in the microenvironment.

Innate and Adaptive Immune System of the Skin

Skin-associated lymphoid tissue contains both innate and adaptive immune systems, which confer protection locally and systemically.^10,11 Disturbance in the above system leads to episodes of opportunistic infections and the development of tumors or other immunological diseases. The skin protects the host from most infectious agents by two mechanisms; antigen-nonspecific and antigen-specific.^10,12 If a physical barrier (stratum corneum or sebaceous gland secretions) is breached, the innate immune system comes into action. Like other parts of the body, the innate immune system is the first-line defence in the skin, and keratinocytes, monocytes, macrophages, Langerhans cells, dendritic cells, mast cells, and complement components are the innate components of the skin. Among them, keratinocytes are the first responders against any insults.^10,11 These innate cells possess a high level of pattern-recognition receptors (PRRs), which sense pathogen-associated molecular pattern molecules (from pathogen)/damage-associated molecular patterns (from UV radiation or physical damage) (Figure 1) followed by the induction of downstream signaling via NF-kB or inflammasome to produce signaling molecules, such as cytokines, chemokines, and others. Specifically, keratinocytes and mast cells secrete antimicrobial peptides, cathelicidins, and β-defensins, which also initiate the inflammatory response.^3,10,11 Although the above-mentioned antigen-nonspecific mechanism is wise enough to prevent the spread of pathogens, the innate system alone is not enough to protect the host from reinfection. Nevertheless, the secreted mediators from the innate immune system activate other bystander cells and tissue-resident lymphocytes, particularly T-cells. Besides cytokines and chemokines secreted by melanocytes, fibroblasts also influence the T lymphocytes.

Innate immune system functions are synergized by the adaptive immune system, composed of T-cells, B-cells, and NK cells. Figure 2 depicts the interactions of the innate and acquired immune systems in cutaneous bacterial infection. Although B-cells have a very limited direct role in protection, T-cells-mediated immunity is well documented in skin diseases. Interestingly, a high amount of T-cells reside in the healthy dermal tissue, which is 2-fold higher than circulating T-cells.^10,11 LCs and DCs in the innate system present the self and non-self-antigens to the T-cells in the skin-draining lymph nodes (Figure 1). The antigen educated T-cells in the lymph nodes become T effector cells (T_EM, effector memory T-cells) and migrate to the site of infection/damage. Some T-cells (T_CM, Central memory T-cells) reside in the lymph nodes, and act as a reservoir of skin T-cells. Upon reaching the skin, T-cells proliferate and expand into different subsets, such as Th1, Th2, Th17, Th22, and Treg cells, and each subset has its role in maintaining homeostasis.^10–12 Further, T helper cells aid in the induction of activation of B-cells and B-cell mediated protection (Figure 2).

Figure 2 Innate and acquired immune systems interactions in cutaneous bacterial infection. Disruption in the aforementioned barrier leads directly to occasional infections. In reaction to bacteria infringing the epithelial barrier, keratinocytes will produce chemokines, antimicrobial peptides, and cytokine,s which leads to an increase in leukocyte extravasation stimulating the migration into the skin and guiding these cells via chemotactic gradients. Dendritic cells convey bacterial antigens to naïve and central T-cells, contributing to pathogen-specific cells being activated producing CD4 and CD8 T-cells which increased targeting of innate responses. Created with BioRender.com.

Once the defence task is completed, either by clearing pathogens or removing damaged cells, the innate cells initiate the resolution phase by producing various immunosuppressive signals, including immunomodulatory cytokines (IL-10, TGF-β) or immunosuppressive mediators (indoleamine 2,3 dioxygenase), selective receptor antagonists (Interleukin-1 receptor antagonist), activating Tregs, and others.³ Functionally, the aforementioned factors regulate the inflammatory cellular response and establish pre-inflammatory/homeostatic conditions in the skin.

In contrast, the aberrations/excessive immune response, such as the antigen-presentation, cytokine secretion, differences in distinguishing self and non-self leads to various disease, including autoimmune diseases. On the other hand, inadequate immune response in the skin is more prone to infectious diseases and tumors. This impairment of immune surveillance can occur by a variety of agents, such as chemicals, microorganisms, radiation, and others.¹²

Skin disorders or diseases may include eczema, fungal infections, benign tumors, and viral warts.¹ Other skin conditions, including acne, atopic dermatitis, wound, skin cancer, psoriasis, iatrogenic dermatitis, infection, and inflammation, may be age-related.¹³ Humans are affected by hundreds of skin disorders. Because some of the symptoms of the most common skin infections are similar, it is essential to know the differences between them. The most common skin diseases are listed in Table 1, which are separated by types. Some other influencing factors include lifestyle, such as diet. For example, high dietary consumption of oily or fatty food, sweet food, chocolates, dairy products, and nuts is related with facial acne or acne worsening.² Other risk factors contributing to a worsening of skin disease include the socioeconomic status of the population. Lower socioeconomic status may have an impact on access to healthcare,¹⁴ resulting in a higher demand for skin infection and eczema treatment in this population group.¹ Skin disorders generally have a greater effect on patients as they mostly affect the quality-of-life. Kassab et al² reported that skin disorders impact the daily physical, social, and psychological features of patients. Physical impact is the severity of the rash and the area which may contribute to itching and flaking. Psoriasis is another important skin condition that leads to severe itching if not carefully treated.² Meanwhile, social impact is the relationship between humans in which an individual with skin disease may isolate himself. Finally, anxiety and depression are two psychological impacts of skin disorders incurred as a result of frustration and embarrassment.²

Role and Importance of Natural Products in Drug Development Against Skin Disorders

Contemporary medicine is a therapy that uses biomedical research, health sciences, genetics, and medical technology to detect, cure, and prevent disease and injury by using pharmacological and non-pharmacological approaches. In addition to that, it also involves ionizing radiation, psychotherapy, and biologics. Natural products or specifically botanicals are very important as a therapeutic approach in contemporary medicine when designed in suitable dosage as they can become an effective therapy to treat the disease, have less side-effects compared to most pharmaceutical drugs, and are not so expensive compared to modern pharmaceutical drugs if these botanicals are used and administered wisely, properly, and rationally. Malik et al¹⁵ reported that herbal medicine is essential and has become the alternative treatment to cure and control skin disorders due to its fewer side-effects and the cost of treatment with high efficacy. In developing countries, the local public usually depend on natural products or traditional drugs to manage their skin conditions and healthcare. Although theories have speculated that natural products give a slower effect compared to modern pharmaceutical drugs, generally, the natural products help to cure acute and chronic ongoing symptoms as they will work slowly and give a cumulative effect.¹⁶ Furthermore, natural products can cover the different targets with multiple active principles in a balanced manner when treating chronic complex disease as they have fewer side-effects.¹⁷ Previous studies stated that natural products had many uses and benefits, like antimicrobial, wound healing, treating burn injuries, and acting as an anti-inflammatory against various skin disorders.¹⁸ According to Malik et al¹⁵ the natural products were usually prepared from the paste of the plant parts, like leaves, roots, and others, with other ingredients.

In drug development, the researchers usually do studies about natural products, especially plants with few constituents. The plant constituents or phytoconstituents are categorised based on their function in a basic metabolic process, into primary and secondary metabolites. Generally, primary metabolites imply the basic life functions, which make them much alike in all living cells, meanwhile secondary metabolites are the product of secondary pathways that can be the lead compounds in the manufacturing of medication.¹⁹ The primary metabolite includes amino acids, nucleic acids, sugars, tricarboxylic acids, polysaccharides, and protein. On the other hand, secondary metabolite classes include phenolics, lipids, saponins, carbohydrate, alkaloids, and terpenes, classed according to their chemical structures.¹⁹ These phytoconstituents have their different therapeutic role. Among the above-mentioned secondary metabolites, the phenolics had a protective role against oxidative damage illness as they usually act as the protector of the plant against pathogens and are also responsible for growth and reproduction of plants. Meanwhile, alkaloids, a nitrogen-containing constituent, are also beneficial as drugs, especially psychoactive drugs, medicine, and poison, as they can be used as a muscle relaxant, to relieve pain, and as an anesthetic.²⁰ Saponins are useful in treating cancer, bone health, blood cholesterol level, and stimulating the immune system.²⁰ Other constituents like terpenes were beneficial for the taste, fragrance, pigment of the plant, thermoprotectant, and signaling functions in the plant, and also therapeutic uses like being an anti-inflammatory, wound healing, and anti-bacteria.²¹ Due to this action of phytoconstituents, the researchers were interested in developing natural products or herbal medicine to treat various diseases, especially skin disorders.

Patients may consume supplements to treat skin problems and improve their conditions. Supplements like vitamins, such as vitamins C and E, honey, and tea tree oil can improve skin condition and decrease the symptoms of skin disease.² Another product commonly used in the treatment of skin diseases like acne is Aloe vera, which has an anti-inflammatory effect and is a good antioxidant.²² Overall, due to the wide range of benefits and versatility, natural products are commonly applied in treating various skin disorders as, besides being safe, they are derived from natural sources such as fruits and vegetables. This review aims to provide an overview of existing knowledge about the effects of natural products such as mangiferin, lutein, curcumin, resveratrol, embelin, naringenin, quercetin, lycopene, gingerol, and apigenin (Figure 3) on skin conditions through an analysis of the most important studies conducted to date, as well as recommendations for future research.

Figure 3 Chemical structure and source of natural products reported against skin disorders. Created with BioRender.com.

Methods

To complete the review, relevant studies and literature were searched from several scientific databases, including PubMed, Google, Google Scholar, and ScienceDirect. The categories of keywords used for the search included “Natural Products” or “Natural Compounds” or “Skin Disorders” or “Skin Disease” or “Mangiferin” and “skin” or “Lutein” and “skin” or “Resveratrol” and “skin” or “Curcumin” and “skin” or “Embelin” and “skin” or “Naringenin” and “skin” or “Quercetin” and “skin” or “Lycopene” and “skin” or “Gingerol” and “skin” or “Apigenin” and “skin”. After screening the literature, ten naturally isolated compounds, which have been investigated widely for the effects against various skin disorders, including in vitro and in vivo models, were included.

The Effect of Natural Products Against Skin Disorders

Mangiferin

Mangiferin is a well-known compound obtained mainly from Mangifera indica (Mango), which belongs to the family of Anacardiaceae. It is also obtained from honeybush (Cyclopia sp). Mangiferin, chemically known as 2-C-β-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone, has various pharmacological and biological properties that have been confirmed in many past studies. It is a strong antioxidant, chemopreventive, and anti-inflammatory agent.²³ Notably, it has cytotoxic properties where there is apoptosis against tumor cells. Coupled with the antioxidant effect, it confers immense benefits to the skin by being absorbed into the deeper skin layers.²³ Additionally, Navarro et al²⁴ reported that mangiferin has antimicrobial, antipyretic, antiviral, antibacterial activities in addition to having gastroprotective and hepatoprotective effects, as well as being applied as a lipid-lowering agent. Some reports claimed that the antiproliferative properties are dependent on mango cultivar and the type of cancer cell lines.²⁴

Mangiferin is used against skin aging as it can preserve the skin and prevent wrinkles by inhibiting elastase and collagenase as well as water loss.²⁵ Skin aging is caused by exposure to sunlight containing ultraviolet (UV) B or UV radiation (UVR), also known as photo-aging, besides being caused by the natural aging process or intrinsic aging.^26,27 Mangiferin can increase the skin collagen bundles, thus protecting it from damaging UVB exposure.²⁶

Skin aging is contributed to by a reduction in collagen that is due to oxidative stress.²⁷ Collagen degeneration leads to an increased in matrix metalloproteinase (MMP) activity; a matrix-degrading enzyme. The increase in MMP activity contributes to photo-aging, enhancing the skin aging process.²⁶ Although there are many types of MMP, Chae et al²⁷ reported that MMP-1 is important and is responsible for collagen reduction due to oxidative stress that is regulated by extracellular signal-regulated (ERK) and JUN-N-terminal kinases (JNK). Mangiferin blocks the MMP-1 expression by suppressing the ERK and JNK pathways and also through inhibition of MEK and SEK pathways as induced by hydrogen peroxide in human epidermal keratinocyte line (HaCat) cells.²⁷ However, Kim et al²⁶ stated that mangiferin inhibits MMP-9 activity that is also generated via the MEK and ERK pathways. Additionally, oral administration of mangiferin decreases wrinkle formation due to UVB radiation, leading to skin aging.^28,29

The inflammatory reaction is one of the conditions associated with a skin disorder. The most common inflammatory skin disease includes contact dermatitis, which causes skin lesions and destruction of the skin barrier, making its treatment challenging.³⁰ Currently, different drugs are being used against inflammatory skin disorders like atopic dermatitis and psoriasis, which reduce the quality-of-life.³¹ In another recent study, mangiferin formulated with nanoemulsions can reduce skin damage induced by transcutol-P (TPA), while improving skin inflammation and wound healing.³² In past studies, mangiferin was reported to inhibit the inflammatory activity caused by macrophages, thus influencing skin inflammation. Inflammatory mediators such as tumor necrosis factor alfa (TNF-α) and its inflammatory biomarkers like inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, and IL-6 that cause skin lesions, eg, psoriasis and dermatitis, are also ameliorated by mangiferin administration.³⁰ In addition, mangiferin can inhibit CD68 activity, which is an important macrophage biomarker contributing to dermatitis.³⁰

Besides its ability to treat skin disorders like a wound and allowing skin regeneration, mangiferin is a good antioxidant. It improves wound healing closure by stimulating cell proliferation and migration of fibroblasts during the wound healing process while reducing myeloperoxidase (MPO) activity which is an enzyme involved in inflammation.³³

In another study on diabetic rats, mangiferin caused a reduction in the oxidative damage in skin tissue by increasing the nuclear factor erythroid 2-related factor (Nrf-2), thus maintaining tissue proliferation and growth while boosting wound healing.³⁴ Due to its anti-inflammatory and antioxidant properties, mangiferin facilitates skin flap regeneration and reduces inflammation.^35,36 Furthermore, mangiferin-loaded liposome is an efficient local treatment for skin flap regeneration as it produces several multipotent flap-protective therapeutics effects.³⁷ According to Mao et al³⁸ mangiferin formulated as a hydrogel delivery system boosts the development of skin flap regeneration and enhances survival.

Due to its anti-angiogenic effect that can block tumors from developing their own blood cell, mangiferin is useful for skin cancer or melanoma. Mangiferin blocks the basic fibroblast growth factor (bFGF), which is a tumor growth factor and a TNF-dependent-cell migration. Additionally, based on Ingenuity Pathway analysis (IPA) enrichment, mangiferin blocks the expression of IL6, TNF, PLAU, kinase insert domain receptor (KDR), vascular endothelial growth factor receptor 2 (VEGFR2), interferon gamma (IFN-γ), fibroblast growth factor 1 (FGF1), chemokine ligand 2 (CCL2), MMP19, and placental growth factor (PGF) to stop angiogenesis, metastasis-invasion motility, cell number growth, and viability in cancer signaling processes.³⁹ Additionally, mangiferin can treat skin infections like bacteria and human herpes viruses, like herpes simplex virus (HSV), although the ideal current drug for HSV is a nucleoside. Jie et al⁴⁰ reported that mangiferin, which is also known as chinonin, can reduce the infectivity of HSV infection in vitro where it can act against animal infection caused by HSV. Figure 4 depicts an overview of mangiferin’s effect on skin disorders as well as its mechanism of action.

Figure 4 Effect of mangiferin against skin disorders and its mechanism of action. Mangiferin possessed a wide spectrum of pharmacological and biological properties, including antioxidant, chemoprotective, and anti-inflammatory properties. Besides, it can also inhibit elastase and collagenase can also help to preserve the skin and prevent wrinkles. Mangiferin has the ability to suppress CD68 activity, a key macrophage biomarker linked to dermatitis. Created with BioRender.com. Abbreviations: CD68 and 163, cluster of differentiation 68 and 163; Th1 and Th2, T helper type 1 and 2; IL-6, 1ß, Interleukin 6 and 1 beta; TNF-α, tumor Necrosis Factor alpha; MMP-7 and 1, matrix metalloproteinase-7 and 1; BUN, blood urea nitrogen; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B-cells; Bcl-2, B-cell lymphoma 2; Bax, BCL2 Associated X, Apoptosis Regulator; t-Bid, truncated Bid; Cyto C, cytochrome complex; PARP, Poly (ADP-ribose) polymerase; LDH, lactate dehydrogenase; iNOS, inducible nitric oxide synthase; H2O2, Hydrogen peroxide; CPK, creatine phosphokinase; GSH, glutathione; SOD, superoxide dismutase; CAT, catalase; ROS, reactive oxygen species; MAPKs, mitogen-activated protein kinases; JNK, c-Jun N-terminal kinase; ERK 1/2, extracellular signal-regulated kinases 1/2.

Lutein

Lutein, with its stereoisomer zeaxanthin, is a lipid-soluble compound from the xanthophyll family of carotenoids. Lutein is an essential component in serum and exists in ocular tissue like lens and macula lutea, important for central vision and visual acuity.^41,42 Lutein is also present in the diet, including in dark and leafy green vegetables.⁴² Lutein is formed with 40 carbon atoms and is arranged into eight isoprene units with two oxygen atoms.⁴³ Although its main function is related to eye health, like in treating age-related macular degeneration (AMD) and cataracts, it also has some beneficial effects on the skin. Furthermore, lutein has shown some anti-inflammatory properties.⁴³

Lutein protects the skin by blocking the damaging blue wavelengths or light, thus ameliorating melisma which is a pigmentation disorder that appears as brown patches on the skin, especially on the face.^44,45 In one study, evaluation on carotenoids with lutein and zeaxanthin oral supplements are being conducted. As a result, these two supplements, lutein (10 mg) and zeaxanthin (2 mg), have been shown to have good benefits to the skin, including enhancement of skin tone, luminance, and color.⁴⁵ Furthermore, lutein also protects the skin against skin-damaging sunlight due to UV radiation.⁴⁴

Skin disorders, especially skin aging, can be effectively treated by lutein. Lutein can defend against gene expression induced by UVA, UVB, and UVA1 on individual skin.⁴⁴ Although the functions of MMP-1 mRNA, intracellular adhesion molecule 1 (ICAM-1), and heme-oxygenase 1 are signs of premature aging, oxidative stress and photo-dermatoses, which can develop into skin rash, lutein, and tomato nutrient complex (TNC), provide a good barrier to the skin from UVR that causes skin damage. A study conducted by a team of Italian researchers involved the evaluation of the effectiveness of lutein and zeaxanthin where healthy middle age women (n=40) have premature skin aging were administered with topical lutein and oral zeaxanthin. Based on this study, the two carotenoids provide multiple advantages to the skin. The carotenoids block skin damage as induced by UV radiation and can boost skin elasticity, hydration, and elevate surface lipids. Both administration routes (topical and oral) can promote the skin condition, especially in skin aging.⁴⁴ The carotenoid can enhance the collagen I/elastin aging index of the skin layer, as shown in past research. This research involved female participants who were given supplements containing 1,650 µg carotenoids daily for ten months.⁴⁴

Lutein is useful against skin inflammation, including skin erythema and psoriasis, as confirmed on a mice skin experiment.⁴⁶ Skin inflammation occurs as a result of sun exposure where harmful UVA and UVB can cause oxidative stress and reduce the level of skin and serum carotenoids. In addition, short wavelength UV radiation, like UVA and UVB, causes oxidative stress, while long wavelength UV, such as UVA1, generates gene expression⁴⁶ leading to skin erythema. Lutein can decrease the skin rash (skin erythema) as well as enhance skin health by blocking the UV radiation.

Lutein is also derived from the leafy part of Galittm aparine which can prevent skin disorders like psoriasis and is commonly used in Western countries for this purpose. Lutein has an anti-inflammatory effect due to its antioxidant activity, which is neuroprotective. Another study evaluated the inflammatory activities of lutein and found that both lutein and zeaxanthin can reduce the extent of ear swelling of female mice exposed to UV radiation following the administration of 0.04/0.03% or 0.4/0.03% lutein/zeaxanthin supplement, respectively. The experiment also suggests that lutein and zeaxanthin ameliorate sunburn by blocking the formation of sunburn cells and also decreasing epidermal hyper-proliferation.⁴⁷

Skin cancer is a fatal skin disorder. The two most common ones are 1) squamous cell carcinoma (SCC) and 2) basal cell carcinoma (BCC), which have high incident rates in Australia, Europe, and the US. The causes of skin cancer are usually due to UV radiation where long exposure to sunlight 1) impairs DNA and the immune system and 2) can produce free radicals. Thus, antioxidants can aid in protecting the skin against UV radiation.⁴⁸ Lutein is a strong antioxidant similar to β-carotene as it can treat the oxidative damage skin caused by UV radiation.⁴⁶ As shown in a community-based study in Australian adults, lutein reduces the risk of SCC by 50% in individuals with a history of skin cancer where both lutein and zeaxanthin that are present in green leafy vegetables confer some protective effect as well.⁴⁸ The study also concluded that the intake of vitamins E, C, and β-carotene cause an increased risk of getting BCC which has a different risk and causal pathway.⁴⁸ Furthermore, Balić and Mokos⁴⁴ suggested that lutein and zeaxanthin increase the tumor-free survival time, specifically the duration following completion of the first cancer treatment when a patient is free from cancer symptoms with reduced tumor volume and multiplicity).

Finally, lutein ameliorates wound healing as shown in one experiment. According to Aziz et al,⁴⁶ esterified lutein produces a wound healing effect with the development of blood vessels in a chick chorioallantoic model. A hole was created on the model which was loaded with esterified lutein isolated from Tagetes erecta flowers. Non-sulfate glycosaminoglycans that had wound healing properties can hydrate the skin and have high water binding capacity due to a hyaluronan component. Since lutein and zeaxanthin can increase the production of hyaluronan, it is also useful in wound healing.⁴⁶

Curcumin

Curcumin originates from turmeric or Curcuma longa and belongs to the family of Zingiberaceae or ginger that is usually used as spice for food flavouring.^49,50 Turmeric is commonly-used in South Asia, India, and Indonesia and is often used as a dye or food color since it exists in bright orange-yellow crystals.⁵¹ According to Panahi et al⁴⁹ turmeric contains curcuminoids which include curcumin or specifically, deferuloymethane (75%), demethoxycurcumin (20%), and bisdemethoxycurcumin (5%). Curcumin is chemically known as [1, 7-bis (4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione]. It is a keto-enol tautomer and is a natural polyphenol that have many important uses.⁴⁹ Additionally, curcumin is used in the treatment of several diseases since the molecule rapidly penetrates the cell membranes and acts on multiple targets in different-cellular pathways. Some studies reported that curcumin is 1) a useful antimicrobial agent, 2) a preservative, and 3) possesses different therapeutic actions against cancer, dyslipidemia, skin diseases, osteoarthritis, diabetes, metabolic syndrome, endothelial dysfunction, autoimmune disease, non-alcoholic fatty liver disease, respiratory disease, depression, premenstrual syndrome, and hyperuricemia.^49,51 Since curcumin has antioxidant and anti-inflammatory properties, it can be used to treat skin disorders. Panahi et al⁴⁹ reported that curcumin has minimal toxicity to humans and animals, while Patel et al⁵¹ stated that, except for gastrointestinal distress, no major toxicity occurs upon oral administration of curcumin.

A type of skin disorder caused by chronic inflammation is psoriasis, as indicated by the presence of TNF, which is an inflammatory mediator. Current treatment of psoriasis focuses on inhibition of the production and action of TNF such as agents like adalimumab, cyclosporine, infliximab, methotrexate, and alefacept, which can cause certain side-effects if used long-term.⁵² The researchers confirmed that curcumin is a beneficial and effective treatment for psoriasis. A low concentration of curcumin is phototoxic against Escherichia coli and Salmonella typhimurium, which can be used in psoriasis phototherapy. In one experiment, curcumin showed some anti-psoriatic activity when used in an animal model which was a modified mouse tail. Curcumin also inhibits the proliferation of human keratinocytes as it blocks the expression of TNF-α-induced IL-1β, IL-6, TNF-α, cyclin E, mitogen-activated protein kinase (MAPKs) (JNK, p38 MAPK and ERK), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) in HaCaT-cells which will result in reversal of the anti-apoptotic function of TNF-α in the skin cell.⁵² In addition, curcumin is an effective TNF blocker, blocking both the action and production of TNF, and is also a potent inhibitor of phosphorylase kinase (PHK), which is seen in psoriasis.^52,53

Gupta et al⁵⁴ indicated that curcumin inhibits inflammation by a direct binding method that perturbs signal transduction between TNF-α and its receptor. Meanwhile, according to Lai et al⁵⁵ other than inhibition of TNF and certain interleukin (IL) like IL-22, IL-1β, IL-17A, and IL-17F, curcumin gel can also inhibit imiquimod-induce psoriasis-like inflammation. Additionally, curcumin obstructs the endosomal toll-like receptor (TLR) that contributes to psoriatic inflammation by blocking NF-κB signaling that produce inflammatory cytokines, thus resulting in reduction in IL-17 and IL-22 levels.⁵⁵

Curcumin is also effective against atopic dermatitis or eczema. In a report by Rawal et al,⁵⁶ a herbal extract cream containing curcumin (Herbavate^®) reduced and improved symptoms of dermatitis including itching, scaling, thickening, and erythema in 150 subjects who suffered from eczema. Nevertheless, it is difficult to evaluate the relevance of the findings due to the small control group, the high dropout rate, and the fact that other components in the cream may also play a role. Another study suggested that curcumin can reduce radiodermatitis when a curcumin cream that contains turmeric oil and sandalwood oil (Vicco^®) is used for radiodermatitis subjects (n=50) compared to baby oil.

A study conducted to evaluate the effect of curcumin in breast cancer patients (n=30) taking 6 g/day oral curcumin C3 Complex found that there was a decreased severity score of radiation dermatitis (radiodermatitis) and moist desquamation but no difference in pain, redness, or symptoms of radiodermatitis were seen.⁵⁷ A phytocomponent known as p-hydroxycinnamic acid (HCA) is derived from various plants including Curcuma longa (C. longa) and can modulate the protein kinase C-θ (PKC-θ) pathway by inhibiting the phosphorylation of PKC-θ that can have an immunosuppressive effect on T-cells and inhibit the activation of T-cells responsible for the development of various autoimmune disorder including dermatitis.^13,58 In a different study involving an experiment on a mini-pig model, curcumin reduces the severity of irradiated skin after 2 weeks administration by relieving the skin injury, decreasing the expression of cyclooxygenase-2 (COX-2) and NF-κB in curcumin-treated irradiated skin when compared to vehicle-treated skin.⁵⁹

Curcumin is useful against wounds caused by oxidative damage and inflammation.⁶⁰ The anti-inflammatory and free-radical scavenging activity of curcumin occur via reduction of lipid peroxidation and reactive oxygen species (ROS).⁶¹ Curcumin protects the skin from oxidative stress as it regulates lipid peroxidation while its antioxidant effect activates the cytoprotective signaling. Furthermore, curcumin confers some protective activity against hydrogen peroxide in human keratinocytes and fibroblasts.⁶² Additionally, it also suppresses inflammation by reducing the transcription factor protein-1 (AP1) while NF-κB reduces the expression of inflammatory cytokines and modulates the pro-inflammatory gene product expression, as shown in a wound model.⁶¹ In an animal study, the anti-inflammatory effect of chrysin-curcumin-loaded nanofibers accelerates wound healing in male rats by decreasing the gene expression for IL-6, TIMP-1, TIMP-2, MMP-2, and iNOS.⁶³ During proliferation, curcumin activates the growth factors, produces ECM proteins,and helps in collagen synthesis and migration of fibroblasts which aid wound repair.^13,64 Overall, curcumin acts on inflammatory, proliferative, and remodeling phases which leads to wound healing.

Based on several studies, curcumin is used in skin aging, especially in the elderly. Sommerfeld,⁶⁵ who conducted a study to evaluate the effectiveness of Tricutan (a herbal containing turmeric, rosemary, gotu kola, and dimethylaminoethanol) in women (n=28), indicated that the formulation enhances the skin firmness and elasticity after 4 weeks as compared to a placebo. Subsequently, a randomized, double-blind, placebo controlled trial in 47 subjects reported that the hot water extract of C. longa inhibits the increase in UVB-induced TNF-α and IL-1β and the increased production of hyaluronan occurring with age which also contribute to skin dryness.⁶⁶ In fact, increasing the hyaluronan content moisturizes the skin better.

Insulin-like growth factor-1 (IGF-1) can cause cancer, while inhibition of IGF-1 reduces tumors. Kim et al⁶⁷ demonstrated that curcumin reduces phosphorylation of the IGF-1 receptor, insulin receptor substrate-1 (IRS-1), S6K, AKT, and 4EBP1 in mouse keratinocyte cell lines, indicating that it has an anticarcinogenic effect acting via inhibition of IGF-1 signaling. Other than that, curcumin modulates some pathways like JAK-2/STAT3 which in turn induces apoptosis and inhibition of melanoma cell migration as well as invasion.⁶⁸ Curcumin also upregulates miRNA expression like mmu-miR-205-5p and reduces proliferating cell nuclear antigen (PCNA) and Bcl-2 number, leading to apoptosis and inhibition of proliferation.⁶⁸ In another study, high curcumin concentration decreases the invasion of squamous cell A431 cells by suppressing the signaling pathway and STAT3 expression.⁶⁹ Curcumin also incites mitochondrial permeability transition pore (mPTP) opening, leading to apoptosis/cell death of WM-115 melanoma cells since mPTP opening is necessary for curcumin-induced cytochrome C release.⁷⁰ A study indicated that topically applied curcumin on UVB-induced carcinogenesis in mice can delay tumor appearance, multiplicity, and volume hile increasing p53 and p21/Cip1-positive cells in the epidermis.⁷¹

As stated in several studies, curcumin is effective against bacterial and fungi infections. Curcumin has activity against methicillin-resistant Staphylococcus aureus (MRSA) when administered singly and shows some synergistic effects when administered in combination with other antibiotics.^72,73 Vollono et al¹³ indicated that vanillin, a curcumin photolytic degradation product in light-irradiated curcumin, interrupts the bacterial cell membrane. Furthermore, curcumin is a photosensitizer and is used in photodynamic therapy against MRSA infection in an intradermal infection model.⁷⁴ According to Vaughn et al⁵⁰ various mechanisms exists, which include bacterial membrane perturbation, damage to bacteria motility, changes in gene expression, and suppression replication machinery.

Curcumin is effective against acne vulgaris.⁷⁵ It is reported that curcumin microemulsions in combination with myristic acid suppresses S. epidermis growth, suggesting that curcumin is effective against acne vulgaris. In another study, curcumin nanoparticles inhibit fungal growth by inducing ROS and reactive nitrogen species (RNS) related to fungal death by apoptosis.⁷⁶

Resveratrol

Resveratrol, a stilbenoid in a phytoalexin group was first discovered in 1939 and is chemically introduced as 3,5,4′-trihydroxy-trans-stilbene.^77,78 Resveratrol, which was first discovered from the white hellebore, also known as the roots of Veratrum grandiflorum and also available from the root of Polygonum cuspidatum, is usually utilized in Japanese and Chinese medicines.⁷⁹ Interestingly, resveratrol is produced by plants in response to stressors like insects, animals, mechanical injury, UV radiation, and also microorganisms including fungal infection.^79,80 Resveratrol exists in more than 70 plant species, although it is most abundant in grape skin⁷⁹ besides being present in other foods and beverages including wine. Ruivo et al⁷⁷ reported that resveratrol is also found in cranberries, peanuts, cocoa, chocolate, and tomatoes.

Resveratrol appears in cis- and trans-isomeric forms with the trans-form being the biologically active version. The cis-form is isomerized from trans-resveratrol via UV irradiation and in the presence of high pH during grape skin fermentation.⁸⁰ Currently, resveratrol is an important significant nutritional supplement as it has various benefits such as cellular defense against oxidative stress. The pharmacological effects include anti-inflammatory, antimicrobial, anti-cancer, anti-aging, and neuroprotective effects,⁷⁹ making resveratrol a potential natural product for human health. In some reports, resveratrol is useful for amelioration of cardiovascular disease, diabetes, skin disorders, and obesity. It is also high in antioxidants and combats free radical damage by acting as a potent radical scavenger.⁷⁷

Skin aging is classified into either extrinsic or intrinsic. The former is primarily caused by environmental factors like pollutants, lifestyle, and solar radiation, while the latter are changes that progress over time, depending on the anatomy, genetics, hormones, and ethnicity.⁸¹ An important factor contributing to skin aging is activated MMPs that cause damage to the skin structural integrity, leading to wrinkle formation. TNF-α-induced expression of inflammatory cytokines and MMPs is inhibited by resveratrol through a sirtuin 1-dependent mechanism.⁸¹ According to the same article, 0.8% of resveratrol analogs, resveratryl triacetate (RTA) confer some anti-aging activity by enhancing sagging, wrinkles, elasticity, and moisture. Furthermore, in a study by Liang et al,⁸² short-term resveratrol injection retards the process of oocytes aging in mice, occurring via 1) enhancement of the expression of the anti-aging molecule sirtuin 1, 2) promotion of the mitochondria function, and 3) reduction in ROS production.

Resveratrol protects normal human fibroblasts from the damaging effects of hydrogen peroxide by attaching to specific epidermal receptors.⁸³ Deloche et al⁸⁴ demonstrated that skincare products containing resveratrol (0.25%) and oligoside (4%) can reduce wrinkles and improve skin firmness. Buonocore et al⁸⁵ investigated a supplement which consisted of dried grape extract containing trans-resveratrol, procyanidin, punicalagin-ellagic acid, and punica granatum, which are strong antioxidants found to enhance skin conditions like a reduction in skin roughness, increased skin moisturization, as well as elasticity. Additionally, resveratrol ameliorates skin inflammation by decreasing the expression of AP-1 and NF-κB transcription factors, collagen breakdown, and inflammation.

Skin cancer occurs due to cell mutation and affects the skin’s normal physiology. In a study, resveratrol shows some chemo-preventive effect where it protects against the main factor affecting non-melanoma skin cancer which is UVB radiation by decreasing COX-2 levels.^86,87 UVB can also elevate the cyclin kinase that enhances growth during the early stage of cancer development. A report demonstrated that resveratrol causes an increase in cyclin kinase inhibitor WAF1/p21 and tumor suppressor p53 which interrupts tumor development.^88,89 Besides, the anti-proliferative activity of resveratrol may contribute to modulation in the expression and function of cell cycle regulatory protein cyclin-D1 and -D2, cdk-2, -4, and -6, and WAF1/p21, suggesting that the retardation of the MAPK pathway was generated by modulation of the cki-cyclin-cdk network.^88,89

A team of researchers discovered that resveratrol and 5-fluorouracil combination can suppress cell proliferation more effectively than administering the drug alone since resveratrol employs its anti-proliferative activity like reducing tumor growth and angiogenesis in B16 melanoma by altering the expression of vasodilator-stimulated phosphoprotein (VASP), COX-2, AMP-activated protein kinase (AMPK), and vascular endothelial growth factor (VEGF).⁹⁰ Yarla et al⁹¹ also reported that 1) pterostilbene; a resveratrol analogue or a methoxylated derivative of resveratrol and 2) the combination of resveratrol with ursolic acid can stop the generation of DMBA/TPA-induced skin cancer by obstructing the MAPK/NF-κB/AP-1/COX-2 pathway.

Herpes simplex virus (HSV) is indicated by a skin lesion affecting several body parts including the nasal cavity, oral, ocular, genital skin, and mucosa. HSV is a double-stranded DNA virus in the Herpesviridae family that can be hidden or latent but it can cause a recurrent infection.⁹² HSV infection is potentially dangerous and can be fatal. HSV-1 infection causes skin lesions at the nasal, oral, and ocular areas, while HSV-2 infection affects the genital skin and mucosa sites. Based on several studies, resveratrol can potentially be an anti-HSV drug. In an in vivo study by Docherty et al,⁹³ topically treated resveratrol cream decreases the development of lesions caused by HSV on SKH1 mice where a 25% resveratrol cream was more efficient than 12.5% and resveratrol ameliorates better when the disease had only recently occurred. It was also reported that resveratrol was as efficacious as acyclovir but is more efficient than 10% of docosanol cream in treating the lesion.^93,94

For in vitro studies, resveratrol suppresses NF-κB stimulation which 1) retards the reproduction of HSV and production of DNA virus and 2) changes the gene stimulation.⁹⁵ Furthermore, resveratrol can stimulate the 50 AMPK/Sirtuin 1 (AMPK/Sirt1) axis which decreases viral genes expression leading to HSV infection suppression.⁹⁶ Other than virus infection, Yang et al⁹⁷ stated that topical application of pterostilbene is useful in the treatment of skin MRSA infection by ameliorating the abscess via reduction in bacteria number and enhancement in the skin structure.⁹⁷

Acne vulgaris is an inflammatory disease affecting all age groups and ethnicities. It occurs due to an imbalance in hormones and some pathogenic factors such as Propionibacterium acnes, increased sebum production, inflammatory mechanism, and unusual follicular hyperkeratinisation.⁹⁸ Nevertheless, a team of researchers have indicated that resveratrol has the potential to exert some antibacterial and anti-inflammatory effects by inhibiting the reproduction process for P. acnes and reducing the inflammatory response that is comparable to other acne vulgaris treatment.⁹⁹ Taylor et al¹⁰⁰ reported that using resveratrol together with benzoyl peroxide can exert a good antibacterial effect by inhibiting bacterial growth since resveratrol can change the surface structure of bacteria with some loss of defined membrane. Additionally, psoriasis can be treated by resveratrol via suppression of imiquimod-induced gene expression of IL-19, IL-17A, IL-17F, and IL-23p19 to reduce the psoriasis-like inflammation since the genes are mainly involved in the production of psoriatic plaque in both humans and animals.^55,101

Skin disorders like wounds occur due to tissue injury caused by trauma and other factors. Therefore, factors influencing the healing process like nutrition, drugs, and age are also important in reduction of scarring and shortening of the healing period.⁸³ In a previous study, the grape seed extract (GSE) which is a source of resveratrol can heal wounds when topically applied as a 2% cream. Its antimicrobial, antioxidant, and anti-inflammatory activities cause wound contraction and closure as by 1) forming a protective area in the epithelium and 2) raising the cell density and elevating the displacement of connective tissue at the wound area which enhances the wound cellular construction.¹⁰²

Chloasma or melasma are two other skin diseases that are usually represented by uneven dark to light brown patches on the forehead, chin, cheeks, nose, and upper lip.⁸³ Other factors causing chloasma include UV exposure (the most common reason since it affects melanin production), genetic disorders, thyroid disturbance, hormone replacement therapy, and the use of photosensitizer drugs.¹⁰³ In an investigation, the GSE which contains proanthocyanidin can decrease the number of melanocytes that cause a lightening effect on the UV-induced pigmented skin of guinea pigs occurring due to the suppression of melanin production by tyrosinase in melanocytes and ROS activity.¹⁰⁴ In another study, 12 months of GSE treatment efficiently decreases the hyperpigmentation seen in chloasma in women without conferring adverse effects. Moreira et al¹⁰⁵ reported that Skin Whitening Complex (SWC) that consists of ursine grape extract, biofermented aspergillus, grapefruit extract, and rice extract decreased the skin melanin and reduced pigmentation.

Embelin

Embelin, from the Embelia ribes Burm that belongs to the Myrsinaceae family and Lysimachia punctata, from Primulaceae family with the chemical formula of 2,5-dihydroxy-3-undecyl-p-benzoquinone.¹⁰⁶ The chemical structure of embelin contains a polar dihydroxy-1, 4-benzoquinone ring which is a two carbonyl oxygen atom adjacent to the two vinyl hydroxyl groups.¹⁰⁶ Embelin, which is frequently referred to as “False Black Pepper”, is an Indo-Malaysian species that originates from Malaysia, Singapore, India, Sri Lanka, and South China. Embelia ribes Burm is also widely used in Tibetan, Folk Indian, Homeopathy, Unani, and Siddha traditional medicinal systems in the treatment of several illnesses including the heart and urinary condition, severe inflammatory disease, tumor, insect, and snake bites.¹⁰⁷

Embelin has various medicinal and pharmacological activities such as analgesic, anti-inflammatory, antibacterial, antioxidant, anticonvulsant, antidiabetic, anxiolytic, hepatoprotective, and antifertility effects.¹⁰⁸ Park et al¹⁰⁹ stated that embelin is a potent inhibitor of NF-κB and X-linked inhibitor of apoptosis protein (XIAP) that halted the binding of XIAP to procaspase-9. Kundap et al¹⁰⁷ also reported that the fruit of Embelia ribes Burm can be used in the treatment of mental disorders, central nervous system (CNS) disease, and as brain tonic in the traditional medicinal system.

Psoriasis is a hyperproliferative skin disorder occurring due to inflammation, as signified by the unusual differentiation and proliferation of keratinocyte, stimulation of T-cells, and polymorphonuclear leukocytes aggregation.¹¹⁰ In their investigation on the effect of embelin on skin inflammation in mice, the researchers also confirmed that the pathogenesis of psoriasis is mainly caused by TNF-α. There was a dose-dependent decrease in LPS-induced TNF-α level when several concentrations of embelin were used with an effective dose 50% (ED50) at 9.8 mg/kg.¹¹⁰ The researchers also investigated chronic dermatitis inflammation by 12-O-tetradecanoyl-phorbol-13-acetate-induced mice ear. Embelin can reduce edema, decrease the thickness of skin and weight, reduce stimulation of inflammatory cytokines, reduce neutrophil initiation, improve histopathological indicators, and lead to the departure of polymorphonuclear leukocyte. It was concluded that the anti-inflammatory effect of embelin is attributed to the suppression of TNF-α and IL-1β as well as the inhibition of leukocyte aggregation,¹¹⁰ overall indicating that embelin is useful against psoriasis and dermatitis.

Swamy et al¹¹¹ reported that embelin extracted from Embelia ribes Burm can treat wounds in a rat model. Wound healing is a process that repairs the damage or injured skin tissue in order to improve tissue integrity and replace damaged tissue. When compared to the control group, embelin accelerated the incision epithelialization, thus contributing to a shorter mean time of epithelialization.¹¹¹ The percentage of wound closure was also high in the embelin-treated group and is comparable with that of a standard drug with reference name framycetin. In fact, the incision tensile strength was higher in the group which received topical application of embelin,¹¹¹ indicating its potential in wound healing.

Oral embelin yielded a higher weight of granulation tissue and tensile strength as seen in a dead space wound model indicating 1) that there is improved collagen development through formation of cross-linking between collagen fibres and 2) the existence of high protein content.¹¹¹ In histology of wound tissue in the embelin-treated group, it can be observed that there was a complete healing process, with many fibroblasts having a higher number of blood vessels and collagen tissue, similar to the control group.¹¹¹ All of these findings indicate that embelin confers a good wound healing activity as an alternative for wound healing.

Naringenin

Naringenin has the IUPAC name 5.7 dihydroxy-2-(hydroxyphenyl) chroman-4-one¹¹² or a chemical name 2, 3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one.¹¹³ Naringenin is found in citrus fruits like grapefruits and oranges or in vegetables like tomatoes and figs.^113,114 According to Salehi et al¹¹⁵ its molecular weight is 272.26, with a chemical formula of C₁₅H₁₂O₅. Naringenin is a flavonoid that is soluble in organic solvent including alcohol, but is insoluble in water.

Naringenin is a flavone from naringin or the hydrolysis of narirutin (its glycone precursor).¹¹⁵ Naringin, which is a bitter principle of grapefruit obtained from the juice, flower, and fruit rind, represents up to 10% of the fruit’s dry weight. Nevertheless, flavonoids including naringenin have some limitations, especially in terms of bioavailability and limited source. Therefore, several efforts aimed at producing naringenin from metabolic engineering of specific pathways in the microbial system like E. coli and Saccharomyces cerevisiae have been made.¹¹⁵ Based on previous in vitro and in vivo studies, naringenin confers some pharmacological activities such as anti-inflammatory, anti-microbial, hepatoprotective, anticancer, anti-atherogenic, and anti-mutagenic effects.^114,115 Furthermore, naringenin also exhibits gastrointestinal, rheumatological, cardiovascular effects, and is useful in controlling malignant and infectious diseases.¹¹⁵ Venkateswara et al¹¹³ reported that naringenin is an antioxidant, is a free radical scavenger, and has the ability to recondition the DNA, indicating that naringenin has many benefits to humans.

A skin disorder that may be impacted by naringenin further is skin cancer. In past studies, high doses of naringenin have been confirmed to decrease the occurrence of papilloma about 20% in mice.¹¹⁴ It also decreases the size and number of papilloma in both pre- and post-treatment groups compared to the control where naringenin suppresses papillomagenesis.¹¹⁴ Additionally, naringenin reduces the expression of glyoxalase-1, which is abundantly present in the skin cell carcinoma to cause cancer cell death.¹¹⁶ Naringenin also suppresses cancer by elevating carbonyl contents,¹¹⁴ indicating that it is a good choice of treatment for skin cancer. Administration of naringenin in combination with curcumin can impede angiogenesis activity since the combination decreases the production of new blood vessels in the peritoneal and inner skin linings of an Ehrlich Ascites Carcinoma (EAC) tumor-bearing mice model.¹¹⁷

Naringenin also causes cell death via apoptosis occurring through several mechanisms against skin cancer in humans. Ahamad et al¹¹⁸ reported that naringenin-induces apoptosis by 1) ROS-mediated mitochondrial membrane depolarization, 2) DNA fragmentation which signifies apoptosis that causes damage to cells, 3) induction of nuclear condensation inside human epidermoid carcinoma A431 cells, and 4) obstruction of cells in G₀ or G₁ phase of cell cycles leading to apoptosis and initiation of caspase-3 that is one of the key roles in apoptosis occurring through cellular substrate splitting. Moreover, García-Bores et al¹¹⁹ also stated that methanolic extract of Lippia graveolens (MELG), a Mexican oregano containing naringenin, galangin, and pinocembrin, has photochemopreventive effects on a mouse skin model that can prevent tumors as the flavonoids have antineoplastic activity.

Skin aging due to UV light (photo-aging) is identifiable by collagen reduction and also elevation in MMP-1 produced in response to UV irradiation.¹²⁰ Jung et al¹²¹ reported that naringenin 1) inhibits the UVB-induced MMP-1 production and the activator protein-1 (AP-1) in a 3D human skin comparable culture and 2) suppresses MMP-13 formation and production of wrinkles in a SKH-1 mice model. Additionally, naringenin blocks the UVB-induced extracellular signal regulated kinase 2 (ERK2) and reduces fos-related antigen 1 (FRA1) stability by suppressing its phosphorylation along with inhibiting the transepidermal water loss, overall suggesting that naringenin is useful against photo-aging.¹²¹ Furthermore, in a study using a nematode model Caenorhabditis elegans, naringenin increases the life span of nematode when exposed to UV radiation by downregulating the aging regulated genes (daf-2 and age-1).¹²² Naringenin also accelerates the UVB-induced cyclobutane pyrimidine dimers lesion removal and suppression of excessive apoptosis, thus suggesting that it can prevent UVB-induced aging and cancer.¹²³

Naringenin is useful against atopic dermatitis; an inflammatory skin disease. Kim et al¹²⁴ reported that naringenin decreases the atopic dermatitis skin lesion growth in NC/Nga mice as initiated by 2,4-dinitrofluorobenzene (DNFB) via 1) inhibition of the formation of interferon-gamma (IFN-γ) by activated CD4+ T-cells and 2) reduction of the infiltration of skin lesions through CD8+ T-cells, CD4+ T-cells, mast-cells, and eosinophils. There was also improvement in the ear swelling in the naringenin-treated group of mice following a histological analysis on the epidermis thickness.¹²⁴ Besides, an in vivo study of naringenin microsponge gel formulation indicated a reduction in inflammation as confirmed by the decrease in the total white blood count and thickness of the earflap in the dermatitis rat model,¹²⁵ overall highlighting the significance of the microsponge gel carrier system that can enhance its therapeutic effect.

Due to its anti-inflammatory effect, naringenin is also useful against psoriasis. Trombino et al¹²⁶ demonstrated that the solid lipid nanoparticle (SLN) containing naringenin, linolenic acid, and cyclosporine synergistically decrease psoriasis-mediated inflammation. In another study, (R)-naringenin 1) suppresses T-cell proliferation, 2) decreases pro-inflammatory cytokines like TNF-α and IL-6, and 3) caused proliferation of human peripheral blood mononuclear cells (hPBMC).¹²⁷ Since a TNF-α blocker is useful in psoriasis, naringenin, which has anti-inflammatory effects, is a good treatment choice. Therefore, naringenin is a good candidate as an anti-psoriatic agent since it inhibits the over-expression of IL-6 and ameliorated psoriasis along with reducing the transepidermal water loss.¹²⁸

Skin allergy, especially type 1, is a common skin disorder common in industrialized countries due to factors such as allergen exposure, decreased activation of immune system, genetic predisposition, and psychosocial effects. Escribano-Ferrer et al¹²⁹ reported that topical and intravenous naringenin exhibit a potent anti-allergic activity by inhibiting mast cell degranulation. Additionally, it was demonstrated that naringenin possessed anti-inflammatory activity against ear edema in a mice model. Naringenin present in tomato skin, particularly naringenin chalcone-2ʹ-O-β-D-glucuronide, shows an anti-allergic affect by suppression of histamine release in rat peritoneal mast-cells.^130,131

Terminalia brownii extract, which contains several compounds including naringenin-4′-methoxy-7-pyranoside, shows an antifungal effect against certain fungi that is traditionally-used against fungal infection.¹³² Nevertheless, it is plausible that the antifungal effect is also contributed by T. brownii itself. Similarly, Orhan et al¹³³ also demonstrated the antifungal effect of naringenin pyranoside against C. krusei and Candida albicans with a minimum inhibitory concentration of 1,600–3,200 μg/mL.

Skin damage such as thermal burns can cause multiple complications if not appropriately treated. Naringenin can treat thermal burn-induced injury in a rat model by suppressing the pro-inflammatory markers like TNF-α, interleukin, NF-kB, caspase-3, nitric oxide (NO) level, leukotriene-B4 (LTB4), PGE2, and also through the antioxidant effect.¹³⁴ As for the oxidative parameter, naringenin caused an increase in glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), while reducing thiobarbituric acid reactive substances (TBARS) after a 7-day treatment.

Quercetin

Quercetin is a flavonoid that originates from natural products including the vegetables, grapes, apple, brassica, berries, onion, tea, spring onions, ginkgo biloba, and tomatoes.¹³⁵ The word quercetin is derived from the Latin word quercetum (oak forest), with C₁₅H₁₀O₇ as the molecular formula.^135,136 Its structure consists of four active groups including the dihydroxy group between the A ring, O-dihydroxy group B, C-ring C2, C3 double bonds, and 4-carbonyl.¹³⁶ According to Basu et al¹³⁷ the chemical name for quercetin is 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one.

Quercetin comes from plants in the form of quercetin-3-o-glucoside that can work as a pigment that colors vegetables and fruits.¹³⁸ In addition, rutin is the most common form of quercetin, which is normally glycosylated, while aglycone is a yellow sugar-free structure quercetin.¹³⁸ Quercetin structure usually has an –OH group while the glycoside structure has a glycosyl group, making its solubility in water higher than the quercetin aglycone. Quercetin has been shown to have anti-inflammatory and antioxidant effects in several studies, besides being an anti-tumor, antibacterial, anti-angiogenic, anti-diabetes, anti-obesity, and anti-allergic, useful for neurological and cardiovascular diseases.^135,136,138

Shin et al¹³⁹ reported that quercetin inhibits UV-induced COX-2, MMP-1, and collagen breakdown in human skin. Furthermore, quercetin protects the skin from UV-induced skin aging by exerting its effect on PKC-delta (PKCδ) and Janus kinase-2 (JAK2) to suppress UV-induced skin aging and inflammation since PKCδ and JAK2 are significant regulators for inflammation.¹³⁹ The researchers also reported that quercetin blocks AP-1 and NF-κB stimulation which was key in quercetin’s anti-aging effects. In another study, quercetin and its derivative quercetin caprylate (QU-CAP) exhibit their anti-aging effects by activating proteasome via the Nrf2 pathway that enhances the antioxidant effect to help protect against skin aging.¹⁴⁰ Additionally, quercetin also affects the cell’s lifespan and growth, as well as fibroblast’s survival.¹⁴¹

Skin cancer is caused by mutation of cancer-related genes, including the tumor suppressor and proto-oncogenes.¹⁴² The major classification of skin cancer includes cutaneous melanoma and non-melanoma that originates from keratinocytes of the epidermis. Quercetin can inhibit the stimulation of signal transducer and activator of transcription (STAT3) via IL-6 by decreasing cyclin D1 and MMP-2 production, leading to suppression of cell proliferation occurring via cell aggregation in particular at the S and G2/M stages.¹⁴² Generally, polyphenol that includes flavones, flavonols like quercetin and myricetin, as well as phenolic acid can act on the anti-cancer effect via various mechanisms. According to Shaik et al,¹⁴³ quercetin suppresses the phosphatidylinositol-3-phosphate kinase (P13K) effect by ousting the binding of ATP from P13K and stimulating AMPK. The suppression of the B16–BL6 melanoma cell growth and DNA synthesis, retardation of the development of tumor, and reduction of cell invasion were among its anti-cancer properties mechanisms.¹⁴⁴ Vargas et al¹⁴⁵ reported that quercetin is useful in melanoma treatment by exploiting the tyrosinase expression and stimulating the p53 expression as well as ROS regulation, ultimately leading to cell apoptosis and death.

Skin infections such as impetigo, folliculitis, cellulitis, furuncles, and erysipelas may affect the quality-of-life. According to Memariani et al,¹³⁵ quercetin has antimicrobial effects against certain pathogens and can inhibit Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Streptococcus mutans, and Escherichia coli through several mechanisms. Brown et al¹⁴⁶ also suggested that consumption of fruits abundant in quercetin protects against H. pylori infection. In fact, an in vitro study suggests that the combination of quercetin with supplements like morin and rutin along with the use of some antibiotics is synergistic against MRSA.¹⁴⁷

Skin dermatitis is a skin disorder characterized by itching, erythema, rash, blisters, and even crust formation in some cases. Two major types exist: 1) atopic dermatitis (chronic skin damage and inflammation) and 2) contact dermatitis (an allergic reaction on the skin that causes a rash and pain). In vitro and in vivo studies in a rat model indicate that quercetin inhibits atopic dermatitis by blocking the inflammatory cytokines and pro-inflammatory factor.¹⁴⁸ Additionally, there was upregulation of heme oxygenase that suppress degranulation of mast-cells via the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated pathway,¹⁴⁹ which contributes to its anti-allergic effect. In a past study, both quercetin and tannic acid 1) reduce the T-helper type 2 (Th2) polarization and 2) inhibit cytokine thymic stromal lymphopoietin (TSLP) as well as thymus activate regulated chemokine (TARC) in atopic dermatitis.¹⁵⁰ Furthermore, quercetin and tannic acid also suppress the neo-angiogenesis that inhibit the atopic dermatitis inflammation. Quercetin inhibits contact dermatitis and photosensitivity by suppressing IL-6, IL-8, and TNF-α, where it shows that quercetin is an effective mast-cell inhibitor.¹⁵¹ Moreover, quercetin decreases the cytosolic calcium level and blocks NF-κB stimulation.

Quercetin enhances wound healing due to its anti-inflammatory and antioxidant activities.¹⁵² Quercetin penetrates into the fibroblast, a deeper layer of membrane which is the main target for wound healing, making a suitable quercetin formulation that can help enhance skin penetration a necessity.¹⁵² In a study by Gomathi et al,¹⁵³ quercetin-incorporated collagen (QIC) film heals the wound more effectively than either control or collagen-treated groups since it enhances cell proliferation and scavenges free radicals. Additionally, quercetin 1) decreases wound contraction, 2) elevates hydroxyproline to improve collagen, and 3) decreases uronic acid and superoxide dismutase levels.¹⁵³ Moreover, quercetin can treat keloid, an extreme dermal scar due to skin trauma, by suppressing the transforming growth factor-beta (TGF-β) and Smads complex (Smad2/3/4) transfer.¹⁵⁴

Lycopene

Lycopene belongs to the plant pigment family (carotenoid) and is found in tomatoes, papaya, pink grapefruit, watermelon, cloudberry, cranberry, grape, and peach.^155,156 Carotenoid gives the color to fruits, including the red color in tomatoes, squash’s yellow, and pumpkin’s orange, besides yielding a certain smell to some. Lycopene is most abundant in tomatoes, contributing up to 80% of carotenoid content, and is present at the chromoplasts of plant-cells.¹⁵⁶ Interestingly, the scientific name for tomato is “Lycopersicon esculentum”.¹⁵⁷

Carotenoid is classified into 1) hydrocarbon carotenoid that consists of only hydrogen and carbon such as in lycopene, and also 2) xanthophylls such as lutein that has the addition of oxygen to hydrogen and carbon.¹⁵⁵ Lycopene with the molecular formula of C₄₀H₅₆ has a molecular weight of 536.89 and constituted about 9.49% of C and 10.51% of H.¹⁵⁶ Its IUPAC name is 2,6,10,14,19,23,27,31-octamethyl-2,6,8,10,12,14,16,18,20,22,24,26,30-dotriacontatridecaene.

Lycopene comes in a variety of cis-configurations while all the transforms are thermodynamically more stable.¹⁵⁸ Meanwhile, other stable forms include 5-cis isomer, 7-cis, 9-cis, 11-cis, 13-cis, and 15-cis. Lycopene is also present in human plasma, tissue, and breast milk, mostly in the cis-isomer form.¹⁵⁵ Lycopene's color is believed to indicate the type of isomer, where the all-trans isomer is red and tetra-cis-lycopene is orange.¹⁵⁵

Lycopene is a good antioxidant, rich in vitamin A. Lycopene is useful in the treatment of asthma, cancer (uterine, prostate, lung, and breast cancers) and cardiovascular diseases (by reducing the possibility of myocardial infarction, blocking oxidation of LDL cholesterol, and lowering blood pressure).^155,159 It is also believed to have therapeutic effects against Alzheimer's and Parkinson's disease.

Due to its strong antioxidant properties, lycopene can reduce skin aging by decreasing the roughness and scaling in the skin, especially when used in combination with other supplements.¹⁶⁰ Besides reducing skin roughness, the high lycopene content in the skin can reduce the formation of wrinkles and furrows.¹⁶¹ Segger and Schönlau¹⁶² reported that a nutritional supplement Evelle^® that contains various compounds including lycopene improves skin elasticity and decreases skin roughness when compared to placebo. Administration of natural kale extract supplement caused a higher lycopene concentration in the skin as compared to the serum, due to the presence of the antioxidant network in the skin which can help prevent skin aging.¹⁶³ According to Marchena et al¹⁶⁴ cosmetics consisting of lycopene and melatonin can improve skin hydration and stratum corneum elasticity along with increasing the pigmentation level, all of which can help prevent photo-damage and enhance skin characteristics.

Lycopene also has anti-cancer effects. According to Fazekas et al,¹⁶⁵ lycopene inhibits UVB irradiation that caused skin damage by 5%. Topical application of lycopene 1) suppresses the activity of ornithine decarboxylase (ODC) which was over-suppressed during cancer development, 2) blocks inflammatory responses like MPO activity and skin thickness, and 3) decreases caspase-3 production related to apoptosis as confirmed by the PCNA staining cell in the epidermis.¹⁶⁵ Basu and Imrhan¹⁶⁶ reported that tomato products rich in lycopene have a chemoprotective effect by decreasing the biomarkers for oxidative stress and carcinogenesis. Cooperstone et al¹⁶⁷ also suggested that tomatoes with high lycopene content can reduce the tumor number in SKH-1 mice with a UVB-induced skin tumor when compared to control, since lycopene can decrease the possibility of keratinocyte cancer by conferring protection against UVA. In another study, Kopec et al¹⁶⁸ confirmed that tangerine tomatoes that contain lycopene can reduce the formation of UV-induced cyclobutane pyrimidine dimers, myeloperoxidase activity, and the percentage of p53 positive epidermal cells in male SKH-1 mice, all of which are attributed to a decrease in inflammation or DNA damage. Antioxidant activity can also contribute to cancer prevention since increased highly reactive free radicals lead to DNA damage which can be neutralized by the antioxidants. Hwang and Bowen¹⁶⁹ reviewed that in in vivo studies, lycopene can prevent DNA damage by its antioxidant effect by reducing serum thiobarbituric acid reactive substance that ameliorate lipid peroxidation, which may protect against tumor development related to oxidative damage.

Exposure to UV causes photo-oxidative damage to cellular lipids, DNA, and proteins which are related to the formation of erythema and other skin disorders.¹⁷⁰ In addition, solar erythema, also known as sunburn, is characterized by blister, pain, tenderness, and second degree burns. The damage to the DNA and protein in skin cells alters keratinocytes morphology, which can be ameliorated with products with a photo-protective effect.¹⁷¹

Stahl et al¹⁷⁰ conducted a study involving volunteers on five forms of lycopene (tomato paste, carrot juice, lycopene supplement, tomato extract, and synthetic lycopene) for 10 to 12 weeks an reported that lycopene confers a photo-protective effect by reducing the sensitivity to UV-induced erythema by reducing the chromametry a-values (Δa-values), a measurement for erythema effective as photo-protection since lycopene absorbs in the UV-range. Sies and Stahl¹⁷² suggested the application of lycopene as a sun protectant due to the prevention of UV-induce erythema production. Grether-Beck et al¹⁷³ stated that lycopene-rich tomato nutrient complex (TNC) suppresses the UVA1- and UVA/B-induced heme-oxygenase 1 (HO1) increase, intercellular adhesion molecule 1 (ICAM-1), and matrix metallopeptidase 1 (MMP-1) mRNA, which protect against sun radiation damage as compared to placebo.

Lycopene also protects against psoriasis. In a previous study, lycopene suppresses the imiquimod (IMQ)-induced psoriasis-like inflammation in keratinocyte, a type of epidermis by inhibiting monocyte adhesion in a mice model.¹⁷⁴ The adhesion molecules include intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecule-1 (VCAM-1), which are significant in inflammatory response.¹⁷⁴ Atopy is associated with an allergic reaction that produces an exaggerated immune response such as eczema, asthma, and allergic rhinitis. Lycopene is useful against atopy occurring in the skin, lungs, and immune-competent cells. Carotenoids like lycopene can stimulate the retinoic acid receptor (RAR) and retinoid-X receptor (RXR) essential in atopy.¹⁷⁵ Furthermore, carotenoid is metabolized to be more bioactive under oxidative circumstance; stimulating the RAR- and peroxisome proliferator-activated receptor (PPAR)-mediated signaling pathways and preventing the NF-κB signaling that confers the anti-inflammatory effect.¹⁷⁵ Additionally, carotenoid transporter-proteins, polymorphism, and local carotenoid levels can inhibit atopic development, making carotenoids including lycopene an important strategy in atopy suppression.¹⁷⁵

Gingerol

Gingerol, a polyphenol present in ginger, belongs to the Zingiberaceae family. It is widely used as a herbal medicine, a food, and a spice, not only in Asia but globally.¹⁷⁶ The molecular formula of gingerol is C₁₇H₂₆O₄ with the IUPAC name (5S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one.¹⁷⁷ In general, ginger contains many components including volatiles such as camphene, geranyl acetate, β-phellandrene, curcumene, borneol, cineole, terpineol, limonene, geraniol, β-elemene, linalool, α-zingiberene, zingiberol, zingibereno, α-Farnesene, β-bisabolene, and β-sesquiphellandrene, and also non-volatiles such as gingerol, zingerone, paradols, and shogaols.¹⁷⁸ The main active component of ginger is 6-gingerol (1-[4ʹ-hydroxy-3ʹ-methoxyphenyl]-5-hydroxy-3-decanone), while other components include 8-gingerol and 10-gingerol.^176,179

Ginger has a strong flavor and an unpleasant taste to some individuals, especially when used in high concentrations.¹⁸⁰ Gingerol has various therapeutic effects including amelioration of fever, vomiting, pain, cramps, arthritis, hypertension, and cardiopathy.¹⁷⁶ Other activities include anti-cancer, anti-inflammatory, antipyretic, decreased blood lipids, anti-angiogenic, anti-aging, improved circulation of blood, cardiotonic, improved digestion, antioxidant, and as an antimicrobial.^176,181 Additionally, Wang et al¹⁷⁸ reported that gingerol has an antifungal effect and anti-platelet aggregation. In Chinese, gingerol is called Shengjiang and ginger is commonly used in traditional Chinese medicine, since it can soothe a cough and overcome phlegm in addition to treating poisons from crab and fish.¹⁸¹

Gingerol exhibits anti-cancer and anti-inflammatory effects in various organs including the skin, gastrointestinal, colorectal, and pancreas.⁹¹ Kim et al¹⁸² reported that 6-gingerol decreases the UVB-induced ROS since UV is the main factor contributing to skin cancer where UVB-induced ROS stimulates inflammation and increases tumor number by lipid peroxidation, DNA damage, and changes in enzyme activity. Additionally, 6-gingerol also suppresses the UVB-induced COX-2 production by inhibiting ROS and activating NF-κB in the HaCat-cell through inhibition of Iκβα phosphorylation; leading to suppression of the UVB-induced apoptotic pathway.¹⁸² In fact, COX-2 is the main target involved in reduction of photo-inflammation that causes tumor production and photo-aging.¹⁸² Yarla et al⁹¹ reported that 6-gingerol acts as an anti-tumor and possesses some chemoprotective effect by inhibiting the arachidonic acid (AA) pathway significant in carcinogenesis. Additionally, 6-gingerol suppresses melanin formation in murine B16F10 melanoma cells which stimulates the Akt/PKB pathway and also inhibits the melanogenesis development in melanoma cells through reductions in microphthalmia-associated transcription factor (MITF) and tyrosinase activity suppression.¹⁸³ Moreover, 6-gingerol also suppresses the TPA-induced COX-2 synthesis by preventing the p38 mitogen-activated protein (MAP) kinase-NF-κB signaling pathway, thus confirming the anti-tumor effect of ginger.¹⁸⁴

Apigenin

Apigenin is from the flavone class and is an aglycone of several natural occurring glycosides.¹⁸⁵ Species like Lamiaceae, which includes Sideritis and Teucrium, and Fabaceae, including Genista, haveapigenin existing in the aglycone form and/or its C- and O-glucosides, glucuronides, acetylated derivatives, and O-methyl ethers.¹⁸⁶ Apigenin which has a molecular formula of C₁₅H₁₀O₅ and molecular weight of 270.24 is also known as 4′,5,7,-trihydroxyflavone.^185,187 In the Biopharmaceutics Classification system (BCS), apigenin is classified as a class II drug due to its low solubility and high permeability.¹⁸⁷

Apigenin is mainly found in Asteraceae species like Artemisia, Matricaria, Achillea, and Tanacetum genera.¹⁸⁶ In addition, apigenin, which exists as a glycosylated form, is found in 1) herbs like thyme, basil, chamomile, and oregano, 2) vegetables such as celery, parsley, and onion, and 3) plant-based beverages like beer, tea, and wine.¹⁸⁶ Other sources of apigenin include red and white sorghum, oranges, wheat sprouts, rutabagas, cilantro, and kumquats.¹⁸⁷

Apigenin is slightly soluble in highly polar solvents like water and non-polar solvents including safflower oil and silicone fluid. However, apigenin is freely soluble in ethanol, dimethylsulfoxide (DMSO), and dimethylformamide (DMF), excluding inert gases at 0.3, 15, and 25 mg/mL, respectively.¹⁸⁷ Apigenin has low toxicity with good biological activities like antioxidant, anti-tumor, anti-allergic, anti-inflammatory, cardioprotective, neuroprotective, antimicrobial, and anti-genotoxic.¹⁸⁵ Moreover, it also has anti-hyperglycemic, anti-apoptotic, anti-atherogenic, antiparasitic effects, and can confer protection against hypertension, autoimmune myocarditis, and cardiac hypertrophy.^185,187

Apigenin inhibits 1) UV-induced skin cancer by stimulating AMPK, leading to inhibition of the mammalian target of rapamycin (mTOR) effect and activation in keratinocytes, and 2) proliferation of cells and development of cell cycles in the mouse model skin and epidermal keratinocyte.¹⁸⁸ Furthermore, apigenin suppresses Akt (protein kinase B) and mTOR signaling independently, leading to AMPK-dependent inhibition of mTOR that intensifies autophagy along with reducing proliferation in keratinocytes.¹⁸⁹ Kiraly et al¹⁹⁰ demonstrated that apigenin inhibits tumorigenesis including tumor multiplicity as well as the incidence of a DMBA/TPA-induced tumor in a SKH-1 mice model by 1) reducing COX-2, EP1, EP2, and PGE2 production, 2) escalating the terminal differentiation, and 3) suppressing cell proliferation that contributes to the blocking of the production of tumors.

Paredes-Gonzalez et al¹⁹¹ concluded that apigenin demethylates the Nrf2 gene promoter in the 15 CpG site in JB6 P+ cells that 1) initiate the Nrf2 nuclear translocation and protein expression and 2) escalate NQO1, the Nrf2 downstream target. In addition, apigenin decreases DNA methyltransferase epigenetic proteins and also histone deacetylase (HDAC), indicating that apigenin can be a good chemoprotective agent or adjuvant. The researchers have reported that in UVB-induced skin cancer, thrombospondin-1 (TSP1) is an important element in chemoprotective activities of apigenin since apigenin suppressed the UVB-induced carcinogenesis in wild-type (WT) mice but not in TSP1 KO (TKO) mice. In summary, conserving normal TSP1 production via apigenin application can reduce the inflammatory cytokines in UVB-irradiated WT mice, indicating that TSP1 that has an anti-inflammatory effect is a significant element of the anti-tumor activities of apigenin in the skin.¹⁹² Overall, the findings indicated that apigenin can treat inflammatory diseases like psoriasis and eczema.

Topical apigenin, which can boost permeability barrier homeostasis, increasethe production of filaggrin, lamellar body, and mRNA levels in lipid synthetic enzymes, is useful in the treatment of skin diseases like atopic dermatitis that is associated with a permeability barrier aa long with decreased degree of filaggrin.¹⁹³ An important source of apigenin includes matricaria chamomile; also known as chamomile. Chamomile ointment can reduce dermatitis or eczema due to its purported anti-inflammatory activities. Topical chamomile extract reduced inflammation in croton oil-induced dermatitis in a rat model. In fact, matricaria ointment that contains apigenin has been reported to be comparable with non-steroidal anti-inflammatory drugs (NSAID) or 0.25% hydrocortisone, and is even more effective compared to 0.75% fluocortin butyl ester and 5% bufexamac against dermatitis.¹⁹⁴ Additionally, topical apigenin can also reduce acute inflammation and subacute dermatitis.¹⁹⁵

In a study with murine models that had acute allergic dermatitis and acute irritant contact dermatitis, apigenin 1) can treat both types of dermatitis, 2) decreases transepidermal water loss, 3) improves skin hydration, and 4) reduces the pH of the skin surface.¹⁹⁵ Due to its antioxidant activities, apigenin is also useful against skin aging. Topical application of apigenin improves skin aging in female participants (n=25) by ameliorating the skin roughness via 1) reduction of the volume of roughness, 2) improvement of fine lines, 3) reducing class 1 wrinkles (depth from 0–55 µm) to about 10% following 4 weeks of treatment, and 4) enhancement of skin elasticity, making the skin firmer following 8 weeks of treatment.¹⁹⁶ Overall, the positive findings indicate that apigenin is a useful anti-aging skin product.

Overview of the Mechanisms of Action of Natural Products Reported for the Treatment/Management of Skin Disorders

The prevalence of skin diseases commonly affects and risks human health of all generations, from children to older people. According to Tabassum and Hamdani,²² there are various skin diseases that are associated with humans including rashes and inflammation like psoriasis and dermatitis, infection like bacteria, virus and parasitic infection, tumor or cancer, wrinkles, pigmentary disorder, and skin aging. Therefore, it is essential to keep the skin healthy to get a healthy body. In fact, the skin actually acts as the body's defence against foreign particles, pathogens, and uncontrolled loss of water, and the skin also functions as insulation, regulating temperature, and is related with certain vitamin like vitamin D and B. According to Wootton et al,¹⁴ the most frequent human disease was skin disease, which will affect the human’s quality-of-life, mental health, and productivity. Furthermore, the study also highlighted that the use of natural products or herbal medicines that come from natural sources like plants, fruits, and vegetables are getting public attention as they are cheap, have less-side effects, good patient tolerance, and are acceptable as they have been used by our ancestors.²²

The present review focused on ten natural products or isolated compounds which are well documented for the treatment of inflammation skin disorders like psoriasis and dermatitis, tumor or cancer, skin infection, skin aging, and wounds, based on the in-vitro and in-vivo experiments. The overall mechanism of action of natural products against skin disorders has been summarized in Table 2 and Figure 5. However, these natural compounds need to be further studied to strengthen the claims, although they have potential against skin disorders.

Table 2 Overall Mechanism of Action for Natural Products Against Skin Disorders

Figure 5 Overview of the mechanisms of action of natural products reported to treat/management of skin disorders. Mangiferin, lutein, curcumin, resveratrol, embelin, naringenin, quercetin, lycopene, gingerol, and apigenin are natural products that are commonly used in the treatment of various skin disorders. Through various pathways, these natural products can aid in wound healing, protect against tumor development due to oxidative damage, prevent further progression of wrinkles from prolonged UV exposure, and reduce atopic dermatitis skin lesion growth. Created with BioRender.com. Abbreviations: UVA, B and C, ultraviolet A, B and C; AP-1, Activator protein 1; c-FOS, proto-oncogene.

On the one hand, the immune system in the skin is tightly regulated, thus protecting the host from extrinsic insults. On the other hand, when people become old, the immune system functions less actively therefore creating pro-inflammatory pathologies and other diseases. Moreover, any injury or infection in the skin changes its physical appearance. In general homogenous skin is considered as beautiful. Visually unappealing skin would affect the psychological health of the patients. An improvement in visible skin appearance enhances confidence. Some skin diseases, which spread throughout the body, induce psychological stress. Besides, stress dysregulates the immune homeostasis, which again drives the inflammatory diseases. A vast number of skin diseases are emerging (Figure 6), and each is categorized based on the type of inflammation intervention. Different levels of scaling have been assigned to track the disease status of the skin. The detailed mechanisms of how several skin diseases originated and progress have yet to be elucidated.

Figure 6 Targets of inflammatory skin diseases. Inflammation is an innate response of the body’s initial response against any insults (damage or infection). The hyperimmune response is the seeding point for several inflammatory skin diseases, including autoimmune diseases. The loss of self-tolerance in the skin sequentially develop as autoimmune diseases. Therefore, targeting excess inflammation would serve as a best strategy to restore the skin homeostasis. Several established targets in inflammatory diseases, such as innate immune system, co-stimulation, downstream pathways, adaptive immune system (including T- and B-cells), and others. Created with BioRender.com. Abbreviations: dDCs, dermal dendritic cells; IVIG, intravenous immunoglobulin; JAK, Janus kinase; KCs, keratinocytes; LCs, Langerhans cells; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B-cells; pDCs, plasmacytoid dendritic cells; STAT, signal transducer and activator of transcription; Syk, spleen tyrosine kinase.

Role and Importance of Nanoformulation Development of the Reported Natural Products for Skin Therapy

Natural products are beneficial due to their low toxicity and high efficiency in delivering a therapeutic effect.¹⁹⁷ However, their disadvantages include low bioavailability, they are not stable, and their poor solubility, which limit their effect. Previous studies stated that one of the ways to overcome these disadvantages is to develop the product into a nanoformulation, a novel drug delivery system, as it can improve the water solubility and permeability of the products to deliver the drug, thus improving the therapeutic effect.¹⁹⁸ Furthermore, nanoformulations help the drug reach the epidermis and dermis in dermatological treatment, specifically in psoriasis disease. The nanoformulation helps the drug reach the epidermis that is difficult to reach due to several scales of psoriasis.¹⁹⁸ According to Taghipour et al,¹⁹⁷ various phytochemicals like curcumin, naringenin, resveratrol, quercetin, and others have been developed into a nanoformulation. Other studies also demonstrated that nanoformulation increases the efficacy of therapeutics activities of natural products which also contribute to a smart healing process, decreasing the doses required for treatment, and improving the healing process of skin disorders like wound, where herbal-based nanostructures help in decreasing the oxidative factor and block the production of inflammatory cytokines and cascades.¹⁹⁸

According to Pleguezuelos-Villa et al,³² mangiferin nanoemulsions that are produced by hyaluronic acid boost the permeation, where the utilization of a TPA-inflamed skin mice model diminished the edema and leucocyte infiltration. Moreover, these nanoformulations show a good anti-inflammatory effect. A previous article also reported that a β-cyclodextrin–curcumin nanoparticle complex enhances the permeability in tissue of a skin model and encapsulated a nanoparticle formulation able to penetrate into the skin and help decrease the UVB-irradiation better than free curcumin.¹⁹⁹ On the other hand, the nanoformulation of naringenin, a flavonoid also used in treating skin diseases, overcomes the poor bioavailability problem and enhances the naringenin availability that leads to increased efficacy.²⁰⁰ Hatahet et al¹⁵² also investigated that quercetin smartcrystals (also known as quercetin nanocrystals) are able to enhance the saturation solubility and dissolution velocity and, more importantly, can preserve the antioxidative effect which will tolerate well with the skin. Besides, resveratrol nanoformulations like solid-lipid nanoparticles, liposomes, nanostructured lipid carriers, niosomes, and lipid-core nanocapsule have been developed toan achieve effective effect of resveratrol that is used to treat skin diseases including skin aging, acne vulgaris, and chloasma.⁸³

Challenges and Opportunities of Natural Products in Transdermal/Topical Delivery Systems and Their Safety Considerations for Skin Disorders

The skin has proven to be beneficial for both localized and systemic drug deliveries by showing various advantages, including 1) bypassing the hepatic first-pass effect, 2) minimizing changes in drug/natural product plasma levels, 3) allowing selective targ,eting 4) flexibility for controlled-release profiles, 5) improved patient compliance, and 6) cost-effectiveness.^201–203 The stratum corneum allows for percutaneous absorption of drugs and natural products. It is 10 µm thick, keratinized epidermal cells that act as a rate limiting barrier for drug/natural products permeation,^204,205 thus restricting the entry of polar, big molecular weight substances.²⁰⁶ The movement of lipophilic moieties into the stratum corneum is also limited, although hydrophilic moieties fail to partition.²⁰⁷ As for transdermal distribution, ideally, a drug candidate should have 1) moderate lipophilicity (log P<5), 2) sufficient solubility in both aqueous and lipophilic phases, 3) low molecular weight: <500, 4) high potency, and 5) a low melting point.^208,209 The natural products described in this review meet almost all of Lipinski’s rules, indicating their drug-likeness in nature, and therefore are good candidates for further investigation on the development of different formulations to deliver active constituents into the skin. The physicochemical properties of the natural products reported in this review are summarized in Table 3.

Table 3 Computed Physicochemical Properties of Natural Products Reported Against Skin Disorders

Although traditional transdermal formulations such as ointments, creams, and lotions exist, they have some drawbacks, such as having a lack of spreadability, being of a sticky nature, and having stability issues, overall contributing to non-compliance.²¹⁰ Transdermal distribution has progressed to the point where transparent gels and emulgels have been developed with improved efficacy and patient compliance. Consequently, these formulations are gaining popularity in both the cosmetics and pharmaceutical industries.

Nevertheless, rather the formulation and development of a suitable delivery system, and the delivery of hydrophobic moieties “across” the skin barrier, which is challenging.²¹⁰ According to the literature, nanosized topical formulations can increase the permeability of natural products by breaking the lipid bilayer²¹¹ and prolonging their retention at the site of action.²¹² Currently, liposomes, lipid nanoparticles, phytosomes, nanoemulsions, transferosomes, ethosomes, niosomes, β-cyclodextrin complexes, and polymeric nanomicelles are some of the most important nano-formulations used for dermatological and transdermal applications of phytomedicines.²¹³

A nanoemulsion is an isotropic, translucent, or transparent heterogeneous mixture made of oil and aqueous phases that is stabilized by the interfacial coating of a surfactant.²¹⁰ Nanoemulsions can improve the solubility of natural products over simple micellar solutions and give higher thermodynamic stability as compared to unstable dispersions like emulsions and suspensions, although they tend to be limited by their low viscosity and spreadability. Nevertheless, a simple change of nanoemulsion to nanoemulgel can be incorporated to tackle the challenges of using a nanoemulsion for transdermal delivery. Nanoemulgels are nanoemulsions that contain a gelling agent and are either water-in-oil (w/o) or oil-in-water (o/w) in nature. When compared to other carriers such as microemulsions, liposomes, or solid lipid nanoparticles, nanoemulgels have several advantages including increased permeability, better drug-loading capacity, and less skin irritation.²¹⁰

When developing nanophytomedicines, a variety of approaches have been used, as discussed in detail by Sahni et al.²¹⁴ The techniques include nanoprecipitation, co-precipitation, complex coacervation, supercritical fluid method, salting out method, solvent emulsification-diffusion method, and self-assembly methods.^214–216 Although nanoformulations of natural products have yielded positive outcomes, a thorough assessment of their safety, including toxicity to either the phytomedicine itself or to a component of the nanosystem is of paramount importance.^217,218

Another exciting new discovery in skin distribution of natural products is the film forming technology, which is a great alternative to traditional transdermal products. Although it is not a solid dosage form, it can turn into a film in situ, following skin application. Film formation is promoted by the presence of film-producing excipients in the system, allowing a film of excipients and drug/natural products into contact with the skin following solvent evaporation. The resulting film can either be a solid polymeric matrix that maintains active ingredient release into the skin or a residual liquid film that can be quickly absorbed in the stratum corneum.²¹⁹ All of the listed strategies have the potential to overcome the drawbacks of natural products in the development of skin formulations to treat a variety of skin disorders (Figure 7).

Figure 7 Effects of natural products on numerous skin conditions and possible drug delivery system. Nanocarriers are currently being used as a vehicle to deliver natural products to specific targeted regions in a regulated manner, as well as to overcome some of the drawbacks pertaining to the free compounds, such as poor bioavailability and rapid degradation. Natural products, along with innovative delivery systems, are a very promising area for future drug discovery against skin problems. For example, naringenin is a good candidate as an anti-psoriatic treatment as it inhibits over-expression of interleukin and ameliorated psoriasis and reduces transepidermal water loss. Resveratrol has protection against the main factor affecting non-melanoma skin cancer, which is UVB exposure by reducing COX-2 levels. Some other bioactive substances also exhibited a similar mode of action against various skin conditions including wound healing. Created with BioRender.com.

Conclusion and Future Perspectives

Natural products, particularly plant-based medicines, have received a lot of attention in the last decade, due to their efficacy in disease prevention and treatment.^220–223 In this review, we provide a comprehensive review on the effects of various natural products against skin disorders. Ten natural products, mangiferin, lutein, resveratrol, curcumin, embelin, naringenin, quercetin, lycopene, gingerol, and apigenin, from fruits, herbs, and vegetables which can usually be found in our daily lives, have been identified herein to be effective against various types of skin disorder. The skin disorders are widely associated with inflammation and/or tumors caused by several factors like UV radiation since the natural products have anti-inflammatory and antioxidant action.

Skin disease is a very common disease in humans, affecting the quality-of-life, mental health, and productivity. In fact, skin disorders have been reported to be the fourth major factor for a nonfatal burden, as indicated by the disability-adjusted life years (DALYs), besides the fact that the skin is also the 18th main origin of health burden worldwide. Overall, most of the natural compounds act on specific pathways to treat skin disorders where most are useful against more than one skin disease, with skin cancer and inflammatory-related diseases being the common ones. These include skin aging, wound, dermatitis or eczema, and psoriasis. In several studies, the action of all of the natural compounds reported in this review against skin disorders are reduction of inflammatory mediators and biomarkers, as anti-oxidant defence, anti-cancer (like chemoprotective and induction of apoptosis in cancer cell), and protection from UV radiation effect.

Two characteristics that these extracts or phytoconstituents must and should have are antimicrobial and wound-healing properties. In addition, extracts, which inhibits histamine release and pro-inflammatory cytokines release, are additional assets. The advantage of using natural products in cosmetics or skincare products is they offer less toxicity when compared to novel synthetic products. In addition, their absorption and systemic concentration of the active ingredients are significantly less.

Nevertheless, several perspectives on the application of natural products for the treatment and prevention of skin diseases are suggested. Further studies are required to strengthen the claims, especially in clinical trials. Bypassing drawbacks associated with natural products such as poor bioavailability and metabolism, broader clinical trials might be done, offering clinicians trustworthy evidence on the safety and possible clinical benefits of natural products for skin health. Natural products in combination with modern drugs, as well as the development of novel delivery mechanisms, represent a very promising area for future drug discovery of these natural leads against skin disorders.