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

Figures & data

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 (T_RM; 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.

Table 1 List of Skin Diseases or Disorders

Disease	Characteristics	Causative Factor	References
Autoimmune disorders
Systemic lupus erythematosus (SLE)	Antigen-antibody complexes deposition at the basement membrane region (place where dermis and epidermis separated)	Autoantibodies	Pires et al^Citation224
Scleroderma and morphea (localized scleroderma)	Collagen overproduction in the dermis	–	Careta and Romiti^Citation225
Mixed connective tissue disease	Elevated blood levels of anti-U1-ribonucleoprotein in at least two connective tissue diseases	–	Sapkota and Al Khalili^Citation226
Dermatomyositis	Symmetrical proximal muscle weakness, elevated serum muscle enzymes, and muscle biopsy and electromyography findings consistent with myositis	Immune system activation that causes immunologic attacks on muscle fibers and endomysial capillaries	Cheeti et al^Citation227 Koler and Montemarano^Citation228
Eczematous disorders
Atopic dermatitis	Genetic, environmental, and immunologic mechanisms play a role in this inflammatory disorder. Pro-inflammatory cytokines are released by keratinocytes in response to neuropeptides, irritation, or pruritus-induced scratching	Defects in skin barrier function, immune dysregulation, and exposure to infectious agents	Siiskonen and Harvima^Citation229; Umehara et al^Citation230
Allergic contact dermatitis	An antigenic agent triggers an immunologic reaction in the skin, which may take several days to occur	Antigenic substance	Corsini et al^Citation231; Kaplan et al^Citation232
Hair loss associated skin disorder
Alopecia areata	Hair loss on the scalp, face, and other parts of the body is caused by an autoimmune skin disease.	Abnormality in the immune system	Pratt et al^Citation233
Immunodeficiencies
Ataxia telangiectasia	Development of reddish lesions of the skin and mucous membranes (Ataxia) due to permanent widening of groups of blood vessels (telangiectasia), and impaired immune system functioning	Mutations in a gene on chromosome 11 (ATM gene)	Folgori et al^Citation234; Goldman^Citation235
Chronic mucocutaneous candidiasis	Candida spp., primarily Candida albicans, cause recurrent or chronic infections of the nails, skin, and oral and genital mucosae	Primary immune deficiency	Beenhouwer^Citation236
Chronic granulomatous disease	Recurrent, life-threatening bacterial and fungal infections as well as granuloma formation	Defects in an essential enzyme in white blood cells that produce oxidants for microbial killing are inherited	Song et al^Citation237
Hyper-Immunoglobulin E syndrome	Recurrent eczema, skin abscesses, lung infections, eosinophilia, and elevated IgE levels in the blood	Genetic mutation in either STAT3 or DOCK8	Freeman and Holland^Citation238; Freeman and Olivier^Citation239
Leukocyte adhesion molecule deficiency	Inability of leukocytes to migrate from circulation into sites of inflammation, resulting in recurrent bacterial infections	Deficiency of adhesive glycoproteins on the surfaces of white blood cells	Snyder^Citation240; Justiz Vaillant and Ahmad^Citation241
Severe combined immunodeficiency	Numerous genetic mutations disrupt the production of functional T- and B-cells, resulting in a wide range of clinical signs	X-linked trait disorder or inherited autosomal recessive genetic trait	Fischer^Citation242; Tasher and Dalal^Citation243
Warts–hypogammaglobulinemia–infections–myelokathexis syndrome (WHIM syndrome)	Neutropenia, lymphopenia, infection susceptibility, and myelokathexis which describes degenerative changes in mature neutrophils and hyperplasia of bone marrow myeloid cells	Primary immunodeficiency caused by heterozygous mutations in the CXCR4	Badolato et al^Citation244
Wiskott–Aldrich syndrome	Rare X-linked disorder that usually includes the triad of immunodeficiency, thrombocytopenia, and eczema	Mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal reorganization in hematopoietic cells	Baharin et al^Citation245; Malik and Masab^Citation246
Papulosquamous disorders	Well-demarcated areas of papules and scale, typically on an erythematous background	–	Errichetti and Stinco^Citation247; Langley et al^Citation248
Psoriasis	Skin disease that produces plaques of thickened, scaly skin	TH1-type cytokines	Armstrong^Citation249
Lichen planus	Itchy, non-infectious rash on the arms and legs	Stress, anxiety, and other factors in relation with the immune system	Arnold and Krishnamurthy^Citation250
Cutaneous graft vs host disease	Maculopapular rash that can begin anywhere in the body but often starts with palm and sole involvement	Immune response against tissue and organ	Villarreal et al^Citation251
Photodermatoses
Polymorphous light eruption	Recurrent, abnormal, delayed reactions to sunlight on sunlight-exposed surfaces, ranging from erythematous papules, papulovesicles, and plaques to erythema multiforme-like lesions	UVA light spectrum, UVB and visible light	Plaza and Prieto^Citation252
Solar urticaria	Recurrent episodes of urticaria overlying regions of the skin that are exposed to sunlight	Antigen-antibody reaction	Harris et al^Citation253
Chronic actinic dermatitis	Persistent eczematous eruption, occasionally associated with infiltrated papules and plaques due to a reaction to sunlight or artificial light	Extrinsic chemicals and intrinsic factors	Smith et al^Citation254
Photoallergic contact dermatitis	Delayed-type hypersensitivity cutaneous reaction in response to a photoantigen applied to the skin in subjects previously sensitized to the same substance	Photoallergen	Foti et al^Citation255
Pigmentary disorders
Vitiligo	Patches of the skin losing their pigment or color	Loss or destruction of melanocytes, which are the cells that produce melanin	Bergqvist and Ezzedine^Citation256
Purpuric disorders	Small bleeding vessels near the surface produce a purplish discoloration of the skin	Deficiency of the anticoagulants protein C, protein S, and antithrombin III	Marks and Miller^Citation257; Reamy et al^Citation258
Leukocytoclastic vasculitis	Inflammation of small blood vessels presenting with petechiae and palpable purpura	Allergic reaction via mechanism like injury by bacteria or viruses, activation of antibodies, and activation of complement	Azanza et al^Citation259; Baigrie et al^Citation260
Medium vessel vasculitides (polyarteritis nodosa, Wegener’s Granulomatosis, and Churg-Strauss vasculitis)	Inflammation and necrosis on the walls of medium blood vessels, resulting in lumen occlusion	Infectious agent or medication such as those associated with hepatitis B or C viruses (HBV or HCV, respectively), cryoglobulinaemic vasculitis, or cutaneous leucocytoclastic vasculitis, preceded by an infection or the use of certain medicine	Baigrie et al^Citation260; Hunder^Citation261
Urticarial disorders
Urticaria and angioedema	Maculae, papules, and edematous, pruriginous erythematous plaques that appear unexpectedly and disappear spontaneously in minutes, hours, or days	Autoantibodies to the alpha subunit of the high-affinity IgE receptor on dermal mast cells and basophils respond with circulating immunoglobulin G (IgG) autoantibodies, prompting chronic activation of these cells and the release of histamine and other inflammatory mediators	Deacock^Citation262; Engin et al^Citation263
Erythema multiforme	Rash with papular (small raised bumps) or vesicular lesions (blisters) and skin reddening or discoloration, usually in concentric zones around the lesion	Allergic reaction usually due to Herpes virus (HSV)	Ely and Stone^Citation264; Hafsi and Badri^Citation265; Paulino et al^Citation266
Stevens Johnson syndrome	Rare but extreme and life-threatening blistering eruptions	Drug-specific CD8+ cytotoxic lymphocytes	Klimas et al^Citation267
Toxic epidermal necrolysis	Blisters and peels of the top layer of skin	Drug-specific CD8+ cytotoxic lymphocytes	Mawson et al^Citation268
Cryopyrin-associated periodic syndromes (Muckle Wells syndrome and Familial cold urticaria)	Recurrent flares or mild to severe systemic inflammation and fever including episodic fever, urticaria-like rash, and joint involvement	Increased activation of the NLRP3-inflammasome and overproduction of IL-1β was associated with mutations in the NLRP3 gene	Azizi et al^Citation269
Neonatal onset multisystem inflammatory disease (NOMID)	Fever, rash, and tissue damage of the nervous system, skin, and joints	Mutations in the CIAS1/NLRP3 gene	Alsharief et al^Citation270; Huttenlocher et al^Citation271
Deficiency of the interleukin-1–receptor antagonist (DIRA)	The neonatal onset of a pustular skin rash, multifocal osteomyelitis, periostitis, and, occasionally, vasculitis	Autosomal recessive mutations in IL1RN	Kutukculer et al^Citation272; Schnellbacher et al^Citation273
Vesiculobullous diseases
Pemphigus Vulgaris	The appearance of blisters that originate in the epidermis suprabasal layer	Anti-desmoglein 1 and 3 antibodies	Kasperkiewicz et al^Citation274
Pemphigus Foliaceus	Blisters in the upper epidermis	Anti-desmoglein 1 antibodies	James et al^Citation275
Bullous pemphigoid	Itching, blistering, and urticarial lesions (hives) that affect a small area of the body or are widespread	Autoantibodies	Bakker et al^Citation276
Paraneoplastic pemphigus	Ulcerated lesions and vesicular eruptions in the mucocutaneous regions	Autoantibodies that target desmoglein 1 and 3; desmocollins 1, 2, and 3; desmoplakins 1 and 2; BP230; BP130; and envoplakin	Yatim et al^Citation277
Epidermolysis bullosa acquisita	Skin fragility, noninflammatory tense bullae, milia, and scarring are all indications of subepidermal blistering disease of the skin and mucus membranes.	Anti-type VII collagen autoantibodies	Gupta et al^Citation278
Dermatitis herpetiformis	Groups of extremely itchy blisters and raised red skin lesions are present	IgA antibodies	Criado et al^Citation279
Linear IgA bullous dermatoses	Blisters with a tense clinical appearance are produced by linear deposition of IgA and disturbance of the dermoepidermal junction	IgA autoantibodies	Chen et al^Citation280
Pemphigus gestationis	Appearance of very itchy red bumps or blisters on the abdomen and trunk, and other parts of the body during second and third trimesters of pregnancy	IgG autoantibodies	Şentürk et al^Citation281; Snarskaya et al^Citation282

Notes: The main body text contains all of the abbreviations.

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.

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

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.

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

Natural Products	Mechanism of Action	References
Mangiferin	Reduce Skin Aging ● By increasing the collagen bundles in skin ● By blocking MMP-1 expression by supressing the ERK and JNK pathway and also through inhibition of MEK and SEK pathways Inflammation Reduction (dermatitis and psoriasis) ● By inhibiting the inflammatory activity via reduction of inflammatory mediators and inflammatory biomarkers ● By inhibiting the CD68 activity Wound Healing ● By instigating the cell proliferation and migration of fibroblasts and reducing MPO activity ● By reducing the oxidative damage on skin tissue by increasing the Nrf-2 degree ● Skin flap regeneration Treat Skin Cancer ● By blocking fibroblast growth factor (bFGF) and expression of IL6, TNF, PLAU, KDR (VEGFR2), IFNG, FGF1, CCL2, MMP19, and placental growth factor (PGF) Treat Skin Infection ● By reducing the infectivity of HSV infection	Allaw et al^Citation33; Chae et al^Citation27; Delgado-Hernández et al^Citation39; Gerber et al^Citation35; Jie et al^Citation40; Kim et al^Citation26; Lwin et al^Citation34; Magcwebeba et al^Citation36; Zhao et al^Citation30
Lutein	Reduce Melisma ● By enhancing skin tone, luminance and color Reduce Skin Aging ● By defending from gene expression and providing a barrier to the skin from UVR ● Block the skin damage and promote the skin component ● Enhance the collagen I/elastin aging index Inflammation Reduction (skin erythema and psoriasis) ● Decrease the skin rash by block UVR ● Due to antioxidant activity ● Decrease the amount of sunburn cells and decrease epidermal hyperproliferation Treat Skin Cancer ● Due to antioxidant activity ● By decreasing risk of SCC ● Increase the tumor free survival time and reduce the tumor volume and multiplicity Wound Healing ● By increasing production of hyaluronan	Aziz et al^Citation46; Balić and Mokos^Citation44; Heinen et al^Citation48; Murillo et al^Citation47; Souyoul et al^Citation45
Curcumin	Inflammation Reduction (psoriasis) ● By inhibiting proliferation of human keratinocytes ● By blocking the expression of TNF-a-induced IL-1b, IL-6, TNF-a, cyclin E, MAPKs (JNK, p38 MAPK and ERK) and NF-κB ● By blocking the action and production of TNF and also a potent inhibitor of phosphorylase kinase (PHK) activity ● Obstruct the endosomal toll-like receptor (TLR) by blocking NF-κB signaling Reduce Dermatitis Symptoms ● By reducing radiodermatitis ● Modulate the protein kinase C-θ (PKC-θ) pathway by inhibiting the phosporylation of PKC-θ ● Reduce the severity of irradiated skin ● Decrease the expression of cyclooxygenase-2 (COX-2) and expression of NF-κB Wound Healing ● By decreasing the lipid peroxidation (LPx) and reactive oxygen species (ROS) ● Produce protective activity ● Reduce expression of inflammatory cytokines and modulate the proinflammatory gene educe transcription factor protein-1 (AP1) and NF-κB, reduce expression of inflammatory cytokines and modulate the proinflammatory gene product expression ● Accelerate wound healing stages ● Activation of growth factors and produce ECM proteins along with helping in collagen synthesis and migration of fibroblast Reduce Skin Aging ● By enhancing the skin firmness and elasticity ● By inhibiting the increase of UVB induced TNF-α and IL-1β and increasing the production of hyaluronan Treat Skin Cancer ● By reducing phosphorylation of IGF-1 receptor, insulin receptor substrate-1 (IRS-1), S6K, AKT, and 4EBP1 ● By inducing cell apoptosis and inhibition of melanoma cell migration and invasion ● Upregulate expression of miRNA and reduce proliferating cell nuclear antigen (PCNA) and Bcl-2 ● Incite mitochondrial permeability transition pore (mPTP) opening and lead to apoptosis/cell death of WM-115 melanoma cells ● Delay the tumor appearance, multiplicity, and volume, along with the increasing of p53 and p21/Cip1-positive cells in the epidermis Treat Skin Infection ● By interrupting the bacterial cell membrane ● Act as a photosensitizer ● Bacterial membrane perturbation, damage the motility, change gene expression and suppression replication machinery ● Suppress the S. epidermis growth to treat acne vulgaris ● Inhibit growth of fungal by inducing the ROS and reactive nitrogen species (RNS)	Aggarwal et al^Citation52; Almeida et al^Citation74; Asada et al^Citation66; Baltazar et al^Citation76; Barchitta et al^Citation64; Heng et al^Citation53; Kim et al^Citation59; Lai et al^Citation55; Lee et al^Citation58; Lelli et al^Citation68; Liu and Huang^Citation75; Mohammadi et al^Citation63; Mohanty and Sahoo^Citation61; Phan et al^Citation62; Qiu et al^Citation70; Sommerfeld^Citation65; Tsai et al^Citation71; Vaughn et al^Citation57; Vaughn et al^Citation50; Vollono et al^Citation13
Resveratrol	Reduce Skin Aging ● By inhibiting TNF-α-induced expression of inflammatory cytokines and MMPs ● By enhancing the sirtuin 1 expression, promoting the mitochondria function and decreasing the ROS production ● By protecting from the damaging effects of hydrogen peroxide ● Decrease the AP-1 and NF-κB transcription factors expression, collagen breakdown, and inflammation Treat Skin Cancer ● Has a chemo-preventive effect by decreasing the COX-2 levels ● Increase cyclin kinase inhibitor WAF1/p21 and tumor suppressor p53 ● Modulation in the expression and function of cell cycle regulatory protein cyclin-D1 and -D2, cdk-2, -4, and -6 and WAF1/p21 ● Alter the expression level of vasodilator-stimulated phosphoprotein (VASP), COX-2, AMP-activated protein kinase (AMPK), and vascular endothelial growth factor (VEGF) ● Obstruct the MAPK/ NF-κB/AP-1/COX-2 pathway Reduction of Skin Infection (HSV) ● By decrease the development of lesion ● Suppress the stimulation of NF-κB ● Stimulate the 50 AMP-activated protein kinase/Sirtuin 1 (AMPK/Sirt1) axis Treat Acne Vulgaris ● Inhibit P.acnes reproduction and reduce the inflammation ● Change the surface structure of bacteria with loss of define membrane ● Suppress imiquimod-induced gene expression of IL-19, IL-17A, IL-17F, and IL-23p19 Wound Healing ● Cause the growth of a protected area ithe n epithelium, raise the cell density and elevate the displacement of connective tissue at the place of wound Reduce Chloasma ● Decrease the number of melanocytes ● Decrease in skin melanin and reduce pigmentation	Aziz et al^Citation86; Boo^Citation81; Buonocore et al^Citation85; Docherty et al^Citation94; Docherty et al^Citation99; Docherty et al^Citation93; Dybkowska et al^Citation87; Faith et al^Citation95; Hemmati^Citation102; Kjær et al^Citation101; Lai et al^Citation55; Lee et al^Citation283; Leyton et al^Citation96; Liang et al^Citation82; Moreira et al^Citation105; Rauf et al^Citation88; Reagan-Shaw et al^Citation89; Soleymani et al^Citation83; Taylor et al^Citation100; Yamakoshi et al^Citation104; Yarla et al^Citation91
Embelin	Inflammation Reduction (psoriasis) ● By suppression of TNF-α and IL-1β and the inhibition of aggregation of leukocyte ● Increase the percentage of wound closure Wound Healing ● By accelerating the incision epithelialization ● Show the complete healing process	Swamy et al^Citation111
Naringenin	Treat Skin Cancer ● By decreasing papilloma occurrence ● By decreasing the size and number of papilloma ● By reducing the expression of glyoxalase-1 ● By elevation of carbonyl contents ● Decreased the production of new blood vessels in peritoneal and inner skin linings ● Induced apoptosis includinginduction of ROS mediated mitochondrial membrane depolarization ● Has photochemopreventive effect Reduce skin aging ● By inhibiting the UVB-induced MMP-1 production and activator protein-1 (AP-1) ● By suppressing MMP-13 formation and production of wrinkles ● By downregulating the aging regulated genes ● Increase lesion removal and suppress excessive apoptosis Inflammation reduction (atopic dermatitis) ● By decreasing the atomic dermatitis skin lesion growth via inhibiting the formation of interferon-gamma (IFN-γ) ● By decreasing the total white blood count (WBC) and the thickness of earflap Inflammation reduction (psoriasis) ● By suppressing T-cell proliferation, decreasiningg proinflammatory cytokine (TNF-α and IL-6) and showing the proliferation of human peripheral blood mononuclear cells (hPBMC) ● By inhibiting the overexpression of IL-6 and decreasing transepidermal water loss Exert Anti-allergic Effect (Skin Allergic) ● By inhibiting the mast cell degranulation ● By suppressing histamine release Treat Skin Infection ● Exhibit an antifungal effect to T. brownii, C. krusei, and Candida albicans Treat Thermal Burn-Induced Injury ● By suppressing the proinflammatory marker and due to antioxidant effect	Ahamad et al^Citation118; Al-Roujayee^Citation134; Alalaiwe et al^Citation128; El‐Mahdy et al^Citation123; Escribano-Ferrer et al^Citation129; Gaggeri et al^Citation127; Jung et al^Citation121; Kim et al^Citation124; Kumar and Bhan^Citation114; Kumar and Tiku^Citation116; Nagula and Wairkar^Citation125; Orhan et al^Citation133; Prasanth et al^Citation122; Salih et al^Citation132; Yamamoto et al^Citation130; Yoshimura et al^Citation131
Quercetin	Reduce Skin Aging ● By inhibited UV-induced COX-2, MMP-1 and breakdown of collagen in human skin ● By exerting its effect on PKC-delta (PKCδ) and Janus kinase-2 (JAK2) ● By blocking AP-1 and NF-κB stimulation ● Activate the proteasome through the Nrf2 pathway Treat Skin Cancer ● By inhibiting the stimulation of signal transducer and activator of transcription (STAT3) via IL-6 by decreasing the cyclin D1 and MMP-2 production ● Suppressing the phosphatidylinosi-tol-3-phosphate kinase (P13K) effect ● Suppressing the B16-BL6 melanoma cell growth and DNA synthesis ● Stimulate the p53 expression and ROS stimulation Treat Skin Infection ● Can inhibit certain pathogens ● Protect from H. pylori infection and have an effect against MRSA Inflammation Reduction (dermatitis) ● By blocking the inflammatory cytokines and proinflammatory factor ● Upregulation of heme oxygenase ● By reducing Th2 polarization, inhibiting cytokine TSLP and TARC ● By inhibiting IL-6, IL-8, and TNF-α Wound healing ● By penetrating into the fibroblast ● By elevating the cell proliferation ● By decreasing the wound contraction, elevating the hydroxproline, decreasing uronic acid content and superoxide dismutase content Reduction of keloid (dermal scar) ● By suppressing the transforming growth factor-beta (TGF-β) and Smads complex (Smad2/3/4)	Amin et al^Citation147; Brown et al^Citation146; Caltagirone et al^Citation144; Chondrogianni et al^Citation140; Gomathi et al^Citation153; Hatahet et al^Citation152; Jung et al^Citation150; Matsushima et al^Citation149; Sajadimajd et al^Citation142; Shaik et al^Citation143; Shin et al^Citation139; Unahabhokha et al^Citation154; Vargas et al^Citation145; Weng et al^Citation151
Lycopene	Reduce Skin Aging ● By reducing the roughness and scaling in human skin ● By improving the skin elasticity ● By improving the skin hydration and elasticity of stratum corneum Treat Skin Cancer ● By suppressing ODC activity, blocking inflammatory responses like MPO activity and skin thickness, decreasing the caspase-3 production and showing a PCNA staining cell ● By decreasing the biomarkers of oxidative stress and carcinogenesis ● Reduction of tumor number ● By reducing the UV-induced cyclobutane pyrimidine dimers formation, myeloperoxidase activity and percentage of p53 positive epidermal cells ● Due to antioxidant activity – DNA damage and reduction of serum thiorbarbituric acid reactive substance Inflammation Reduction (Skin erythema) ● By reducing the sensitivity to UV induced erythema ● By suppressing the UVA1- and UVA/B-induced HO1 increase, ICAM-1 and MMP-1 mRNA ● By demonstrating higher phenol content that make it as a good capacity of antioxidant Inflammation Reduction (psoriasis) ● By suppressing IMQ-induced psoriasis-like inflammation by inhibiting the monocyte adhesion Reduce Atopy Disease (eczema) ● By stimulating the retinoic acid receptor (RAR) and retinoid-X receptor (RXR)ing ● By block the atopy development	Basu and Imrhan^Citation166; Cooperstone et al^Citation167; Darvin et al^Citation161; Fazekas et al^Citation165; Grether-Beck et al^Citation173; Hwang and Bowen^Citation169; Kopec et al^Citation168; Marchena et al^Citation164; Meinke et al^Citation163; Rühl^Citation175; Segger and Schönlau^Citation162; Shih et al^Citation174; Sies and Stahl^Citation172; Stahl et al^Citation170
Gingerol	Treat Skin Cancer ● By decreasing the UVB-induced ROS ● By suppressing the UVB-induced COX-2 production ● Exert chemoprotective effect through targeting the arachidonic acid (AA) pathway ● By suppressing the melanin formation and inhibiting melanogenesis development ● By suppressing the TPA-induced COX-2 synthesis through prevention of p38 mitogen-activated protein (MAP) kinase- NF-κB signaling pathway	Huang et al^Citation183; Kim et al^Citation182; Kim et al^Citation184; Yarla et al^Citation91
Apigenin	Treat Skin Cancer ● By stimulating the AMP-activated protein kinase (AMPK) and inhibiting proliferation of the cell and development of cell cycle ● By suppressing Akt (protein kinase B) and mTOR signaling ● Inhibiting the tumorigenesis by reducing COX-2, EP1, EP2, and PGE2 production, escalating the terminal differentiation and suppressing the cell proliferation ● By demethylates the Nrf2 gene promoter ● By decreased DNMT epigenetic proteins and HDAC ● By suppressing the UVB-induced carcinogenesis due to the presence of TSP1 Inflammatory Reduction (psoriasis and eczema) ● By reducing the inflammatory cytokines due to TSP1 Dermatitis Reduction ● By boosting permeability barrier homeostasis, increasing production of filaggrin, lamellar body, and mRNA level in lipid synthetic enzymes ● Reduce inflammation Reduce Skin Aging ● By reducing the skin roughness and improve the fine lines and wrinkles due antioxidant activity	Arterbery and Gupta^Citation196; Bridgeman et al^Citation189; Hou et al^Citation193; Imran et al^Citation188; Kiraly et al^Citation190; Man et al^Citation195; Mirzoeva et al^Citation192; Paredes-Gonzalez et al^Citation191; Zari and Zari^Citation194

Notes: The main body text contains all of the abbreviations.

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.

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.

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

Property	Mangiferin	Lutein	Resveratrol	Curcumin	Embelin	Naringenin	Quercetin	Lycopene	6-Gingerol	Apigenin
Molecular formula	C19H18O11	C40H56O2	C14H12O3	C21H20O6	C17H26O4	C15H12O5	C15H10O7	C40H56	C17H26O4	C15H10O5
Molecular weight	422.3	568.9	228.24	368.4	294.4	272.25	302.23	536.9	294.4	270.24
Hydrogen bond donors	8	2	3	2	2	3	5	0	2	3
Hydrogen bond acceptors	11	2	3	6	4	5	7	0	4	5
Rotatable bonds	2	10	2	8	10	1	1	16	10	1
Log P (Partition coefficient, Predicted value)	−0.16	9.31	2.99	2.30	4.62	2.12	1.68	9.98	3.22	2.46
Melting point	279 °C	196 °C	254 °C	183 °C	142.5 °C	251 °C	316.5 °C	175 °C	31 °C	347.5 °C
Molar refractivity ±0.3 (cm^3)	96.91	189.11	69.29	104.04	81.33	70.25	73.31	186.85	82.94	69.85
Molar volume ±3.0 (cm^3)	229.1	566.1	167.9	287.8	260.1	183.2	167.9	604.2	271.7 ± 3.0	174.5
Topological polar surface area	197 Å^2	40.5 Å^2	60.7 Å^2	93.1 Å^2	74.6 Å^2	87 Å^2	127 Å^2	0 Å^2	66.8 Å^2	87 Å^2

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.

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