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20 June 2023

The PI3K-Akt-mTOR and Associated Signaling Pathways as Molecular Drivers of Immune-Mediated Inflammatory Skin Diseases: Update on Therapeutic Strategy Using Natural and Synthetic Compounds

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1
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA
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Department of Toxicology and Cancer Biology, Center for Research on Environmental Diseases, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
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Division for Research and Innovation, POHOFI Inc., Madison, WI 53744, USA
4
School of Nursing and Allied Health Sciences, Louisiana Delta Community College, Monroe, LA 71203, USA
Cells2023, 12(12), 1671;https://doi.org/10.3390/cells12121671
This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0
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Abstract

The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders.

1. Introduction to the Structure and Function of the Skin

The skin is the largest and outermost organ in humans, located at the boundary between the interior and exterior environment, and plays a crucial role in the body’s functions. It is composed of distinct tissue layers, including the epidermis, dermis, and hypodermis. The epidermis consists of four to five cell layers primarily composed of keratinocytes, which produce keratins essential for maintaining skin integrity. Other cell types in the epidermis include melanocytes, Langerhans, mastocytes, and Merkel cells (Figure 1A) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16].
Figure 1. Schematic representation of the cross section of the skin (A) and structure of the epidermis and papillary dermis ((B), Inset).
The epidermis is composed of distinct layers of keratinocytes at different stages of maturation and function, including the germinative and proliferative cell layer (stratum basale; SB), the spinous or prickle cell layer (stratum spinosum; SS), the granular cell layer (stratum granulosum; SG), and the cornified or horny cell layer (stratum corneum, SC). In palmoplantar skin, the stratum lucidum comes before the horny layer to maintain healthy skin with functional barriers (Figure 1B) [3,5,17,18,19,20,21,22].
The dermis supports the epidermis and contains blood and lymphatic vessels, sensory elements, and various cells. Skin adnexal structures, such as sweat glands, sebaceous glands, and hair follicles, arise from invaginations of the epidermis. Stem cells can be found in the bulge region of hair follicles, the basal layer of the interfollicular epidermis, and in sebaceous glands. The dermis is a dense connective tissue underlying the epidermis that provides skin’s strength and flexibility through its extracellular matrix mainly composed of collagen, elastin, fibrillin, and glycoproteins [5]. It is composed of the papillary and reticular layers and contains blood vessels, hair follicles, nerve endings, sweat, and sebaceous glands. Additionally, it houses diverse skin resident cell types, including fibroblasts responsible for the production of collagen, elastin, and GAGs for tissue elasticity and histiocytes, such as macrophages, lymphocytes, and mast cells that provide immune responses [5].
The hypodermis is the innermost skin layer, mainly comprised of adipose tissue and other structures, providing insulation and energy storage. The three skin tissue compartments interact via various mechanisms to maintain healthy skin and a functional barrier [5,21,22].
The skin is located on the exterior of the body and serves various functions, including protecting against external insults, such as chemical and biological agents, physical factors, and injuries, as well as regulating the exchanges of body fluids and substances involved in homeostasis, metabolism, and energy storage [2,21,23,24,25,26]. The skin’s visible and exterior location is also important in social and sexual relationships.
Dysregulation of the skin’s tightly regulated homeostasis and immune responses due to modifiable or non-modifiable risk factors can lead to various chronic inflammatory dermatoses.

3. Overview of the Structure and Function of the PI3K-Akt-mTOR Signaling Pathway

The PI3K-Akt-mTOR signaling pathway plays a critical role in various physiological and pathological conditions, particularly in cell growth, differentiation, and survival. The inter-connectivity of PI3K, Akt, and mTOR with other signaling cascades, such as HIFs, AP-1, JNK, Notch, FOXO, RAS, ERK1/2, Wnt, and Rho small GTPases, has been widely recognized [5,61]. This pathway serves as a hub in cellular response to external stimuli like EGF, FGF, insulin, and IGF-1. It is also connected with upstream regulators such as chemokine receptor-9, TLRs, and IL-6 and plays crucial roles in cell growth, proliferation, survival, migration, and differentiation. Therefore, it has emerged as a central regulator of tissue and organ homeostasis and a key driver of immune-mediated dermatoses [62].
In the 1980s, the importance of PI3K was discovered when a physio-functional relationship was observed between its activity and the transformation activity of the viral oncogene and with activated protein-tyrosine kinases [63]. PI3Ks are characterized as a family of lipid kinases capable of phosphorylating the inositol ring 3′-OH group in inositol phospholipids. The PI3K consists of three distinct classes of regulatory, functional, and structural molecules, with class I PI3K being the most extensively studied [62,63,64,65].

3.1. Class I PI3Ks and the Key Intracellular Effectors

Class I PI3Ks are the most studied PI3K family members, with similar structures and substrate specificities, including PI, PIPs, and PIP2. Class I PI3Ks are a family of lipid kinases that play important roles in cellular physiology. They are composed of a catalytic domain (p110 subunit) and a regulatory subunit (p85) and are divided into two subfamilies, IA and IB. They are activated via cell surface receptors and phosphorylate PIP2 to generate PIP3, which regulates several cellular processes and activates downstream signaling pathways, including Akt/mTOR. The different isoforms of p110 have distinct functions in skin cells and are expressed in various cell types involved in inflammatory dermatoses [63,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82].
The p110δ isoform of PI3K is expressed in cell types such as keratinocytes, synovial fibroblasts, and endothelial cells, which are frequently involved in the pathophysiology of inflammatory dermatoses [81,82]. PI3K activation occurs via cell surface receptors that bring them into proximity with their substrates (PI, PIPs, and PIP2) [44]. Activation of class IA PI3K via RTKs is mediated by the p85 regulatory subunit, which directly binds to cell membrane receptors, stimulating the receptors and leading to the recruitment of the p85 subunit and subsequent activation of PI3K p110 by binding to RTKs’ intracellular phosphorylated tyrosine residues [81,82]. Once activated, PI3K p110 phosphorylates PIP2 to generate PIP3, which regulates various cell physiological processes and downstream Akt/mTOR signaling pathways by binding and phosphorylating/activating other proteins, including Akt [5,83].

3.2. Class II and Class III PI3Ks

Class II PI3Ks contain obligatory regulatory subunits encompassing a Ras-binding motif and have substrates such as PIP2s and phosphatidylinositol (PI). They are able to interact with other possible adaptor proteins and may be activated via cytokine receptors, integrins, and RTKs. The Class II PI3Ks serve a role in the cellular cortex by modulating cell migration, membrane trafficking, glucose transport, insulin signaling, as well as receptor internalization [84,85].
Furthermore, the only known class III PI3K is Vps34, which is thought to regulate membrane trafficking functions such as autophagy flux, endosome-lysosome maturation, endosomal protein sorting, and cytokinesis using PI as a substrate. The downstream targets of class III PI3Ks/Vps34 are also controlled in response to cellular stress, growth and survival, and accessibility of amino acids [84,85].

3.3. PKB/Akt

PKB (Protein kinase B)/Akt, a serine/threonine (Ser/Thr) kinase, regulates many cellular and physiological functions including protein synthesis, glucose metabolism, cell cycle progression, cell proliferation, and survival (Reviewed in [5] and Figure 2).
Figure 2. Schematic illustration of the PI3K/Akt/mTOR signaling pathway and the processes they regulate to control growth.
Indeed, Akt plays an important role in maintaining epidermal homeostasis and sustaining keratinocyte function, promoting keratinocyte differentiation and survival, and is fully functional upon activation at two specific amino acids via phosphorylation at Ser473 and Thr308. The process is initiated upon binding of PIP3 to Akt, leading to its recruitment to the plasma membrane, where it gets phosphorylated in Thr308 by phosphoinositide-dependent kinase-1 (PDK1) [5]. From there, mTORC2 (see below and Figure 2) phosphorylates Akt at Ser473 resulting in fully activated Akt, which subsequently phosphorylates mTORC1 [5]. Akt regulates a plethora of signaling proteins and cellular processes. For example, Akt also phosphorylates and inhibits pro-apoptotic proteins (BAD and procapase-9) and FOXO transcription factor. FOXO functions as a negative modulator for cell proliferation; inhibition of FOXO increases cell proliferation. Furthermore, Akt indirectly induces several anti-apoptotic genes by affecting NF-κB [6]. Akt also negatively regulates the tuberous sclerosis complex (TSC) activity [62]. The TSC1/2 complex acts as a GTPase-activating protein (GAP) for Rheb (Ras homolog enriched in the brain) small GTPase [5] GTP-bound Rheb directly binds to and activates mTORC1 [5]. Inactivation of TSC1/2 increases the level of GTP-Rheb, thus activating mTORC1 [5]. Akt also inhibits another mTOR inhibitor called the proline-rich Akt substrate of 40Kda (PRAS40) by dissolving the bond between mTOR and PRAS40 [5] (See Figure 2).

3.4. The Mammalian Target of Rapamycin (mTOR)

mTOR is a Ser/Thr kinase present in mammalian cells, and it plays a vital role in regulating cell growth, survival, and proliferation by controlling the biosynthesis of proteins, nucleotides, and lipids [5,84]. It is a part of the PI3K/Akt pathway and exists as two multi-protein complexes, mTORC1 and mTORC2, with different compositions and functions. mTORC1 regulates mRNA translation by phosphorylating S6K1, S6K2, and 4E-BP, while mTORC2 controls cell growth and survival through Akt phosphorylation [86]. Positive growth regulators, such as growth factors and their receptors, including EGF/EGFR, IGF-1/IGF-1R, and VEGF/VEGFR, activate mTOR signaling via the PI3K/Akt pathway, while negative regulators, including PTEN, TSC1/2, AMPK, HIF1, and REDD1, inhibit mTOR signaling. TSC2 is phosphorylated by Akt, which leads to its release of Rheb and activates mTOR. In addition, mTORC1 and mTORC2 have been shown to regulate skin morphogenesis, epidermal barrier formation, and other pathways such as Wnt and keratin-17 [5,87,88] (see Figure 2).

5. Therapeutic Strategies for Chronic Immune-Mediated Inflammatory Skin Disorders

An array of agents from natural products, small molecules, and biologics are currently being employed to modulate the molecular pathological presentations of various skin inflammatory conditions. Natural products are effective therapeutic options owing to their ability to concurrently target multiple pathways that are involved in these disorders including the PI3K-AKT-mTOR, the core interest of the current review, most of which have low to no side effects even after long-term usage. Small molecules tend to be stable and are readily absorbed with multiple dosage forms available, though they most often have severe side effects, and long-term use may also cause drug tolerance. On the other hand, biologics are target-specific and present unequivocal advantages over other forms of molecules. Nevertheless, bioactive molecules often have limitations in their benefit owing to their unstable nature, complex structure, invasive parenteral route of administration, and/or skyrocketing costs. In general, the selection of a suitable molecule (small molecule, natural product, or biologics) for medicinal use depends on multiple factors, but most importantly on the benefit-to-risk ratio, availability, and cost.

5.1. Natural Products Targeting the PI3K/Akt/mTOR Pathway in Inflammatory Dermatoses

Natural products are substances derived from living organisms or simply organic compounds of biological origin, and exist as either primary or secondary metabolites, based on the intrinsic and extrinsic influences they pose for the survival of the organisms [306,307,308]. Primary metabolites (e.g., carbohydrates, lipids, and proteins) are generally indispensable for the growth, development, and reproduction of the organisms, whereas secondary metabolites (e.g., terpenoids, phenolic, and nitrogen/sulfur-containing compounds) are useful for ecological survival or defense [309].
Some active agents under the sub-classes of these main categories such as alkaloids, flavonoids, and tannins, have attained the emblem of dominance for their therapeutic worth over the years. In the past four decades, natural products-based drug discoveries have garnered considerable attention with an estimate of at least one-third of the top 20 newly approved drugs in the market originating from natural sources or were lead derivatives of natural products resources [310]. They have thus emerged as the best resource for drug discovery in lead identification as exemplified by the over 60% of currently marketed therapeutics entities and those at diverse stages of clinical development [310]. Researchers have attempted to explore the mechanism of action of various natural products on the modulation of PI3K-Akt-mTOR and associated signaling pathways as therapeutic targets for human diseases. The use of natural products for the management of chronic inflammatory skin disease has been in medical practice since before the inception of modern medicine [311]. Evolutional transition and natural selection producers of these agents account for their numerous pharmacological and biological activities that render them suitable for the management of these complex disease conditions. This adaptive modification is evident from the physiochemical and structural similarities existing between the members of various classes of natural products [312,313]. We discuss below various natural and related synthetic products that have been evaluated with promising potentials targeting the PI3K-Akt-mTOR and related pathways in diverse cutaneous inflammatory skin disorders.

5.1.1. Flavonoids

Flavonoids are polyphenolic compounds, which are well-distributed in plants for their nutraceutical value and notable for their ability to sequester free radicals. In plants, flavonoids exist in free forms (aglycones) or in a glycosylated form, where a glycosidic bond is found in the A or C ring of the central core to produce O-glycoside or C-glycosides [314]. Chemically, flavonoids comprise about 12 classes, elaborating on a core phenyl-substituted benzopyran (e.g., 2-phenyl-4H-chromene, i.e., a C6-C3-C6 arrangement as the key scaffold with C6 being a benzene ring I, Figure 3) scaffold, and differing from each other prominently by the degree of oxidation of the C ring [11,13]. The resulting major classes include flavones, flavonols, flavans, flavanones, flavanonols, flavanols, chalcones and dihydrochalcones, isoflavones, aurones, anthocyanins, anthocyanidins, and catechins (Figure 3) [14]. These sub-families of secondary metabolites are utilized as prophylaxis or treatment options for various human diseases including cancer and especially chronic inflammatory disorders affecting the cardiovascular, nervous, muscular, respiratory, immune, digestive, integumentary, and other systems of the body [315,316]. This cocktail of benefits in relation to nutritional, medicinal and cosmeceutical value with no or minimal side-effects, affords them as appropriate alternative for the management of chronic conditions which mostly requires long-term usage of drugs [317].
Figure 3. Core 2-phenyl-4H-chromene scaffold of flavonoids; different classes of flavonoids and their possible interchangeability are depicted.
A common long list of active flavonoid agents discovered in use or that are extensively being investigated against chronic inflammatory skin conditions include: apigenin, baicalin/baicalein, delphinidin, EGCG, fisetin, hersperidin, kaempferol, luteolin, naringenin, quercetin, tectogenin, wogonin, etc.
Apigenin
Apigenin (4′, 5, 7-trihydroxyflavone) is mostly found in plants used as vegetables, fruits, and herbs such as onion, chamomiles, spinach, orange, cilantro, parsley, sorghum, and rutabaga. It is an aglycone and exists abundantly in glycosylated form as either or C- glycosides with apiin, vitexin, isovitexin, rhoifolin, and schaftoside being the common native forms [318,319]. The medicinal value of apigenin spans from anti-inflammation to anti-diabetes, neuro-regeneration, anticancer, etc., [320]. Apigenin has been proven to effectively improve the dysfunctional epidermal permeability barrier that is often observed in inflammatory dermatoses [321,322], and has led to its modified dosage forms that are superior over or as substitutes for corticosteroids that are often used in inflammatory skin disorders [323].
Baicalin and Baicalein
Baicalin and baicalein, predominantly obtained from the root of Scutellaria baicalensis or Chinese skullcap in the family Lamiaceae, are flavones: the latter being the aglycone form of the former [324]. They are reported to exert anti-cancer, neuroprotective, cognitive enhancement, anti-ulcerative colitis, antioxidant, antiviral, photo-protective, and anti-inflammatory properties [325]. Baicalein has been shown to be therapeutically effective in reducing dermatophagoides pteronyssinus-induced atopic dermatitis-like skin lesions in NC/Nga mouse model [121]. It immunologically regulates innate immune toll-like receptors [326]. In psoriasis, the long-standing proof for the use of baicalin alternative medicine was established via in vivo studies, where common symptoms such as epidermal thickening, erythema, and desquamation backed with IL-17A, IL-22, and IL-23 level were significantly reduced after treatment [165].
Delphinidin
Delphinidin (3,3′,4′,5,5′,7-hexahydroxyflavylium) is a dominant dietary bioactive water-soluble anthocyanidin, abundantly found in pigmented fruits and vegetables including cranberries, bilberries, grapes, and pomegranates. Delphinidin and its glycosides possess pleiotropic biological effects including anti-inflammatory, antioxidant, antiproliferative, proapoptotic, anticancer, and prodifferentiation properties in diverse human diseases including inflammatory skin disorders [144,145,146,327]. Delphinidin has been shown to be beneficial in the treatment of psoriasis [140,144,145,146], and UVB-induced skin inflammation [147].
EGCG
EGCG (epigallocatechin-3-gallate) is the major catechin-based polyphenolic constituent of green tea with a limited amount in some fruits and nuts. Since ancient times, EGCG has been used in dietary adaptive interventions in the management of chronic conditions such as cardiovascular disease, diabetes, cancer, obesity, neurodegenerative disorders, stress, and inflammation [328,329,330]. Emerging findings from our and other research teams have identified the beneficial role of EGCG as well as the advantage of its nano-formulated form in reducing pathological biomarkers associated with psoriasis in preclinical psoriasiform models [127,331,332]. Mechanistically, EGCG, as a potential anti-itch agent, attenuates compound 48/80-induced itch [333] and imiquimod-induced chronic itch [334,335] behavior by suppressing the phosphorylation of ERK and Akt in the spinal cord of mice model. This was accompanied by a reduction in the expression of IL-23 mRNA, TRPV1 mRNA, and intracellular ROS in ND7-23 cells using chloroquine as an inducer [336]. It has been shown to have clinically improved acne in humans through the modulation of intracellular molecular targets as well as inhibiting P. acnes [337,338,339].
Fisetin
Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a bioactive flavonol commonly found in pigmented fruits and vegetables such as strawberries, grapes, apples, persimmons, lotus root, and cucumber. Fisetin has antioxidant, antineoplastic, anti-inflammatory, senolytic, antiangiogenic, antidiabetic, antihyperlipidemic, antimicrobial, and cardio-protective effects [340,341,342,343,344]. Its effect on mTOR, NF-κB, lipoxygenase, glutathione, superoxide dismutase, and catalase, which are mostly involved in inflammation, provides general insight into the mechanism of action useful in the management of chronic inflammatory skin disease [345,346,347]. The therapeutic effect of fisetin has been observed in a chronic photo-damage in vivo study, where MMP-1, MMP-2, and COX-2 expressions were reduced along with restoration of the barricading characteristic of the skin in fisetin-treated mice [137]. Fisetin has also been shown to be beneficial in treating psoriasis [347] and AD in in vitro and in vivo models [348,349,350] with diverse molecular mechanisms.
Hesperidin
Hesperidin is a flavonone sourced mainly from citrus fruits and has pharmacological activity similar to the aforementioned polyphenolics, ranging from antihyperlipidemic, cardioprotective, antihypertensive, anticancer, antimicrobial to antidiabetic effects [351]. In the deglycosylated state, hesperidin is known as hesperidine, which has better bioavailability [352]. Its topical usage has been shown to improve the integrity of the epidermal permeability barrier function, which is mostly tampered with in aged skin and even most chronic skin inflammatory conditions [353]. In AD-like skin lesions in NC/Nga mice studies, hesperidin treatment reduced the levels of cytokines (IL-17 and IFN-α) levels, which are normally elevated in this disease [354].
Kaempferol
Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is found in a variety of plants sources such as kale, cabbage, beans, and broccoli [355]. Its ability to downregulate ROS and cytokine involved in immune-mediated responses accounts for its therapeutic role in inflammatory and immune-mediated diseases [316]. Kaempferol has been demonstrated to effectively enhance the healing of chronic wounds. The healing of incisional and excisional wounds in both diabetic and non-diabetic rats was found to be significantly enhanced with a corresponding increase in wound tensile strength, closure, and reepithelization along with the levels of hydroxyproline and collagen in the wounds [356].
Luteolin
Luteolin (3′,4′,5,7-tetrahydroxyflavone) is a potent antioxidant and anti-inflammatory flavone obtained from a number of edible plants such as thyme, oregano, rosemary, celery, carrot, and peppermint [357]. Luteolin can inhibit or modulate pathways/molecules such as NF-κB, MAPK, PI3K as well as pro-inflammatory mediators, hence it has been used in the management of chronic inflammatory and metabolic diseases such as contact dermatitis, psoriasis, cancer, diabetes, neurocognitive and neurodegenerative disease [358,359,360].
Naringenin
Naringenin (5,7-dihydroxy-2-(4-hydroxyphenyl)-chroman-4-one) is a colorless and tasteless flavanone often found in citrus and tomato. This aglycone results from the cleavage of the sugar moiety in either of the following glycosides; naringin, narirutin, or naringenin-7-glycoside [361,362]. Its ability to induce an endogenous antioxidant effect in addition to the ROS scavenging potential of the hydroxyl groups makes it useful in the management of several metabolic and inflammatory conditions such as pain, atherosclerosis, obesity, diabetes, fibrosis, hepatosis, and cancer [363,364]. Recently it has also been demonstrated that naringenin has anti-inflammatory and anti-allergic features against arachidonic acid- (AA) and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema as well as IgE-mediated passive cutaneous anaphylaxis in vivo [365]. Furthermore, naringenin can significantly improve the construction of wound abrasions in vivo [366].
Quercetin
Quercetin (3,3′,4′5,7-pentahydroxyflavone) is an abundant pigment in plants such as apples, berries, citrus fruits, onion, broccoli, green tea and kale, and has anti-oxidant, anti-inflammatory, antiviral, antihypertensive, antihyperglycemic, psycho-stimulating and anticancer effects [367,368]. In skin, quercetin has been shown to mitigate the inflammatory responses in lipopolysaccharide (LPS)-induced RAW264.7 macrophages and 2,4-dinitrochlorobenzene (DNCB)-induced AD-like lesions mouse models. These responses were credited to its modulating the levels/activities of NF-κB, Erk1/2, JNK, IgE, and cytokines in chronic skin inflammatory conditions such as AD, psoriasis, and chronic wound [369,370,371].
Other Flavonoids
Other flavonoids, such as wogonin, nobiletin, and tectogenin, have also been identified for their salutary effects in chronic inflammatory skin conditions [372,373,374,375,376].

5.1.2. Resveratrol and Analogues, Geniposide

Resveratrol (RSV), a natural phytoalexin abundantly present in grapes and berries, has been reported as a potent mTORC1 inhibitor and has the potential to treat chronic inflammatory cutaneous disorders [377,378]. It has been shown to be beneficial in enriching food including resveratrol-enriched rice-related clearance of skin inflammation and pruritus in mouse models of AD as well as the use of RSV in cutaneous function enhancement [379,380].

5.1.3. Red Ginseng Extract

Red ginseng extract (RGE) is a popular traditional plant medicine prepared by repeatedly steaming and drying fresh ginseng to a moisture content of less than 15% to increase its bioactivity, which is frequently used in the East Asian countries including China, Japan, and Korea [101]. RGE is an anti-inflammatory agent with a demonstrated potential for AD treatment [101]. Osada-Oka et al. reported an anti-allergic effect of RGE through a significant reduction of 2,4-dinitrofluorobenzene (DNFB)-induced ear swelling and scratching behavior [101]. Treatment with RGE has been shown to decrease the chemokine C-C ligand 2 production in lesional keratinocytes in the AD mouse model [101].

5.2. Small Molecule Drugs

A majority of drugs in conventional medicine are small molecules, which are well-characterized organic or chemically synthesized active compounds with low molecular weights, making their pharmacokinetic and pharmacodynamic profiling straightforward [381]. Small molecules such as corticosteroids, immunomodulators, keratolytics, and antimicrobial drugs are often used to mitigate the discomforts associated with chronic inflammatory dermatoses. However, in order to minimize the side effects akin to these agents, topical formulations are mostly preferred.

5.2.1. Corticosteroids

Corticosteroids are potent anti-inflammatory drugs that bind intracellularly to form steroid- receptor complex, which translocates into the nucleus to induce the production of annexin A1. This secondary messenger then inhibits the activation of phospholipase A2, which is necessary for the production of arachidonate-derived eicosanoids such as prostaglandin, prostacyclins, leukotrienes, and thromboxanes. Consequently, the inflammatory and mitogenic mediators that ignite the PI3K-Akt-mTOR, MAPKs, and other associated arms are precluded from being hyper-stimulated. Examples of commonly used steroids include clobetasol 17-propionate, betamethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinonide, desonide and fluradrenolide [382].

5.2.2. Immunomodulators

Immunomodulators are a cluster of agents that inhibit or activate the function of the immune system. They may act by inhibiting the activation/maturation of T-cells and reducing the number and mast cell degranulation, langerhans cells, inflammatory dendritic epidermal cells, the production of IL-2, 4 & 5, TNF-α, IFN-ɣ and the expression of the high-affinity receptor for immunoglobulin class E (FcεRI). In addition, some immunomodulators enhance the production of anti-inflammatory cytokines such as IFN-α, IL-1, 6, 8, 10, and 12. The macrolactams (tacrolimus, sirolimus, everolimus, and cyclosporine), contact sensitizers (diphenylcyclopropenone and dinitrochlorobenzene), immune-stimulators (imiquimod and resiquimod) and others (vitamin D3 analogs, anthralin, and zinc) are examples of immune-modulators with effects in cutaneous manifestations [159,167].

5.2.3. Keratolytics

Keratolytics are topically formulated preparations, which soften and reduce the adhesion between keratinocytes. This thinning is achieved via the desquamation of hyper-keratotic epithelium and reduction in turnover of over-proliferative cells. Common keratolytics commercially available include anthralin, salicylic acid, retinoic acid, and coal tar [383,384].

5.2.4. Antimicrobial Drugs

Antimicrobial drugs are pertinent for chronic inflammatory skin diseases (CISD) with bacteria or fungi as a causative or exacerbating factor, for instance, acne vulgaris (Propionibacterium acnes), AD (Staphylococcus aureus and Malassezia spp.) and buruli ulcer (Mycobacterium ulcerans). Potent agents with bacteriostatic, bactericidal, or fungicidal properties such as clindamycin, tetracyclines, rifampicin, ketoconazole, and fluconazole are employed [385,386].

5.3. Biologics

The future of protein-based therapeutics looks promising, considering the impact of biologics on numerous diseases. Biologics are products obtained using biotechnological tools from humans, animals, or microorganisms [387]. They include vaccines, gene therapies, blood components, whole blood, allergenics, recombinant fusion proteins, and many more that are also used in treating inflammatory skin disorders [388,389,390,391,392,393,394,395]. Under immune-mediated inflammatory disease, biologics are classified as, TNF inhibitors, interleukin (IL) inhibitors, B-cells inhibitors, and T-cells inhibitors (https://www.arthritis-health.com/treatment/medications/biologics-ra-and-other-autoimmune-conditions (accessed on 27 January 2023)).

5.3.1. Tumor Necrosis Factor (TNF) Inhibitors

Tumor necrosis factor (TNF) inhibitors such as infliximab, adalimumab, and etanercept have been approved for the management of psoriasis and other inflammatory conditions [395], and have extensively discussed guidelines for such therapies [396]. They act by suppressing the activation of T-cells, macrophages, and B-cells, and the expression of IL-1, IL-6, IL-8, and CCL5, which are involved in inflammation [397]. Treatment with TNF inhibitors can effectively mitigate the influence of the PI3K-Akt on TNF and related signaling pathways, hence netting the signs and symptoms of CISD [398].

5.3.2. Interleukin (IL) Inhibitors

Interleukin (IL) inhibitors are effective against CISD, owing to the involvement of IL family of cytokines in these conditions when dysregulated [399]. Ustekinumab, Secukinumab, Ixekizumab, Guselkumab, and Risankizumab are some examples, which act on targets known as IL proteins such as IL-1,12, 17, 23, and 24, hence decreasing the affinity to their natural receptors [400,401]. (https://go.drugbank.com/categories/DBCAT002105 (accessed on 24 January 2023)).

5.3.3. B-Cells Inhibitors

B-cell inhibitors directly act against surface markers on B-cells or restrain the survival and signaling factors vital for their activation [402]. A typical example is ritumab, an anti-CD20 monoclonal antibody, which has been shown to be active in some inflammatory disorders including pemphigus, systemic sclerosis (SSs), AD, and Psoriasis [403].

5.3.4. T-Cells Inhibitors

T-cell inhibitors have been applied in CISD, given the fact that T-cells play a crucial role in the advancement of CISD. Most of these inhibitors, such as etanercept, infliximab, adalimumab, uskekinumab, and siplizumab, act by halting the activation, proliferation, and migration of T-cells, thus alleviating the sign and symptoms of CISD [386,404,405].
Table 1, Table 2, Table 3 and Table 4 showcase a comprehensive compilation of available products, both natural and synthetic, employed in the management of various inflammatory skin conditions.
Table 1. Summary of Phytochemical Agents targeting the PI3K/Akt/mTOR Signaling Pathway for Chronic Inflammatory Skin Diseases Management.
Table 2. Summary of extracts used for Chronic Inflammatory Skin Diseases Management.
Table 3. Summary of Synthetic Agents used In Chronic Inflammatory Skin Diseases.
Table 4. Summary of Biologics used In Chronic Inflammatory Skin Diseases.

5.4. Antioxidant Natruceuticals

Guarneri et al. in their systematic review summarised several clinical studies that have investigated the potential of herbal derivatives and micronutrients in the treatment of inflammatory skin diseases. Curcumin, derived from turmeric, has shown efficacy in moderate to severe psoriasis, both topically and orally. Silymarin from milk thistle has demonstrated antioxidant properties and a reduction in depigmented areas in vitiligo patients. Anthocyanins, a group of polyphenols, have high bioavailability and have been effective in treating oral lichen planus (OLP). Ginkgo biloba extract, rich in polyphenols, has shown anti-inflammatory and antioxidant effects, resulting in repigmentation in vitiligo patients. Polypodium leucotomos, a tropical fern plant, exhibits antitumoral and anti-inflammatory properties, and when combined with narrowband ultraviolet B (NB-UVB), it promotes repigmentation in vitiligo. Purslane, an herbaceous weed, possesses anti-inflammatory, antioxidant, and immunoregulatory properties, leading to clinical improvement in OLP patients. Chamomile has active flavonoids with antioxidant and anti-inflammatory effects, providing relief in OLP symptoms [452,453,454].

6. Conclusions

The dysregulation of the PI3K/Akt/mTOR and associated signaling pathways is crucial in the development of chronic immune-mediated cutaneous disorders. Traditional immunomodulatory and therapeutic agents have shown limited efficacy against these diseases. However, phytochemicals have demonstrated promising results in targeting these signaling pathways and inhibiting skin cell proliferation and survival, with relatively low toxicities making them attractive adjuvant treatment options. Despite limitations in the availability of safe and durable remedies, lead compounds derived from natural and synthetic products hold the potential for managing chronic inflammatory skin diseases. Further investigations are necessary to test the efficacy of these strategies and assess the toxicity and adverse effects of lead therapeutic compounds on healthy tissues and systems. Nevertheless, the development of safe and efficacious lead compounds remains crucial in the fight against chronic inflammatory disorders. Future studies are necessary to identify bioactive compounds that can target molecular inflammation targets and decipher the underlying mechanisms of natural products and chemical libraries that can represent promising therapeutic leads. This review summarizes the progress made in synthetic small molecule inhibitors, biologics, phytochemicals, and extracts in developing therapies for chronic immune-mediated cutaneous disorders.

Author Contributions

Conceptualization: T.R. and J.C.C.; methodology, T.R., S.B.-M., S.T.B., J.T.F. and J.C.C.; software, S.B.-M., T.R. and X.S.-N.; writing-original draft preparation, T.R., M.B.U., S.T.B., S.B.-M., C.R.B., R.K.Y., J.T.F. and J.C.C.; writing-review and editing, T.R., J.T.F., A.L.W., J.A.K., X.S.-N., C.B., S.H. and J.C.C.; supervision, X.S.-N. and J.C.C.; and project administration, J.C.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partially funded by the following grants and funding: a Start-up fund from the University of Louisiana at Monroe (ULM) College of Pharmacy (COP), and a Faculty Research Seed grant #5CALHN-260615 awards from the ULMCOP; a Pilot and a full research project awards from an Louisiana Biomedical Research Network (LBRN)-IDeA Networks of Biomedical Research Excellence (INBRE) award from the National Institute of General Medical Sciences of the National Institutes of Health (NIGMS/NIH) grant number P2O GM103424-18, an LBRN-INBRE-COBRE Administrative Supplement Award from NIGMS/NIH grant 3P20GM103424-18S1, and a Louisiana Board of Regents Support Fund grant LEQSF (2021-24)-RD-A-22 (awarded to JCC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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