Potential of Mushrooms Bioactive for the Treatment of Skin Diseases and Disorders

undeniably harbor an array of compounds that can be instrumental in treating various skin conditions, thereby underscoring their potential in dermatological applications. However, an understanding of their dual nature, acting both as a remedy and a trigger for certain skin reactions, is essential for their judicious application in skin care. Further research is mandated to unravel the comprehensive pharmacological spectrum of these fungal treasures.

Mushrooms have long been revered not only as a staple food source but also for their potential medicinal properties.Teir role as a natural repository of bioactive compounds positions them uniquely in the pharmaceutical domain, with particular relevance to cosmeceuticals and nutricosmetics.Te global ethnobotanical and ethnopharmacological chronicles highlight the traditional application of mushrooms against many diseases, with many even fnding their way into cosmetic formulations.Tis review aims to consolidate the existing knowledge regarding the efcaciousness of mushroom-derived bioactives in the realm of skin disorders and diseases.In addition, it sheds light on the instances where certain mushroom species have been implicated in causing dermatological reactions, underscoring the dual nature of these fungal entities.A comprehensive assessment was undertaken involving ethnobotanical databases and relevant scientifc literature to identify mushrooms used traditionally for treating skin conditions.In addition, contemporary research elucidating the biological activities of these mushrooms, specifcally their antioxidant, anti-infammatory, antimicrobial, and wound-healing capabilities, was scrutinized.Special attention was accorded to instances of contact dermatitis induced by mushrooms, notably the shiitake fungus.Preliminary fndings reinforce the therapeutic potential of certain mushrooms in managing skin ailments, attributed primarily to their antioxidant, anti-infammatory, and antimicrobial properties.Conversely, some species, prominently shiitake, emerged as potent dermatitis triggers.Mushrooms

Introduction
Te skin is the outermost organ, covering and protecting the body from the external environment Reference [1] and its structure has three layers: epidermis, dermis, and subcutaneous fat tissues [2].Among the several functions of the skin, layers are protected from the external environment, internal homeostasis maintenance, protection from ultraviolet light damage, and defense after microorganism entry (Figure 1).Skin diseases are shared worldwide, constituting over 30% of general disorders [3].Skin diseases and disorders (SDDs) vary greatly in symptoms and severity.Tey can be temporary or permanent and may be painless or painful.Terefore, a considerable amount of research has focused on bioresources to develop novel drugs for skin diseases, where mushrooms are present as a source of valuable compounds.Mushrooms are regarded worldwide as a component of gourmet cuisine and valued by humankind as a culinary wonder for their unique favor.Although more than 2,000 species of mushrooms exist in nature, merely 25 are widely accepted as food, and few are commercially cultivated (Supplementary File 1).In addition, mushrooms comprise a vast yet largely untapped source of powerful new potential pharmaceutical substances.Polysaccharides, notably beta-glucans, activate Langerhans cells and macrophages, modulating immune responses and infammatory processes in skin conditions [4].Triterpenoids play a key role in skin health by inhibiting the synthesis of proinfammatory cytokines such as TNF-alpha and IL-6 and suppressing COX-2 expression, which is pivotal in the infammation cascade [5].Similarly, phenolic compounds bolster skin's defenses by upregulating endogenous antioxidant enzymes while also inhibiting oxidative enzymes like xanthine oxidase, mitigating the efects of oxidative stress [4].Lectins contribute to cancer management by inducing apoptosis in malignant cells through both intrinsic and extrinsic pathways and curbing angiogenesis, which is vital in halting the progression of melanoma and other skin tumors [6].Furthermore, ergothioneine, a compound that accumulates in mitochondria, provides a shield against mitochondrial DNA damage, maintaining cellular integrity and skin function [7].Te active form of Vitamin D, calcitriol, has a profound infuence on skin health, modulating keratinocyte growth and diferentiation, which are key in conditions like psoriasis [8].Kojic acid, a well-known inhibitor of the melanin-producing enzyme tyrosinase, alters melanogenesis, ofering a lightening efect on hyperpigmented areas [9].Te essential trace element selenium is integral in protecting against UV-induced cellular damage and inhibiting apoptosis of keratinocytes, due in part to its incorporation into antioxidant selenoproteins [10].Omega-3 fatty acids, present in some mushrooms, are potent antiinfammatory agents capable of inhibiting the NF-kB pathway, thereby reducing infammatory mediators in skin diseases such as atopic dermatitis [11,12].Lastly, chitin and chitosan, components of mushroom cell walls, are shown to enhance fbroblast proliferation and collagen synthesis, speeding up wound healing and fortifying the skin barrier, underscoring the extensive therapeutic potential of mushrooms in dermatological applications [13].On this basis, multiple biological activities have been documented related to skin disease.Mushrooms like Trametes versicolor (Turkey Tail) contain polysaccharides, which are believed to have immunomodulatory efects; these can potentially help in conditions like psoriasis, where the immune response is misdirected towards skin cells [14].Ganoderma lucidum contains triterpenoids, which might have antiinfammatory and antihistamine properties, benefcial for skin conditions exacerbated by infammation and allergic reactions [15].Te antioxidant activity of polysaccharides from several species such as Pleurotus spp.and Agaricus spp.[16][17][18], the potential of mushroom extract to decrease the secretion of proinfammatory mediators [19,20], the antimicrobial activity of phytochemicals coming from mushroom extracts against bacteria and fungi activity [21], and the wound healing of mushroom species as adjuvants in new forms of treatment of skin damage, in diferent diseases, such as diabetes [22,23], have been documented.However, some mushrooms also cause dermatitis, and one of the most common is that generated by the shiitake fungus, this being the best known and used.Tus, this review aimed to investigate the ethnobotanical data regarding the use of mushrooms for the potential treatment of SDDs, the biological activity in both in vivo and in vitro studies, and some contact dermatitis caused by mushrooms.

Methodology
Te primary objective of this comprehensive review was to collate and assess the ethnobotanical evidence surrounding the utilization of mushrooms in the treatment of skin diseases and disorders (SDDs), to explore their biological activity in in vivo and in vitro studies, and to catalog any reported cases of contact dermatitis associated with mushroom exposure.To achieve a comprehensive literature search, multiple databases were scoured, including ethnobotanical databases, PubMed/MEDLINE, ScienceDirect, Web of Science, Google Scholar, Embase, and the Cochrane Library; a combination of keywords and MeSH (Medical Subject Headings) terms were employed to maximize search 2 Journal of Food Biochemistry precision: "Mushrooms," "Ethnobotany," "Skin diseases," "Dermatology," "Fungal extracts," "Contact dermatitis," "In vivo," "In vitro."Boolean operators (AND, OR) were used to further refne the search, e.g., "Mushrooms" AND "Ethnobotany" OR "Bioactive compounds" AND "Dermatology." 2.1.Inclusion Criteria.Ethnobotanical records specifying the use of mushrooms for SDDs; studies focusing on the biological efcacy of mushroom extracts or compounds in both in vivo and in vitro setups; reports of contact dermatitis due to mushroom exposure; experimental, clinical trials, observational studies, and case studies; full-text articles available in English; articles published within the last 10 years.

Exclusion Criteria.
Articles not directly related to the therapeutic or adverse efects of mushrooms on skin conditions; studies lacking direct ethnobotanical relevance or those not emphasizing in vivo or in vitro activity; articles unavailable in full text or not in English; non-peer-reviewed publications, such as literature reviews, opinion pieces, and editorials; studies deemed to have insufcient data or ambiguous methodologies.
For each article that met the inclusion criteria, a structured data extraction form was used to capture: authors, year of publication, article title, and source; traditional uses, regions, and cultural practices linked with mushroom use; design, mushroom type under study, targeted skin condition, main fndings, and conclusions drawn; specifc compounds identifed, their quantities, and their roles (therapeutic or harmful); occurrences, symptomatic presentations, the mushroom species responsible, and resulting outcomes.Te most representative data were methodically organized, summarized, and reported to present a holistic understanding of the current knowledge on the topic.

Ethnobotanical Data regarding the Use of Mushrooms in the Treatment of SDDs
Skin diseases constitute over 30% of general disorders [3] worldwide.A large amount of research has focused on bioresources to develop novel drugs for skin diseases, where mushrooms are a source of valuable compounds.On the other hand, the ethnobotanical and ethnopharmacological use of mushrooms against various skin diseases has been documented in diferent countries, and a number of species have been used as cosmetic ingredients [24] (Table 1).Mushroom species Ganoderma lucidum (Reishi) have been a part of traditional Chinese medicine formulations to treat various skin conditions, including rashes, wounds, and even more severe conditions like eczema and psoriasis; also, the native American tribes have been known to use certain mushrooms in poultices to treat skin infections and minor burns [41,42].Traditionally used in Siberian folk medicine, Chaga has been applied topically to treat various skin conditions [37,43]; recent studies suggest that its high content of antioxidants might play a role in reducing skin infammation and improving overall skin health [41].Apart

Pakistan
Against wounds [26] Against wounds and as a skin tonic

Agrocybe dura (Bolton) Singer
Used as a skin tonic

Against skin diseases and wounds
Ganoderma lucidum (Curtis) P. Karst.

India
Against wounds [30] Journal of Food Biochemistry

India
Against skin diseases and wounds [30] Scleroderma sp.Pers.

Country used
Ethnobotanical use

India
For curing eczema [25] Journal of Food Biochemistry from its culinary uses, shiitake (Lentinula edodes) has been employed in traditional East Asian practices for its skinhealing properties; it was believed to rejuvenate the skin and reduce signs of aging [44].Looking over the ethnobotanical/ ethnopharmacological data related to mushrooms may keep light on the medical/pharmaceutical research relevant to skin diseases.For this purpose, our survey through literature using PubMed/MEDLINE and Scopus databases indicated the use of a limited number of mushroom species in ethnobotany/ethnopharmacology against skin-related diseases.
Given the increasing interest in natural and botanical ingredients in skincare, many modern cosmetic and therapeutic formulations now integrate mushroom extracts for their potential benefts; for instance, Reishi and Cordyceps extracts are commonly found in creams and serums aiming to provide antiaging and skin rejuvenating benefts [45].While traditional evidence supports the benefts of mushrooms for skin health, rigorous clinical trials and scientifc validations are essential; the precise mechanisms, safety profles, and dosage regimens need to be established.Mushrooms, with their rich ethnobotanical history and a plethora of bioactive compounds, present promising potential for the treatment of various skin diseases; bridging the gap between traditional practices and modern medicine requires a comprehensive understanding and validation of their pharmacological actions.

Mushrooms-Derived Biological Effects:
Therapeutic Potential for Managing SDDs

Antioxidant and Anti-Infammatory Activity.
Oxidative stress plays a pivotal role in the pathophysiology of skin infammation, acting as both a trigger and a consequence of infammatory processes.Various studies recognize mushrooms 'therapeutic activity and nutritional value [46][47][48].Tese fungi have shown antioxidant activity highlighting polysaccharides as their primary metabolites [49,50], which is essential in several species such as Pleurotus spp.and Agaricus spp.[16,17].In addition, studies indicate that polysaccharides, phenols, favonoids, fatty acids, and tocopherols, among other compounds, are responsible for antioxidant activity [51].For example, phenolic compounds might stimulate the endogenous production of antioxidant molecules in cells [52], inhibiting free radicals, sequestering oxygen, decomposing peroxide, and chelating metal ion [53].A comprehensive review carried out by Sanchez [54] found that the active components in mycelia extracts, sporocarps, and cultures of these structures were responsible for the antioxidant efect.Te frst report on the antioxidant activity of aqueous and methanolic extracts of Pleurotus ostreatus in distinct growth stages was conducted by González-Palma et al. [55].
In the study, favonoids and undetermined metabolites were responsible for antioxidant activity, showing greater reduction power in the case of aqueous extracts.In addition, Boonsong et al. [56] studied the antioxidant activity of the edible mushroom species Lentinus edodes, Volvariella volvacea, Pleurotus eous, Pleurotus sajor-caju, and Auricularia auricular from extracts rich in phenols and favonoids.L. edodes ethanolic extract showed the highest antioxidant, chelating, and superoxide radical scavenging activity, positively correlated with total favonoid and phenol content [56].In an investigation carried out by Gebreyohannes et al. [57], the antioxidant potential of the Auricularia spp.and Termitomyces spp. was evaluated using the DPPH free radical method and expressed by the inhibitory concentration value (IC 50 ).Extracts of both species revealed suitable antioxidant activities in the range of IC 50 40-70 μg/mL.Te antioxidant capacity extracts from four species of wild edible mushrooms (Pleurotus cystidiosus, P. fabellatus., P. forida, and P. ostreatus) were evaluated in a study conducted by Vishwakarma [58].All species exhibited signifcant antioxidant properties; however, P. ostreatus showed the highest antioxidant activity using the DPPH, β-carotene and H 2 O 2 elimination assays.Chen et al. [59] evaluated the antioxidant activity of melanin, extracted from Auricularia auricula-judae in terms of its capacity to eliminate free radicals and its antioxidant efects in C. elegans.It was observed that at a concentration of 1 mg/mL, the free radical scavenging capacity exceeded 85%, infuencing the half-life and locomotion of C. elegans [59].On the basis of the fact that the production of reactive oxygen species signifcantly impacts the destruction of collagen in the skin, Choi et al. studied the antioxidant activity of Auricularia auricula-judae (Bull.)and its relationship with collagen production in human keratinocytes.Te extract obtained from this mushroom species showed a positive efect in eliminating DPPH free radicals and superoxide anions, with potential use in the skincare industry [60].An in vivo study by Son et [64].Tere is growing evidence of the antimicrobial efect of volatile compounds produced by P. spadiceum against plant fungi and bacteria [65].In fruit growing, the activity of the hydroalcoholic extract obtained from the mushroom Lactarius deliciosus against Monilinia fructicola, a pathogenic fungus that infects stone fruits such as peach, nectarine, and plum in Brazil, was evaluated [66].Te antimicrobial activity of mushroom extracts and the production of phytochemicals known for their action against bacteria and fungi depend on genetic factors, culture conditions, pH, and the substrate composition infuencing the metabolic pathway that allows the production of these phytochemicals of biological interest [21].Worldwide, more studies are needed to clarify the role of these microbial communities in both human health and pathology [67].
Table 2 shows examples of mushroom species with antimicrobial and antifungal activity in SDDs.

Healing Activity
Te wound healing process consists of four main phases: homeostasis, infammation, proliferation, and remodeling [76,77].Fibroblasts play a fundamental role in the process by participating in the extracellular matrix generation.Several investigations describe the wound healing role of mushrooms, as potential adjuvants in skin damage treatment for diferent diseases, such as diabetes [22].Polysaccharides found abundantly in various mushroom species play a crucial role in enhancing skin hydration, improving its barrier function; they also possess antiinfammatory properties, aiding in reducing skin redness and irritation [78].Exhibiting antiinfammatory and antioxidant properties, triterpenoids derived from mushrooms like Ganoderma lucidum (Reishi) help soothe skin irritations and protect against oxidative damage.Phenolic compounds present in mushrooms such as Agaricus bisporus also act as powerful antioxidants, combating free radicals that accelerate skin aging [78].Commonly found in mushrooms, ergosterol, when exposed to UV light, converts to provitamin D2, which is benefcial for skin health [78]; the presence of essential amino acids and antioxidants in mushrooms accelerates the wound healing process by promoting collagen synthesis and reducing oxidative stress at the wound site [78].A review by Jones et al. [13] summarized the role of chitin, chitosan, and other polysaccharides in the cell walls of wound healing by mushrooms (Figure 2).Tese polysaccharides can accelerate proliferation in cells (such as fbroblasts and keratinocytes), acting as a support matrix for cell expansion and regeneration of damaged tissue [13].A study conducted by Wen et al. [79] revealed that the polysaccharides extracted from Tremella fuciformis increased collagen production, thus contributing to the wound healing process [79].Ganoderma lucidum is a mushroom species studied for the healing activity of its extracts, rich in polyphenols and favonoids [80], as for its interaction with the skin microbiota and its relationship with the infammatory processes associated with wound healing [81].In addition, G. lucidum, studied by Abate et al. [82], showed the ethanolic potential of its extract, rich in ganoderic acid, in increasing cell migration patterns and accelerating the healing process, mainly re-epithelialization [82].One study showed that Auricularia auricula-judae extract promoted the proliferation, migration, and invasion of fbroblasts and keratinocytes, as well as increasing the wound-healing process by raising collagen synthesis and decreasing E-cadherin expression [83].In the same way, Metacordyceps neogunnii extract, another type of edible mushroom, slightly improved the fbroblast cells (BJ-1) migration after 24 hours of exposure to the extract [84].Another study evaluated silver nanoparticles using extracts from Boletus edulis and Coriolus versicolor showing improvements in the migration of murine L929 fbroblast cells at low extract concentrations [75].Research conducted on extracts of immature bamboo mushrooms (Dictyophora indusiate) improved the healing process by reducing metalloproteinase 2 (MMP-2) in fbroblasts.Tese mushrooms are highlighted as essential natural ingredients for skin-healing pharmaceutical products [85].A study that evaluated the efect of ethanolic extracts from 4 mushroom species (Pisolithus tinctorius, Russula capensis, Imleria badia, and Pleurotus ostreatus) on in vitro models (characteristic of the diabetic state), showed positive efects on wound healing [86].Mapoung et al. [83] investigated the nutrient-rich macrofungi Auricularia auricula-judae in terms of its wound-healing efects from the high amount of watersoluble polysaccharide-rich extracts (AAP).Te BALB/c mice, six to eight weeks old males, were employed to observe the wound closure in their skin by examination of three groups, in which the wounds were sterilized with 0.9% of normal saline, 1.0% w/v of AAP, and 2.5% w/v of AAP.Te results revealed that the group receiving 2.5% w/v of AAP showed an observable wound contraction on day 9.In addition, the 2.5 and 1 w/v of AAP showed a strong wound contraction on day 12, thus supporting the signifcant potential for accelerating the wound healing of polysaccharides obtained from Auricularia auricula-judae [83].In another in vivo study by Krupodorova et al. [87]; the wound healing activity of the aqueous extracts obtained from mushrooms Ganoderma lucidum 1900 (Curtis) P. Karst and Crinipellis schevczenkovi 31 Buchalo was investigated.Te three months old white albino male mice line FVB/Cg, were separated into three groups, and treated with 20 μL G. lucidum mycelium extract and 20 μL C. schevczenkovi mycelium extract for six days, and the control group was treated with sterile distilled water.Te results demonstrated that the wound healing process was more active on day 3 in mice treated with a C. schevczenkovi extract than the treated group with a G. lucidum extract.In contrast, the healing process was similar on day 5 for both groups treated with mushroom extracts.Terefore, the wound-healing process in both groups Journal of Food Biochemistry 10 Journal of Food Biochemistry was better compared to the control group, indicating the high wound-healing activity of the mushroom extracts [87].

Efects on Skin
Melanoma.Skin melanoma, while comprising only 5% of skin cancers, is notoriously aggressive and often resistant to conventional therapies, driving the exploration of novel anticancer agents [88].Recent studies have focused on the efective anticancer agents such as bioactive compounds found in mushrooms [89].Betaglucans, predominantly found in mushrooms such as shiitake and Maitake have been shown to modulate the immune system and inhibit the growth and proliferation of melanoma cells [90,91].Lectins as protein molecules, abundant found in certain mushroom species can recognize and bind specifcally to cancer cells, leading to their apoptosis (programmed cell death), thus curbing melanoma progression [92].Mushrooms like Ganoderma lucidum (Reishi) contain triterpenoids that exhibit antiinfammatory and antioxidant activities, targeting melanoma cells and preventing metastasis [92].Potential mechanisms of mushrooms bioactives against melanoma [91,92]: (i) Inhibition of cell proliferation by mushroom extracts, particularly from species like Agaricus blazei, have demonstrated an ability to halt the proliferation of melanoma cells, inducing cell cycle arrest [91,92] (ii) Induction of apoptosis, mushroom-derived bioactives can activate the intrinsic apoptotic pathways in melanoma cells, leading to cell death and preventing tumor progression [91,92] (iii) Antimetastatic activity; certain mushrooms have compounds that inhibit melanoma cell migration and invasion, thereby curbing the metastasis, which is a signifcant challenge in melanoma management [91, 92] (iv) Immunomodulation; beta-glucans bolster the body's immune response against melanoma, enhancing the activity of macrophages and natural killer cells, which play a role in targeting and destroying cancer cells [91] Liu et al. [93] investigated the in vivo antitumor and antimetastatic activities of chloroform extract from Cordyceps taii (CFCT).Male mice aged between 5 and 7 weeks, average weight of 18.0 ± 2.0 g, were injected with melanoma B16F10.After the tumor growth, the mice were divided into three groups for CFCT treatment according to the applied dose of CFCT, which were 20, 50, and 100 mg/kg.A model group was treated only with saline, and a combined administration group was treated with 20 mg/kg CFCT and 20 mg/kg cyclophosphamide (CTX).Te results showed that the tumor growth of melanoma B16F10 in the mice group treated with 100 mg/kg CFCT and the combined administration was signifcantly inhibited with CFCT treatment.Te antimetastatic activity of CFCT for melanoma B16F10 in mice was observed by considering the common metastasis of melanoma to lung tissue in mice.According to the results, only the model group and the group treated with 20 mg/kg CFCT showed a metastatic focus of melanoma B16F10, indicating that CFCT was infuential in the inhibition of melanoma metastasis in mice [93].In a similar in vivo study by Harhaji Trajković et al. [94], the tumor growth inhibition in inoculated C57BL/6 mice with syngeneic B16 tumor cells was observed as a result of treatment with methanol extract from Cariolus versicolor (50 mg/kg) for 14 days.Te direct focus on skin melanoma in these studies substantiates the specifc impact of mushroom-derived bioactives on this form of skin cancer; as research progresses, the translation of these fndings to clinical applications could improve the treatment landscape for skin melanoma.Figure 3 shows the antimelanoma efect of mushrooms bioactive compounds.

Efects on Atopic Dermatitis. Atopic dermatitis (AD),
often referred to as eczema, is a chronic infammatory skin disorder characterized by itchiness, redness, and a rash.AD is induced by a combination of genetic, psychologic, pharmacologic, environmental, and immunological factors.Tough its etiology is multifactorial, involving genetic, environmental, and immunological factors, there's been a growing interest in alternative therapeutic agents, including mushroom-derived bioactives, for its treatment and management [95,96].Many mushrooms exhibit antiinfammatory activities, which are critical in managing atopic dermatitis since infammation is a signifcant contributor to its pathogenesis [97].For instance, polysaccharides extracted from Ganoderma lucidum (Reishi mushroom) have demonstrated the ability to suppress the expression of proinfammatory cytokines, potentially mitigating the infammatory response associated with AD [97].Skin barrier dysfunction is also a hallmarking feature of atopic dermatitis, and certain mushroom derivatives have been shown to bolster the skin barrier.Chitin, a component present in the cell walls of mushrooms, can be transformed into chitosan, which is known for its moisturizing efect on the skin, potentially helping to restore the skin barrier [98].Itching associated with AD can signifcantly reduce the quality of life for patients; mushrooms like Pleurotus ostreatus (oyster mushroom) possess compounds that exhibit antipruritic (antiitching) efects, ofering potential symptomatic relief [99].An imbalance in immune responses is a critical aspect of AD pathophysiology; many mushroom species are renowned for their immunomodulatory efects.β-glucans, which are abundant in mushrooms like shiitake (Lentinula edodes), may modulate immune responses, thus potentially ofering therapeutic advantages for AD patients [99].Oxidative stress plays a pivotal role in the aggravation of atopic dermatitis, and many mushrooms, such as the Cordyceps species, are rich in antioxidants, which can counteract oxidative stress, further aiding in the alleviation of AD symptoms [100].Secondary bacterial infections are common in AD lesions due to compromised skin integrity; mushroom extracts like those from Agaricus bisporus (white button mushroom) have shown antimicrobial properties, potentially preventing or treating these secondary infections [101].Watanabe et al. [96] examined the efects of hot water extract of the mushroom Basidiomycetes-X (BDM-X) on atopic dermatitis (AD) skin lesions in NC/Nga mice, which can develop AD clinically very similar to humans.A cream is used to cause AD-like skin lesions in mice; one-third was kept untreated with the cream as the control group.Te reminder with skin lesions were divided into two groups, one of which was treated with the BDM-X extracts.Te results showed that AD skin lesions in BDM-X-treated mice were rapidly decreased, whereas the other group with AD still had the skin lesions.Tis signifcant result revealed the high potential of BDM-X extracts in AD treatment [96].Another study focusing on the treatment of AD, conducted by Choi et al. [102], analyzed the ethanolic extract efciency of Lentinula edodes, including polyphenols, favonoids, β-carotene, and lycopene.Te eight weeks old female BALB/ c mice were employed to investigate various efects of AD.Te AD lesion in mice ears was induced through exposure to Dermatophagoides farinae extract (DFE) and 4dinitrochlorobenzene (DNCB).Mice were divided into four groups: one with only AD lesions, another with AD receiving 250 mg/kg L. edodes extract, a group with AD receiving 500 mg/kg L. edodes extract, and the control group.Two groups with AD receiving 500 mg/kg and 250 mg/kg L. edodes extract showed considerably better results than other groups within 28 days after the induction of AD.Overall results indicated that L. edodes extract efectively decreased several AD symptoms by reducing the severity of AD lesions, cervical lymph nodes, and infammatory cytokines in the ears of mice [102].

Efects on
Hyperpigmentation.Hyperpigmentation, one of the common skin disorders observed in all skin conditions, including acne or atopic dermatitis, with various symptoms such as dark spots, darker skin, and irregular grey patches, can be treated with depigmentation agents [103,104].Te therapeutic potential of mushroom bioactives in addressing hyperpigmentation has been a subject of growing research interest; certain mushroom extracts have demonstrated inhibitory efects on tyrosinase, the key enzyme responsible for melanin synthesis.For instance, Agaricus bisporus (white button mushroom) contains compounds that have been found to inhibit tyrosinase activity, thus potentially reducing melanin production and aiding in the treatment of hyperpigmentation [105].Oxidative stress is one of the factors that can trigger or exacerbate hyperpigmentation.Many mushrooms, such as Ganoderma lucidum (Reishi mushroom), are rich in antioxidants that can combat oxidative stress, ofering a twopronged approach to addressing both melanin production and the underlying triggers [92].Infammation-induced hyperpigmentation, or postinfammatory hyperpigmentation (PIH), is a common concern following acne, skin injuries, or infammatory skin conditions.Mushrooms like Cordyceps and shiitake (Lentinula edodes) exhibit antiinfammatory properties, which might help in reducing the occurrence or severity of PIH [45].Some mushroom extracts can promote an even skin tone and improve overall skin radiance.A healthy skin barrier is crucial for preventing external triggers, like UV radiation and environmental pollutants, from inducing hyperpigmentation; components like beta-glucans, present in several mushrooms, can bolster the skin's barrier function [106].Trametes versicolor, also known as the Turkey tail mushroom, has been incorporated into skincare products for its potential skin-brightening efects [106].Given their multifaceted action on skin health, mushroom bioactives might enhance the efcacy of other depigmenting agents or treatments; they could be incorporated into comprehensive treatment regimens for hyperpigmentation, ensuring more holistic care [106].An in vivo study conducted by Pavic et al. [107], explored the toxicity of antimelanogenic compounds found in mushrooms to inhibit excessive skin pigmentation.Te zebrafsh was preferred as the preclinical experimental model to evaluate the toxicity by carrying six diferent doses of ethanol extracts of each of the fve mushrooms for fve days.Te results revealed the toxicity of fve selected mushroom extracts subjected to application doses.Te greatest toxicity profles have been achieved for Laetiporus sulphureus (LSE) and Agaricus silvaticus (ASE), which were not toxic at high doses of up to 400-500 mg/ mL.In contrast, the remaining three extracts were detected as possibly toxic and unsafe for humans.Tis study showed that the tyrosinase activity and melanin synthesis in zebrafsh were inhibited by LSE and ASE extracts without infammatory, immunosuppressive, or toxic efects, indicating their safety for possible usage in cosmetics and other applications [107].Generally, mushroom-derived bioactives have exhibited a favorable safety profle when compared to some chemicals often used to treat hyperpigmentation, and this makes them attractive alternatives, especially for individuals with sensitive skin.Te most representative pharmacological studies on the therapeutic potential of mushrooms against diferent skin diseases and/ or skin disorders are summarized in Table 3.

Clinical Studies Related to Bioactive Compounds of Mushrooms and SDDs
Several investigations on the efects of diferent mushroom extracts and/or their bioactive compounds on skin conditions and aging processes are found in the literature.Yamamoto and Kimura [23] investigated the mushroom Sparasis crispa (SC) in terms of its therapeutic efects on skin conditions in humans.To understand the efects of SC on skin conditions in humans, 26 healthy volunteers, between the ages of 20 and 60 years, were divided into two groups: orally SC-administered and placebo.According to the results obtained after four weeks, the cheek transepidermal water loss was considerably lower in the SC-administered group than in the placebo group.Tus, it supported the positive efect of SC administration on improving human skin conditions [23].Another recent clinical study was conducted by Lee et al. [123] to investigate the antioxidant, anti-infammatory, antiallergic, antidiabetic, and antiangiogenic efects of veratric acid derived from the mushroom Sparassis crispa and demonstrate its clinical efects.A cream including veratric acid isolated from Sparassis crispa and the control was applied for 12 weeks on the right and left periorbital areas of 20 women, average of 47.7 ± 4.8 years old.
Te results showed that the veratric acid extract improved facial wrinkle formation from Sparassis crispa by increasing Journal of Food Biochemistry Acidic polysaccharide from Phellinus linteus Antimetastatic ↓melanoma cell metastasis in mice [112] ↓adhesion, ↓invasion of cancer cells through the extracellular matrix not directly infuential on the growth of cancer cell 14 Journal of Food Biochemistry

References
Hot water extract of Ganoderma lucidum

Skin wounds
Wound healing/Antioxidant Te highest wound closure in streptozotocin-induced diabetic rats with the treatment of 10% (w/w) aqueous extract cream compared to treated groups with Intrasite gel (positive control) and aqueous cream (negative control) [113] Te shortest reepithelization period with the treatment of 10% (w/w) aqueous extract cream Considerable higher in vivo antioxidant activity with 15% (w/w) aqueous extract compared to negative and positive control groups Lower oxidative protein products and lipid damage in treated diabetic rats with aqueous extract compared to negative and positive control groups

Skin wounds (circular excision and linear incision wound models)
Wound healing/ Antiinfammatory ↑healing activity for treated rats with extract of C. cibarius, and Madecassol (reference drug) compared to nontreated and vehicle-treated rats completely repairing the epidermal layer, increasing collagen production, considerable neovascularization and epithelization degree in the treated rats with the extract [114] ↓COX-2 in treated rats with extract than in nontreated and vehicle-treated rats

Extract of Antrodia camphorate (ethanol extraction)
Skin wounds (excision model) Wound healing/ Anti-infammatory ↑wound healing closure in treated rats with extract (for both doses of 100 mg/kg and 200 mg/kg) and Intrasite gel (reference drug) compared to treated rats with vehicle [115] Considerably less scar width at wound closure and less infammatory cells, more collagen, and more fbroblast in granulation tissue with extract treatment than vehicle treatment Journal of Food Biochemistry

Skin wounds
Wound healing ↑healing activity with an increase in wound contraction, accumulation of collagen, hexosamine, and total protein content for treated rats with extract [80] Sparassis crispa ↑wound closure in streptozotocin-induced diabetic rats with oral administration of S. crispa [116] ↑migration of macrophage and fbroblast, ↑regeneration of collagen, and epithelialization with S. crispa treatment compared to the control group (nontreated with S. crispa)

Aqueous extract of Hericium erinaceus
Wound healing Higher and quick wound healing in rats treated with the extract and Intrasite gel than in rats treated with sterilized distilled water [117] Considerably less scar width in healed wound area and lower macrophages and higher collagen in the healed wound for treated rats with extract than treated rats with sterilized distilled water 16 Journal of Food Biochemistry   18 Journal of Food Biochemistry cell proliferation, inhibiting the collagen decrease in the dermis, increasing tissue inhibitors of metalloproteinases, and increasing flaggrin against UV radiation [123].Although several studies indicated that mushrooms have therapeutic potential on several skin diseases, more in vivo and clinical studies should be performed to understand the working mechanisms of the mushroom extracts in both animal and human body and their efects on the whole-body system.

Allergic Contact Dermatitis Caused by Mushrooms
Among allergic dermatitis as skin side efects caused by mushrooms, the most common and well-known is that caused by the shiitake.Dermatitis produced by the shiitake fungus is characterized by skin eruptions due to a toxic reaction to lentinan, a thermolabile polysaccharide.Nakamura frst described shiitake dermatitis in 1977, when he reported 23 cases of people who consumed the fungus and presented erythematous lesions, reminiscent of selffagellation from the Middle Ages [124].In Japan, shiitake dermatitis is traditionally associated with the consumption of shiitake mushrooms.Although shiitake mushroom generates this dermatitis because lentinan is thermolabile, its toxicity can be avoided if the mushroom is consumed cooked [125].Shiitake dermatitis is a rare skin reaction to lentinan, a polysaccharide component in the cell walls of shiitake mushrooms (Lentinula edodes).Lentinan is a β-(1 ⟶ 3)-d-glucan.Lentinus edodes corresponds to a biologically active macromolecule with remarkable anticancer activity, which is given through the activation of the human immune system [126].It has been shown that the chemical structure of lentinan is β-(1 ⟶ 3)-d-glucan which has 2 (1 ⟶ 6)-glucopyranoside branches for every fve linear (1 ⟶ 3)-β-glucopyranoside linkages, which can be characterized instrumentally by techniques such as highperformance liquid chromatography (HPLC), FITT, and nuclear magnetic resonance (NMR).Additional cases of hypersensitivity reactions to mushrooms have been documented.For instance, contact dermatitis has also been reported after handling or ingesting other mushroom species, such as the common button mushroom (Agaricus bisporus) and other edible varieties [13,127].Tese reactions are typically characterized by pruritic and eczematous eruptions, which are histologically similar to shiitake dermatitis, suggesting a common immunological pathway in the hypersensitivity response to diferent mushroom species [128].
Other instances include reports of airborne contact dermatitis from spores of various mushroom types, which can occur in both occupational settings, such as mushroom farming, and in environments with high spore concentrations [127].Tese reactions can be more complex, involving respiratory symptoms alongside dermatological manifestations, illustrating the diverse immunological challenges posed by mushroom bioactives [127].To address these adverse reactions comprehensively, it is crucial to investigate the full spectrum of immunogenic components in mushrooms, their potential cross-reactivity with other allergens, and the conditions under which they become pathogenic.Further research into the identifcation of specifc allergenic proteins and polysaccharides, as well as their mechanisms of action, will be vital in developing preventive strategies and therapeutic interventions for mushroom-related hypersensitivity reactions [129].Beta-glucans and immune modulation: beta-glucans, prevalent in varieties like shiitake and maitake, have been shown to enhance the skin's immune defense by activating dendritic cells and macrophages, leading to a more robust response to pathogenic challenges and potentially reducing the incidence and severity of infammatory skin conditions [128].Triterpenoids and infammatory pathways: the triterpenoids present in Reishi mushrooms exhibit an ability to modulate infammation through the suppression of NF-kB activation, which could play a role in mitigating chronic infammatory states associated with conditions such as psoriasis and atopic dermatitis [130,131].Antioxidant phenolics and skin integrity: the antioxidant properties of phenolic compounds in mushrooms like Chaga may protect dermal fbroblasts from oxidative stress, thus preserving skin integrity and preventing the premature aging associated with oxidative damage [17].Lectins and tumor inhibition: certain mushroom lectins demonstrate specifcity in binding to aberrant cell membranes, initiating apoptosis, and potentially ofering a targeted approach to managing melanoma and nonmelanoma skin cancers [6].Ergothioneine and mitochondrial protection: ergothioneine has shown promise in protecting skin cells from mitochondrial DNA damage induced by UV radiation, suggesting a role for this compound in the prevention of photoaging and photocarcinogenesis [7].Tese detailed mechanistic pathways highlight the potential of mushroom bioactives as adjunctive or alternative therapies in the management and prevention of various SDDs.Continued research in these areas may yield signifcant advancements in dermatological treatments.

Cytotoxicity and Allergenicity Efects of Mushroom
Bioactives.Te therapeutic benefts of mushrooms are balanced by a need to understand their potential cytotoxic and allergenic efects [48].Research into various mushroom species has revealed a spectrum of bioactive compounds with diverse biological activities, some of which may exhibit cytotoxicity and allergenicity under certain conditions [48].For example, compounds such as hydrazine derivatives found in certain edible mushrooms have shown cytotoxic properties, which could pose a risk if consumed in large quantities or if the mushrooms are not properly processed [132].Similarly, the potential allergenicity of mushrooms is Journal of Food Biochemistry an area of ongoing research, with instances of hypersensitivity reactions documented in susceptible individuals upon exposure to specifc mushroom species [132].Te cytotoxic efects of mushrooms are often a result of their defense mechanisms, producing compounds that can be harmful to cells.While these properties can be leveraged in fghting cancer cells, as with the antitumor efects of polysaccharide-K (PSK) extracted from Trametes versicolor [14], they may also cause adverse efects in nontarget cells.It is, therefore, crucial to characterize these efects fully to mitigate risks associated with mushroom consumption or therapeutic use.Allergenicity, on the other hand, may manifest as hypersensitivity reactions, such as contact dermatitis or respiratory allergies, particularly in occupational settings or among mushroom cultivators [13,127].For instance, shiitake mushroom dermatitis is a well-documented condition caused by lentinan, a polysaccharide that can trigger an infammatory response upon skin contact [128].Recent investigations into these efects have emphasized the importance of identifying the molecular mechanisms underlying these responses.Techniques such as proteomics and immunoblotting have been employed to pinpoint the specifc mushroom proteins that elicit immune reactions [133].Furthermore, understanding the role of mushroom-derived compounds in modulating the immune system can provide insights into mitigating allergenic responses while preserving their health benefts [15].Overall, while mushrooms are a rich source of bioactives with signifcant health benefts, it is imperative to balance their therapeutic potential with safety considerations.Ongoing research and rigorous clinical trials are necessary to elucidate the full scope of cytotoxic and allergenic efects posed by mushroom bioactives and to establish guidelines for safe consumption and therapeutic application.

Limitations, Challenges, and Clinical Pitfalls.
Te potential therapeutic properties of mushroom bioactives have stirred considerable interest in the dermatological community.However, like all emerging treatments, there are limitations, challenges, and potential pitfalls that need to be acknowledged.Much of the evidence supporting the efcacy of mushroom bioactives in skin therapy comes from in vitro studies or in vivo animal models, but the number of randomized controlled trials in humans is still limited, necessitating further research to confrm efcacy, safety, and optimal dosing.Variability in mushroom composition depend on factors such as growth conditions, harvesting time, and postharvest processing, the bioactive compound profle of a given mushroom species can vary signifcantly and this poses challenges in ensuring consistent therapeutic efects.Other species of mushrooms can cause allergic contact dermatitis or other hypersensitivity reactions; identifying and categorizing allergenic mushrooms are crucial, especially when recommending topicals containing mushroom extracts.Some mushroom bioactives might interact with other medications, either enhancing or inhibiting their effects; this can be particularly concerning for patients on multiple medications or those with underlying health conditions.Te method used to extract bioactives from mushrooms can signifcantly infuence their potency and therapeutic value; standardizing these methods is crucial for ensuring consistent results and safety profles.While many mushroom bioactives have been deemed safe for short-term use, long-term safety data is often lacking; potential cumulative efects or long-term side efects must be assessed through extended clinical trials.Te surge in interest surrounding "natural" treatments might lead some individuals to self-prescribe mushroom-based remedies without proper guidance, risking incorrect dosages, potential side efects, or suboptimal outcomes.Also, challenges persist in the utilization of mushroom extracts and their associated metabolites as ingredients in cosmeceutical and nutricosmetic products; these challenges range from optimizing extraction processes, validating efcacy and safety claims, using microcarriers and nanocarriers for controlled release, and weighing the advantages and disadvantages of using extracts versus individual compounds [103].Despite these clinical challenges, the diverse biomolecules contained in mushrooms ofer a sustainable option for developing cosmeceutical and nutricosmetic formulations, although more research is needed to address concerns regarding stability, compatibility, safety assessments, and toxicological studies [103].Given the vast number of mushroom species and their bioactives, regulatory agencies might fnd it challenging to evaluate and categorize each one; this can lead to delays in approvals or inconsistencies in quality control.Researching, developing, and standardizing mushroom-based treatments can be expensive; these costs might be passed on to patients, limiting access to these treatments, especially in regions where insurance does not cover alternative therapies.Careful and rigorous scientifc evaluation is vital to harness their potential while ensuring patient safety and optimal therapeutic outcomes.

Overall Conclusions and Future Prospects
Diferent biologically active compounds, including polysaccharides, proteins, peptides, vitamins, minerals, dietary fbers, alcohols, terpenoids, and phenolics, are present in mushrooms.Tese compounds exhibit antidiabetic, antiobesity, anticancerous, antitumor, anti-infammatory, antimicrobial, antiviral, antiallergic, antiaging, antiwrinkle, antioxidant, immunomodulating, hepatoprotective, hypoglycemic, and skin whitening activities.Diferent skin problems-induced by infammation and the high activity of free radicals can be treated with mushroom extracts with antioxidant and anti-infammatory activities.In addition, extracts of bioactive compounds from mushrooms with antiinfammatory, antioxidant, photoprotective, antityrosinase, antielastase, and anticollagenase activities can reduce the severe efects of infammatory skin diseases, providing photoprotection and correcting skin hyperpigmentation.Terefore, mushrooms are considered essential and original ingredients for developing new pharmaceutical products due to their health benefts and protective activities against diferent SDDs.After exploring their therapeutic and/or healing potentials against diferent types of diseases across 20 Journal of Food Biochemistry diferent in vitro, in vivo, and clinical studies, it has been observed that mushrooms have attracted signifcant attention from researchers in recent years.Fungal compounds from large mushrooms Basidiomycetes species present several biological activities such as antioxidant, antiinfammatory, and antimicrobial, some associated with pharmaceutical, cosmeceutical, and nutricosmetic potential, in in vitro and in vivo studies.However, ethnobotanical/ ethnopharmacological data shows a limited number of mushroom species related to the treatment of skin diseases.Mainly polysaccharides, followed by phenols, favonoids, fatty acids, and tocopherols, from fungal species Agaricus spp., Auricularia spp., Lentinus spp., and Pleorotus spp.
(among other mushroom species), showed antioxidant activity.Te metabolisms of several mushroom species present antimicrobial activity against a wide variety of fungi, Grampositive, and Gram-negative bacteria including Staphylococcus aureus, Salmonella enteritidis, and Escherichia coli.Te results obtained from scientifc studies revealed the potential antiageing efects of the enzyme-assisted extract mushroom Agaricus bisporus and their purifed forms with reduction of the lipid peroxidation, increasing the antioxidant enzymes, improving the organ functions, and enabling the lipid metabolism.Te antimicrobial activity of fungal extract depends upon genetic factors and environmental conditions that can infuence the metabolic pathway that allows the production of these phytochemicals.Mushroom chitin and chitosan play a key role in the treatment of wounds by accelerating the proliferation of fbroblast, keratinocytes, and polysaccharides.Some fungi species can cause dermatitis or superfcial mycosis.Many scientifc studies have demonstrated the natural antioxidant potential of mushrooms.Teir extracts rich in a wide variety of metabolites, could be incorporated, for example, as dietary supplements to complement the natural production of antioxidants at a cellular level.In summary, diferent mushroom compounds as polysaccharides, proteins, peptides, vitamins, minerals, dietary fbers, alcohols, terpenoids, and phenolics present in vitro and in vivo biological activities for potential use on several skin diseases.However, greater biomedical and clinical studies are necessary to prove these preliminary data.

Figure 1 :
Figure1: Te structures of the skin.Te epidermis, the outermost layer of the skin, is mainly composed of keratinocytes which undergo a process of maturation and eventually form a protective layer.Te epidermis contains four to fve sublayers, including the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum (only in thick skin like palms and soles), and stratum corneum.Dermis, situated below the epidermis, the dermis consists of two sublayers: the papillary dermis and reticular dermis; it provides strength and elasticity to the skin due to the presence of collagen and elastin fbers.Hypodermis (subcutaneous layer) is the deepest layer of the skin, primarily made up of adipose tissue (fat cells).Accessory structures include hair follicles, sweat and sebaceous glands, and nails.Hair follicles give rise to hair which ofers protection and plays a role in sensory functions.Sweat glands help in thermoregulation through perspiration, while sebaceous glands produce sebum, an oily secretion that moisturizes the skin and hair.

Table 1 :
Ethnopharmacological use of mushroom species relevant to SDDs.
[57]etes spp.(Arabuko-Sokoke forest), Trametes spp., and Microporus spp.(Kakamega forest) exhibited antimicrobial activities against a wide variety of bacterial strains[57].Another in vitro study evaluated the extract from fve edible mushrooms against Gram-positive bacteria (Bacillus cereus and Staphylococcus aureus) and Gram-negative bacteria (Salmonella enteritidis and Escherichia coli).Of the fve mushroom species, A. brasiliensis presented the highest responses for antioxidant and antibacterial activity [63]revealed the antiinfammatory efect of mushroom extracts on ear thickness, ear epidermal thickness, and eosinophil infltration in the skin tissues of mice.Teir antiinfammatory efect improved more signifcantly with the aqueous fractions produced by solid fermentation of Ganoderma lucidum on Artemisia capillaris leaves than with aqueous samples of Artemisia capillaris leaves or Ganoderma lucidum[61].According to another study by Ramya et al.[62]focusing on the preventive efect on infammation of the bioactive extract of the mushroom Morchella elata, skin thickness, level of lipid peroxidation, and histopathological alterations of mice were reduced, indicating the antiinfammatory efect of Morchella elata extracts[62].nocompromisedpatients,providing alternative therapeutic strategies in the context of hospital-acquired infections and the challenge of invasive diseases following procedures like allogeneic transplants[63].Mushrooms need antibacterial components to survive in their natural environment; they have phytochemicals with antimicrobial action, positioning them as potential pharmacological resources to control resistant pathogens efectively.A study evaluated 35 wild mushrooms from Kenyan forests.

Table 2 :
Overview of mushroom-derived compounds with antimicrobial and antifungal properties for skin disease management.

Table 3 :
Summary of preclinical studies on animal models about the therapeutic potential of mushrooms on SDDs.