Polyphenol chrysin for management of skin disorders: Current status and future opportunities

3.1 Acne

Acne vulgaris is a skin disorder that affects people of all ethnicities and ages all over the world. The androgen hormones are responsible for the first appearance of acne during puberty. The condition is characterized by chronic inflammation of the pilosebaceous gland (Soleymani et al., 2020) Although not life-threatening, the condition affects the confidence of the individuals having the acne outbreaks and makes them avoid social appearances as in many cases it leaves your skin scarred, it results in loss of self-esteem and has a negative psychosocial impact (Darji et al., 2017) Propionibacterium acnes are the key pathogen responsible for colonization in the skin that results in increased sebum production, increased concentration of inflammatory markers, and finally the appearance of acne lesions. Acne is characterized by the growth of comedones, nodules, pustules, papules, and cysts scars on the skin, particularly on the face (Soleymani et al., 2020).

Antibiotics, both oral and topical, tretinoins and hormones are conventional treatment modalities for acne. The antibiotic resistance of acne nodules, on the other hand, poses a challenge to dermatologists who have been treating this problem (Habeshian and Cohen 2020) Recently, polyphenols have shown promising efficiency in treating acne. Chrysin is present in honey, propolis, and bee venom (Kurek-Górecka et al., 2020). Honey treats several skin infections owing to its antimicrobial properties. It has shown antibacterial effect against Propionibacterium acnes, a common cause for acne (McLoone et al., 2016).

In another study carried out in 40 patients with facial acne, topical application of propolis alcoholic extract showed bactericidal effect against gram-positive anaerobic bacteria (Propionibacterium acnes) and gram-positive aerobic (Staphylococcus epidermidis). The antimicrobial and anti-inflammatory effects of chrysin can make it a good candidate for treating acne (Mani and Natesan 2018).

3.2 Wound healing

Chronic wounds may eventually lead to cancer, so it is necessary to accelerate the process of wound healing. Venous ulcers, gastric ulcers, diabetic foot ulcers, or pressure ulcers are typically chronic wounds that take a long time to heal completely. Until the wound is completely healed, it goes through a series of events (Deldar et al., 2018). Wound healing is a complex biological process that necessitates the proliferation, differentiation, and migration of endothelial cells, keratinocytes, immune cells, and fibroblasts. The matrix metalloproteinases (MMPs), gene P 53, nitric oxide synthase (iNOS), interleukin-6 (IL-6), inducible, and play a vital role in the wound healing process (Mohammad Ali et al., 2015). To promote rapid wound closure, the essential measures in treating wounds include lowering inflammation and eliminating free radicals.

Several research studies have demonstrated that chrysin has a good antioxidant and anti-inflammatory potential (Cho et al., 2004, Deldar et al., 2018). The biological effect of chrysin-loaded nanofibers on wound healing and associated genes in rats was investigated in another investigation. The results showed a considerable reduction in p53 and iNOS expression, which resulted in wound healing (Mohammadi et al., 2019).

Another study looked into the influence of chrysin–curcumin-loaded nanofibers on the wound-healing process in male rats. The results of this study show accelerated wound healing using the chrysin-curcumin nanofibers (Mohammadi et al., 2019).

The therapeutic efficacy of a sodium alginate-chitosan scaffold loaded with chrysin in wound management was investigated. The wound healing was studied in vitro on cell lines and in vivo in rats. Both investigations revealed a faster wound healing time and a shorter period of re-epithelization. The researchers concluded that the chrysin-loaded scaffolds could be used for tissue regeneration and healing of wounds (Kaparekar et al., 2021).

3.3 Psoriasis

Psoriasis is a persistent inflammatory skin condition that has no known etiology. It is thought to be an immune-related skin condition characterized by scaling and lesions on the skin. According to the previous clinical research, it is known that IL-22, IL-17A, and TNF-α are involved in the pathogenesis of psoriasis (Di Cesare et al., 2009, Raychaudhuri 2013). The condition affects the skin, joints, and even the nails (Sobolewski et al., 2017). The inflammatory chemicals act on the keratinocytes and produce the symptoms of this condition. Dermatologists face a difficult task because of the condition's high prevalence, chronic nature, incapacity, and disfigurement of bodily parts. Treatment success is contingent on a thorough understanding of the interplay between the innate and adaptive immune systems of the individual (Boehncke and Schön 2015).

Severe side effects and frequent recurrence has forced researchers to search for safer alternatives to treat this condition. Chrysin is a potent antioxidant and has a good free radical scavenging activity. It is also a good anti-inflammatory agent. Besides, it is inexpensive and can be easily extracted from natural sources.

In an in-vitro study, they tested the efficacy of chrysin in an animal model in which psoriasis-like inflammation was induced. Inflammatory symptoms improved, and the area and severity index of psoriasis were reduced, according to histological studies of the chrysin-treated skin. On application to the skin, chrysin significantly reduced the loss of moisture and redness of the skin. It also improved skin suppleness. The cell line studies helped study the mechanism of chrysin’s antipsoriatic activity. Chrysin pretreatment on the epidermis keratinocytes attenuated activation of the NF-κB pathway.

Furthermore, chrysin inhibited the release of antimicrobial peptides from epidermal keratinocytes generated by CCL20, IL-22, TNF, and IL-17A. Chrysin has the potential to be an effective treatment drug for chronic inflammatory disorders like psoriasis (Li et al., 2020).

Another study found that chrysin can enhance human keratinocyte differentiation by boosting vitamin D receptor transcriptional activity (Choo and Lee 2013). Vitamin D is important for maintaining cutaneous barrier homeostasis in psoriasis, and there has been a link discovered between vitamin D receptor polymorphisms and psoriasis susceptibility (Barrea et al., 2017).

3.4 Atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin condition. Redness, itching, and scratching are common symptoms. Genetic and environmental factors, skin architectural faults, and cell-mediated immune dysfunction may all play a role in the development of the illness. The multifunctional mast cells play an essential role in producing inflammatory mediators, growth factors, interleukins (IL)-1β, tumor necrosis factor-alpha (TNFα), lipid mediators, IL-4, cytokines, and IL-6 that are responsible for the symptoms of AD (Kawakami et al., 2009, Sirufo et al., 2020).

Several investigations have been conducted to assess the activity of chrysin in Alzheimer's disease, and scientists have sought to discover a mechanism of chrysin action in AD. In one such study, chrysin was orally administered to mice induced with atopic dermatitis. Histopathological investigation showed reduced AD symptoms. Chrysin inhibited Th1, Th2, and Th17 cell inflammatory responses in the lymph nodes and ears of mice. Tumor necrosis factor downregulation of p38 MAPK, NF-B, and STAT1 reduced the production of Th2 chemokines, cytokines, and C–C motif chemokine ligand (TNF) interferon-negative/interferon-positive /interferon-negative/ interferon-positive/ interferon-negative/ interferon-negative/interferon-negative/interferon-negative/inter (IFN) Keratinocytes from humans that have been triggered. Chrysin also inhibited TNF-α/IFN-γ-stimulated IL-33 expression in human and mouse keratinocytes. The interesting findings suggest the use of chrysin in the treatment of AD (Choi et al., 2017).

Another study found that a derivative of chrysin reduced the symptoms of Alzheimer's disease. The compounds demonstrated lower cytotoxicity while still having anti-inflammatory properties. They demonstrated that upregulation of tumor necrosis factor, interleukin (IL)-6, and nitric oxide can be inhibited to decrease inflammation in Alzheimer's disease (Song et al., 2019).

Another study was carried out in vivo in animals and in-vitro on cell lines to study the mechanism of action of chrysin in AD. The cell line studies indicated that chrysin inhibited the gene expression of all cytokines. The researchers also found that the inhibitory effect of chrysin on the pro-inflammatory cytokine was NF-κB and caspase-1 dependent. Chrysin's anti-inflammatory properties in vitro and in vivo make it a promising candidate for the treatment of allergic inflammatory illnesses like asthma and Alzheimer's disease (Bae et al., 2011).

In AD-like settings, the molecular mechanism underlying the chrysin-induced suppression of 5 (CCL5) gene expression was studied. According to their findings, chrysin inhibited CCL5 expression by targeting IKK and reducing mast cell infiltration, lowering inflammation (Yeo et al., 2020).

3.5 Photoaging and skin aging

Skin aging is an unavoidable intrinsic process. Several external factors are also responsible to trigger or fasten this process, most importantly the ultraviolet (UV) radiations. The formation of oxidative reactive species and changes in skin collagen are vital events that occur during skin aging (Kohl et al., 2011). Deep penetration of the UVA into the dermis causes sunburn, tanning, photoaging and eventually may also result in skin cancer. Photoaged skin is rough and fragile, with wrinkles, purpura, pigmentation, and a decreased ability to repair wounds (Tobin 2017).

Photoprotection and photosensitizers are needed to control the process of photoaging of the skin. In-vitro studies have shown the effectiveness of chrysin on photoaging of the skin. The ability of chrysin to protect keratinocytes from UV damage was investigated. The findings revealed that chrysin can reduce UVB and UVA-induced apoptosis, reactive oxygen species generation, and cyclooxygenase 2 expression. It also corrected UVB-induced downregulation of aquaporin 3 (AQP-3) as well as JNK activation. It also showed mild inhibition of p38 activation triggered by UVA and UVB. The researchers also studied the topical application of chrysin in animals was non-irritant and showed efficient dermal penetration. The study showed that chrysin has good photoprotective ability on the skin and can be included in preparations for skin aging (Wu et al., 2011).

Another group of researchers attempted to evaluate the effects and mechanisms of chrysin on photoaging and melanogenesis. The in-vitro studies showed that chrysin increased the synthesis of collagen I, reduced its degradation, and decreased the synthesis of melanin by suppressing the melanogenic proteins. The results of the study show that chrysin may be included in the cosmetic formulation for its use as anti-photoaging and its anti-melanogenesis use (Zhu et al., 2016).

One more study evaluated the photostability and low phototoxicity of chrysin and other related naturally occurring compounds. However, chrysin showed a lesser photoprotective effect than the other polyphenols under investigation (Kostyuk et al., 2018).

3.6 Skin cancer

Skin cancer is a common type of cancer across the globe. It is typically either melanoma or non-melanoma type of skin malignancy. Most types of skin cancers are non-melanomatous. They arise from keratinized epithelial cells and include basal cell carcinoma and squamous cell carcinoma. Melanoma accounts only for 2% of skin cancer cases but causes most of the skin cancer deaths (Linares et al., 2015, Patil and More 2020). Non-melanoma skin cancers can be treated by surgical excision, topical chemotherapy, or other treatments such as electrodesiccation. Melanoma requires surgical treatment and chemotherapy to treat cancer that has spread to deeper tissues.

Several researchers have looked into the anticancer properties of chysin and chysin derivatives. Chrysin derivatives suppressed human epidermoid carcinoma cells and reduced tumor growth in an in vitro investigation on cancer cell lines. The mechanism of action is the loss of phosphorylation sites on the retinoblastoma. Chrysin also reduced the kinase activity by direct binding to cyclin-dependent kinases 2 and 4 (Liu et al., 2013).

Another in vitro study carried out on a derivative of chrysin inhibits tumorigenesis by directly acting on the mitogen- and stress-activated kinase enzyme. The chrysin derivative has the potential to be exploited as a chemoprotective agent in the treatment of skin cancer, according to the researchers (Liu et al., 2014).

The effect of chrysin on migration and metastasis in human melanoma is investigated in one study. Chrysin prevents cells from migrating and infiltrating by reducing MMP-2 activity. It also affects the key metastasis-related proteins and the translocation of NF-κBp65. As a result, chrysin inhibits cell migration, invasion, and mobility in A375.S2 cells in vitro. It also halts the spread of cancer (Chen et al., 2019).

The effects of nano encapsulated chrysin and curcumin on the mouse B16F10 melanoma tumor model were investigated in a similar study. MMP-2, 9, TIMP-1, 2, and TERT expression levels were assessed as significant genes in tumor growth and metastasis. The results revealed that the nano encapsulated chrysin and curcumin arrested the tumor growth and inhibited the expression of the genes (Tavakoli et al., 2018).

In a recent study, we looked at the effectiveness of a topical chrysin nanoemulgel in the treatment of skin cancer. We carried the cytotoxicity studies on the cancer cell lines using the topical nanoemulgel loaded with chrysin. The results showed a significant effect on the cancer cell lines A375 and SK-MEL-2 (Nagaraja et al., 2021).

Chrysin is also present in a medicinal plant Indigofera tinctoria used widely in the Indian and Chinese medical systems. After the isolation of this bioactive compound, its effect was studied in vitro on the epidermoid carcinoma cells. The results of the study reveal that chrysin arrested the cell cycle at the Sub G1 phase. Furthermore, it also enhanced the expression of cytochrome C, caspase 9, caspase 3. It caused remarkable cell death by promoting apoptosis (Boothapandi and Ravichandran 2018).

Another study involved studying the chemoprotective potential of chrysin in skin cancer. The probable mechanisms proposed after the histopathological and biochemical examination reveal anti-lipid peroxidative effect, antioxidant effect, and ability to modulate carcinogen detoxification (Prabhakar et al., 2012).

3.7 Cutaneous leishmaniasis

Cutaneous leishmaniasis is a less severe form of the disease, Leishmaniasis, caused by a protozoan parasite, and characterized by ulcerative skin lesions. The condition is common in tropical and temperate regions of the world and affects the immune system of the body. The Leishmanial Mitogen-Activated Protein kinases play an important role in the survival and infection-causing capacity of the parasite (Raj et al., 2019).

The current treatment of the condition is based on chemotherapy which has limited effects and several side effects. Hence, the recent focus is on the natural phytochemicals for treating cutaneous leishmaniasis.

MAPK3 is involved in the regulation of flagellar length in Leishmania donovani. It also plays a crucial role in the spread of disease. As a result, this enzyme could be used as a new therapeutic target. This enzyme has been demonstrated to be inhibited by chrysin (Raj et al., 2019).

Chrysin is an important ingredient in propolis and some research papers have studied the effect of propolis on cutaneous leishmaniasis. In one such study, the researchers have studied the effect of Brazilian green propolis hydroalcoholic extract in-vitro and in-vivo. The in-vitro studies have shown that the high concentration of this extract had an anti-leishmanial effect. The in-vivo studies were carried out in lesions induced by Leishmania amazonensis on the paw of mice. Results revealed that oral administration of the extract in animal models decreased the parasites and induced macrophage infiltration in the lesion (Cunha et al., 2020).

Another study carried out research on the Brazilian and Bulgarian propolis on different species of Leishmania. The results indicated that the extracts had leishmanicidal activities on the different species in the invitro assays (Machado et al., 2007).

A recently published review article also emphasizes that the Leishmania MPK1 and MPK2 enzymes are the targets for the treatment of cutaneous leishmaniasis and natural compounds such as chrysin may act on the macrophage or parasitic enzymes (Efstathiou and Smirlis, 2021).