Anti-psoriatic potential of medicinal plants, Alstonia scholaris, Wrightia tinctoria, and Solanum xanthocarpum, using human HaCaT keratinocytes by multi-parametric analysis

Psoriasis is a chronic, autoimmune, genetically influenced, skin-affecting inflammatory disease distinguished by keratinocyte hyper-proliferation, abnormal differentiation, and an inflammatory environment (Das et al., 2009). Red, itchy, flaky, crusty, and scaly patches with silvery scales appear on the cranium, ears, elbows, knees, genital region, buttocks, and the entire body (Rendon and Schäkel, 2019). Psoriasis onset and progression entail a complex interaction between genetic and environmental factors. This skin disorder has been identified as a multifactorial disease that reportedly affects over 2% of the global population (Gupta et al., 2014).

Skin inflammation in psoriasis pathophysiology is driven by migration and interactions among Th1 cells, antigen-presenting cells, and keratinocytes, resulting in the overproduction of inflammatory mediators such as tumor necrosis factor (TNF), interferons (IFN), interleukins (IL), nitric oxide (NO), and secreted phospholipase A (sPLA) (Furue et al., 2020; Jiang et al., 2019). Key proinflammatory chemokines in the recruitment of these immune cells to the skin lesions include IL-8 (also known as CXCL8) and RANTES (regulated upon activation, normal T Cell expressed and presumably secreted [also known as CCL5]). IL-8 and RANTES overproduction at psoriatic lesion site has a significant neutrophil/T-cell chemotactic effect (Zdanowska et al., 2021). The resulting neutrophil infiltration leads to the release of even more IL-8, further enhancing neutrophilic influx and promoting the inflammatory progression of psoriasis (Lu et al., 2023). This uncontrolled IL-8 cascade dysregulates angiogenesis, increasing vascularity within skin lesions, and stimulates keratinocyte hyperproliferation and autoantigen formation (Heidenreich et al., 2009; Sieminska et al., 2024). This correlates with psoriasis severity and the characteristic tissue damage. Meanwhile, RANTES attracts innate and adaptive immune cells to psoriatic skin, exacerbating the IL-8 driven immunopathology (Sieminska et al., 2024). Notably, elevated IL-8 levels in the blood of psoriasis patients positively correlate with disease (Fukuoka et al., 1998). These cytokines, along with TNF-α, IL-17A, IL-1, and CXCL10, play a pivotal role in the pathogenesis of psoriasis, suggesting them as potential therapeutic targets (Navarini and Trüeb, 2010).

Psoriasis treatment varies based on severity. For moderate cases, topical treatments like calcineurin inhibitors, corticosteroids, and retinoids, along with phototherapy (UVB or PUVA light), are recommended (Rosso and Rosso, 2020a). Severe psoriasis may require systemic medications such as oral retinoids, methotrexate, cyclosporine, biologics (TNF and IL-17 inhibitors), and the oral phosphodiesterase-4 inhibitor apremilast (Gisondi et al., 2017). Conventional treatments for psoriasis may elicit several adverse effects (Kleyn et al., 2019). These may include skin atrophy, telangiectasia, immunosuppression-related infections, hepatotoxicity, nephrotoxicity, and an increased risk of malignancies due to prolonged systemic immune modulation. Additionally, phototherapy can lead to skin aging and an elevated risk of skin cancer, particularly with long-term or excessive exposure to ultraviolet radiation (Rosso and Rosso, 2020a). The systemic nature of these treatments may also pose risks of long-term complications. Compared to conventional medications, herbal therapies generally pose a lower risk of adverse effects and offer a holistic approach to psoriasis management by addressing underlying imbalances.

Medicinal plants offer a promising avenue for treating psoriasis due to their rich reservoir of bioactive compounds, including flavonoids, terpenoids, alkaloids, and polyphenols, which exhibit anti-inflammatory, antioxidant, and immunomodulatory effects (Gendrisch et al., 2021). In Ayurveda and Siddha medicinal systems, numerous herbal preparations are utilized for treating psoriasis, with anti-psoriatic agents such as quercetin, isothiocyanates, and thalidomide derivatives (Chen et al., 2017; Tang et al., 2018; Yehuda et al., 2012). These constituents can target various pathways involved in psoriasis pathogenesis, addressing inflammation, abnormal keratinocyte proliferation, and immune dysregulation (Das et al., 2009). For identifying and characterizing unique bioactive compounds, numerous techniques exist, facilitating their standardization and enhancement for therapeutic purposes. We have identified three such plants that show anti-psoriatic potential. Alstonia scholaris (L.) R.Br. (Apocynaceae) is a widely utilized medicinal plant in Northern India, known for its efficacy in treating various skin disorders. It exhibits wound-healing and anti-inflammatory properties and has been shown to inhibit retinoid-induced inflammation and atopic dermatitis. However, the anti-psoriatic potential of this plant needs to be explored (Bagheri et al., 2016; Lee et al., 2012). Commonly utilized preparation in treating psoriasis is derived from Wrightia tinctoria (Roxb.) R.Br. (Apocynaceae), known by various names such as 777, Psorolin, and Wrightia Oil. However, its mechanism of action at the cellular level still needs to be clarified (Mahadevan et al., 1998; Srivastava, 2014). The third plant used in this study is Solanum xanthocarpum Schrad. & Wendl (Solanaceae), which exhibits various biological activity, but the anti-psoriatic potential using human keratinocytes is not known (Parmar et al., 2017)). These facts prompted us to determine the mechanism of action of these medicinal plants at the cellular level using in vitro model and evaluate their effects on the inflammatory biomarkers in psoriasis such as IL-8 and RANTES.

Considering the above research gap, this work is a comprehensive report on the anti-psoriatic potential of three Indian-origin plants traditionally used in Ayurveda and Siddha Medicinal systems: Alstonia scholaris, Wrightia tinctoria, and Solanum xanthocarpum. The ethyl acetate and ethanolic extracts of the leaves of these herbal plants were investigated by determining their antiproliferative, pro-apoptotic and anti-inflammatory activity.