Phytotherapeutic Potential of Medicinal Plants for Atopic Dermatitis: Centella asiatica, Clinacanthus nutans, Senna alata, and Coccinia grandis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with significant global health implications, particularly in low-resource settings. In many Asian countries, traditional herbal medicine remains an integral part of healthcare and presents promising alternatives for managing AD. This review examines the therapeutic potential of four ethnomedicinal plants; Centella asiatica, Clinacanthus nutans, Senna alata, and Coccinia grandis, focusing on their anti-inflammatory, antimicrobial, and antioxidant activities. Evidence from preclinical and clinical studies highlights key bioactive compounds and underlying mechanisms, demonstrating their efficacy in alleviating AD symptoms and supporting skin barrier restoration. Comparative analysis suggests complementary and potentially synergistic effects across these species, targeting multiple aspects of AD pathophysiology. However, translation into clinical practice is constrained by inconsistent formulations, limited human trials, bioavailability challenges, and regulatory variability. Future directions include the development of standardized extracts, nanotechnology-based delivery systems, integration with conventional therapies, omics-driven precision medicine, and harmonized regulatory frameworks. Collectively, these strategies outline a therapeutic development pipeline for advancing plant-based interventions for AD from traditional use to clinical application.

INTRODUCTION

Atopic dermatitis (AD), commonly known as eczema, is a chronic, relapsing inflammatory skin disease that poses a substantial global health burden. It affects approximately 230 million people worldwide, with prevalence rates ranging from 2% to 20% in children and up to 3% in adults, depending on the region (Hay et al., 2014). Notably, the incidence of AD continues to rise, particularly in low- and middle-income countries (Kim et al., 2016; Odhiambo et al., 2009). Beyond its physical manifestations, AD significantly impairs quality of life through persistent itching, sleep disturbance, emotional distress, and reduced productivity, with up to 40% of cases persisting into adulthood (Beattie and Lewis-Jones, 2006).

The pathogenesis of AD reflects a complex interaction between genetic predisposition, immune dysregulation, and environmental factors (Chaiyamahapurk and Warnnissorn, 2021; Langan et al., 2009) (Fig. 1). Central mechanisms include skin barrier dysfunction, infiltration of T cells, mast cells, and dendritic cells, elevated IgE, and overexpression of Th2 cytokines such as IL-4, IL-5, and IL-13 (Brunner et al., 2017; Peng and Novak, 2015; Roesner et al., 2016). Environmental triggers, such as allergens, microbial exposure, and pollutants, further amplify this inflammatory cycle.

Fig. 1.

The vicious cycle of AD pathogenesis. Genetic predisposition (e.g., filaggrin mutations and barrier protein defects) and environmental triggers synergistically impair skin barrier function. This allows increased allergen penetration and dendritic cell activation, initiating a type 2 immune response characterized by elevated IgE and Th2 cytokines (IL-4, IL-5, IL-13). The resulting immune-mediated inflammation leads to clinical manifestations such as itching and erythema, and importantly, further exacerbates skin barrier dysfunction, creating a self-perpetuating inflammatory cycle.

Current management strategies include avoidance of triggers, emollients, and topical anti-inflammatory agents such as corticosteroids and calcineurin inhibitors (Williams, 2005; Wollenberg et al., 2016). While effective, their long-term use is limited by side effects including skin atrophy and systemic toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs) offer some benefit but carry gastrointestinal and cardiovascular risks (Dinarello, 2010). These limitations underscore the need for safer, sustainable alternatives.

Medicinal plants have been traditionally employed for centuries to treat skin disorders such as eczema, psoriasis, and cellulitis (Moradi et al., 2016). Rich in bioactive compounds with anti-inflammatory, antioxidant, and antimicrobial properties, natural products are increasingly investigated as potential adjuncts or alternatives for AD therapy (Ren et al., 2019; Yang et al., 2020). In Asia, herbal remedies remain integral to healthcare, with nearly 80% of populations in developing countries relying on traditional medicine (Ekor, 2014; Patwardhan et al., 2005).

Building on this foundation, the present review focuses on four medicinal plants; Centella asiatica (L.) Urban, Clinacanthus nutans (Burm. f.) Lindau, Senna alata (L.) Roxb., and Coccinia grandis (L.) Voigt (Fig. 2), that show particular promise as therapeutic candidates for AD. These species were selected based on their longstanding ethnomedicinal use in the treatment of inflammatory skin disorders, their rich phytochemical profiles, and emerging pharmacological evidence relevant to AD pathophysiology. Extracts and bioactive constituents from these plants have been reported to exhibit anti-inflammatory, antioxidant, immunomodulatory, and antimicrobial activities, all of which align with key pathological processes in AD. This review consolidates traditional knowledge with recent experimental findings to provide an integrated perspective on their therapeutic potential. We summarize their phytochemical constituents, molecular targets, and mechanistic pathways, and discuss available in vivo and clinical data, along with safety considerations and standardization challenges, offering a balanced evaluation of their translational applicability and highlighting research gaps for future investigation.

Fig. 2.

Medicinal plants reviewed in this study. (A) Asiatic pennywort (Centella asiatica), showing its characteristic kidney- shaped leaves. (B) Sabah snake grass (Clinacanthus nutans), with opposite leaves and tubular red flowers tipped with yellow. (C) Candle bush (Senna alata), displaying compound leaves and bright yellow, candle-like inflorescences. (D) Ivy gourd (Coccinia grandis), showing its leaves, white flower, and ripe red fruit. Scale bars=1 cm.

CENTELLA ASIATICA (FAMILY APIACEAE)

Centella asiatica (Fig. 2A), commonly known as Gotu kola, Indian pennywort, or Jalbrahmi, is a medicinal herb with a long history in traditional medicine, particularly across Asia (Matsuda et al., 2001). This herb has been a part of the Ayurvedic tradition in India for millennia and is even mentioned in the historic Sushruta Samhita, an ancient Indian medical text (Matsuda et al., 2001; Sun et al., 2020). Furthermore, it is used by the people of Java and other Indonesian islands and has been described as one of the world’s “miracle elixirs of life” (Gohil et al., 2010; Sun et al., 2020). C. asiatica finds application in traditional medicine for alleviating various conditions, including body aches, headaches, insanity, asthma, leprosy, ulcers, eczemas, and wound healing (Gohil et al., 2010). The systematic screening of medicinal plants is crucial in the search for new potential compounds for treatment (Sun et al., 2020). In recent years, scientific interest in this plant has surged due to its diverse therapeutic applications. C. asiatica extracts can reduce inflammation, improve skin barrier function, and accelerate wound healing, making it a promising candidate for AD treatment.

C. asiatica has been found to contain a significant amount of the flavonoid quercetin, known for its therapeutic effects in the context of AD induced by 2,4-dinitrochlorobenzene (Lee et al., 2018). The various extracts obtained from C. asiatica are rich in bioactive compounds like quercetin, asiaticoside, and madecassoside, which offer anti-inflammatory, antioxidant, wound-healing, and skin barrier restoration benefits (Table 1). These properties make C. asiatica extracts valuable in both traditional and modern dermatological applications. This aromatic plant is rich in major pentacyclic triterpenes, with the most prominent bioactive being madecassoside (MO), asiaticoside (AO), madecassic acid (MA), and asiatic acid (AA), which contribute to its medicinal efficacy (Hashim et al., 2011). The distribution of pentacyclic triterpenes in the plant varies depending on the plant part, cultivation zone, and harvesting period (Puttarak and Panichayupakaranant, 2012). Studies have shown that C. asiatica and its triterpenes possess properties that aid in wound healing, memory improvement, and the treatment of conditions such as asthma, psoriasis, ulcers, and cancer (Hashim et al., 2011). Additionally, they exhibit anti-allergic, anti-inflammatory, antifibrotic, cardioprotective, neuroprotective, antioxidant, antidepressant, anticancer, antibacterial, and antifungal properties, and they inhibit the expression of inflammatory cytokines (Table 1). These properties can effectively alleviate AD symptoms such as increased epidermal and dermal thickness and the infiltration of mast cells and eosinophils into the dermis (Adtani et al., 2017; George et al., 2009; Ju Ho et al., 2018; Lokanathan et al., 2016; Razali et al., 2019). The anti-inflammatory properties of AA have been particularly emphasized in both in vitro and in vivo studies (Dong et al., 2017; Hao et al., 2017; Lee et al., 2016). In fact, AA treatment was found to inhibit the LPS-induced inflammatory response in human gingival fibroblasts (Hao et al., 2017).

Table 1.

Phytochemicals, chemical classes, and AD-relevant bioactivities of selected medicinal plants

Plant	Key active compounds	Major chemical classes	Plant part used	AD-relevant pharmacological properties	Mechanism of action	Skin effects	Key references
C. asiatica	Asiaticoside	Triterpenoids	Leaf, Stem	Anti-inflammatory	Inhibits TNF-α, IL-6; reduces histamine	Relieves eczema inflammation	Rachpirom et al., 2023; Wu et al., 2024
	Madecassoside			Antioxidant	Free radical scavenging	Protects from oxidative damage	Buranasudja et al., 2021; Matthews et al., 2019
	Asiatic acid			Barrier repair/Wound healing	↑Filaggrin, loricrin, collagen; ECM remodeling	Improves hydration; accelerates healing	Adtani et al., 2017; Hashim, 2014; Maquart et al., 1999
	Madecassic acid			Antimicrobial	Inhibits microbial growth	Prevents secondary infections	Bhuyar et al., 2021; Harnvoravongchai et al., 2018
C. nutans	Lupeol Stigmasterol	Flavonoids, Sterols, Glycosides, Flavonols, Glycolipids	Leaf, Stem	Anti-inflammatory/Immunomodulatory	Suppresses Th2 cytokines via JAK/STAT & MAPK	Reduces dermatitis inflammation	Azemi et al., 2021; Ong et al., 2022
	Vitexin Isovitexin			Antiviral	Inhibits viral replication	Reduces risk of eczema herpeticum	Ismail et al., 2020; Yusuf et al., 2020
	Shaftoside Isoorientin Cerebrosides			Barrier repair/Wound healing	Promotes collagen synthesis & wound contraction	Supports minor wound repair	Aliyu et al., 2020
S. alata	Anthraquinone glycosides Kaempferol 3-O-sophoroside	Anthraquinones, Flavonoids, Fatty acids, Sterols	Leaf, Flower, Stem, Seed	Antimicrobial	Inhibits bacterial & fungal growth	Reduces secondary infections in AD lesions	Aung et al., 2023; Rahmawati and Hady, 2022
	Saponin Palmitic acids			Anti-inflammatory	Downregulates cytokines	Alleviates swelling & irritation	Uwazie et al., 2020
	Stigmasterol Tannins			Antioxidant	Neutralizes free radicals	Protects from oxidative damage	Pamulaparthi et al., 2016
C. grandis	Glycosides Flavonoids	Polyphenols, Glycosides	Leaf, Fruit, Stem, Root	Anti-inflammatory	Inhibits histamine, prostaglandins, bradykinin	Reduces skin inflammation	Albrahim et al., 2020
	Phenols Tannins			Antioxidant	Scavenges radicals	Protects barrier from oxidative stress	Meenatchi et al., 2017
	Cucurbitacins			Antimicrobial/Wound healing	Disrupts bacterial/fungal walls; promotes cell regeneration	Treats infections; aids healing	Muthulakshmi and Neelanarayanan, 2020; Sivaraj et al., 2011

While side effects of using C. asiatica are rare, they may include skin allergies and a burning sensation when applied externally. When consumed in high doses, potential side effects include headache, stomach upset, nausea, dizziness, and excessive drowsiness (Gohil et al., 2010). C. asiatica appears to be a safe and effective option for managing atopic dermatitis, particularly in topical applications. Its anti-inflammatory and skin-healing properties can help alleviate symptoms and promote better skin health. However, individual responses may vary, and it is essential to monitor for any adverse reactions, particularly in individuals with sensitive skin. Consulting with a healthcare provider before incorporating C. asiatica into a treatment regimen is recommended to ensure safety and efficacy.

CLINACANTHUS NUTANS (FAMILY ACANTHACEAE)

Clinacanthus nutans (Fig. 1B), an exotic plant indigenous to Kerala, India (Chia et al., 2021), is widely recognized in traditional Southeast Asian medicine, particularly in Malaysia, Thailand, and Indonesia (Sakdarat et al., 2009; Wanikiat et al., 2008). This medicinal plant has a long history in treating various ailments, including skin conditions, inflammatory disorders, insect bites, and viral infections. Traditionally, C. nutans leaves are prepared as decoctions or poultices and applied topically to alleviate symptoms such as itching, inflammation, and pain associated with skin disorders like eczema and dermatitis.

Phytochemical investigations have revealed that C. nutans is rich in flavonoids, terpenoids, phenolic compounds, and polysaccharides (Table 1). These bioactive constituents contribute to its anti-inflammatory, antioxidant, antiviral, and wound-healing activities (Alam et al., 2016). Several studies have demonstrated that C. nutans extracts can inhibit the production of pro-inflammatory cytokines and mediators associated with skin inflammation, supporting its potential as a natural therapy for managing AD (Alam et al., 2016). Furthermore, its antiviral properties against various viruses suggest additional utility in treating viral skin infections, which can exacerbate AD symptoms (Tuntiwachwuttikul et al., 2004). Extracts of C. nutans have also been shown to promote wound healing by stimulating fibroblast proliferation, enhancing collagen synthesis, and inducing angiogenesis, which collectively contribute to skin barrier repair and regeneration.

Recognizing its therapeutic potential, C. nutans was included in Thailand’s National List of Essential Medicines in 2011 and is recommended by the Thai Ministry of Public Health for treating skin inflammations (Wanikiat et al., 2008). It has also been prioritized under Malaysia’s National Key Economic Area grant for therapeutic development and commercialization (Sakdarat et al., 2009). Further research into its mechanisms of action and optimization of formulation strategies could significantly advance its application in holistic skin disorder management, including AD. In traditional Chinese medicine, C. nutans is used alone or in combination with other herbs to treat inflammation, musculoskeletal strains, rheumatism, anemia, and jaundice (Zulkipli et al., 2017). In Thailand, the plant is revered as a “snakebite antidote” and is also used for treating herpes simplex and varicella-zoster virus infections, particularly in immunocompromised individuals (Sakdarat et al., 2009).

Pharmacological studies confirm the diverse bioactivities of C. nutans extracts, including anti-inflammatory, antioxidant, antiviral, and anti-diabetic effects (Alam et al., 2016). For example, ethanolic leaf extracts demonstrate strong antioxidant potential and provide protection against free radical-induced hemolysis (Pannangpetch et al., 2007). In an ethyl phenylpropiolate-induced ear edema model, whole-plant extracts dose-dependently inhibited edema formation, confirming their anti-inflammatory effects (Wanikiat et al., 2008). Additionally, significant inhibition of myeloperoxidase activity in rat ears further substantiates its anti-inflammatory properties. In Thailand’s national pharmacopeia, C. nutans is available in multiple formulations: creams and tinctures for treating herpes simplex and herpes zoster; lotions for dermatitis and urticaria; and ointments for reducing inflammation from insect bites (Neamsuvan and Bunmee, 2016). Importantly, no adverse effects have been reported with topical application of C. nutans extracts, supporting its safety and therapeutic viability for dermatological use (Chia et al., 2021; Lin et al., 2023). Recent studies also suggest that C. nutans extracts can downregulate inflammatory cytokines and relieve itching, offering symptom relief for AD patients.

SENNA ALATA (FAMILY LEGUMINOSAE)

Senna alata (Fig. 1C), commonly referred to as the “candle bush,” is an annual or occasionally biennial herbaceous plant that typically grows to a height of 1-4 meters and thrives in sunny, humid climates. Its characteristic morphology includes oblong leaves with 5 to 14 pairs of leaflets, sturdy petioles (2-3 mm), and abundant, bright yellow zygomorphic flowers comprising seven stamens and a pubescent ovary. The fruit is a tetragonal pod (10-16×1.5 cm), with thick, flattened wings that turn brown upon ripening and contain numerous diamond-shaped seeds. The plant is propagated by seeds and found at altitudes up to 1,500 meters above sea level (Abo et al., 2008; Hennebelle et al., 2009). S. alata is widely distributed across regions such as Ghana, Brazil, Australia, Egypt, India, Somalia, Sri Lanka, and much of Africa (Oladeji et al., 2020), and is also extensively cultivated for medicinal purposes in countries like the Philippines, Thailand, and Indonesia (Saokaew et al., 2011). Traditionally, S. alata has played a central role in various medicinal systems including Ayurvedic, Sinhala, Chinese, and African medicine. In northern Nigeria, decoctions prepared from the stem, leaf, and root are used to treat skin wounds, respiratory tract infections, burns, diarrhea, and constipation (Adedayo et al., 2001; Atanu et al., 2022). In Cameroon, the stem bark and leaves are employed in treating gastroenteritis, hepatitis, ringworm, and dermal infections (Kuete and Efferth, 2010). In India, the Philippines, and China, it is used for managing hemorrhoids, inguinal hernia, syphilis, intestinal parasitosis, and diabetes (Igoli et al., 2005). The plant is widely regarded for its antifungal and laxative properties, with the leaves and flowers commonly used in traditional preparations (Ezemba et al., 2021). Additionally, in Guatemala, Brazil, and Guinea, the whole plant is used to treat conditions such as influenza and malaria (Hennebelle et al., 2009). Pharmacological studies have demonstrated the antimicrobial efficacy of S. alata, particularly against Staphylococcus aureus, a key pathogen implicated in skin infections and wound healing complications (Geoghegan et al., 2018). A hydrogel formulated using S. alata leaf extract has shown notable antimicrobial effects, supporting its potential utility in wound care (Donkor et al., 2023). Its antimicrobial action facilitates wound closure and recovery, making it a promising candidate for managing skin lesions and secondary infections commonly associated with AD.

In addition to antimicrobial activity, S. alata also exhibits significant anti-inflammatory effects. It functions by suppressing the expression of pro-inflammatory cytokines and enhancing the activity of anti-inflammatory transcription factors, enzymes, and cytokines, mechanisms that may help reduce inflammation in chronic skin disorders (Riaz et al., 2018). Topical applications of S. alata extracts have been reported to reduce skin inflammation and pruritus, suggesting their suitability as adjunct therapies for managing AD symptoms. While toxicological studies have generally shown a favorable safety profile, further validation using in vitro and in vivo models, especially with clinical isolates, is required. Toxicological assessments should include analyses of both fresh and dried plant materials, focus on low-dose ranges, and evaluate impacts on vital organs such as the brain, intestines, and bladder (Oladeji et al., 2020). Ethnobotanical evidence also advises caution in using S. alata in individuals with peptic ulcers, pregnant women, and children under two years of age.

With its diverse phytochemical composition, S. alata holds significant promise in modern medicine as an antifungal, antimicrobial, and anti-inflammatory agent (Table 1). Its efficacy in reducing microbial burden and inflammation in skin disorders underscores its potential as a complementary therapy for conditions such as AD. Future research should prioritize the identification of its active compounds, optimization of delivery methods, and clarification of pharmacodynamic mechanisms to facilitate safe and effective therapeutic applications.

COCCINIA GRANDIS (FAMILY CUCURBITACEAE)

Coccinia grandis (Fig. 1d), commonly known as ivy gourd, telachucha, tindora, or scarlet-fruited gourd, is a climbing perennial herb belonging to the Cucurbitaceae family (Jebadurai et al., 2019). Native to Central Africa, India, China, and tropical Asia, including Pakistan, Bangladesh, Sri Lanka, Indonesia, Malaysia, the Philippines, and Thailand, it is also found in Australia and parts of Africa. Widely regarded as a valuable wild vegetable, C. grandis is commonly consumed and cultivated in Southeast Asia and India (Sakharkar and Chauhan, 2017). The plant propagates through seeds and features green, ribbed stems that develop white spots as they mature. Its flexible tendrils allow it to climb and attach to nearby structures (Jebadurai et al., 2019).

Various plant parts are utilized in traditional medicine for their wide-ranging therapeutic effects. The stem and roots are traditionally used to manage skin conditions, asthma, bronchitis, and joint pain, while the leaves are particularly valued for their anti-diabetic, anti-inflammatory, antipyretic, analgesic, antispasmodic, and antimicrobial properties (Kondhare and Lade, 2017). The fruits have also been used medicinally, especially in the treatment of eczema, tongue ulcers, and conditions related to oxidative stress (Kondhare and Lade, 2017). Scientific research has substantiated many of these traditional applications. For instance, ethanol extracts of C. grandis leaves have demonstrated significant antifungal activity (Bhattacharya et al., 2010), and antibacterial properties effective against Streptococcus pneumoniae, Escherichia coli, Bacillus cereus, Klebsiella pneumoniae, and Staphylococcus aureus (Sivaraj et al., 2011). Traditionally, the leaves are applied to treat jaundice, bronchitis, skin eruptions, burns, and eczema. Anti-inflammatory effects have also been documented in experimental models, such as in formaldehyde-induced paw edema in rats, where leaf and stem extracts of C. grandis significantly reduced swelling, likely through modulation of histamine and prostaglandin pathways (Deshpande et al., 2011; Mary et al., 1998).

The therapeutic efficacy of C. grandis in dermatological applications can be attributed to its rich phytochemical profile, which includes tannins, glycosides, saponins, carotenoids, phytosterols, and triterpenoid cucurbitacins, compounds known for their anti-inflammatory, antioxidant, antimicrobial, and wound-healing properties (Lee and Joo, 2022) (Table 1). Cucurbitacins, particularly abundant in the leaves, promote cell regeneration and tissue repair, thus enhancing wound healing, an essential aspect in the management of skin lesions and abrasions associated with AD. The plant’s anti-inflammatory properties help mitigate redness and swelling during AD flare-ups, while its antioxidants, such as carotenoids and tannins, counteract oxidative stress, a key factor that exacerbates skin inflammation. Furthermore, the antimicrobial activity of C. grandis, especially against S. aureus, may help prevent secondary infections common in AD (Lee and Joo, 2022).

Although C. grandis presents a promising candidate for managing AD symptoms, further research, particularly clinical trials, is needed to confirm its efficacy and safety. Potential adverse effects, such as allergic reactions or skin irritation, especially among sensitive individuals, should be carefully evaluated before recommending its topical application.

COMPARATIVE ANALYSIS OF PHYTOTHERAPEUTIC POTENTIAL OF C. ASIATICA, C. NUTANS, S. ALATA, AND C. GRANDIS IN AD

The pathophysiology of AD is multifactorial, involving immune dysregulation, barrier dysfunction, and microbial colonization (Weidinger et al., 2018; Zeldin et al., 2023). Conventional management relies on emollients to restore skin hydration and topical corticosteroids to control inflammation (Carr, 2013). However, long-term corticosteroid use carries risks such as skin atrophy and systemic absorption (Russell, 2002), driving growing interest in complementary herbal approaches. In Asia, medicinal plants have traditionally been employed to alleviate inflammatory skin disorders, and several species are now being systematically investigated for their anti-inflammatory, antimicrobial, antioxidant, and barrier-restoring properties (Choi et al., 2012; Hon et al., 2007; Kim et al., 2011). Despite these advances, rigorous preclinical evaluation, toxicity testing, and clinical validation remain limited, underscoring the need for critical comparative analyses of promising candidates. Among the medicinal plants with emerging evidence of benefit in AD are C. asiatica, C. nutans, S. alata, and C. grandis. Each exhibit distinct phytochemical profiles and therapeutic activities that target different aspects of AD pathophysiology (Table 1).

C. asiatica contains triterpenoids such as asiaticoside and madecassoside, which downregulate NF-κB, TNF-α, and IL-6, thereby exerting strong anti-inflammatory effects. These compounds also enhance collagen synthesis, keratinocyte proliferation, and extracellular matrix remodeling, contributing significantly to skin barrier repair. C. nutans, rich in flavonoids and sulfur-containing glycosides, modulates JAK/STAT and MAPK pathways, leading to Th2 cytokine suppression. Beyond its immunomodulatory role, C. nutans also demonstrates antiviral activity, which may be relevant in AD cases complicated by eczema herpeticum.

Microbial colonization, especially by S. aureus and fungi, is a common feature of AD that exacerbates disease severity. S. alata, characterized by anthraquinones, shows potent antimicrobial and antifungal activity, making it particularly advantageous for preventing and managing secondary infections. C. grandis, although less extensively studied, contains cucurbitacins and flavonoids that suppress pro-inflammatory mediators and provide strong antioxidant support. By mitigating oxidative stress, C. grandis may indirectly preserve skin barrier integrity.

Taken together, C. asiatica emerges as the most promising for skin barrier repair and inflammation control, S. alata offers strong antimicrobial defense, C. nutans provides broader immunomodulatory and antiviral activity, and C. grandis serves as a supportive antioxidant and anti-inflammatory agents. Their phytochemical diversity suggests that a combined or sequential therapeutic approach could address multiple aspects of AD pathophysiology more effectively than any single plant alone (Fig. 3).

Fig. 3.

Comparative mechanisms of action of C. asiatica, C. nutans, S. alata, and C. grandis in AD. C. asiatica (gray) promotes barrier repair and reduces inflammation via triterpenoids. C. nutans (blue) modulates Th2-mediated cytokine signaling and support epidermal repair through flavonoids, sterols, and glycosides. S. alata (magenta) exerts antimicrobial and anti-inflammatory effects, reducing Staphylococcus aureus colonization and pruritus via anthraquinones, fatty acids, and sterols. C. grandis (green) regulates immune balance and inhibits inflammatory cytokine through phenolics and glycosides. Collectively, these plants target immune regulation, oxidative stress, antimicrobial protection, and barrier restoration, highlighting complementary therapeutic potential.

Importantly, triterpenoids, flavonoids, sterols, glycosides, flavonols, glycolipids, anthraquinones, fatty acids, and polyphenols, commonly found across these four species, are known to act synergistically when combined. Although most studies have traditionally examined isolated compounds, increasing evidence highlights the therapeutic potential of phytochemical combinations. For example, quercetin and galangin, individually and in combination, significantly reduced serum IgE levels and suppressed DNCB-induced ear swelling, indicating enhanced anti-allergic and anti-inflammatory effects (Lee et al., 2018). Similarly, mixtures of phenolics and flavonoids have shown superior antioxidant activity compared to single agents, effectively enhancing free radical scavenging (Hajimehdipoor et al., 2014). Synergistic strategies have also been reported against drug-resistant bacteria, suggesting that multi-compound interactions may overcome therapeutic limitations of single agents (Alnour et al., 2022).

Extrapolating these findings to AD, combining the triterpenoid-rich extracts of C. asiatica with the antimicrobial anthraquinones of S. alata, the immunomodulatory flavonoids of C. nutans, and the antioxidant cucurbitacins of C. grandis may offer broad, complementary benefits. Such combinations could simultaneously restore the epidermal barrier, suppress inflammatory cascades, limit microbial colonization, and reduce oxidative stress, addressing the interconnected mechanisms of AD more comprehensively than any single plant alone. Future studies should therefore prioritize systematic evaluation of these plants in combination, with careful attention to dosage, safety, and mechanistic interactions, to unlock their full synergistic therapeutic potential.

CHALLENGES IN CLINICAL TRANSLATION

Although C. asiatica, C. nutans, S. alata, and C. grandis have shown promising anti-inflammatory, antimicrobial, and barrier-restoring properties in preclinical studies, clinical evidence supporting their efficacy in AD remains limited. Table 2 summarizes the currently available clinical studies for these four plants. These preliminary studies indicate potential benefits, such as reductions in lesion severity, pruritus, and inflammation, with generally mild or no reported adverse effects. However, the limitations of current clinical evidence are notable:

Table 2.

Clinical evidence of C. asiatica, C. nutans, S. alata, and C. grandis in AD and related skin conditions

Plant	Study design/subjects	Formulation/dose	Key findings/mechanism	Skin effects	Safety	References
C. asiatica	RCT, 30 AD patients, 4 wks	Topical cream (Pentacyclic triterpenoid-rich extract; 106 mg/g PRE)	↓EASI; Anti-inflammatory via inhibition of TNF-α, IL-6; enhances collagen, ECM, filaggrin, loricrin	Relieves inflammation, improves barrier repair, accelerates healing	Mild irritation	Lee et al., 2018; Rachpirom et al., 2023; Wu et al., 2024
	Clinical Trial Phase I, 84 diabetic wound patients	Oral capsule (50 mg asiaticoside, madecassoside, asiatic acid)	Stimulates collagen & glycosaminoglycan synthesis; wound healing	Accelerates healing, reduces scarring	No systemic side effects	Hashim, 2014; Maquart et al., 1999; Paocharoen, 2010
C. nutans	Pilot study, 20 AD patients, 2 wks	Leaf gel/50-200 mg/kg oral or topical	↓Pruritus & inflammation; Suppresses Th2 cytokines (JAK/STAT, MAPK); antiviral against HSV; promotes collagen & wound contraction	Reduces dermatitis inflammation; prevents viral complications; supports minor wound repair	None	Aliyu et al., 2020; Azemi et al., 2021; Chia et al., 2021; Ong et al., 2022; Yusuf et al., 2020
	In vivo rat model, 12-60 rats	Leaf extract 500 mg/kg or phenolic/flavonoid 2 g/kg	Anti-inflammatory, antioxidant; free radical scavenging	Protects against oxidative skin damage	No toxicity, lethality, or adverse effects	Chiu et al., 2021; Peng and Novak, 2014; Wanikiat et al., 2008
S. alata	Case series, 12 AD patients	Leaf poultice/75-500 mg/kg	↓Lesion size; anti-inflammatory (↓cytokines), antimicrobial (bacterial/fungal), antioxidant, photoprotective	Alleviates swelling, irritation; prevents secondary infections; protects from UV & oxidative damage	Mild redness	Aung et al., 2023; Donkor et al., 2023; Oliveira et al., 2023; Pamulaparthi et al., 2016; Uwazie et al., 2020
	In vivo rat/rabbit models, 18-91	Leaf/flower extract creams 5-95%	Wound healing, antimicrobial, antioxidant	Accelerates burn healing, prevents infections	Not reported	Kanedi et al., 2016; Midawa et al., 2010; Nasution et al., 2019
C. grandis	Case report, 1 AD patient	Leaf paste/50-200 mg/kg	↓Inflammation; anti-inflammatory via inhibition of histamine, prostaglandins, bradykinin; antioxidant & antimicrobial	Reduces inflammation; protects barrier; treats infections	Not reported	Albrahim et al., 2020; Bhattacharya et al., 2010; Meenatchi et al., 2017; Sivaraj et al., 2011

1. Limited clinical evidence: Most studies have small sample sizes (≤30 participants) and short durations (1-4 weeks), limiting statistical power and assessment of long-term efficacy. Study designs vary widely, ranging from randomized controlled trials to case reports, using diverse formulations such as creams, gels, poultices, or pastes.

2. Standardization of extracts: The content of active compounds can vary by plant part, origin, and extraction method, affecting reproducibility and efficacy. Chemical fingerprinting and quantification are essential to ensure consistent potency across studies and formulations.

3. Safety and toxicology: While adverse effects reported in existing studies are generally mild, systematic evaluation of acute, subchronic, and chronic toxicity is lacking. Potential allergenicity, herb-drug interactions, and long-term safety require thorough investigation.

4. Formulation development: Optimized delivery systems such as nanoemulsions, liposomes, or hydrogels may improve stability, skin penetration, and bioavailability. Current formulations are often crude extracts, which may limit clinical efficacy.

5. Regulatory considerations: Approval pathways for herbal products, whether as medicinal drugs or functional cosmetics, vary across countries and require robust evidence of quality, safety, and efficacy. Regulatory compliance remains a significant hurdle for clinical adoption.

6. Synergistic complexity: Although preclinical studies suggest that combinations of these plants may act synergistically to target multiple AD pathways, this potential remains largely untested in human studies. Understanding optimal combinations, ratios, and interactions is essential to realize their full therapeutic potential.

Collectively, these challenges highlight the need for well-designed, adequately powered clinical trials using standardized formulations. Evaluating single-plant and combination therapies, alongside comprehensive safety and mechanistic assessments, will be essential to translate the phytotherapeutic potential of these plants into safe and effective AD treatments.

FUTURE PERSPECTIVES

Despite growing interest in phytotherapeutics for AD, significant gaps remain between preclinical promise and clinical application. Future research and development efforts should prioritize the following directions:

1. Development of standardized herbal formulations for AD. Consistency in bioactive compound content is essential to ensure reproducible therapeutic outcomes. Advanced chromatographic and metabolomic profiling should be applied to establish chemical fingerprints and quality standards for C. asiatica, C. nutans, S. alata, and C. grandis. This will enable the creation of standardized extracts or phytopharmaceutical formulations with predictable efficacy and safety.

2. Combination therapy with existing dermatological treatments. Given the multifactorial nature of AD, combining herbal preparations with conventional treatments such as topical corticosteroids, calcineurin inhibitors, or biologics may provide synergistic effects. Such strategies could reduce drug doses, minimize side effects, and improve long-term disease control. Rigorous clinical trials are needed to validate these integrated approaches.

3. Nanotechnology-based delivery systems. Emerging platforms such as liposomes, nanoemulsions, solid lipid nanoparticles, and hydrogels hold promise in enhancing the solubility, stability, and skin penetration of plant-derived compounds. Incorporating these technologies into herbal formulations could overcome pharmacokinetic limitations and increase patient compliance.

4. Precision medicine and herbal drug discovery. Integration of omics technologies, including genomics, metabolomics, and proteomics, can facilitate the identification of patient subgroups who are most likely to benefit from specific phytotherapeutics. Systems biology approaches may also uncover novel bioactive compounds from these plants and their mechanisms of action, paving the way for targeted phytochemical-based drug discovery.

5. Regulatory and commercialization pathways. Clear guidelines for herbal medicines remain heterogeneous across countries, creating barriers to clinical adoption. Harmonization of regulatory frameworks, along with evidence-based demonstrations of efficacy and safety, will be critical for moving phytotherapeutics from the laboratory to the clinic. Furthermore, investment in scalable manufacturing, stability studies, and intellectual property protection will facilitate commercialization and wider accessibility.

To translate the therapeutic promise of plant-based interventions into clinically validated treatments, a structured development pathway is essential. Fig. 4 outlines a proposed therapeutic development pipeline for plant-based AD treatments, beginning with ethnobotanical use and progressing through phytochemical characterization, preclinical validation, safety assessment, formulation optimization, clinical trials, and eventual regulatory approval. This pipeline underscores the multidisciplinary effort required to bridge traditional knowledge with modern drug development standards.

Fig. 4.

Translational pathway of herbal medicine development from traditional use to commercialization. The schematic presents a funnel-shaped pipeline illustrating the multi-stage process of herbal drug development. It begins with ethnobotanical knowledge and phytochemical isolation, followed by preclinical studies (in vitro and in vivo), toxicological and safety assessments, formulation and standardization, and clinical trials (Phases I–III), culminating in regulatory approval and commercialization. The funnel shape emphasizes the high attrition rate, with only a small fraction of candidate compounds advancing to market. Representative examples at each stage include: traditional use of C. asiatica for skin inflammation, isolation of triterpenoids, anti-inflammatory testing of C. nutans flavonoids, toxicological evaluation, formulation of topical products, and eventual FDA authorization for marketing.

CONCLUSIONS

This review underscores the phytotherapeutic potential of C. asiatica, C. nutans, S. alata, and C. grandis in the management of AD. Evidence from traditional medicine and emerging scientific studies demonstrates their multifaceted properties, including anti-inflammatory, antimicrobial, antioxidant, and wound-healing effects, which collectively target key aspects of AD pathophysiology. Such a multi-targeted approach highlights the value of these plants as complementary candidates to conventional dermatological therapies. Nevertheless, significant gaps remain in standardization, formulation, dosing, and long-term safety evaluation. To fully realize their clinical promise, rigorous translational and clinical studies are required, alongside efforts to integrate modern pharmaceutical technologies and regulatory frameworks. Advancing in these directions will be essential for transforming traditional plant-based remedies into evidence-based therapeutic options for AD.