Introduction

Inflammation is a critical and evolutionarily conserved process that activates both immune and non-immune cells to protect the host from bacteria, viruses, toxins, and diseases, thereby facilitating tissue repair and recovery [1]. Acute inflammation involves a series of cellular and molecular events designed to mitigate harm or infection, ultimately restoring tissue homeostasis. However, when acute inflammation is not properly regulated, it can progress into chronic inflammation, leading to various chronic inflammatory diseases [2]. At the tissue level, infection or injury triggers local immune, vascular, and inflammatory cell responses, resulting in redness, swelling, heat, pain, and tissue loss [3]. Proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and vascular endothelial growth factor (VEGF), play crucial roles in this process. Several biological therapies have been developed to manage inflammation, including those that target specific cytokines or their receptors, inhibit lymphocyte trafficking, prevent monocyte-lymphocyte costimulatory molecule binding, or deplete B lymphocytes [4]. Kinase inhibitors that act downstream of cytokine receptors represent a promising frontier in anti-inflammatory drug development. These orally active small-molecule inhibitors target intracellular signaling pathways. Determining an effective concentration that avoids organ toxicity is critical, given the involvement of many intracellular signaling molecules in normal cellular functions. Statins, commonly used for lowering serum cholesterol, also exhibit anti-inflammatory properties. Nonetheless, a major side effect of biologicals is a reduced host defense against infections, which, if detected early, can be effectively treated with antibiotics [5]. Non-steroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed medications for inflammation [6]. In elderly patients over 60, approximately 7.3% filled at least one NSAID prescription within a year [7]. The adverse effects of NSAIDs are primarily due to the inhibition of the cyclooxygenase (COX) enzyme, with gastrointestinal complications, renal disturbances, and cardiovascular events being the most significant side effects [8].

Unlike modern allopathic drugs, which typically consist of single active components targeting specific pathways, herbal medicines often rely on a synergistic approach, where multiple plantderived molecules act on various elements of complex cellular pathways [9]. For instance, garlic (Allium nigrum) contains sulfur compounds with significant biological activities useful in managing inflammatory disorders. Similarly, hesperidin is recognized for its anti-inflammatory properties [10]. Curcumin, the primary component of turmeric (Curcuma longa), has been used in Ayurvedic medicine for centuries to treat inflammatory disorders [11]. Numerous studies have documented the role of various herbs in inflammation remission, with Curcuma longa showing the most clinical evidence for treating different inflammatory conditions such as rheumatoid arthritis (RA), uveitis, and inflammatory bowel disease (IBD) [12]. Arctium lappa L. (Asteraceae), known as “Bardana,” is a traditional anti-inflammatory agent in folk medicine. Arctigenin, a bioactive lignin isolated from A. lappa, inhibits the production of inducible nitric oxide synthase, interleukin-6, interleukin-2, interferon-gamma, and TNF-α in macrophages [13]. Both arctigenin and its glycoside, arctiin, are key active components of Arctium lappa L., with arctigenin showing potent anti-inflammatory effects and various other biological activities, including anti-tumor, anti-leukemic, anti-colitis, antiviral, and vascular protective effects [14]. This review explores arctigenin’s anti-inflammatory properties, elucidates its molecular mechanisms, evaluates its therapeutic applications, and identifies clinical use challenges, consolidating findings from preclinical and clinical studies to understand its potential in medical research and treatment.

Arctigenin: Multifaceted Bioactive Molecule

The chemical structure of arctigenin is characterized by a dibenzylbutyrolactone skeleton, which plays a crucial role in its bioactivity. This structure allows arctigenin to interact with various molecular targets, facilitating its diverse pharmacological effects. The unique configuration of arctigenin’s chemical structure underpins its multifaceted biological activities, which include significant anti-inflammatory and antioxidant effects. As research progresses, the therapeutic potential of arctigenin continues to expand, highlighting its role in the development of treatments for a variety of inflammatory and oxidative stress-related conditions.

Figure 1: Chemical structure of arctigenin.

In traditional Chinese medicine, A. lappa has been employed to treat a range of ailments, including sore throats, infections, and inflammatory conditions, underscoring the ethnomedical significance of arctigenin. The ethnopharmacological applications of arctigenin are extensive due to its diverse and potent biological activities. It has garnered significant attention for its antiinflammatory, anti-oxidant, anti-viral, and anti-cancer properties, making it a promising candidate for the development of novel therapeutic agents. Arctigenin’s anti-inflammatory effects are particularly noteworthy. Research indicates that arctigenin can effectively inhibit the production of pro-inflammatory cytokines and mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2). This inhibition is primarily achieved through the suppression of nuclear factor-kappa B (NF-κB) activation, a critical regulator in the inflammatory response [15]. Moreover, arctigenin has been shown to modulate oxidative stress pathways, contributing further to its anti-inflammatory properties. It reduces the levels of reactive oxygen species (ROS) and enhances the activity of antioxidant enzymes, thereby mitigating oxidative damage and inflammation [16]. These dual actions of reducing inflammation and oxidative stress position arctigenin as a valuable agent in treating chronic inflammatory diseases.

Mechanistic Aspect of Arctigenin

Arctigenin exhibits significant anti-inflammatory properties by targeting multiple inflammatory pathways. It inhibits nuclear factor kappa B (NF-kB) activation in lipopolysaccharide (LPS)- or peptidoglycan (PGN)-stimulated peritoneal macrophages, decreasing the expression of pro-inflammatory cytokines as Interleukin-1-beta (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) [17-19], while increasing Interleukin 10 (IL10) and CD204 levels [20]. Additionally, arctigenin inhibits LPSinduced phosphorylation of phosphoinositide 3-kinase (PI3K), Ak strain transforming (AKt), and IKK-β, but not interleukin-1 receptor-associated kinase 1 (IRAK-1) phosphorylation [21]. It also suppresses the nuclear translocation of NF-kB p65 and the binding of PI3K antibody in LPS-stimulated macrophages. In systemic inflammation models, arctigenin reduces blood levels of IL-1β and TNF-α and mitigates symptoms in trinitrobenzene sulfonic acid (TNBS)-induced colitic mice by regulating various cytokines and signaling pathways [22]. Arctigenin blocks LPSinducible nitric oxide synthase (iNOS) expression by inhibiting I-kBa phosphorylation and the nuclear translocation of p65, contributing to its anti-inflammatory effects [23]. It also inhibits activator protein 1 (AP-1) binding and TNF-α production in LPSexposed cells [24], significantly reducing NF-kB DNA binding and phosphorylation of IkB and IKK [25]. Arctigenin modulates immune responses by regulating TNF-α and nitric oxide production and lymphocyte proliferation [26]. In LPS-stimulated RAW264.7 cells, arctigenin reduces the phosphorylation of the signal transducer and activator of transcription 1 (STAT1), signal transducer and activator of transcription 3 (STAT3), and Janus kinase 2 (JAK2) [27]. It decreases iNOS phosphorylation by inhibiting extracellular signal-regulated kinase (ERK) and Src activation, thereby suppressing iNOS enzyme activity [28]. Inactivated human T lymphocytes, arctigenin inhibits proliferation, interleukin-2 (IL-2), and interferon‐gamma (IFN‐γ) production and decreases NF-AT-mediated reporter gene expression [29]. Additionally, it impacts AKT and protein kinase C (PKC) expression, affecting downstream genes like NF-κB and Mitogen-activated protein (MAP) kinases [30]. Arctigenin also alleviates LPS-induced acute lung injury by downregulating NF-κB p65 and promoting the phosphorylation of IκBα and adenosine monophosphate-activated protein kinase (AMPKα) activation [31]. It enhances heme oxygenase-1 expression and decreases MAPK phosphorylation [32]. In colonic tissues, it reduces inflammatory cell infiltration and downregulates multiple inflammatory markers [33]. In TNBS-induced colitis, arctigenin lowers levels of TNF-α and IL-6, while increasing IL-10 levels, promoting neuronal survival [34]. It inhibits the differentiation of T helper 17 (Th17) and Th1 cells and suppresses the mammalian target of the rapamycin complex 1 (mTORC1) pathway in T cells using Electrophoretic mobility shift assay (EMSA) and Western blotting, respectively [35]. Furthermore, arctigenin inhibits NFκB signaling in porcine circovirus 2 (PCV2) infection, reducing inflammatory cell infiltration and cytokine expression [36,37]. It protects against liver necroinflammation and enhances IL-10 production, thereby improving hepatic function [38]. Arctigenin also safeguards tubular epithelial cells from transforming growth factor-beta (TGF-β1)-induced changes by inhibiting the ROS/ ERK1/2/NF-κB pathway [39]. Lastly, it ameliorates psoriatic manifestations in an imiquimod-induced murine model by reducing inflammatory cell adhesion and chemotaxis [40].

Table 1: Summary of preclinical studies on arctigenin’s anti-inflammatory effects and its impact on inflammatory markers.