Both CM and CI belong to the Compositae family and are utilized both medicinally and for environmental applications. The dried flower heads of CM are commonly utilized as medicinal parts for treatment, while both the dried flower heads and whole plants of CI serve as primary medicinal components for treating various diseases. To better differentiate between CM and CI, we conducted a macroscopic identification, as detailed in Table 1.

CM (Juhua) has been utilized in China for over 3,000 years, with historical records dating back to the Qin and Han dynasties (Liang et al., 2014). It was introduced to Japan during the Tang Dynasty (AD 710–784) as a highly regarded spice and subsequently spread Europe and the United States in the 17th century (Li, 1993). The genus CM comprises 41 species, which are widely distributed across Asia, including Mongolia, Russia, China, Japan, and Korea, as well as eastern Europe (Chen et al., 2020; Committee FoCE, 1983). In China, excluding Tibet and the Northwest regions, approximately 21 species are predominantly found in humid areas at middle and low altitudes (Chen et al., 2020). The botanical morphological characteristics of CM are described as follows: 1) Life form: Perennial herb. 2) Stem: Erect, either branched or unbranched, covered with pubescent. 3) Leaves: Ovate to lanceolate in shape, measuring 5–15 cm in length, pinnately lobed or semi-lobed, short-petioled, and white pubescent on the underside. 4) Flowers: The capitulum ranges from 2.5 to 20 cm in diameter. The involucrum consists of multiple layers, with the outer layer being pilose. The ray florets exhibit a variety of colors, whereas the disk florets are yellow. 5) Fruits: Achenes measure approximately 1.3 mm in length, slightly pointed at the apex, flat-wedge shaped, longitudinally ribbed on the surface, and brown in color (Committee FoCE, 1983).

The application of CI (Yeju) in TCM can be traced back to the Qin and Han dynasties (Chen Caiying et al., 2015). The native range of CI includes China, the Eastern Himalayas, Inner Mongolia, Japan, South Korea, Nepal, etc. Additionally, it has a broad distribution across various Asian countries, as well as in several European and South American nations (Committee FoCE, 2011). This plant thrives in wide range of habitats, from grasslands on mountain slopes and thickets to wet areas near rivers, fields, roadsides, saline zones by seashores, and under scrub, typically at altitudes ranging from 100 to 2,900 m (Committee FoCE, 2011). The botanical morphological characteristics of CI are as follows: 1) Life form: Perennial herb. 2) Stem: Long or short procumbent rhizomes, with erect or diffuse stems that branch and are sparsely pilose; lower leaves senesce by anthesis. 3) Leaves: Middle stem leaves have petioles measuring 1–2 cm, with leaf blades ovate to long-ovate or elliptic-ovate, ranging from 3–7 (-10) × 2–4 (-7) cm. Both surfaces are pale green or olive-green, with the adaxial surface being sparsely pubescent and the abaxial surface less densely. The leaves are pinnatifid, pinnatilobed, or inconspicuously divided, with a truncate, somewhat cordate, or broadly cuneate base. 4) Flowers: The synflorescence is a lax terminal flat-topped cyme, bearing numerous or few capitula. Phyllaries are arranged in 5 rows, featuring broad scarious margins that are white or brown, with obtuse or rounded apices. Outer phyllaries are ovate or ovate-triangular, measuring 2.5–3 mm, while middle phyllaries are ovate at 6–8 mm, and inner phyllaries are narrowly elliptic, approximately 1.1 cm. Ray floret laminae are yellow, measuring 1–1.3 cm, with entire or 3-denticulate apices. 5) Fruits: Achenes measure 1.5–1.8 mm (Committee FoCE, 2011). (Figure 1).

CM has a long history as a TCM. The earliest record of CM can be traced back to the Shennong’s Herbal Classic, which described its taste as bitter and neutral, and indicated its primary use for dizziness and pain caused by wind, and other conditions. The Mingyi Bielu noted CM tastes sweet and is non-toxic. According to The Compendium of Materia Medica, Juhua is widely believed to dispel wind-heat, benefit the liver, and tonify Yin”. A Qing Dynasty doctor, Xu Dachun, recorded that prolonged consumption of Juhua can tonify blood and Qi, enhance physical wellbeing, and promote longevity. Since Juhua can survive for a long time, there is a belief that consuming it can extend human life. ChP recorded that CM disperses wind and clears heat, pacifies the liver and brightens the eyes, and detoxifies. Clinically, it is used to treat wind-heat colds, headaches and dizziness, red and swollen eyes, diminished eyesight, sores, and abscess swelling (Commission CP, 2020). CM is extensively utilized in TCM, particularly as a primary ingredient in TCM prescription formulations such as Sangju Ganmao Wan, Huanglian Shangqing Wan, and Jinsang Kaiyin Wan. The 2020 edition of the ChP lists 1605 TCM formula and single-botanical drug preparations, among which 55 containing CM, accounting for approximately 3.4% of the total (Commission CP, 2020).

There are limited records of CI in ancient medical literature. The earliest record of CI can be traced back to the Sheng Nong’s herbal classic and it was recorded as “Jiehua” (Chen Caiying et al., 2015). In the Bencao Qiuzhen, CI is described as having the properties of “entering the lung and liver meridians”. The Bencao Huiyan noted: “CI has a bitter taste, is cold in nature, and slightly toxic. It functions to break up blood stasis, soothe the liver, and detoxify whitlow. Additionally, it can be used as a douche for scabies to dispel wind and kill parasites”. The 2020 edition of ChP recorded that CI has the functions of clearing heat, detoxifying, purging fire, and pacifying the liver, and clinically, it is used to treat conditions such as whitlow, sores, abscesses, and swelling, as well as symptoms like redness of the eyes, headache, and dizziness (Commission CP, 2020). The 2020 edition of ChP includes 16 TCM formula preparations containing CI (Commission CP, 2020). Table 2 provides details on the utilization of CM and CI as monarch medications.

CM and CI extracts exhibit potent antimicrobial effects, demonstrating potential to inhibit a wide range of microorganisms including bacteria, fungi, viruses, mycobacteria, and parasite and others (Kuang et al., 2018; Liu et al., 2022; Youssef et al., 2020; Shunying et al., 2005; Gu et al., 2013; Zhang et al., 2020; Akihisa et al., 2005; Lee et al., 2003). The differences in the types of inhibited microorganisms between CM and CI may be attributed to variations in their primary compounds, such as terpenoids and flavonoids.

When an infection occurs, the immune system initiates an inflammatory response to combat invading pathogens (Zhang and Wang, 2014). However, excessive or prolonged inflammation can cause tissue damage and exacerbate disease severity. In severe cases, uncontrolled inflammation may lead to sepsis, widespread tissue injury, and organ failure (Esposito et al., 2017). Reducing inflammation can mitigate pathogen-induced tissue damage and bodily discomfort. Studies have shown that both CM and CI extracts exhibit significant anti-inflammatory effects by modulating inflammation-related pathways (Liu et al., 2020; Lee et al., 2021; Zhou et al., 2023; Yu et al., 2019; Zeng et al., 2020; Wu et al., 2014; Lee et al., 2009; Cheon et al., 2009).

CM and CI extracts demonstrated potential efficacy in treating acute lung injury (ALI). In a mouse model of lipopolysaccharide (LPS)-induced, both extracts significantly alleviated lung histopathological damage, reduced the wet-to-dry lung weight ratio and lung injury score, and were associated with decreased levels of pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF)-α (Liu et al., 2020; Wu et al., 2014). CM extract can attenuate the production of pro-inflammatory cytokines (such as IL-6 and TNF-α), enhance the secretion of anti-inflammatory cytokines (including transforming growth factor-β1 (TGF-β1) and IL-10), and mitigate the oxidative stress by increasing total antioxidant capacity (TAC) and reducing malondialdehyde (MDA) levels in mice with ALI. However, the precise mechanisms underlying these effects remain to be elucidated (Liu et al., 2020). The therapeutic efficacy of CI may be attributed to its ability to downregulate both the Toll-like receptor 4 (TLR4) and MyD88-dependent NF-κB signaling pathways (Wu et al., 2014).

The other TLR4 signaling pathway is MyD88-independent and TRIF-dependent, leading to the phosphorylation and nuclear translocation of IRF3. A newly discovered compound, bisepoxylignan dendranlignan A (BDA), isolated from CM, has been shown to reduce the production of inflammatory cytokines TNF-α, IL-2, and interferon (IFN)-γ in LPS-stimulated H9c2 cells (Zeng et al., 2020). BDA significantly decreased the nuclear translocation and phosphorylation levels of IRF3, the NF-κB heterodimer component p65, and one of the AP-1 components, c-Jun. However, it did not significantly affect the protein expression of TLR4, MyD88, or TRIF, suggesting that BDA inhibits TLR4 signaling downstream of these proteins (Zeng et al., 2020). Additionally, molecular docking studies revealed that BDA can occupy the ligand-binding site of the TLR4-MD2 complex, indicating that it may inhibit inflammation by blocking the TLR4 signaling pathway (Zeng et al., 2020).

Hyaluronidase (HAase) is an endoglycosidase important for the metabolism of hyaluronic acid (HA), a linear acidic mucopolysaccharide. HAase plays a significant role in inflammation by enhancing the production of cytokines IL-1β and TNF-α by macrophages, as well as their allostimulatory capacity (Sudha and Rose, 2014; Jiang et al., 2011; Termeer et al., 2000). Studies have found that inhibiting HAase can prevent HA degradation, thereby mitigating inflammatory responses (Shibata et al., 2002). For example, in an in vitro inflammatory model, Zhou et al. (2023) reported that CM extract dose-dependently inhibited HAase activity. Further screening identified four compounds 56, 61, 62 and 63 as the key inhibitors, and these compounds significantly reduced the production of inflammatory mediators nitric oxide (NO) and IL-6, and suppressed the mRNA expression of inducible NO synthase (iNOS) and IL-1β in both mouse and human macrophages.

In addition, the anti-inflammatory mechanism of CI may be associated with the regulation of apoptosis-associated speck-like protein (ASC) phosphorylation and the MAPKs and NF-κB-dependent signaling pathways (Yu et al., 2019; Cheon et al., 2009). For instance, in vivo studies have demonstrated that CI can inhibit the recruitment of total cells and Ly6G⁺/F4/80^- neutrophils as well as reduce the secretion of inflammatory cytokines in peritonitis mice. In vitro, CI has been shown to inhibit the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR)3 and the HIN-200 family member absent in melanoma 2 (AIM2) inflammasomes, leading to decreased production of IL-1β and caspase-1 (Yu et al., 2019). The phosphorylation of ASC regulates the activity of inflammasomes such as NLR3 and AIM2 inflammasomes through the formation of ASC specks (Hara et al., 2013). In studies, treatment with CI resulted in reduced translocation formation and inhibited phosphorylation, while JNK phosphorylation was not implicated in this pathway (Yu et al., 2019). Given that JNK phosphorylation is recognized as an upstream regulator of ASC phosphorylation (Hara et al., 2013), the observed effects may be associated with the modulation of ASC phosphorylation. However, the specific pathway through which this occurs remains to be elucidated.

LPS can activate a signaling pathway involving mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK1/2 and p38MAPK (Moens et al., 2013). MAPKs inhibitors have been shown to suppress the regulation of iNOS and cyclooxygenase (COX)-2 genes (Kim and Kim, 2005). Overexpression of iNOS and COX-2 leads to NF-κB activation, resulting in increased production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), which exacerbates inflammatory responses (D'Acquisto et al., 1997). CI extract significantly inhibited the LPS-induced production of inflammatory mediators NO and PGE₂, as well as inflammatory cytokines TNF-α and IL-1β, in RAW 264.7 macrophages in a dose-dependent manner (Cheon et al., 2009). Additionally, CI extract suppressed the mRNA and protein expression of iNOS and COX-2. Further studies revealed that CI can inhibit the nuclear translocation of NF-κB p65 subunits by preventing IκBα phosphorylation and also inhibit the phosphorylation of ERK and JNK, suggesting that the anti-inflammatory effects of CI are mediated through both MAPK and NF-κB pathways (Cheon et al., 2009). More details are provided in Table 5.

Treating oxidative imbalance is crucial in the management of infectious diseases (Ashique et al., 2025). Reactive oxygen species (ROS), which are by-products of cellular metabolism, exhibit a dual nature: they are beneficial to cells at low concentrations but become detrimental at high levels (Sander et al., 2022). For instance, ROS contribute to pathogen destruction; however, their excessive accumulation can induce damage to cellular components such as lipids, proteins, and DNA (Sander et al., 2022). Moreover, overproduction of ROS leads to oxidative stress, resulting in bodily damage, various disease states, impaired immune function, and exacerbated inflammatory responses. This creates a vicious cycle that hinders recovery (Ashique et al., 2025). In contrast, inflammation can result in the recruitment of intravascular neutrophils to the alveolar space and lung parenchyma (Looney et al., 2006), leading to the subsequent release of proteases and generation of ROS. Moreover, ROS are closely associated with lipid peroxidation products such as myeloperoxidase (MPO) and MDA, as well as the modulation of antioxidant enzyme activities, including SOD, CAT, and GPX (Looney et al., 2006). Antioxidants can neutralize ROS, thereby protecting cells from oxidative damage and enhancing the immune system’s ability to combat infections effectively. Essential oils derived from CM and CI exhibit potential as natural preservatives due to their antioxidant properties (Lii et al., 2010; Zheng et al., 2015; Zhan et al., 2022; Hao et al., 2021; Lin et al., 2010; Tian et al., 2019; Zhang et al., 2019; Kim et al., 2017).

CM extract and its flavonoids, apigenin and luteolin, exhibit potent antioxidant properties by resisting oxidative stress (Lii et al., 2010; Zhan et al., 2022; Hao et al., 2021). They enhance the levels of antioxidant enzymes such as SOD, CAT, and GPX, upregulate the expression of the antioxidant gene heme oxygenase-1 (HO-1), and decrease the production of reactive oxygen species (ROS), MDA, MPO, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals (Lii et al., 2010; Zheng et al., 2015; Zhan et al., 2022; Hao et al., 2021; Lin et al., 2010; Tian et al., 2019). Moreover, CM can inhibit cell apoptosis, modulate cell cycle progression, and reduce the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase (PARP) (Zheng et al., 2015; Hao et al., 2021; Tian et al., 2019). Further studies suggest that these effects may be mediated through several signaling pathways, such as arginine and purine metabolism, phosphatidylinositol 3-kinase (PI3K)/Akt, PI3K/Akt-mediated nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1, and Nrf2 signaling pathways (Lii et al., 2010; Zhan et al., 2022; Hao et al., 2021; Tian et al., 2019).

CI also exhibits comparable antioxidant effects to CM, such as significantly enhancing the activities of antioxidant enzymes (Zhang et al., 2019; Kim et al., 2017). In addition, CI could not only inhibit the increased Bax/Bcl-2 ratio and activation of cleaved caspase-3 in the liver and brain but also reduce the levels of inflammatory cytokines, including IL-1β, IL-6, and TNF-α (Zhang et al., 2019). Furthermore, studies have found that both CM and CI exhibit peak antioxidant capacity when heated at 100°C for 45 min (Yu et al., 2023). Detailed information is provided in Table 6. Moreover, the anti-inflammatory effects of CM and CI are discussed in Section 3.2, while their antioxidant properties are summarized in Table 5 (Liu et al., 2020; Lee et al., 2021; Wu et al., 2014; Lee et al., 2009).

The immune system responds to exogenous factors encountered by the body and employs defense mechanisms to counteract these challenges. For instance, LPS, a major component of the outer membrane of Gram-negative bacteria, can bind to TLR4 and activate the MyD88-mediated NF-κB signaling pathway, ultimately leading to inflammatory responses (Hamad et al., 2023). Consequently, LPS is frequently utilized to induce inflammatory models in experimental settings. Moreover, abnormal immune responses are prevalent in infectious diseases such as influenza and COVID-19 (Han et al., 2018; Chen et al., 2024). Furthermore, with the increasing prevalence of antibiotic resistance, immunomodulatory agents have emerged as promising alternatives for treating infectious diseases (Yang et al., 2017). Studies have shown that CM polysaccharides and the butanol-soluble fraction of CI exhibit immunomodulatory effects and hold potential as therapeutic agents for infectious diseases (Xie et al., 2009; Sun et al., 2012; Liang et al., 2014; Li, 1993).

Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by dysregulation of multiple immune-related pathways and cells, including the NF-κB signaling pathway, helper T (Th) cells, and regulatory T (Treg) cells (Chen et al., 2020; Committee FoCE, 1983; Chen Caiying et al., 2015; Committee FoCE, 2011). Numerous studies have demonstrated that inflammatory cytokine genes involved in IBD pathogenesis, such as IL-1β, IL-2, TNF-α, and IL-6, contain NF-κB binding sites and are transcriptionally regulated by NF-κB (Chen et al., 2020; Committee FoCE, 1983). Recent research has shown that CM polysaccharides can mitigate intestinal pathological changes in colitis rats, reduce levels of inflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β), and alleviate oxidative stress responses (e.g., SOD and MPO). Furthermore, these effects are associated with decreased mRNA expression levels of TLR4, Janus kinase (JAK)2, and signal transducer and activator of transcription (STAT)3, as well as reduced protein levels of p65, TLR4, p-STAT3, and p-JAK2. Additionally, improvements were observed in the metabolic profiles of plasma and urine (Xie et al., 2009). All these findings indicate that the NF-κB/TLR4 and IL-6/JAK2/STAT3 signaling pathways play a role in the mechanism by which CM exerts its effects on IBD. Further studies have demonstrated that CM polysaccharides can reduce the production of pro-inflammatory cytokines and promote the production of anti-inflammatory cytokines by regulating the imbalance between Th1/Th2 and Th17/Treg (Sun et al., 2012). Additionally, improvements in gut microbiota have also been observed (Sun et al., 2012). However, while the effects of CM polysaccharides on IBD have been extensively studied, the depth of investigation is limited. Consequently, the specific mechanisms remain unclear, particularly regarding the rigorous validation of the signaling pathways involved.

Moreover, the immunomodulatory abilities of polysaccharides from different varieties of CM vary. Wang et al. (2022) investigated the immunomodulatory effects of polysaccharides from five cultivars: Qiju, Gongju, Boju, Hangbaiju, and Huaiju. The study found that all these polysaccharides could enhance the phagocytosis and proliferation of RAW264.7 cells without significant cytotoxicity, and upregulate the release of TNF-α, IFN-γ, and NO. Notably, polysaccharides from Boju and Hangbaiju exhibited superior immune-enhancing activities, making them more suitable for developing functional foods aimed at boosting immunity. These findings provide a reference for selecting appropriate varieties based on specific immune requirements, which are related to their relative molecular mass, glucuronic acid and arabinose content, and microstructure (Wang et al., 2022). Additionally, the potential role of these polysaccharides as vaccine adjuvants is currently under investigation (Han et al., 2021).

Additionally, the butanol soluble fraction of CI exhibited a significant inhibitory effect on dimethylbenzene-induced ear edema in mice and markedly enhanced the 2, 4-dinitro-fluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) response (Cheng et al., 2005). Furthermore, CI was found to elevate the levels of sheep red blood cell (SRBC) antibodies, serum IgG, and IgM, while significantly enhancing the phagocytic function of monocytes in cyclophosphamide (CP)-induced immunosuppressed mice (Cheng et al., 2005). These findings indicate that CI possesses anti-inflammatory properties, as well as humoral and cellular immunomodulatory activities, including enhancement of mononuclear phagocytic function. The presence of flavonoids (53%) may contribute to these effects (Cheng et al., 2005).

Although the diseases examined in the aforementioned studies are not infectious in nature, the findings indicate that CM and CI possess certain immunomodulatory effects, which hold significant reference value for the subsequent management of infectious diseases. Further details are provided in Table 7.

In the acute toxicity study, a single oral dose of 15 g/kg body weight (bw) CM extract was administered to rats, then the rats were observed for 14 days. No treatment-related death was observed, and the maximal tolerance dose estimated was greater than 15 g/kg bw in rats. For long-term toxicity studies, rats were given daily intragastric doses of 320, 640, and 1,280 mg/kg bw/day for 26 weeks, followed by a 4-week recovery period (Li et al., 2010). The results showed that there were no toxicological changes in body weight, food intake, water intake, blood biochemistry, organ weight and histopathological examination in each treatment group. Thus, CM extract is generally safe for rats at limited dose levels. Dosage of annotation in the ChP for 5–10 g (Commission CP, 2020).

Different doses of CI extract prepared in saline were given orally to groups of 10 mice. For 30 days subsequent to treatment, the animals were observed daily, and dead animals were subjected to postmortem examination for determination of the cause of death. No animals died during the acute toxicity test, nor were any adverse effects detected in animals treated with different doses of CI extract. This indicates that CI extract was nearly nontoxic in mice up to an oral dose of 2.0 g/kg body weight (Lee et al., 2009). No studies have investigated the long-term toxicity of CI. Dosage of annotation in the ChP for 9–15 g (Commission CP, 2020). In addition to oral administration, it can also be used for external use, decoction for washing or paste for external application.