Flavonoids are characteristic secondary metabolites in JHC and show significant structural diversity in chemical taxonomy and biological activity. The flavonoids identified to date mainly include Flavonols (1–3), Flavanols (5–8), Biflavonoids (16), and their derivatives (Fig. 4). The highest content is catechin (39.31%) and quercetin (38.20%) [14]. From the perspective of structural characteristics, this type of component typically has the following substitution patterns: hydroxyl substitution at the C-5 position of the parent nucleus A ring (1–10), with the B ring mainly characterized by a single hydroxyl substitution (19, 23–28). In terms of glycosylation modification, the flavonoids in JHC mostly exist in the form of glycosides (18–60) (Fig. 5), with their glycosylation connection sites showing obvious regularity. The C-3 hydroxyl group often forms $\beta$-configuration side bonds with hexose sugars, e.g., glucose and galactose (18–34), while the C-7 hydroxyl group tends to be different from monosaccharides or disaccharides (35–41). This differentiated sugar group substitution pattern has a significant impact on molecular polarity. From the perspective of structure-activity relationships, the $\alpha$,$\beta$-unsaturated ketone conjugated system formed by the 2,3-position double bond of the C ring of the flavonoid parent nucleus with the 4-position carbonyl group (1–4, 16) can effectively stabilize the free radical intermediate through $\pi$-$\pi$ stacking. This constitutes the core pharmacophore of antioxidant activity.

For instance, the antioxidant activity of Quercetin (1) is primarily attributed to the $\alpha$,$\beta$-unsaturated ketone conjugated system formed by the double bond at the 2,3-position and the carbonyl group at the 4-position, as well as the 3^′,4^′-ortho-dihydroxyl group in the B ring. Additionally, the hydroxyl groups at the 5-position and 7-position in the A ring and the free hydroxyl group at the C-3 position play a significant regulatory role in electron delocalization, metal chelation, and stabilization of free radicals. The antibacterial activity of Quercetin is mainly due to the insertion of its hydrophobic flavonoid backbone into bacterial cell membranes, resulting in membrane disruption, along with enzyme inhibition mediated by the diphenolic hydroxyl group on the B ring, and interference with bacterial biofilm formation by the entire molecular structure. The antioxidant activity of kaempferol (2) is largely derived from the catechol-like structure in the B ring and the conjugated system involving the C2=C3 double bond, which enables efficient scavenging of free radicals and stabilization of phenoxyl radicals. Its antibacterial properties are associated with the molecule’s hydrophobicity, the positioning of phenolic hydroxyl groups, and molecular planarity—features that facilitate disruption of microbial membrane integrity and inhibition of essential enzymatic activities. The primary antioxidant capacity of (-)-Catechin (5) and (+)-catechin (6) is rooted in the 3^′,4^′-dihydroxyl configuration on the B ring [15]. Their antibacterial effects are predominantly mediated through a synergistic interaction between this catechol moiety and the overall hydrophobic character of the molecule, acting via mechanisms including induction of oxidative stress, metal ion chelation, and perturbation of cellular membranes.

3.1.1 Flavones

Fig. 4.

Flavones compounds in JHC.

3.1.2 Flavone Glycosides

Fig. 5.

Flavone glycosides in JHC.

The above-mentioned structural specificity establishes chemical classification markers for JHC, e.g., the combined characteristics of C-5 hydroxyl-substituted flavonols and B-ring monohydroxylation mode. More importantly, it also provides a clear molecular framework for the targeted structural modification of flavonoid components. Based on existing structure-activity relationships, the lipophilicity and bioavailability of JHC can be regulated through strategies such as directed glycosylation/acylation and selective hydroxyl protection, while its antioxidant efficacy can be enhanced through the design of metal chelating sites. This lays a solid chemical foundation for the development of new flavonoid functional molecules.

The structural diversity and chemical characteristics of terpenoids in JHC have become an important direction in phytochemical research. From the perspective of biosynthesis, the molecular skeletons of terpenoids all originate from the directional polymerization and c-ring modification of isoprene units. Moreover, their structural complexity increases significantly as the degree of polymerization increases.

Monoterpenoids are based on the head-tail connection of two isoprene units and form various types of skeletons through different cyclization mechanisms. These include acyclic monoterpenoids (61–68), which have characteristic terminal allyl alcohol groups within their molecules, as well as monocyclic and iridoid glycosides (69–76) (Fig. 6). The structural characteristics of sesquiterpenes are reflected in their unique ring system combinations and oxidation modification sites. Their skeletal structure includes chain-like and single-ring sesquiterpenoids (77–88), and bicyclic sesquiterpenes (89–100) (Fig. 7). The sesquiterpene components undergo oxidation at C4, C7, or C11 positions to form polar groups such as hydroxyl, ketone, or epoxide groups, highlighting their structural diversity. Triterpenoids are characteristic secondary metabolites of higher plants and exhibit a significant structural evolution from linear to highly cyclized. They are typically represented by the oleane-type pentacyclic system (102–103), with the carboxyl group at the C17 position often forming an ester bond with a sugar group to constitute a saponin (116–123) (Fig. 8). The diverse structures of terpenoids in JHC not only reveal the biosynthesis rules of its secondary metabolites, but also provide a theoretical basis at the molecular level for further in-depth development of its medicinal value.

3.2.1 Monoterpenoids

Fig. 6.

Monoterpenoids in JHC.

3.2.2 Sesquiterpenes

Fig. 7.

Sesquiterpenes in JHC.

3.2.3 Triterpenoids

Fig. 8.

Triterpenoids in JHC.

The aglycone types of steroidal saponins are based on cholestane and stigmastane as the basic framework (132–133). The hydroxyl group at the C-3 position is combined with the sugar chain through glycosidic bonds. The length of the sugar chain ranges from monosaccharides to disaccharides (134–136) (Fig. 9). The structural diversity provides a key molecular basis for the classification of chemical components and the evolution of secondary metabolic pathways in JHC.

Fig. 9.

Steroids in JHC.

The phenylpropyl compounds in JHC include three major structural types: phenylpropionic acid, coumarin, and lignan. Their molecular characteristics show systematic chemical diversity. The phenylpropionic acid class is based on the C6-C3 type phenylpropane skeleton, and its core compounds include cinnamic acid and its ester derivatives (137–139). Coumarins have the benzo $\alpha$-pyranone parent nucleus as the core (140–141, 145, 147), with some molecules undergoing isoprene formation at the C5/C8 position. Lignans form a dibenzylbutane-type (142–143) skeleton through the connection of phenylpropyl units, and some contain lactone rings or glycoside modifications (145–149) (Fig. 10). This type of structural system has led to a unique chemical map of the secondary metabolites of JHC through multi-dimensional modifications such as hydroxylation, methoxylation, cyclization, and glycosylation.

Fig. 10.

Phenylpropanoids in JHC.

Other compounds have also been found in JHC, including essential oils (150–163) (Fig. 11), organic acid (164–168) (Fig. 12), long-chain fatty acids and their glycosides (169–177) (Figs. 13,14), as well as alkaloids.

3.5.1 Essential Oils

Fig. 11.

Essential oils in JHC.

3.5.2 Organic Acid

Fig. 12.

Organic acid in JHC.

3.5.3 Long-Chain Fatty Acids

Fig. 13.

Long-chain fatty acids in JHC.

3.5.4 Alkaloids

Fig. 14.

Alkaloids in JHC.

Multiple studies have confirmed that JHC exerts inhibitory effects on various human cancers such as lymphoma, esophageal squamous cell carcinoma, gastric cancer, lung cancer, colon cancer, and liver cancer. This function is related to various components in JHC, such as flavonoids, terpenoids, polyphenols, saponins, and polysaccharides (Table 2, Ref. [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]).

A new flavonoid glycoside extracted from JHC (quercetin 7-O-[600-O-E-caffeoyl]-B-D-glucopyranoside) could enhance the activity of caspase-3 in human lymphoma U937 cells and induce their apoptosis [46]. The water extract of JHC can inhibit the growth of human esophageal squamous cell carcinoma cells (Eca109) in the G0/G1 phase and induce apoptosis of these cells [18]. The n-Butanol extract of JHC (JHC-4) was found to significantly inhibit the proliferation of human gastric cancer cells and induce autophagy. As an autophagy agonist, JHC-4 could synergically increase the sensitivity of gastric cancer cells to paclitaxel, while significantly enhancing the growth inhibitory effect of paclitaxel by inducing autophagy and apoptosis. The synergistic anti-proliferative effect of JHC-4 and paclitaxel was related to the PI3K/Akt/mTOR signaling pathway [21]. Hou et al. [47] analyzed the components of JHC and screened their anti-tumor activity. They identified a new oleane-type triterpene, A1-barrigenol22a-angelate, that has strong anti-tumor activity and can induce apoptosis and significantly inhibit the proliferation of the EGFR-mutant lung cancer cell line NCI-H1975. Wang et al. [48] found that polyphenols and saponins present in JHC have a significant inhibitory effect on non-small cell lung cancer (NSCLC) cells through cytokine-cytokine receptor interaction and the PI3K-Akt and MAPK signaling pathways. The key targets through which JHC exerted its anti-tumor effects in vitro were TGFB2 (Transforming Growth Factor Beta 2), INHBB (Inhibin Subunit Beta B), PIK3R3 (Phosphatidylinositol-3-Kinase Regulatory Subunit 3), ITGB8 (Integrin Subunit Beta 8), TrkB (Tropomyosin Receptor Kinase B), and CACNA1D (Calcium Voltage-Gated Channel Subunit Alpha1 D).

Zhou et al. [22] reported that JHC can cause G0/G1 and S phase cell cycle arrest, increase intracellular ROS levels, promote the expression of apoptotic proteins Bax and Caspase-3, and simultaneously regulate the expression of core proteins EGFR (Epidermal Growth Factor Receptor), SRC (Proto-Oncogene Tyrosine-Protein Kinase Src), and AKT, thereby inhibiting lung cancer cells by inducing apoptosis. Li et al. [23] confirmed that the n-butanol and water extracts of JHC could significantly reduce the incidence of colon cancer in a mouse model of colitis generated by the injection of azomethane oxide (AOM) and sodium dextrin sulfate (DSS). Studies have confirmed that JHC mainly inhibits the development of colon cancer by increasing the activities of antioxidant enzymes (CAT (Catalase), SOD (Superoxide Dismutase)) in serum, reducing the level of lipid peroxidation product (MDA (Malondialdehyde)), and regulating multiple pathways such as glycolysis, amino acid metabolism, oxidative stress, and nucleic acid metabolism.

Chen et al. [25] found that a JHC extract regulates multiple pathways in colon cancer cells, including apoptosis, cell cycle, and ferroptosis. This extract exerts its anti-colon cancer effect by regulating the expression of GPX4 (Glutathione Peroxidase 4), HO1 (Heme Oxygenase 1), SLC7A11 (Solute Carrier Family 7 Member 11), FTH1 (Ferritin Heavy Chain 1), p53, and ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) proteins. Xu et al. [41] reported that (3$\beta$,6$\alpha$,12$\beta$)-3,6,12-trihydroxydammar-24-en-20-yl-2-O-$\beta$-D-glucopyranosyl-(2$\to$1)-O-$\beta$-D-glucopyranosyl-(2$\to$1)-O-$\alpha$-L-rhamnopyranoside from JHC could inhibit the proliferation and migration of the human hepatoma cell lines Bel-7402 and SMMC-7721. Zhou et al. [26] found that JHC polysaccharides can promote apoptosis (especially early apoptosis), increase the ROS level in hepatoma cells (MHCC-97H and SMMC-7721), up-regulate the expression of Bax and caspase-3, and down-regulate EGFR expression to inhibit the proliferation and migration of these cells.

At present, only a minority of research on the anti-tumor activity of JHC has employed animal models, with most experimental studies being at the in vitro cellular stage. Further animal experiments are needed to confirm the reliability of JHC anti-tumor activity.

Published studies have shown that a JHC extract (CNEF) can lower blood lipids by inhibiting the activities of pancreatic lipase (PL) and cholesterol esterase (CEase). Moreover, water extract (AEC) and ethanol extract (EEC) of the flower can reduce blood lipids by increasing the activities of SOD and GSH-Px(Glutathione Peroxidase), and reducing the level of serum MDA. CNEF inhibited the activities of PL and CEase by simultaneously binding to free enzymes and enzyme-substrate complexes, with the inhibition of PL and CEase being dose-dependent. The median inhibitory concentrations (IC₅₀) of CNEF for PL and CEase were 320 µg/mL and 200 µg/mL, respectively, with the inhibitory effect of CEase being stronger than that of PL. Moreover, CNEF reduced cholesterol absorption by lowering the solubility of artificially prepared cholesterol micelles in a dose-dependent fashion, thereby reducing blood lipids and improving obesity [27]. After treatment of PL with CNEF, the content of $\alpha$-helix decreased, $\beta$-folding and $\beta$-turning increased, and the fluorescence intensity decreased, indicating changes in the conformation of pancreatic enzymes [49].

Animal experiments showed that adding CNEF to a high-fat feed can significantly reduce the food intake of rats in a dose-dependent manner. This indicates that CNEF delays the digestive process by inhibiting the activities of PL and CEase, thereby reducing the body’s food requirements. Compared with the high-fat feed group, fecal excretion of total triglycerides (TG) and total cholesterol (TC) in the high-dose CNEF group increased significantly by 37 $\pm$ 6% and 92 $\pm$ 12%, respectively (p $\le$ 0.01). The increase in TC excretion was significantly higher than that of TG, supporting the conclusion that the inhibitory effect of CNEF was stronger on CEase than on PL [27]. A high-fat diet has been shown to induce the production of free radicals, leading to hypercholesterolemia and oxidative stress. SOD and GSH-Px are two important antioxidant enzymes in the human body. These help to reduce the production of ROS and prevent lipid peroxidation and metabolic intermediates from disrupting normal functions of the body. The occurrence of hyperlipidemia is related to the production of MDA. Low- and high-doses of AEC, as well as high-dose EEC, were found to significantly increase SOD activity in mice fed a high-fat diet. Low-dose AEC, and low- and high-doses of EEC were found to significantly increase GSH-Px activity. High-dose AEC and low- and high-dose EEC significantly reduced the accumulation of serum MDA. Moreover, compared with the lovastatin group, AEC and EEC treatment in mice fed a high-fat diet had no significant effects on SOD and GSH-Px activities, nor on the level of serum MDA [50].

AEC and EEC showed significant differences in lipid-lowering capabilities in cell and animal experiments. Cell experiments showed that AEC has greater potential to prevent fatty liver than EEC. AEC and EEC (both 100 µg/mL) significantly reduced lipid accumulation and TG levels in oleic acid-induced HepG2 cells (Human Hepatocellular Carcinoma G2 cell line), with a stronger effect by AEC. AEC (100 µg/mL) was found to down-regulate the mRNA levels of fatty acid synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and glycerol-3-phosphoacyltransferase in HepG2 cells, whereas EEC (150 µg/mL) only down-regulated the mRNA level of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [29]. Animal experiments showed that high-dose AEC, low- and high-dose EEC, and lovastatin significantly reduced the serum levels of TC, TG, and LDL-C, while increasing serum HDL-C. At the same dose, EEC had a stronger lipid-lowering effect than AEC [50]. The above results indicate that further studies are needed to determine which polar parts or chemical components in JHC have greater lipid-lowering capabilities.

The antioxidant activity of essential oil extracted from JHC leaves was evaluated by Ge et al. [24] through DPPH and ABTS free-radical scavenging experiments. The antioxidant capacity of JHC essential oil, mainly composed of phytolol (58%), geraniol (5.6%), and n-hexanal (3.3%), was significantly stronger than the essential oil, which is mainly composed of linalool (35.8%), phytolol (7.9%), geraniol (7.3%), and methyl salicylate (6.8%). This was the first report on the antioxidant activity of JHC. Wang et al. [51] found that the ethanol extract exhibited strong antioxidant activity close to that of vitamin C due to its rich polyphenol content, which was significantly superior to that of the essential oils. Tian et al. [16] found that the JHC ethanol extract exhibited DPPH and ABTS radical scavenging rates of 84.61% and 95.51%. Currently, the screening of active ingredients in natural products is often time-consuming and labor-intensive. Cheng et al. [30] established an efficient screening method for active ingredients that integrates molecular network multi-data processing technology, chromatographic fingerprinting, and the evaluation of efficacy. The core antioxidant components of JHC (gallic acid, catechins, and salicylic acid) were screened using an HPLC-UV-FLD post-column derivatization system. Based on their structural similarity, seven potentially active components related to active markers were rapidly identified by Molecular Networking analysis. The free-radical scavenging and enzyme protective activities of the novel antioxidant component okicamelliaside were discovered and confirmed for the first time, demonstrating a successful example of the discovery of trace components and offering new ideas for the research and development of active natural products. Wang et al. [31] discovered that 3-cinnamoyltribuloside (3-CT) extracted from JHC could inhibit the production of nitric oxide, as well as the mRNA expression of its key synthetase (iNOS) in LPS-activated RAW 264.7 cells. In addition, through mRNA detection and ELISA analysis, these authors confirmed that 3-CT could inhibit the production of inflammatory factors such as TNF-$\alpha$, IL-1$\beta$, and IL-6.

JHC extract can protect the liver and treat colitis through its antioxidant and anti-inflammatory effects. Zhang et al. [32] found that an extract from JHC leaves could reduce the levels of ALT, AST, and MDA in serum and liver tissue, reduce histopathological damage, inhibit the generation of ROS, and reduce levels of the inflammatory factors TNF-$\alpha$, IL-1$\beta$, and IL-6. Moreover, it could dose-dependently block the phosphorylation of p65 protein, regulate the Nrf2 pathway, and increase the levels of HO1, SOD, and GSH in rats with acute liver injury induced by CCl₄, thereby exerting a protective effect on the liver. Cheng et al. [33] confirmed that JHC extract could significantly increase the activity of alcohol dehydrogenase or aldehyde dehydrogenase, improve the oxidative stress and inflammatory states of the liver, regulate intestinal flora, and protect against acute alcohol exposure. Li et al. [34] found that JHC extract could significantly reduce weight loss in mice with DSS-induced acute ulcerative colitis, maintain colon length, and lower the DAI(Disease Activity Index) score. The effect of high-dose JHC extract was comparable to that of mesalazine. Moreover, the JHC extract could reduce inflammatory cell infiltration and colonic mucosal damage, improve the histopathological score, reduce MPO (Myeloperoxidase) activity and the level of MDA, increase the activities of CAT and T-AOC (Total Antioxidant Capacity), alleviate oxidative damage, inhibit pro-inflammatory factors (NO, PGE2 (Prostaglandin E2), IL-1$\beta$, IL-6, TNF-$\alpha$), and increase the level of the anti-inflammatory factor IL-10. The responsible mechanism involved down-regulating the protein expression of TLR4, p-NF-$\kappa$B p65, and p-I$\kappa$B$\alpha$, and inhibiting the TLR4/NF-$\kappa$B signaling pathway.

Studies have shown that JHC essential oil has inhibitory effects on Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. The dichloromethane extract component (DF) of JH can also significantly inhibit Pseudomonas aeruginosa. Six active components detected by DF, namely gallic acid, catechin, ellagic acid, chlorogenic acid, quercetin, and kaempferol, could all inhibit the production and motility of Pseudomonas aeruginosa, with ellagic acid having the strongest effect [24, 36]. Jiang et al. [37, 52] isolated methyl gallate and 1,2,6-tri-O-galloyl-beta-d-glucose from JHC. Methyl gallate could effectively inhibit the hemolytic, protease, and lipase activities of Aeromonas hydrophila (SHAe 115), weaken its ability to swim and form biofilms, down-regulate positive regulatory genes (ahyR, fleQ), and up-regulate negative regulatory genes (litR, fleN). 1,2,6-tri-O-galloyl-beta-d-glucose inhibited the production of key virulence factors for Proteus penneri (ALK 1200), such as protease and EPS. The cell membrane structure was affected by down-regulating hfq and flhD, and up-regulating bssS, thereby reducing its pathogenicity.Notably, the compound isolated from JHC by Wang et al. [53] did not exhibit significant inhibitory effects on pyocyanin synthesis regulated by quorum sensing in Pseudomonas aeruginosa PAO1.

He et al. [54] reported that the antidepressant activity of the water extract of JHC might be due to the regulation of the hypothalamic-pituitary-adrenal axis and the monoaminergic nervous system. Moreover, they confirmed that JHC extract could effectively antagonize corticosterone-induced neuronal damage. The protective mechanism may involve inhibition of the mitochondrial-mediated apoptotic pathway and activation of the PKA-CREB-BDNF signaling pathway [38]. Tsoi et al. [39] confirmed that JHC extract can significantly improve depressive behaviors in mice by promoting hippocampal neurogenesis. The mechanism of action involves regulating the function of the hypothalamic-pituitary-adrenal axis, promoting serotonin reuptake, and activating the Akt/GSK3$\beta$/CREB signaling pathway.

The therapeutic effect of JHC on diabetes is mainly achieved by inhibiting the formation of advanced glycation end products (AGE) and suppressing the activities of $\alpha$-amylase and $\alpha$-glucosidase. Phenolic substances in JHC can inhibit the formation of AGE by eliminating methylglyoxal. AGE is known to have significant effects on diabetic complications, Alzheimer’s disease, aging, and atherosclerosis [40, 55]. Six new saponins (128, 120–124) were shown to inhibit $\alpha$-glucosidase [42, 56]. Zhang et al. [43] reported that JHC extract could inhibit the activities of $\alpha$-amylase and $\alpha$-glucosidase, with the best inhibitory effect achieved by administering before meals.

Recent studies have demonstrated that luteolin derived from JHC alleviates endoplasmic reticulum stress and mitochondrial dysfunction in rodent models of autism [44]. Ellagic acid has been shown to improve hepatic function in male rats and to mitigate diabetes-induced liver injury [45]. Additionally, Rutin exhibits protective effects against cisplatin-induced oxidative damage in the skeletal muscle tissue of rats [57].