Biological properties and potential application of extracts and compounds from different medicinal parts (bark, leaf, staminate flower, and seed) of Eucommia ulmoides: A review

Abstract

Eucommia ulmoides (E. ulmoides) is a relict plant belonging to the Eucommiaceae family. Each part of E. ulmoides including the bark, leaf, staminate flower, and seed, contains various active ingredients, that are edible and have medicinal value. This review summarizes the literatures on the functional properties of flavonoids, phenols, terpenoids, and polysaccharides in different parts of E. ulmoides. The prospects for application of the different parts of E. ulmoides as functional foods are also discussed. This review provides a reference for further research and development of the medicinal application of E. ulmoides.

Highlights

• •Eucommia ulmoides is a good source of health food and medicine.
• •The extracts and compounds derived from different medicinal parts of Eucommia ulmoides were systematically reviewed.
• •Eucommia ulmoides exhibited beneficial effects on anti-osteoporosis, anti-oxidant, anti-inflammatory, and anti-diabetic.
• •Carrying out clinical research on Eucommia ulmoides is an important research direction in the future.

1. Introduction

Eucommia ulmoides (E. ulmoides) is a rare and endangered Class II protected plant from the Eucommiaceae family that exists in China, and its bark, leaves, staminate flowers, and seeds are edible, and have medicinal value. Research indicates that these parts of E. ulmoides contain a variety of chemical components, including flavonoids, polysaccharides, and other compounds [1,2]. E. ulmoides has various pharmacological effects, including anti-osteoporosis, anti-oxidant, anti-inflammatory, anti-diabetic, immunomodulatory effects, and improved gastrointestinal function and hypoglycemic activity. E. ulmoides is widely used as medicine, healthy food, food additives, and daily chemical supplements [3,4]. However, research on E. ulmoides is limited (Fig. 1). Using existing literatures, this review attempts to summarize the functional characteristics and applications of E. ulmoides (leaf, bark, staminate flower, and seed) which provides a comprehensive view of its benefits to aid future systematic research on its functional applications and promote the development of deep-processing technologies of E. ulmoides in the food industry.

Fig. 1.

The main molecular mechanisms of E. ulmoides. Note: “-”, inhibitory effect; “+”, promoting effect.

2. Methodology and literature search strategy

A literature search was conducted using articles and papers from the CNKI, PubMed, and Web of Science. The search strategy was based on the combination of different keywords, such as Du-Zhong, Eucommia ulmoides, E. ulmoides, Eucommia ulmoides leaf, Eucommia ulmoides bark, Eucommia ulmoides staminate flower, Eucommia ulmoides seed, osteoporosis, inflammation, oxidants, diabetes mellitus, and gastrointestinal function. The literature search results included publications from 1980 to 2023, with the aim of providing a reference for further research and development of medicinal value of different parts of E. ulmoides. The literature screening process is illustrated in Fig. 2.

Fig. 2.

Literature screening flowchart.

3. Anti-osteoporosis of E. ulmoides

Osteoporosis (OP) is a chronic bone metabolic disease that is prone to causing bone fracture. This results from the reduction in bone density and destruction of bone tissue microstructure, and thereby bone strength. It is associated with a high incidence rate and mortality [5]. E. ulmoides inhibits osteoclast differentiation, promotes osteoblast differentiation, reduces calcium loss, and causes estrogenic-like effects [6] (Fig. 3).

Fig. 3.

Anti-osteoporosis of E. ulmoides.

3.1. E. ulmoides bark and its extracts

Dry E. ulmoides bark (EB) is harvested from April to June. As early as the Ming Dynasty, Li Shizhen's “Compendium of Materia Medica (Bencao Gangmu in Chinese)” recorded that the EB benefited qi and strengthened muscles and bones [7]. The proliferation and differentiation of osteoblasts is crucial for bone formation. In vitro experiments showed that EB and its extracts promote osteoblast proliferation and differentiation. The crude extract of EB increases the secretion of alkaline phosphatase (ALP), upregulates type I collagen (Col1) α mRNA and protein expression, and thereby promotes the proliferation and differentiation of osteoblasts [8]. The polysaccharide EuOCP-c isolated from EB promotes the osteogenic differentiation of MC3T3-E1 cells by increasing the expression of the osteogenic differentiation-related proteins RUNX family transcription factor 2 (Runx2), osterix (Osx), osteocalcin (OCN), and osteopontin (OPN) [9]. Ethanol extract from EB enhances the mRNA expression of Rho kinase (ROCK)1, Ras homolog gene family member A (RhoA), OPN, Runx2, and OCN in the RhoA/ROCK signaling pathway in bone marrow mesenchymal stem cells (BMSCs), promoting osteogenic differentiation and proliferation of BMSCs [10]. It also promotes the proliferation and secretion of ALP and osteoprote-gerin (OPG) and the inhibition of nuclear factor κB receptor activating factor ligand (RANKL) secretion, increases the ratio of OPG/RANKL, and exerts a protective effect on MC3T3-E1 subclone 14 osteoblasts [11]. Flavonoids extracted from EB, including astragaloside and scutellarin, promote the proliferation and differentiation of MC3T3-E1 subclone 14 osteoblasts, downregulate the protein expression of RANKL, upregulate the protein expression of OPG and Osx, and restore the OPG/RANKL ratio, thereby exerting an anti-osteoporotic effect [12]. Total lignans from EB induce primary osteoblastic cell proliferation and differentiation, inhibit osteoclastogenesis through an increase in OPG, and decrease RANKL expression in vitro [13].

In vivo studies have confirmed the anti-osteoporotic effects of EB and its extracts. Salted EB granules can reduce the loss of calcium and phosphorus in the urine of rats with ovariectomy (OVX)-induced OP; increase the mRNA and protein expression of OPG, RANKL, and RANK; promote bone formation; and increase bone mineral density (BMD). Moreover, its effect on urinary calcium, phosphorus, and the OPG/RANK/RANKL signaling pathway is more significant than that of alpha-calcitol [14]. Salted EB not only reduces the levels of OPG, type I procollagen amino terminal peptide (PINP), C-terminal peptide of type 1 collagen (CTX), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), but also increases the estradiol (E₂) levels and BMD of the femur and vertebrae, exerting a bone protective effect on rats with retinoic acid-induced OP [15]. It also counteracts OVX-induced osteoporosis by increasing the levels of osteocalcin, OCN, and ALP, reducing tartrate-resistant acid phosphatase (TRAP) activity, and increasing BMD in the whole body, femur, and vertebrae of rats [16]. The EB extract alleviates OP caused by estrogen deficiency by increasing serum phosphorus and reducing IL-6 levels in rats with OVX-induced OP, reducing bone trabecular structure loss, and inhibiting femoral tissue cell apoptosis [17]. It also exerts a bone-protective effect in mice with disuse OP by reducing the levels of bone transition markers and urinary calcium and phosphorus levels, enhancing the biomechanical strength of bone, and preventing the deterioration of trabecular microstructures [18]. The ethanol extract of EB can prevent OP caused by estrogen deficiency and diabetes. Its mechanism of action involves improving the BMD of the femur and tibia in diabetic rats with OVX-induced OP, reducing the levels of serum bone turnover markers ALP, CTX-1, OC, and PINP, and increasing serum calcium, phosphorus, OPG, RUNX2, and the OPG/RANKL ratio [19]. The ethanol extract of EB can also exert bone-protective effects against glucocorticoid-induced osteoporosis in rats by reducing urinary calcium and phosphorus levels, improving femoral biomechanical strength, increasing femoral BMD, the mRNA expression levels of Runx2, ALP, and OPG, and the OPG/RANKL ratio in proximal tibial tissues [20]. The total flavonoids of EB can exert a protective effect on bone tissue by increasing the concentration of PINP, reducing the concentration of type β-I collagen cross-linked carboxyl terminal peptide (β-CTXⅠ) in the serum and the loss of bone minerals and collagen, and inhibiting the decrease in BMD, in rats with OVX-induced OP [21]. Zhang et al. [13] found that lignin from EB significantly prevents an OVX-induced decrease in the biomechanical quality of the femur, such as maximum stress and Young's modulus, inhibiting a decrease in BMD in the femur, reducing the levels of bone transition markers, and inhibiting the deterioration of bone trabecular structure. In vitro evidence suggests that this could be through actions on both osteoblasts and osteoclasts. Quercetin, a flavonoid compound extracted from EB, can reduce urinary Ca and P levels in rats with OVX-induced OP, increase the femoral metaphysis BMD, and the number and thickness of bone trabeculae, and enhance biomechanical indicators such as femoral elastic radius, maximum radius, and elastic load. It can reduce the skeletal muscle index values, improve the bone microstructure, and reduce bone loss, thereby exerting anti-OP effects [22,23]. Song et al. [24] found that acidic polysaccharides in EB can increase cortical bone thickness, mineralized bone area, and osteoblast count in dexamethasone-induced OP mice while reducing the number of osteoclasts on the cortical bone surface, demonstrating its potential role in anti-OP treatment.

3.2. E. ulmoides leaf and its extracts

Similar to EB and its extracts, E. ulmoides leaf (EL) and its extracts promote osteoblast proliferation and differentiation in vitro. The EL extract induces the differentiation and proliferation of sheep BMSCs isolated and purified in vitro towards osteoblasts by increasing the expression of osteoblast-specific transcription factor/core binding factor a1 (Osf2/Cbfal) mRNA while inhibiting their differentiation into adipocytes, achieving a bidirectional regulatory effect [25]. TRAP activity is an important osteoclast biochemical marker. The aqueous extract of EL significantly reduces TRAP activity, inhibits the transformation of bone marrow cells into osteoclasts induced by macrophage colony-stimulating factor(M-CSF) combined with RANKL, and reduces the area of bone pits [26]. It also promotes osteoblast proliferation, differentiation, and mineralization and prevents osteoblast apoptosis. These effects are achieved by increasing the expression of genes that promote cell proliferation, such as Rpl10a, Frat2, Pex1, Adnp, Inpp4a, and Pcdhga1, reducing the expression of genes that inhibit cell proliferation, such as Eif3e, Npm1, Cbx3, Ddx3x, Fgf7, Fxr1, Mbnl1, Psmc6, and Cdc27, and increasing the expression of osteogenic markers Col5a2, Ubap2l, Dkk3, Foxm1, Col16a1, Col12a1, Usp7, Col4a6, Runx2, Sox4, and Bmp4 [27]. The EL extract, resveratrol, promotes the differentiation of BMSCs into osteoblasts in rats with OVX-induced OP and improves bone metabolism. This mechanism may be related to increased ALP activity in cells, which upregulates the mRNA and protein expression of Runx2 and Osx [28]. β-glutinosterol, separated from EL, directly downregulates osteoclast differentiation factor (ODF) in osteoblasts, upregulates OPG, the OPG/ODF ratio, and promotes osteogenesis. Moreover, β-glutinosterol also induces E₂ synthesis in ovarian granulosa cells and maintains bone metabolism balance by promoting E₂ binding to the estrogen receptor on bone cell and osteoclast membranes [29].

In vivo studies confirmed the anti-osteoporotic effects of EL and its extracts. EL extract improves the bone tissue morphology and BMD of laying hens in the late stage of egg laying, increases bone elasticity, improves bone quality, and alleviates OP in cage laying hens. The mechanism thereof is related to the upregulation of OPG, sphingosine kinase 1 (SPHK1), and sphingosine 1-phosphate receptor (S1PR) mRNA expression in the tibia of laying hens, the reduction of RANK and RANKL mRNA expression, and regulation of the OPG/RANK/RANKL and SPHK/S1P signaling pathways [30]. The EL extract also has a certain therapeutic effect on rats with OVX-induced OP, and its mechanism is related to the reduction of the levels of serum calcium, phosphorus ALP, and CTX-1, increase in OC levels, and femoral and tibial BMD, positive regulation of the wnt/β-catenin signaling pathway, and promotion of bone formation [31,32]. The aqueous extract of EL reduces the risk of age-induced OP, as was shown by the increasing bone density and the number of trabeculae in the distal femur of aging-accelerated mouse model P6 (SAMP6) [26]. The alcohol extract of EL significantly increases femoral density, enhances tibial bending resistance, and improves OP status in rats with OVX-induced OP. The mechanism may be related to reducing the ratio of calcium/creatinine, phosphorus/creatinine in urine, decreasing the levels of ALP, OCN, IL-6, TNF-α in serum, and increasing serum E₂ to regulate the dynamic balance of bone metabolism, inhibit bone resorption, and promote bone formation [33,34]. The alcohol extract of EL also reduces bone loss and prevents the occurrence of diabetes-induced OP by increasing the linear and surface densities of the femur and the serum E₂ content [35]. The total flavonoids of EL significantly increase femoral BMD, bone volume fraction, bone trabecular thickness and quantity, and reduce bone trabecular separation and structural model index, ultimately improving the microstructure of the femur, increasing bone density, and exerting bone-protective effects in rats with OVX-induced OP [36]. It also corrects the symptoms of OP in perimenopausal rats by increasing serum E₂ and OCN levels [37].

3.3. E. ulmoides seed and its extracts

E. ulmoides seed (ES) extract regulates bone metabolism, increases bone density, enhances bone strength and hardness, and improves bone tissue microstructure by reducing serum OCN and RANKL levels; increasing OPG and E₂ levels, the ratio of OPG/RANKL, BMD in the femur, humerus, tibia, and lumbar vertebrae; enhancing femur crushing force and first lumbar vertebral crushing force; and reducing bone trabecular loss in rats with OVX-induced OP [38]. The ES meal (waste residue produced after extracting oil from E. ulmoides kernels) promotes bone formation and inhibits bone resorption in postmenopausal osteoporotic rats, and its mechanism of action is related to improving specific and non-specific immune functions [39]. The total saponins of ES enhances the activity, ALP activity, and calcium deposition of adipose-derived mesenchymal stem cells (ADSCs), thereby promoting the osteogenic differentiation of ADSCs. An increase in the number, thickness, and connectivity of bone trabeculae in rats with OVX-induced OP increases the mRNA and protein expression of Osx, OCN, and Runx2 in the femur, improves the microstructural changes of bone tissue in the distal femur, promotes bone formation, and reverses bone loss caused by OVX [40]. In addition, the total saponins of ES increases the serum ALP, creatinine, and urea nitrogen levels in mice with glucocorticoid-induced OP; increases the weight, length, fracture stress, and crushing force of the femur; and have a bone-protective effect [41].

3.4. E. ulmoides staminate flower and its extracts

At present, there are no reports on direct in vitro and in vivo experiments using E. ulmoides staminate flower (ESF) or its extracts for OP. However, its bone protective effect in arthritic rats suggests that it has anti-OP effect [42]. The alcohol extract of ESF exerts bone-protective effects in rats with Collagen II-induced arthritis (CIA) by inhibiting oxidative stress and inflammatory reactions in the joints, inhibiting bone erosion in the joints, and regulating bone metabolism. Further analysis revealed that the above mechanisms were related to significant inhibition of serum interleukin-1β (IL-1β), TNF-α, IL-6, nitric oxide (NO), and malonic dialdehyde (MDA) levels, increased superoxide dismutase (SOD) content, decreased mRNA expression of IL-6, IL-17, and TNF-α in the spleen, and decreased mRNA expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and RANKL in articular cartilage [43]. The alcohol extract of ESF inhibits proliferation of HFLS-RA synovial cells and promotes cell apoptosis in a dose-dependent manner. It can also inhibit osteoclast differentiation by inhibiting the activation of the nuclear factor-kappa B (NF-κB) signaling pathway, thereby reducing joint inflammation in rats with CIA, delaying the destruction of joint cartilage and bone, and exerting bone protective effects [44]. In summary, ESF regulates bone metabolism, inhibits osteoclast formation and bone erosion in the joints, and has potential anti-osteoporotic effects.

4. Anti-oxidant of E. ulmoides

Anti-oxidant is any substance that can act on free radicals directly or indirectly to delay, prevent, or eliminate oxidative damage to target molecules [[45], [46], [47], [48], [49]]. Bioactive components with antioxidant effects reported in recent years are mainly phenolics, polysaccharides, flavonoids, and alkaloids, which different parts of E. ulmoides are rich in Ref. [50].

4.1. E. ulmoides bark and its extracts

The EB ethanol extract reduces MDA levels, increases SOD, glutathione peroxidase (GSH-Px), and NO synthetase levels, activates the anti-oxidant system in the brain tissue, and protects the neurons of rats with Parkinson's induced by 6-hydroxydopamine (6-OHDA) [51]. The polysaccharides in EB have strong DPPH, ABTS, and OH radical-scavenging abilities, which increase with increasing concentration. When the concentration of EB polysaccharides was increased to 1, 0.5, and 30 mg/mL, their ability to scavenge DPPH, ABTS, and OH radicals reached 87.05%, 101.17%, and 65.92%, respectively, indicating good in vitro antioxidant capacity. These polysaccharides also increase the levels of SOD, CAT, GSH-Px, and total antioxidant capacity (T-AOC) in the serum of oxidative stress model mice, reduce MDA levels, and upregulate the mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and quinone oxidoreductase 1 (NQO1) in the liver and kidney tissues, downregulating the mRNA expression of Keap1 [52]. These polysaccharides further increase the levels of CAT, T-AOC, SOD, and GSH-Px in the colon tissue of mice with dextran sulfate sodium (DSS)-induced colitis, reduce MDA levels, and significantly enhance antioxidant capacity in vivo [53] The total flavonoids of EB have strong reducing ability for iron ions and strong scavenging ability for OH radicals [54]; reduce the serum MDA and reactive oxygen species (ROS) levels induced by vomiting toxins in weaned piglets, and increase the activities of SOD and GSH-Px [55]. They also increase the content of anti-oxidant factor T-AOC and increase the activity of SOD and CAT in the serum of mice with type two diabetes mellites (T2DM), while reducing the content of ROS in pancreatic mitochondria, indicating that EB flavonoids have strong in vivo and in vitro anti-oxidant capacity [56].

4.2. E. ulmoides leaf and its extracts

Research has shown significant differences in antioxidant activity among ELs at different altitudes (within a gradient range of 67–974 m), with the highest DPPH radical-scavenging rate and total reduction capacity at an altitude of 610 m [57]. The water, 50% alcohol, and 75% alcohol EL extracts showed strong scavenging activity against DPPH and superoxide anion radicals, and strong reducing ability against Fe³⁺. The antioxidant activity of the alcohol extracts was higher than that of the water extract [58]. The EL polysaccharides have good DPPH and ABTS radical scavenging abilities and reduce serum MDA levels, increase GSH-Px and SOD levels, reduce the degree of oxidative stress in pancreatic tissue, inhibit the formation of lipid peroxide, and improve free radical scavenging capacity in diabetic rats [59]. The non-extractable and extractable polyphenols in EL have strong DPPH and ABTS radical scavenging and iron ion reduction abilities [60]. According to previous reports, the reducing ability and ability to scavenge superoxide anion radicals of the total flavonoid extract of EL were significantly higher than those of vitamin C at the same concentration, and the activity showed a significant increase with increasing total flavonoid extract concentration [61]. The ethyl acetate fraction of EL reduces the MDA content in the lung and brain tissues of BALB/c mice with cognitive impairment induced by PM2.5, and increases the activities of SOD and GSH-Px [62].

4.3. E. ulmoides seed and its extracts

The ES oil increases T-AOC, GSH-Px, and SOD activity and reduces MDA content in mice exposed to brominated benzene [63]. The ethanolic extract of ES meal reduces the production of skin wrinkles induced by ultraviolet B (UVB) in aging mice, lowers MDA levels in the skin tissue, and increases SOD and CAT levels [64]. The ES meal protein hydrolytic peptide (8 mg/mL) has a strong scavenging ability against DPPH, superoxide anions, and ABTS radicals, with clearance rates of 78.6%, 75.4%, and 96.1%, respectively [65]. The clearance rates of DPPH, ABTS, and OH radicals by the products of ES meal protein digested by digestive enzymes in vitro reached 63.34%, 58.16%, and 71.11%, respectively, indicating that ES meal protein is a promising antioxidant resource that deserves further in-depth research [66].

4.4. E. ulmoides staminate flower and its extracts

According to previous reports, the maximum radical scavenging rates of ABTS, OH, and DPPH in ESF tea fermented with Lactobacillus plantarum were 59.2%, 65.7%, and 97.7%, respectively [67]. The ESF polysaccharides showed strong scavenging abilities against DPPH, ABTS, and OH radicals. Compared to the solution of ESF polysaccharides without dynamic high-pressure microjet (DHPM, 140 MPa) treatment, the scavenging rates of OH, ABTS, and DPPH radicals increased by 15.1%, 16.2%, and 40.7%, respectively [68]. The flavonoids in ESF scavenge DPPH free radicals, and their scavenging ability is significantly affected by Cu²⁺, Zn²⁺, pH, and light. This suggests that in the preparation and use of total flavonoids from ESF, strong alkalis or light should be avoided, as well as contact with high concentrations of Cu²⁺ and Zn²⁺ [69]. Geniposidic acid from ESF Tea induces oxidative stress in hydrogen peroxide (H₂O₂)-induced HaCaT cells by activating the protein kinase B (Akt)/Nrf2/8-oxoguanine DNA glycosylase (OGG1) signaling pathway [70]. The total flavonoids in ESF pollen significantly increase SOD and T-AOC activity in the liver, brain, and serum; significantly reduce the MDA content in the liver and brain of mice; improve antioxidant capacity; reduce the production of lipid peroxides; and alleviate the damage caused by oxidative stress in d-galactose-induced aging mice [71].

5. Anti-inflammatory activity of E. ulmoides

Inflammation is the body's response to destructive stimuli, microbial pathogens, and inflammatory factors for pathological activities caused by stimulation, thereby harming the organs or tissues of the body [72]. Additionally, inflammatory reactions exacerbate disease progression and affect treatment, prognosis, and outcomes [[73], [74], [75]]. E. ulmoides bark, leaves, staminate flowers, and seeds contain numerous bioactive compounds with various pharmacological activities. These components reduce the release of inflammatory factors such as IL-1β, IL-6, IL-12, IL-17, and TNF-α by inhibiting the NF-κB, phosphatidylinositol3-kinase (PI3K)/Akt, mitogen-activated protein kinases (MAPK), and c-Jun N-terminal protein kainse (JNK) signaling pathways, thereby alleviating the body's inflammatory response [76] (Fig. 4). Therefore, EL is used as a functional food to regulate intestinal, gastric tissue, neuro-, joint, and oral inflammation, and cognitive impairment.

Fig. 4.

Anti-inflammatory activity of E. ulmoides.

5.1. E. ulmoides bark and its extracts

The EB extracts significantly inhibit pathways PI3K/Akt, NF-κB, JNK, MAPK, and activate pathway Nrf2/HO-1, thereby inhibiting the production of two inflammatory mediators, NO and prostaglandin E₂ (PGE₂), and suppressing the expression and release of multiple molecules involved in inflammation, including NF-κB, phosphorylated inhibitor-α of NF-κB, p-IκBα, PI3K, Akt, inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), TNF-α, and IL-1β in lipopolysaccharide (LPS)- stimulated microglial BV-2 cells. It also increases the protein expression of HO-1 and Nrf2, reducing nerve cell damage caused by inflammation [77]. The aqueous extract of EB inhibit inflammatory response by reducing the levels of IL-1β and TNF-α in serum, and exert a liver protective effect on liver ischemia-reperfusion rats [78]. The alcohol extract of EB can exert a protective effect on rats with periodontitis by reducing the mRNA expression of IL-1β and NF-κB in periodontal ligament fibroblasts, the levels of IL-6, IL-1β, and TNF-α in serum, as well as the protein expressions of NF-κB and IL-1β in maxillary tissue [79]. The EB polysaccharides reduce the levels of pro-inflammatory factors IL-1β, IL-6, IL-12, IL-17, and TNF-α in the colon tissue of mice with DSS-induced colitis, increase the levels of anti-inflammatory factor IL-10, inhibit the mRNA expression of IL-1β, IL-6, IL-17, and TNF-α, and increase the mRNA expression of IL-10 in LPS-induced IEC-6 and Caco-2 cells. The mechanism is related to the inhibition of the activity of the Toll-like receptor 4(TRL4)/NF-κB signaling pathway [80]. In addition, the EB polysaccharides inhibit the activation of the TLR4/NF-κB/MAPK signaling pathway mediated by microglia by reducing the release of LPS. This weakens the inflammatory response of hippocampal tissue and helps to restore the rhythm of hippocampal neurogenesis and alleviate behavioral abnormalities in mice with chronic, unpredictable, and mild stress [81]. The iridoid and triterpenoid components of EB reduce foot volume and arthritis index in rats with CIA, and their effects are related to downregulating TNF-α, IL-17, and IL-23 levels in serum and spleen, ultimately inhibiting inflammatory response [82,83]. The EB polysaccharides reduce the levels of TNF-α, NO, interferon-γ (IFN-γ), and IL-6 in the supernatant of the IL-1β-induced osteoarthritis chondrocyte inflammation model, as well as the protein expression of NF-κBp65 and p–NF–κBp65 in cells, thereby alleviating inflammatory damage [84].

5.2. E. ulmoides leaf and its extracts

The EL extract reduces the levels of IL-6, IL-1β, and TNF-α, increases the level of IL-10 in serum, and lowers mRNA expression of NF-κB, TLR4, IL-6, IL-1β, and TNF-α in the colon tissue of piglets with LPS-induced intestinal inflammation [85]. In addition, the EL extract also alleviates the inflammatory response in rats with gastric ulcers, and its mechanism is related to the inhibition of the PI3K/Akt/NF-κB signaling pathway and reduction of the levels of inflammatory factors IL-1β, TNF-α, and IL-6 [86]. The total flavonoids in young and mature leaves of E. ulmoides have been shown to alleviate LPS-induced neuroinflammatory responses in BV-2 cells by inhibiting the production of NO, IL-1β, TNF-α, and IL-6, and decreasing the protein expression of p-IκB, IκB, p–NF–κBp65, NF-κBp65, JNK, and p-JNK. Moreover, at the same drug concentration, the anti-inflammatory effect of total flavonoids in young leaves of E. ulmoides was stronger [87]. The ethyl acetate fraction of EL down-regulated the expression of p-JNK, p-IκBα, Cysteinyl aspartate specific proteinase-1 (Caspase-1), IL-1β, and TNF-α in the lung and the expression of p-JNK, p-IκBα, Caspase-1, IL-1β, and TNF-α in the olfactory bulb caused by PM2.5 toxicity [58]. The alcohol extract of EL reduces the levels of IL-6 and TNF-α in the serum of rats with collagen-induced CIA, decreases the mRNA expression of TNF-α, IL-1β, and IL-17 in the spleen tissue, and the protein expression of phosphorylated inhibitor of NF-κB kinaseα/β (p-Iκκα/β), p-IκBα, and p-p65 in the knee joint tissue, reducing the degree of inflammatory bone damage [88].

5.3. E. ulmoides seed and its extracts

The ES iridoid compounds, including aucubin, bartsioside, linaride, geniposidic acid, scyphiphin D, ulmoidoside, and ulmoidoside B, inhibit NO production in LPS-induced microglial BV-2 cells. Among them, aucubin has the highest anti-inflammatory activity, with an IC₅₀ value of 29.25 μM [89]. The ES meal extract can reduce serum IL-6 and TNF-α levels in osteoporotic rats, and alleviate inflammation induced bone destruction [90]. The total glycosides of ES significantly reduce the volume of ear swelling caused by xylene in mice, reduce the rate of foot swelling caused by carrageenan in rats, increase the pain threshold caused by hot plates and photoelectric therapy in mice, reduce the number of body twists caused by acetic acid, and have strong anti-inflammatory and analgesic effects [91].

5.4. E. ulmoides staminate flower and its extracts

Similar to the total flavonoids of the EL, the total flavonoids of the ESF also alleviate LPS-induced neuroinflammatory response in BV-2 cells by reducing the levels of NO, TNF-α, IL-1β, and IL-6 in the supernatant of BV-2 cells, inhibiting the protein expression of p–NF–κBp65, NF-κBp65, p-JNK, and JNK in BV-2 cells. This provides data support and a theoretical basis for the development of drugs to prevent or improve related diseases caused by neuroinflammation [92]. The alcohol extract of ESF reduces the levels of TNF-α, IL-1β, and IL-6 serum, the mRNA expression of IL-6, IL-17, TNF-α in the spleen tissue, alleviates the degree of foot swelling in CIA model rats, and lowers arthritis scores [43]. The alcohol extract of ESF also reduces the levels of ovalbumin specific IgE, IL-4, and IL-13 in serum, inhibiting the mRNA expression of IL-6 in the lung tissue of mice with airway allergic inflammation [93]. According to previous reports, 70% ethanol extract of SF has anti-inflammatory effects both in vivo and in vitro, which are related to the inhibition of pro-inflammatory cytokines and neutrophils [94]. In addition, the peach leaf coral glycoside contained in the ESF also has a certain anti-inflammatory effect, mainly manifested in inhibiting the production of TNF-α by mouse macrophages [95]. Simultaneously, ESF and their extracts counteract the inflammatory response in rats with rheumatoid arthritis. The mechanism is related to inhibiting the activation of the NF-κB signaling pathway, reducing the mRNA expression of IL-1β, IL-6, VEGF, and matrix metalloproteinase 9 (MMP-9), thereby inhibiting osteoclast differentiation and delaying joint cartilage and bone damage [96,97].

6. Anti-diabetic effects of E. ulmoides

Diabetes mellitus (DM) is a metabolic disease characterized by long-term hyperglycemia, which can cause dysfunction and failure of multiple tissues and organs, seriously threatening human life and health [98]. In the ranking of mortality, diabetes ranks third after malignant tumors and cardiovascular and cerebrovascular diseases [99]. In 2023, the National Health Commission issued a diet guide for adults with diabetes, which included the traditional Chinese medicinal culture of "medicine and food come from the same source" in one of the recommendations [100]. As a medicinal and edible raw material, E. ulmoides is rich in flavonoids, polysaccharides, and lignans, which are recognized as important active substances with hypoglycemic effects [101,102].

6.1. E. ulmoides bark and its extracts

The water extract of EB reduces fasting blood glucose (FBG) levels and increases the insulin sensitivity index (ISI) in mice with streptozotocin (STZ)- induced DM. Its mechanism is related to an increase in serum GSH-Px and SOD activities, and antioxidant capacity, a decrease in MDA activity, Caspase-3 and Caspase-7 protein expression in pancreatic tissue, and the inhibition of pancreatic cell apoptosis in mice [103]. The total flavonoids in EB can reduce the level of FBG and inhibit apoptosis of pancreatic cells in mice with T2DM induced by STZ combined with a high-fat and high-sugar diet. Its mechanism is related to increasing the content of C-peptide, reducing that of TNF-α, IL-6, ROS, transmembrane protein Fas, and transmembrane protein ligand Fasl in serum, inhibiting the protein expression of Bax, increasing that of Bcl-2 in pancreas, and improving the pathological pancreatic damage caused by inflammatory factors and oxidative stress [104]. The EB polysaccharide regulates inflammatory reaction and oxidative stress by reducing serum IL-8, IL-1β, IL-6, MDA levels, inhibiting liver NF-κBp65 protein expression, increasing serum GSH-Px and SOD levels and liver HO-1 protein expression, thereby improving obesity, hyperglycemia, hyperlipidemia and liver damage in mice with T2DM, and reducing liver pathological changes and steatosis [105]. The EB lignans can reduce the level of FBG in rats with DM-induced renal injury by increasing serum insulin concentration, enhancing the expression of GSH-Px and SOD, reducing the content of MDA, inhibiting oxidative stress response in the body, and playing a role in kidney protection by activating the Nrf2/HO-1 signaling pathway [106].

6.2. E. ulmoides leaf and its extracts

The water extract of EL regulates the metabolism of blood sugar and lipids in rats with DM by reducing the levels of FBG, total cholesterol (TC), total triglycerides (TG), low-density fatty acids (LDL-C), and MDA and increasing the levels of high-density fatty acids (HDL-C) and SOD in serum, thus playing a protective role [107]. The ethanol extract of EL reduces FBG levels in rats with STZ-induced DM and reduces bone turnover by increasing the content of femoral BMD and serum E₂, inhibiting bone absorption and effectively preventing bone loss in diabetic rats [108]. Inhibiting the activity of α-glucosidase activity plays an important role in reducing postprandial blood glucose concentrations. Polyphenolic compounds of EL, such as gallic acid, salicylic acid, catechins, and caffeic acid, all have varying degrees of inhibitory effects on α-glucosidase, and inhibit the activities of sucrase and maltase, as well as their absorption of glucose, without affecting the activity of Caco-2 cells. Among them, caffeic acid has the strongest inhibitory effect on α-glucosidase, catechins have the strongest inhibitory effect on disaccharidase, and gallic acid and caffeic acid have the strongest inhibitory effect on glucose absorption in cells [109]. The EL polysaccharides protect pancreatic islet tissue and reduce the FBG level of rats with DM by inhibiting α-glucosidase, reducing MDA levels, increasing GSH-Px and SOD levels, inhibiting Caspase-3, p38MAPK, and TGF-1 protein expression in pancreatic islet tissue [110].

6.3. E. ulmoides seed and its extracts

The ES oil plays a protective role in T2DM KKAy mice by reducing FBG, insulin, the area under the sugar tolerance curve, TC, TG, and LDL-C, alleviating the degree of liver steatosis, and improving glucose and lipid metabolism [111]. However, Zhao et al. [89] showed that the iridoid compounds aucubin, bartsioside, linaride, geniposidic acid, scythiphin D, ulmoidoside A, and ulmoidoside B in ES do not exhibit α-glucosidase inhibitory activity, preliminarily ruling out the hypoglycemic effect of iridoid compounds. However, there is relatively little experimental research on the hypoglycemic effect of ES, and a large amount of experimental investment is needed to clarify the active sites and confirm their hypoglycemic effects.

6.4. E. ulmoides staminate flower and its extracts

The glycemic generation index (GI) of food represents the effects of food entering the human body on blood sugar fluctuations. A GI value > 70 indicates high GI food that is not suitable for individuals with abnormal blood sugar metabolism to consume; 55 ≤ GI ≤ 70 refers to foods with medium GI values, while GI < 55 refers to foods with low GI values. Individuals with abnormal blood sugar metabolism can consume low GI foods in moderation [112]. At present, no experimental report on the use of ESF in diabetes research has been published, but the experiment [113] shows that the GI of the meal substitute powder composed of ESF is approximately 45, which can stabilize blood sugar after consumption, is suitable for obese people and people with abnormal glucose metabolism, and is a more nutritious and healthy functional food.

7. Improve gastrointestinal function of E. ulmoides

The gastrointestinal tract is not only the main site for food breakdown, digestion, and absorption but also the main site for bacterial colonization. Dysfunction can induce various diseases and affect physical health [114]. Research has shown that interactions between the host gut microbiota are involved in the maturation of gastrointestinal function and structure. Traditional Chinese medicine has recorded E. ulmoides as a method of treatment of gastroenteric diseases because the intake of E. ulmoides acts as a prebiotic to improve the intestinal flora and gastrointestinal function [115,116].

7.1. E. ulmoides bark and its extracts

Adding EB extract to the diet can increase the diversity of the gut microbiota in rainbow trout, and reduce the abundance of harmful bacteria, such as Erysipelotrichaceae, Peptostreptococcaceae, Aeromonas, Aeromonas, and Clostridium, and increase the abundance of beneficial bacteria, such as Bradyrhizobiaceae and Comamonadaceae, thereby affecting the nutritional digestion process and utilization efficiency of feed fiber in rainbow trout [117]. The height of the duodenal villi and depth of the crypts are key parameters for evaluating intestinal morphology. The height of the intestinal villi is positively correlated with the efficiency of nutrient uptake by the intestine. A shallow crypt indicates an increase in the maturation rate of intestinal cells and an acceleration of intestinal secretion. Dietary supplementation with EB extract can effectively improve growth performance and nutrient digestibility; increase the villus length of the duodenum; reduce crypt depth; increase the activity of pancreatic protease, amylase, and lipase in the duodenum; and improve duodenum morphology in broiler chickens [118]. The EB extract can also promote the proliferation of adult neural stem cells and the differentiation and survival of new cells in the dentate gyrus of mice, thereby improving their learning and memory abilities. The main mechanism may be to regulate the body's ability to decompose, digest, and absorb polysaccharides by affecting the gut microbiota in mice [119]. Adding EB extract to the diet not only improved the feed conversion rate of three yellow chickens, reduced the number of conditional pathogenic bacteria such as Escherichia coli in the cecum, but also promoted the proliferation of beneficial bacteria such as Lactobacillus and Bifidobacterium in the cecum and ileum [120]. Purified polysaccharides from EB significantly alter the composition of the gut microbiota in osteoporotic mice, reduce the abundance of harmful bacterial genera such as Alistipes, Shigella, Clostridium, and Dehalobacteria, and increase the abundance of beneficial bacterial genera such as Allobaculum, Ruminococcus, Paraacteroides, and Prevotella, thereby affecting bone metabolism and exerting bone-protective effects in vivo [9]. The EB reduces mortality during Nocardia seriolae attacks and starch-induced intestinal inflammation. EB supplementation altered the intestinal flora during fatty acid degradation, bacterial chemotaxis, porphyrin metabolism, and flagella assembly caused by high starch content [115]. Further analysis revealed that EB supplementation reduced the increase in the abundance of Limnochordaceae, Nitrolancea, Lysinibacillus, and Hydrogenispora induced by high starch levels, which was negatively correlated with the levels of the immunoreactive substance lysozyme in fish [115].

7.2. E. ulmoides leaf and its extracts

Both young and mature EL leaves exhibit strong prebiotic activity by promoting the proliferation of short-chain fatty acids (SCFA)-producing bacteria, modulating the gut microbiota, and increasing SCFAs in in vitro fermentation products. These effects benefit the intestinal immune system by preventing intestinal barrier damage and suppressing lipopolysaccharide-induced inflammatory factor secretion by macrophages [116]. The EL extract increases the abundance of Firmicutes and Verrucomycota at the phylum level in the gut of rats with hyperlipidemia induced by high-fat and high sugar feed combined with lard, while reducing the abundance of Bacteroidetes, Proteobacteria, and Unidentified_Bacteria. It further increases the abundance of Firmicutes, Verrucomycetes, Lactobacillus, Ackermann's bacteria, Prevotellaceae NK3B31_group and other bacterial communities at the genus level, and reduces the abundance of Bacteroidetes and Proteobacteria, indicating that it improves the disorder of intestinal microbiota caused by hyperlipidemia by increasing the abundance of beneficial bacteria and reducing that of harmful bacteria [121]. Adding EL extract to the diet increases lipase activity in the duodenum and trypsin activity in the jejunum of weaned piglets, reduces crypt depth, increases the ratio of villus height to crypt depth and the gene expression level of claudin-3, a tight junction-related protein in the jejunal mucosa, and enhances the richness and diversity of the colonic microbiota community in piglets. This enhances their digestive and absorption capacities, improving their intestinal morphology, reducing intestinal permeability, and increasing intestinal microbial diversity to maintain intestinal functional health [122,123]. The total flavonoids of EL affect the alpha and beta diversity and composition of the gut microbiota in rats with OVX-induced OP, increase Firmicutes abundance, and reduce Bacteroidota abundance [124].

7.3. E. ulmoides seed and its extracts

The gut microbiota plays an important role in nutrient acquisition, digestion, and metabolic processes, and is a key factor in the occurrence and development of high-fat diet-induced glucose and lipid metabolism disorders, inflammation, and intestinal barrier disruption in obese mice with T2DM. The ES oil improves the intestinal flora disorder in KKAy mice with T2DM by reducing the proportion of Firmicutes/Bacteroidetes, increases the relative abundance of Blautia and Lactobacillus, and improves their microbial diversity [111].

7.4. E. ulmoides staminate flower and its extracts

Currently, there are no reports on the direct use of ESF to improve gastrointestinal function. However, evidence suggests that quercetin, chlorogenic acid, ursolic acid, and aucubin have protective effects on the gastrointestinal tract, such as enhancing digestive function, increasing gut microbiota diversity, and inhibiting the malignant behavior of gastric and colon cancer cells [[125], [126], [127]]. Quercetin, chlorogenic acid, ursolic acid, and aucubin are the main active ingredients in ESF, indicating that ESF can be developed as a related product.

8. Conclusion

Several studies have shown that E. ulmoides has various health benefits. Dozens of biologically active substances from E. ulmoides can be extracted for healthcare foods. At present, many health products related to E. ulmoides have appeared on the market, such as E. ulmoides beverages, EL tea, ESF meal replacement powder, and ES oil-filled gummies. This review showed that E. ulmoides has multiple beneficial effects such as anti-OP, anti-oxidation, anti-inflammatory, anti-diabetic effects, and gastrointestinal protection. It is an important medicinal and edible plant with that can be developed into a food or health product to make use of these effects. However, there are still many problems and shortcomings in the research and development process. For example, it is has not been clear whether the reported active compounds exist in each part of E. ulmoides (bark, leaf, staminate flower, and seed) and in what quantities. Moreover, health foods made from E. ulmoides mainly focus on its anti-OP, blood sugar-lowering, and anti-oxidant properties, leading to a limited audience for the product and restricting the development of E. ulmoides health foods. The EB has a bitter and spicy taste, whereas EL has a bitter and slightly grassy taste, limiting the development of E. ulmoides health food formulations. Capsules and wine remain the main products in the market [128]. In addition, because of the complex composition of E. ulmoides, numerous samples and experiments are required to verify its effectiveness and safety. Moreover, most recent studies on E. ulmoides have focused on the effects on cell lines, animal models, or enzyme assays; however, these effects may not be directly translatable to humans. Therefore, exploring E. ulmoides functional food represents a significant challenge for the future.

Funding

This study was supported by Science and Technology Research projects in Henan Province (Effects of total flavonoids from Eucommia ulmoides Oliv. leaves on improving HPO axis function and metabolic disorders in polycystic ovary syndrome) and Hebei Provincial Administration of Traditional Chinese Medicine supported project (No. 2023195).

Data availability statement

No data was used for the research described in the article.

CRediT authorship contribution statement

Mengfan Peng: Writing – original draft, Investigation, Conceptualization. Yuhui Zhou: Writing – review & editing, Project administration, Funding acquisition. Baosong Liu: Writing – review & editing, Investigation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

ADSCs

adipose derived mesenchymal stem cells

Akt

protein kinase B

ALP

alkaline phosphatase

BMD

bone mineral density

BMSCs

bone marrow mesenchymal stem cells

Caspase-1

cysteinyl aspartate specific proteinase-1

Cbfal

core binding factor a1

CIA

Collagen II-induced arthritis

Col1α

type I collagen α

COX-2

cycloxygenase-2

CTX

C-terminal peptide of type 1 collagen

DM

Diabetes mellitus

DSS

dextran sulfate sodium

E₂

estradiol

EB

E. ulmoides bark

ES

E. ulmoides seed

ESF

E. ulmoides staminate flower

FBG

fasting blood glucose

GI

glycemic generation index

GSH-Px

glutathione peroxidase

HDL-C

high-density fatty acids

HIF-1α

hypoxia-inducible factor-1α

H₂O₂

hydrogen peroxide

HO-1

heme oxygenase-1

IFN-γ

interferon-γ

IL-6

interleukin-6

IL-1β

interleukin-1β

ISI

insulin sensitivity index

JNK

c-Jun N-terminal protein kainse

LDL-C

low-density fatty acids

LPS

lipopolysaccharide

MAPK

mitogen-activated protein kinases

M-CSF

macrophage colony-stimulating factor

MDA

malonic dialdehyde

MMP-9

matrix metalloproteinase 9

NF-κB

nuclear factor-κB

NO

nitric oxide

NQO1

quinone oxidoreductase 1

Nrf2

nuclear factor erythroid 2-related factor 2

OCN

osteocalcin

ODF

osteoclast differentiation factor

OGG1

8-oxoguanine DNA glycosylase

OP

Osteoporosis

OPG

osteoprote-gerin

OPN

osteopontin

Osf2

osteoblast specific transcription factor

Osx

Osterix

OVX

ovariectomy

PGE₂

prostaglandin E₂

p-Iκκα/β

phosphorylated inhibitor of NF-κB kinaseα/β

p-IκBα

phosphorylated inhibitor α of NF-κB (p-IκBα)

PI3K

phosphatidylinositol3-kinase, PINP, type I procollagen amino terminal peptide

RANKL

nuclear factor κB receptor activating factor ligand

RhoA

Ras homologous gene family member A

ROCK1

Rho kinase 1

Runx2

RUNX family transcription factor 2

SCFAs

short-chain fatty acids

SOD

superoxide dismutase

SPHK1

sphingosine kinase 1

S1PR

sphingosine 1-phosphate receptor

STZ

streptozotocin

T-AOC

total antioxidant capacity

TC

total cholesterol

TG

total triglycerides

TNF-α

tumor necrosis factor

TRAP

tartrate resistant acid phosphatase

TRL4

Toll-like receptor 4

UVB

ultraviolet B

VEGF

vascular endothelial growth factor

6-OHDA

6-hydroxydopamine

β-CTXI

β-I collagen cross-linked carboxyl terminal peptide.