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Pharmacology & Pharmacy
Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y.Hu (E. sessiliflorus), a member of the Araliaceae family, is a valuable plant widely used for medicinal and dietary purposes. The tender shoots of E. sessiliflorus are commonly consumed as a staple wild vegetable. The fruits of E. sessiliflorus, known for their rich flavor, play a crucial role in the production of beverages and fruit wines. The root barks of E. sessiliflorus are renowned for their therapeutic effects, including dispelling wind and dampness, strengthening tendons and bones, promoting blood circulation, and removing stasis. To compile a comprehensive collection of information on E. sessiliflorus, extensive searches were conducted in databases such as Web of Science, PubMed, ProQuest, and CNKI.
- Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y.Hu
- herbal metabolites
- pharmacological effects
- triterpenoids
1. Antioxidant Activity
Antioxidants are known for their ability to reduce oxidative stress, slow down oxidation processes, and preserve food quality while preventing degenerative diseases. E. sessiliflorus exhibits potent antioxidant activity due to the synergistic effect of its chemical constituents [79]. The flavonoids present in E. sessiliflorus extract have shown a strong correlation with hydroxyl radical scavenging activity. E. sessiliflorus methanol extract has been found to possess the highest capacity for scavenging hydroxyl radicals (82.35 ± 1.54%) compared to other plants, including Astragalus membranaceus, Polygonatum stenophyllum, and Angelica gigas [80].
Moreover, the polyphenols found in E. sessiliflorus also exhibit notable antioxidant activity. The extracts derived from the roots, stems, leaves, and fruits of E. sessiliflorus have demonstrated significant nitrite-scavenging capacity (76.00–81.50%) at pH 1.2. Therefore, the aqueous extract of E. sessiliflorus has shown the ability to inhibit the formation of nitrosamines in food [81]. E. sessiliflorus fruit extract (2 mg/mL) has also been found to inhibit the production of TNF-α (decrease of 19 ± 6%) and IL-6 (decrease of 24 ± 3%) induced by lipopolysaccharide, as well as suppress COX-2 luciferase activity (decrease of 98 ± 2%) [82]. These antioxidant and anti-inflammatory effects have led to the incorporation of E. sessiliflorus as a functional food ingredient in products such as spicy chicken sauce and wine. For instance, in spicy chicken sauce, E. sessiliflorus extract is added at a concentration of 2%, resulting in a high total polyphenol content and strong DPPH and ABTS free radical scavenging activity (12.51 ± 0.33% and 8.43 ± 0.29%) along with anti-bacterial activity [83]. Another popular application of E. sessiliflorus is incorporating E. sessiliflorus seeds into pork meat Wanja. In this case, E. sessiliflorus seeds are added at a concentration of 0.5%, along with Cinnamomum lureitri at 1.0% and Angelica gigas Nakai at 0.5%. This combination significantly reduces the acidity and peroxide values of pork meat Wanja, extending its shelf life by up to ten days [84].
The antioxidant activities of E. sessiliflorus can also be harnessed in beverages and wine. The addition of E. sessiliflorus juice to fruit juice or E. sessiliflorus extract to wine not only enhances the antioxidant activity (scavenging rates of DPPH and ABTS were 64.80% and 73.30%) of the products but also improves their taste by reducing acidity and bitterness [85,86].
2. Anti-Aging Activity
The antioxidative activity of E. sessiliflorus is particularly noteworthy. Free radicals and oxidative stress play a crucial role in the aging process, and E. sessiliflorus has shown potential in combating these challenges. Cellular antioxidants, endogenous (such as glutathione and vitamin E) and derived from dietary sources, can scavenge free radicals and alleviate cellular oxidative stress. Recognizing the importance of identifying natural and safe plant sources with potent free radical scavenging capabilities, research has focused on exploring E. sessiliflorus extracts. These extracts have exhibited significant improvements in resistance to oxidative stress. For instance, E. sessiliflorus extract has been found to enhance the survival rate of Caenorhabditis elegans under oxidative stress conditions. The 500 mg/L stem extract has demonstrated a notable improvement in the thermotolerance of Caenorhabditis elegans, increasing their survival time after exposure to ultraviolet radiation by 13.3% [87].
Similarly, the leaf extract (500 mg/L) has been shown to enhance thermotolerance, increasing the survival of Caenorhabditis elegans up to 57.2 ± 5.30% without affecting their reproductive capacity [88]. Notably, the root extract has augmented the antioxidant capacity of mice, increasing their survival time after heat shock (77.7 ± 8.87%) and ultraviolet irradiation (31.1%). Additionally, the 500 mg/L root extract has shown a protective effect against human Aβ amyloid-induced toxicity in Caenorhabditis elegans (p < 0.001), suggesting a potential role in regulating the aging process in these nematodes [89]. It is worth noting that the effects of E. sessiliflorus extracts may vary among different plant parts. For instance, various parts’ extracts show varying resistances to ultraviolet radiation, with only the stems’ extract significantly reducing DNA oxidative damage in rat lymphocytes. Therefore, it is essential to study the distinct parts of E. sessiliflorus separately to further explore its medicinal and nutritional applications in the future.
Furthermore, investigations have been carried out to uncover the anti-aging effects of E. sessiliflorus using Drosophila melanogaster as a model organism. Results have indicated that the ethyl acetate extract fraction and n-butanol extract fraction of the alcohol extract from E. sessiliflorus leaves exhibited significant extensions in the lifespan of Drosophila melanogaster (8.20–21.43%) within the concentration range of 0.25 mg/mL to 2.5 mg/mL. Interestingly, a concentration-dependent trend was observed, where the extension rate initially increased with the rise in extract concentration. Drosophila melanogaster had the longest lifespan at 1.25 mg/mL, subsequently decreasing. The above findings provide additional evidence supporting the potential anti-aging properties of E. sessiliflorus [90]. However, the precise underlying mechanism of action behind these effects is yet to be fully elucidated.
3. Anti-Stress Activity
The fruits of E. sessiliflorus contain polymeric and glycosidic compounds composed of a series of monosaccharides, including mannose, rhamnose, and glucose. These compounds have demonstrated significant anti-stress effects, such as anti-fatigue properties, tolerance to hypoxia, and the enhancement of immune regulatory capacity. Notably, these effects have been observed at two different dosage levels of the fruit polysaccharides (200 mg/kg and 400 mg/kg), highlighting their pronounced anti-fatigue properties. Specifically, mice administered the 400 mg/kg dose showed a doubling of swimming time compared to the control group, indicating improved carbon particle clearance ability with enhanced swallow index (0.0613 ± 0.0067) and swallow coefficient (6.559 ± 0.518) in mice. Furthermore, a dose of 200 mg/kg significantly improved the survival time of mice under hypoxia (32.48 ± 2.99 min) [78,91].
Furthermore, the polyphenols present in E. sessiliflorus (100 mg/kg and 200 mg/kg) have been shown to significantly prolong the exhaustive swimming time of mice by 14.35 and 17.38 min, respectively. These polyphenols inhibit the depletion of liver glycogen, raising its levels from 2.53 mg/mL in the control group to 2.92 mg/mL and 3.03 mg/mL. Moreover, they increase muscle glycogen content by 28.82% and 35.08%, enhance the activity of glutathione peroxidase in mice (114.67 U/mL and 109.62 U/mL), and reduce lactate levels by 10.96% and 17.44% and creatine kinase levels by 26.43 ng/mL and 26.57 ng/mL. Collectively, these effects contribute to elevated resistance to fatigue in mice [92].
E. sessiliflorus also exhibits sedative and hypnotic effects. The combination of E. sessiliflorus fruit extract (1175 mg/kg and 585 mg/kg) with barbiturate drugs (60 mg/kg) synergistically prolongs the sleep time induced by pentobarbital sodium. In animals administered sub-threshold hypnotic doses (30 mg/kg) of pentobarbital sodium, E. sessiliflorus induces a sleep state. Additionally, E. sessiliflorus fruit extract (810 mg/kg) reduces animal locomotion and impairs motor coordination [93].
Similarly, the combined administration of the aqueous and alcohol extracts of E. sessiliflorus leaves and fruits with 5-hydroxytryptophan has been shown to induce sleep in mice. Notably, the ethanolic extract of the fruits (32 mg/kg) significantly increased the mice’s sleep onset rate. Additionally, the aqueous and alcoholic extracts of fruits or leaves (8 mg/kg) exhibited a synergistic effect with 5-hydroxytryptophan (2.5 mg/kg). This combination also alleviated insomnia induced by p-chlorophenoxyacetic acid. These extracts counteracted the stimulatory effects caused by flumazenil and thiosemicarbazide in mice, suggesting a correlation between their sedative effects and the neurotransmitter systems involving 5-hydroxytryptamine and γ-aminobutyric acid.
Moreover, the alcohol extract of E. sessiliflorus leaves and fruits exhibited stronger sedative and hypnotic activities than the aqueous extract. This difference can be attributed to higher levels of isofraxidin, a component known for its sedative and hypnotic effects, in the alcohol extract. Saponin components also significantly contributed to the sedative and hypnotic effects [94,95].
Network pharmacology analysis has identified the targets underlying the sedative and hypnotic effects of E. sessiliflorus. Enzymes constitute the highest proportion of these targets (17.44%), followed by receptors (25.00%), including 5-hydroxytryptamine and γ-aminobutyric acid-A receptors. This finding suggests that the sedative and hypnotic effects of E. sessiliflorus primarily involve modulating specific enzymes and receptors [20].
4. Anti-Platelet Aggregation Activity
Platelet aggregation, which occurs when platelets are exposed to external stimuli, is a crucial step in the formation of platelet thrombi, leading to thrombotic diseases. These diseases pose a significant threat to human health, with high mortality and disability rates. While various medications have been developed to treat thrombotic conditions, their adverse reactions, such as bleeding tendencies, gastrointestinal discomfort, and hepatotoxicity, have propelled researchers to focus on developing naturally safe therapeutic agents.
Studies have investigated the effects of water decoctions and active components (total saponins, total flavonoids, and lupane-type triterpenoid saponins) derived from the leaves of E. senticosus and E. sessiliflorus (concentrations of both 25 mg/kg and 100 mg/kg) on adenosine diphosphate-induced anti-platelet aggregation and antithrombotic activity. These investigations assessed toxicity-related parameters, including mouse platelet toxicity, prothrombin time, bleeding time, mouse tail length, and the occurrence rate of tail necrosis. The results revealed that the flavonoids in both E. senticosus and E. sessiliflorus leaves exhibited varying degrees of inhibition of thrombus formation induced by carrageenan in mice. This inhibition led to a reduction in the length of thrombus formation in the mouse tail. Moreover, the flavonoids (25 mg/kg and 100 mg/kg) increased the levels of serum cAMP (3.10 ± 0.22 nM and 3.19 ± 0.31 nM) in mice and suppressed the abnormally elevated serum TXB2 induced (1.28 ± 0.20 nM and 0.95 ± 0.12 nM) by carrageenan, with the most prominent effects observed with the total flavonoids from E. sessiliflorus leaves [96].
Furthermore, E. sessiliflorus fruits contain a significant amount of oleanolic acid, which has demonstrated a notable anti-platelet aggregation effect [18]. Additionally, three novel triterpenoids isolated from the fruits have exhibited similar anti-platelet aggregation effects to acetylsalicylic acid in vitro experiments. Administration of a 70% ethanol extract of E. sessiliflorus fruits at a dose of 1000 mg/kg in rats resulted in the highest inhibition of platelet aggregation, reaching 61.3%. Both in vitro and in vivo studies have confirmed the significant anti-platelet aggregation and antithrombotic effects of these compounds. Furthermore, they have been shown to influence the release of adenosine diphosphate, thus impacting platelet aggregation [97].
The above findings highlight the potential of E. sessiliflorus, particularly its flavonoids and triterpenoids, as effective natural agents for inhibiting platelet aggregation and preventing thrombotic diseases. Further research and exploration of the underlying mechanisms behind these effects are warranted to fully understand the therapeutic potential of E. sessiliflorus in the context of thrombotic conditions.
5. Effects on Glucose Metabolism
E. sessiliflorus roots (5 mg/kg) have shown promising effects in accelerating the decline in alimentary hyperglycemia concentration and increasing hepatic glycogen content [98]. Moreover, E. sessiliflorus leaves have demonstrated the ability to significantly lower blood glucose levels in diabetic rats, improve lipid metabolism, reduce total cholesterol and low-density lipoprotein levels, and elevate high-density lipoprotein levels. Notably, the concentration of triglycerides decreased by 60.80% compared to the control group [99]. Additionally, an herbal formulation containing E. sessiliflorus, along with Panax ginseng, Astragalus membranaceus, Glycyrrhiza uralensis, and other herbs, has exhibited remarkable improvements in blood glucose (442.50 ± 36.00 mg/dL), cholesterol (159.20 ± 18.40 mg/dL), blood glycated hemoglobin (6.30 ± 0.8 mg/dL), and plasma triglyceride levels (99.40 ± 15.00 mg/dL) in db/db mice (C57BL/Ks mice), which are commonly used as a model for diabetes. This formulation holds potential for the prevention and treatment of diabetes and its complications [100]. Further research has shown that the stems of E. sessiliflorus affect diabetes and its complications by inhibiting the activity of aldose reductase [101]. Moreover, the flavonoids present in the stems of E. sessiliflorus (100 mg/kg and 300 mg/kg) can regulate the upregulation of INSRR, HNF1A, and GLUT10 expression, thereby modulating blood glucose levels and alleviating disruptions in lipid metabolism [102].
The above findings emphasize the potential of E. sessiliflorus as a natural remedy for managing glucose metabolism and addressing issues associated with diabetes. However, further research is necessary to explore the underlying mechanisms and optimize the utilization of E. sessiliflorus in diabetes treatment.
6. Effects on the Cardiovascular System
The polyphenols extracted from E. sessiliflorus fruits (75 mg/kg and 150 mg/kg) have been found to significantly reduce the protein expression levels of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, phospho-p38, and phospho-ERK1/2. As a result, they can effectively lower serum lipid levels, adhesion molecule levels, and inflammatory factor levels in rats, reducing lipid deposition in the aorta. This demonstrates a preventive effect against atherosclerosis [103].
Furthermore, the 3,4-seco-lupane triterpenoids (chiisanoside, divaroside, sessiloside-A, and chiisanogenin) found in E. sessiliflorus leaves exhibit potent antiarrhythmic activity. They are capable of reducing malondialdehyde levels, increasing serum superoxide dismutase levels, and maintaining the expression levels of Na+-K+-ATPase, Ca2+-Mg2+-ATPase, and apoptosis-related proteins. Among these, divaroside (41.6 mg/kg) has shown superior efficacy in treating ventricular arrhythmias induced by BaCl2. The unique glycosyl chain structure of divaroside may contribute to its effectiveness in sustaining the expression of PKA, thus improving its antiarrhythmic properties [104]. Other terpenoids found in E. sessiliflorus have also demonstrated potent inhibitory activity against ACE, ranging from 1.8 μg/mL to 2.9 μg/mL, enhancing blood flow and exerting antihypertensive effects [8].
Moreover, the ethanol extract of E. sessiliflorus fruits (2, 20, and 200 μg/mL) has shown the ability to enhance the expression of endothelial nitric oxide (NO) synthase, thereby increasing the production of endothelial NO. This was assessed by measuring the fluorescence intensity of 4-amino-5-methylamino-2′,7′-difluoro-luorescein diacetate (with the control group set at 100%), which showed values of 127.54 ± 14.10%, 141.47 ± 8.16%, and 167.54 ± 8.41%, respectively. This enhanced endothelium-dependent NO release is known to improve vasodilation and blood circulation, providing significant benefits to the cardiovascular system. The vasorelaxation capability of E. sessiliflorus fruits is similar to that of Ginkgo biloba leaf extract, further contributing to its potential cardiovascular benefits. Additionally, the ethanol extract of E. sessiliflorus fruits is similar to captopril, a commonly used ACE inhibitor, in significantly reducing ACE activity and improving vasodilation in spontaneously hypertensive rats, thereby lowering blood pressure. The hypotensive effect of a high-dose ethanol extract of E. sessiliflorus fruits (600 mg/kg) is comparable to that of captopril (100 mg/kg) [11,105].
During metabolomic investigations of E. sessiliflorus fruits, significant variations in the metabolic process have been observed. The hypotensive effect of E. sessiliflorus fruits is achieved through the amelioration of negative metabolic effects associated with hypertension. This mechanism differs slightly from the metabolic process induced by captopril, a commonly used hypotensive medication. Notably, the presence of succinate and betaine within the metabolic products of E. sessiliflorus fruits suggests their potential utility as biomarkers for its hypotensive effect [106].
In addition to its hypotensive effects, E. sessiliflorus demonstrates remarkable potential in ameliorating various parameters associated with metabolic health. Animal studies have revealed that the ethanol extract of E. sessiliflorus roots (500 mg/kg and 700 mg/kg) can effectively mitigate adverse changes induced by a high-fat diet. Specifically, E. sessiliflorus has been found to improve body weight management by preventing excessive weight gain. After administering 500 mg/kg to mice, their body weight decreased to 84.00 ± 7.00% (compared to the blank group) [107]. Moreover, the aqueous-alcohol extract of E. sessiliflorus fruits (3 mg) significantly influences lipid metabolism, as evidenced by its ability to reduce total cholesterol, triglyceride, and free fatty acid levels. This comprehensive modulation of lipid profiles contributes to the potential therapeutic role of E. sessiliflorus in combating hyperlipidemia [108]. The above findings highlight the diverse metabolic effects of E. sessiliflorus fruits, contributing to their potential therapeutic applications in managing hypertension, hyperlipidemia, and related cardiovascular conditions.
7. Effects on the Immune System
Polysaccharides are considered vital bioactive components in plants and hold immense research potential and economic value. E. sessiliflorus is rich in polysaccharides, which exhibit diverse effects, including scavenging free radicals, combating fatigue, enhancing tolerance to hypoxia, and boosting immune regulatory capabilities. Initial studies on E. sessiliflorus have isolated three polysaccharides that demonstrate varying degrees of immune regulatory activity within the concentration range of 25–200 μg/mL. These polysaccharides have shown the ability to stimulate lymphocyte proliferation, enhance phagocytosis in peritoneal macrophages, elevate NO release, and activate the cytokine TNF-α [109]. This comprehensive array of activities highlights their immunomodulatory effects, underscoring their vast prospects and economic significance.
In addition, E. sessiliflorus extracts have been found to positively affect the immune system in both normal and tumor-bearing mice. In normal animals, the roots of E. sessiliflorus extract (300 mg/kg) enhance the restoration of spleen and thymus weights after forced swimming experiments while increasing spleen cell counts and immune-related cytokine TNF-α levels. However, their impact on the expression of IFN-γ and IL-2 is comparatively less pronounced [110]. In tumor-bearing mice, the ethanol extract of E. sessiliflorus roots (500 mg/kg) demonstrates anticancer effects by promoting immune cell proliferation and enhancing macrophage NO production without adversely affecting the proliferation of normal mouse spleen cells [111].
The immunomodulatory effects of E. sessiliflorus are not limited to the pharmaceutical industry but also play a significant role in enhancing disease resistance in livestock. The ethanol extract of E. sessionliflorus fruits has been demonstrated to enhance the vitality and growth rate of 3D4/31 porcine macrophages in a concentration-dependent manner. At 120 μg/mL, it maximally increased cell viability by 11.73% ± 2.02% while upregulating intracellular reactive oxygen species (ROS) levels. Furthermore, pretreatment with the fruits’ ethanol extract augments the in vitro bactericidal activity of these cells against Escherichia coli. Intriguingly, the fruits’ ethanol extract, similar to phorbol 12-myristate 13-acetate, effectively improves the expression levels of NF-κB and TNF-α, which in turn influence lipid synthesis and fatty acid oxidation metabolism.
Moreover, the combination of both the fruits’ ethanol extract (120 μg/mL) and phorbol 12-myristate 13-acetate demonstrates therapeutic potential in restoring NF-κB, TNF-α, and lipid metabolism levels. This combination holds promise as an effective feed additive to enhance the immunity of livestock [112]. The above findings highlight the multifaceted immunomodulatory effects of E. sessiliflorus, not only in human health but also in the agricultural sector, showcasing its potential for commercial applications in medicine and livestock feed supplements.
8. Anti-Tumor Activity
E. sessiliflorus has been found to possess significant anti-tumor activity, primarily attributed to its diverse array of bioactive compounds. Triterpenoids isolated from E. sessiliflorus have shown promising anti-tumor effects. For instance, chiisanoside, derived from E. sessiliflorus, exhibits in vivo anti-tumor activity by promoting cell apoptosis and inhibiting angiogenesis. In mice bearing the H22 tumor, chiisanoside (120 mg/kg and 240 mg/kg) effectively suppresses tumor growth while upregulating the expression of cytokines such as IL-2, TNF-α, and IFN-γ. Furthermore, it demonstrates rapid absorption in vivo and shows targeting properties towards the liver and small intestine [113].
Another triterpenoid with anti-tumor potential in E. sessiliflorus fruits is calenduloside E 6′-methyl ester, an oleanane-type compound. This triterpenoid has been reported to induce apoptosis in CT-26 mouse colon cancer cells in the range of 2.5 to 25 µM. The number of cells in the sub-G1 population increased from 5.1% to 99.1%, respectively. Furthermore, it can inhibit tumor growth in the CT-26 animal model. The induction of apoptosis by calenduloside E 6′-methyl ester is mediated by activating the caspase cascade, which plays a crucial role in apoptotic mechanisms [34]. Similarly, sessiligenin, another compound found in E. sessiliflorus, exerts its effects by modulating multiple targets within the PI3K/AKT signaling pathway, ultimately leading to apoptosis induction in HepG2 cells [114].
E. sessiliflorus also contains other compounds that exhibit significant anti-tumor activities. Hyperoside, for example, stands out for its ability to inhibit ERK activity, which suppresses the transactivation of activator protein 1 and the phosphorylation of p90RSK, CREB, and STAT3 induced by ultraviolet radiation. Activator protein 1 is a key transcription factor involved in inflammation and various cancers, including skin, breast, and cervical [115]. Cyanidin-3-O-sambubioside, another compound in E. sessiliflorus, has been found to effectively reduce the secretion and expression of matrix metalloproteinase-9 within the concentration range of 1–30 μg/mL, thereby suppressing the metastatic process of breast cancer cells, particularly in aspects related to angiogenesis and invasion [12].
Furthermore, the stem bark extract of E. sessiliflorus (50 μg/mL) has demonstrated the ability to inhibit tumor growth and modulate immune activity through various pathways. On the one hand, it induces non-apoptotic cell death in human breast cancer cells (MDA-MB-231 and MCF-7) through ROS-dependent and ROS-independent mechanisms involving mitochondrial induction [116]. On the other hand, it (1 μg/mL and 10 μg/mL) exerts tumor-inhibitory effects by promoting NO production by macrophages, accelerating thymocyte proliferation, and inhibiting tumor cell proliferation [117]. The above findings highlight E. sessiliflorus as a valuable medicinal herb with diverse anti-tumor constituents, positioning it as a significant asset in anti-tumor therapies.
9. Other Pharmacological Effects
E. sessiliflorus possesses a wide range of pharmacological effects recognized in recent studies. One notable effect is its potential as an analgesic agent. E. sessiliflorus has shown the ability to ameliorate formalin-induced pain, making it suitable for relieving both general and neuropathic pain from nerve injury [118]. Triterpenoids and polyphenols in E. sessiliflorus have inhibited BV2 and RAW264.7 cells induced by lipopolysaccharides. These compounds effectively reduce the production of inflammatory mediators such as NO, PGE2, TNF-α, IL-1β, and IL-6, thereby exerting potent anti-inflammatory effects [9,16,83]. Additionally, the root barks of E. sessiliflorus have been found to inhibit osteoclast differentiation activated by RANKL in bone marrow macrophages and prevent bone loss induced by ovariectomy [119]. Moreover, E. sessiliflorus has demonstrated chondrogenic regulatory activity by enhancing the mRNA expression of markers associated with cartilage formation [120]. The above findings highlight the therapeutic potential of E. sessiliflorus in treating various bone-related disorders. Furthermore, E. sessiliflorus possesses neuroprotective effects [121], hepatoprotective effects [122], and protective effects on the gastrointestinal tract [123]. These additional pharmacological effects further broaden the potential applications of E. sessiliflorus in various health conditions.
This entry is adapted from the peer-reviewed paper 10.3390/molecules28186564
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