Phytochemistry and Pharmacology of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y.Hu: A Review.

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. This review aims to provide a detailed exposition of E. sessiliflorus from various perspectives, including phytochemistry and pharmacological effects, to lay a solid foundation for further investigations into its potential uses. Moreover, this review aims to introduce innovative ideas for the rational utilization of E. sessiliflorus resources and the efficient development of related products. To date, a total of 314 compounds have been isolated and identified from E. sessiliflorus, encompassing terpenoids, phenylpropanoids, flavonoids, volatile oils, organic acids and their esters, nitrogenous compounds, quinones, phenolics, and carbohydrates. Among these, triterpenoids and phenylpropanoids are the primary bioactive components, with E. sessiliflorus containing unique 3,4-seco-lupane triterpenoids. These compounds have demonstrated promising properties such as anti-oxidative stress, anti-aging, antiplatelet aggregation, and antitumor effects. Additionally, they show potential in improving glucose metabolism, cardiovascular systems, and immune systems. Despite some existing basic research on E. sessiliflorus, further investigations are required to enhance our understanding of its mechanisms of action, quality assessment, and formulation studies. A more comprehensive investigation into E. sessiliflorus is warranted to delve deeper into its mechanisms of action and potentially expand its pharmaceutical resources, thus facilitating its development and utilization.

Protective Effects of 3,4-Seco-Lupane Triterpenes from Food Raw Materials of the Leaves of Eleutherococcus Senticosus and Eleutherococcus Sessiliflorus on Arrhythmia Induced by Barium Chloride.

As a traditional wild vegetable and food raw material, the leaves of Eleutherococcus senticosus and Eleutherococcus sessiliflorus are rich in 3,4-seco-lupane triterpenes, including chiisanoside (CSS), divaroside (DVS), sessiloside-A (SSA), and chiisanogenin (CSG). This study was conducted to evaluate the anti-arrhythmic effects of these 3,4-seco-lupane triterpenes. Evaluation of the cytotoxicity of compounds was performed by measuring cell viability and apoptosis with the CCK-8 assay. In vivo, arrhythmia was induced by rapid injection of BaCl2 via rat caudal vein. The occurrence time and duration of arrhythmias in rats were studied. The levels of SOD and MDA in serum, and Na+ -K+ -ATPase and Ca2+ -Mg2+ -ATPase in myocardial homogenate were detected by ELISA. The histopathological changes of rats myocardial were observed by HE staining. Changes in the expression of PKA and related proteins were detected by Western blot. The 3,4-seco-lupane triterpenes interactions with protein kinase A were analyzed by molecular docking. In the present study, we found that 3,4-seco-lupane triterpenes exhibited powerful anti-arrhythmic activity, especially DVS completely relieved the ventricular arrhythmia induced by BaCl2 . This study suggests that the leaves of E. senticosus and E. sessiliflorus might be used as functional food materials to prevent arrhythmia, and DVS can potentially be further developed as an anti-arrhythmic drug.

Eleutherococcus sessiliflorus Inhibits Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-Induced Osteoclast Differentiation and Prevents Ovariectomy (OVX)-Induced Bone Loss.

The aim of this study was to evaluate the effects of root bark of Eleutherococcus sessiliflorus (ES) on osteoclast differentiation and function in vitro and in vivo. In vitro, we found that ES significantly inhibited the RANKL-induced formation of TRAP-positive multinucleated osteoclasts and osteoclastic bone resorption without cytotoxic effects. ES markedly downregulated the expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1); c-Fos; and osteoclast-related marker genes, such as TRAP, osteoclast-associated receptor (OSCAR), matrix metalloproteinase-9 (MMP-9), calcitonin receptor, cathepsin K, the 38 kDa d2 subunit of the vacuolar H+-transporting lysosomal ATPase (Atp6v0d2), dendritic cell-specific transmembrane protein (DC-STAMP), and osteoclast-stimulatory transmembrane protein (OC-STAMP). These effects were achieved by inhibiting the RANKL-mediated activation of MAPK signaling pathway proteins, including p38, ERK, and JNK. In vivo, ES attenuated OVX-induced decrease in bone volume to tissue volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and bone mineral density, but increased trabecular separation (Tb.Sp) in the femur. Collectively, our findings showed that ES inhibited RANKL-activated osteoclast differentiation in bone marrow macrophages and prevented OVX-mediated bone loss in rats. These findings suggest that ES has the potential to be used as a therapeutic agent for bone-related diseases, such as osteoporosis.

Effects of Eleutherococcus Extract Mixture on Endochondral Bone Formation in Rats.

Eleutherococcus extract mixture (EEM) is an herbal mixture of dried stem of Eleutherococcus sessiliflorus and germinated barley, which has been highly effective, in previous screening and among the traditional medicines to tonify innate qi and acquired qi, respectively. In this study, we investigate the effects of EEM on endochondral bone formation. Female adolescent rats were given EEM, growth hormone or vehicle for 10 days. Tetracycline was intraperitoneally injected to light the fluorescent band 72 h before sacrifice to determine endochondral bone formation. In order to evaluate endocrine or paracrine/autocrine mechanisms, expressions of insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), or bone morphogenetic protein 2 (BMP2) were evaluated after EEM administration in liver or growth plate (GP). EEM oral administration significantly increased endochondral bone formation and proliferative and hypertrophic zonal heights of tibial GP. EEM also upregulated hepatic IGF1 and IGFBP3 mRNA expressions, and IGF1 and BMP2 expressions in GP. Taken together, EEM increases endochondral bone formation through stimulating proliferation and hypertrophy with upregulation of hepatic IGF1 and IGFBP3 expressions. Considering immunohistochemical studies, the effect of EEM may be due to increased local IGF1 and BMP2 expression in GP, which may be considered growth hormone (GH)-dependent endocrine and autocrine/paracrine pathways.

Triterpenoids from the leaves of Eleutherococcus sessiliflorus, and their antiproliferative activities in TNF-α induced HFLS-RA cells.

Five undescribed elesesterpenes L-U, along with nine known 3,4-seco-lupane-type triterpenoids were isolated from the leaves of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S. Y. Hu. Elesesterpene L-S, and U were lupane-type triterpenoids, whereas elesesterpene T was an oleanane-type triterpenoid, probably artifact, as suggested by LC-MS analysis. Out of the nine known compounds, five were initially identified in E. sessiliflorus. Moreover, their structures were definitively determined using spectroscopic analyses, and the absolute configurations of elesesterpenes L-M and sachunogenin 3-O-glucoside were clarified using X-ray crystallographic techniques. The absolute configuration of elesesterpene T was determined by measuring and calculating its ECD. In addition, all compounds were tested to examine their ability to inhibit the proliferation of HFLS-RA cells induced by TNF-α in vitro. Elesesterpene M, chiisanogenin, chiisanoside, and 3-methylisochiisanoside significantly inhibited HFLS-RA proliferation.

Cytotoxic and anti-tumor effects of 3,4-seco-lupane triterpenoids from the leaves of Eleutherococcus sessiliflorus against hepatocellular carcinoma.

A rich of 3,4-seco-lupane triterpenoids (3,4-SLT), including chiisanoside (CSS), divaroside (DVS), sessiloside-A1 (SSA), chiisanogenin (CSG), sessiligenin (SSG), were isolated from the ethanol extract of the leaves of Eleutherococcus sessiliflorus (LES). The present study was performed to explore the cytotoxic and anti-tumor effects of the isolated five ones, as well as potential molecular mechanisms. The results of a CCK-8 assay demonstrated that these 3,4-SLT can inhibit the growth of HepG2 cells, and SSG showed the most significant cytotoxicity. Hoechst 33258 fluorescence staining and Annexin V-FITC/PI staining indicated that 3,4-SLT in LES can induce HepG2 cell apoptosis effectively. The AutoDock Vina program was used to simulate molecular docking of drugs and targets to discuss possible pharmacological mechanisms. Besides, western blot and qRT-PCR results indicated that SSG can inhibit PI3K/AKT signaling pathway through controlling multi-targets. This study suggested that 3,4-SLT might become a new research hotspot for antineoplastic drugs.

Elesesterpenes A-K: Lupane-type Triterpenoids From the Leaves of Eleutherococcus sessiliflorus.

Elesesterpenes A-K (1-11), eleven new lupane-type triterpenoids, triterpenoid glycosides, and nortriterpenoid were isolated from the leaves of Eleutherococcus sessiliflorus. Their structures and relative configurations were completely elucidated by a combination of diverse methods including physical, spectroscopic data. The absolute configuration of elesesterpenes A-B (1-2) was defined by single-crystal X-ray diffraction. Meanwhile, all the isolates were evaluated for anti-inflammatory activities on lipopolysaccharide-induced nitric oxide production in BV2 microglial cells, and antiproliferative activities against human hepatoma (HepG2), human lung adenocarcinoma (A549), and human glioma cells (LN229) in vitro. It was found that some of them exhibited obvious anti-inflammatory activities and potent antiproliferative activities.

3,4-seco-lupane triterpene derivatives with cytotoxic activities from the leaves of Eleutherococcus sessiliflorus.

A new 3,4-seco-lupane triterpene, named sessiligenin (1), along with four known 3,4-seco-lupane triterpene derivatives (chiisanogenin 2, chiisanoside 3, divaroside 4, and sessiliside-A1 5) were isolated from the ethanol extract of the leaves of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y. Hu by silica gel column chromatography, and their structures were determined by spectroscopic data. Furthermore, all these compounds were tested for their cytotoxicities against cancer cell lines HepG2, B16-F10, Lewis and YAC-1, as well as normal cell lines NCTC1469 and HL-7702, and significant cytotoxicities had been found for this new compound (sessiligenin 1) which exhibited much lower cytotoxicities against normal cell lines NCTC1469 and HL-7702. It was deduced that the reduce of glycosyl from the structures of these 3,4-seco-lupane triterpenoids enhanced the cytotoxicities. Furthermore, with the complete removal of glycosyl group and the 11-hydroxyl and 3-carboxyl formed by the opening of the lactone ring, the cytotoxicity increased significantly.

A new 3,4-seco-lupane triterpenene glycosyl ester from the leaves of Eleutherococcus sessiliflorus.

A new minor 3,4-seco-lupane triterpenene glycosyl ester, named sessiloside-A1 (1), along with three known 3,4-seco-lupane triterpenenes were isolated from the which alcohol extract of the leaves of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y. Hu by silica gel column chromatography, and their structures were determined by spectroscopic methods (UV, IR, NMR and HRMS). Compound 1 was elucidated to be ß-D-glucopyranosyl ester of chiisanogenin. At the same time, a new efficient two-step enzymatic hydrolysis method was established to transform chiisanoside (2) → divaroside (3) → 1.

Chemical constituents of Eleutherococcus sessiliflorus extract and its sedative-hypnotic effect.

The present study was designed to investigate the chemical constituents and bioactivities of the roots of Eleutherococcus sessiliflorus (E. sessiliflorus). The compounds were isolated through various chromatography techniques and elucidated by mass spectrometric (MS), 1D- and 2D-NMR analyses. The sedative-hypnotic effect of E. sessiliflorus ethanol extract and its fractions (acetic ether, n-butanol and water fraction) were also investigated. In the chemical constituent study, one new compound, 3-ethyl-5-hydroxy-3-(hydroxymethyl) pentyl-3-(3,4-dihydroxyphenyl) acrylate and fourteen known compounds were isolated and identified. The chromatographic fingerprint of E. sessiliflorus was established by UPLC-PDA-MS/MS analysis. In bioactivity study, it was found that the water fraction of E. sessiliflorus extract could prolong pentobarbital-induced sleeping time more than that of the other fractions of E. sessiliflorus extract in mice, which provided a basis for future study on sedative-hypnotic effect of the chemical constituents in E. sessiliflorus.

Contrasting genetic patterns between two coexisting Eleutherococcus species in northern China.

Climate oscillations are the key factors to understand the patterns in modern biodiversity. East Asia harbors the most diverse temperate flora, largely because an extensive terrestrial ice cap was absent during repeated Pleistocene glaciation-interglacial cycles. Comparing the demographic histories of species that are codistributed and are close relatives may provide insight into how the process of climate change influences species ranges. In this study, we compared the spatial genetic structure and demographic histories of two coexisting Eleutherococcus species, Eleutherococcus senticosus and E. sessiliflorus. Both species are distributed in northern China, regions that are generally considered to be sensitive to climatic fluctuations. These regions once hosted temperate forest, but this temperate forest was replaced by tundra and taiga forest during the Last Glacial Maximum (LGM), according to pollen records. Using three chloroplast DNA fragments, we assessed the genetic structure of 20 and 9 natural populations of E. senticosus and E. sessiliflorus, respectively. Extremely contrasting genetic patterns were found between the two species; E. sessiliflorus had little genetic variation, whereas E. senticosus had considerably higher levels of genetic variation (15 haplotypes). We speculated that a recent severe bottleneck may have resulted in the extremely low genetic diversity in E. sessiliflorus. In E. senticosus, populations in Northeast China (NEC) harbored all of the haplotypes found in this species and included private haplotypes. The populations in NEC had higher levels of genetic diversity than did those from North China (NC). Therefore, we suggest that both the NC and NEC regions can sustain LGM refugia and that lineage admixture from multiple refugia took place after the LGM elevated the local genetic diversity in NEC. In NEC, multiple genetic hot spots were found in the Changbai Mountains and the Xiaoxing'an Range, which implied that multiple locations in NEC may sustain LGM refugia, even in the Xiaoxing'an Range.