Eleutheroside E Research Articles

Decoding the mechanism of Eleutheroside E in treating osteoporosis via network pharmacological analysis and molecular docking of osteoclast-related genes and gut microbiota.

Eleutheroside E (EE) is an anti-inflammatory natural compound derived from the edible medicinal herb Acanthopanax senticosus. This study aims to investigate the underlying mechanism of the anti-osteoporosis action of EE through network pharmacology, molecular docking and gut microbiota. Network pharmacology was used to explore the potential core targets and main pathways mediated by EE in osteoporosis (OP) treatment. Molecular docking was exploited to investigate the interactions between the active anti-OP compounds in EE and the potential downstream targets. Following the multi-approach bioinformatics analysis, ovariectomy (OVX) model was also established to investigate the in vivo anti-OP effects of EE. The top 10 core targets in PPI network were TP53, AKT1, JUN, CTNNB1, STAT3, HIF1A, EP300, CREB1, IL1B and ESR1. Molecular docking results that the binding energy of target proteins and the active compounds was approximately between -5.0 and -7.0 kcal/mol, which EE has the lowest docking binding energy with HIF1A. Enrichment analysis of GO and KEGG pathways of target proteins indicated that EE treatment could potentially alter numerous biological processes and cellular pathways. In vivo experiments demonstrated the protective effect of EE treatment against accelerated bone loss, where reduced serum levels of TRAP, CTX, TNF-α, LPS, and IL-6 and increased bone volume and serum levels of P1NP were observed in EE-treated mice. In addition, changes in gut microbiota were spotted by 16S rRNA gene sequencing, showing that EE treatment increased the relative abundance of Lactobacillus and decreased the relative abundance of Clostridiaceae. In summary, these findings suggested that the characteristics of multi-target and multi-pathway of EE against OP. In vivo, EE prevents the onset of OP by regulating gut microbiota and inflammatory response and is therefore a potential OP drug.

Protective effects of Eleutheroside E against high-altitude pulmonary edema by inhibiting NLRP3 inflammasome-mediated pyroptosis

Eleutheroside E (EE) is a primary active component of Acanthopanax senticosus, which has been reported to inhibit the expression of inflammatory genes, but the underlying mechanisms remain elusive. High-altitude pulmonary edema (HAPE) is a severe complication of high-altitude exposure occurring after ascent above 2500 m. However, effective and safe preventative measures for HAPE still need to be improved. This study aimed to elucidate the preventative potential and underlying mechanism of EE in HAPE. Rat models of HAPE were established through hypobaric hypoxia. Mechanistically, hypobaric hypoxia aggravates oxidative stress and upregulates (pro)-inflammatory cytokines, activating NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis, eventually leading to HAPE. EE suppressed NLRP3 inflammasome-mediated pyroptosis by inhibiting the nuclear translocation of nuclear factor kappa-Β (NF-κB), thereby protecting the lung from HAPE. However, nigericin (Nig), an NLRP3 activator, partially abolished the protective effects of EE. These findings suggest EE is a promising agent for preventing HAPE induced by NLRP3 inflammasome-mediated pyroptosis.

Effect of Eleutheroside E on an MPTP-Induced Parkinson's Disease Cell Model and Its Mechanism.

This research investigated the effects of eleutheroside E (EE) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease cell model and its mechanism. Methods: To create a cell model of Parkinson's disease, MPTP (2500 μmol/L) was administered to rat adrenal pheochromocytoma cells (PC-12) to produce an MPTP group. Selegiline (50 μmol/L) and MPTP had been administered to the positive group beforehand. The eleutheroside E group was divided into low-, medium-, and high-concentration groups, in which the cells were pretreated with eleutheroside E at concentrations of 100 μmol/L, 300 μmol/L, and 500 μmol/L. Next, MPTP was added to the cells separately. The CCK-8 method was used to measure the cell survival rate. Apart from the CCK-8 method, mitochondrial membrane potential detection, cell reactive oxygen species (ROS) detection, and other methods were also adopted to verify the effect of low, medium, and high concentrations of eleutheroside E on the MPTP-induced cell model. Western blot analysis was used to detect changes in the expression of intracellular proteins CytC, Nrf2, and NQO1 to clarify the mechanism. The results are as follows. Compared with the MPTP group, the survival rates of cells at low, medium, and high concentrations of eleutheroside E all increased. The mitochondrial membrane potential at medium and high concentrations of eleutheroside E increased. The ROS levels at medium and high concentrations of eleutheroside E decreased. Moreover, the apoptosis rate decreased and the expression levels of the intracellular proteins CytC, Nrf2, and NQO1 were upregulated. Conclusion: Eleutheroside E can improve the MPTP-induced apoptosis of PC-12 cells by increasing the mitochondrial membrane potential and reducing the level of intracellular reactive oxygen species (ROS). Moreover, the apoptosis of cells is regulated by the expression of CytC, Nrf2, and NQO1 proteins.

The protective effect of Eleutheroside E against the mechanical barrier dysfunction triggered by lipopolysaccharide in IPEC-J2 cells

Eleutheroside E (EE) exhibits immunocompetence, antioxidant, and anti-inflammatory activity. Lipopolysaccharide (LPS) can elicit a strong immune response. In vitro experiments were used to explore whether EE protects intestinal porcine jejunum epithelial cells (IPEC-J2) barriers from LPS stress. The experiment was divided into group C (control group: complete medium), group E (group C + 0.1 mg/mL EE), group L (group C + 10 μg/mL LPS), and group EL (adding 0.1 mg/mL EE for 6 h, and then adding 10 μg/mL LPS for culture). Finally, the cell proliferation, permeability, mRNA expression of cytokines, mRNA and protein expression of tight junctions (TJs) were analyzed. The result show that, when compared to the C group, EE significantly promoted the proliferation of IPEC-J2 at 58 h and showed low permeability (P < 0.05), the anti-inflammatory cytokines IL-10 and TGF-β mRNA expression were increased extremely significantly, the inflammatory cytokines IL-6, TNF-α, and IFN-γ mRNA expression were extremely significantly decreased (P < 0.01), the mRNA and protein expression of TJ were significantly increased in group E (P < 0.05). However, LPS showed a damaging effect. EL group compared with L group, the cell index (CI) value was higher at 58 h (P < 0.05), the permeability was significantly lower (P < 0.05), the mRNA expressions of the inflammatory cytokines were down-regulated(P < 0.01), and the TJ mRNA and protein relative expression were increased (P < 0.05). In summary, the addition of EE protects the LPS-induced increase in permeability of IPEC-J2, potentially by expressing high levels of TJ proteins and inhibiting the increase of inflammatory cytokines.

Eleutheroside E functions as anti-cervical cancer drug by inhibiting the phosphatidylinositol 3-kinase pathway and reprogramming the metabolic responses.

Cervical cancer (CC) is the common female malignant tumour with non-negligible morbidity and mortality. Eleutheroside E (EE) has anti-oxidative stress, anti-inflammatory and anti-proliferation effects in diverse disease models. However, its anti-tumour role remains unclear. The cell viability, apoptosis rate and protein expressions were detected by CCK-8, flow cytometry and western blot assays, respectively. The metabolic profile was performed by GC/MS analysis. Furthermore, the effect of EE on CC was verified in nude mice. EE notably decreased the viability and increased the cell apoptosis, which could be reversed with 740Y-P treatment. EE treatment changed the metabolic categories of SiHa cells. The fatty acids signalling pathway was the most outstanding differential pathway. Myo-inositol prominently enhanced the level of phosphorylated Akt in a dose-dependent way. Moreover, EE declined the tumour volume and weight and the proliferation, but promoted the apoptosis in vivo. EE reduced the relative expression of phosphorylated PI3K and Akt. However, all these in-vivo results were observably antagonized with myo-inositol treatment. EE plays an anti-tumour role in CC via inhibiting the PI3K pathway and reprogramming the metabolic responses.

Eleutheroside E supplementation prevents radiation-induced cognitive impairment and activates PKA signaling via gut microbiota

Radiation affects not only cognitive function but also gut microbiota. Eleutheroside E (EE), a principal active compound of Acanthopanax senticosus, has a certain protective effect on the nervous system. Here, we find a four-week EE supplementation to the 60Co-γ ray irradiated mice improves the cognition and spatial memory impairments along with the protection of hippocampal neurons, remodels the gut microbiota, especially changes of Lactobacillus and Helicobacter, and altered the microbial metabolites including neurotransmitters (GABA, NE, ACH, 5-HT) as well as their precursors. Furthermore, the fecal transplantation of EE donors verifies that EE alleviated cognition and spatial memory impairments, and activates the PKA/CREB/BDNF signaling via gut microbiota. Our findings provide insight into the mechanism of EE effect on the gut-brain axis and underpin a proposed therapeutic value of EE in cognitive and memory impairments induced by radiation.

Eleutheroside E alleviates cerebral ischemia-reperfusion injury in a 5-hydroxytryptamine receptor 2C (Htr2c)-dependent manner in rats

ABSTRACT Stroke is the central disorder underlined by ischemia-reperfusion (I/R) injury. Eleutheroside E (EE) is administered as the shield in some ischemia tissues with anti-inflammatory action. However, whether EE defends I/R-induced damage in the brain remains unknown. Here, we demonstrated that EE significantly alleviated the cerebral I/R injury and reduced the apoptosis of hippocampal neuron cells in rats. During the anti-apoptosis process, EE significantly upregulated the expression of 5-hydroxytryptamine receptor 2C (Htr2c) gene. Silencing Htr2c expression dramatically weakened the protective effect of EE on I/R-induced apoptosis of rat hippocampal neuron. EE-regulated Htr2c also remarkably inhibited the expression of caspase-3, −6 and −7, thereby suggesting a plausible anti-apoptosis mechanism associated with Htr2c/caspase axis. These findings elicit the potentially clinical strategy that targets Htr2c to improve outcome of ischemia brain.

Eleutheroside E reduces intestinal fat accumulation in Caenorhabditis elegans through neuroendocrine signals.

Acanthopanax senticosus, a small woody shrub of the family Araliaceae, can be used as a functional food with multiple biological activities. Eleutheroside E (EE), an important active component of A. senticosus, has significant effects on neurological diseases. However, whether EE can regulate lipid metabolism has not been reported. The brain can mediate communication between neurons and intestinal cells through long-distance neuroendocrine signals. We speculated that EE might regulate the intestinal lipid metabolism of Caenorhabditis elegans through neuroendocrine signals. First, we found that EE reduced the intestinal fat content of C. elegans, without affecting development, reproduction, food intake or movement. In addition, EE significantly regulated genes and metabolites related to lipid metabolism. EE extensively affected fatty acid synthesis, β-oxidation and lipolysis processes, and regulated the content of various fatty acid and lipid metabolism intermediates. We finally proved that EE reduced intestinal fat storage through serotonin and neuropeptide flp-7-npr-22 pathways in the nervous system. EE is expected to be a functional food that regulates lipid metabolism. © 2022 Society of Chemical Industry.

Identification of targets and mechanisms for Eleutheroside E in the treatment of cancer

Eleutheroside E (EE) is a monomer compound isolated from Acanthopanax senticosus , which has functions of antifatigue, antioxidation, and immune regulation. However, the function of EE in inhibiting cancer has rarely been reported. In this study, we used bioinformatics to determine the role and mechanisms of EE in inhibiting breast cancer (BRCA), prostate cancer (PRAD), lung cancer (LUAD), and bladder cancer (BLCA). Finally, the MTT method was used to evaluate the inhibitory effect of EE on breast cancer MDA-MB-231 cells, and the target genes were determined by qRT-PCR. The results showed that the survival rate of MDA-MB-231 cells was reduced by 27.33% after 400 μg/mL EE treatment. The results of qRT-PCR showed that EE down-regulated target genes in breast cancer cells, which was consistent with our predicted results. Moreover, our results indicated that EE may have impact on the transcription and translation of BLCA cells by targeting ADCY2, ADCY5 and JUN. In BRCA, we identified three targets for EE. In addition, EE affected DNA repair and the development of BRCA by affecting the expression of RAD51. In LUAD, we identified 9 targets for EE, 8 of which were related to DNA repair. EE inhibited PRAD by targeting ADCY8. Our research was the first report on the targets and mechanisms of EE for suppressing cancer combined with clinical data. Our research also provides theoretical support for using EE to suppress cancer.

The Therapeutic Effect of Acanthopanax senticosus Components on Radiation-Induced Brain Injury Based on the Pharmacokinetics and Neurotransmitters.

Acanthopanax senticosus (AS) is a medicinal and food homologous plant with many biological activities. In this research, we generated a brain injury model by 60Co -γ ray radiation at 4 Gy, and gavaged adult mice with the extract with AS, Acanthopanax senticocus polysaccharides (ASPS), flavones, syringin and eleutheroside E (EE) to explore the therapeutic effect and metabolic characteristics of AS on the brain injury. Behavioral tests and pathological experiments showed that the AS prevented the irradiated mice from learning and memory ability impairment and protected the neurons of irradiated mice. Meanwhile, the functional components of AS increased the antioxidant activity of irradiated mice. Furthermore, we found the changes of neurotransmitters, especially in the EE and syringin groups. Finally, distribution and pharmacokinetic analysis of AS showed that the functional components, especially EE, could exert their therapeutic effects in brain of irradiated mice. This lays a theoretical foundation for the further research on the treatment of radiation-induced brain injury by AS.

Mitigative effects of Eleutheroside E against the mechanical barrier dysfunction induced by soybean agglutinin in IPEC-J2 cell line.

Soybean agglutinin (SBA) is an anti-nutritional factor which decreases the mechanical barrier function in intestinal porcine jejunum epithelial cells (IPEC-J2). Eleutheroside E (EE) is a key part of Acanthopanax senticosus to exert pharmacological effects. This study aims to investigate the effects of EE on the barrier function in IPEC-J2 cells and to determine the ability of EE to enhance the protective effect of barrier function against SBA exposure. The IPEC-J2 cells were cultured in mediums with concentration of 0.1mg/ml EE, 0.5ml/ml SBA and 0.1mg/ml EE pre-treated then treated with 0.5mg/ml SBA. Then, the transepithelial electric resistance (TEER) value, inflammatory cytokines mRNA expression, tight junction mRNA and protein expression were tested by epithelial Voltohm meter, q-PCR and Western blot method respectively. The results showed that cells treated with 0.1mg/ml EE had lower permeability (p<0.05) while 0.5mg/ml SBA treatment had higher permeability through tested TEER, and higher tight junction proteins (Claudin-3 and ZO-1) expressions and genes (Claudin-3, Occludin and ZO-1) expressions (p<0.05) in 0.1mg/ml EE group. IPEC-J2 cells pre-treated with 0.1mg/ml EE could significantly improve the inflammatory response caused by 0.5mg/ml SBA by up-regulation for IL-10, TGF-β, and down-regulation gene expression of IL-6, TNF-α and IFN-γ (p<0.05). In conclusion, 0.1mg/ml EE can improve the mechanical barrier function and could protect the effects while 0.5mg/ml of SBA-induced barrier dysfunction in IPEC-J2.

Eleutheroside E Enhances the Long-Term Memory of Radiation-Damaged C. elegans through G-Protein-Coupled Receptor and Neuropeptide Signaling Pathways.

Eleutheroside E (EE), a principal active compound of Acanthopanax senticosus, has been shown to have a certain neuromodulation effect. Our previous study indicates that EE protects nerve damage caused by radiation. However, its specific function and underlying mechanism remain unknown. Therefore, the objective of this study is to apply the C. elegans model to illuminate the property and mechanism of EE protecting against nerve damage caused by radiation. Here, we found that EE significantly improved the long-term memory of radiation-damaged C. elegans. Through transcriptome sequencing, the results showed that EE protected radiation-damaged C. elegans mainly through G-protein-coupled receptor and neuropeptide signaling pathways. Further research indicated that EE affected the activity of CREB by cAMP-PKA, Gqα-PLC, and neuropeptide signaling pathways to ultimately improve the long-term memory of radiation-damaged C. elegans. In addition, the activity of Gqα and neuropeptides in AWC neurons and the activity of CREB in AIM neurons might be crucial for EE to function.

Unveiling the Pharmacological Mechanisms of Eleutheroside E Against Postmenopausal Osteoporosis Through UPLC-Q/TOF-MS-Based Metabolomics.

Postmenopausal osteoporosis (PMOP) is a common metabolic bone disease in postmenopausal women in the Worldwide, and seriously affects the quality of life of middle-aged and elderly women. Therefore, there is an urgent need to discover a highly effective drug for PMOP treatment. In this study, ultra-high performance liquid tandem quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to analyze the urine metabolic profiling and potential biomarkers, the relevant metabolic network of PMOP rats, and further to evaluate the intervention effect of Eleutheroside E (EE) against PMOP. Using multivariate statistical analysis combined with UPLC-Q/TOF-MS, a total of 27 biomarkers were identified, which related with 16 metabolic pathways, mainly involving steroidogenesis, beta oxidation of very long chain fatty acids, glutathione metabolism, carnitine synthesis, estrone metabolism, oxidation of branched chain fatty acids, etc. After treatment of EE, these biomarkers were markedly regulated, mainly involving steroid hormone biosynthesis, arachidonic acid metabolism, primary bile acid biosynthesis, indicating that EE had the therapeutic effect on PMOP. This study identified the potential urine metabolic markers and related metabolic pathways of the PMOP, explained the metabolic effect and pharmacological mechanisms of EE against PMOP, and provided a basis for the pharmacological study of EE.

Eleutheroside E decreases oxidative stress and NF-κB activation and reprograms the metabolic response against hypoxia-reoxygenation injury in H9c2 cells

Ischemia-reperfusion (I/R) injury causes cardiac dysfunction through several mechanisms including oxidative stress and pro-inflammation. Eleutheroside E (EE) has protective effects in ischemia tissue and anti-inflammatory action. However, the effect of EE on I/R-injured cardiomyocytes is unknown. In this study, we used in vitro H9c2 cell model to investigate the favorable role of EE on myocardial I/R injury. We found that EE administration attenuated the cardiomyocyte apoptosis induced by hypoxia-reoxygenation (H/R) injury. Further, pre-treatment with EE dramatically inhibited mitochondrial oxidative stress, IκBα phosphorylation and nuclear factor kappa B (NF-κB) subunit p65 translocation into nuclei. EE might suppress the MAPK signaling pathway to inhibit the H/R-induced NF-κB activation. Moreover, we had analyzed the metabolomic profile of H/R-injured and H/R + 100 EE-treated H9c2 cells and found that the abundance of most metabolites changed by H/R could be re-modulated by EE treatment. Pathway analysis highlighted the inhibition of fatty acid biosynthesis and alternation of arginine and proline metabolism as two potential links to the favorable effect of EE on H/R-injured cardiomyocytes. The further demonstration showed that nitric oxide (NO), a product that is solely catabolized by l-arginine and has profound anti-oxidative stress activity during H/R in cardiomyocytes, was augmented by EE. Altogether, our results provide evidence that EE may be a potential drug for myocardial I/R injury by reducing oxidative stress, NF-κB activation, and metabolic reprogramming.

Eleutheroside E attenuates isoflurane-induced cognitive dysfunction by regulating the α7-nAChR-NMDAR pathway.

There is growing evidence that cognitive dysfunction induced by anesthetics is adversely affecting a large number of elderly surgical patients. Eleutheroside E (EE), a principal component of Eleutherococcus senticosus, exerts obvious protective effects on cognition. The aim of this study was to investigate the neuroprotective effect of EE on isoflurane (ISO)-induced cognitive dysfunction and explore the possible mechanisms. Learning and memory are assessed in novel object recognition and Morris water maze. We found that with ISO exposure, aged rats had a lower preference for the new object and spent less time in the target quarter. However, the amnesia can be alleviated by EE (50 mg/kg, intraperitoneally). Further research focused on the possible protective molecules associated with learning and memory, such as acetylcholine (ACh) and choline acetyltransferase (ChAT), nicotinic acetylcholine receptors (α7-nAChR), and NR2B, is required. The ACh in the hippocampus and serum was decreased after ISO exposure; meanwhile, the expression of ChAT, α7-nAChRs, and NR2B was downregulated. This abnormal state can be reversed by the administration of EE. Here, our results suggested that EE may be a potential therapeutic agent against ISO-induced cognitive dysfunction. The possible mechanism can be attributed to its neuroprotection through enhancing ChAT, which promotes the synthesis of ACh, further influencing the expression of the α7-nAChR-NR2B complex.

Eleutheroside E inhibits doxorubicin-induced inflammation and apoptosis in rat cardiomyocytes by modulating activation of NF-κB pathway

Purpose : To identify the effects of eleutheroside E (EE) on apoptosis and inflammation induced by doxorubicin (DOX) in H9c2 cells and to investigate the underlying mechanisms. Methods : The effect of EE on H9c2 cell viability was determined using Cell Counting Kit-8 (CCK8). EE effect on DOX-induced apoptosis and inflammation in H9c2 cells was studied by comparison between cells treated with DOX alone and DOX+EE; the relationship between EE effects and NF-κB signaling pathway was evaluated by the addition of NF-κB inhibitor PDTC. Cell apoptosis was examined by flow cytometry while IL-1β, IL-6, and TNF-α levels were determined by ELISA. The phosphorylation level of NF-κB p65 was measured by Western blot. Results : Compared with control group, cell viability was notably elevated after treatment with 50-100 μM EE for 48 or 72 h. DOX induced higher rates of cell apoptosis in H9c2 cells (29.5 ± 3.56 %) compared with control group (6.39 ± 0.67 %); however, with EE pretreatment (50 and 80 μM), apoptosis rate decreased to 16.8 ± 2.16 and 13.54 ± 2.08 %, respectively, which are significantly lower than that of DOX group; furthermore, the levels of IL-1β, IL-6, and TNF-α also reduced. In addition, DOX-induced phosphorylation of NF-κB p65 was suppressed by EE pretreatment (10, 50 and 80 μM) to 11.51 ± 1.25, 40.2 ± 5.17 and 52.97 ± 6.74 %, respectively Conclusion : The results suggest that EE treatment reduced DOX-induced apoptosis and inflammation by interacting with NF-κB signaling pathway. This finding sheds some light on probable new strategies on the application of DOX for cancer treatment. Keywords : Eleutheroside E, Doxorubicin, Inflammation, Apoptosis, Cardiomyocytes, NF-κB

High glucose induces rat mesangial cells proliferation and MCP-1 expression via ROS-mediated activation of NF-κB pathway, which is inhibited by eleutheroside E

Glomerular hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy (DN). High glucose-induced oxidative stress is implicated in the etiology of DN. This study aims to investigate the effect of eleutheroside E (EE) on high glucose mediated rat mesangial cells (MCs) proliferation and monocyte chemoattractant protein-1 (MCP-1) expression and the underlying mechanism. MCs proliferation was assessed by MTT assay. Reactive oxygen species (ROS) level and MCP-1 expression were evaluated by ELISA kit. The protein expression of p47, NF-κB p65, p-NF-κB p65, IκBα, p-IκBα, IKKβ and p-IKKβ were determined by Western blot. The results showed that treatment with EE markedly attenuated high glucose induced MCs proliferation and in a dose-dependent manner. Intervention with EE also significantly blocked high glucose induced intracellular ROS production by decreasing NADPH oxidase activity. Meanwhile, EE administration could effectively alleviate the high glucose-stimulated activation of NF-κB, the degradation of IκBα and the expression of MCP-1. These results demonstrate that high glucose enhances MCs proliferation and MCP-1 expression by activating the ROS/NF-κB pathway and can be inhibited by EE. Our findings provide a new perspective for the clinical treatment of DN.

Eleutheroside E ameliorates arthritis severity in collagen-induced arthritis mice model by suppressing inflammatory cytokine release.

Rheumatoid arthritis is the most common arthritis and is mainly characterized by symmetric polyarticular joint disorders. Eleutheroside E (EE), a principal active constituent of Acanthopanax senticosus, is reported to have anti-inflammatory effect by inhibiting NF-κB activities. However, the effects of EE on rheumatoid arthritis (RA) severity are largely unknown. The purpose of this study was to indicate whether EE could ameliorate arthritis and reduce inflammatory cytokine release in collagen-induced arthritis (CIA) mice. The results showed that EE attenuated the severity of arthritis by reducing the mean arthritis score and arthritis incidence. EE also significantly decreased the inflammatory cell infiltration, pannus formation, cartilage damage, and bone erosion of CIA mice. Furthermore, EE caused a marked decrease of the production of TNF-α and IL-6 in vivo and in vitro. These observations identify a novel function of EE that results in inhibition of cytokine release, highlighting EE was a potential therapeutic agent for RA.

Effects of Eleutheroside B and Eleutheroside E on activity of cytochrome P450 in rat liver microsomes

BackgroundChemicals of herbal products may cause unexpected toxicity or adverse effect by the potential for alteration of the activity of CYP450 when co-administered with other drugs. Eleutherococcus senticosus (ES), has been widely used as a traditional herbal medicine and popular herbal dietary supplements, and often co-administered with many other drugs. The main bioactive constituents of ES were considered to be eleutherosides including eleutheroside B (EB) and eleutheroside E (EE). This study was to investigate the effects of EB and EE on CYP2C9, CYP2D6, CYP2E1 and CYP3A4 in rat liver microsomes in vitro.MethodProbe drugs of tolbutamide (TB), dextromethorphan (DM), chlorzoxazone (CLZ) and testosterone (TS) as well as eleutherosides of different concentrations were added to incubation systems of rat liver microsomes in vitro. After incubation, validated HPLC methods were used to quantify relevant metabolites.ResultsThe results suggested that EB and EE exhibited weak inhibition against the activity of CYP2C9 and CYP2E1, but no effects on CYP2D6 and CYP3A4 activity. The IC50 values for EB and EE were calculated to be 193.20 μM and 188.36 μM for CYP2E1, 595.66 μM and 261.82 μM for CYP2C9, respectively. Kinetic analysis showed that inhibitions of CYP2E1 by EB and EE were best fit to mixed-type with Ki value of 183.95 μM and 171.63 μM, respectively.ConclusionsThese results indicate that EB and EE may inhibit the metabolism of drugs metabolized via CYP2C9 and CYP2E1, and have the potential to increase the toxicity of the drugs.

Eleutheroside E, An Active Component ofEleutherococcus senticosus, Ameliorates Insulin Resistance in Type 2 Diabetic db/db Mice

Eleutheroside E (EE), a principal component of Eleutherococcus senticosus (ES), has anti-inflammatory and protective effects in ischemia heart. However, it is unknown whether it ameliorates insulin resistance and reduces hyperglycemia in diabetes. This study investigated the effect of EE-containing ES extracts, as well as EE, on hyperglycemia and insulin resistance in db/db mice. EE increased the insulin-provoked glucose uptake in C2C12 myotubes. Moreover, EE improved TNF-α-induced suppression of glucose uptake in 3T3-L1 adipocytes. Five-week-old db/db mice were fed a diet consisting of ES extract or EE for 5 weeks. Both were effective in improving serum lipid profiles and significantly decreased blood glucose and serum insulin levels. ES and EE supplementation effectively attenuated HOMA-IR. Glucose tolerance and insulin tolerance tests showed that EE increased insulin sensitivity. Immunohistochemical staining indicated that ES and EE protected pancreatic alpha and beta cells from diabetic damage. In addition, ES and EE improved hepatic glucose metabolism by upregulating glycolysis and downregulating gluconeogenesis in obese type 2 diabetic mice. These data suggest that EE mediates the hyperglycemic effects of ES by regulating insulin signaling and glucose utilization. The beneficial effects of EE may provide an effective and powerful strategy to alleviate diabetes.