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Background: Cancer-related fatigue (CRF) is a major obstacle to quality of life. Acanthopanax senticosus Harms (ASH) is available as a botanical adaptogen food worldwide. Objective: This study aimed to assess the feasibility and safety of ASH in patients with CRF. Methods: Fifteen patients with CRF consumed ASH drink for 28 days. The primary endpoint was the completion rate of the study, and the secondary endpoints were changes in brief fatigue inventory (BFI), oxidative stress markers, and adverse events. Results: Seven patients successfully completed the study. Four patients who had BFI <5.5 at enrollment revealed a decrease in BFI. The biological antioxidant potential/diacron-reactive oxygen metabolites ratio, potential antioxidant capacity, was increased but not significant (p = 0.063). No adverse events attributable to ASH were observed. Conclusions: Approximately 50% patients were successful in consuming ASH for 28 days. Patients with mild CRF showed improvement by using ASH. However, further investigations are needed to validate these findings.

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Background: Cardiac autonomic function (CAF) decreases with aging, and Acanthopanax senticosus Harms (ASH) consumption reportedly induces anti-stress effects. This study aimed to assess the effect of continuous supplementation of ASH on CAF during resting and standing tests in the elderly population. Methods: This double-blind, randomized controlled trial was conducted in the morning in a laboratory setting and was carried out between June 2017 and July 2017 at Kambaikan, Doshisha University (Karasuma-higashi-iru, Imadegawa-dori, Kamigyo-ku, Kyoto 602-8580, Japan). In total, 28 community-dwelling elderly individuals (mean ± standard deviation = 72.5 ± 4.5 years) were included. Each subject was instructed to consume ASH or placebo supplements twice daily for 4 weeks. An autonomic reflex orthostatic tolerance recorder was used to measure CAF in pre- and post-intervention phases. Parameters were measured in a seated position and included coefficient of variation of R-R intervals (CVRR), low frequency (LF), high frequency (HF), LF/HF ratio, blood pressure, and heart rate (HR). Changes in each parameter were evaluated before and after standing. All parameters were defined as the difference between the mean value obtained in a standing position for 2 min and that obtained in a 2-min seated position. Results: A two-way analysis of variance revealed a significant group-time interaction effect on CVRR, HF, and ΔLF/HF ratio. Following the intervention, CVRR, HF, LF/HF ratio, systolic blood pressure (SBP), HR, ΔLF/HF ratio, ΔSBP, and ΔHR improved significantly in the ASH group only. Conclusions: Four-week supplementation of ASH improved CAF in community-dwelling elderly individuals during resting and standing tests. Clinical Trial Registration: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000031218, UMIN Clinical Trials Registry (UMIN000027251).

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Parkinson's disease (PD) is the second most common neurodegenerative disease, with an increasing prevalence as the population ages, posing a serious threat to human health, but the pathogenesis remains uncertain. Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASH) (aqueous ethanol extract), a Chinese herbal medicine, provides obvious and noticeable therapeutic effects on PD. To further investigate the ASH's mechanism of action in treating PD, the structural and functional gut microbiota, as well as intestinal metabolite before and after ASH intervention in the PD mice model, were examined utilizing metagenomics and fecal metabolomics analysis. α-syn transgenic mice were randomly divided into a model and ASH groups, with C57BL/6 mice as a control. The ASH group was gavaged with ASH (45.5 mg/kg/d for 20d). The time of pole climbing and autonomous activity were used to assess motor ability. The gut microbiota's structure, composition, and function were evaluated using Illumina sequencing. Fecal metabolites were identified using UHPLC-MS/MS to construct intestinal metabolites. The findings of this experiment demonstrate that ASH may reduce the climbing time of PD model mice while increasing the number of autonomous movements. The results of metagenomics analysis revealed that ASH could up-regulated Firmicutes and down-regulated Actinobacteria at the phylum level, while Clostridium was up-regulated and Akkermansia was down-regulated at the genus level; it could also recall 49 species from the phylum Firmicutes, Actinobacteria, and Tenericutes. Simultaneously, metabolomics analysis revealed that alpha-Linolenic acid metabolism might be a key metabolic pathway for ASH to impact in PD. Furthermore, metagenomics function analysis and metabolic pathway enrichment analysis revealed that ASH might influence unsaturated fatty acid synthesis and purine metabolism pathways. These metabolic pathways are connected to ALA, Palmitic acid, Adenine, and 16 species of Firmicutes, Actinobacteria, and Tenericutes. Finally, these results indicate that ASH may alleviate the movement disorder of the PD model, which may be connected to the regulation of gut microbiota structure and function as well as the modulation of metabolic disorders by ASH.

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Objective: Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASH) is a traditional herbal medicine widely known for its antifatigue and antistress effects, as well as tonifying qi, invigorating spleen and kidney, and tranquilizing the mind. Recent evidence suggests that ASH has a therapeutic effect on major depressive disorder (MDD), but its mechanism is still unclear. The current study aimed to investigate the effect of ASH on MDD and potential therapeutic mechanisms. Materials and Methods: The chemical compound potential target network was predicted based on network pharmacology. Simultaneously, chronic unpredictable mild stress (CUMS) model mice were orally administrated ASH with three dosages (400, 200, and 100 mg/kg) for 6 weeks, and hepatic metabolomics based on gas chromatography-mass spectrometry (GC-MS) was carried out to identify differential metabolites and related metabolic pathways. Next, the integrated analysis of metabolomics and network pharmacology was applied to find the key target. Finally, molecular docking technology was employed to define the combination of the key target and the corresponding compounds. Results: A total of 13 metabolites and four related metabolic pathways were found in metabolomics analysis. From the combined analysis of network pharmacology and metabolomics, six targets (DAO, MAOA, MAOB, GAA, HK1, and PYGM) are the overlapping targets and two metabolic pathways (glycine, serine, and threonine metabolism and starch and sucrose metabolism) are the most related pathways. Finally, DAO, MAOA, MAOB, GAA, HK1, and PYGM were verified bounding well to their corresponding compounds including isofraxidin, eleutheroside B1, eleutheroside C, quercetin, kaempferol, and acacetin. Conclusion: Based on these results, it was implied that the potential mechanism of ASH on MDD was related to the regulation of metabolism of several excitatory amino acids and carbohydrates, as well as the expression of DAO, MAOA, MAOB, GAA, HK1, and PYGM.

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The effects of current treatment strategies used in ischemic stroke are weakened by cerebral ischemia-reperfusion (CIR) injury. Suitable treatment regimens targeting CIR injury are still lacking. Two herbs, namely, Acanthopanax senticosus (Rupr. & Maxim.) Harms (ASE) and Gastrodia elata Blume (GEB), have been used as traditional Chinese medicine and are indicated in the treatment of stroke and cerebrovascular diseases. However, there are no studies that report the effects of ASE combined with GEB in the treatment of CIR injury. In this study, we used the Zea Longa method to induce CIR injury in male Wistar rats. Results of the pharmacodynamic studies revealed that co-administration of ASE and GEB may improve neuronal injury and prevent neuronal apoptosis by reducing oxidative stress and inflammation, and also help prevent CIR injury. On the basis of our hypothesis, we combined the results from transcriptomic and metabonomic analyses and found that ASE and GEB could prevent CIR injury by targeting phenylalanine, pyrimidine, methionine, and sphingolipid metabolism. Therefore, our study provides the basis for the compatibility and efficacy of ASE and GEB.

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Acanthopanax senticosus (Rupr. et Maxim) Harms (ASH), also known as Siberian ginseng or eleuthero, is a hardy shrub native to China, Korea, Russia and the northern region of Japan. ASH is used for the treatment of several diseases such as heart disease, hypertension, rheumatoid arthritis, allergies, chronic bronchitis, diabetes and cancer. In the present study, the inhibitory effect of the root extract of ASH (ASHE) on HuH­7 and HepG2 liver cancer cells was examined. ASHE suppressed liver cancer cell proliferation by inducing cell cycle arrest at the G0/G1 phase, as well as apoptosis, as indicated by the increased number of Annexin V and 7­AAD­positive cells. Furthermore, the expression of LC3­II, an autophagy marker, in these cells also increased post treatment with ASHE. LC3­II induction was further enhanced by co­treatment with chloroquine. Fluorescence and transmission electron micrographs of ASHE­treated liver cancer cells showed the presence of an increased number of autophagic vesicles. A decreased protein expression level of run domain Beclin­1­interacting and cysteine­rich domain­containing, an autophagy inhibitor, with no change in RUBCN mRNA expression was observed, indicating activation of the autophagosome­lysosome fusion step of autophagy. In conclusion, ASHE exerts cytostatic activity on liver cancer cells via both apoptosis and autophagy, and may serve as a potential therapeutic agent for management of liver cancer and autophagy­related diseases.

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OBJECTIVE: To investigate the neuro-protective effects of Acanthopanax senticosus Harms (EAS) on mesencephalic mitochondria and the mechanism of action, using a mouse model of Parkinson's disease (PD). METHODS: The chemical fingerprint analysis of the extract of Acanthopanax senticosus Harms (EAS) was performed using the ultra performance liquid chromatograph and time of flight mass spectrometry. Thirty mice were randomly divided into the control group, the MPTP model group, and the EAS treated group with MPTP (MPTP+EAS group, 10 in each group). The MPTP model group and the MPTP+EAS group received MPTP-HCl (30 mg/kg i.p) once a day for 5 days. The control group received an equal volume of saline (20 mL/kg i.p) once a day for 5 days. Induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride daily (MPTP-HCl, 30 mg/kg) for 5 days, the PD mice were treated with EAS at 45.5 mg/kg daily for 20 days. The behavioral testing of mice was carried out using the pole-climbing test. The integrity and functions of neurons were examined in mesencephalic mitochondria in a PD mouse model, including nicotinamide adenine dinucleotide dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 1 (MT-ND1), succinate dehydrogenase complex subunit A (SDHA), and succinate dehydrogenase cytochrome b560 subunit (SDHC). RESULTS: After treatment with EAS, the behavioral changes induced by MPTP were attenuated significantly (P<0.05). EAS protected the mesencephalic mitochondria from swelling and attenuated the decreases in their membrane potential (both P<0.05), which was supported by an ultra-structural level analysis. The changes in reactive oxygen species (ROS), malonic dialdehyde (MDA), oxidative phosphorylation (OXPHOS) system 4 subunits levels and PD-related proteins expressions (parkin, Pink1, DJ-1, α-synuclein, and Lrrk2) reverted to near normal levels (all P<0.05), based on the results of immune-histological and Western blotting observations. CONCLUSIONS: The neuro-protective effects of EAS are linked to protecting mice against MPTP-induced mitochondrial dysfunction and structural damage. Therefore, EAS is a promising candidate for the prevention or treatment of mitochondrial neurodegenerative disorders, such as PD.

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Mental stress, such as anxiety and conflict, causes physiological changes, such as changes in autonomic nervous activity and gastric ulcers. In addition, stress induces glucocorticoids and changes the hippocampal brain-derived neurotrophic factor (BDNF) expression levels. We previously reported that Acanthopanax senticosus HARM (ASH) prevents stress-induced gastric ulcers. Thus, we investigated the potential anxiolytic effect and influence of ASH on the hippocampus BDNF-related protein in male Sprague-Dawley rats fed 1% and 5% ASH extract-containing food for one week using novelty suppressed feeding (NSF) and improved elevated beam walking (IEBW) tests. ASH treatment significantly decreased latency to eat in the NSF test and increased the time spent on the open arm in the IEBW test. ASH5% treatment showed a significant decrease in LFnu, indicative of sympathetic nervous activity, and a significant increase in HFnu, indicative of parasympathetic nervous activity, in the NSF test. In addition, ASH1% and ASH5% treatments significantly decreased LFnu and significantly increased HFnu in the IEBW test. ASH5% treatment significantly increased hippocampal BDNF protein expression in both Western blotting and immunohistochemistry experiments. Our findings suggest that anxiolytic effects of ASH occur via the regulation of autonomic function and increased hippocampal BDNF signaling.

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<p><b>OBJECTIVE</b>To investigate the neuro-protective effects of Acanthopanax senticosus Harms (EAS) on mesencephalic mitochondria and the mechanism of action, using a mouse model of Parkinson's disease (PD).</p><p><b>METHODS</b>The chemical fingerprint analysis of the extract of Acanthopanax senticosus Harms (EAS) was performed using the ultra performance liquid chromatograph and time of flight mass spectrometry. Thirty mice were randomly divided into the control group, the MPTP model group, and the EAS treated group with MPTP (MPTP+EAS group, 10 in each group). The MPTP model group and the MPTP+EAS group received MPTP-HCl (30 mg/kg i.p) once a day for 5 days. The control group received an equal volume of saline (20 mL/kg i.p) once a day for 5 days. Induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride daily (MPTP-HCl, 30 mg/kg) for 5 days, the PD mice were treated with EAS at 45.5 mg/kg daily for 20 days. The behavioral testing of mice was carried out using the pole-climbing test. The integrity and functions of neurons were examined in mesencephalic mitochondria in a PD mouse model, including nicotinamide adenine dinucleotide dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 1 (MT-ND1), succinate dehydrogenase complex subunit A (SDHA), and succinate dehydrogenase cytochrome b560 subunit (SDHC).</p><p><b>RESULTS</b>After treatment with EAS, the behavioral changes induced by MPTP were attenuated significantly (P<0.05). EAS protected the mesencephalic mitochondria from swelling and attenuated the decreases in their membrane potential (both P<0.05), which was supported by an ultra-structural level analysis. The changes in reactive oxygen species (ROS), malonic dialdehyde (MDA), oxidative phosphorylation (OXPHOS) system 4 subunits levels and PD-related proteins expressions (parkin, Pink1, DJ-1, α-synuclein, and Lrrk2) reverted to near normal levels (all P<0.05), based on the results of immune-histological and Western blotting observations.</p><p><b>CONCLUSIONS</b>The neuro-protective effects of EAS are linked to protecting mice against MPTP-induced mitochondrial dysfunction and structural damage. Therefore, EAS is a promising candidate for the prevention or treatment of mitochondrial neurodegenerative disorders, such as PD.</p>

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ETHNOPHARMACOLOGICAL RELEVANCE: Ciwujia (CWJ), one of the most commonly used Chinese materia medicas (CMMs), is derived from the roots, rhizomes, and stems of Acanthopanax senticosus harms (AS). CWJ has been used for the treatment of various central nervous system (CNS) and peripheral system diseases. Drug-likeness prediction can help to analyze the absorption, distribution, metabolism, and excretion (ADME) processes of the compounds in CWJ, as well as their potential therapeutic and toxic effects, which is of significance in the confirmation of the active material bases of CWJ. MATERIALS AND METHODS: The ADME properties of the compounds were calculated through web based PreADMET program and ACD/I-Lab 2.0. The potential therapeutic and toxicity targets of these compounds were screened by the ChemQuery tool in DrugBank and T3DB. RESULTS: 14/39 compounds had moderate or good oral bioavailability (OB). 29/39 compounds bound weakly to the plasma proteins. 18/39 compounds might pass across the blood-brain barrier (BBB). Most of these compounds showed low renal excretion ability. 25/39 compounds had 99 structurally similar drugs and 158 potential therapeutic targets. Additionally, 17/39 compounds had 53 structurally similar toxins and 126 potential toxicity targets. CONCLUSION: Our study suggests that these compounds have a certain drug-likeness potentials, which are also likely to be the material bases of CWJ. These results may provide a reference for the safe use of CWJ and the expansion of its application scope.

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α-Synuclein is a key player in the pathogenesis of neurodegenerative disorders with Lewy bodies. Our previous studies have also showed that Acanthopanax senticosus harms (AS) could significantly suppress α-synuclein overexpression and toxicity. Identifying the RNAs related to α-synucleinopathies may facilitate understanding the pathogenesis of the diseases and the safe application of AS in the clinic. Microarray expression profiling of long non-coding RNAs (lncRNAs) and mRNAs was undertaken in control non-transgenic and human α-synuclein transgenic mice. The effects of AS on central nervous system (CNS) in pathology and physiology were investigated based on the lncRNA/mRNA targets analysis. In total, 341 lncRNAs and 279 mRNAs were differentially expressed by α-synuclein stimulus, among which 29 lncRNAs and 25 mRNAs were involved in the anti-α-synucleinopathies mechanism of AS. However, the levels of 19/29 lncRNAs and 12/25 mRNAs in AS group were similar to those in α-synuclein group, which may cause potential neurotoxicity analogous to α-synuclein. This study demonstrated that some of lncRNAs/mRNAs were involved in α-synuclein related pathophysiology, and AS produced the bidirectional effects on CNS under pathological and physiological conditions.

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ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax senticosus Harms (AS), also called "Ciwujia" in Chinese and "Siberian ginseng" in the Siberian Taiga region, is the herb used in traditional medicinal systems of China, Russia, Japan and Korea for the treatment of various nervous and cerebrovascular diseases. AIM OF THE STUDY: Our pre-study has showed that AS can significantly suppress α-synuclein overexpression and toxicity. Neuronal protein α-synuclein is a key player in the development of neurodegenerative diseases called α-synucleinopathies. Identifying the potential biomarkers related to α-synucleinopathies may facilitate understanding the pathogenesis of the diseases and the safe application of AS in the clinic. METHODS AND RESULTS: Ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods was integrated to examine the cerebral metabolic signature of human α-synuclein transgenic mice and the effects of AS on central nervous system (CNS) in pathology and physiology. Totally, 17 differentially expressed metabolites in wild type (WT) group and 26 in A30P mutant (A30P) group were identified and considered as potential biomarkers. Among them, 11 endogenous metabolites in WT+AS group and 18 in A30P+AS group were involved in the anti-α-synucleinopathies mechanism of AS. However, western blot and metabolomics analysis showed the effects of AS on CNS in physiology were opposite to those in pathology, which may cause potential neurotoxicity. CONCLUSIONS: This study demonstrated that endogenous metabolites perturbation was involved in the pathogenesis of α-synucleinopathies and AS produced the dual effects on pathological and physiological CNS.

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Syringaresinol exists either exclusively as one enantiomer or enantiomeric mixtures in plant foods. We found that (+)-syringaresinol, but not (-)-syringaresinol, upregulates silent information regulator two ortholog 1 (SIRT1) gene expression, and thus, Panax ginseng berry with predominantly high contents of (+)-syringaresinol exhibits higher activity in inducing SIRT1 gene expression than Acanthopanax senticosus Harms stem with almost equal proportion of the two enantiomers. These findings highlight the importance of the absolute configuration of syringaresinol for the biological activity.

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ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax senticosus harms (AS), also called "Ciwujia" in Chinese and "Siberian ginseng" in the Siberian Taiga region, is the herb used in traditional medicinal systems in China and Russia, which has been applied to the treatment of various nervous and cerebrovascular diseases, such as depression, mental fatigue, and transient global cerebral ischemia. The previous research works usually tended to focus on the neuroprotective effects of AS, but ignored its additional effects that are not entirely beneficial to the nervous system. Therefore, to discover the potential intervention targets of AS and evaluate their roles in the nervous system are the urgent problems. MATERIALS AND METHODS: Ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods were integrated to investigate the metabolic profiles of AS-treated rats. The analysis of possible pathways influenced by AS was performed by ingenuity pathway analysis (IPA) with MetPA. RESULTS: Treated with AS, 16 modulated metabolites were identified and considered as the potential intervention targets of AS, out of which 3 metabolites had protective effects on the nervous system, whereas 7 metabolites showed the neurotoxicity. CONCLUSION: These results may reveal that the effects of AS on nervous system had two sides, and it could not only exert the neuroprotection but also produce some potential neurotoxicity.

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Evidences are accumulating that extract of Acanthopanax senticosus Harms (ASH; syn Eleutherococcus senticosus [Rupr. & Maxim.] Maxim), a shrub native to Northeastern Asia, has antiinflammatory effects. In this study, we examined prophylactic and therapeutic effects of ASH extract (ASHE) on rheumatoid arthritis using collagen-induced arthritis (CIA) mouse model. Acanthopanax senticosus Harms extract was administered before the onset of arthritis in the prophylaxis model. In the therapeutic model, ASHE was administered after the onset of arthritis with or without anti-TNF-α antibody. The ASHE treatment showed efficacy before onset of CIA but there was no effect after CIA was established. The ASHE treatment delayed the onset and decreased severity of CIA. In vitro examinations showed that ASHE is an antioxidant and that ASHE suppresses TNF-α and interleukin-6 production in human peripheral blood mononuclear cells. The combination therapy with ASHE and anti-TNF-α antibody reduced the severity of arthritis compared with anti-TNF-α antibody alone. The present study shows that ASHE has prophylactic effect against CIA and support therapeutic effect of anti-TNF-α antibody.

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Extract of Acanthopanax senticosus harms (EAS) has been shown to have neuroprotective effects on Parkinson's disease (PD) cell model against α-synuclein overexpression and toxicity. However, studies of its anti-PD mechanism are challenging, owing to the complex pathophysiology of PD, and complexity of EAS with multiple constituents acting on different proteomic pathways. Here, we have investigated the proteomic profiles and potential biomarkers in a cell model of A53T mutant α-synuclein (A53T-α-Syn) overexpression after treatment of EAS. Using an iTRAQ (isobaric tags for relative and absolute quantitation)-based proteomics research approach, we identified 3425 modulated proteins, out of which 84 were found to be altered by A53T-α-Syn and considered as potential biomarkers. After treatment with EAS, the group showed the tendency to correct the abnormal expressions of 16 proteins out of 84 potential biomarkers, which were associated with the formation of Lewy body, mitochondrial energy metabolism, protein synthesis and apoptosis, etc. This study indicated that EAS might be a promising candidate for prevention or treatment of PD by regulating the related proteomic pathways in A53T-α-Syn transgenic SH-SY5Y cells.

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Extract of Acanthopanax senticosus harms (EAS) has been shown to have neuroprotective effects on dopaminergic neurons in Parkinson's disease (PD) mice model. α-Synuclein is a key player in the pathogenesis of PD, the elevated level of which is deleterious to dopaminergic neurons, and enhancing its clearance might be a promising strategy for treating PD. To assess the potential of EAS in this regard, we investigated its effect on the SH-SY5Y cells overexpressing wild-type α-synuclein (WT-α-Syn) or A53T mutant α-synuclein (A53T-α-Syn), and the implicated pathway it might mediate. After treatment with EAS, the changes of α-synuclein, caspase-3, parkin, phospho-protein kinase B (Akt), phospho-glycogen synthase kinase 3 beta (GSK3ß), and phospho-microtubule-associated protein tau (Tau) in WT-α-Syn or A53T-α-Syn transgenic cells were reverted back to near normal levels, demonstrated by the western blotting and quantitative real-time PCR outcomes. The neuroprotective effects of EAS may be able to protect WT-α-Syn or A53T-α-Syn transgenic SH-SY5Y cells from α-synuclein overexpression and toxicity. Therefore, we speculate that EAS might be a promising candidate for prevention or treatment of α-synuclein-related neurodegenerative disorders such as PD.

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OBJECTIVE: To study the constituents isolated from Acanthopanax senticosus Harms and their inhibitory activity on protein tyrosine phosphatase 1B(PTP1B). METHODS: Kaurane-type diterpenes with PTP1 B inhibitory activity were obtained by bio-assay-guided fractionation. RESULTS Nine compounds were identified as 17-isobutyryloxy-16αH-kauran-19-oic acid(1), 17-hydrox-y-16αH-kauran-19-oic acid(2), 17-acetoxy-18-isobutyryloxy-16αH-kauran-19-oic acid (3), ent-kaur-16-en-19-oic acid (4), ent-kaur-16-en-19-oic acid (kaurenoic acid 5), 4-epirulopezol(6), 16α-hydroxy-ent-kauran-19-oic acid(7), 16αH, 17-isovaleryloxy-ent-kauran-19-oic acid(8) and 16α-hydroxy-17-isovaleryloxyent-kauran-19-oic acid(9). CONCLUSION: Compounds 1-3, 5 and 6 are obtained from the plant for the first time. Compounds 1,3-6 and 8 exhibite inhibitory effects on PTP1 B with IC50 values ranging from (5.6 ± 0.8) to (22.8 ± 1.2) μmol · L-1.

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<b>Objective:</b> By using human liver microsomes (HLM), we analyzed the effects of 14 known components of <i>A.senticosus</i> Harms on the activities of CYP2C9 and CYP3A4.<br> <b>Methods and Results:</b> Sesamin and quercetin inhibited both enzyme activities, whereas quercitrin strongly inhibited CYP3A4 activity. The 50% inhibitory concentrations (IC₅₀s) of sesamin and quercetin on CYP2C9 activity were approximately 124- and 59-fold higher and the IC₅₀s of sesamin, quercetin, and quercitrin on CYP3A4 activity were approximately 427-, 135-, and 22-fold higher than that of <i>A. senticosus</i> Harms extract (ASE), respectively. All these components inhibited both CYP3A4 and CYP2C9 in a non-competitive manner. However, these components are present in small amounts in ASE.<br> <b>Conclusion:</b> Therefore, the food-drug interactions caused by <i>A. senticosus </i>Harms are presumed to be due to the additive or synergistic interaction of these components or the other existing components, including their metabolites.<br>

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<b>Objective:</b> <i>Acanthopanax senticosus</i> Harms extract (ASE) is an ingredient of functional foods, such as health supplements, in Japan. We investigated the effects of ASE on CYP2C9 activity.<br> <b>Methods and Results:</b> CYP2C9-catalyzed diclofenac 4′-hydroxylase activities in human intestinal and liver microsomes (abbreviated as HIM and HLM, respectively) were significantly decreased by the addition of ASE in a concentration-dependent manner. Kinetic studies of diclofenac 4′-hydroxylase in HLM revealed that ASE addition significantly decreased <i>V</i>_max but had no effect on <i>K</i>_m. These results suggest that diclofenac 4′-hydroxylase activity is suppressed by ASE addition in a non-competitive manner. Then, we investigated the time courses of diclofenac 4′-hydroxylase activity in rat liver microsomes after ASE oral administration (50 to 400 mg/kg). Diclofenac 4′-hydroxylase activities were significantly lowered by the administration of 200 and 400 mg/kg ASE at 0.5 to 4 hr compared with control (0 hr). Furthermore, we investigated the effects of ASE oral administration on the pharmacokinetics of tolbutamide (substrate for CYP2C9) in rats. The area under the concentration-time curve of tolbutamide after ASE oral administration (400 mg/kg) was enhanced by approximately 1.6 times compared with that without ASE oral administration.<br> <b>Conclusion:</b> These findings indicated that ASE inhibits human intestinal and hepatic CYP2C9 activities.<br>