Xinmin Liu

Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression.

Ginseng total saponins (GTS) are the major active components of Panax ginseng C.A. Meyer, which has been used as a popular tonic herb for 2000 years in Far East countries. In the present study, two classic animal models: the forced swimming test (FST) and the chronic mild stress (CMS) model were used to evaluate the antidepressant-like activities of GTS. It was observed that GTS at doses of 50 and 100 mg/kg significantly reduced the immobility time in the FST in mice after 7-day treatment. GTS also reversed the reduction in the sucrose preference index, decrease in locomotor activity as well as prolongation of latency of feeding in the novelty environment displayed by CMS rats. In addition, HPLC-ECD and immunohistochemical staining analysis indicated that the CMS-induced decrease in monoamine neurotransmitter concentration and brain-derived neurotrophic factor (BDNF) expression in the hippocampus were almost completely reversed by GTS. In conclusion, GTS exerts antidepressant-like effects in two highly specific and predictive animal models of depression. The activity of GTS in antidepression may be mediated partly through enhancing the monoamine neurotransmitter concentration and BDNF expression in the hippocampus.

Comparison of ginsenosides Rg1 and Rb1 for their effects on improving scopolamine-induced learning and memory impairment in mice.

Rg1 and Rb1 are two major active compounds of ginseng that facilitate learning and memory. The present study aimed to compare the nootropic effects of Rg1 and Rb1 in a scopolamine induced dementia mice model. After 6 and 12 mg/kg of Rg1 and Rb1 intraperitoneal administration to mice for 7 days, their effects were assessed using the step‐down passive avoidance (SD) and the Morris water maze (MWM) tests, the acetylcholinesterase (AChE) activity, acetylcholine (ACh) content and serotonin (5‐HT) level in the hippocampus were analysed after SD and MWM tests. The results showed that Rg1 and Rb1 ameliorated cognition‐deficiency in mice with dementia. Rg1 showed stronger effects than Rb1 on escape acquisition in MWM. Both Rg1 and Rb1 increased ACh levels in the hippocampus, but Rg1 inhibited AChE activity while Rb1 had no effect on AChE activity. Both Rg1 and Rb1 inhibited the decrease of 5‐HT induced by scopolamine, but Rb1 was more active than the same dose of Rg1. These results demonstrate that multiple administrations of Rg1 and Rb1 are effective in improving memory deficiency induced by scopolamine. Rg1 appears to be more potent than Rb1 in improving acquisition impairment, and the two ginsenosides may act through different mechanisms. Copyright

The total flavonoids extracted from Xiaobuxin-Tang up-regulate the decreased hippocampal neurogenesis and neurotrophic molecules expression in chronically stressed rats.

Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, has been used for the treatment of depressive disorders for centuries in China. Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of XBXT reversed behavioral alterations and serotonergic dysfunctions in chronically stressed rats. Recently, accumulating studies have suggested the behavioral effects of chronic antidepressants treatment might be mediated by the stimulation of hippocampal neurogenesis. In present study, we explored the effect of XBXT-2 on hippocampal neurogenesis and neurotrophic signal pathway in chronically stressed rats. Our immunohistochemistry results showed that concomitant administration of XBXT-2 (25, 50 mg/kg, p.o., 28 days, the effective doses for behavioral responses) significantly increased hippocampal neurogenesis in chronically stressed rats. Four weeks after BrdU injection, result in double immunofluorescence labeling showed that some of the newly generated cells in hippocampus co-expressed with NSE or GFAP, markers for neurons or astrocytes, respectively. Furthermore, XBXT-2 treatment reserved stress-induced decrease of hippocampal BDNF and pCREB (Ser133) expression, two important factors which were closely related to hippocampal neurogenesis. As a positive control drug, imipramine (10 mg/kg, p.o.) exerted same effects. In conclusion, the increase of neurogenesis, as well as expression of BDNF and pCREB in hippocampus may be one of the molecular and cellular mechanisms underlying the antidepressant action of XBXT-2.

Role for serotonin in the antidepressant-like effect of a flavonoid extract of Xiaobuxin-Tang.

Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, has been used for the treatment of depressive disorders for centuries in China. Herein, we explored the antidepressant-like effect and its monoaminergic mechanism of the total flavonoids (XBXT-2) isolated from the extract of XBXT. In present study, single XBXT-2 (25, 50, 100 mg/kg, p.o.) administration significantly potentiated the mouse head-twitch response induced by 5-hydroxytryptophan (5-HTP, a metabolic precursor to serotonin), and also, decreased the immobility time in mouse tail suspension test, which was completely prevented by p-chlorophenylalanine (PCPA, an inhibitor of serotonin synthesis) pretreatment. However, single treatment with XBXT-2 had no effect on yohimbine toxicity and high dose of apomorphine-induced hypothermia in mice. These results indicated that acute treatment with XBXT-2 produced serotonergic, but not noradrenergic activation. In addition, chronic XBXT-2 (25, 50 mg/kg, p.o., 28 days) treatments significantly reversed the depressive-like behaviors in chronically mildly stressed (CMS) rats, including the reduced sucrose preference, deficient locomotor activity and prolonged latency to novelty-suppressed feeding. Furthermore, XBXT-2 normalized the neurotransmitter changes, including the decreased serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in hippocampus and prefrontal cortex in CMS rats. These findings confirm the antidepressant-like effect of XBXT-2 in CMS model of rats, which may be primarily based on its serotonergic activation.

Neuroprotective effects of forsythiaside on learning and memory deficits in senescence-accelerated mouse prone (SAMP8) mice

Forsythiaside (3,4-dihydroxy-β-phenethyl-O-α-L-rhamnopyranosyl-(1→6)-4-O-caffeo yl-β-d-glucopyranoside, C29H36O15), which is isolated from air-dried fruits of Forsythia suspensa, has been shown to possess anti-oxidant, anti-bacterial and anti-inflammatory activities. The aim of this study is to investigate the neuroprotective effects of forsythiaside on learning and memory deficits in the senescence-accelerated mouse prone 8 (SAMP8, a model of age-dependent neurodegenerative disorders such as Alzheimers disease). Forsythiaside (60, 120 and 240mg/kg) was orally administered to aged (8months old) SAMP8 mice for 45days followed by evaluating cognitive impairment (Morris water maze and step-through passive avoidance), inflammation (interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels), oxidative stress (glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) activities; malondialdehyde (MDA) and nitric oxide (NO) contents) and neurotransmitter such as norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), glutamate (GLU) gamma-aminobutyric acid (GABA) and acetyl choline (ACh). In Morris water maze, forsythiaside had significantly reduced the latency time, the crossing numbers and time spent in target quadrant compared to aged SAMP8 mice. In passive avoidance test, a significant decline in number of errors while increase in latency was observed when compared with aged SAMP8 mice. Furthermore, a significant decrease in IL-1β, NO, MDA and NE levels, and an increase in T-SOD and GSH-Px activities and GLU and Ach levels were evident in the brain homogenates of forsythiaside-treated mice compared to aged SAMP8 mice. These findings demonstrated that forsythiaside may be a useful treatment against amnesia.

Duchesnea Phenolic Fraction Inhibits In Vitro and In Vivo Growth of Cervical Cancer Through Induction of Apoptosis and Cell Cycle Arrest

Duchesnea indica (Andr.) Focke has been commonly used to treat cancer in Asian countries for centuries, and recently has been shown to possess anticancer properties in vitro and in vivo. But the underlying mechanism of the anticancer action is unclear, especially in in vivo studies. In this study, we investigated the anticancer effect and associated mechanisms of Duchesnea phenolic fraction (DPF) on cervical cancer in vitro and in vivo. Our results showed that DPF significantly inhibited cervical cancer cell proliferation in dose- and time-dependent manners. DPF induced apoptosis as determined by AO/EB staining, DNA fragmentation and flow cytometry. Some apoptosis correlated proteins were altered following DPF treatment. Bax was up-regulated while Bcl-2 was down-regulated, and the expression ratio of Bax/Bcl-2 was increased. These resulted in the translocation of Bax to mitochondria, the release of cytochrome c from the mitochondria to the cytosol and caspase-3 activation. Concurrently, DPF provoked S phase arrest along with significant down-regulation of S phase-associated proteins, such as cyclin A, cyclin E, cyclin D1 and cdk2. Transplanted U14 cervical cancer mouse model was used to evaluate the antitumor effect of DPF in vivo. Compared with control, DPF treatment markedly prolonged survival of tumor-bearing mice and dose-dependently reduced the tumor weight. DPF could induce apoptosis in tumor tissues as evidenced by increased TUNEL-positive cells, activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. In addition, DPF significantly decreased the expression of cell proliferation markers PCNA and ki67 in tumors. All together, these data sustain our contention that DPF has anticancer properties and merits further investigation as a potential therapeutic agent.

Total Flavonoids Extracted from Xiaobuxin-Tang on the Hyperactivity of Hypothalamic-Pituitary-Adrenal Axis in Chronically Stressed Rats

Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, ameliorated behavioral alterations and hippocampal dysfunctions in chronically stressed rats. Studies over the last decades have suggested that the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in stress-related depression. Herein, we used the same chronic mild stress model of rats as before to further investigate the effect of XBXT-2 on the hyperactivity of HPA axis, including the stress hormones levels and glucocorticoid receptors (GRs) expression. Our ELISA results showed that chronic administration of XBXT-2 (25, 50 mg kg−1, p.o., 28 days, the effective doses for behavioral responses) significantly decreased serum corticosterone level and its upstream stress hormone adrenocorticotropic hormone (ACTH) level in chronically stressed rats. Furthermore, western blotting result demonstrated XBXT-2 treatment ameliorated stress-induced decrease of GRs expression in hippocampus, an important target involved in the hyperactivity of HPA axis. These results were similar to that of classic antidepressant imipramine treatment (10 mg kg−1, p.o.). In conclusion, the modulation of HPA axis produced by XBXT-2, including the inhibition of stress hormones levels and up-regulation of hippocampal GRs expression, may be an important mechanism underlying its antidepressant-like effect in chronically stressed rats.

Protective effect of Dammarane Sapogenins against chemotherapy-induced myelosuppression in mice:

Chemotherapy is the most common way to treat malignancies, but myelosuppression, one of its common side-effects, is a formidable problem. The present study described the protective role of Dammarane Sapogenins (DS), an active fraction from oriental ginseng, on myelosuppression induced by cyclophosphamide (CP) in mice. DS was orally administered at different dosages (37.5, 75, and 150 mg/kg) for 10 d after CP administration (200 mg/kg intraperitoneally). The results showed that DS increased the number of white blood cells (WBC) on day 3 and day 7 (P < 0.05), such that WBC levels were increased by 105.7 ± 29.5% at 75 mg/kg of DS on day 3 (P < 0.05, compared with the CP group). Similar results were observed in red blood cells and platelets in DS-treated groups. The colony-forming assay demonstrated that the depressed numbers of CFU-GM (colony-forming unit-granulocyte and macrophage), CFU-E (colony-forming unit-erythroid), BFU-E (burst-forming unit-erythroid), CFU-Meg (colony-forming unit-megakaryocyte) and CFU-GEMM (colony-forming unit-granulocyte, -erythrocyte, -monocyte and -megakaryocyte) induced by CP were significantly reversed after DS treatment. Moreover, the ameliorative effect of DS on myelosuppression was also observed in the femur by hematoxylin/eosin staining. In DS-treated groups, ConA-induced splenocyte proliferation was enhanced significantly at all the doses (37.5, 75, 150 mg/kg) on day 3 at the rate of 50.3 ± 8.0%, 77.6 ± 8.5% and 44.5 ± 8.4%, respectively, while lipopolysaccharide-induced proliferation was increased mainly on day 7 (P < 0.01), with an increased rate of 39.8 ± 5.6%, 34.9 ± 6.6% and 38.3 ± 7.3%, respectively. The thymus index was also markedly increased by 70.4% and 36.6% at 75 mg/kg on days 3 and 7, respectively, as compared with the CP group. In summary, DS has a protective function against CP-induced myelosuppression. Its mechanism might be related to stimulating hematopoiesis recovery, as well as enhancing the immunological function.

Anti-cancer effects of 20(S)-protopanoxadiol on human acute lymphoblastic leukemia cell lines Reh and RS4;11

Although the treatment outcome of acute lymphoblastic leukemia (ALL) has been improved in the past decades by combination chemotherapy, toxic side-effects of chemotherapeutics remain a major problem. Therefore, new alternative agents with low toxicity are urgently needed. Natural products provide a rich source of screening potential anti-cancer drugs. 20(S)-protopanoxadiol (PPD), a major gastrointestinal metabolic product of ginsenosides, exhibits promising anti-cancer activity with low toxicity. However, the anti-cancer activity of PPD against ALL has not been evaluated. In this study, we examined the anti-cancer effect of PPD on ALL cell lines Reh and RS4;11. The growth of leukemia cells and normal cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell cycle, apoptosis and differentiation was determined by flow cytometry. The results showed that PPD inhibited the growth of Reh and RS4;11 cells, but had little toxicity to peripheral blood mononuclear cells (PBMC). PPD also blocked cell cycle progression from G0/G1 phase and induced cell differentiation. However, cell apoptosis was not affected. These data indicate that PPD exerts anti-cancer effects by stimulating differentiation and inhibiting growth and cell cycle progression of ALL cells.

Memory-Enhancing Effects of the Crude Extract of Polygala tenuifolia on Aged Mice

Learning and memory disorders arise from distinct age-associated processes, and aging animals are often used as a model of memory impairment. The root of Polygala tenuifolia has been commonly used in some Asian countries as memory enhancer and its memory improvement has been reported in various animal models. However, there is less research to verify its effect on memory functions in aged animals. Herein, the memory-enhancing effects of the crude extract of Polygala tenuifolia (EPT) on normal aged mice were assessed by Morris water maze (MWM) and step-down passive avoidance tests. In MWM tests, the impaired spatial memory of the aged mice was partly reversed by EPT (100 and 200 mg/kg; P < 0.05) as compared with the aged control mice. In step-down tests, the nonspatial memory of the aged mice was improved by EPT (100 and 200 mg/kg; P < 0.05). Additionally, EPT could increase superoxide dismutase (SOD) and catalase (CAT) activities, inhibit monoamine oxidase (MAO) and acetyl cholinesterase (AChE) activities, and decrease the levels of malondialdehyde (MDA) in the brain tissue of the aged mice. The results showed that EPT improved memory functions of the aged mice probably via its antioxidant properties and via decreasing the activities of MAO and AChE.