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Shen-Zhi-Ling (SZL) is a Chinese medicine formulated from a Kai-Xin-San decoction that is commonly used to treat depression caused by dual deficiencies in the heart and spleen. However, the underlying mechanisms remain unclear. We investigated biological changes in depression patients (DPs) exhibiting antidepressant responses to SZL treatment using proteomic techniques. We performed label-free quantitative proteomic analysis and liquid chromatography-tandem mass spectrometry to discover and examine altered proteins involved in depression and antidepressant treatment. Serum samples were collected from DPs, DPs who underwent 8 weeks of SZL treatment and healthy controls (HCs). The proteins that differed among the three groups were further validated by Western blot analysis. By performing multivariate analyses, we identified 12 potential serum biomarkers that were differentially expressed among the HC, DP, and SZL groups. We then confirmed the significant changes in alpha-1-antitrypsin, von Willebrand factors, apolipoprotein C-III, and alpha-2-macroglobulin among the three groups by performing Western blot analysis, which supported the proteomic results. Profiling the proteomic changes in DPs treated with SZL could improve our understanding of the pathways involved in SZL responses, such as alterations in platelet activation, inflammatory regulation, and lipid metabolism. Future studies involving larger patient cohorts are necessary to draw more definitive conclusions.

Fifteen cycloartane triterpenes were isolated from Beesia calthaefolia and among them one was new cycloartane triterpenoid. The structure of new compound was determined by the application of spectroscopic analyses and chemical methods. The fifteen compounds were evaluated for their anticomplement activity by classic pathway. The structure-activity relationship analysis indicated that the configurations of 12-OH is preferable to be α than β, and 18-OH can decrease while 15-OH can increase the anticomplement activity, but saponin with both 15-OH and 18-OH lost most of its activity. The glycosyl moiety of most isolated cycloartane triterpenes is xylosyl. When xylosyl was substituted by glucosyl or galactosyl, their anticomplement activities were decreased or increased, respectively. Further structure-activity relationship (SAR) studies must be carried out to achieve general conclusions regarding the effect of further functionalizations on the anticomplement saponins.

Ding-Zhi-Xiao-Wan (DZXW) is a traditional Chinese medicine widely used for treating depression. To clarify the bioactive constituents of DZXW, a new rapid ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS(E)) method was established in this study, with the whole extract of the formula separated into multiple components to facilitate the analytical process. In total, 97 compounds were detected and 88 were identified in DZXW. Based on their exact masses, fragmentation characteristics, and retention times, 85 of the 88 compounds were confirmed either conclusively or tentatively, and three potentially novel compounds were identified. In addition, following a three-day oral administration of DZXW, 60 and 28 compounds were observed in the plasma of normal and depressive rats, respectively. Finally, by combining our data with pharmacological information, 10 compounds were predicted as the likely bioactive constituents of DZXW as an antidepressant agent. Our approach provided a rapid method for characterising the chemical constituents of DZXW, and we were the first to screen for bioactive indexes in the plasma of depressive rats. Furthermore, our results provide useful chemical information that could be employed for further study of the pharmacodynamic material basis of DZXW's antidepressant effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Dingzhi Xiaowan is a widely used traditional Chinese medicine in treating depression, which is a similar formula of Kaixinsan. In this research, a rapid ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS(E)) method was established to analyze the metabolites of Dingzhi Xiaowan in depressive model rat plasma, bile, urine and feces. After we established Chronic unpredictable mild stress (CUMS) model rats and orally administrated Dingzhi Xiaowan, rat plasma, bile, urine and feces samples were collected and prepared. Using Waters Cortects UPLC C18 column (2.1 mm x 50 mm, 1.6 μm), acetonitrile-0.1% formic acid mobile phase gradient, these samples were analyzed and 33 metabolites of nine bioactive compounds were detected and tentatively identified by Metabolynx. Among the 33 metabolites, three metabolites were identified from plasma sample, three came from bile sample, and 27 metabolites were identified from urine and feces samples. This approach provided a rapid method for characterizing the metabolites of Dingzhi Xiaowan and gave the truly active structures and the action mechanism of their antidepressant effects.

Tenuifoliside A (TFSA) is a bioactive oligosaccharide ester component of Polygala tenuifolia Wild, a traditional Chinese medicine which was used to manage mental disorders effectively. The neuroprotective and anti-apoptotic effects of TFSA have been demonstrated in our previous studies. The present work was designed to study the molecular mechanism of TFSA on promoting the viability of rat glioma cells C6. We exposed C6 cells to TFSA (or combined with ERK, PI3K and TrkB inhibitors) to examine the effects of TFSA on the cell viability and the expression and phosphorylation of key proteins in the ERK and PI3K signaling pathway. TFSA increased levels of phospho-ERK and phospho-Akt, enhanced release of BDNF, which were blocked by ERK and PI3K inhibitors, respectively (U0126 and LY294002). Moreover, the TFSA caused the enhanced phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 site, the effect was revoked by U0126, LY294002 and K252a. Furthermore, when C6 cells were pretreated with K252a, a TrkB antagonist, known to significantly inhibit the activity of brain-derived neurotrophic factor (BDNF), blocked the levels of phospho-ERK, phospho-Akt and phosphor-CREB. Taking these results together, we suggested the neuroprotection of TFSA might be mediated through BDNF/TrkB-ERK/PI3K-CREB signaling pathway in C6 glioma cells., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. Previous studies have demonstrated that the herbal medicine formula, 'kaixinsan' (KXS), could ameliorate the severity of depression and increase cAMP response element-binding protein expression. There is direct evidence suggesting that the reduction of the BDNF protein in specific brain sites can provoke depressive-like behaviour or affect neurogenesis in vivo. However, the biological mechanisms between the antidepressant and neuroprotective effect of KXS and the alterations in BDNF levels in in vivo and in vitro models remain unclear. Using BDNF knockdown mediated by lentiviral vectors (LV-shBDNF-3) transfected with primary hippocampal neurons and following injection into the dentate gyrus of the hippocampus, it was demonstrated that a reduction in BDNF expression affects cell viability and animal behaviours associated with depression. During treatment with KXS after the lentiviral shRNA silencing of BDNF in cell and animal, cell viability, body weight, the sucrose preference test (SPT), the open field test (OFT) the Morris Water Maze (MWM) task and BDNF expression were measured. KXS attenuated LV-shBDNF-3-induced cell death in primary hippocampal neurons and also improved the sucrose intake in SPT, ambulatory response in OFT and learning ability in MWM against LV-shBDNF-3-induced depressive-like syndromes. Moreover, immunoblot analysis confirmed that KXS could reverse LV-shBDNF-induced BDNF reduction either in vitro or in vivo. These findings provide substantial evidence for supporting a neurotrophic hypothesis of depression and specify BDNF targets for potential antidepressant interventions. Moreover, the antagonism between LV-shRNA BDNF knockdown and KXS may depend on multiple compounds with synergistic mechanisms that modulate the different signal transduction networks directly or indirectly, increasing BDNF expression and exerting its neuroprotective and antidepressant-like effects., (© 2014 S. Karger AG, Basel.)

The aim of this study was to explore whether the ethanolic extract of Ardisia gigantifolia rhizomes (AGB-5), a traditional herbal medicine from China, could affect the proliferation of human breast adenocarcinoma (MCF-7) cells in vitro and to explore the antitumor effects of AGB-5 in BALB/c mice engrafted with MCF-7 cells. The results showed that AGB-5 markedly inhibited the proliferation of MCF-7 cells with an IC50 value of 11.89±1.12 µg/mL, increased the S phase and decreased the G2/M phase without influence on G1 phase. MCF-7 cells treated with AGB-5 presented a dose-dependent increase of apoptosis compared with the control group. AGB-5 also significantly increased the activity of caspase-3 and -9 in a dose-dependent manner in MCF-7 cells. Furthermore, in an in vivo model, AGB-5 reduced tumor volume, brought back the red blood cell (RBC) and white blood cell (WBC) count near to normal value, enhanced superoxide dismutase and catalase level of MCF-7 bearing mice. This is the first study to verify the antitumor activity of A. gigantifolia in vivo. The results suggest that AGB-5 may have potential beneficial effects against human breast adenocarcinoma.

Ethnopharmacological Relevance: Ding-Zhi-Xiao-Wan (DZ, also known as Kai-Xin-San) is a famous traditional Chinese medicine used for the treatment of emotional disease. Previously, we have found that in a variety of animal models of depression (such as tail suspension model, model of chronic fatigue and forced swimming model) DZ demonstrated significant antidepressant behavior and promoted the production of 5-hydroxytryptamine (5-HT). However, the mechanisms of 5-HT regulation are still unclear. Therefore, the current study is designed to further investigate the antidepressant effect of DZ by observing its influence on 5-HT synthesis, metabolism, transport and other key links, so as to clarify the molecular mechanism of its 5-HT regulation., Materials and Methods: Solitary rising combined with the chronic unpredictable mild stress (CMS) was used to establish the rat model of depression. The rats were given DZ for 3 weeks, the behavior change and the following items in hippocampus and prefrontal cortex were detected simultaneously: 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and 5-HT transporter (5-HTT) were observed., Results: Our results showed that treatment with the DZ significantly improved the behavior and simultaneously increased the 5-HT level in the hippocampus, prefrontal cortex tissues and hippocampus extracellular of depressive rats. In future studies revealed that DZ could significantly increase the protein and mRNA expression of the key enzymes TPH during the 5-HT synthesis process in the hippocampus and prefrontal cortex of the depressed rats, and suppress the expression of 5-HTT protein and mRNA at the same time. But it had no effects on MAO-A and MAO-B activities., Conclusion: We believe that antidepressant effect of DZ is caused by the increase of 5-HT synthesis and reduction of 5-HT re-uptake, and eventually increase the content of 5-HT in the brain and the synaptic gaps., (© 2013 Published by Elsevier Ireland Ltd.)

Ethnopharmacological Relevance: Kai-Xin-San (KXS) is a famous traditional Chinese medicine (TCM) formula. It has been used in the treatment of diseases including neurasthenia, Alzheimer's disease and neurosis., Aim of the Study: To provide information on the potential toxicity of KXS, we evaluated the acute and subchronic toxicity in rodents., Materials and Methods: In acute study, a single administration of KXS was given orally to mice at doses ranging from 19.67 to 60.04 g/kg. In the sub-chronic oral toxicity study, KXS was administered to rats at 0, 1, 3 and 9 g/kg for 13 weeks. Moreover, 30 days of post treatment (withdrawal study) was conducted. Mortalities, clinical signs, body weight changes, food and water consumption, haematological and biochemical parameters, gross findings and organ weights were monitored during the study period., Results: In the sub-chronic study in rats, daily oral administration of KXS at the dose of 9 g/kg/day result in significant increase in WBC, lymphocyte, alkaline phosphatase, blood sugar and significant decrease in bodyweight, serum Cre, CK and CHO at the last week of treatment. Recovery except for the body weight was observed after 30 days of post treatment., Conclusions: KXS is relatively safe for oral medication. The LD(50) of KXS was over 32.59 g/kg for mice. The no-observed-adverse-effect-level (NOAEL) was considered to be 19.67 g/kg/day for rats., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)