Xiaoyaosan exerts antidepressant-like effects by regulating the functions of astrocytes and EAATs in the prefrontal cortex of mice.

BACKGROUND: Mounting evidence indicates that the cerebral cortex is an important physiological system of emotional activity, and its dysfunction may be the main cause of stress. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), which initiates rapid signal transmission in the synapse before its reuptake into the surrounding glia, specifically astrocytes (ASTs). The astrocytic excitatory amino acid transporters 1 (EAAT1) and 2 (EAAT2) are the major transporters that take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with depression. Therefore, we hypothesized that the underlying antidepressant-like mechanism of Xiaoyaosan (XYS), a Chinese herbal formula, may be related to the regulation of astrocytic EAATs. Therefore, we studied the antidepressant mechanism of XYS on the basis of EAAT dysfunction in ASTs. METHODS: Eighty adult C57BL/6 J mice were randomly divided into 4 groups: a control group, a chronic unpredictable mild stress (CUMS) group, a Xiaoyaosan (XYS) treatment group and a fluoxetine hydrochloride (Flu) treatment group. Except for the control group, mice in the other groups all received chronic unpredictable mild stress for 21 days. Mice in the control and CUMS groups received gavage administration with 0.5 mL of normal saline (NS) for 21 days, and mice in the XYS and Flu treatment groups were administered dosages of 0.25 g/kg/d and 2.6 mg/kg/d by gavage. The effects of XYS on the depressive-like behavioral tests, including the open field test (OFT), forced swimming test (FST) and sucrose preference test (SPT), were examined. The glutamate (Glu) concentrations of the prefrontal cortex (PFC) were detected with colorimetry. The morphology of neurons in the PFC was observed by Nissl staining. The expression of glial fibrillary acidic protein (GFAP), NeuN, EAAT1 and EAAT2 proteins in the PFC of mice was detected by using Western blotting and immunohistochemistry. Quantitative real-time PCR (qPCR) was used to detect the expression of the GFAP, NeuN, EAAT1 and EAAT2 genes in the PFC of mice. RESULTS: The results of behavioral tests showed that CUMS-induced mice exhibited depressive-like behavior, which could be improved in some tests with XYS and Flu treatment. Immunohistochemistry and Western blot analysis showed that the protein levels of GFAP, NeuN, EAAT1 and EAAT2 in the PFC of CUMS mice were significantly lower than those in the control group, and these changes could be reversed by XYS and Flu. The results of qPCR analysis showed that the expression of GFAP, NeuN, EAAT1 and EAAT2 mRNAs in the PFC of CUMS mice was not significantly changed, with the exception of EAAT2, compared with that of the control group, while the expression of the above mRNAs was significantly higher in the XYS and Flu groups than that in the CUMS group. CONCLUSION: XYS may exert antidepressant-like effects by improving the functions of AST and EAATs and attenuating glutamate-induced neuronal damage in the frontal cortex.

Evaluating the Anti-depression Effect of Xiaoyaosan on Chronically-stressed Mice.

In addition to the standardized use of antidepressant medications and psychotherapy, the usage of traditional Chinese medicine has lead to an overall improvement of patients with major depressive disorder (MDD). Therefore, the purpose of this study was to establish the mouse depressive model, observe the behavior changes associated with chronic unpredictable mild stress (CUMS), and then evaluate the anti-depression effect of Xiaoyaosan. Mice were randomly divided into four groups: a control group, a model group, a treatment group with Xiaoyaosan, and a treatment group with fluoxetine. All mice were individually kept in cages, and depression was induced in the mice by exposing them to several designed manipulations of CUMS for 21 days, as described in the protocol. Mice in the control group and model group received 0.5 mL of distilled water, while mice in the treatment groups received either Xiaoyaosan (0.25 g/kg/day) or fluoxetine (2.6 mg/kg/day). The drugs used in the study were given intragastrically daily during the entire three weeks. To estimate the depressive-like behaviors, a series of parameters including the coat state, body weight, open field test score, and sucrose preference test score were recorded. Data analysis showed that behaviors of model mice were significantly changed compared to behaviors of mice in the control group, which were improved by the treatment of Xiaoyaosan and fluoxetine. The current findings demonstrated the anti-depression effects of Xiaoyaosan on the behaviors of CUMS-induced mice and revealed that compounds from the Xiaoyaosan prescription may be worthwhile for treating depression, considering their beneficial effects on depressive-like behaviors.

THE USE OF RHEUM PALMATUM L. IN THE TREATMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME: A META-ANALYSIS OF RANDOMIZED, CONTROLLED TRIALS.

BACKGROUND: Chinese medicine theory shows that "lung being connected with large intestine", and the modern western medicine also shows that the lung and intestinal tract affect each other in physiological and pathological conditions. If the lung ventilation dysfunction is caused by inflammatory exudate or secretions obstruction of the small airway ventilation, blood gas partial pressure is increased and intestinal gas absorption difficulty may lead to intestinal inflation and dysfunction (Wang N et al., 2011). Rheum palmatum L. can play the roles of anti-coagulation and anti-thrombosis, and improve microcirculation through lowering the endotoxin-induced permeability of microvascular tissue, reducing tissue oedema, decreasing inflammatory exudation and necrosis, and enhancing cyto-protection mechanism (Yang TZ et al., 2014). Therefore, systemic evaluation of the evidence pertaining to the usage of Rheum palmatum L. in treating acute lung injury and acute respiratory distress syndrome (ARDS) has significant clinical significance. MATERIALS AND METHODS: Various Electronic Databases CBM, CNKI, VIP, Wanfang, PubMed and Cochrane Library were searched until December 2015. Numerous randomized-controlled trials (RCTs) evaluating the efficacy of Rheum palmatum L. for the treatment of acute lung injury and acute respiratory distress syndrome were collected. The quality of the included studies was evaluated and a meta-analysis was performed using the RevMan5.0 software. RESULTS: Eight RCTs involving 489 patients were selected for this review. The results of the Meta-analysis revealed that Rheum palmatum L. therapy, combined with routine comprehensive treatment, was significantly superior to that of routine comprehensive treatment alone, in the areas of decreasing mortality, the mechanical ventilation time, the level of interleukin-6,8 and the untoward effect, and also in improving arterial blood gas (PaO2/FiO2, PaO2) (P<0.05). CONCLUSION: Compared with treatment with routine comprehensive alone, Rheum palmatum L. treatment combined with routine comprehensive, has been shown to effectively decrease the mortality, mechanical ventilation time and ameliorate the arterial blood gas, the cytokine levels, and the untoward effect. However, the evidence appears not to be very compelling due to the poor quality of the original studies.

Involvement of the glutamate/glutamine cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice.

BACKGROUND: Xiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960-1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with  alterations in glutamate/glutamine cycle and glutamate transporters. METHODS: Mice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1-2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated. RESULTS: After CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS. CONCLUSION: The studies indicated that XYS may have therapeutic actions on depression -like behavior s induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine cycle and glutamate transporter GLT-1 in the hippocampus.

Involvement of Normalized Glial Fibrillary Acidic Protein Expression in the Hippocampi in Antidepressant-Like Effects of Xiaoyaosan on Chronically Stressed Mice.

The research has only yielded a partial comprehension of MDD and the mechanisms underlying the antidepressant-like effects of XYS. Therefore, in this study, we aimed to explore the effects of XYS on chronic unpredictable mild stress- (CUMS-) induced changes in the neuronal and the astrocytic markers in the mouse hippocampus. The physical states and depressive-like behaviors in mice with CUMS were recorded. The serum contents of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured. The protein and mRNA expressions and the immunoreactivities of glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) in mouse hippocampus were detected using a Western blot, qRT-PCR, and immunohistochemical staining, respectively. XYS treatment markedly improved the physical state and depressive-like behaviors in mice subjected to CUMS compared with the model group, and the serum contents of BDNF and GDNF were significantly upregulated. XYS treatment also elevated the protein and mRNA levels, as well as the immunoreactivity of GFAP in the hippocampus. However, CUMS did not influence NeuN expression. In conclusion, these results reveal that chronic administration of XYS elicits antidepressant-like effects in a mouse model of depression and may normalize glial fibrillary acidic protein expression in the hippocampi of mice with CUMS.

From a pro-apoptotic peptide to a lytic peptide: One single residue mutation.

Further discovery and design of new anticancer peptides are important for the development of anticancer therapeutics, and study on the detailed acting mechanism and structure-function relationship of peptides is critical for anticancer peptide design and application. In this study, a novel anticancer peptide ZXR-1 (FKIGGFIKKLWRSKLA) derived from a known anticancer peptide mauriporin was developed, and a mutant ZXR-2 (FKIGGFIKKLWRSLLA) with only one residue difference at the 14th position (Lys→Leu) was also engineered. Replacement of the lysine with leucine made ZXR-2 more potent than ZXR-1 in general. Even with only one residue mutation, the two peptides displayed distinct anticancer modes of action. ZXR-1 could translocate into cells, target on the mitochondria and induce cell apoptosis, while ZXR-2 directly targeted on the cell membranes and caused membrane lysis. The variance in their acting mechanisms might be due to the different amphipathicity and positive charge distribution. In addition, the two Ile-Leu pairs (3-10 and 7-14) in ZXR-2 might also play a role in improving its cytotoxicity. Further study on the structure-function relationship of the two peptides may be beneficial for the design of novel anticancer peptides and peptide based therapeutics.

TRADITIONAL CHINESE MEDICINE COMBINED WITH HORMONE THERAPY TO TREAT PREMATURE OVARIAN FAILURE: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS.

BACKGROUND: This meta-analysis aimed to provide critically estimated evidence for the advantages and disadvantages of Chinese herbal medicines used for premature ovarian failure (POF), which could provide suggestions for rational treatments. MATERIALS AND METHODS: The databases searched included MEDLINE, EMBASE, CNKI, VIP, China Dissertation Database, China Important Conference Papers Database, and online clinical trial registry websites. Published and unpublished randomized controlled trials of traditional Chinese medicine (TCM) combined with hormone therapy (HT) and HT alone for POF were assessed up to December 30, 2015. Two authors extracted data and assessed trial quality independently using Cochrane systematic review methods. Meta-analysis was used to quantitatively describe serum hormone levels and Kupperman scores associated with perimenopause symptoms. RESULTS: Seventeen randomized controlled trials involving 1352 participants were selected. Compared with HT alone, although no significant effects were observed in the levels of luteinizing hormone, therapy with TCM combined with HT compared to HT alone effectively altered serum hormone levels of follicle stimulating hormone (P<0.01) and estradiol (P < 0.01), and improved Kupperman index scores (P< 0.01). CONCLUSIONS: The reported favorable effects of TCM combined with HT for treating POF patients are better than HT alone.However, the beneficial effects derived from this combination therapy cannot be viewed conclusive. In order to better support the clinical use, more rigorously designed trials are required to provide.

Xiao Yao San Improves Depressive-Like Behaviors in Rats with Chronic Immobilization Stress through Modulation of Locus Coeruleus-Norepinephrine System.

Most research focuses on the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamus-pituitary-thyroid (HPT) axis, and hypothalamus-pituitary-gonadal (HPGA) axis systems of abnormalities of emotions and behaviors induced by stress, while no studies of Chinese herbal medicine such as Xiao Yao San (XYS) on the mechanisms of locus coeruleus-norepinephrine (LC-NE) system have been reported. Therefore, experiments were carried out to observe mechanism of LC-NE system in response to chronic immobilization stress (CIS) and explore the antidepressant effect of XYS. Rat model was established by CIS. LC morphology in rat was conducted. The serum norepinephrine (NE) concentrations and NE biosynthesis such as tyrosine hydroxylase (TH), dopamine-ß-hydroxylase (DBH), and corticotrophin-releasing-factor (CRF) in LC were determined. Results showed that there were no discernible alterations in LC in rats. The serum NE concentrations, positive neurons, mean optical density (MOD), and protein levels of TH, DBH, and CRF in model group were significantly increased compared to the control group. But XYS-treated group displayed a significantly decreased in NE levels and expressions of TH, DBH, and CRF compared to the model group. In conclusion, CIS can activate LC-NE system to release NE and then result in a significant decrease in rats. XYS treatment can effectively improve depressive-like behaviors in rats through inhibition of LC-NE neurons activity.