Genome-wide analysis of hippocampal transfer RNA-derived small RNAs identifies new potential therapeutic targets of Bushen Tiansui formula against Alzheimer's disease.

OBJECTIVE: Bushen Tiansui formula (BSTSF), a traditional Chinese medicine prescription, has been widely used to treat Alzheimer's disease (AD). However, the mechanisms underlying its effects remain largely unknown. In this study, a rat AD model was used to study the effects of BSTSF on cognitive performance and expression of transfer RNA-derived small RNAs (tsRNAs) in the hippocampus, to determine whether treatment of AD with BSTSF could regulate the expression of tsRNAs, a novel small non-coding RNA. METHODS: To generate a validated AD model, oligomeric amyloid-ß1-42 (Aß1-42) was injected intracerebroventricularly into rats. The Morris water maze (MWM) test was used to evaluate rat cognitive performance, and tsRNA-sequencing was conducted to examine tsRNA expression in the rat hippocampus. Potential targets were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatic analyses were conducted to investigate the biological function of candidate tsRNAs. RESULTS: The learning and memory deficits of Aß1-42-induced AD rats, assessed by MWM tests, were clearly ameliorated by BSTSF treatment. A total of 387 tsRNAs were detected in the rat hippocampus. Among them, 13 were significantly dysregulated in AD rats compared with sham control rats, while 57 were markedly altered by BSTSF treatment, relative to untreated AD rats (fold change ≥ 2 and P < 0.05). Moreover, six BSTSF treatment-related tsRNAs were identified and validated by qRT-PCR. Bioinformatic analyses indicated that the six treatment-related tsRNAs had potential therapeutic roles, via multiple signaling pathways and Gene Ontology biological functions, including cyclic adenosine monophosphate and retrograde endocannabinoid signaling. CONCLUSION: This study identified a previously uncharacterized mechanism underlying the effects of BSTSF in alleviating the learning and memory deficits in Aß1-42-induced AD rats, demonstrating that tsRNAs are potential therapeutic targets of BSTSF in the treatment of AD.

Nine traditional Chinese herbal formulas for the treatment of depression: an ethnopharmacology, phytochemistry, and pharmacology review.

Depression is a major mental disorder, and is currently recognized as the second-leading cause of disability worldwide. However, the therapeutic effect of antidepressants remains unsatisfactory. For centuries, Chinese herbal formulas (CHFs) have been widely used in the treatment of depression, achieving better therapeutic effects than placebo and having fewer side effects than conventional antidepressants. Here, we review the ethnopharmacology, phytochemistry, and pharmacology studies of nine common CHFs: "banxia houpo" decoction, "chaihu shugansan", "ganmaidazao" decoction, "kaixinsan", "shuganjieyu" capsules, "sinisan", "wuling" capsules, "xiaoyaosan", and "yueju". Eight clinical trials and seven meta-analyses have supported the theory that CHFs are effective treatments for depression, decreasing Hamilton Depression Scale scores and showing few adverse effects. Evidence from 75 preclinical studies has also elucidated the multitarget and multipathway mechanisms underlying the antidepressant effect of the nine CHFs. Decoctions, capsules, and pills all showed antidepressant effects, ranked in descending order of efficacy. According to traditional Chinese medicine theory, these CHFs have flexible compatibility and mainly act by soothing the liver and relieving depression. This review highlights the effective treatment choices and candidate compounds for patients, practitioners, and researchers in the field of traditional Chinese medicine. In summary, the current evidence supports the efficacy of CHFs in the treatment of depression, but additional large-scale randomized controlled clinical trials and sophisticated pharmacology studies should be performed.

The effect of Chaihu-Shugan-San and its components on the expression of ERK5 in the hippocampus of depressed rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu-Shugan-San (CSS) is a well-known, Chinese traditional medicine used to treat depression. Little is known about the antidepressant mechanism of CSS. The main aims of the this study were to evaluate the antidepressant-like effects of CSS and its components and further explore the CSS׳s effect upon signal transduction of extracellular signal-regulated kinase 5 (ERK5) expressions in the hippocampus of rats with depression induced by chronic unpredicted mild stress. MATERIALS AND METHODS: SD rats were randomly divided into six groups: Normal; Model; CSS; Component I; Component II; and Fluoxetine. Antidepressant-like effects of CSS and two of its constituents, Components I and II in aqueous extract, were assessed using rats exposed to chronic unpredictable mild stress (CUMS) by measuring weight change, observing the open-field test and measuring sucrose water consumption. Antidepressant mechanism were examined by measuring the effect of CSS, and two of its constituents, on extracellular signal-regulated kinase 5 (ERK5) expression, phosphorylation-ERK5 (p-ERK5), and ERK5 mRNA in the hippocampus by using western blotting and Real-time Polymerase Chain Reaction (PCR). Three preparations were prepared: (1) an aqueous extract of CSS (5.9 g/kg·d); (2) Component I (3.3 g/kg·d); and (3) Component II (2.6 g/kg·d). During the 28-day CUMS, the three preparations were intragastrically administered all three preparations. Simultaneously a parallel positive fluoxetine control group was given fluoxetine hydrochloride (1.8mg/kg·d). Normal and Model groups were intragastrically administered with a isovolumic distilled water (4.5 ml/kg·d). RESULTS: Depressed rats had decreased weight gain; decreased locomotor activity as measured by the open field test; and reduced sucrose consumption. The rats׳ hippocampus ERK5 activation was significantly suppressed. CSS reduced the incidence of depressive-like behaviors and increased ERK5 activation in depressed rats at the same rate as fluoxetine. Component I, and II, each had only a partial effect on the depression indicators measured. CONCLUSIONS: CSS aqueous extract has antidepressant-like effects on CUMS-induced depression model rats. The antidepressant effect of CSS is greater than that of either the two separate components measured. CSS׳s antidepressant mechanism may be mediated by reversing the stress-induced disruption of ERK5 activity.

[Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San].

OBJECTIVE: To screen microRNAs with specific expression of in hippocampus of rats with chronic stress induced depression model, and observe the effect of traditional Chinese medicine Chaihu Shugan San on the expression of microRNA in hippocampus. METHOD: SD rats were randomly divided into 3 groups: the normal control group, the model control group and the Chaihu Shugan San group. The depression model was replicated by unpredictable chronic mild stress combined with separation. Behavioral changes of the rats were observed by Open-field test and sucrose solution consumption test, and the expression of microRNAs in hippocampus was assayed by microRNA micro-array. RESULT: Compared with the normal control group, there were 13 specific miRNAs in hippocampus in the model control group with the expression difference of more than 2 times. Among them, down-regulating miRNAs included miR298, miR-130b, miR-135a, miR-323, miR-503, miR-15b, miR-532, and miR-125a, and the up-regulation miRNAs included miR7a, miR-212, miR-124, miR-139, and miR-182. Among the 13 specific miRNAs, miR-125a and miR-182 recovered to normal after intervention with Chaihu Shugan San in the Chaihu Shugan San group. CONCLUSION: This study preliminarily found that 13 specific miRNAs in hippocampus are related to depression. Among them, miR-125a and miR-182 recover to normal after intervention with Chaihu Shugan San, which may be the target points of the antidepressant effect of Chaihu Shugan San. We shall further analyze the target genes and their mechanisms.

[Effects of chaihu shugan powder on the behavior and expressions of BDNF and TrkB in the hippocampus, amygdala, and the frontal lobe in rat model of depression].

OBJECTIVE: To investigate the effects of Chaihu Shugan Powder (CHSGP) on the behavior and the expressions of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase receptors B (TrkB) in the hippocampus, amygdala, and the frontal lobe of depression model rats. METHODS: Sixty adult Sprague-Dawley rats were randomly divided into 6 groups, i. e., the normal control group (NC), the model control group (MC), the CHSGP group, the disassembly 1 group (CI), the disassembly 2 group (CII), and the Fluoxetine control group (FC), 10 in each group. Except those in the NC, the rest rats were singly housed and exposed on an unpredicted sequence of mild stressor. From the fifteenth day, all rats were administered with equal volume of normal saline (to the NC group and the MC group) and of corresponding medicinal liquid (5.9 g/kg to the CHSGP group, 3.3 g/kg to the CI group, 2.6 g/kg to the CII group, and 1.8 mg/kg to the FC group) by gastrogavage for 2 successive weeks. The rats' body weight, sucrose consumption volume in the sucrose preference test, and times of grooming in the open field test were detected on the 0, 7th, 14th, 21st, 28th day, respectively. The mRNA expressions of BDNF and TrkB in the hippocampus, amygdala, and the frontal lobe were detected by immunohistochemical assay and Real-time fluorescent quantitation PCR. RESULTS: Compared with the NC group, the rats' body weight was put up slowly in the MC group. The scores in the open field test decreased. The times of grooming and sucrose consumption volume were both reduced. The time of staying in central square was postponed. The mRNA expressions of BDNF and TrkB in the hippocampus, amygdala, and the frontal lobe decreased with statistical significance (P<0.05, P<0.01). Compared with the MC group, the behavior indices of rats in the CHSGP, CI, CII, and FC groups were significantly improved. The mRNA expressions of BDNF and TrkB in the hippocampus, amygdala, and the frontal lobe were obviously enhanced with statistical significance (P<0.05, P<0.01). CONCLUSIONS: CHSGP could obviously improve the depressive state of the model rats. Its mechanism might be correlated with increasing the mRNA expressions of BDNF and TrkB in the hippocampus, amygdala, and the frontal lobe.

[Relationship between symptom stratification and syndrome differentiation of traditional Chinese medicine for depressive episode].

On the basis of medical literature review and clinical research experience, the authors analyzed the reasons for low recognition rate of depression and poor progress of traditional Chinese medicine (TCM) differentiation of depression in this paper and put forward that depressive episode symptoms and the corresponding common terminology classification of Chinese and Western medicine should be the breakthrough points. Through symptom stratification and combination, as well as distinguishing between primary and secondary symptoms, the comprehensive integrative medicine clinical assessment of depression was explored so as to further obtain expert consensus and provide a methodology reference for the TCM differentiation of depression and the research of etiology and pathogenesis.

[Effects of Chaihu Shugan San on behavior and plasma levels of corticotropin releasing hormone and adrenocorticotropic hormone of rats with chronic mild unpredicted stress depression].

OBJECTIVE: To investigate the effects of Chaihu Shugan San (CHSGS), a compound traditional Chinese herbal medicine, on behavior and plasma levels of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) of rats with chronic mild unpredicted stress depression. METHODS: Forty male Sprague-Dawley rats were randomly divided into 4 groups: normal control group, untreated group, fluoxetine group and CHSGS group. Except the normal control group, rats were singly housed and exposed to an unpredicted sequence of mild stressor for continuous 4 weeks to induce depression. Since the fifteenth day, rats were intragastrically administered with equal volume agents respectively for 2 weeks [normal saline for the normal control group and the untreated group, fluoxetine (1.8 mg/kg) for the fluoxetine group and CHSGS (5.9 g/kg) for the CHSGS group]. Behavioral scores of rats were detected by open-field test and sucrose preference test, and the plasma levels of CRH and ACTH in different groups were detected by radioimmunoassay. RESULTS: Compared with the normal control group, body weights of the rats in the untreated group were significantly decreased. Scores of crossing, rears and grooming in open-field test were reduced significantly. Pure water consumption in sucrose preference test was increased significantly. The levels of plasma CRH and ACTH were significantly increased. The depressive behaviors of the rats were improved significantly and the levels of plasma CRH and ACTH were obviously reduced in the CHSGS group. CONCLUSION: Chronic mild unpredicted mild stress can affect the neuroendocrine and behavior and cause depression in rats. CHSGS can regulate HPA hyperactivity of rats caused by chronic stress and has antidepressive effects.

[Mechanism and protective effect of glossy ganoderma decoction on the activities of RNA polymerase in hepatocyte of rabbits with Amanita mushroom poisoning].

OBJECTIVE: To investigate the mechanism of glossy ganoderma decoction in Amanita mushroom poisoning. METHODS: Twenty male New Zealand white rabbits were randomly divided into 4 groups, including a normal control, a model poison group, and 2 treatment groups (different doses of glossy ganoderma decoction). The activities of hepatocyte RNA polymerase were measured by ultraviolet spectrophotometry and liver function were measured. RESULTS: The activities of hepatocyte RNA polymerase of the model group significantly decreased, and those of the 2 treatment groups were significantly higher than those of the model group. There was a dose-dependent manner between the 2 treatment groups ( all Ps<0.01), and the differences of liver function test including total bilirubin (TBIL), direct bilirubin (DB), total bile acid (TBA), and alanine aminotransferase (ALT) in the 4 groups were significant (P<0.01). CONCLUSION: Glossy ganoderma decoction may protect the liver from Amanita mushroom poisoning. Its mechanism may be related to the increase of the activities of hepatocyte RNA polymerase.

Clinical experience in treatment of Amanita mushroom poisoning with Glossy Ganoderma Decoction and routine Western medicines.

OBJECTIVE: To assess the effects of treatment of Amanita mushroom poisoning with Glossy anoderma Decoction (, GGD). METHODS: Twelve patients with acute Amanita mushroom poisoning received conventional treatment (penicillin and reduced glutathione) combined with oral administration of GGD (treated group), which was prepared out of 200 g Glossy ganoderma decocted in water to 600 mL, and 200 ml was given once, three times a day for 7 successive days; while conventional treatment alone was given to the other 11 patients assigned to the control group. The therapeutic efficacy and changes in serum levels of total bilirubin (TBil), bile acids (BA), alanine transaminase (ALT), and aspartate transaminase (AST) activities in the two groups were compared. RESULTS: The cured-markedly effective rate in the treated group was more significant than that in the control group (P<0.01). Elevation in TBil, BA, ALT, and AST activities were observed in both groups 3 days after poisoning, which progressively increased thereafter in the control group. In the treated group, they reached their peak on the 3rd day and then declined gradually. The differences between pre-treatment and post-treatment in both groups were obviously significant (P<0.01), so were the differences between the two groups at corresponding time points (P<0.01). CONCLUSION: GGD shows excellent clinical efficacy in the treatment of acute Amanita mushroom poisoning and can reduce mortality significantly.

[Anti-depressive effect of Baisong tablets on the chronic mild unpredicted stress depression in rats].

OBJECTIVE: To investigate the effect of Baisong tablets on the nerve-biochemistry and neuroendocrine of chronic mild unpredicted stress depression in rats. METHODS: Sixty male Sprague-Dawley rats were randomly allocated to 4 groups: a normal control (NC), a model control (MC), a fluoxetine control (FC) and a Baisong tablet treatment group (BST). All rats except the control group were singly housed and exposed to an unpredicted sequence of mild stressor. The levels of serotonin (5-HT), glutamate (Glu) and gama-aminobutyric acid (GABA) of the hippocampus were measured by high-performance liquid chromatography. The concentration of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol (CORT) in the plasma of the rats were detected by radio-immunity. The CRHmRNA expressions in the hypothalamus and prefrontal cortex were semiquantified by RT-PCR method. The differences of BDNF and TrkB protein expression in CA1 and CA3 pyramidal and dentate gyrus granule cells layers of hippocampus were investigated with immunohistochemistry technique. RESULTS: In comparison with NC group, the levels of 5-HT, and GABA of the hippocampus in MC rats reduced significantly (P<0.01), and the concentration of CRH, ACTH, and CORT of the plasma and the level of Glu of the hippocampus and CRH mRNA expression in the brain increased significantly. Fluoxetine or Baisong could significantly regulate the abnormal changes of all the above. CONCLUSION: Chronic mild unpredicted stress can affect neuroendoerine and cause depression, and Baisong tablet has antagonism against it.

[The effects of Baisong tablet on the behaviors and CRHmRNA expression in the brain of rats following chronic stress].

OBJECTIVE: To investigate the effects of Baisong tablet on the behaviors and CRHmRNA expression in the chronic stress rats. METHOD: Rats were exposed to different ways of chronic stress. Body weight and behaviors were investigated during the whole procedure, the CRHmRNA expressions in the hypothalamus and prefrontal cortex were semiquantified by the RT-PCR method. RESULT: In comparision with the normal group, rats exposed to chronic stress showed decreased body weight and a significant reduction of consumption of sucrose solution, and the duration of immobility during the forced swimming test was increased significantly. The chronic stress rats was in depression of behavior. CRHmRNA expression in the brain of the chronic stress rats was upregulated significantly, while it was downregulated in the groups of Baisong tablet and the group of fluoxetin. CONCLUSION: Baisong tablet has the effect of antidepressant, and it may be related to the effect of the downregulated CRHmRNA expression in brain.