Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics.

Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.

Mapping the scientific research on bipolar disorder: A scientometric study of hotspots, bursts, and trends.

Bipolar disorder (BD) is a severe psychiatric illness with an increasing prevalence worldwide. Although the pathological mechanism of and pharmacological interventions for BD have been extensively investigated in preclinical and clinical studies, a scientometric analysis of the developmental trends, interdisciplinary frontiers, and research hotspots in this field has not yet been conducted. Therefore, we performed a comprehensive scientometric review of 55,358 published studies on BD over the past two decades (2002-2021) to identify the most frequently used keywords and explore research hotspots and trajectories. The present findings revealed the main distribution, knowledge structure, topic evolution, and emerging topics of BD research. Analysing the risk factors, pathogenesis, key brain regions, comorbid conditions, and treatment strategies for BD contributed to understanding of the aetiology, progression, and treatment of this disorder. These findings provided substantial support for continued research in this area.

Research progress on classical traditional chinese medicine formula xiaoyaosan in the treatment of depression.

Depression is an emotional disorder that is problematic in psychiatry owing to its unclear etiology and unknown pathogenesis. Traditional Chinese medicine formulations such as Xiaoyaosan have been widely used throughout history to treat depression. In this review, we have focused on recent evidences elucidating the links between Xiaoyaosan and the treatment of depression. Data from animal and clinical studies, focusing on the pharmacological mechanisms, clinical applications, and effective materials that form the basis for the treatment of depression are presented and discussed. We found that the antidepressant effects of Xiaoyaosan are related to the effects of monoamine neurotransmitters, regulation of the hypothalamic-pituitary-adrenal axis, neuroplasticity, synaptic plasticity, inflammatory response, neuroprotection, brain-gut axis, regulation of intestinal microbiota, oxidative stress, and autophagy for reducing neuronal apoptosis. This review highlights the current evidence supporting the use of Xiaoyaosan as an antidepressant and provides an overview of the potential mechanisms involved.

Xiaoyaosan Ameliorates Chronic Restraint Stress-Induced Depression-Like Phenotype by Suppressing A2AR Signaling in the Rat Striatum.

Depression is a common mental disorder characterized by pessimism and world-weariness. In our previous study, we found that Xiaoyaosan (XYS) could have antidepressive effects, however the underlying mechanisms remain unclear. Several studies have shown that adenosine A (2 A) receptor (A2AR) in the brain is a key point in the treatment of depression. Our present study aimed to investigate the effects of XYS on A2AR signaling in the striatum of rats exposed to chronic restraint stress (CRS). Ninety-six male Sprague-Dawley rats were randomly divided into 8 groups (control, model, negative control, XYS, A2AR antagonist, A2AR antagonist + XYS, A2AR agonist, A2AR agonist + XYS). The rats in the model group, XYS group, A2AR antagonist group and A2AR antagonist + XYS group were subjected to CRS for 3 h a day. The XYS decoction [2.224 g/(kg·d)] was intragastrical administered by oral gavage to the rats in the negative control group, XYS group, A2AR antagonist + XYS group, and A2AR agonist + XYS group. The rats in the A2AR antagonist group and A2AR antagonist + XYS group were treated with SCH 58261 [0.05 mg/(kg·d)], and the rats in the A2AR agonist and A2AR agonist + XYS group were treated with CGS 21680 [0.1 mg/(kg·d)]. These procedures were performed for 21 consecutive days. Behavioral studies including the open field test, elevated plus maze test, sucrose preference test and forced swimming test, were performed to examine depression-like phenotypes. Then, the effects of XYS on CRS- or A2AR agonist-induced striatal subcellular damage, microglial activation and A2AR signaling changes in the striatum were examined. Here, we report that XYS ameliorates depression-like phenotypes (such as body weight loss as well as depression- and anxiety-like behaviors) and improves synaptic survival and growth in the stratum of the CRS rats. Moreover, XYS reduces A2AR activity and suppresses hyper-activation of striatal microglia. The tissue and cellular effects of XYS were similar to those of the known A2AR antagonists. In conclusion, XYS alleviates depression in the CRS rats via inhibiting A2AR in the striatum.

Integrating Metabolomics and Network Analysis for Exploring the Mechanism Underlying the Antidepressant Activity of Paeoniflorin in Rats With CUMS-Induced Depression.

Background: Paeoniflorin (PF) represents the major bioactive constituent of the traditional Chinese medicine plant Paeonia suffruticosa (Ranunculaceae), which has a long history as a folk medicine in Asian. Paeoniflorin, a bitter pinene monoterpene glycoside, has antidepressant effects, but its potential therapeutic mechanism has not been thoroughly explored. Methods: Experimental depression in rats was established by the chronic unpredictable mild stress (CUMS) combined with orphan method, and the efficacy of paeoniflorin on depression was evaluated by the sucrose preference test and open field test. The antidepressant mechanism of paeoniflorin was investigated by metabolomic and network pharmacology. The relevant pathways of biomarkers highlighted in metabolomics were explored, and the possible targets of paeoniflorin in the treatment of depression were further revealed through network analysis. The binding activity of paeoniflorin to key targets was verified by molecular docking. Results: Metabolomics showed that rats with CUMS-induced depression had urine metabolic disorders, which were reversed by paeoniflorin through the regulation of metabolic pathways. Metabolites that play a key role in the function of paeoniflorin include citric acid, thiamine monophosphate, gluconolactone, 5-hydroxyindoleacetic acid and stachyose. Key predicted targets are SLC6A4, TNF, IL6 and SLC6A3. An important metabolic pathway is the Citrate cycle (TCA cycle). Conclusion: Network integrative analysis in this study showed that paeoniflorin could improve depressive-like symptoms in model rats with CUMS-induced depression and overall correct the disordered metabolic profile through multiple metabolic pathways.

Saikosaponin D exerts antidepressant effect by regulating Homer1-mGluR5 and mTOR signaling in a rat model of chronic unpredictable mild stress.

BACKGROUND: Many studies about depression have focused on the dysfunctional synaptic signaling in the hippocampus that drives the pathophysiology of depression. Radix Bupleuri has been used in China for over 2000 years to regulate liver-qi. Extracted from Radix Bupleuri, Saikosaponin D (SSD) is a pharmacologically active substance that has antidepressant effects. However, its underlying mechanism remains unknown. MATERIALS AND METHODS: A chronic unpredictable mild stress (CUMS) paradigm was used as a rat model of depression. SD rats were randomly assigned to a normal control (NC) group or one exposed to a CUMS paradigm. Of the latter group, rats were assigned to four subgroups: no treatment (CUMS), fluoxetine-treated (FLU), high-dose and low-dose SSD-treated (SSDH and SSDL). SSD was orally administrated of 1.50 mg/kg and 0.75 mg/kg/days for three weeks in the SSDH and SSDL groups, respectively. Fluoxetine was administrated at a dose of 2.0 mg/kg/days. SSD's antidepressant effects were assessed using the open field test, forced swim test, and sucrose preference test. Glutamate levels were quantified by ELISA. Western blot and immunochemical analyses were conducted to quantify proteins in the Homer protein homolog 1 (Homer1)-metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) pathways in the hippocampal CA1 region. To measure related gene expression, RT-qPCR was employed. RESULTS: CUMS-exposed rats treated with SSD exhibited increases in food intake, body weight, and improvements in the time spent in the central are and total distance traveled in the OFT, and less pronounced pleasure-deprivation behaviors. SSD also decreased glutamate levels in CA1. In CA1 region of CUMS-exposed rats, SSD treatment increased mGluR5 expression while decreasing Homer1 expression. SSD also increased expressions of postsynaptic density protein 95 (PSD95) and synapsin I (SYP), and the ratios of p-mTOR/mTOR, p-p70S6k/p70S6k, and p-4E-BP1/4E-BP1 in the CA1 region in CUMS-exposed rats. CONCLUSIONS: SSD treatment reduces glutamate levels in the CA1 region and promotes the expression of the synaptic proteins PSD-95 and SYP via the regulation of the Homer1-mGluR5 and downstream mTOR signaling pathways. These findings suggest that SSD could act as a natural neuroprotective agent in the prevention of depression.

Extracellular Vesicles: Emerging Roles in Developing Therapeutic Approach and Delivery Tool of Chinese Herbal Medicine for the Treatment of Depressive Disorder.

Extracellular vesicles (EVs) are lipid bilayer-delimited particles released by cells, which play an essential role in intercellular communication by delivering cellular components including DNA, RNA, lipids, metabolites, cytoplasm, and cell surface proteins into recipient cells. EVs play a vital role in the pathogenesis of depression by transporting miRNA and effector molecules such as BDNF, IL34. Considering that some herbal therapies exhibit antidepressant effects, EVs might be a practical delivery approach for herbal medicine. Since EVs can cross the blood-brain barrier (BBB), one of the advantages of EV-mediated herbal drug delivery for treating depression with Chinese herbal medicine (CHM) is that EVs can transfer herbal medicine into the brain cells. This review focuses on discussing the roles of EVs in the pathophysiology of depression and outlines the emerging application of EVs in delivering CHM for the treatment of depression.

Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis.

Background: Depression is a stress-related disorder that seriously threatens people's physical and mental health. Xiaoyaosan is a classical traditional Chinese medicine formula, which has been used to treat mental depression since ancient times. More and more notice has been given to the relationship between the occurrence of necroptosis and the pathogenesis of mental disorders. Objective: The purpose of present study is to explore the potential mechanism of Xiaoyaosan for the treatment of depression using network pharmacology and experimental research, and identify the potential targets of necroptosis underlying the antidepressant mechanism of Xiaoyaosan. Methods: The mice model of depression was induced by chronic unpredictable mild stress (CUMS) for 6 weeks. Adult C57BL/6 mice were randomly divided into five groups, including control group, chronic unpredictable mild stress group, Xiaoyaosan treatment group, necrostatin-1 (Nec-1) group and solvent group. Drug intervention performed from 4th to 6th week of modeling. The mice in Xiaoyaosan treatment group received Xiaoyaosan by intragastric administration (0.254 g/kg/d), and mice in CUMS group received 0.5 ml physiological saline. Meanwhile, the mice in Nec-1 group were injected intraperitoneally (i.p.) with Nec-1 (10 mg/kg/d), and the equivalent volume of DMSO/PBS (8.3%) was injected into solvent group mice. The behavior tests such as sucrose preference test, forced swimming test and novelty-suppressed feeding test were measured to evaluate depressive-like behaviors of model mice. Then, the active ingredients in Xiaoyaosan and the related targets of depression and necroptosis were compiled through appropriate databases, while the "botanical drugs-active ingredients-target genes" network was constructed by network pharmacology analysis. The expressions of RIPK1, RIPK3, MLKL, p-MLKL were detected as critical target genes of necroptosis and the potential therapeutic target compounds of Xiaoyaosan. Furthermore, the levels of neuroinflammation and microglial activation of hippocampus were measured by detecting the expressions of IL-1ß, Lipocalin-2 and IBA1, and the hematoxylin and eosin (H&E) stained was used to observe the morphology in hippocampus sections. Results: After 6-weeks of modeling, the behavioral data showed that mice in CUMS group and solvent group had obvious depressive-like behaviors, and the medication of Xiaoyaosan or Nec-1 could improve these behavioral changes. A total of 96 active ingredients in Xiaoyaosan which could regulate the 23 key target genes were selected from databases. Xiaoyaosan could alleviate the core target genes in necroptosis and improve the hippocampal function and neuroinflammation in depressed mice. Conclusion: The activation of necroptosis existed in the hippocampus of CUMS-induced mice, which was closely related to the pathogenesis of depression. The antidepressant mechanism of Xiaoyaosan included the regulation of multiple targets in necroptosis. It also suggested that necroptosis could be a new potential target for the treatment of depression.

Potential therapeutic effect and methods of traditional Chinese medicine on COVID-19-induced depression: A review.

COVID-19 (coronavirus) has spread all over the world with a high infection rate. Currently, there are no targeted therapeutic drugs for COVID-19 as well as for stress induced by COVID-19. The unpredictable events of COVID-19 can trigger feelings of fear, worry, or unease in people, leading to stress-related disorders such as depression and anxiety. It has been reported that individuals, including COVID-19 patients, medical staff, and ordinary people, are under both physical and psychological pressure, and many of them have developed depression or anxiety during this pandemic. Traditional Chinese medicine (TCM) has been widely used in treating depression with relatively better safety and efficacy and may have an important role in treating stress-related disorders induced by COVID-19. In this review, we collected the common TCM treatment methods including Qigong, Acupuncture, Five Elements Musical Therapy, Five Elements Emotional Therapy, and Chinese herbal medicine from the databases of PubMed and the China National Knowledge Internet to illustrate the effect of TCM on depression. The better knowledge of TCM and implementation of TCM in COVID-19 clinics may help to effectively improve depression induced by COVID-19, may assist people to maintain a healthy physical and mental quality, and may alleviate the current shortage of medical resources.

Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus.

BACKGROUND: At present, the pathogenesis of depression is not fully understood, and nearly half of depression patients experience no obvious effects during treatment. This study aimed to establish a depression mouse model to explore the possible role of ferroptosis in the pathogenesis of depression, and observe the effects of Xiaoyaosan on PEBP1-GPX4-mediated ferroptosis in the hippocampus. METHODS: Forty-eight male C57BL/6 mice were randomly divided into a control group, CUMS group, Xiaoyaosan group and fluoxetine group, and the model was established by chronic unpredictable mild stress (CUMS) for a successive 6 weeks. The medication procedure was performed from the 4th to the 6th week of modeling. The behavioral evaluations were measured to evaluate depressive-like behaviors. The expressions of GPX4, FTH1, ACSL4 and COX2 were detected as ferroptosis-related indicators. Then, the total iron and ferrous content in the hippocampus were measured. The levels of PEBP1 and ERK1/2 were observed, and the expressions of GFAP and IBA1 were also detected to measure the functions of astrocytes and microglia in the hippocampus. RESULTS: Eight herbs of Xiaoyaosan had 133 active ingredients which could regulate the 43 ferroptosis-related genes in depression. After 6 weeks of modeling, the data showed that mice in the CUMS group had obvious depressive-like behaviors, and medication with Xiaoyaosan or fluoxetine could significantly improve the behavioral changes. The expressions of GPX4, FTH1, ACSL4, COX2, PEBP1, ERK1/2, GFAP and IBA1 changed in the CUMS group mice, while the total iron and ferrous content also changed. Xiaoyaosan and fluoxetine had obvious curative effects that could significantly alleviate the above changes in the hippocampus. CONCLUSION: Our results revealed that the activation of ferroptosis might exist in the hippocampi of CUMS-induced mice. The PEBP1-GPX4-mediated ferroptosis could be involved in the antidepressant mechanism of Xiaoyaosan. It also implied that ferroptosis could become a new target for research into the depression mechanism and antidepressant drugs.

Bioinformatics analysis of a TF-miRNA-lncRNA regulatory network in major depressive disorder.

Major depressive disorder (MDD) is a highly prevalent disease and one of the main causes of disability worldwide. Although many studies have partially revealed the occurrence and development process of MDD, the pathogeny and molecular mechanisms are not fully understood. Weighted gene coexpression network analysis (WGCNA) was used to explore the co-expression modules and hub genes in MDD. A protein-protein interaction (PPI) network of the most significant module and a TF-miRNA-lncRNA regulatory network of MDD were constructed using bioinformatics analysis tools. A KEGG pathway and gene ontology (GO) functional enrichment analysis of the genes in the significant module was performed using DAVID. Five hub genes in the PPI network and 10 genes in the TF-miRNA-lncRNA regulatory network with high degree values were identified, which may provide new insights for the investigation of key pathways, diagnostic bio-markers, and therapeutic targets of MDD. This study brings a novel perspective and provides valuable information to explore the molecular mechanism of MDD.

Xiaoyaosan regulates depression-related behaviors with physical symptoms by modulating Orexin A/OxR1 in the hypothalamus.

The functional regulation of the orexin system in the central nervous system is closely related to the occurrence and development of psychotic disorders. Abnormal changes in the lateral region of the hypothalamus are associated with the comorbidity of depression and physical symptoms, and how the traditional Chinese formula Xiaoyaosan regulates these changes may reveal aspects of the pathogenesis of depression. This study aimed to establish a rat model of depression in order to examine changes in Orexin A/OxR1 expression in the lateral region of the hypothalamus and the effects of Xiaoyaosan. Sixty specific pathogen-free (SPF) male healthy Sprague-Dawley (SD) rats were used in the experiment and randomly divided into the control group, the model group, the Xiaoyaosan group and the fluoxetine group. The depression model was established by 21-day chronic immobilization stress (CIS). Food intake and body weight were recorded, and the sucrose preference test (SPT) and open field test (OFT) were used to evaluate the model. Then, the expression of Orexin A/OxR1 in the hypothalamus was measured by ELISA, Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The expression of Orexin A and OxR1 in the lateral hypothalamic area was significantly down regulated in the model group, compared with the control group. Xiaoyaosan significantly reversed these changes with obvious curative effects. Abnormal changes in Orexin A/OxR1 in the lateral hypothalamic area of rats with depression caused by chronic stress are closely related to the pathogenesis of depression accompanied by physical symptoms. Xiaoyaosan can improve depression accompanied by physical symptoms by regulating Orexin A/OxR1.

Four targeted genes for predicting the prognosis of colorectal cancer: A bioinformatics analysis case.

The molecular mechanisms underlying the development and progression of colorectal cancer (CRC) have not been clarified. The purpose of the present study was to identify key genes that may serve as novel therapeutic targets or prognostic predictors in patients with CRC using bioinformatics analysis. Four gene expression datasets were downloaded from the Gene Expression Omnibus database, which revealed 19 upregulated and 34 downregulated differentially expressed genes (DEGs). The downregulated DEGs were significantly enriched in eight pathways according to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. A protein-protein interaction network was constructed with 52 DEGs and 458 edges. Ten key genes were identified according to the degree value, betweenness centrality and closeness centrality. Survival analysis revealed that low expression of four of the ten genes, carcinoembryonic antigen related cell adhesion molecule 7 (CEACAM7), solute carrier family 4 member 4 (SLC4A4), glucagon (GCG) and chloride channel accessory 1 (CLCA1) genes, were associated with unfavorable prognosis in CRC. Furthermore, gene set enrichment analysis revealed that two pathways were significantly enriched in the CEACAM7 low-expression group. Thus, CEACAM7, SLC4A4, GCG and CLCA1 may be prognostic markers or therapeutic targets of CRC. Low CEACAM7 expression may be associated with the activation of glycosaminoglycan biosynthesis-chondroitin sulfate and extracellular matrix receptor interaction pathways and may affect the prognosis of CRC.