Search

Depression is a clinically common co-morbidity in breast cancer cases that brings negative outcomes on quality of life and potentially survival. Jiawei Xiaoyao Wan (JXW) is widely used in treating breast cancer and depressive disorder, but its potential pharmacological mechanisms remain elusive. We aimed to explore the dual therapeutic effects and mechanisms of JXW acting on breast cancer complicated with depression (BCCD) by network pharmacology and in vivo experimental verification. The chemical constituents of JXW were characterized using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-Q-TOF/MS). The targets related to constituents of JXW were predicted by the TCMSP and Swiss Target Prediction databases, and targets of breast cancer and depression were screened by the GeneCards and OMIM databases. Gene Ontology annotation and KEGG enrichment analysis were performed with the DAVID database. Ultimately, a BCCD mouse model induced by chronic restraint stress (CRS) was used to explore therapeutic effects and mechanisms of JXW against BCCD. The efficacy of JXW in the treatment of BCCD was evaluated based on behavioral tests, tumor volume and weight, and pathological examination. Additionally, the underlying mechanisms were explored by measuring the levels of neurotransmitter and inflammatory factors, as well as detecting the expression of genes or proteins associated with candidate targets and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway through RT-PCR, western blotting, and immunohistochemistry. Totals of 108 components were identified in JXW using LC-Q-TOF/MS. By network pharmacology analysis, 714 compound targets of JXW, 2114 breast cancer targets, 1122 depression targets, and 98 overlapping proteins were obtained. PPI network and KEGG analysis implied that TP53, ESR1, VEGFA, AKT1, IL6, TNF, EGFR and the JAK/STAT pathway might be the potential targets of JXW in treating BCCD. In vivo experiments indicated that JXW significantly ameliorated depressive symptoms and tumor progression in BCCD mice. Further mechanistic studies showed that JXW could reduce the levels of inflammatory factors, increase 5-HT level, and regulate mRNA expression levels of TP53, VEGFA, AKT1, IL6, TNF, and EGFR targets. Moreover, the expression levels of proteins related to the JAK2/STAT3 signaling pathway in BCCD mice were effectively regulated by JXW. JXW exerts dual therapeutic effects in a BCCD mouse via multiple targets. The underlying mechanisms might be associated with regulating the levels of neurotransmitter and inflammatory factors; more importantly, the JAK2/STAT3 pathway plays a significant role in this process. [Display omitted] [ABSTRACT FROM AUTHOR]

The depressant-like effects of albiflorin (AF) were studied on stressed chronic restraint stress (CRS) rats. Experimental rats were subjected to immobilization stress for a daily 6 h-restraining in a plastic restrainer for continuous 21 d and were treated with 30 or 15 mg·kg−1 of AF for 21 d. Control rats were maintained in completely non stressed conditions. Behavioral tests and biochemical analysis were applied to investigating a regulatory mechanism of anti-stress of AF. Treatment with AF significantly restored the depressant-like behaviors. Besides, AF increased the levels of 5-hydroxytryptophan (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NE) and dopamine (DA) in the hippocampus and increased the level of brain-derived neurotrophic factor (BDNF) in serum and protein expression in hippocampus. In addition, AF decreased the levels of hypothalamo-pituitary-adrenal (HPA) cascade, reduced the level of NO and cGMP in serum and inhibited the overexpression of 5-HT 2A R mRNA and protein expression. Taken together, AF can modulate the NO-mediated network pathway in the hippocampus against stress-induced depressive-like behaviors. These physiological and behavioral changes allow rats to avoid potential deleterious effects of stress that may result from chronically elevated levels of glucocorticosteroids over days. [ABSTRACT FROM AUTHOR]

Vaccinium bracteatum Thunb. leaves (VBL) are used in traditional herbal medicines to treat various biological diseases. p -coumaric acid (CA), the main active component of VBL, has neuroprotective effects against corticosterone-induced damage in vitro. However, the effects of CA on immobility induced by chronic restraint stress (CRS) in a mouse model and 5-HT receptor activity have not been investigated. We investigated the antagonistic effects of VBL, NET-D1602, and the three components of Gαs protein-coupled 5-HT receptors. Additionally, we identified the effects and mechanism of action of CA, the active component of NET-D1602, in the CRS-exposed model. For in vitro analyses, we used 1321N1 cells stably expressing human 5-HT 6 receptors and CHO-K1 expressing human 5-HT 4 or 5-HT 7 receptors cell lines to study the mechanism of action. For in vivo analyses, CRS-exposed mice were orally administered CA (10, 50, or 100 mg/kg) daily for 21 consecutive days. The effects of CA were analyzed by assessing behavioral changes using a forced swim test (FST), measuring levels of hypothalamic-pituitary-adrenal (HPA) axis-related hormones in ntial therapeutic effects as 5-HT6 receptor antagonists for neurodegenerative diseases and depressioserum, and acetylcholinesterase (AChE), monoamines, including 5-HT, dopamine, and norepinephrine, using enzyme-linked immunosorbent assay kits. The underlying molecular mechanisms of the serotonin transporter (SERT), monoamine oxidase A (MAO-A), and extracellular signal-regulated kinase (ERK)/protein kinase B (Akt)/mTORC1 signaling were detected using western blotting. CA was confirmed to be an active component in the antagonistic effects of NET-D1602 on 5-HT 6 receptor activity through decreases in cAMP and ERK1/2 phosphorylation. Moreover, CRS-exposed mice treated with CA showed a significantly reduced immobility time in the FST. CA also significantly decreased corticosterone, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) levels. CA enhanced 5-HT, dopamine, and norepinephrine levels in the hippocampus (HC) and prefrontal cortex (PFC) but decreased MAO-A and SERT protein levels. Similarly, CA significantly upregulated the ERK, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Akt/mTOR/p70S6K/S6 signaling pathways in both HC and the PFC. CA contained in NET-D1602 may play the antidepressant effects against CRS-induced depression-like mechanism and the selective antagonist effect of 5-HT 6 receptor. [Display omitted] [ABSTRACT FROM AUTHOR]

• Integrated chinmedomics and network pharmacology method revealed 11 active components of SZRD. • SZRD showed obvious anxiolytic effect as well as hypnotic effect with no muscle relaxation effects. • A total of 110 compounds from SZRD were identified and 20 of them were absorbed in blood. • SZRD altered 21 biomarkers related to arachidonic acid, tryptophan and sphingolipid metabolism. Suanzaoren decoction (SZRD) is a classical traditional Chinese prescription. It is widely used to treat mental disorders, including insomnia, anxiety, and depression, in China and other Asian countries. However, the effective components and mechanisms underlying SZRD remained unclear. We aimed to develop a new strategy to discover the effects and potential mechanisms of SZRD against anxiety and to further reveal the effective components of SZRD in treating anxiety. First, the chronic restraint stress (CRS)-induced mouse model of anxiety was orally administered SZRD, and behavioral indicators and biochemical parameters were applied to assess efficacy. A chinmedomics strategy based on UHPLC-Q-TOF-MS technology and network pharmacology were then used to screen and explore potentially effective components and therapeutic mechanisms. Finally, molecular docking was applied to further confirm the effective components of SZRD, and a multivariate network for anxiolytic effects was constructed. SZRD exerted anxiolytic effects by increasing the percentage of entries into open arms and the time spent in open arms; improving hippocampal 5-HT, GABA, and NE levels; and increasing serum corticosterone (CORT) and corticotropin-releasing hormone (CRH) levels caused by CRS challenge. Beside, SZRD exerted a sedative effect by decreasing sleep time and prolonging sleep latency with no muscle relaxation effect in CRS mice. A total of 110 components were identified in SZRD, 20 of which were absorbed in the blood. Twenty-one serum biomarkers involved in arachidonic acid, tryptophan, sphingolipid, and linoleic acid metabolism were identified after SZRD intervention. Finally, a multivariate network including prescription-effective components-targets-pathway of SZRD treating anxiety, including 11 effective components, 4 targets and 2 pathway was constructed. The current study demonstrated that integrating chinmedomics and network pharmacology was a powerful approach to investigating the effective components and therapeutic mechanisms of SZRD and provided a solid basis for the quality marker (Q-marker) of SZRD. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Chronic restraint stress exacerbates pain and inflammation. The present study was designed to evaluate the effect of chronic restraint stress on inflammatory pain induced by subcutaneous injection of bee venom (BV). Methods: First, we investigated: (1) the effect of two-week restraint stress with daily 2 or 8 h on the baseline paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), and paw circumference (PC); (2) the effect of chronic stress on the spontaneous paw-flinching reflex (SPFR), decrease in PWMT and PWTL and increase in PC of the injected paw induced by BV. Results: The results showed that (1) chronic restraint decreased significantly the PWMT and inhibited significantly the increase in PC, but had no effect on PWTL, compared with control group; (2) chronic restraint enhanced significantly BV-induced SPFR and inflammatory swelling of the injected paw. In a second series of experiments, the role of P2X7 receptor (P2X7R) in the enhancement of BV-induced inflammatory pain produced by chronic restraint stress was determined. Systemic pretreatment with P2X7R antagonist completely reversed the decrease in PWMT produced by chronic restraint, inhibited significantly the enhancement of BV-induced inflammatory pain produced by chronic restraint stress. Conclusion: Taken together, our data indicate that chronic restraint stress-enhanced nociception and inflammation in the BV pain model, possibly involving the P2X7R. [ABSTRACT FROM AUTHOR]

The effects of the peptide ACTH(6–9)-Pro-Gly-Pro at doses of 5; 50; 500 μg/kg on the Wistar rats' behaviour and gut mucosal microbiota composition under conditions of chronic immobilization stress (CRS) were studied. CRS increased anxiety-like and depressive-like behaviour, disturbances in locomotor activity and gut dysbiosis. Administration of ACTH(6–9)-Pro-Gly-Pro showed many phenotypic results. Peptide demonstrated anti-depressant activity at doses of 5 and 500 μg/kg by a decrease in the total immobile time in the FST. ACTH(6–9)-Pro-Gly-Pro administered at a dose of 50 μg/kg resulted in an anxiolytic effect which is shown by an increase in the time in the open arms of EPM (p < 0.05) and a decrease in the time in the closed arms (p < 0.05). Moreover, the peptide led to a decrease in alpha- and beta-diversity of the gut microbiota (p < 0.01). Correlation and linear regression analysis demonstrated central mechanisms of ACTH(6–9)-Pro-Gly-Pro anxiolytic activity and both central and peripheral ones in an anti-depressant effect. In this way, peptide ACTH(6–9)-Pro-Gly-Pro could prevent the development of behavioural disturbances and gut dysbiosis caused by chronic restraint stress. [ABSTRACT FROM AUTHOR]

Abstract: This study was aimed at investigating the feasibility of establishing premenstrual syndrome (PMS) liver-qi depression rat model with resident-intruder paradigm compared to chronic restraint stress. The PMS liver-qi depression rat model was prepared with chronic restraint stress and resident-intruder paradigm. The effect was systematically evaluated through behavioral methods such as open-field test and tail suspension test. Then, results from both groups were compared. The results showed that both chronic restraint stress and resident-intruder paradigm can effectively simulate the state of premenstrual depression and postmenstrual disappearance. The results of the open-field test suggested that there was no significant difference between these two methods (P > 0.05). It was concluded that as a social psychological stress method the resident-intruder paradigm can preferably simulate the process of clinical PMS liver-qi depression caused by emotional abnormality and overcome the disadvantage of obvious body stress of the chronic restraint stress method. But the success ratio was too low, and further inspection was needed to examine its stability. [Copyright &y& Elsevier]

Background: Depressive symptoms are thought to promote cancer development and depressive remission has been reported to be effective for defeating cancer. The herbal formula Xiao-Chai-Hu-Tang (XCHT), that has an anti-depressive efficacy, has been widely utilized in China. However, its anti-cancer effect and underlying mechanisms remain unclear.Purpose: The present study aims to investigate the effects of XCHT on the depression-associated tumor and its potential mechanisms.Methods: A placebo-controlled trial was conducted in cancer patients comorbid with depressive symptoms to evaluate the effects of XCHT on depressive scales, tumor-related immune indicators, and gut microbial composition. A xenografted colorectal cancer (CRC) mouse model exposure to chronic restraint stress (CRS) was established to examine XCHT effects on tumorigenesis in vivo. Further, by manipulating gut bacteria with fecal microbial transplantation (FMT) or antibiotics-induced bacterial elimination in CRS-associated xenografted model, gut microbiota-mediated anti-tumor mechanism was explored.Results: In cancer patients comorbid with depressive symptoms, XCHT showed substantial effects on improvement of depressive scales, system inflammatory levels and gut dysbiosis. In vivo, XCHT inhibited tumor growth and prolonged survival time in addition to showing anti-depressive effect. Similarly, in our clinical trial, XCHT partially reversed gut dysbiosis, particularly through reducing abundances of Parabacteroides, Blautia and Ruminococcaceae bacterium. Manipulation of gut bacteria in CRS-associated xenografted model further proved that the inhibition of XCHT on tumor progression was mediated by gut microbiota and that the underlying mechanism involves in downregulation of TLR4/MyD88/NF-κB signaling.Conclusions: We demonstrated that gut microbiota mediates the anti-tumor action of the formula XCHT in cancer patients and models that were comorbid with depressive symptoms. This study implies a novel clinical significance of anti-depressive herbal medicine in the cancer treatment and clarifies the important role of gut microbiota in treating cancer accompanied by depressive symptoms. [ABSTRACT FROM AUTHOR]