UNASSIGNED: The incidence rate of adolescent depression and anxiety has been increasing since the outbreak of COVID-19, which there are no effective therapeutic drugs available. Si-ni San is commonly used in traditional Chinese medicine for the treatment of depression-like as well as anxiety-like behavior, but its mechanism for treating depression combined with anxiety during adolescence is not yet clear.
UNASSIGNED: Network pharmacology was used to explore potential drug molecules and related targets, molecular docking and molecular dynamics (MD) simulation were used to evaluate the interaction between the potential drug molecules and related targets, and a model of anxiety combined with depression in adolescent rats as well as the following behavioral tests and molecular biology tests were used to verify the results from network pharmacology and molecular docking.
UNASSIGNED: As a result, 256 active ingredients of Si-ni San and 1128 potential targets were screened out. Among them, quercetin, Luteolin, kaempferol, 7-Methoxy-2-methyl isoflavone, formononetin showed to be the most potential ingredients; while STAT3, IL6, TNF, AKT1, AKT1, TP53, IL1B, MAPK3, VEGFA, CASP3, MMP9 showed to be the most potential targets. AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway and TNF signaling pathway, which are involved in anti-inflammation processes, showed to be the most probable pathways regulated by Si-ni San. Molecular docking and MD simulation between the compounds to inflammation-associated targets revealed good binding abilities of quercetin, Luteolin, kaempferol, nobiletin and formononetin to PTGS2 and PPARγ. In the experiment with adolescent rats, Si-ni San markedly suppressed early maternal separation (MS) combined with adolescent chronic unpredictable mild stress (CUMS)-induced depression combined with anxiety. The qPCR results further indicated that Si-ni San regulated the oxidative stress and inflammatory response.
UNASSIGNED: This study demonstrates that adolescent anxiety- and depression-like behavior induced by MS combined CUMS can be ameliorated by Si-ni San by improved inflammation in hippocampus via targeting TNF pathway and Nrf2 pathway, helping to reveal the mechanism of Si-ni San in treating adolescent depression combined with anxiety.

The efficacy and tolerability of current antidepressants for adolescent depression are inadequate. S-adenosylmethionine (SAMe), known for its effectiveness and minimal side effects in adult depression, remains unstudied in adolescents. This study explored the potential of SAMe to address depression-like behaviors in juvenile rats induced by chronic unpredictable mild stress (CUMS), with a focus on gut microbiome interactions. Adolescent male Wistar rats were subjected to a 4-week CUMS regimen and received daily intraperitoneal injections of 300 mg/kg SAMe. Behavioral assessments included the sucrose preference test, elevated plus maze test, open field test, and Y-maze test. Histopathological changes of the hippocampus and colon were observed by Nissl staining and hematoxylin and eosin staining, respectively. Gut microbiome composition was analyzed using Accurate 16S absolute quantification sequencing. The results showed that SAMe significantly improved behavioral outcomes, reduced histopathological damages in hippocampal neurons and colon tissues, and modulated the gut microbiota of depressed rats. It favorably altered the ratio of Bacteroidetes to Firmicutes, decreased the absolute abundance of Deferribacteres, and adjusted levels of key microbial genera associated with depression-like behaviors. These results suggested that SAMe could effectively counter depression-like behaviors in CUMS-exposed adolescent rats by mitigating hippocampal neuronal and colon damage and modulating the gut microbiota. This supports SAMe as a viable and tolerable treatment option for adolescent depression, highlighting the importance of the gut-brain axis in therapeutic strategies.

Chronic unpredictable and unavoidable stress is associated with mental health problems such as depression and anxiety, whereas cycles of stress and stress relief strengthen resilience. It has been suggested that increased breakdown of brain endocannabinoids (eCB) promotes a feeling of adversity. To assess the impact of stress on bioactive lipid homeostasis, we analyzed eCB, sphingolipids, and ceramides in seven brain regions and plasma in a mouse model of chronic unpredictable mild stress. Chronic unpredictable mild stress (CUMS) was associated with low levels of anandamide in hippocampus and prefrontal cortex in association with indicators of anxiety (elevated plus maze). Oppositely, CUMS caused elevated levels of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0) in the midbrain and thalamus, which was associated with readouts of increased stress resilience, i.e., marble burying and struggling in the tail suspension tests. In the periphery, elevated plasma levels of ceramides revealed similarities with human major depression and suggested unfavorable effects of stress on metabolism, but plasma lipids were not associated with body weight, sucrose consumption, or behavioral features of depression or anxiety. The observed brain site-specific lipid changes suggest that the forebrain succumbs to adverse stress effects while the midbrain takes up defensive adjustments.

Depression is a mental disorder characterised by persistent low mood, anhedonia and cognitive impairment that affects an estimated 3.8% of the world\'s population, including 5% of adults. Peganum harmala L. (P. harmala) is a medicinal plant and has been reported to be effective against Alzheimer\'s disease, Parkinson\'s disease and depression. The present study was aimed to evaluate the behavioral and pharmacological effects of P. harmala seed extract in rats exposed to chronic unpredictable mild stress (CUMS) in vivo and to investigate the mechanism of action. CUMS-exposed rats were treated with P. harmala extract (75 and 150 mg/kg, i.p.) for 2 weeks. HPLC analysis was used to determine the concentration of harmaline and harmine alkaloids in the extract. Heavy metal analysis in seeds was performed by ICP-MS. Our results showed that P. harmala at the dose of 150 mg/kg significantly reduced the depressive-like behaviors in CUMS-exposed rats, as evidenced by increased sucrose consumption in the sucrose preference test (SPT), decreased immobility time in the forced swim test (FST) and plasma corticosterone levels, increased the time spent in open arms in the elevated plus maze (EPM), and improved memory and learning in the passive avoidance test (PAT). In addition, P. harmala decreased monoamine oxidase-A (MAO-A) levels, and increased serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels in the brains of rats exposed to CUMS. P. harmala decreased the expression of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB), and increased the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) in rat brain. Furthermore, P. harmala improved brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) protein expression in rat brain. In conclusion, P. harmala at a dose of 150 mg/kg is more effective in preventing depressive-like behavior in CUMS-exposed rats by improving neurotransmitter levels, reducing oxidative stress, suppressing neuroinflammation and activating the BDNF/TrkB pathway, all of which are important in the pathogenesis of depression.

OBJECTIVE: Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are widely expressed in the brain and are associated with the development of neurological and neurodegenerative diseases. However, their roles and molecular mechanisms in major depressive disorder (MDD) remain largely unknown. This study aimed to identify lncRNAs and miRNAs involved in the development of MDD and elucidate their molecular mechanisms.
METHODS: Transcriptome and bioinformatic analyses were performed to identify miRNAs and lncRNAs related to MDD. C57 mice were subjected to chronic unpredictable mild stress (CUMS) to establish a depression model. Lentiviruses containing either lncRNA NPTN-IT1-201 or miR-142-5p were microinjected into the hippocampal region of these mice. Behavioral tests including the sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST) were conducted to evaluate depressive-like behaviors.
RESULTS: The results revealed that overexpression of lncRNA NPTN-IT1-201 or inhibition of miR-142-5p significantly ameliorated depressive-like behaviors in CUMS-treated mice. Dual-luciferase reporter assays confirmed interactions between miR-142-5p with both brain-derived neurotrophic factor (BDNF) and NPTN-IT1-201. ELISA analysis revealed significant alterations in relevant biomarkers in the blood samples of MDD patients compared to healthy controls. Histological analyses, including HE and Nissl staining, showed marked structural changes in brain tissues following CUMS treatment, which were partially reversed by lncRNA NPTN-IT1-201 overexpression or miR-142-5p inhibition. Immunofluorescence imaging demonstrated significant differences in the levels of BAX, Bcl2, p65, Iba1 among different treatment groups. TUNEL assays confirmed reduced apoptosis in brain tissues following these interventions. Western blotting showed the significant differences in BDNF, BAX, and Bcl2 protein levels among different treatment groups.
CONCLUSIONS: NPTN-IT1-201 regulates inflammation and apoptosis in MDD by targeting BDNF via miR-142-5p, making it a potential therapeutic target for MDD.

The parameters of the cytokine profile and functional activity of the complement system in the blood of rats were studied during different time periods of chronic unpredictable mild stress using a model of sequentially alternating low-intensity stress effects for 1, 2, 3, and 4 weeks. In the dynamics of observation, a general tendency towards multidirectional fluctuations in the concentration of cytokines was revealed: an increase in IL-10, but a decrease in IL-4 in comparison with the control. Statistically significant changes in the level of IL-10 were noted after 2, 3, and 4 weeks, IL-4 - after 2 and 4 weeks of stress loads. The percentage of lysis of the C3 component in rats gradually increased by the 2nd week of chronic stress, but then decreased and practically did not differ from the control values (intact animals) by the end of the study. These results illustrate the specificity of changes in the indicators of the C component of the complement system and the cytokine profile of the blood reflecting activity of the cellular and humoral components of the immune response in rats exposed to repeated stress factors of different origins and duration.

UNASSIGNED: Xiaoyaosan (XYS), a renowned classical traditional Chinese medicinal formula utilized in addressing major depressive disorder (MDD), has garnered significant acclaim for its remarkable efficacy in clinical application. The onset of major depressive disorder (MDD) often correlates with chronic unpredictable mild stress (CUMS), a pivotal instigating factor in its development.Aim of the study: This study aims to clarify the potential anti-inflammatory mechanisms of XYS in treating CUMS model mice.
UNASSIGNED: Utilizing cutting-edge ultra high-performance liquid chromatography - high-resolution mass spectrometry (UPLC-HRMS), the active constituents of XYS were discerned, while employing proteomics analysis to delve into the potential mechanisms of its efficacy. Molecular docking studies, alongside subsequent in vivo experiments utilizing CUMS model mice, were conducted to corroborate the findings derived from the proteomics analysis.
UNASSIGNED: In vivo experiments demonstrated that XYS not only markedly ameliorated behavioral markers but also attenuated serum inflammatory markers and suppressed IL-6 and TNF-α expression within the brains of CUMS model mice. Proteomics analysis suggested that the pivotal anti-inflammatory mechanism of XYS against CUMS-induced damage might involve modulation of the MAPK signaling pathway. Utilizing UPLC-HRMS, the active constituents of XYS were successfully identified, while molecular docking investigations explored interactions between XYS and MYDGF, PKC, MAP4K4, P-p65, p65, P-IKBα, and IKBα. The findings revealed XYS\'s regulatory influence on the MYDGF/MAP4K4/NF-κB signaling cascade.
UNASSIGNED: This study is the first to our knowledge to demonstrate that XYS can alleviate inflammation in CUMS model mice by modulating the MYDGF/MAP4K4/NF-κB signaling pathway.

OBJECTIVE: Chronic psychological stress is associated with impaired follicular development and ovarian dysfunction. Many aspects of this dysfunction and the underlying mechanisms remain unclear. Using a chronic unpredictable mild stress (CUMS) mouse model, we investigate the influence of chronic stress on ovarian function and explore potential mechanisms.
METHODS: A CUMS mouse model was constructed over eight months, covering the period from sexual maturity to the onset of declining fertility in mice. At the end of the 2nd, 4th, 6th, and 8th months of exposure to CUMS, behavioral and physiological assays, including the sucrose preference test, tail suspension test, and serum corticosterone levels, were conducted to validate the effectiveness of the stress model. Fertility and ovarian function were assessed by analyzing the estrous cycle, number of offspring, sex hormone levels, follicle counts, granulosa cell proliferation and apoptosis, and the expression levels of fibrosis markers. Furthermore, proteomic analyses were performed on the ovaries to investigate the molecular mechanisms of ovarian fibrosis induced by CUMS.
RESULTS: With continued CUMS exposure, there was a gradual decline in both the ovary-to-body weight ratio and the number of offspring. Moreover, the percentage of atretic follicles was notably higher in the CUMS-exposed groups compared to the control groups. It is noticeable that CUMS triggered granulosa cell apoptosis and halted proliferation. Additionally, increased expression of α-SMA and Collagen I in the ovaries of CUMS-exposed mice indicated that CUMS could induce ovarian fibrosis. Proteomic analysis provided insights into the activation of specific biological processes and molecules associated with fibrosis induced by chronic stress.
CONCLUSIONS: Our results strongly suggest that exposure to CUMS induces ovarian fibrosis, which influences follicular development and ultimately contributes to fertility decline. These findings offer novel perspectives on the impact of chronic stress on ovarian dysfunction.

Stress is an emotional state caused by an unexpected external environmental change or stimulus, and several experiments have demonstrated its negative impact on ovarian function, ultimately affecting reproductive ability. Melatonin (MT) has been shown to facilitate oocyte maturation and enhance ovarian function by regulating mitochondrial function. However, the specific effect and underlying molecular mechanisms of MT on stress-induced ovarian dysfunction remain largely unknown. In this study, we established a mouse model of chronic unpredictable mild stress (CUMS) to investigate its impact on ovarian function. Our findings revealed that CUMS led to premature ovarian insufficiency (POI) in mice, characterized by a reduction in follicle numbers and decreased levels of anti-Müllerian hormone (AMH) and bone morphogenetic protein 15 (BMP15). Furthermore, CUMS caused decreased expression of mitochondrial fission protein 1 (FIS1) and enhanced level of mitochondrial fusion protein optic atrophy 1(OPA1), mitofusin1(MFN1), as well as nucleus-encoded protein succinate dehydrogenase complex A (SDHA), reflecting mitochondrial dyshomeostasis. Additionally, CUMS resulted in excessive autophagy and apoptosis. However, MT reversed these effects and improved ovarian damage. Importantly, the protective effects of MT were mediated through the inhibition of the eIF2α-AFT4 pathway. Overall, this study provides valuable insights into the treatment of POI caused by CUMS.

Major depressive disorder is a chronic mental health condition that seriously impacts afflicted individuals. Although electroacupuncture has proven to be an effective therapy for depression, its underlying biological mechanism remains largely unknown. In this study, we aimed to investigate the effects of electroacupuncture on depression-like behavior and to identify potential target genes related to those effects. To achieve this, we subjected rats to chronic unpredictable mild stress (CUMS) and used sucrose preference, forced swimming, and open-field tests to determine their depression-like behavior in the absence or after receipt of electroacupuncture treatment. RNA sequencing technology was then used to reveal the differentially expressed genes associated with depression and electroacupuncture treatment effects in the medial prefrontal cortex (mPFC). Repeated electroacupuncture treatments at the Baihui (GV20) and Taichong (LR3) acupoints significantly alleviated depression-like behavioral defects in the animals. Genomic RNA sequencing revealed several significant changes in the mPFC transcriptome of rats that received treatment. Through differential gene expression analysis, we found that electroacupuncture reversed the CUMS-induced downregulation of 46 genes and upregulation of 13 genes. Among the differentially expressed genes, Casr, Bdkrb2, Gnb3, and Ccl1 were found to be associated with depression and electroacupuncture treatment effects. In conclusion, we verified that electroacupuncture treatment has an effective antidepressant effect, and the underlying mechanism involves multiple systems and targets.