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Keywords = chronic unpredictable mild stress (CUMS)

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17 pages, 5091 KiB  
Article
Immunomodulatory Effects of Cucurbita pepo L. Extract in Chronic Stress-Induced Dysregulation of Lymphoid Organs in Rats
by Safa H. Qahl, Hailah M. Almohaimeed, Sami A. Algaidi, Ashwaq H. Batawi, Zuhair M. Mohammedsaleh, Tarek Hamdy Abd-Elhamid, Nawal H. Almohammadi, Nasra N. Ayuob and Amany Refaat Mahmoud
Pharmaceuticals 2025, 18(7), 1046; https://doi.org/10.3390/ph18071046 - 17 Jul 2025
Viewed by 389
Abstract
Objectives: Recently, increased attention has been given to pumpkin due to its proved nutritional components, which include antioxidant, antifatigue, and anti-inflammatory effects. The aim of the present work was to assess the impact of Cucurbita pepo L. (CP) on chronic [...] Read more.
Objectives: Recently, increased attention has been given to pumpkin due to its proved nutritional components, which include antioxidant, antifatigue, and anti-inflammatory effects. The aim of the present work was to assess the impact of Cucurbita pepo L. (CP) on chronic unpredictable mild stress (CUMS)-induced changes in lymphoid organs through evaluating its effect on the histological structure of spleen, thymus gland, and lymph nodes compared to the antidepressant fluoxetine (FLU). Materials and Methods: Fifty male albino rats equally distributed into five groups that included control, control + CP, CUMS-exposed, FLU-treated, and CP-treated groups were used in this study. Rats were exposed to CUMS for 4 weeks, and treatment (either with FLU or CP) was started after 14 days of exposure. Behavior of the rats, serum corticosterone, oxidants/antioxidants profile, proinflammatory cytokines, and gene expression of glucocorticoid receptor (GR) and β-adrenergic receptor (β2-AR) were assessed after 28 days. Spleen, thymus gland, and lymph nodes were histopathologically assessed. Results: CP administration significantly reduced the CUMS-induced behavioural changes evident by the significant reduction in immobility time (p = 0.02) and corticosterone level (p < 0.001). Biochemically, CP reduced TNF-α and IL-6 (p < 0.001) and markedly alleviated the changes in oxidants/antioxidants in the serum and lymphoid organs compared to fluoxetine. CP significantly (p < 0.001) reduced CUMS-induced changes in GR and (β2-AR). Histopathologically, CP alleviated changes observed in the spleen, lymph nodes, and thymus gland. It significantly reduced the number of CD4, CD8, CD68, CD20, and caspase-3 immunopositive cells in the studied organs. Conclusions: This study proved the potential efficacy of CP in alleviating depression-associated immunodysregulation either alone or in combination with antidepressant therapy. Full article
(This article belongs to the Section Pharmacology)
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27 pages, 15733 KiB  
Article
Effects of Lactation Lactoferrin Deficiency on Intestinal Microbiota in Different Mice Models
by Wenli Wang, Qin An, Yunxia Zou, Qingyong Meng and Yali Zhang
Nutrients 2025, 17(13), 2248; https://doi.org/10.3390/nu17132248 - 7 Jul 2025
Viewed by 514
Abstract
Background/Objectives: The establishment of early gut microbiota is crucial for host health. Lactoferrin (LF), which is present in breast milk, positively impacts gut microbiota composition. However, the effect of lactation LF on the establishment and composition of early gut microbiota in different disease [...] Read more.
Background/Objectives: The establishment of early gut microbiota is crucial for host health. Lactoferrin (LF), which is present in breast milk, positively impacts gut microbiota composition. However, the effect of lactation LF on the establishment and composition of early gut microbiota in different disease models in adulthood remains unclear. Methods: Lactation-LF-deficient mice were established using systemically LF–knocked-out maternal mice. This study assessed the maturity of the gut microbiota in LF feeding-deficient mice in relation to age and changes in the gut microbiota in adult high-fat diet (HFD)-induced obesity, dextran sodium sulfate (DSS)-induced acute colitis, and chronic unpredictable mild stress (CUMS)-induced depression models. Results: Compared to LF intake during lactation, LF deficiency during lactation increased the abundance of potentially pathogenic bacteria in the gut, resulting in abnormal microbial maturation. LF intake during lactation aggravated gut microbiota dysbiosis induced via HFD, DSS, and CUMS in adulthood and may change the function of Enterorhabdus, GCA-900066575, Peptococcus, Tuzzerella, Akkermansia, and Desulfovibrio. Comparing the different models revealed that bacteria that were jointly upregulated via HFD and DSS exhibited increased levels of inflammation and oxidation. LF deficiency during lactation may weaken the association between an HFD and inflammatory bowel disease (IBD). The changing trends in many gut microbes caused by DSS and HFD were opposite to those that changed with age. Conclusions: Lactoferrin deficiency increases the abundance of potential pathogens and disrupts microbial maturation. This lack of LF exacerbates dysbiosis in models of obesity, colitis, and depression. Regulating the gut microbiota according to the rules of microbial succession during the maturation process of gut microbiota may improve gut microbiota dysbiosis in patients with obesity and IBD. Full article
(This article belongs to the Section Pediatric Nutrition)
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19 pages, 20720 KiB  
Article
Anti-Anxiety Effects of Essential Oil Microemulsion in Chronic Unpredictable Mild Stress-Induced Rats: Preparation, Characterization, and Mechanisms
by Wenxia Tang, Pan Jiang, Ke Hu, Duo Mei, Qinghao Jiao, Yan Li, Yanping Deng, Jun Wang, Ran Gao, Xin Chen and Jie Yu
Molecules 2025, 30(12), 2652; https://doi.org/10.3390/molecules30122652 - 19 Jun 2025
Viewed by 541
Abstract
Anxiety disorders, as common neurological diseases in clinical practice, often coexist with depression. Epidemiological surveys indicate that approximately 85% of patients with depression exhibit significant anxiety symptoms. This comorbid state not only exacerbates clinical symptoms but also leads to treatment resistance and prolonged [...] Read more.
Anxiety disorders, as common neurological diseases in clinical practice, often coexist with depression. Epidemiological surveys indicate that approximately 85% of patients with depression exhibit significant anxiety symptoms. This comorbid state not only exacerbates clinical symptoms but also leads to treatment resistance and prolonged disease duration. This study innovatively developed a compound aromatic plant essential oil (EO) formulation with remarkable anxiolytic and antidepressant effects and systematically elucidated its mechanism of action. The study found that the essential oil formulation, administered via inhalation, could significantly improve behavioral abnormalities in animals subjected to the chronic unpredictable mild stress (CUMS) model, specifically manifesting as (1) the reversal of stress-induced weight gain retardation; (2) a significant increase in sucrose preference; (3) an increase in the total distance of spontaneous activity; and (4) the prolongation of exploration time in the open arms of the elevated plus maze. Neuropathological examinations confirmed that the formulation could effectively protect the structural integrity of hippocampal neurons and alleviate CUMS-induced neural damage. In terms of mechanism of action, the study revealed that the formulation regulates the neurotransmitter system through multiple targets: (1) the upregulation of serotonin (5-HT) and γ-aminobutyric acid (GABA) levels; (2) the downregulation of glutamate (GLU) concentration; and (3) key targets identified via network pharmacological analysis, such as ESR1, STAT3, and PPARG. These findings provide molecular-level evidence for understanding the neuromodulatory effects of aromatic essential oils. Pharmaceutical formulation studies showed that the oil-in-water (O/W) type compound essential oil microemulsion, prepared using microemulsification technology, has a uniform particle size and excellent stability, maintaining stable physicochemical properties at room temperature for an extended period, thus laying a foundation for its clinical application. This study not only validates the practical value of traditional medicine but also provides new ideas for the development of novel anxiolytic and antidepressant drugs, achieving an organic integration of traditional experience and modern technology. Full article
(This article belongs to the Section Medicinal Chemistry)
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17 pages, 2067 KiB  
Article
Pro-Arrhythmic Effect of Chronic Stress-Associated Humoral Factors in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
by Shi Su, Jinglei Sun, Suhua Qiu, Wenting Wu, Jiali Zhang, Yi Wang, Chenxia Shi and Yanfang Xu
Biology 2025, 14(6), 652; https://doi.org/10.3390/biology14060652 - 4 Jun 2025
Viewed by 490
Abstract
Under chronic stress, the pro-arrhythmic effect and mechanism of circulating humoral factors in human cardiomyocytes remain unknown. In the present study, we observed the effect of serum from chronic-stress mice on the electrical activity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Male C57/BL6J [...] Read more.
Under chronic stress, the pro-arrhythmic effect and mechanism of circulating humoral factors in human cardiomyocytes remain unknown. In the present study, we observed the effect of serum from chronic-stress mice on the electrical activity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Male C57/BL6J mice were subjected to 35 days of chronic unpredictable mild stress (CUMS). The serum from CUMS mice induced arrhythmia-like events (cell arrhythmias) in hiPSC-CMs in a time- and concentration-dependent manner. Patch clamp recordings in the heterologous expression system demonstrated that the serum derived from CUMS mice exerted an inhibitory effect on the cloned human potassium currents (Ito, IKr, IKs) that mediate action potential repolarization. In addition, serum from CUMS reduced the expression of relevant channel proteins. Moreover, both heat-inactivated serum and deproteinized serum evoked similar severity of cell arrhythmias in hiPSC-CMs as the untreated serum, indicating that circulating substances with small molecules were mainly involved in the occurrence of arrhythmias. Furthermore, metabolomics analysis showed that 90 small-molecule metabolites increased and 390 decreased in CUMS serum. We concluded that circulating humoral substances under chronic stress conditions have direct arrhythmogenic effects by inducing ion channel dysfunction in myocardial cells. Full article
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27 pages, 6846 KiB  
Article
Chronic Stress Modulates Microglial Activation Dynamics, Shaping Priming Responses to Subsequent Stress
by Junyu Chen, Jiacheng Huang, Taolei Han and Nobuhiko Kojima
Brain Sci. 2025, 15(5), 534; https://doi.org/10.3390/brainsci15050534 - 21 May 2025
Viewed by 1283
Abstract
(1) Background: The high recurrence rate and individual differences in stress susceptibility contribute to the diverse symptoms of depression, making full recovery and relapse prevention challenging. Emerging evidence suggests that fluctuations in microglial activity are closely linked to depression progression under chronic stress [...] Read more.
(1) Background: The high recurrence rate and individual differences in stress susceptibility contribute to the diverse symptoms of depression, making full recovery and relapse prevention challenging. Emerging evidence suggests that fluctuations in microglial activity are closely linked to depression progression under chronic stress exposure. Changes in the brain microenvironment can elicit microglial priming, enhancing their sensitivity to external stimuli. However, few studies have longitudinally examined how microglial characteristics evolve throughout depression progression. (2) Methods: In this study, we investigated microglial morphological changes and their responses to acute stress at different stages of depression using the chronic unpredictable mild stress (CUMS) paradigm in mice. (3) Results: Our findings reveal that in the dentate gyrus, microglial activation indices, including cell number and morphology, exhibit distinct dynamic patterns depending on CUMS exposure duration. Notably, after 2 and 4 weeks of CUMS exposure followed by acute stress re-exposure, microglia display opposing response patterns. In contrast, after 6 weeks of CUMS exposure, primed microglia exhibit dysfunction, failing to respond to acute stress. Notably, depressive behaviors are not prominent after 2 weeks of CUMS exposure but become more pronounced after 4 and 6 weeks of exposure. Additionally, regardless of CUMS duration, body weight demonstrates an intrinsic capacity to normalize after stress cessation. (4) Conclusions: These findings suggest that microglial priming responses are state-dependent, either enhancing or suppressing secondary stimulus responses, or exceeding physiological limits, thereby preventing further activation. This study provides novel insights into the role of microglial priming in stress vulnerability and its contribution to depression progression. Full article
(This article belongs to the Special Issue Stress, Resilience and Susceptibility)
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19 pages, 3886 KiB  
Article
Hippocampal Transcriptome Analysis in a Mouse Model of Chronic Unpredictable Stress Insomnia
by Shuo Zhang, Changqing Tong, Na Cao, Dong Tian, Linshan Du, Ya Xu, Weiguang Wang, Zijie Chen and Shuangqing Zhai
Biomedicines 2025, 13(5), 1205; https://doi.org/10.3390/biomedicines13051205 - 15 May 2025
Viewed by 733
Abstract
Background: This study aimed to develop a model for understanding stress-induced sleep disturbances and to explore the potential interactions between sleep disturbances and mood disturbances. Methods: The chronic unpredictable mild stress (CUMS) group was established using the CUMS method, while the [...] Read more.
Background: This study aimed to develop a model for understanding stress-induced sleep disturbances and to explore the potential interactions between sleep disturbances and mood disturbances. Methods: The chronic unpredictable mild stress (CUMS) group was established using the CUMS method, while the CUMS+Noise group was subjected to an additional 8-h exposure to noise in conjunction with the CUMS protocol. Each group was tested for anxiety and depressive-like behavior using the open-field, elevated plus maze, tail suspension, and forced swimming tests in male C57BL/6J mice. Subsequently, we assessed sleep status using sleep recordings and a standardized scoring system alongside the pentobarbital sodium-induced sleep test. Results: The mice in both model groups exhibited anxiety-like behavior. Sleep disturbances observed in the CUMS+Noise group were characterized by disruptions in sleep duration and circadian rhythm. This observation was supported by a marked reduction in multiple sleep time intervals and single sleep duration, as well as a significant increase in sleep duration at the final time interval of ZT23-24. To further investigate the potential mechanisms of interaction, we conducted an analysis of hub genes present in the hippocampal sequencing data utilizing weighted gene co-expression network analysis (WGCNA). Pearson correlation analysis revealed a significant association between the hub genes Alb, P2rx1, and Npsr1 and key phenotypic traits. However, PCR experiments indicated that only Alb showed a significant difference, which aligns with the sequencing results. Conclusions: Albumin is a crucial transporter protein for thyroid hormones and plays a vital role in their metabolism. The interaction between sleep disorders and anxiety-like behavior may be closely linked to the dysfunctional transportation of thyroid hormones by albumin. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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16 pages, 2034 KiB  
Article
Preliminary Exploration on the Effects of a Novel Antidepressant Formula Food in a Mouse Model
by Xu Chen, Ruoxi Mao, Yunxia Zou, Wentian Yue, Wenwen Dong and Yali Zhang
Foods 2025, 14(9), 1640; https://doi.org/10.3390/foods14091640 - 7 May 2025
Viewed by 650
Abstract
Depression poses increasing public health challenges, and alternative dietary strategies are gaining attention for their potential therapeutic effects. This study evaluates a natural ingredient-based formula powder (FP) for its antidepressant effects in a chronic unpredictable mild stress (CUMS) mouse model under both a [...] Read more.
Depression poses increasing public health challenges, and alternative dietary strategies are gaining attention for their potential therapeutic effects. This study evaluates a natural ingredient-based formula powder (FP) for its antidepressant effects in a chronic unpredictable mild stress (CUMS) mouse model under both a standard diet and high-fat high-sugar diet (HFHSD) conditions. Behavioral tests demonstrated that FP significantly reduced immobility time in the forced swimming test and tail suspension test, and improved anxiety-like behavior in the open field test, particularly by increasing the central zone activity in mice fed a standard diet. FP supplementation also mitigated CUMS- and HFHSD-induced organ damage, as indicated by increased small intestine and colon coefficients. At the molecular level, FP downregulated the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and upregulated brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase-2 (TPH2) in the hippocampus and colon. These findings suggest that FP exerts antidepressant-like effects by alleviating neuroinflammation and supporting the gut–brain axis, offering a promising functional food approach for managing depression. Full article
(This article belongs to the Special Issue Functional Foods for Health Promotion and Disease Prevention)
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22 pages, 22151 KiB  
Article
The Behavioral and Neuroinflammatory Impact of Ketamine in a Murine Model of Depression and Liver Damage
by Mădălina Iuliana Mușat, Ana-Maria Ifrim-Predoi, Smaranda Ioana Mitran, Eugen Osiac and Bogdan Cătălin
Int. J. Mol. Sci. 2025, 26(8), 3558; https://doi.org/10.3390/ijms26083558 - 10 Apr 2025
Viewed by 929
Abstract
Non-alcoholic fatty liver disease (NAFLD) has been associated with depression and inadequate response to antidepressants. While ketamine has demonstrated efficacy in treating depression, its impact on pre-existing liver injury and depression remains unclear. This study aimed to evaluate the effects of ketamine treatment [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) has been associated with depression and inadequate response to antidepressants. While ketamine has demonstrated efficacy in treating depression, its impact on pre-existing liver injury and depression remains unclear. This study aimed to evaluate the effects of ketamine treatment in a murine model of depression and liver damage, considering age-related differences. Young and aged male C57BL/6N mice were submitted to chronic unpredictable mild stress (CUMS) and methionine–choline-deficient (MCD) diet to induce depressive-like behavior and NAFLD. Behavioral testing (sucrose preference test, open field test, novel object recognition test, Crawley’s sociability test) were used to assess ketamine’s (50 mg/kg) effect on behavior. Hepatic ultrasonography was utilized to evaluate liver status. The cortical and hippocampal NeuN+, GFAP+, and Iba1+ signals were quantified for each animal. Ketamine administration proved effective in relieving anhedonia and anxiety-like behavior, regardless of liver damage. Although ketamine treatment did not improve memory in animals with liver damage, it enhanced sociability, particularly in aged subjects. The acute administration of ketamine did not affect the severity of liver injury, but seems to affect astrogliosis and neuronal loss. Although animal models of depression only replicate certain clinical features of the condition, they remain valuable for evaluating the complex and varied effects of ketamine. By applying such models, we could demonstrate ketamine’s therapeutic versatility, and also indicate that responses to the treatment may differ across different age groups. Full article
(This article belongs to the Section Molecular Immunology)
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21 pages, 7346 KiB  
Article
1,8-Cineole Alleviates Hippocampal Oxidative Stress in CUMS Mice via the PI3K/Akt/Nrf2 Pathway
by Wenze Wu, Dequan Wang, Yuzhu Shi, Yichen Wang, Yongzi Wu, Xinyan Wu, Basit Ali Shah and Gang Ye
Nutrients 2025, 17(6), 1027; https://doi.org/10.3390/nu17061027 - 14 Mar 2025
Cited by 2 | Viewed by 1070
Abstract
Background: This study investigates the neuroprotective effects of 1,8-cineole (1,8-CH), against hippocampal oxidative stress in a chronic unpredictable mild stress (CUMS) mice model of depression, focusing on the underlying molecular mechanisms. Methods: The effects of CUMS exposure were assessed by measuring [...] Read more.
Background: This study investigates the neuroprotective effects of 1,8-cineole (1,8-CH), against hippocampal oxidative stress in a chronic unpredictable mild stress (CUMS) mice model of depression, focusing on the underlying molecular mechanisms. Methods: The effects of CUMS exposure were assessed by measuring oxidative stress markers, antioxidant activity, and neuronal damage in the hippocampus using histopathology, network pharmacology, Western blot analysis, and small interfering RNA (siRNA) knockdown experiments. Results: 1,8-CH significantly alleviated depression-like behaviors in CUMS mice. CUMS exposure induced oxidative stress in the hippocampus, evidenced by elevated MDA levels, decreased antioxidant activity, and neuronal damage. DHE staining revealed ROS accumulation. Treatment with 1,8-CH alleviated oxidative stress by reducing MDA, restoring antioxidant activity, and lowering ROS levels, while improving neuronal structure. Network pharmacology identified the PI3K/Akt/Nrf2 pathway as a key mediator of 1,8-CH’s neuroprotection, which was supported by Western blot results, demonstrating PI3K/Akt activation and a potential enhancement of Nrf2 nuclear translocation. Furthermore, in corticosterone-induced PC12 cells, the antioxidant effects of 1,8-CH were abolished by Nrf2 inhibition and siRNA knockdown, confirming Nrf2’s role. Conclusions: These findings suggest that 1,8-CH alleviates hippocampal oxidative stress in CUMS-induced depression via the PI3K/Akt/Nrf2 pathway, highlighting its potential as a health supplement for managing depression. Full article
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18 pages, 6315 KiB  
Article
Lactiplantibacillus plantarum GOLDGUT-HNU082 Alleviates CUMS-Induced Depressive-like Behaviors in Mice by Modulating the Gut Microbiota and Neurotransmitter Levels
by Wanggao Li, Meng Xu, Yaning Liu, Silu Zhang, Jun Wang, Zhizhu Zhang, Guoxun Xiao, Ruimin Wang, Jiachao Zhang and Hui Xue
Foods 2025, 14(5), 813; https://doi.org/10.3390/foods14050813 - 26 Feb 2025
Cited by 1 | Viewed by 1224
Abstract
Emerging evidence links depressive disorders to the gut microbiota via the gut–brain axis. Probiotics, which are microorganisms that modulate the gut microbiota, have shown promising results in alleviating depression and are increasingly recognized as functional food components with potential health benefits. This study [...] Read more.
Emerging evidence links depressive disorders to the gut microbiota via the gut–brain axis. Probiotics, which are microorganisms that modulate the gut microbiota, have shown promising results in alleviating depression and are increasingly recognized as functional food components with potential health benefits. This study examines the effects of Lactiplantibacillus plantarum GOLDGUT-HNU082 (Lp082), a probiotic strain with potential applications in functional foods, on chronic unpredictable mild stress (CUMS)-induced depression in mice. Behavioral tests, measurements of the neurotransmitters and inflammatory cytokines in the serum and colon tissue, and the metagenomic sequencing of the gut microbiota were used to investigate potential mechanisms. The results demonstrated that Lp082 significantly alleviated depressive-like behaviors in CUMS mice, restored the balance of key neurotransmitters like serotonin (5-HT), reduced the levels of inflammatory cytokines like TNF-α, and enhanced brain neuroplasticity by promoting hippocampal neurogenesis. Additionally, Lp082 altered the composition of the gut microbiota in CUMS mice and promoted the growth of Bifidobacterium, improving metabolic pathways related to neurotransmitter synthesis. These findings indicate that Lp082, as a potential functional food ingredient, alleviates depressive-like behaviors in mice by reshaping the gut microbiota, offering new insights into the use of probiotics in functional foods for mental health management. Full article
(This article belongs to the Section Nutraceuticals, Functional Foods, and Novel Foods)
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13 pages, 1690 KiB  
Article
Schaftoside Reduces Depression- and Anxiogenic-like Behaviors in Mice Depression Models
by Yue Hu, Yaoxue Gan, Jia Lei, Jinhui Cai, Yecheng Zhou, Hao Chen, Qian Zhang and Yan Shi
Brain Sci. 2025, 15(3), 238; https://doi.org/10.3390/brainsci15030238 - 24 Feb 2025
Viewed by 984
Abstract
Background: Major depressive disorder is a common mental health issue characterized by persistently low mood and high morbidity and mortality. The major pathophysiology is neuroinflammation, as evidenced by elevated cytokine levels. Patients often fail to achieve full remission with the use of currently [...] Read more.
Background: Major depressive disorder is a common mental health issue characterized by persistently low mood and high morbidity and mortality. The major pathophysiology is neuroinflammation, as evidenced by elevated cytokine levels. Patients often fail to achieve full remission with the use of currently available antidepressants, prompting the search for new treatment options. Schaftoside (SS), a flavonoid found in traditional Chinese herbs, has both antioxidant and anti-inflammatory properties. However, its antidepressant effects are poorly understood. Methods: Male C57BL/6 mice underwent chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS) treatment to induce depression- and anxiety-like behaviors. SS was administered at 40, 80, and 160 mg/kg for 28 days. The effect on depression-like behaviors was assessed using behavioral assays, and ELISA was used to measure pro-inflammatory cytokines in the serum and hippocampus. Results: SS significantly decreased immobility in the forced swim and tail suspension tests, increased sucrose preference in the sucrose preference test, and reduced feeding latency in the novelty-suppressed feeding test. These findings indicate improved depression and anxiety-like behaviors. ELISA showed that SS lowered interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha levels in the serum and hippocampus of CUMS mice. Conclusions: Our study indicates that SS has antidepressant and anxiolytic effects, possibly through neuroinflammatory processes, making it a promising therapeutic candidate for depression, and thus deserves further investigation into its mechanisms and clinical efficacy. Full article
(This article belongs to the Section Neuropsychiatry)
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20 pages, 17818 KiB  
Article
The Long-Term Effects of Chronic Unpredictable Mild Stress Experienced During Adolescence Could Vary Depending on Biological Sex
by Olesya M. Shirokova, Daria M. Kuzmina, Olga G. Zaborskaya, Natalia A. Shchelchkova, Elizaveta V. Kozliaeva, Svetlana A. Korotchenko, Vladimir I. Pershin, Petr I. Vasilchikov and Irina V. Mukhina
Int. J. Mol. Sci. 2025, 26(3), 1251; https://doi.org/10.3390/ijms26031251 - 31 Jan 2025
Cited by 2 | Viewed by 1661
Abstract
Sex differences in the neurobiology of responses to chronic stress have been widely discussed but remain poorly understood. We found that chronic unpredictable mild stress (CUMS) experienced during adolescence induced different behavioral patterns in adult males and females. Immunohistochemical analysis of the CA1 [...] Read more.
Sex differences in the neurobiology of responses to chronic stress have been widely discussed but remain poorly understood. We found that chronic unpredictable mild stress (CUMS) experienced during adolescence induced different behavioral patterns in adult males and females. Immunohistochemical analysis of the CA1 field of the dorsal and ventral hippocampus revealed no quantitative or morphological changes in astrocytes in the long term after CUMS. Real-time PCR analysis showed no increase in the expression level of SigmaR1 after CUMS relative to individual housekeeping genes. Analysis of mouse cerebral cortex homogenates showed that IL-1β levels only decreased after CUMS in males. However, the SigmaR1 levels were significantly higher in the CUMS groups than in the control groups in both sexes. It can be concluded that biological sex and age influence the response to CUMS, although not in all cases. Further studies are needed to understand the effects of chronic stress on males and females. This is important because men and women have different risks for stress and mental disorders. Full article
(This article belongs to the Section Molecular Neurobiology)
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17 pages, 4727 KiB  
Article
The Antidepressant Effect of Resveratrol Is Related to Neuroplasticity Mediated by the ELAVL4-Bdnf mRNA Pathway
by Hailong Ge, Lujia Si, Chen Li, Junjie Huang, Limin Sun, Lan Wu, Yinping Xie, Ling Xiao and Gaohua Wang
Int. J. Mol. Sci. 2025, 26(3), 1113; https://doi.org/10.3390/ijms26031113 - 27 Jan 2025
Viewed by 1944
Abstract
Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and [...] Read more.
Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and mechanism of resveratrol in neuroplasticity in depression. Here, we adopted the chronic unpredictable mild stress (CUMS) model and resveratrol intervention by oral gavage. Thereafter, behavioral tests confirmed resveratrol’s antidepressant effect, and Nissl staining, Golgi staining, and Western blotting (WB) were employed to assess the neuronal plasticity. Moreover, proteomic analysis and WB were used to screen and identify the key proteins. To investigate the downstream target of ELAV-like RNA-binding protein 4 (ELAVL4) (one of candidate genes), the RNA Interactome Database and the National Center for Biotechnology Information databases were utilized to predict the targets of ELAVL4. Finally, Quantitative PCR, WB, and Immunofluorescence were used to verify the prediction. Our results indicate that resveratrol alleviates CUMS-induced depressive-like behaviors accompanied by the restoration of impaired hippocampal neuroplasticity. Then, proteomic analysis shows that 351 differentially expressed proteins (DEPs) decrease after CUMS, while 24 DEPs increase remarkably with the resveratrol treatment. Among which, ELAVL4 is downregulated by CUMS, simultaneously increasing after resveratrol intervention, which acts as a protective protein in this process. Finally, brain-derived neurotrophic factor (Bdnf) mRNA is predicted to be the potential target of ELAVL4 and validated by molecular technologies. In conclusion, our findings demonstrate that resveratrol’s antidepressant efficacy is closely associated with ELAVL4, an RNA-binding protein, a mediated neuroplasticity pathway, potentially intersecting with the Bdnf mRNA. Overall, this research sheds light on the role of the ELAVL4-Bdnf mRNA pathway through neuroplasticity in resveratrol’s antidepressant action, which provides an mRNA regulation perspective for the development of novel antidepressants and understanding depression pathology. Full article
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19 pages, 8065 KiB  
Article
Effects of Lutjanus erythropterus Protein on Depression-like Behavior and Gut Microbiota in Stressed Juvenile Mice
by Jinjin Luo, Chen Wang, Weichang Ye, Ruiyang He, Ling Huang, Zhijia Fang, Qi Deng, Mei Qiu, Lijun Sun and Ravi Gooneratne
Foods 2025, 14(2), 330; https://doi.org/10.3390/foods14020330 - 20 Jan 2025
Viewed by 1453
Abstract
Lutjanus erythropterus protein (Lep) exhibits anti-inflammatory effects, but its antidepressant activity is unknown. This study used a 44-day chronic unpredictable mild stress (CUMS) model to determine whether Lep has a beneficial effect through the gut–brain axis in 3-week-old male C57BL/6 mice. Gavaging with Lep [...] Read more.
Lutjanus erythropterus protein (Lep) exhibits anti-inflammatory effects, but its antidepressant activity is unknown. This study used a 44-day chronic unpredictable mild stress (CUMS) model to determine whether Lep has a beneficial effect through the gut–brain axis in 3-week-old male C57BL/6 mice. Gavaging with Lep solution alleviated the depression-like behavior and anxiety symptoms in CUMS growing mice. Administration of Lep decreased serum IL-1β, IL-2, IL-6, and TNF-α levels and restored colonic mucosal damage. In addition, Lep improved the disturbance of 5-hydroxytryptamine (5-HT) secretion in the gut–brain axis. Pearson analysis revealed that gut short-chain fatty acid (SCFAs) concentration significantly (p < 0.05) correlated with mucosal damage scores and the depression-like behavior index. Lep was able to prevent the gut SCFA enrichment. Lep upregulated gut Muribaculaceae and downregulated SCFA-producing bacteria by replenishing deficient amino acid (AA) (tryptophan, alanine, aspartate, glutamate) and decreased (p < 0.01) the gene abundance of the AA metabolism pathway of SCFA-producing bacteria, thereby preventing gut SCFA enrichment and alleviating associated depression-like behavior. These findings indicate that Lep could attenuate depression in CUMS juvenile mice via the gut microbiota-SCFA–brain axis. Full article
(This article belongs to the Special Issue Food Bioactive Compounds: Extraction, Identification and Application)
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16 pages, 5139 KiB  
Article
Cichorium intybus L. Oligo-Polysaccharides (CIO) Exerts Antianxiety and Antidepressant Effects on Mice Experiencing Behavioral Despair and Chronic Unpredicted Mild Stress
by Yanqin Luo, Xueyi Bei, Yiwen Zhang, Xinran Sun, Yongzhi Zhao, Fang Chen, Ruile Pan, Qi Chang, Qinghu He, Xinmin Liu and Ning Jiang
Foods 2025, 14(1), 135; https://doi.org/10.3390/foods14010135 - 6 Jan 2025
Cited by 1 | Viewed by 1294
Abstract
Cichorium intybus L. oligo-polysaccharides (CIOs), obtained from Cichorium intybus L., is a mixture of oligosaccharides and polysaccharides. This study explores the antianxiety and antidepressant effects and mechanisms of CIOs by using acute behavioral despair and chronic unpredictable mild stress mice models and measuring [...] Read more.
Cichorium intybus L. oligo-polysaccharides (CIOs), obtained from Cichorium intybus L., is a mixture of oligosaccharides and polysaccharides. This study explores the antianxiety and antidepressant effects and mechanisms of CIOs by using acute behavioral despair and chronic unpredictable mild stress mice models and measuring the levels of 5-HT and the expression of proteins related to the BDNF/ERK and PI3K/Akt/mTOR pathways. Moreover, 56 male C57BL/6N mice were used to test behavioral despair. They were randomized into seven groups (Control, Citalopram, CIO 12.5 mg/kg, CIO 25 mg/kg, CIO 100 mg/kg, and CIO 200 mg/kg) based on body weight; they were administered with the corresponding medication daily for 7 days; and behavioral tests were conducted on them (forced swimming test (FST) and tail suspension test (TST)) after 7 days. Seventy male C57BL/6N mice were adopted in the next part of the experiment and randomly divided into seven groups (Control, CUMS, Fluoxetine, MOO, CIO 25 mg/kg, and CIO 100 mg/kg) based on the sucrose preference index. Except for the control group, the other groups were subjected to 6 weeks of CUMS. From the fifth week of stress, the corresponding drugs were administered by gavage until the end of the behavioral tests. In the behavioral despair tests, the immobility time was significantly reduced in the FST and TST after the CIO (25 and 100 mg/kg) treatment of 7 days. After 6 weeks of chronic unpredicted mild stress (CUMS) treatment, CIO (25, 50, and 100 mg/kg) administration significantly reduced the number of buried beads in the marble burying test (MBT), decreased the latency in the novelty-suppressed feeding test (NSFT), and shortened the immobility time in the FST and TST. CIO administration significantly increased the sucrose preference index in the sucrose preference test (SPT). Additionally, CIO treatment increased hippocampal 5-HT levels while upregulating the expression of BDNF, P-PI3K/PI3K, P-ERK/ERK, P-Akt/Akt, and P-mTOR/mTOR. In summary, CIO exerted promising antidepressant effects in behavioral despair and antianxiety and antidepressant effects in CUMS-induced depressive mice. Moreover, CIO therapy was facilitated by increasing the 5-HT content, alleviating the damage of hippocampal neurons, and upregulating the BDNF/ERK and PI3K/AKT/mTOR cascade. Thus, CIO is a substance with the potential to treat anxiety and depression. Full article
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