scholarly journals Therapeutic STING activation boosts microglia phagocytosis and ameliorates depression-like behaviors during chronic restraint stress

2021 ◽  
Author(s):  
Qian Zhai ◽  
Yanpeng Zhang ◽  
Shuwen Tan ◽  
Jianyu Sun ◽  
Mao Ye ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Restraint Stress ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Chronic Restraint Stress ◽  
Expression Levels ◽  
Cell Counts ◽  
Latex Beads ◽  
Plus Maze

Abstract Background The STING-TBK1-IRF3 signaling pathway involves in modulating host innate immunity, however, the potential role of STING signaling pathway in chronic restraint stress model has not been determined. The aim of this study is to explore the underlying role of STING signaling pathway in regulating neuroinflammation, as well as to evaluate the therapeutic potential of STING agonist during chronic restraint stress. Methods C57BL/6 mice were subjected to 14-day intermittent restraint stress. Sucrose preference, elevated plus maze and tail suspension tests were measured in chronic restraint stress mice. Expression levels of proinflammatory cytokines were tested by QT-PCR and Luminex cytokine assays. The fluorescence-labeled latex beads, flow cytometry and CD68 positive cell counts were utilized to evaluate phagocytic abilities of microglia. Then, the ability of intracerebroventricular injection of STING agonist, 2’3-cGAMP, to reverse the depression-like behaviors and inflammatory cytokines was examined. Results We found that the expression levels of STING, p-TBK1, and p-IRF3 were remarkably decreased in chronic restraint stress mice, which was associated with decreased IFN-β secretion. Moreover, the STING agonist, 2’3-cGAMP, significantly alleviated the neuroinflammation and ameliorated depression-like behavior which depends on the functional STING activation. Furthermore, 2’3-cGAMP promoted microglia phagocytosis through STING-dependent IFN-β release, which was essential for recovery from neuroinflammation during chronic restraint stress. Conclusions These findings demonstrate that STING signaling pathway is a critical mediator in regulating microglia phagocytosis and may serve as a novel therapeutic target for chronic stress-related psychiatric diseases.

scholarly journals Therapeutic STING activation boosts microglia phagocytosis and ameliorates depression-like behaviors during chronic restraint stress

2021 ◽  
Author(s):  
Qian Zhai ◽  
Yanpeng Zhang ◽  
Shuwen Tan ◽  
Jianyu Sun ◽  
Mao Ye ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Restraint Stress ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Chronic Restraint Stress ◽  
Expression Levels ◽  
Cell Counts ◽  
Latex Beads ◽  
Plus Maze

Abstract Background The STING-TBK1-IRF3 signaling pathway involves in modulating host innate immunity, however, the potential role of STING signaling pathway in chronic restraint stress model has not been determined. The aim of this study is to explore the underlying role of STING signaling pathway in regulating neuroinflammation, as well as to evaluate the therapeutic potential of STING agonist during chronic restraint stress. Methods C57BL/6 mice were subject to 14-day intermittent restraint stress. Sucrose preference, elevated plus maze and tail suspension tests were measured in chronic restraint stress mice. Expression levels of proinflammatory cytokines were tested by QT-PCR and Luminex cytokine assays. The fluorescence-labeled latex beads, flow cytometry and CD68 positive cell counts were utilized to evaluate phagocytic abilities of microglia. Then, the ability of intracerebroventricular injection of STING agonist, 2’3-cGAMP, to reverse the depression-like behaviors and inflammatory cytokines was examined. Results We found that the expression levels of STING, p-TBK1, and p-IRF3 were remarkably decreased in chronic restraint stress mice, which was associated with decreased IFN-β secretion. Moreover, the STING agonist, 2’3-cGAMP, significantly alleviated the neuroinflammation and ameliorated depression-like behavior which depends on the functional STING activation. Furthermore, 2’3-cGAMP promoted microglia phagocytosis through cGAMP-STING-dependent IFN-β release, which was essential for recovery from neuroinflammation during chronic restraint stress. Conclusions These findings demonstrate that STING signaling pathway is a critical mediator in regulating microglia phagocytosis and may serve as a novel therapeutic target for chronic stress-related psychiatric diseases.

scholarly journals The Role of MAPK and Dopaminergic Synapse Signaling Pathways in Antidepressant Effect of Electroacupuncture Pretreatment in Chronic Restraint Stress Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Xinjing Yang ◽  
Zhuo Guo ◽  
Jun Lu ◽  
Bingcong Zhao ◽  
Yutong Fei ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Restraint Stress ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Antidepressant Effect ◽  
Control Group ◽  
Group Model ◽  
Chronic Restraint Stress

Acupuncture has demonstrated the function in ameliorating depressive-like behaviors via modulating PKA/CREB signaling pathway. To further confirm the antidepressant mechanism of EA on the mitogen-activated protein kinase (MAPK) and dopaminergic synapse signaling pathways, 4 target proteins were detected based on our previous iTRAQ analysis. Rats were randomly divided into control group, model group, and electroacupuncture (EA) group. Except for the control group, all rats were subjected to 28 days of chronic restraint stress (CRS) protocols to induce depression. In the EA group, EA pretreatment at Baihui (GV20) and Yintang (GV29) was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes) prior to restraint. The antidepressant-like effect of EA was measured by body weight and open-field test. The protein levels of DAT, Th, Mapt, and Prkc in the hippocampus were examined by using Western blot. The results showed EA could ameliorate the depression-like behaviors and regulate the expression levels of Prkc and Mapt in CRS rats. The effect of EA on DAT and Th expression was minimal. These findings implied that EA pretreatment could alleviate depression through modulating MAPK signaling pathway. The role of EA on dopaminergic synapse signaling pathways needs to be further explored.

scholarly journals Xiaoyaosan Exerts Therapeutic Effects on the Colon of Chronic Restraint Stress Model Rats via the Regulation of Immunoinflammatory Activation Induced by the TLR4/NLRP3 Inflammasome Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Hui-Zheng Zhu ◽  
Yu-Dan Liang ◽  
Wen-Zhi Hao ◽  
Qing-Yu Ma ◽  
Xiao-Juan Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Restraint Stress ◽  
Gastrointestinal Diseases ◽  
Chronic Restraint Stress ◽  
Colonic Inflammation ◽  
Depressive Behavior ◽  
Expression Levels ◽  
Caspase 1 ◽  
Tnf Α

Depression is the neurological manifestation most commonly associated with gastrointestinal diseases. The release of inflammatory cytokines mediated by TLR4/NLRP3 inflammasome signaling-induced immunoinflammatory activation may represent a common pathogenic process underlying the development of gastrointestinal diseases and depression. Clinical studies have indicated that Xiaoyaosan (XYS) can relieve depressive behavior by improving gastrointestinal symptoms. We previously demonstrated that XYS can reduce colonic inflammation in a rat model of chronic unpredictable mild stress; however, the precise anti-inflammatory mechanisms involved remain unclear. Here, we investigated whether XYS can ameliorate depressive behavior through regulating the TLR4/NLRP3 inflammasome signaling pathway, thereby inhibiting immunoinflammatory activation and reducing colonic proinflammatory cytokine levels. Fifty-two healthy male Sprague–Dawley rats were randomly divided into four groups (control, model, XYS, and fluoxetine). The latter three groups were subjected to 21 days of chronic restraint stress to generate a model of stress-induced depression. XYS and fluoxetine were administered intragastrically. Behavioral changes in the rats were assessed after 21 days. Serum and colon samples were collected, and the relative levels of the inflammation indicators IL-6, IL-1β, and TNF-α were determined by ELISA. Pathological changes in colon tissue were assessed by hematoxylin and eosin staining. The levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, and TRAF6 were detected by immunohistochemistry, while the gene and protein expression levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, TRAF6, NLRP3, ASC, and caspase-1 were detected by quantitative polymerase chain reaction (qPCR) and Western blotting. The results indicated that XYS could improve the depressive-like behavior and the weight loss of rats with stress-induced depression. Furthermore, depressed rats treated with XYS exhibited decreased expression levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, TRAF6, NLRP3, ASC, and caspase-1 in colonic tissue; reduced colon and serum concentrations of the inflammatory factors IL-6, IL-1β, and TNF-α; and lowered levels of colonic inflammation.

scholarly journals Chronic restraint stress impairs cognition via modulating HDAC2 expression

2021 ◽  
Vol 12 (1) ◽  
pp. 154-163
Author(s):  
Jie Wu ◽  
Cui Liu ◽  
Ling Zhang ◽  
Bing He ◽  
Wei-Ping Shi ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Hippocampal Neurons ◽  
Restraint Stress ◽  
Glucocorticoid Receptors ◽  
Chronic Restraint Stress ◽  
Akt Signaling Pathway ◽  
Object Recognition Test ◽  
Protein Levels ◽  
Synaptic Functions ◽  
Plus Maze

Abstract Background To investigate the effects of chronic restraint stress on cognition and the probable molecular mechanism in mice. Methods In the current work, a restraining tube was used as a way to induce chronic stress in mice. The protein levels were determined with ELISA and western blot. A series of behavior tests, including the Morris water maze, elevated plus maze, open field test, and novel object recognition test, were also performed to examine the anxiety and the ability of learning and memory. Moreover, murine neuroblastoma N2a cells were used to confirm the findings from mice under chronic stress. Results Decreased synaptic functions were impaired in chronic stress with the downregulation of PSD95, GluR-1, the neurotrophic factor BDNF, and immediate-onset genes Arc and Egr. Chronic restraint decreased the histone acetylation level in hippocampal neurons while HDAC2 was increased and was co-localized with glucocorticoid receptors. Moreover, chronic stress inhibited the PI3K/AKT signaling pathway and induced energy metabolism dysfunctions. Conclusion This work examining the elevated levels of HDAC2 in the hippocampus may provide new insights and targets for drug development for treating many neurodegenerative diseases.

Antidepressant-like effects of albiflorin involved the NO signaling pathway in rats model of chronic restraint stress

2020 ◽  
Vol 18 (11) ◽  
pp. 872-880
Author(s):  
Ying-Li ZHU ◽  
Lin-Yuan WANG ◽  
Dan-Ping ZHAO ◽  
Cheng-Long WANG ◽  
Rui ZHANG ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Restraint Stress ◽  
Chronic Restraint Stress ◽  
No Signaling

Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance

Tumor Biology ◽  
2016 ◽  
Vol 37 (11) ◽  
pp. 15107-15114 ◽  
Author(s):  
M. H. Shahi ◽  
S. Farheen ◽  
M. P. M. Mariyath ◽  
J. S. Castresana
Keyword(s):  
Signaling Pathway ◽  
Potential Role

Antidepressant-Like Effects of Vaccinium bracteatum in Chronic Restraint Stress Mice: Functional Actions and Mechanism Explorations

2018 ◽  
Vol 46 (02) ◽  
pp. 357-387 ◽  
Author(s):  
Dool-Ri Oh ◽  
Yujin Kim ◽  
Eun-Jin Choi ◽  
Myung-A Jung ◽  
Kyo-Nyeo Oh ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Signaling Pathway ◽  
Restraint Stress ◽  
Forced Swim Test ◽  
Akt Signaling ◽  
Antagonistic Effect ◽  
Chronic Restraint Stress ◽  
Akt Signaling Pathway ◽  
Neuroprotective Effects ◽  
Immobility Time

The fruit of Vaccinium bracteatum Thunb. (VBF) is commonly known as the oriental blueberry in Korea. The aim of this study was to evaluate the antidepressant-like effects of water VBF extract (VBFW) in a mouse model of chronic restraint stress (CRS) and to identify the underlying mechanisms of its action. The behavioral effects of VBFW were assessed in the forced swim test (FST) and open field test (OFT). The levels of serum corticosterone (CORT), brain monoamines, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway were evaluated. VBFW treatment significantly reduced the immobility time and increased swimming time in FST without altering the locomotor activity in unstressed mice. Furthermore, CRS mice treated with VBFW exhibited a significantly decreased immobility time in FST and serum CORT, increased locomotor activity in OFT, and enhanced brain monoamine neurotransmitters. Similarly, VBFW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and PFC. In addition, VBFW may reverse CORT-induced cell death by enhancing cyclic AMP-responsive element-binding protein expression through the up-regulation of ERKs/Akt signaling pathways. In addition, VBFW showed the strong antagonistic effect of the 5-HT[Formula: see text] receptor by inhibiting 5-HT-induced intracellular Ca[Formula: see text] and ERK1/2 phosphorylation. Our study provides evidence that antidepressant-like effects of VBFW might be mediated by the regulation of monoaminergic systems and glucocorticoids, which is possibly associated with neuroprotective effects and antagonism of 5-HT[Formula: see text] receptor.

Abstract 14297: Potential Role of the Tumor Suppressor WWOX in Mediating Skeletal Muscle-Lung Vasculature Crosstalk in PH-HFpEF

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Gunner Halliday ◽  
Yang Bai ◽  
Marta T Gomes ◽  
Dmitry Goncharov ◽  
Elena Goncharova ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Tumor Suppressor ◽  
Potential Role ◽  
Pulmonary Vascular Remodeling ◽  
Expression Levels ◽  
Promote Cell Proliferation ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Group 2

Introduction: Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), particularly in the context of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide. At present, no specific effective therapy has been identified mainly due to the fact that major pathways involved in the regulation of PH-HFpEF are still not well understood. Results: We have recently reported on a role of skeletal muscle sirtuin-3 (SIRT3) in modulating PH-HFpEF. Using skeletal muscle-specific SIRT3 knockout mice ( Sirt3 skm-/- ), we showed that absence of SIRT3 in skeletal muscle drastically reduced the pulmonary vascular tree accompanied by vascular proliferative remodeling. Interestingly, we found that expression levels of the tumor suppressor WW domain-containing oxidoreductase (WWOX) were decreased in pulmonary arterial smooth muscle cells (PASMCs) obtained from Sirt3 skm-/- mice, while no changes in SIRT3 activation levels were detected. Reduced WWOX expression levels were also found in PASMCs isolated from SU5416/Obese ZSF1 (Ob-Su) rat model of PH-HFpEF, in which the levels of SIRT3 activation were found to be decreased in skeletal muscle, but not in the lungs and PASMCs. No changes of WWOX levels were observed in skeletal muscle of Ob-Su rats or in pulmonary artery endothelial cells (PAECs) treated with plasma obtained from Ob-Su rats. Conclusions: Since reduction of WWOX in PASMCs has been shown to promote cell proliferation, HIF1α stabilization and pulmonary arterial hypertension (PAH; Group 1), our data suggest a potential role of WWOX in mediating skeletal muscle SIRT3 deficiency-associated remote pulmonary vascular remodeling in PH-HFpEF.

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