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 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 Intraventricular T3 reverses chronic restraint stress-induced depressive-like behaviors: Inhibition of NF-κB/ NLRP3 inflammasome pathway in the hippocampus

2021 ◽  
Author(s):  
Tahmineh Mokhtari ◽  
AymanEl-Meghawry El-Kenawy ◽  
Li Hu
Keyword(s):  
Nlrp3 Inflammasome ◽  
Restraint Stress ◽  
Male Rats ◽  
Control Group ◽  
Therapeutic Effects ◽  
Chronic Restraint Stress ◽  
Model Group ◽  
Nissl Staining ◽  
Caspase 1 ◽  
Ca1 Region

Abstract In this study, the effects of triiodothyronine (T3) were evaluated on the NLR family pyrin domain containing 3 (NLRP3) inflammasome complex formation in the rat's hippocampus with restraint stress-induced depressive-like behaviors.Thirty-six Wistar male rats were randomly allocated to following groups: Control, Model, and Model + T3. In the Model or Model+T3 group, a single dose of PBS or T3 was administered into the lateral ventricle. Depressive-like behaviors were induced by chronic restraint stress. The forced swimming (FST), tail suspension (TST), and open field (OFT) tests were used to investigate the depression. The rats were sacrificed, and brain tissues were stored for molecular and pathological evaluations. Chronic stress increased the immobility of rats in the Model group according to FST, TST, and OFT (P < 0.05). T3 significantly improved depressive-like behaviors (P < 0.05). The gene expression and protein level of hippocampal nuclear factor kappa B (NF-κB), NLRP3, apoptosis-associated speck-like protein (ASC), and Caspase-1 significantly increased in the Model group compared to the control group (P < 0.05). The reduced hippocampal levels of NF-κB, NLRP3, ASC, and Caspase-1 were observed in the T3 group compared to the Model group (P < 0.05). The Nissl staining of the CA1 region showed an increased number of dark neurons (P < 0.05) and reduced pyramidal layer thickness (P < 0.05) in the Model group. These histopathological alterations were changed by T3 administration compared to the Model group (P < 0.05). The findings confirmed the therapeutic effects of intraventricularly T3 on depressive-like behaviors induced by restraint stress via surviving pyramidal neurons of the CA1 region and inhibition of NF-κB/NLRP3 inflammasome pathway.

scholarly journals Sparstolonin B Exerts Therapeutic Effects on Collagen-Induced Arthritis by Inhibiting the NLRP3 Inflammasome and Reducing the Activity of α1,3-Fucosyltransferase

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yue Sun ◽  
Yun Guo ◽  
Jing Zhang ◽  
Lihua Chang ◽  
Haiyan Zhao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Western Blotting ◽  
Nlrp3 Inflammasome ◽  
Synovial Cells ◽  
Expression Levels ◽  
Caspase 1 ◽  
Tnf Α ◽  
Sparstolonin B

Objective. To explore the role of α1,3-fucosyltransferase in the mediation of rheumatoid arthritic inflammation, the protective effect of Sparstolonin B on rheumatoid arthritis (RA), and the mechanisms that regulate the NLRP3 inflammasome. Methods. Forty, weighing from 260-300 g, male Sprague-Dawley rats were randomly divided into the following groups: a sham operation group (Sham group), a rheumatoid arthritis model group (RA group), an RA+Sparstolonin B treatment group (RAS group), an RA+Iguratimod group (RAI group), and an RA+SsnB+NLRP3 inflammasome activator (Nigericin) group (RASN group); ten animals were allocated to each group. We determined the arthritis index for each group of rats, and pathological changes were evaluated by hematoxylin-eosin staining. We also used ELISAs to determine the serum levels of IL-17, IL-6, TNF-α, TGF-β, IL-18, and IL-1β. TUNEL staining was used to investigate apoptosis in synovial cells. IF was used to detect the release of ROS, ASC formation, and the expression levels of FucT-V and NLRP3. Western blotting was used to detect the protein expression levels of Bc1-2, Bax, TLR4, MYD88, NF-κB, pro-caspase-1, NLRP3, FucT-V, E-Selectin, and P-Selectin. We also performed in vitro experiments with Sparstolonin B and detected changes in 1,3-fucosyltransferase activity by ELISA. The pyroptosis-related phenotype, including ASC, was identified by immunofluorescence, while levels of NLRP-3, pro-IL-1, and pro-caspase-1 were detected by western blotting. Results. Sparstolonin B was showed to alleviate joint swelling in RA rats, inhibited inflammatory cell infiltration and the release of ROS, reduced damage caused by oxidative stress, and suppressed the rate of apoptosis in synovial cells. The administration of Sparstolonin B inhibited the secretion of IL-17 from Th17 cells and triggered the secretion of TGF-β from Treg cells, thus leading to the reduced expression of TLR4, MyD88, and NF-κB, and the suppression of TNF-α secretion. Moreover, Sparstolonin B downregulated the expression of NLRP3, inhibited ASC formation in vivo and in vitro, and reduced the levels of IL-18 and IL-1β. The expression levels of FucT-V, E-Selectin, and P-Selectin were also inhibited. Interestingly, these protective effects of Sparstolonin B could be blocked in RA rats by inhibiting the activation of the NLRP3 inflammasome. Conclusion. Sparstolonin B improved inflammatory responses and oxidative stress by inhibiting the NLRP3 inflammasome, inhibiting the expression of FucT-V and downregulating the TLR4/MYD88/NF-𝜅B signaling pathway in order to rescue RA.

scholarly journals Effect of Tripterygium wilfordii Polycoride on the NOXs-ROS-NLRP3 Inflammasome Signaling Pathway in Mice with Ulcerative Colitis

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Ma Fangxiao ◽  
Ke Yifan ◽  
Zhong Jihong ◽  
Shen Yan ◽  
Liu Yingchao
Keyword(s):  
Ulcerative Colitis ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Tripterygium Wilfordii ◽  
Expression Levels ◽  
Caspase 1 ◽  
Model Control ◽  
Mrna Expression Levels

Objective. To explore the effect of Tripterygium wilfordii polycoride (TWP) on the NADPH oxidases (NOXs)-reactive oxygen species (ROS)-NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway and the possibility of using TWP to treat ulcerative colitis (UC). Methods. BALB/c mice were randomly divided into five groups: model control, low TWP, middle TWP, high TWP, and normal control groups. A UC model was established with dextran sulfate sodium. The determination of ROS was carried out by using the fluorescent probe DCFH-DA, and NOXs activity was detected based on the NADPH consumption rate. The mRNA expression levels of NLRP3, ASC, and caspase-1 in the colon tissues and neutrophils were assessed via real-time PCR. Results. The colon tissues were abnormal with different degrees in TWP groups with disease activity index and histopathological scores lower than those in the model group. In TWP groups, ROS generation, NOXs activity, and the mRNA expression levels of NLRP3, ASC, and caspase-1 in the colon tissues and colon-isolated neutrophils were remarkably lower than those in the model control group (P<0.05) and higher than those in the normal group (P<0.05). The results of pairwise comparison for the efficacy of TWP administration showed that the above indexes were statistically significant with the lowest expression in the high TWP group (P<0.05) and the highest expression in the low TWP group (P<0.05). Conclusion. TWP demonstrated anti-inflammatory effects on UC by decreasing the expression of proinflammatory factors in the NOXs-ROS-NLRP3 signaling pathway.

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 Intraventricular T3 Reverses Chronic Restraint Stress-Induced Depressive-Like Behaviors: Inhibition of NF-κB/ NLRP3 Inflammasome Pathway in the Hippocampus

2021 ◽  
Author(s):  
Tahmineh Mokhtari ◽  
AymanEl-Meghawry El-Kenawy ◽  
Li Hu
Keyword(s):  
Nlrp3 Inflammasome ◽  
Restraint Stress ◽  
Male Rats ◽  
Control Group ◽  
Therapeutic Effects ◽  
Chronic Restraint Stress ◽  
Model Group ◽  
Nissl Staining ◽  
Caspase 1 ◽  
Ca1 Region

Abstract In this study, the effects of triiodothyronine (T3) were evaluated on the NLRP3 inflammasome complex formation in the hippocampus of the rat with restraint stress-induced depressive-like behaviors.Thirty-six Wistar male rats were randomly allocated to the following groups: Control, Model, and Model + T3. In Model or Model + T3 group, a single dose of PBS or T3 () was administered into the lateral ventricle. Depressive-like behaviors were induced by chronic restraint stress. The forced swimming (FST), tail suspension (TST), and open field (OFT) tests were used to investigate depression. The rats were sacrificed, and brain tissues were stored for molecular and pathological evaluations. Chronic stress increased the immobility of rats in the Model group according to FST, TST, and OFT (P < 0.05). T3 significantly improved depressive-like behaviors (P < 0.05). The gene expression and protein level of hippocampal NF-κB, NLRP3, ASC, and Caspase-1 significantly increased in the Model group compared to the control group (P < 0.05). The reduced hippocampal levels of NF-κB, NLRP3, ASC, and Caspase-1 were seen in the T3 group compared to the Model group (P < 0.05). Also, the Nissl staining of the CA1 region showed an increased number of dark neurons (P < 0.05) and reduced pyramidal layer thickness (P < 0.05) in the Model group. These histopathological alterations were changed by T3 administration compared to the Model group (P < 0.05). The findings of confirmed the therapeutic effects of intraventricularly T3 on depressive-like behaviors induced by restraint stress via surviving pyramidal neurons of the CA1 region and inhibition of NF-κB/NLRP3 inflammasome pathway.

scholarly journals Curcumin suppresses neuroinflammation to protect neurons by preventing NLRP3 inflammasome activation

2021 ◽  
Vol 19 ◽  
pp. 205873922110586
Author(s):  
Qiang Shi ◽  
Ying-ying Zheng ◽  
Le Wang ◽  
Yi-dong Xue ◽  
Yan-ling Yang
Keyword(s):  
Nlrp3 Inflammasome ◽  
Neuroprotective Effect ◽  
Cell Activity ◽  
Learning Ability ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Expression Levels ◽  
Caspase 1 ◽  
Bv2 Cells ◽  
Tnf Α

Introduction Nucleotide-binding and oligomerization domain like receptors protein 3 (NLRP3) inflammasome-mediated interleukin (IL)-1β secretion plays an important role in the progression of Alzheimer’s disease (AD). Curcumin has been shown to improve cognitive impairment and learning ability of AD mice by reducing IL-1β secretion. However, its exact mechanism of action remains unclear. In the present study, we explored the relationship between the neuroprotective effect of curcumin and activation of the NLRP3 inflammasome pathway. Methods BV2 cells were primed with 500 ng/mL lipopolysaccharide (LPS) for 4 h and subsequently treated with 50 μM Aβ25-35 for 24 h or pretreated with 2.5–10 μM curcumin for 4 h and exposed to 50 μM Aβ25-35 for 24 h. The effects of curcumin and Aβ25-35 were assessed by the CCK8 assay. ELISA was used for the detection of IL-1β, IL-6, and tumor necrosis factor (TNF)-α levels in the supernatant of the cell culture medium. The viability of SH-SY5Y cells, which were incubated with conditioned medium (CM) was assessed using the CCK8 assay. The percentage of apoptotic SH-SY5Y cells incubated with CM was assessed using Annexin V-FITC/PI staining flow cytometry analysis. The expression levels of NLRP3, caspase-1 and IL-1β were observed by western blot and immunofluorescence staining analyses; the mRNA levels of nlrp3, caspase-1 and IL-1β were analyzed using qRT-PCR. Results Low (2.5 μM), medium (5 μM), and high (10 μM) concentrations of curcumin and 50 μM Aβ25-35 were used to perform the experiments in the present study. Curcumin attenuated the IL-1β, IL-6, and TNF-α release and increased SH-SY5Y cell activity, while decreasing the apoptotic percentage of SH-SY5Y cells using Aβ25-35 for cell stimulation ( p < 0.05). Furthermore, curcumin inhibited the expression of NLRP3, caspase-1 and IL-1β and nlrp3 in BV-2 cells ( p < 0.05), However, curcumin did not affect the expression levels of caspase-1 and IL-1β ( p > 0.05) Conclusion Overall, the data indicated that curcumin is a promising neuroprotective agent for suppressing neuroinflammation by inhibiting the NLRP3 inflammasome pathway.

scholarly journals MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway

2018 ◽  
Vol 49 (2) ◽  
pp. 798-815 ◽  
Author(s):  
Tao  Zhou ◽  
Dao-Kang Xiang ◽  
Sui-Ning Li ◽  
Lie-Hong Yang ◽  
Lu-Fang Gao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Signaling Pathway ◽  
Inflammatory Reaction ◽  
Nlrp3 Inflammasome ◽  
Microvascular Endothelial Cell ◽  
Protein Levels ◽  
Caspase 1 ◽  
Tnf Α ◽  
Cardiac Microvascular Endothelial Cell

Background/Aims: In recent years, microRNA-495 (miR-495) has been reported to be a tumor-suppressor miR that is down-modulated in cancers. However, its potential mechanism remains unknown. Therefore, this study aimed to demonstrate the role of miR-495 in cardiac microvascular endothelial cell (CMEC) injury and inflammatory reaction by mediating the pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway. Methods: Overall, 40 mice were assigned into myocardial ischemia/reperfusion injury (MIR) and sham groups. After model establishment, the levels of troponin T (TnT), troponin I (TnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatine kinase isoenzyme MB (CK-MB), myoglobin (MYO), tumor necrosis factor-alpha (TNF-α), and interleukin 1beta (IL-1β) were detected by Enzyme-Linked Immunosorbent Assay (ELISA). Apoptosis was evaluated using Terminal deoxy (d)-UTP nick end labeling (TUNEL) staining, the level of NLRP3 protein was determined by immunohistochemical assay, and miR-495 was detected by in situ hybridization (ISH). The infarct size was determined using 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The expression of miR-495 and the mRNA and protein levels of NLRP3, TNF-α, IL-1β, IL-18 and caspase-1 were evaluated by RT-qPCR and western blot analysis. After transfection, the cells were treated with a miR-495 mimic, a miR-495 inhibitor, or siNLRP3. Cell proliferation was measured by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and cell cycle and apoptosis by flow cytometry. Results: Mice with myocardial I/R injury had elevated levels of TnT, TnI, NT-proBNP, CK-MB, MYO, TNF-α and IL-1β; enhanced cell apoptosis; increased expression of NLRP3, TNF-α, IL-1β, IL-18 and caspase-1; and decreased miR-495 expression. MiR-495 was confirmed to target NLRP3. Moreover, miR-495 reduced the mRNA and protein levels of NLRP3, TNF-α, IL-1β, IL-18 and caspase-1, inhibited cell apoptosis and decreased cells at the G0/G1 phase while improving cell proliferation and increasing cells at the S phase. However, the effects of NLRP4 were proved to be reciprocal. Conclusion: In conclusion, the current study indicated that miR-495 improved CMEC injury and inflammation by suppressing the NLRP3 inflammasome signaling pathway.

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
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